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

Description

CROSS-REFERENCE TO RELATED APPLICATIONSBACKGROUND

[0001] 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[1,5-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. US 2012 / 0277247 describes certain pyrazolopyridine compounds as JAK inhibitors.

[0002] 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.

[0003] RET signaling is mediated by the binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN) and persephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev., 2005, 16, 441-67). Unlike other receptor tyrosine kinases, RET does not directly bind to GFLs and requires an additional co-receptor: that is, one of four GDNF family receptor-α (GFRα) family members, which are tethered to the cell surface by a glycosylphosphatidylinositol linkage. GFLs and GFRα family members form binary complexes that in turn bind to RET and recruit it into cholesterol-rich membrane subdomains, which are known as lipid rafts, where RET signaling occurs.

[0004] 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.

[0005] Aberrant RET expression and / or activity have been demonstrated in different cancers, gastrointestinal disorders and irritable bowel syndrome (IBS).SUMMARY OF THE INVENTION

[0006] It has now been found that substituted pyrazolo[1,5-a]pyridine compounds are inhibitors of RET kinase, and are useful for treating proliferative diseases and cancers.

[0007] Accordingly, provided herein is a compound of the Formula I: or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X 1< , X 2< , X 3< , X 4< , Ring D, E, R a< , R b< , n and m are as defined herein.

[0008] 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.

[0009] 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.

[0010] 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.

[0011] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.

[0012] 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, and diarrhea, associated with treatment, including chemotherapeutic treatment.

[0013] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of RET kinase activity.

[0014] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a RET-associated disease or disorder.

[0015] Also provided herein is a pharmaceutical combination for treating cancer (e.g., a RET-associated cancer, and RET-associated cancer having one or more RET inhibitor resistance mutations) in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, wherein the compound of Formula I or the pharmaceutically acceptable salt or solvate thereof and the additional therapeutic are formulated as separate compositions or dosages for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the cancer. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of cancer. Also provided herein is a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use.

[0016] 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.

[0017] Also provided herein is a process for preparing a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[0018] 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.

[0019] 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.

[0020] 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

[0021] 1. A compound of the Formula I: and pharmaceutically acceptable salts thereof, wherein: X 1< , X 2< , X 3< and X 4< are independently CH, CCH 3 , CF or N, wherein zero, one or two of X 1< , X 2< , X 3< and X 4< is N; A is H, CN, Cl, methyl, ethyl or cyclopropyl; B is: (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(=O)-; (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents; (h) (C3-C6 cycloalkyl)C1-C3 alkyl-, (i) (hetCyc a< )C1-C3 alkyl-, (j) hetCyc a< , (k) (R 1< R 2< N)C(=O)C1-C6 alkyl- where R 1< and R 2< are independently selected from H and C1-C6 alkyl, (l) (R 1< R 2< N)C(=O)-, where R 1< and R 2< are independently selected from H and C1-C6 alkyl, or (m) hetCyc a< C(=O)C1-C6 alkyl-; 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), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl)C(=O)-, C1-C6 alkoxy, oxo, and (C1-C6 alkoxy)C(=O)-; Ring D is (i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, each R a< is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R b< is (a) hydroxy, (c) hetCyc b< CH 2 - wherein hetCyc b< is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and wherein hetCyc b< is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), (e) R c< R d< N- or (f) R c< R d< NCH 2 -; R c< is hydrogen or C1-C6 alkyl; and R d< is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros); n is 0, or 1; m is 0 or 1; E is: (d) Ar 1< C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr 2< C1-C6 alkyl-, (g) Ar 1< O-, (h) hetAr 2< O-, (l) Ar 1< C(=O)NR g< - where R g< is H or C1-C6 alkyl, or (m) hetAr 2< C(=O)NR g< (CH 2 ) p - where p is 0 or 1; Ar 1< 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), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO 2 -, R e< R f< N- and (R e< R f< N)C1-C6 alkyl- where each R e< and R f< is independently H or C1-C6 alkyl; hetAr 2< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr 2< is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyC1-C6 alkoxy.

[0022] For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, methoxyethyl comprises an ethyl backbone with a methoxy substituent.

[0023] The term "halogen" means -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl, -Br and -I.

[0024] The terms "C1-C3 alkyl", "C3-C6 alkyl", "C1-C6 alkyl", and "C2-C6 alkyl" as used herein refer to saturated linear or branched-chain monovalent hydrocarbon radicals of one to three, three to six, one to six, or two to six carbon atoms, respectively. Examples include, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0025] The term "C1-C6 alkyl optionally substituted with 1-3 fluoros" as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one to three hydrogen atoms is replaced with one to three fluoro atoms, respectively. Examples include, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-and trifluoroethyl.

[0026] The term "C1-C6 alkoxy" as used herein refer to saturated linear or branched-chain monovalent alkoxy radicals of one to six carbon atoms, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

[0027] The term "(C1-C6 alkoxy)C1-C6 alkyl" as used herein refers to saturated linear or branched-chain monovalent radicals of one to six carbon atoms, wherein one of the carbon atoms is substituted with a C1-C6 alkoxy group as defined herein. Examples include methoxymethyl (CH 3 OCH 2 -) and methoxyethyl (CH 3 OCH 2 CH 2 -).

[0028] The term "(C1-C6 alkoxy)C1-C6 alkoxy" as used herein refers to a C1-C6 alkoxy radical as defined herein, wherein one of the carbon atoms is substituted with a C1-C6 alkoxy group as defined herein. Examples include methoxymethoxy (CH 3 OCH 2 O-) and ethoxymethoxy (CH 3 CH 2 O-CH 2 O-).

[0029] The terms "hydroxyC1-C6 alkyl" and "hydroxyC2-C6 alkyl", as used herein refers to saturated linear or branched-chain monovalent alkyl radicals of one to six or two to six carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy group.

[0030] The term "dihydroxyC3-C6 alkyl" as used herein refers to a C3-C6 alkyl radical as defined herein, wherein two hydrogen atoms are replaced with a hydroxy group, provided the hydroxy groups are not on the same carbon.

[0031] The term "(R 1< R 2< N)C1-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 R 1< R 2< N- group, wherein R 1< and R 2< are as defined herein.

[0032] The term "hetAr 1< C1-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 hetAr 1< group, wherein hetAr 1< is as defined herein.

[0033] The term "C3-C6 cycloalkyl" as used herein refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0034] The term "C3-C6 cycloalkylidene ring" as used herein refers to a divalent C3-C6 cycloalkane ring derived from a saturated 3-6 membered hydrocarbon ring by removal of two hydrogen atoms from the same carbon atom, for example, cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene. It can be represented in illustrative fashion by the following structure in which n is 1, 2 or 3:

[0035] The term "(C3-C6 cycloalkyl)C1-C3 alkyl" as used herein refers to a C1-C3 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a C3-C6 cycloalkyl ring. An example is cyclobutylmethyl.

[0036] The term "(hetCyc a< )C1-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.

[0037] The term "Ar 1< C1-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 Ar 1< group, wherein Ar 1< is as defined herein.

[0038] The terms "hetAr 2< C1-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 hetAr 2< group, wherein hetAr 2< is as defined herein.

[0039] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom, i.e., =O. For example, in one embodiment when referring to hetCyc a< , a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and substituted with an oxo may be, for example, a pyrrolidinyl ring substituted with oxo (e.g., a pyrrolidinonyl ring), which may be represented by the structure:

[0040] The term "spirocyclic ring" as used herein refers to a group having two rings joined by a spirocyclic linkage through a common single carbon atom, wherein each ring is a 4-7-membered ring (including the common carbon atom).

[0041] The term "heterospirocyclic" as used herein refers to a group having two rings joined by a spirocyclic linkage through a carbon atom, wherein each ring has 4 to 6 ring atoms (with one ring carbon atom being common to both rings), and wherein one of the ring atoms is a nitrogen atom.

[0042] 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.

[0043] 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.

[0044] 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, a racemic mixture, or in an enantiomerically pure form.

[0045] In certain embodiments of Formula I, X 1< , X 2< , X 3< and X 4< are independently CH or CF. In certain embodiments, each of X 1< , X 2< , X 3< and X 4< is CH.

[0046] In certain embodiments of Formula I, X 1< , X 2< , X 3< and X 4< are independently CH, CF or N, wherein one of X 1< , X 2< , X 3< and X 4< is N and the remainder are independently CH or CF. In certain embodiments of Formula I, X 1< is N, and X 2< , X 3< and X 4< are independently CH or CF. In certain embodiments, X 1< is N, and X 2< , X 3< and X 4< are CH.

[0047] In certain embodiments of Formula I, X 1< , X 2< , X 3< and X 4< are independently CH, CF or N, wherein two of X 1< , X 2< , X 3< and X 4< are N. In certain embodiments of Formula I, X 1< and X 3< are N and X 2< and X 4< are independently CH or CF. In one embodiment, X 1< and X 3< are N and X 2< and X 4< are CH.

[0048] In certain embodiments of Formula I, A is H.

[0049] In certain embodiments of Formula I, A is Cl.

[0050] In certain embodiments of Formula I, A is CN.

[0051] In certain embodiments of Formula I, A is methyl.

[0052] In certain embodiments of Formula I, A is ethyl.

[0053] In certain embodiments of Formula I, A is cyclopropyl.

[0054] In certain embodiments of Formula I, B is hydrogen.

[0055] In certain embodiments of Formula I, B is C1-C6 alkyl optionally substituted with 1-3 fluoros. Examples include methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, 2-ethylbutyl, neopentyl, difluoromethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. In certain embodiments, B is methyl or ethyl.

[0056] In certain embodiments of Formula I, B is hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In certain embodiments, the alkyl portion is unsubstituted. Examples include the structures:

[0057] In certain embodiments of Formula I, B is dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. An example includes 2,3-dihydroxypropyl.

[0058] 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. Examples include the structures:

[0059] In certain embodiments of Formula I, B is (R 1< R 2< N)C1-C6 alkyl-, where R 1< and R 2< are independently H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(=O)- and (C1-C6 alkoxy)C(=O)-. Examples of (R 1< R 2< N)C1-C6 alkyl- include the structures:

[0060] In certain embodiments of Formula I, B is hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents. In certain embodiments, hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O and is optionally substituted with C1-C6 alkyl. Examples of hetAr 1< C1-C3 alkyl- include the structures:

[0061] In certain embodiments of Formula I, B is (C3-C6 cycloalkyl)C1-C3 alkyl- wherein said cycloalkyl is optionally substituted with OH. An example is cyclobutylmethyl.

[0062] In certain embodiments of Formula I, B is (hetCyc a< )C1-C3 alkyl-, where hetCyc a< is as defined for Formula I. In certain embodiments of Formula I, B is (hetCyc a< )C1-C3 alkyl-, where hetCyc a< is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl-, halogen, (C1-C6 alkyl)C(=O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=O)-. Examples include the structures:

[0063] In certain embodiments of Formula I, B is hetCyc a< , where hetCyc 2< is as defined for Formula I. In certain embodiments, 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 hydroxyC1-C6 alkyl-. Examples include the structures:

[0064] In certain embodiments of Formula I, B is (R 1< R 2< N)C(=O)C1-C6 alkyl- where R 1< and R 2< are independently selected from H and C1-C6 alkyl. Examples include the structures:

[0065] In certain embodiments of Formula I, B is (R 1< R 2< N)C(=O)-, where R 1< and R 2< are independently selected from H and C1-C6 alkyl. Examples include the structure:

[0066] In certain embodiments of Formula I, B is hetCyc a< C(=O)C1-C6 alkyl- where hetCyc a< is as defined for Formula I. An example includes the structure:

[0067] In certain embodiments of Formula I, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In certain embodiments of Formula I, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (c) hydroxyC2-C6 alkyl-.

[0068] Referring now to Ring D of Formula I, Ring D is (a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen. The phrase "having one ring heteroatom which is nitrogen" when Ring D is a saturated monocyclic 4-7 membered heterocyclic ring means that said ring nitrogen atom is the nitrogen atom shown in Ring D of Formula I. Examples include the structures:

[0069] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , the asterisk indicates the point of attachment of Ring D to the E group, and R a< , n, R b< and m are as defined for Formula I . In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0.

[0070] In one embodiment of Formula I, Ring D is a saturated monocyclic 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen selected from the structures

[0071] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , the asterisk indicates the point of attachment of Ring D to the E group, and R a< , n, R b< and m are as defined for Formula I . In one embodiment, n is zero. In one embodiment, n is one. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1.

[0072] In certain embodiments of Formula I, Ring D is a saturated monocyclic 5-6 membered heterocyclic ring having one ring heteroatom which is nitrogen having the structure:

[0073] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , the asterisk indicates the point of attachment of Ring D to the E group, and R a< , n, R b< and m are as defined for Formula I . In one embodiment, each R a< is independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, Ring D is a saturated monocyclic 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, Ring D is a saturated monocyclic 5 membered heterocyclic ring having one ring heteroatom which is nitrogen

[0074] In certain embodiments of Formula I, Ring D is a saturated monocyclic 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen selected from the structures:

[0075] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , the asterisk indicates the point of attachment of Ring D to the E group, and R a< , n, R b< and m are as defined for Formula I . In one embodiment, each R a< is independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros) or (C1-C6 alkoxy)C1-C6 alkyl-. In one embodiment, n is 0. In one embodiment, n is one. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 or 1 and m is 0 or 1. Examples when Ring D is an optionally substituted saturated 4-7 membered heterocyclic ring include the structures: wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , and asterisk indicates the point of attachment to the E group.

[0076] In one embodiment, Ring D is a saturated monocyclic 6 membered heterocyclic ring having one ring heteroatom which is nitrogen which may be represented by the structure: where n and m are zero, that is, Ring D may be represented by the structure: wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , and the asterisk indicates the point of attachment to the E group.

[0077] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, R b< is (a) OH, (c) hetCyc b< CH 2 -wherein hetCyc b< is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b< is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), (e) R c< R d< N- or (f) R c< R d< NCH 2 -; R c< is hydrogen or C1-C6 alkyl; and R d< is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros).

[0078] In one embodiment, Ring D is a saturated monocyclic 6-membered heterocyclic ring having one ring heteroatom which is nitrogen which may be represented by the structure: wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , and the asterisk indicates the point of attachment to the E group, and R a< is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-. In one embodiment, R a< is C1-C6 alkyl.

[0079] In one embodiment, Ring D is a saturated monocyclic 6-membered heterocyclic ring having one ring heteroatom which is nitrogen which may be represented by the structures: wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , and the asterisk indicates the point of attachment to the E group, and R b< is (a) OH, (c) hetCyc b< CH 2 - , (e) R c< R d< N- or (f) R c< R d< NCH 2 -; R c< is hydrogen or C1-C6 alkyl; R d< is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros); and hetCyc b< is as defined for Formula I. In one embodiment, R b< is (c) hetCyc b< CH 2 - , (e) R c< R d< N- or (f) R c< R d< NCH 2 -; R c< is hydrogen or C1-C6 alkyl; R d< is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros); and hetCyc b< is as defined for Formula I.

[0080] In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, R b< is OH. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1. Examples include the structures:

[0081] In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, R b< is (a) hydroxy, (e) R c< R d< N-Examples include the structures:

[0082] In one embodiment, Ring D is a saturated 4 or 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. Examples include the structures:

[0083] In one embodiment, Ring D is a saturated 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, Ring D is a saturated 5-6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, R a< is C1-C6 alkyl. In one embodiment, R b< is R c< R d< N-. Examples include the structures:

[0084] . In one embodiment, Ring D is a saturated 5-6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, n is 1 and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, R a< is C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyC1-C6 alkyl. In one embodiment, R b< is R c< R d< NCH 2 - where R c< is H or C1-C6 alkyl and R d< is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, R b< is hydroxyl. Examples include the structures:

[0085] In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, R a< is C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyC1-C6 alkyl. In one embodiment, R b< is hydroxy, hetCyc b< CH 2 -, R c< R d< NCH 2 -, where hetCyc b< , R c< and R d< are as defined for Formula I. In one embodiment, R b< is hetCyc b< CH 2 - where hetCyc b< is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b< is optionally substituted with one or more substituents independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, R b< is R c< R d< NCH 2 - where R c< is H or C1-C6 alkyl and R d< is C1-C6 alkyl (optionally substituted with 1-3 fluoros). Examples include the structures:

[0086] In one embodiment, Formula I includes compounds of Formula I-D, wherein: X 1< and X 3< are N, and X 2< and X 4< are CH or CF; and A, B, E, R a< , R b< , m and n are as defined for Formula I.

[0087] In one embodiment of Formula I-D, A is CN.

[0088] In one embodiment of Formula I-D, B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(=O)- and (C1-C6 alkoxy)C(=O)-, (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyc a< )C1-C3 alkyl-; and 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), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl)C(=O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=O)-.

[0089] In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(=O)- and (C1-C6 alkoxy)C(=O)-, (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyc a< )C1-C3 alkyl-; and 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), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl)C(=O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=O)-.

[0090] In one embodiment of Formula I-D, E is (l) Ar 1< C(=O)NR g< - where R g< is H or C1-C6 alkyl, or (m) hetAr 2< C(=O)NR g< (CH 2 ) p - where p is 0 or 1 and R g< is H or C1-C6 alkyl.

[0091] In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(=O)- and (C1-C6 alkoxy)C(=O)-, (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyc a< )C1-C3 alkyl-; 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), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl)C(=O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=O)-; and E is (l) Ar 1< C(=O)NR g< - where R g< is H or C1-C6 alkyl, or (m) hetAr 2< C(=O)NR g< (CH 2 ) p - where p is 0 or 1 and R g< is H or C1-C6 alkyl.

[0092] In one embodiment of Formula I-D, m is 1; and n is 0 or 1.

[0093] In one embodiment of Formula I-D, m is 1; and n is 0.

[0094] In one embodiment of Formula I-D, m is 1; n is 0; and R b< is hydroxy.

[0095] In one embodiment of Formula I-D, m is 0; and n is 0 or 1.

[0096] In one embodiment of Formula I-D, m is 0; n is 0 or 1; and R a< is C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0097] In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(=O)- and (C1-C6 alkoxy)C(=O)-, (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyc a< )C1-C3 alkyl-; 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), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl)C(=O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=O)-; E is (l) Ar 1< C(=O)NR g< - where R g< is H or C1-C6 alkyl, or (m) hetAr 2< C(=O)NR g< (CH 2 ) p - where p is 0 or 1 and R g< is H or C1-C6 alkyl; m is 0 or 1; n is 0 or 1; R a< is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R b< is hydroxy. In one embodiment, m is 1, n is 0, and R b< is hydroxy. In one embodiment, m is 0, n is 1, and R b< is C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0098] In one embodiment of Formula I-D, Ring D is wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , the asterisk indicates the point of attachment of Ring D to the E group.

[0099] In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(=O)- and (C1-C6 alkoxy)C(=O)-, (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyc a< )C1-C3 alkyl-; 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), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl)C(=O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=O)-; E is (l) Ar 1< C(=O)NR g< - where R g< is H or C1-C6 alkyl, or (m) hetAr 2< C(=O)NR g< (CH 2 ) p - where p is 0 or 1 and R g< is H or C1-C6 alkyl; m is 0 or 1; n is 0 or 1; R a< is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring D is wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< , the asterisk indicates the point of attachment of Ring D to the E group. In one embodiment, m is 1, n is 0, and R b< is hydroxy. In one embodiment, m is 0, n is 1, and R b< is C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0100] In one embodiment, compounds of Formula I include compounds of Formula I-F where E is (d) Ar 1< C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros or (e) hetAr 2< C1-C6 alkyl-; R b< is (a) hydroxy, or (e) R c< R d< N-; and X 1< , X 1< , X 3< , X 4< , A, B, Ar 1< , hetAr 2< , R c< and R d< are as defined for Formula I.

[0101] In one embodiment of Formula I-F, X 1< is N; and X 2< , X 3< and X 4< are CH. In one embodiment, E is (d) Ar 1< C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr 2< C1-C6 alkyl-.

[0102] In one embodiment of Formula I-F, A is CN. In one embodiment, E is (d) Ar 1< C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr 2< C1-C6 alkyl-.

[0103] In one embodiment of Formula I-F, B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-F, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-. In one embodiment, E is (d) Ar 1< C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr 2< C1-C6 alkyl-.

[0104] In one embodiment of Formula I-F, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-. In one embodiment, E is (d) Ar 1< C1-C6 alkyl-wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr 2< C1-C6 alkyl-.

[0105] In one embodiment of Formula I-F, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and R b< is (a) hydroxy. In one embodiment, E is (d) Ar 1< C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr 2< C1-C6 alkyl-.

[0106] In one embodiment of Formula I-F, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and R b< is (e) R c< R d< N-where R c< and R d< are as defined for Formula I . In one embodiment, E is (d) Ar 1< C1-C6 alkyl-wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr 2< C1-C6 alkyl-.

[0107] In one embodiment of Formula I-F, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and R b< is (e) R c< R d< N-where R c< and R d< are as defined for Formula I . In one embodiment, E is (d) Ar 1< C1-C6 alkyl-wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr 2< C1-C6 alkyl-.

[0108] In one embodiment, compounds of Formula I include compounds of Formula I-G where E is (l) Ar 1< C(=O)NR g< - where R g< is H or C1-C6 alkyl or (m) hetAr 2< C(=O)NR g< (CH 2 ) p - where p is 0 or 1 and R g< is H or C1-C6 alkyl; R a< is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ar 1< , hetAr 2< , X 1< , X 1< , X 3< , X 4< , A and B are as defined for Formula I.

[0109] In one embodiment of Formula I-G, X 1< is N; and X 2< , X 3< and X 4< are CH.

[0110] In one embodiment of Formula I-G, A is CN.

[0111] In one embodiment of Formula I-G, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(=O)- and (C1-C6 alkoxy)C(=O)-, (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyc a< )C1-C3 alkyl-, where hetCyc a< is as defined for Formula I.

[0112] In one embodiment of Formula I-G, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0113] In one embodiment of Formula I-G, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.

[0114] In one embodiment of Formula I-G, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(=O)- and (C1-C6 alkoxy)C(=O)-.

[0115] In one embodiment of Formula I-G, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[0116] In one embodiment of Formula I-G, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is (hetCyc a< )C1-C3 alkyl-, where hetCyc a< is as defined for Formula I.

[0117] In one embodiment, compounds of Formula I include compounds of Formula I-H where E is (l) Ar 1< C(=O)NR g< - where R g< is H or C1-C6 alkyl or (m) hetAr 2< C(=O)NR g< (CH 2 ) p - where p is 0 or 1 and R g< is H or C1-C6 alkyl; R b< is (a) hydroxy, (c) hetCyc b< CH 2 -, (f) R c< R d< NCH 2 -; and Ar 1< , hetAr 2< , X 1< , X 1< , X 3< , X 4< , A, B, hetCyc b< , R c< and R d< are as defined for Formula I.

[0118] In one embodiment of Formula I-H, X 1< is N; and X 2< , X 3< and X 4< are CH.

[0119] In one embodiment of Formula I-H, A is CN.

[0120] In one embodiment of Formula I-H, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0121] In one embodiment of Formula I-H, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0122] In one embodiment of Formula I-H, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R b< is (a) hydroxy.

[0123] In one embodiment of Formula I-H, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R b< is (c) hetCyc b< CH 2 -.

[0124] In one embodiment of Formula I-H, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R b< is (f) R c< R d< NCH 2 -.

[0125] In one embodiment, compounds of Formula I include compounds of Formula I-K where E is (l) Ar 1< C(=O)NR g< - where R g< is H or C1-C6 alkyl or (m) hetAr 2< C(=O)NR g< (CH 2 ) p -where p is 0 or 1 and R g< is H or C1-C6 alkyl; Ring D is where the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< ; R a< is C1-C6 alkyl optionally substituted with 1-3 fluoros; and X 1< , X 1< , X 3< , X 4< , A, B, Ar 1< and hetAr 2< are as defined for Formula I.

[0126] In one embodiment of Formula I-K, X 1< is N; and X 2< , X 3< and X 4< are CH.

[0127] In one embodiment of Formula I-K, A is CN.

[0128] In one embodiment of Formula I-K, X 1< is N; X 2< , X 3< and X 4< are CH; and A is CN.

[0129] In one embodiment of Formula I-K, B is (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(=O)-, (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyc a< )C1-C3 alkyl-, where hetCyc a< is as defined for Formula I.

[0130] In one embodiment of Formula I-K, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is (a) hydrogen.

[0131] In one embodiment of Formula I-K, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0132] In one embodiment of Formula I-K, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

[0133] In one embodiment of Formula I-K, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is (f) (R 1< R 2< N)C1-C6 alkyl- where R 1< and R 2< are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(=O)-.

[0134] In one embodiment of Formula I-K, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is (g) hetAr 1< C1-C3 alkyl-, where hetAr 1< is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[0135] In one embodiment of Formula I-K, X 1< is N; X 2< , X 3< and X 4< are CH; A is CN; and B is (i) (hetCyc a< )C1-C3 alkyl-, where hetCyc a< is as defined for Formula I.

[0136] In one embodiment, compounds of Formula I include compounds of Formula I-L where E is (g) Ar 1< O- or (h) hetAr 2< -O-; Ring D is where the wavy line indicates the point of attachment of Ring D to the ring comprising X 1< , X 2< , X 3< and X 4< ; and X 1< , X 1< , X 3< , X 4< , A, B, Ar 1< and hetAr 2< are as defined for Formula I.

[0137] In one embodiment of Formula I-L, X 1< is N; and X 2< , X 3< and X 4< are CH.

[0138] In one embodiment of Formula I-L, A is CN.

[0139] In one embodiment of Formula I-L, X 1< is N; X 2< , X 3< and X 4< are CH; and A is CN.

[0140] In one embodiment of Formula I-L, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (i) (hetCyc a< )C1-C3 alkyl- or (k) (R 1< R 2< N)C(=O)C1-C6 alkyl- where R 1< and R 2< are independently selected from H and C1-C6 alkyl.

[0141] In one embodiment of Formula I-L, X 1< is N; X 2< , X 3< X 4< are CH; and A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0142] In one embodiment of Formula I-L, X 1< is N; X 2< , X 3< X 4< are CH; and A is CN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

[0143] In one embodiment of Formula I-L, X 1< is N; X 2< , X 3< X 4< are CH; and A is CN; and B is (i) (hetCyc a< )C1-C3 alkyl- or (k) (R 1< R 2< N)C(=O)C1-C6 alkyl- where R 1< and R 2< are independently selected from H and C1-C6 alkyl.

[0144] 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. 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.

[0145] In one embodiment, the compounds of Formula I include the compounds of Examples 1-819 and stereoisomers and pharmaceutically acceptable salts thereof. In one embodiment, the compounds of Examples 1-819 are in the free base form. In one embodiment, the compounds of Examples 1-819 are dihydrochloride or trifluoroacetic acid salts.

[0146] 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.

[0147] 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 1< H, 2< H, 3< H or mixtures thereof; when carbon is mentioned, it is understood to refer to 11< C, 12< C, 13< C, 14< C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to 13< N, 14< N, 15< N or mixtures thereof; when oxygen is mentioned, it is understood to refer to 14< O, 15< O, 16< O, 17< O, 18< O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to 18< F, 19< F or mixtures thereof. The compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0148] 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.

[0149] Scheme 1 shows a general scheme for the synthesis of compound X where A is CN, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , n, m and E are as defined for Formula I.

[0150] Compound 2 is obtained by treating 3-bromo-5-methoxypyridine (compound 1), which is commercially available, with O-(mesitylsulfonyl)hydroxylamine. The O-mesitylsulfonylhydroxylamine may be prepared as described in Mendiola, J., et al., Org. Process Res. Dev. 2009, 13(2), 263-267. Compound 2 may be reacted with ethyl propiolate to provide a mixture of compounds 3A and 3B, which typically are obtained in a ratio of approximately 2:1 to 9:1, respectively. The mixture of compounds 3A and 3B may be treated with 48% HBr at elevated temperatures, followed by recrystallization or chromatography purifications, to isolate compound 4A as the minor isomer and compound 4B as the major isomer. After isolation, compound 4A may be treated with POCl 3 to provide compound 5. The formyl group may be converted to an oxime group using NH 2 OH 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.

[0151] When group B is hydrogen, compound 12 may be prepared by coupling compound 8 with the corresponding boronic ester compound 10 (where Ring D, E, X 1< , X 2< , X 3< and X 4< are as defined for Formula I; Z is -B(OR x< )(OR y< ) and R z< and R y< are H or (1-6C)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 11a using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh 3 ) 4 and Na 2 CO 3 in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an appropriate amino protecting group prior to coupling. The amino protecting group if present on a substituent of Ring D of compound 11a may be removed under standard conditions (for example, a Boc group may be removed by treating compound 11a to acidic conditions, e.g., HCl) to provide compound 12 where B is hydrogen. Alternatively, the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions described below to provide compound 12 where B is hydrogen and E is as defined for Formula I except that E is not hydrogen.

[0152] Alternatively, when group B is as defined for Formula I other than hydrogen, Compound 11a may be reacted with C1-C6 alkyl-OH, (C1-C6 alkoxy)C1-C6 alkyl-OH optionally substituted with 1-3 fluoros, hetAr 1< C1-C3 alkyl-OH, (C3-C6 cycloalkyl)C1-C3 alkyl-OH, (hetCyc a< )C1-C3 alkyl-OH, hetCyc a< OH or hetCyc a< C(=O)C1-C6 alkyl-OH, where hetAr 1< and hetCyc a< are as defined for Formula I, under Mitsunobu reaction conditions (PPh 3 and diisopropyl azodicarboxylate) to provide compound 11. Compound 12 may then be prepared from compound 11 as described above.

[0153] Alternatively, when group B is as defined for Formula I other than hydrogen, compound 9 may be prepared by reacting compound 8 with C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R 1< R 2< N)C1-C6 alkyl-X, hetAr 1< C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc a< )C1-C3 alkyl-X, hetCyc a< -X, or hetCyc a< C(=O)C1-C6 alkyl-X, where R 1< , R 2< , hetAr 1< , and hetCyc a< are as defined for Formula I and X is a leaving atom or group (halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if the B group has one or two additional hydroxy groups), in the presence of a base (for example, potassium carbonate). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 8 with a C1-C6 alkyl-X, where X is Br or Cl, or 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(PPh 3 ) 4 and Na 2 CO 3 in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an appropriate amino protecting group prior to coupling. Compound 12 may then be prepared from compound 11 as described above.

[0154] Scheme 2 shows another general scheme for the synthesis of compound 17 where A is CN, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , n, m and E are as defined for Formula I.

[0155] Compound 9 (prepared, e.g., as described in Scheme 1) in which B is as defined for Formula I, may be coupled with compound 13 (where X 1< , X 2< , X 3< and X 4< are as defined for Formula I ; L 2< is a leaving group such as a triflate or halide); Z is -B(OR x< )(OR y< ) and R z< and R y< are H or (1-6C)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(PPh 3 ) 4 and Na 2 CO 3 in dioxane at elevated temperatures) to provide compound 14. Compound 16 may be prepared by coupling compound 14 with compound 15 under appropriate S N Ar conditions (for example, optionally in the presence of K 2 CO 3 and at elevated temperature), wherein if Ring D of compound 15 is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an appropriate amino protecting group prior to coupling. The amino protecting group if present may then be removed under standard conditions (for example, a Boc group may be removed by treating compound 1 to acidic conditions, e.g., HCl) to provide compound 17 where E is H.

[0156] Alternatively, the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions described below to provide compound 17 where E is as defined for Formula I except that E is not H.

[0157] Scheme 3 shows a general scheme for the synthesis of Compound 21 where A is H, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , n, m and E are as defined for Formula I.

[0158] Compound 18 may be prepared by coupling compound 4A (prepared e.g., as described in Scheme 1) with the corresponding boronic ester compound 10 (where Ring D, X 1< , X 2< , X 3< and X 4< are as defined for Formula I; Z is -B(OR x< )(OR y< ) and R z< and R y< are H or (1-6C)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(PPh 3 ) 4 and Na 2 CO 3 in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an appropriate amino protecting group prior to coupling. Compound 19 may be prepared by treating compound 18 with aluminum trichloride.

[0159] When B is as defined for Formula I other than hydrogen, compound 20 may be prepared by reacting compound 19 with C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R 1< R 2< N)C1-C6 alkyl-X, hetAr 1< C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc a< )C1-C3 alkyl-X, hetCyc a< -X or hetCyc a< C(=O)C1-C6 alkyl-X, where R 1< , R 2< , hetAr 1< , and hetCyc a< are as defined for Formula I and X is a leaving atom or group (halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 19 with C1-C6 alkyl-X, where X is Br or Cl, or triflate. Compound 21 may then be prepared from compound 20. If Ring D comprises a substituent having an amino protecting group, the amino protecting group may be removed under standard conditions (for example, a Boc group may be removed by treating compound 20 to acidic conditions, e.g., HCl) to provide compound 21 where E is H.

[0160] Alternatively, the E group of compound 20 may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions described below to provide compound 21 where E is as defined for Formula I except that E is not H.

[0161] Alternatively, when group B is hydrogen, compound 21 may be prepared from compound 19 according to the deprotection and optional functionalization steps described herein.

[0162] Scheme 4 shows an alternative general scheme for the synthesis of Compound 21 where A is H, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , n, m and E are as defined for Formula I.

[0163] Compound 22 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.

[0164] When group B is hydrogen, compound 19 may be prepared by coupling compound 22 with the corresponding boronic ester compound 10 (where Ring D, X 1< , X 2< , X 3< and X 4< are as defined for Formula I; Z is -B(OR x< )(OR y< ) and R z< and R y< are H or (1-6C)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(PPh 3 ) 4 and Na 2 CO 3 in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an appropriate amino protecting group prior to coupling. Compound 21 may be prepared from compound 19 according to the process described for Scheme 3.

[0165] Alternatively, when group B is as defined for Formula I other than hydrogen, compound 23 may be prepared by reacting compound 22 with C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R 1< R 2< N)C1-C6 alkyl-X, hetAr 1< C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc a< )C1-C3 alkyl-X, hetCyc a< -X or hetCyc a< C(=O)C1-C6 alkyl-X, where R 1< , R 2< , hetAr 1< , and hetCyc a< are as defined for Formula I and X is a leaving atom or group (halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 22 with C1-C6 alkyl-X, where X is Br or Cl, or 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.

[0166] Alternatively, when group B is as defined for Formula I other than hydrogen, compound 20 may be prepared by reacting compound 19 with (C1-C6 alkyl)OH, an appropriately substituted (C1-C3 alkyl)OH, an appropriately substituted (C1-C6 alkyl)OH, or hetCyc a< OH (i.e., where hetCyc a< 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 hydroxyC1-C6 alkyl) under Mitsunobu reaction conditions (PPh 3 and diisopropyl azodicarboxylate). Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.

[0167] Scheme 5 shows an alternative general scheme for the synthesis of Compound 21 where A is H, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , n, m and E are as defined for Formula I.

[0168] Compound 22 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.

[0169] When group B is as defined for Formula I other than hydrogen, compound 23 may be prepared by reacting compound 22 with C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R 1< R 2< N)C1-C6 alkyl-X, hetAr 1< C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc a< )C1-C3 alkyl-X, hetCyc a< -X or hetCyc a< C(=O)C1-C6 alkyl-X, where R 1< , R 2< , hetAr 1< , and hetCyc a< are as defined for Formula I and X is a leaving atom or group (halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 22 with C1-C6 alkyl-X, where X is Br or Cl, or triflate.

[0170] Compound 24 may be prepared by reacting compound 23 with compound 13 (where X 1< , X 2< , X 3< and X 4< are as defined for Formula I ; L 2< is a triflate or halide); Z is -B(OR x< )(OR y< ) and R z< and R y< are H or (1-6C)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(PPh 3 ) 4 and Na 2 CO 3 in dioxane at elevated temperatures).

[0171] When group B is hydrogen, compound 24 may be prepared by reacting compound 22 directly with compound 13 as described above.

[0172] Compound 20 may be prepared by coupling compound 24 with compound 15 where Ring D and E are as defined for Formula I under appropriate S N Ar conditions (for example, optionally in the presence of K 2 CO 3 and at elevated temperature). If Ring D of compound 15 comprises a substituent having a primary or secondary ring nitrogen atom, the nitrogen atom is protected with an appropriate amino protecting group prior to coupling, and then the amino protecting group may be removed subsequent to coupling as described above.

[0173] Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.

[0174] Scheme 6 shows a general scheme for the synthesis of Compound 31 where A is Cl, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , n, m and E are as defined for Formula I.

[0175] Compound 25 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.

[0176] Compound 26 may be prepared by treating compound 25 with aluminum trichloride.

[0177] When group B is as defined for Formula I other than hydrogen, compound 27 may be prepared by reacting compound 26 with C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R 1< R 2< N)C1-C6 alkyl-X, hetAr 1< C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc a< )C1-C3 alkyl-X, hetCyc a< -X or hetCyc a< C(=O)C1-C6 alkyl-X, where R 1< , R 2< , hetAr 1< , and hetCyc a< are as defined for Formula I and X is a leaving atom or group (halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 26 with C1-C6 alkyl-X, where X is Br or Cl, or triflate.

[0178] Compounds 28 (when group B is methyl), 29 (when group B is hydrogen) and 30 (when group B is other than hydrogen) may be prepared by coupling compounds 25, 26 and 27, respectively, with the corresponding boronic ester compound 10 (where Ring D, E, X 1< , X 2< , X 3< and X 4< are as defined for Formula I ; Z is -B(OR x< )(OR y< ) and R z< and R y< are H or (1-6C)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(PPh 3 ) 4 and Na 2 CO 3 in dioxane at elevated temperatures), wherein if Ring D of is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an appropriate amino protecting group prior to coupling. The amino protecting group if present on a substituent of Ring D of compound 29 or 30 may be removed under standard conditions (for example, a Boc group may be removed by treating compound 1 to acidic conditions, e.g., HCl) to provide compound 31 where E is H.

[0179] Alternatively, the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions described below to provide compound 31 where E is as defined for Formula I except that E is not H.

[0180] The E group of compounds 11, 11a, 16, 19, 20, 29 and 30 described in Schemes 1-6 may be functionalized (i.e., reacted or treated with an appropriate reagent) to introduce an E group, where E is any of the E groups defined for Formula I with the exception of hydrogen, using standard chemistry well known to persons skilled in the art. As used herein, the term "functionalized" refers to a process step in the E group of a compound of general Formula I is reacted or treated with an appropriate reagent to provide a compound of Formula I where E is as defined for Formula I except that E is other than hydrogen.

[0181] For example, an amide derivative (e.g., where E is Ar 1< C(=O)NR g< -, hetAr 2< C(=O)NR g< (CH 2 ) p - p is 0 or 1, or R 4< R 5< NC(=O)NR g< -, may be obtained by reacting compound 11 wherein E is -NH 2 with an acid chloride using conventional amide bond formation conditions, for example in the presence of a base (e.g., DIEA) in an appropriate solvent (DCM) to provide a functionalized compound 12. Alternative, compound 11 wherein E is -NH 2 may be reacted with an carboxylic acid using conventional amide bond formation conditions, for example by treating the carboxylic acid with an activating agent (e.g., HATU) followed by addition of compound 11 in the presence of a base ((e.g., DIEA) in an appropriate solvent (DMA) to provide a functionalized compound 12. The same chemistry may be utilized with compounds 11a, 16, 19, 20, 29 and 30 to prepare functionalized compounds 12, 17, 21 and 31.

[0182] As another example, a urea derivative, (e.g., where E is R 4< R 5< NHC(=O)NR g< -) may be prepared reacting a compound 11 where E is -NH 2 with a compound having the formula R 4< R 5< N=C(=O) where R 4< and R 5< are as defined for Formula I in the presence of an appropriate base (e.g., DIEA) to provide a functionalized compound 12. The same chemistry may be utilized with compounds 11a, 16, 19, 20, 29 and 30 to prepare functionalized compounds 12, 17, 21 and 31.

[0183] As another example, an alkoxy, aryloxy or heteroaryloxy derivative (e.g., where E is (C1-C6 alkoxy)C1-C6 alkoxy, Ar 1< O- or hetAr 2< O-), may be prepared by reacting a compound 11 where E is hydroxy with a compound having the formula (C1-C6 alkoxy)C1-C6 alkyl-X, Ar 1< -X or hetAr 2< -X, where X is a halogen, in the presence of an inorganic base (e.g., sodium hydride or potassium hydride) in an appropriate solvent (e.g., DMA). The same chemistry may be utilized with compounds 11a, 16, 19, 20, 29 and 30 to prepare functionalized compounds 12, 17, 21 and 31.

[0184] Accordingly, further provided herein is a process for preparing of a compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein which comprises:

[0185] (b) for a compound of Formula I where A, B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , m, n, and E are as defined for Formula I with the exception that E is not hydrogen, functionalizing a corresponding compound of the formula wherein Ring D, B, X 1< , X 2< , X 3< ,X 4< , R a< , R b< , m and n are as defined for Formula I and E 1< is -NH 2 or OH; or (c) for a compound of Formula I where A is CN and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , m, n, and E are as defined for Formula I, reacting a corresponding compound of the formula 14 wherein Ring D, B, X 1< , X 2< , X 3< , and X 4< are as defined for Formula I and L 2< is halogen or triflate, with a compound of the formula 15 wherein Ring D, R a< , R b< , m, n, and E are as defined for Formula I and wherein if Ring D is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an appropriate amino protecting group prior to coupling, in the presence of a base, optionally followed by removal of the amino protecting group if present; or (e) for a compound of Formula I where A is H, B is H, and X 1< , X 2< , X 3< , X 4< , Ring D and E are as defined for Formula I, treating a corresponding compound of formula 18 where A is H, B is H, and X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , m, n, and E are as defined for Formula I wherein if Ring D is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an amino protecting group, with aluminum trichloride to provide compound 19 optionally followed by removal of the amino protecting group if present; or (f) for a compound of Formula I where A is H, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , m, n, and E are as defined for Formula I, (i) treating a corresponding compound of formula 18 where A is H, and X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , m, n, and E are as defined for Formula I, wherein if Ring D is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an appropriate amino protecting group, with aluminum trichloride to provide compound 19 (ii) reacting compound 19 with C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R 1< R 2< N)C1-C6 alkyl-X, hetAr 1< C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc a< )C1-C3 alkyl-X, hetCyc a< -X or hetCyc a< C(=O)C1-C6 alkyl-X, where R 1< , R 2< , hetAr 1< , and hetCyc a< are as defined for Formula I and X is a leaving atom or group, optionally followed by removal of the amino protecting group if present; or (g) for a compound of Formula I where A is H or Cl, B is H, and X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , m, n, and E are as defined for Formula I, coupling a compound of formula where A is H or Cl with a boronate ester having formula 10 where Z is -B(OR x< )(OR y< ) and R x< and R y< are H or (1 -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), and Ring D, E, X 1< , X 2< , X 3< , X 4< , R a< , R b< , m and n are as defined for Formula I, wherein if Ring D is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an amino protecting group prior to said coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, optionally followed by removal of the amino protecting group if present; or (h) for a compound of Formula I where A is H or Cl, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , m, n, and E are as defined for Formula I, coupling a compound of the formula where A is H or Cl, with a corresponding boronate ester compound of formula 10 where Z is -B(OR x< )(OR y< ) and R x< and R y< are H or (1-6C)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), and Ring D, E, X 1< , X 2< , X 3< , X 4< , R a< , R b< , m and n are as defined for Formula I, wherein if Ring D is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an amino protecting group prior to said coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, and optionally followed by removal of the amino protecting group if present; or (i) for a compound of Formula I where A is H, and B, X 1< , X 2< , X 3< , X 4< , Ring D, R a< , R b< , m, n, and E are as defined for Formula I, coupling a compound of formula 24 where B, X 1< , X 2< , X 3< and X 4< , are as defined for Formula I and L 2< is a leaving group or atom, with a corresponding compound of formula 15 where Ring D, R a< , R b< , m, n, and E are as defined for Formula I wherein if Ring D is substituted with an R b< substituent that is R c< R d< N- wherein one or both of R c< and R d< is hydrogen, the nitrogen atom of R b< may be protected with an amino protecting group, optionally followed by removal of the amino protecting group if present; and removing any additional protecting groups if present and optionally forming a pharmaceutically acceptable salt thereof.

[0186] 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. Examples of amino protecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz") and 9-fluorenylmethyleneoxycarbonyl ("Fmoc"). Further examples of these groups, and other protecting groups, are found in T. W. Greene, et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

[0187] 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 and silyl ethers.

[0188] Nitrogen atoms in compounds described in any of the above methods may be protected with any convenient nitrogen protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of nitrogen protecting groups include acyl and t-butoxycarbonyl (BOC), phenoxycarbonyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0189] The ability of test compounds to act as RET inhibitors may be demonstrated by the assay described in Example A. IC 50 values are shown in Table 5.

[0190] In some embodiments, the compounds provided herein exhibit potent and selective RET inhibition. For example, the compounds provided herein exhibit nanomolar potency against wild type RET and select RET mutants, including the KIF5B-RET fusion and V804M gatekeeper mutation, with minimal activity against related kinases.

[0191] In some embodiments, the compounds of Formula I or a pharmaceutically acceptable salt or solvate thereof, selectively target a RET kinase. For example, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, can selectively target a RET kinase over another kinase or non-kinase target.

[0192] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, exhibits at least a 30-fold selectivity for a RET kinase over another kinase. For example, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, exhibits at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 90-fold selectivity; at least 100-fold selectivity; at least 200-fold selectivity; at least 300-fold selectivity; at least 400-fold selectivity; at least 500-fold selectivity; at least 600-fold selectivity; at least 700-fold selectivity; at least 800-fold selectivity; at least 900-fold selectivity; or at least 1000-fold selectivity for a RET kinase over another kinase. In some embodiments, selectivity for a RET kinase over another kinase is measured in a cellular assay (e.g., a cellular assay as provided herein).

[0193] In some embodiments, the compounds provided herein can exhibit selectivity for a RET kinase over a KDR kinase (e.g., VEGFR2). In some embodiments, the selectivity for a RET kinase over a KDR kinase is observed without loss of gatekeeper mutant potency. In some embodiments, the selectivity over a KDR kinase is at least 10-fold (e.g., at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 90-fold selectivity; at least 100-fold selectivity; at least 150-fold selectivity; at least 200-fold selectivity; at least 250-fold selectivity; at least 300-fold selectivity; at least 350-fold selectivity; or at least 400-fold selectivity) as compared to the inhibition of KIF5B-RET (i.e. the compounds were more 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 dose-limiting toxicities observed with such compounds.

[0194] In some embodiments, inhibition of V804M was similar to that observed for wild-type RET. For example, inhibition of V804M was within about 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of inhibition of wild-type RET (i.e. the compounds were similarly potent against wild-type RET and V804M). In some embodiments, selectivity for a wildtype or V804M RET kinase over another kinase is measured in an enzyme assay (e.g., an enzyme assay as provided herein). In some embodiments, the compounds provided herein exhibit selective cytotoxicity to RET-mutant cells.

[0195] 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., 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.

[0196] 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.

[0197] Compounds of Formula I are useful for treating diseases and disorders which can be treated with a RET kinase inhibitor, RET-associated diseases and disorders, e.g., proliferative disorders, cancers, including hematological cancers and solid tumors, and gastrointestinal disorders and IBS.

[0198] As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, 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.

[0199] As used herein, the terms "subject," "individual," or "patient," are used interchangeably, refers to any animal, including mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (a RET-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a RET gene, a RET protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a RET-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (and 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.

[0200] 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 & 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 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.

[0201] In certain embodiments, compounds of Formula 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.

[0202] The term "RET-associated disease or disorder" as used herein refers to diseases or disorders associated with or having a dysregulation 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 dysregulation 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). Examples of a RET-associated disease or disorder include, for example, cancer and gastrointestinal disorders and irritable bowel syndrome (IBS).

[0203] The term "RET-associated cancer" as used herein refers to cancers associated with or having a dysregulation of a RET gene, a RET kinase (also called herein RET kinase protein), or expression or activity, or level of any of the same. Examples of a RET-associated cancer are described herein.

[0204] The phrase "dysregulation 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 dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same, 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 dysregulation 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, dysregulation 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. Examples of fusion proteins are described in Table 1. 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 Examples of RET inhibitor resistance mutations are described in Tables 3 and 4.

[0205] 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 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), 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).

[0206] 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).

[0207] 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 dysregulation 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 dysregulation 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. Examples of RET gene fusion proteins are described in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, the dysregulation 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. 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.

[0208] In some embodiments of any of the uses described herein, the cancer (e.g., RET-associated cancer) is a hematological cancer. In some embodiments of any of the uses described herein, the cancer (e.g., RET-associated cancer) is a solid tumor. In some embodiments of any of the 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), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer (e.g., 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 uses described herein, the cancer (e.g., RET-associated cancer) is selected from the group of: acute lymphoblastic leukemia (ALL), acute 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, 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, 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, macroglobulinemia, 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, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, 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, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach cancer, T-cell lymphoma, testicular cancer, 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.

[0209] In some embodiments, a hematological cancer (e.g., hematological cancers that are RET-associated cancers) is selected from the group consisting of leukemias, lymphomas (non-Hodgkin'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), 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

[0210] 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.

[0211] In some embodiments, the cancer is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

[0212] In some embodiments, the patient is a human.

[0213] Compounds of Formula I and pharmaceutically acceptable salts thereof are also useful for treating a RET-associated cancer.

[0214] Dysregulation 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 dysregulation 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.

[0215] In some embodiments, the dysregulation 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 dysregulation 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.

[0216] In some embodiments, the dysregulation 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 dysregulation 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.

[0217] Examples of RET fusion proteins are shown in Table 1. Table 1. Exemplary RET Fusion Partners and Cancers Fusion Partner Exemplary RET-Associated Cancer(s) BCRChronic Myelomonocytic Leukemia (CMML)CLIP1AdenocarcinomaKIF5BNSCLC, Ovarian Cancer, Spitzoid Neoplasms; Lung Adenocarcinoma 3, 4, 14, 28< ; Adenosquamous Carcinomas 15< CCDC6 (also called PTC1, D10S170, or H4)NSCLC, Colon Cancer, Papillary Thyroid Cancer; Adenocarcinomas; Lung Adenocarcinoma; Metastatic Colorectal Cancer 5< ; Adenosquamous Carcinomas 15< , Breast Cancer 30< PTC1ex9 (a novel CCDC6 rearrangement)Metastatic papillary thyroid cancer 2< NCOA4 (also called PTC3, ELE1, and RFG)Papillary Thyroid Cancer 21< , NSCLC, Colon Cancer, Salivary Gland Cancer, Metastatic Colorectal Cancer 5< ; Lung Adenocarcinoma 15< ; Adenosquamous Carcinomas 15< Diffuse Sclerosing Variant of Papillary Thyroid Cancer 16< Breast Cancer 30< , Acinic Cell Carcinoma 32< , Mammary Analog Secretory Carcinoma 33< TRIM33 (also called PTC7 and RFG7)NSCLC, Papillary Thyroid CancerERC1 (also called ELKS)Papillary Thyroid Cancer, Breast CancerFGFR1OPCMML, Primary Myelofibrosis with secondary Acute Myeloid LeukemiaMBD1 (also known as PCM1)Papillary Thyroid CancerRAB61P2Papillary Thyroid CancerPRKAR1A (also called PTC2)Papillary Thyroid CancerTRIM24 (also called PTC6)Papillary Thyroid CancerKTN1 (also called PTC8)Papillary Thyroid CancerGOLGA5 (also called PTC5)Papillary Thyroid Cancer, Spitzoid NeoplasmsHOOK3Papillary Thyroid CancerKIAA1468 (also called PTC9 and RFG9)Papillary Thyroid Cancer, Lung Adenocarcinoma 8, 12< TRIM27 (also called RFP)Papillary Thyroid CancerAKAP13Papillary Thyroid CancerFKBP15Papillary Thyroid CancerSPECC1LPapillary Thyroid Cancer; Thyroid Gland CarcinomaTBL1XR1Papillary Thyroid Cancer; Thyroid Gland CarcinomaCEP55Diffuse Gastric Cancer 7< CUX1Lung AdenocarcinomaACBD5Papillary Thyroid CarcinomaMYH13Medullary Thyroid Carcinoma 1< UncharacterizedInflammatory Myofibroblastic Tumor 6< PIBF1Bronchiolus Lung Cell Carcinoma 9< KIAA1217 (also called SKT)Papillary Thyroid Cancer 10,< 13 Lung Adenocarcinoma 14< NSCLC 14< MPRIPNSCLC 11< HRH4-RETThyroid cancer and / or paillary thyroid carcinoma 17< Ria-RETThyroid cancer and / or papillary thyroid carcinoma 17< RFG8Papillary thyroid carcinoma 18< FOXP4Lung adenocarcinoma 19< MYH10Infantile myofibromatosis 20< HTIF1Various 22< TIF1GVarious 22< H4LVarious 22< PTC4 (a novel NCO4 / ELE1 rearrangement)Papillary thyroid cancer 23< FRMD4ANSCLC 24< SQSTM1Papillary thyroid carcinoma 25< AFAP1L2Papillary thyroid carcinoma 25< AFAP1NSCLC 31< PPFIBP2Papillary thyroid carcinoma 25< EML4Papillary thyroid cancer 26< PARD3NSCLC 27< UVELDPapillary thyroid cancer 29< RASGEF1ABreast cancer 30< TELIn vitro 34< RUFY1Colorectal Cancer 35< OLFM4Small-Bowel Cancer 36< UEVLDPapillary Thyroid Carcinoma 37< DLG5Non-Anaplastic Thyroid (NAT) Cancer 38< RRBP1Colon Cancer 39< 1< Grubbs et al., J. Clin. Endocrinol. Metab. 100:788-793, 2015. 2< Halkova et al., Human Pathology 46:1962-1969, 2015. 3< 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. 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. 13< 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., Transl. 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. 19< Bastien et al., Journal of Molecular Diagnostics, 18(6):1027, Abstract Number: S120, 2016 Annual Meeting of the Association for Molecular Pathology, Charlotte, NC, 2016. 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. 24< Velcheti et al., J Thorac Oncol., 12(2):e15-e16. doi: 10.1016 / j.jtho.2016.11.274, 2017. 25< Iyama et al., Thyroid, doi: 10.1089 / thy.2016.0673, 2017. 26< Demeure et al., World J Surg.. 38(6):1296-305. doi: 10.1007 / s00268-014-2485-3, 2014. 27< Sabari et al., Oncoscience, Advance Publications,www.impactjournals.com / oncoscience / files / papers / 1 / 345 / 345. pdf, 2017. 28< U.S. Patent Application Publication No. 2017 / 0014413. 29< Lu et al., Oncotarget, doi: 10.18632 / oncotarget.17412, [Epub ahead of print], 2017. 30< Hirshfield et al., Cancer Research, (February 2017) Vol. 77, No. 4, Supp. 1. Abstract Number: P3-07-02. Meeting Info: 39th Annual CTRC-AACR San Antonio Breast Cancer Symposium. San Antonio, TX, United States. 06 Dec 2016-10 Dec 2016. 31< Morgensztern et al., Journal of Thoracic Oncology, (January 2017) Vol. 12, No. 1, Supp. 1, pp. S717-S718, Abstract Number: P1.07-035, Meeting Info: 17th World Conference of the International Association for the Study of Lung Cancer, IASLC 2016. Vienna, Austria. 04 Dec 2016. 32< Dogan et al., Laboratory Investigation, (February 2017) Vol. 97, Supp. 1, pp. 323A. Abstract Number: 1298, Meeting Info: 106th Annual Meeting of the United States and Canadian Academy of Pathology, USCAP 2017. San Antonio, TX, United States. 33< Dogan et al., MODERN PATHOLOGY, Vol. 30, Supp. [2], pp. 323A-323A. MA 1298, 2017. 34< PCT Patent Application Publication No. WO 2017 / 146116. 35< PCT Patent Application Publication No. WO 2017 / 122815. 36< Reeser et al., J. Mol. Diagn., 19(5):682-696, doi: 10.1016 / j.jmoldx.2017.05.006, 2017. 37< Lu et al., Oncotarget, 8(28):45784-45792, doi: 10.18632 / oncotarget.17412, 2017. 38< Ibrahimpasic et al., Clin. Cancer Res., doi: 10.1158 / 1078-0432.CCR-17-1183, 2017. 39< Kloosterman et al., Cancer Res., 77(14):3814-3822. doi: 10.1158 / 0008-5472.CAN-16-3563, 2017.

[0218] In some embodiments, the dysregulation 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 dysregulation 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.

[0219] In some embodiments, the dysregulation 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 ). Table 2. Activating RET Kinase Protein Point Mutations / Insertions / Deletions Exemplary RET Point Mutations Amino acid position 2Amino acid position 3Amino acid position 4Amino acid position 5Amino acid position 6Amino acid position 7Amino acid position 8Amino acid position 11Amino acid position 12Amino acid position 13Amino acid position 20Amino 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., R114H)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 200Amino acid position 292 (e.g., V292M)Amino acid position 294Amino 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 432Amino 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., E511K)Amino acid position 513 (e.g., G513D) 7∗< Amino acid position 515 (e.g., C515S, C515W 4< )Amino acid position 525 (e.g., R525W) 7∗< Amino acid position 531 (e.g., C531R, or 9 base pair duplication 2< )Amino acid position 532 (e.g., duplication) 2< 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) 18< Amino acid position 600 (e.g., R600Q)Amino acid position 602 (e.g., I602V) 6< Amino acid position 603 (e.g., K603Q, K603E 2< )Amino acid position 606 (e.g., Y606C)Amino acid position 609 (e.g., C609Y, C609S, C609G, C609R, C609F, C609W, C690C 32< )Amino acid position 611 (e.g., C611R, C611S, 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, 11< )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 duplication 2< )Amino acid position 634 (e.g., C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, or C634T, or an insertion ELCR 2< , or a 12 base pair duplication 2< ) (e.g., causing MTC)Amino acid position 635 (e.g., R635G)Amino acid position 636 (e.g., T636P 2< , T636M 4< )Amino acid position 640 (e.g., A640G)Amino acid position 641 (e.g., A641S, A641T 8< )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)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, P766M 6< )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., I788I 32< )Amino acid position 790 (e.g., L790F)Amino acid position 791 (e.g., Y791F, Y791N 24< )Amino acid position 802Amino acid position 804 (e.g., V804L 15, 16< , V804M 15, 16< , V804E 12< ) (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, Y806S 12< , Y806G, Y806C 2, 12, 14< , Y806E 14< , Y806H 12< , Y806N 12< , Y806Y 32< )Amino acid position 810 (e.g., G810R 12< , G810S 12< , G810A 13< )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< Amino acid position 873 (e.g., R873W)Amino acid position 876 (e.g., A876V)Amino acid position 881 (e.g., L881V)Amino acid position 882Amino 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, S891S 32< )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, S904C 2< )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., G911D)Amino acid position 912 (e.g., R912P, R912Q)Amino acid position 918 (e.g., M918T 2< , M918V, M918L 6< ) (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., M1009V)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+3 1< (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< (del632-636 ins6) 31< Amino acid positions 791 and 852 (e.g., Y791F + I852M) 31< Amino acid positions 634 and 852 (e.g., C634R + I852M) 31< 1< U.S. Patent Application Publication No. 2014 / 0272951. 2< Krampitz et al., Cancer 120:1920-1931, 2014. 3< Latteyer, et al., J. Clin. Endocrinol. Metab. 101(3):1016-22, 2016. 4< Silva, et al. Endocrine 49.2:366-372, 2015. 5< Scollo, et al., Endocr. J. 63(1):87-91, 2016. 6< Jovanovic, et al., Prilozi 36(1):93-107, 2015. 7< 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. 11< Scollo et al., Endocr. J. 63:87-91, 2016. 12< PCT Patent Application Publication No. WO 2016 / 127074. 13< Huang et al., Mol. Cancer Ther., 2016 Aug 5. pii: molcanther.0258.2016. [Epub ahead of print]. 14< Carlomagno, et al., Endocr. Rel. Cancer 16(1):233-41, 2009. 15< Yoon et al., J. Med. Chem. 59(1):358-73, 2016. 16< U.S. Patent No. 8,629,135. 17< Cranston, et al., Cancer Res. 66(20): 10179-87, 2006. 18< Kheiroddin et al., Clin. Lab. 62(5):871-6, 2016. 19< Ceolin et al., PLoS One. 11(2): e0147840, doi: 10.1371 / journal.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. 23< Grey et al., Endocrine Pathology, doi:10.1007 / sl2022-016-9451-6, 2016. 24< De Almeida et al., Endocrine Reviews, 2016, Vol. 37, No. 2, Supp. Supplement 1. Abstract Number: SUN-068; 98th 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; 41st European Society for Medical Oncology Congress, ESMP 2016. Copenhagen, Denmark. 07 Oct 2016-11 Oct 2016. 26< Romei et al., European Thyroid Journal (August 2016) Vol. 5, Supp. Supplement 1, pp. 75; 39th Annual 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.14172, 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. 30< Corsello et al., Endocrine Reviews, (JUN 2014) Vol. 35, No. 3, Suppl. S, pp. SUN-0322, Meeting Info.: 96th Annual Meeting and Expo of the Endocrine-Society, Chicago, IL, USA, June 21-24, 2014. 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 / s12022-017-9487-2, 2017.

[0220] In some embodiments, the dysregulation 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 ).Exemplary activating RET Kinase Protein Point Mutations / Insertions / Deletions

[0221] Exemplary RET Point Mutations Amino acid position 20Amino 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)Amino acid position 114 (e.g., R114H)Amino acid position 145 (e.g., V145G)Amino acid position 200Amino acid position 292 (e.g., V292M)Amino acid position 294Amino 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 432Δ 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., E511K)Amino acid position 513 (e.g., G513D)Amino acid position 515 (e.g., C515S, C515W 4< )Amino acid position 525 (e.g., R525W)Amino acid position 531 (e.g., 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., I602V)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., C611R, C611S, C611G, C611Y, C611F, 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)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 802Amino 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 882Amino 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)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, K907M)Amino acid position 908 (e.g., R908K)Amino acid position 911 (e.g., G911D)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)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)

[0222] In some embodiments, the dysregulation 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.

[0223] 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 (IC 50 ) 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 inhibitor can exhibit inhibition activity (IC 50 ) 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.

[0224] 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.

[0225] In some embodiments, the dysregulation 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 V max , a decreased K m for ATP, and an increased K D 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.

[0226] In other embodiments, the dysregulation 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 V max , a decreased K m , and a decreased K D 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.

[0227] 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 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 including 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 C-helix. Specific residues or residue regions that may be changed (and are RET inhibitor resistance mutations) include those listed in Table 3 based on the human wildtype RET protein sequence (e.g., 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.

[0228] Exemplary Sequence of Mature Human RET Protein (SEQ ID NO: 1)

[0229] In some embodiments, compounds of Formula I and pharmaceutically acceptable salts 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 cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864.

[0230] In some embodiments, compounds of Formula I or pharmaceutically acceptable salts 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). Examples of RET inhibitor resistance mutations are listed in Tables 3 and 4. Table 3. RET Inhibitor Resistance MutationsExemplary RET Resistance Mutations Amino acid position 732 (e.g., E732K) 7< Amino acid position 788 (e.g., I788N) 8< Amino acid position 804 (e.g., V804M 1, 2< , V804L 1, 2< , V804E 6< )Amino acid position 804 / 805 (e.g., V804M / E805K) 3< Amino acid position 806 (e.g., Y806C 4, 6< , Y806E 4< , Y806S 6< , Y806H 6< , Y806N 6< )Amino acid position 810 (e.g., G810A 5< , G810R 6< , G810S 6< )Amino acid position 865 (e.g., L865V 6< )Amino acid position 870 (e.g., L870F 6< ) 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. Transl. Med., 9(394), doi: 10.1126 / scitranslmed.aah6144, 2017. Table 4. Additional Exemplary Amino Acid Positions of RET Inhibitor Resistance Mutations RET Amino Acid and Position Exemplary Mutation Mechanistic Resistance Rationale L730PSteric hindrance and / or active conformational effectG731VSteric hindrance and / or active conformational effectE732KSteric hindrance and / or active conformational effectG733VSteric hindrance and / or active conformational effectE734KSteric hindrance and / or active conformational effectL760MActive conformational effectK761EActive conformational effectE762KActive conformational effectN763DActive conformational effectA764VActive conformational effectS765NActive conformational effectP766AActive conformational effectS767CActive conformational effectE768KActive conformational effectL779MSteric hindrance and / or active conformational effect1788MSteric hindrance and / or active conformational effectM868RSteric hindrance and / or active conformational effectK869ESteric hindrance and / or active conformational effectL870QSteric hindrance and / or active conformational effectV871MSteric hindrance and / or active conformational effectH872RSteric hindrance and / or active conformational effectR873PSteric hindrance and / or active conformational effectD874YSteric hindrance and / or active conformational effectL881RSteric hindrance and / or active conformational effectL895MActive conformational effectS896NActive conformational effectR897CActive conformational effectD898YActive conformational effectV899GActive conformational effectY900DActive conformational effectE901KActive conformational effectE902KActive conformational effectD903YActive conformational effectS904CActive conformational effectY905DActive conformational effectV906MActive conformational effectK907EActive conformational effectR908PActive conformational effectS909CActive conformational effectQ910RActive conformational effectG911CActive conformational effectR912PActive conformational effect

[0231] 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. To date, a variety of fusion partners have been identified, all providing a protein / protein interaction domain that induces ligand-independent RET dimerization and constitutive kinase activity (see, e.g., Table 1). 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). 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 KIF5B-RET (Ju et al., Genome Res., 2012, 22, 436-45; Kohno et al., 2012, Nature Med., 18, 375-7; Takeuchi et al., Nature Med., 2012, 18, 378-81; Lipson et al., 2012, Nature Med., 18, 382-4). The fusion transcripts are highly expressed and all the resulting chimeric proteins contain the N-terminal portion of the coiled-coil region of KIF5B, which mediates homodimerization, and the entire RET kinase domain. None of 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, the CCDC6-RET fusion protein, which has been found to play a key role in the proliferation of the human lung adenocarcinoma cell line LC-2 / ad (Journal of Thoracic Oncology, 2012, 7(12):1872-1876). RET inhibitors have been shown to be useful in treating lung cancers involving RET rearrangements (Drilon, A.E. et al. 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).

[0232] 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 ligand-independent homodimerization and constitutive RET activation. Patients develop MTC at a young 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 (< 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 colorectal cancer (Wood et al., Science, 2007, 318, 1108-13) and small cell lung carcinoma (Jpn. J. Cancer Res., 1995, 86, 1127-30).

[0233] 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, 4648-57), 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).

[0234] RET is also expressed in 30-70% of invasive breast cancers, with expression being relatively more frequent in estrogen receptor-positive tumors (Plaza-Menacho, I., et al., Oncogene, 2010, 29, 4648-4657; Esseghir, S., et al., Cancer Res., 2007, 67, 11732-11741; Morandi, A., et al., Cancer Res., 2013, 73, 3783-3795; Gattelli, A., EMBO Mol. Med., 2013, 5, 1335-1350).

[0235] The identification of RET rearrangements has been reported in a subset of (patient-derived 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).

[0236] An increasing number of tumor types are now being shown to express substantial 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. Int. Med. Res. 2008, 36, 656-664).

[0237] 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).

[0238] 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).

[0239] 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).

[0240] 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).

[0241] 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 dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, where the presence of a dysregulation 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 assay on a sample obtained from the patient to determine whether the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same where the presence of dysregulation 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 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 dysregulation 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. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the dysregulation 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.

[0242] 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 a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in 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 RET-associated 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, e.g., FDA-approved, kit for identifying dysregulation 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.

[0243] In some embodiments of any of the uses described herein, the patient has been identified or diagnosed as having a cancer with a dysregulation 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 dysregulation 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 uses described herein, the patient can be a patient with a tumor(s) that is positive for a dysregulation 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 uses described herein, the patient can be a patient whose tumors have a dysregulation 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 uses described herein, 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 dysregulation 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 dysregulation 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. Examples of RET gene fusion proteins are described in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, the dysregulation 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. 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 dysregulation 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. 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 dysregulation 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. In some embodiments, the tumor that is positive for a dysregulation 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 dysregulation 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.

[0244] In some embodiments of any of the uses described herein, the patient has a clinical record indicating that the patient has a tumor that has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same (e.g., 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 of Formula I or a pharmaceutically acceptable salts thereof or compositions provided herein. In some embodiments, the cancer with a dysregulation 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 dysregulation 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. In some embodiments, the tumor that is positive for a dysregulation 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 dysregulation 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.

[0245] Also provided is the compound of Formula I or a pharmaceutically acceptable salt thereof for for use in treating a RET-associated cancer in a patient having a clinical record that indicates that the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. Some embodiments of these uses can further include: a step of performing an on a sample obtained from the patient to determine whether the patient has a dysregulation 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 dysregulation 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 dysregulation 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.

[0246] 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, 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. For example, the compounds can be used in the treatment of one or more of gliomas , 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. Acta Neuropathol 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 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. 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.

[0247] In some embodiments of any of the uses described herein, an assay used to determine whether the patient has a dysregulation 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 labelled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation 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 dysregulation 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)

[0248] 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, 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.

[0249] In some embodiments, 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.

[0250] Examples of additional therapeutic agents include: other RET-targeted therapeutic agents (i.e. a first or second RET kinase inhibitor), receptor tyrosine kinase-targeted therapeutic agents, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g. obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.

[0251] 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 (IC 50 ) 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 (IC 50 ) 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.

[0252] 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-3-carboxamide), BLU6864, BLU-667, DCC-2157, GSK3179106, NVP-AST487 (1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea), PZ-1, RPI-1 (1,3-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-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), SPP86 (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), and TG101209 (N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]amino]-benzenesulfonamide).

[0253] 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: wherein R 1 is C 6 -C 24 alkyl or polyethylene glycol; or a pharmaceutically acceptable salt form thereof. In some embodiments, the other RET inhibitor is 4-{5-[bis-(chloroethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyric acid dodecyl ester.

[0254] 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: wherein Rings A and B are each independently selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; each L 1< and L 2< is independently selected from a bond, -(C1-C6 alkylene)-, -(C2-C6alkenylene)-, -(C2-C6 alkynylene)-, -(C1-C6 haloalkylene)-, -(C1-C6 heteroalkylene)-, -C(O)-, -O-, -S-, -S(O), -S(O) 2 -, -N(R 1< )-, -O-(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-, -N(R 1< )-C(O)-, - C(O)N(R 1< )-, -(C1-C6 alkylene)-N(R 1< )-, -N(R 1< )-(C1-C6 alkylene)-, -N(R 1< )-C(O)-(C1-C6 alkylene)-, -(C1-C6 alkylene)-N(R 1< )-C(O)-, -C(O)-N(R 1< )-(C1-C6 alkylene)-, -(C1-C6 alkylene)-C(O)-N(R 1< )-, -N(R 1< )-S(O) 2 -, -S(O) 2 -N(R 1< )-, -N(R 1< )-S(O) 2 -(C1-C6 alkylene)-, and-S(O) 2 -N(R 1< )-(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 -N(R 1< )(R 1< ); 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)R 1< , -OC(O)R 1< , -C(O)OR 1< , -(C1-C6 alkylene)-C(O)R 1< , -SR 1< ,-S(O) 2 R1, -S(O) 2 -N(R 1< )(R 1< ), -(C1-C6 alkylene)-S(O) 2 R 1< , -(C1-C6 alkylene)-S(O) 2 -N(R 1< )(R 1< ), -N(R 1< )(R 1< ) -C(O)-N(R 1< )(R 1< )-N(R 1< )-C(O)R 1< , -N(R 1< )-C(O)OR 1< , -(C1-C6 alkylene)-N(R 1< )-C(O)R 1< , -N(R 1< )S(O) 2 R 1< , and -P(O)(R 1< )(R 1< ); 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 R 1< is independently selected from hydrogen, hydroxyl, halo, thiol, C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, 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 R 1< 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; m is 0, 1, 2, or 3; 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: and or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, a RET inhibitor is selected from the group consisting of: ABT-348 (N-[4-[4-Amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl]phenyl]-N'-(3-fluorophenyl)urea); AD-57, which has the structure: AD-80 (1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea); ALW-II-41-27 (N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide); Amuvatinib (MP470) (N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide); BPR1J373 (a derivative of 5-phenylthhiazol-2-ylamine-pyriminide); CLM3; doramapimod (BIRB-796) (1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea); DS-5010; famitinib (5-[2-(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one); fedratinib (SAR 302503, TG101348) (N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide); GSK3179106; GSK3352589; HG-6-63-01 ((E)-3-(2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide); NVP-BBT594 (5-((6-acetamidopyrimidin-4-yl)oxy)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide); PP2 (4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine); PP242 (2-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol); quizartinib (AC220) (1-(5 -(tert-butyl)isoxazol-3 -yl)-3 -(4-(7-(2-morpholinoethoxy)benzo [d]imidazo [2,1 - b]thiazol-2-yl)phenyl)urea); semaxanib (SU5416, VEGFR2 Kinase Inhibitor III) ((Z)-3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one); SU4984 (3-[4-(1-formylpiperazin-4-yl)benzylidenyl]-2-indolinone); Withaferin A ((4β,5β,6β,22R)-4,27-Dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-1,26-dione); XL-999 ((Z)-5-((1-ethylpiperidin-4-yl)amino)-3-((3-fluorophenyl)(5-methyl-1H-imidazol-2-yl)methylene)indolin-2-one); XMD15-44 (N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)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).

[0256] Further examples of RET inhibitors include: N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2"-benzamido)pyridin-4"-ylamino]phenyl}urea; 1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(imidazo[1,2-a]pyridin-6-yl)phenyl)acetamide; N-(5-(tert-butyl)isoxazol-3-yl)-2-(3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl)acetamide; 2-amino-6-{[2-(4-chlorophenyl)-2-oxoethyl]sulfanyl}-4-(3-thienyl)pyridine-3,5-dicarbonitrile; and 3-arylureidobenzylidene-indolin-2-ones.

[0257] Yet other therapeutic agents include RET inhibitors described, for example, in U.S. Patent Nos. 7,504,509; 8,012,966; 8,299,057; 8,399,442; 8,067,434; 8,629,135; 8,895,744; 8,937,071; 9,006,256; and 9,035,063; U.S. Publication Nos. 2015 / 0272958; 2015 / 0238477; 2014 / 0121239; 20160176865; 2011 / 0053934; 2011 / 0301157; 2010 / 0324065; 2009 / 0227556; 2009 / 0130229; 2009 / 0099167; 2005 / 0209195; International Publication Nos. WO 2017 / 043550; WO 2017 / 026718; 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,.

[0258] 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, 1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2- methylpyrimidin-5-yl)-1 -phenyl- 1H-pyrazol-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Gö 6976, GNF-5837, GTx-186, GW 441756, LOXO-101, 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.

[0259] 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, described in Cancer Chemother. Pharmacol. 75(1):131-141, 2015; and GNF-5837 (N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]-urea), described in ACS Med. Chem. Lett. 3(2):140-145, 2012.

[0260] 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 Trk 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-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine), described in Mol. Cancer Ther. 8:1818-1827, 2009; and AZD7451.

[0261] 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.

[0262] Further examples of Trk inhibitors include CEP-751, described in Int. J. Cancer 72:672-679, 1997; CT327, described in Acta Derm. Venereol. 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-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-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)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-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 PLoS One 8(12):e83380, 2013; K252a ((9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one), as described in Mol. Cell Biochem. 339(1-2):201-213, 2010; 4-aminopyrazolylpyrimidines, e.g., AZ-23 (((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-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; Gö 6976 (5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile), as described in J. Neurochem. 72:919-924, 1999; GW441756 ((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-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-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide); altiratinib (N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); cabozantinib (N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); lestaurtinib ((5S,6S,8R)-6-Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5, 8-methanodibenzo [b,h] cycloocta[jkl] cyclopenta[e] -as-indacen-13(6H)-one); dovatinib (4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one mono 2-hydroxypropanoate hydrate); sitravatinib (N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); ONO-5390556; regorafenib (4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate); and VSR-902A

[0263] 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

[0264] In some embodiments, signal transduction pathway inhibitors include Ras-Raf-MEK-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, 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-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1Hpyrrolo[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-1-yl)phenylamino)pyrimidin-4- ylamino)benzenesulfonamide).

[0265] Examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.

[0266] 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.

[0267] Examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.

[0268] 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.

[0269] 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): 101-108). 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 ™< ).

[0270] 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 (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.

[0271] 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 (TDM-1; Kadcyla ®< ), mirvetuximab soravtansine (IMGN853) or anetumab ravtansine

[0272] In some embodiments, the immunotherapy includes blinatumomab (AMG103; Blincyto ®< ) or midostaurin (Rydapt).

[0273] In some embodiments, the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak ®< ).

[0274] 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 (IFNα) 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 erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin ®< ). In some embodiments, the IFNα therapy is IntronA ®< (Roferon-A ®< ). In some embodiments, the G-CSF therapy is filgrastim (Neupogen ®< ).

[0275] 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 PD-L1 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 ™< ).

[0276] 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 Vaccin Immunother 10(11): 3146-52; and Kubler et al. (2015) J. Immunother Cancer 3:26).

[0277] In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG) therapy.

[0278] In some embodiments, the immunotherapy is an oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC; Imlygic ®< ).

[0279] 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 ®< , GVAX, ADXS11-001, ALVAC-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).

[0280] 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) OncoImmunology 5(2): e1069940).

[0281] In some embodiments, immune-targeted agents are selected from aldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

[0282] Examples of radiotherapy include radioiodide therapy, external-beam radiation, and radium 223 therapy.

[0283] 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 2009 / 014637; 2009 / 152083; WO 2010 / 111527; WO 2012 / 109075; WO 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.

[0284] 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.

[0285] 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 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.

[0286] 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

[0287] 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.

[0288] 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.

[0289] 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 vary depending upon 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.

[0290] 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. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., 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 and thickeners may be necessary

[0291] 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, semisolid, 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.

[0292] 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 unitary 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 desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0293] 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.

[0294] In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One having ordinary 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.

[0295] 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.

[0296] In 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 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.

[0297] 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, response of the individual patient, and the severity of the patient's symptoms.

[0298] Provided herein are pharmaceutical kits useful, for example, in the treatment of RET-associated diseases or disorders, 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, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, 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.

[0299] 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.

[0300] One skilled in the art will further recognize that human clinical trials including first-in-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

[0301] The following examples illustrate the invention.Biological ExamplesExample A RET Enzyme Assay

[0302] 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 mutant RET cytoplasmic domain (aa 658-end) from Millipore (0.25 nM enzyme; Catalog No. 14-760) 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 MgCl 2 , 0.01% Triton X-100, and 2% DMSO in a volume of 8 µL. Compounds were typically prepared 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 µL 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 IC 50 is defined as the concentration of inhibitor at which the POC equals 50 for the fitted curve. The IC 50 values for the compounds tested in this assay are provided in Table 5.Example B RET cell assay

[0303] 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 washed with PBS-0.05% Tween20, 100 µL PBS was added to each well, and the plates were read on a LI-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 µM of a control inhibitor. The POC values were fit to a 4 parameter logistic curve. The IC 50 value is the point where the curve crosses 50 POC. The IC 50 values for the compounds tested in this assay are provided in Table 5.Example C RET G810R mutant assay

[0304] The potency of a compound inhibiting G810R 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 - p1982 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 MgCl 2 , 0.01% Triton X-100, and 2% DMSO in a volume of 8 µL. Compounds were typically prepared as a three-fold 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 µL of quench solution containing 31.25 nM Sa-XL665 and 1x 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 HTRF 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 IC 50 value was the point where the best-fit curve crossed 50 POC. Table 5. IC 50 's of compounds tested in the assay of Examples A,B and C Ex. # RET Enzyme (wild type) IC 50 (nM) RET enzyme (V804M) IC 50 (nM) KIF5B-RET pTYR1062 Cell IC 50 (nM) RET Enzyme (G810R) IC50 (nM) 9 18.824.69.812810 61.2264.4163.8N / A27 15.350.48.363629 15.554.68.461331 75.8316.4137.9N / A35 8.417.32.713336 820.26.3N / A37 1639.34.7N / A38 13.3223.6N / A40 18.57016.863241 80.2248.948N / A42 6.713.61.5N / A43 12.2215.4N / A44 20.7108.231.619545 6.320.92.93746 14.544.511.2N / A47 13.734.84.26452 20.149.72N / A53 14.427.91.3N / A54 10.821.11.2N / A55 22.970.73.4N / A56 13.935.91.2N / A57 14.894.512.5N / A58 68.6692.1153.1N / A59 74.3401.5170.7N / A60 50.5194.293N / A61 22.497.517.8N / A62 13.431.91.79263 66.5511.9150.1N / A64 19.2691062865 9.145.76.1N / A66 9.127.51.5N / A67 21.649.911.4N / A68 1964.813.3N / A69 14.949.711.7N / A70 16.446.410.1N / A71 74.6586.880N / A72 14.746.22N / A73 16.349.11.9N / A74 11.557.410.3N / A75 24.650.24.7N / A76 23.977.654.9N / A77 16.533.33N / A78 2534.5228079 43.3105.76.375580 13.925.92N / A81 11.2272.6N / A82 61.3250.658.5N / A83 34.279.66.8171184 25.5128.845.6N / A85 39.8150.891.3N / A86 16.772.520N / A87 5.330.79.746388 26.2714.2N / A89 26.9282.838.7N / A90 29.3153.930.8N / A91 13.352.77.9N / A92 11.340.36.4N / A93 9.4191.8N / A94 16.828.83.7N / A100 38100.510.6N / A101 12.829.71.2N / A102 11.827.51N / A103 61.8323.257.7N / A104 10.720.43.1N / A105 11.2251.296106 24.790.312.2N / A107 12.451.69.4N / A108 12.673.95.6N / A109 18.365.230N / A112 40.4243.548.5N / A113 70.5237.4168.4N / A115 155.9321.8N / AN / A119 69.9119.734.9N / A122 124.3580.7N / AN / A123 51.1123.473.6N / A124 31.3104.48.9N / A127 43.2191.126.5N / A128 94.8584.7113.7N / A129 21.737.83.2N / A130 2140.53.5N / A131 2140.73.5N / A132 24.868.47.6N / A133 1631.12.4N / A134 34.5187.968.2N / A135 22.1151.241.8N / A136 31.9196.3130.5N / A137 30.3242.4226.8N / A139 12.422.81.4N / A140 7.9479.2N / A141 48.1346.6115.6N / A142 56405.5169.2N / A144 9.822.21.1N / A145 32.3118.39.1N / A146 19.147.61.6N / A147 18.544.75.6N / A148 102.71153.6N / AN / A149 131.81076.2N / AN / A150 133.21117.3N / AN / A151 39.5129.677.2N / A152 49.9163.6106N / A153 230.62403.5N / AN / A154 142.6962.4N / AN / A155 21.397.244.1N / A156 28.410831N / A157 21.347.210.2N / A159 25.3181.249.7N / A160 91512.3294.2N / A161 8.719.26.1N / A162 17.445.79.8N / A163 28.8104.434.9N / A164 358.24281.1N / AN / A165 14.660.137.6N / A166 1023.910000N / AN / A167 16.739.39.2N / A168 5.814.65.2N / A169 8.235.313.7N / A170 44.3260.8162.6N / A171 29.3134.289.7N / A172 338.73403.3N / AN / A174 9.817.83.2N / A175 75.8417.4272.4N / A176 26.477.518.4N / A177 20.94613.3N / A178 73.2429.1354.2N / A179 27.113959.6N / A180 68.6328.6362.8N / A181 83.647878.6N / A182 191.51299.6N / AN / A183 15.441.223.4N / A184 40379.3271N / A185 10.493.950N / A186 15.568.925.4N / A187 515.28.3N / A188 13.775.544.6N / A189 9.23536.7N / A192 12.950.527.3N / A193 21.173.826.2N / A194 70.3585.5165.6N / A197 45.3316.2179.3N / A201 10.522.74.5165202 11.626.518.9181203 9.268.323.3N / A204 82.3813.1N / A495205 10.762.16.5275206 13.891.144.2N / A207 1892.727496208 2087.223.9N / A209 11141.836.3N / A210 19.7272.894.71600211 84767.9445.18099212 19.269.412286213 16.3137.434.3N / A214 21.438.414.2N / A215 30.2272110.6N / A224 14.484.514.5N / A226 16.9152.420.9N / A227 18140.526.5N / A228 33.5411.464.8N / A229 10.3213.5140.45N / A231 12.856.97.6N / A233 10.5445.3N / A234 15.149.85.2N / A235 26.915532.1N / A236 30.3132.722.4N / A237 23.974.712.61169239 11.933.84.6253240 15.4514.5245241 21.713118.1834242 13.296.218.9284243 10.669.39.4303244 19.991.120.9353245 36.1218.556.31675246 38.5299.6853494247 55.2306145.4N / A248 11.355.225.4N / A249 46.4181.627.5N / A250 76.5508.298.8N / A251 8.431.716.7N / A252 816.85.4N / A253 25.361.338.8N / A254 120.1298.9N / AN / A255 30.769.112.4N / A256 24.586.851.2N / A257 20.388.730.6N / A258 12.319.21.2N / A259 16.839.110.8N / A264 30.4118.726.8N / A265 7.619.310.8N / A266 29.4182.532.5N / A267 18.167.115.9N / A268 23.3128.623.1N / A269 18.870.24.9N / A270 16.944.810.5N / A271 44.9137.38.6N / A272 17.955.214.7N / A273 21.341.67.9N / A274 16.564.220.2N / A275 39.9460.1124.3N / A277 29.8242.674.9779278 22.7186.3108.5858289 18119.452.4N / A290 17.3158.380.5N / A292 14.7122.636.4N / A293 106.2904.7N / AN / A294 15.1244.4111.3N / A301 6.132.64.752302 11.826.713.774303 14.128.74.673304 22.168.310.3136305 10.747.25.875306 23.395.24.3239307 25.539.8395.1N / A308 11.328.814.5329309 7.618.118N / A310 14.730.83.267311 8.315.43.728312 7.735.31043313 52.1230.2107.6N / A314 14.230.713.966315 16.550.212164316 18.847.59.4165317 25.969.76.6104318 6.615.83.532319 17.885.69.3160320 20.659.33.7N / A321 9.837.314.365322 13.727.48.973323 16.130.53.669324 8.7221.430325 17.170.923.4255326 103.9661.8203.1N / A331 18.9137.334.5N / A332 1148.329.8N / A333 963.66081N / AN / A336 16.688.930.8241337 391.61085.9N / A1000339 726.92657.9N / A5804340 12.933.52.292341 7.6124.421342 12.4327.658343 15.150.42080350 21.7185.643.4N / A354 53542.9137.6N / A358 7.641.37.638359 10.956.97123360 88.9833.3277.9N / A361 11.774.49.290362 4.416.94.719363 5.522.73.335364 104.8972.1N / AN / A373 29.7233.8116.5N / A379 8.821.84.854383 21.543.418.362384 5.7142.622389 13.4261.3124390 11.137.24.363391 6.710.6221398 230.72422.2N / A8419399 26.156.94.1319400 13.736.68.2189401 1933.62.9109402 11.718.53.271403 22.337.12.1182404 12.231.220.794405 828.212.7N / A406 12.254.919.173407 1447.519.742408 30.2239.872.6N / A409 8.912.73.3N / A410 8.714.33.9N / A411 150.21078.2N / AN / A412 17.389.713.6N / A413 6373424.7N / A5467414 15.850.116.5145415 6.9245.6N / A416 8.638.68.6N / A417 3258204.989418 340.2473.3N / AN / A419 106.5176.3N / AN / A420 147.4227.9N / AN / A421 25.761.970.1159422 16.530.728.9116423 23.654.138.2144424 42.232.4137.4273425 31.270.374195426 238.4457N / AN / A427 41.872.8152.31122428 47.5104.2141.5N / A429 56.2222.5745.34107431 38.210247.8854432 32.281.29.5239433 20.248.52.790434 6.245.27.732435 12.435.22.757436 19.396.28.7182437 21.887.29.495438 14.992.828.268439 22142.616.3118440 13.2305N / A441 12.449.913.8231442 1556.26.970443 12.647.76.5111444 15.260.412.7N / A445 19.6161.317.289447 24.816398.3N / A448 22.9161.980.1N / A453 21.4158.424.8245454 20.7189.564.3195455 25.883.816.6231456 17.742.911.975457 74.8395238.5470458 35.6239.482.4414459 12.770461.8297460 12.387.422.9401461 45.9357.665.6725462 22.99363.2283463 34.6190.736.4454464 39.5211.932.7312465 28.6121.421.7383485 3.730.732.3N / A487 5.535.18878488 8.47323.9N / A498 71.9216.1171.4194523 11.239.37.463528 6.414.7318529 115.81111.9N / A698570 7.228.96.544571 8.955.35.348597 613.62.225598 10.959.110.248599 1735.84.894616 23.667.910.9N / A625 105.1718.3N / A3513674 39.3105.43.2279675 30.2912.4249676 12.930.18141677 13.526.8561678 17.938.42.355679 1833.32.3135680 5.228.91288681 42.9226.125.2311682 24.953.34.9106683 16.590.211.5196684 15.240.94.3122685 19.653.27.7498686 1140.78.6174687 14.845.413.281688 511.55.4109689 12.750.49165690 3.712.63.742691 21.931.5385692 9.338.97.8128693 663.314.1183694 27.774.24.8161695 21.882.128.6204696 42.46111.7277697 34.7938.4382698 6.11681.5114699 1626.58.8153700 78.788.5N / A357701 6.121.325.1162702 10.748.310.5130703 7.226.314.763704 21.987.410.9218705 4.617.824.3131706 17121.716.54540707 9.136.311.659709 1132883710 53517103467711 611326712 2019129315713 1727690284714 32303103747715 3413266158717 234732681405718 3431085607722 210315723 310213724 15951140725 415216729 7211335730 512516731 515827734 5232180694735 56568N / A6169736 53993N / A10000737 6929510510000738 403041810000739 683019610000740 433201198460741 2171315N / A5702742 4245648743 126361119744 40218361109745 128966N / A10000746 2897151283747 1966121490748 1481121999749 25152152584750 42212234308751 48256391530752 1432665N / A10000753 13727943754 77316543755 14311974831305756 6502281757 19537412375758 2916415570759 1113711338760 53508762594761 1813413394762 1211611239763 22124163272764 79247418351765 5783799N / A10000766 2336154351767 2319613592768 11118161984769 12162366870771 926452772 824430773 1210000910000774 845651775 316526776 10461194777 313325778 2312919192779 19661358780 219115328781 41907154782 3322192520783 3436276784 247717796785 37142201475786 4817913965787 22608541788 23939983789 2315981022790 83534268791 167719107792 131061892793 8471176794 532729795 1624525122796 534721797 103011423798 9911222799 213728274800 921686803 62213N / A384806 3318059276N / A = not available Synthetic Examples Synthesis of Synthetic Intermediates

[0305] 4-Bromo-6-hydroxypyrazolo[1.5-a]pyridine-3-carbonitrilePart A: Preparation of O-(mesitylsulfonyl)hydroxylamine

[0306] Step 1: Preparation of tert-butyl (mesitylsulfonyl)oxycarbamate. To a 0 °C solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (10.0 g, 45.72 mmol) and tert-butyl hydroxycarbamate (6.088 g, 45.72 mmol) in MTBE (100 mL) was added TEA (14.46 mL, 48.01 mmol) drop-wise while stirring. The resulting suspension was stirred at 0 °C for an additional 30 min and then warmed to ambient temperature. The reaction was then diluted with water (100 mL), adjusted to pH 4 with 1 N HCl (aq) . The organic layer was dried (Na 2 SO 4 ), filtered and concentrated to yield the title compound initially as a yellowish oil, which upon drying overnight under high vacuum became a white solid (12.89 g, 89% yield). 1< H NMR (CDCl 3 ) δ 7.66 (br s, 1H), 6.98 (s, 2H), 2.67 (s, 6H), 2.32 (s, 3H), 1.31 (s, 9H).

[0307] Step 2: Preparation of O-(mesitylsulfonyl)hydroxylamine. To TFA (117 mL, 1521 mmol) at 0 °C was slowly added tert-butyl (mesitylsulfonyl)oxycarbamate (39.0 g, 124 mmol) over 25 min. The reaction mixture was stirred at 0 °C for 1.5 h and then quenched with the sequential addition of crushed ice and water. The resulting thick suspension was vigorously stirred at ambient temperature for 5 min. Without allowing the filter cake to run dry, the solids were collected by careful vacuum filtration followed by subsequent rinsing with water (4 L) until the filtrate reached pH 6 (Caution: explosion risk exists with dry compound at ambient temperature). The wet filter cake was taken up in DCM (150 mL) and the resulting biphasic solution was separated. The DCM layer was dried over MgSO 4 for 30 min and then filtered and rinsed with DCM (420 mL) to provide the title compound as a 0.22 M solution in DCMPart B: Preparation of 4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0308] Step 1: Preparation of 1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate. To a solution of O-(mesitylsulfonyl)hydroxylamine (Part A, 26.6 g, 117 mmol) in DCM (570 mL) cooled to 0 °C was added 3-bromo-5-methoxypyridine (22.1 g, 117 mmol) in portions. The reaction mixture was stirred for 1 h at 0 °C then treated with additional 3-bromo-5-methoxypyridine (250 mg, 1.39 mmol) and stirred for an additional 2 h at 0 °C. The reaction mixture was diluted with Et 2 O (600 mL), stirred at 0 °C for 10 min and then vacuum filtered, rinsed with Et 2 O (3 × 250 mL). Upon reduction in volume by about 1 / 3, the filtrate yielded additional precipitate which was collected by filtration. Both filter cakes were dried in vacuo to provide the title compound (39.3 g, 83% yield). 1< H NMR (CDCl 3 ) δ 9.25 (br s, 1H), 8.99 (m, 1H), 8.74 (m, 1H), 7.46 (m, 1H), 6.83 (s, 2H), 3.92 (s, 3H), 2.65 (s, 6H), 2.22 (s, 3H).

[0309] Step 2: Preparation of Ethyl 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and Ethyl 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate. To a magnetically stirred white suspension of 1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by 1< H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w / w) was directly used in Step 3 without further purification. MS (apci) m / z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1< H NMR (CDCl 3 ) δ 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer).

[0310] Step 3: Preparation of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (P1) and 4-bromo-6-methoxypyrazolo[1,5-a]pyridine. The isomeric mixture of ethyl 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl 4-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80 °C for 90 min followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to yield 6-bromo-4-methoxypyrazolo[1,5-a]pyridine as a beige solid (about 98:2 6- / 4- Br; 5.08 g). MS (apci) m / z = 226.9, 228.9 (M+H). 1< H NMR (CDCl 3 ) δ 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently the original aqueous reaction mixture filtrate was extracted with EtOAc. The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc / hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (Intermediate P1) as white solid (upper R f spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate P2) also as white solid (lower R f spot, 1.32 g). MS (apci) m / z = 226.9, 228.9 (M+H). 1< H NMR (CDCl 3 ) δ 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).

[0311] Step 4: Preparation of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde: A solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (5.0 g, 22 mmol) in DMF (220 mL) was cooled to 0 °C and then slowly treated with POCl 3 (6.2 mL, 66 mmol). The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was cooled to 0 °C, quenched with water (220 mL), and basified with 6 M NaOH (aq) to pH 9-10. The reaction mixture was stirred for 1 h and then vacuum filtered. The solids were rinsed sequentially with water and MTBE. The collected solid was suspended in DCM (500 mL) and stirred in a sonicating bath for 30 min and then vacuum filtered. The filtrate was retained, while the filter cake was taken up in water (300 mL) and extracted with DCM. The organic extracts, along with the retained DCM filtrate, were combined and dried over anhydrous Na 2 SO 4 , then filtered and concentrated in vacuo to provide the title compound (4.84 g, 86% yield). MS (apci), m / z = 256.9 (M+H).

[0312] Step 5: Preparation of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde oxime. To a suspension of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (4.84 g, 19.0 mmol) in EtOH (253 mL) at ambient temperature was added water (127 mL) and hydroxylamine hydrochloride (1.98 g, 28.5 mmol). After stirring at 50 °C overnight, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was suspended in water (150 mL) and then quenched slowly with saturated NaHCO 3(aq) (30 mL). After stirring for 1 hour at ambient temperature the suspension was vacuum filtered and the filter cake rinsed sequentially with H 2 O (500 mL) and MTBE (100 mL) to yield the title compound as a 2:1 E / Z mixture (5.13 g, quantitative yield), which was used in the next step without further purification. MS (apci) m / z = 271.9 (M+H).

[0313] Step 6: Preparation of .4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile The E / Z mixture of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (4.95 g, 18.33 mmol) in acetic anhydride (172.9 mL, 1833 mmol) was stirred at 140 °C for 25 h, and then cooled to ambient temperature. The resulting suspension was further cooled in an ice bath for 15 min and then vacuum filtered and rinsed sequentially with water and MTBE to provide the title compound (3.74 g, 81% yield). 1< H NMR (d 6< -DMSO) δ 8.70 (s, 1H), 8.60 (s, 1H), 7.78 (s, 1H), 3.83 (s, 3H).

[0314] Step 7: Preparation of 4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile: A slurry of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50.0 g, 198.4 mmol) in DCE (500 mL) was treated with AlCl 3 (79.34 g, 595.1 mmol). Under a N 2(g) atmosphere, the resulting mixture was stirred 19 h at 76 °C, before cooling to room temperature. Using THF (1750 mL) as a rinse solvent, the reaction mixture was poured into a mechanically stirred suspension of sodium sulfate decahydrate (10 eq, 639 g) in THF (1000 mL). After stirring overnight at ambient temperature, the resulting suspension was filtered, and the solids were rinsed with additional THF (2 × 250 mL). The filtrate was concentrated in vacuo, and the resulting solid was dried under high vacuum for 3 days to afford the title compound (46.18 g, 98% yield) in sufficient purity for subsequent use. 1< H NMR (d 6< -DMSO) δ 10.48 (s, 1H), 8.58 (s, 1H), 8.38 (d, 1H), 7.64 (3, 1H). 4-Bromo-6-ethoxypyrazolo[1,5-a]pyridine-3 -carbonitrile

[0315] A solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P1; 4.0 g, 16.80 mmol) in DMA (100 mL) was treated with K 2 CO 3(s) (7.0 g, 51 mmol) and iodoethane (2.0 mL, 25 mmol) and then stirred for 3 hrs at 60 °C. The reaction mixture was cooled to ambient temperature and then quenched with 1:1 NH 4 OH / Water. The resulting suspension was filtered, and the solids were isolated to provide the title compound (4.35 g, 97% yield) in sufficient purity for subsequent use. 6-Ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0316] In a pressure vessel, a solution of 4-bromo-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P5; 500 mg, 1.88 mmol) in dioxane (9.40 mL) was treated sequentially with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (629 mg, 2.82 mmol), Pd(PPh 3 ) 4 (217 mg, 0.188 mmol) and 2 M Na 2 CO 3(aq) (4.70 mL, 9.40). The resulting mixture was sparged with Ar (g) and then the vessel was sealed. The mixture was stirred 8 h at 90°C, and then overnight at ambient temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na 2 SO 4(s) , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (25-100% EtOAc in hexanes as the gradient eluent) to cleanly provide the title compound (500 mg, 94% yield). MS (apci) m / z = 283.1 (M+H). 4-Bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0317] A mixture of (2-bromoethoxy)(tert-butyl)dimethylsilane (451 µL, 2.10 mmol), 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P1; 500 mg, 2.10 mmol) and K 2 CO 3(s) (871 mg, 6.30 mmol) in DMF (10.5 mL) was stirred for 1 day at 50 °C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic extracts were directly purified by silica chromatography (0-100% EtOAc / hexanes as the gradient eluent) to cleanly provide the title compound (420 mg, 49% yield). 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-('6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3 -carbonitrile

[0318] In a pressure vessel, a solution of 4-bromo-6-(2-((tertbutyldimethylsilyl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P25; 420 mg, 1.06 mmol) in dioxane (10.6 mL) was treated sequentially with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (355 mg, 1.59 mmol), Pd(PPh 3 ) 4 (61.2 mg, 0.530 mmol) and 2 M Na 2 CO 3(aq) (2.65 mL, 5.30). The resulting mixture was sparged with Ar (g) and the vessel was sealed. The mixture was stirred 8 h at 90°C, and then overnight at ambient temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water (10 mL) and brine (10 mL), then were dried over anhydrous Na 2 SO 4(s) , filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (using 0-15% MeOH in DCM as the gradient eluent) to afford impure title compound. The impure material was re-subjected to silica chromatography (0-50% EtOAc in Hexanes as the gradient eluent) to cleanly provide the title compound (351 mg, 80% yield). 1< H NMR (400 MHz, DMSO-d 6 -) δ: 8.81 (d, 1H, J=2.0 Hz), 8.61 (s, 1H), 8.48 (d, 1H, J=2.7 Hz), 8.25 (td, 1H, J=7.8, 2.7 Hz), 7.47 (d, 1H, J=1.9 Hz), 7.38 (dd, 1H, J=7.8, 2.3 Hz), 4.21 (t, 2H, J=4.3 Hz), 3.97 (t, 2H, J=4.7 Hz), 0.86 (s, 9H), 0.08 (s, 6H). 4-Bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1.5-a]pyridine-3-carbonitrile

[0319] In a pressure vessel, a mixture of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P1; 10.0 g, 42.0 mmol) and K 2 CO 3(s) (17.4 g, 126 mmol) in DMF (50 mL) was treated with 2,2-dimethyloxirane (36.9 mL, 420 mmol). After sealing the vessel, the reaction mixture was stirred for 12 h at 60 °C, then for 12 h at 85 °C. The mixture was allowed to cool to ambient temperature. The room temperature mixture was poured into water (400 mL), then stirred for 1 hour at ambient temperature. The resultant suspension was vacuum filtered and the filter cake was rinsed with water. The solids were collected and dried in vacuo to cleanly provide the title compound (11 g, 84% yield). 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0320] A mixture of 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P41; 10.0 g, 32.2 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10.8 g, 48.4 mmol) and Pd(PPh 3 ) 4 (1.12 g, 0.967 mmol) in dioxane (200 mL) was treated with 2 M Na 2 CO 3(aq) (64.5 mL, 129 mmol). The resulting mixture was sparged with Ar (g) , then stirred for 12 h at 85 °C under an atmosphere of N 2(g) . After cooling to ambient temperature, the resultant mixture was poured into cold water (1.5 L). The pH of the mixture was adjusted to about pH 6 with the addition of 10% citric acid. After stirring for 1 hour at ambient temperature, the resultant suspension was vacuum filtered. The solids were collected and dried in vacuo to cleanly provide the title compound (10 g, 95% yield). 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0321] Step 1: Preparation of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate. A solution of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P42; 100 mg, 0.306 mmol) in DMA (2.04 mL) was treated sequentially with tert-butyl (4-methylpiperidin-4-yl)carbamate (98.5 mg, 0.460 mmol) and DIEA (107 µL, 0.613 mmol). The resulting mixture was sparged with Ar (g) , then stirred overnight at 90 °C. After cooling to ambient temperature, the reaction mixture was diluted with water and washed with DCM. The combined organic extracts were washed with water and brine, then dried over anhydrous Na 2 SO 4(s) , filtered and concentrated in vacuo to afford the title compound (22.4 mg, 50% yield) in sufficient purity for step 2. MS (apci) m / z = 521.3 (M+H).

[0322] Step 2: Preparation of 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile. A solution of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (160 mg, 0.307 mmol) in DCM (1.54 mL) was treated with TFA (1 mL, 13.8 mmol). After stirring for 30 min at ambient temperature, the mixture was treated with additional TFA (1 mL) and stirred an additional 1 hour at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica chromatography (1-9% MeOH in DCM with 0.1-0.9% NH 4 OH as the gradient eluent) to cleanly provide the title compound (110 mg, 85% yield). MS (apci) m / z = 421.2 (M+H). 4-(6-(4-amino-4-methylpiperidin-1 -yl)pyridin-3 -yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride

[0323] Step 1: Preparation of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate. A solution of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P42; 2.535 g, 7.768 mmol) in DMSO (6.1 mL) was treated sequentially with tert-butyl (4-methylpiperidin-4-yl)carbamate (1.998 mg, 9.322 mmol) and DIEA (4.06 mL, 23.3 mmol). The resulting mixture stirred overnight at 90 °C. After cooling to ambient temperature, the reaction mixture was poured into 80 mL water and diluted with 80 mL heptane and stirred for 1 hour. The suspension was filtered and the solids were rinsed with 25 mL water then 25 mL heptane. The isolated solids were dried under vacuum for 18 hours to afford the title compound (4.04 g, 99.9% yield) in sufficient purity for step 2. MS (apci) m / z = 521.3 (M+H)

[0324] Step 2: Preparation of 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride. A solution of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (4.04 g, 7.76 mmol) in DCM (20 mL) was cooled to 0°C. The reaction was treated with TFA (5.98 mL) and allowed to warm to RT. After stirring for 30 min at ambient the reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH (20 mL) and cooled to 0°C and then treated with Hydrochloric acid, 5 to 6N solution in 2-propanol (15.5 mL, 77.5 mmol) and stirred f0or 15 min at 0°C. The reaction was diluted with 20 mL MTBE, filtered, and solids were rinsed with 20 mL 1:1 MTBE: MeOH. The isolated solids were dried under vacuum to cleanly provide the title compound (3.37 g, 88% yield). MS (apci) m / z = 421.2 (M+H). (R)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate)

[0325] Step 1: Preparation of tert-butyl (R)-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate. To a mixture of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P42; 750 mg, 2.30 mmol) and (R)-(3-Methyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester HCl (644 mg, 3.22 mmol) in DMSO (4.6 mL) was added DIEA (1.2 mL, 6.89 mmol). The reaction mixture was stirred 12 h at 90°C. After cooling to ambient temperature, the reaction mixture was diluted into cold water and stirred for 2 h at ambient temperature. The suspension was filtered and the solids were rinsed with water. The isolated solids were dried under vacuum for 48 h to afford the title compound (1.05 g, 90% yield) in sufficient purity for step 2. MS (apci) m / z = 507.3 (M+H)

[0326] Step 2: (R)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate). To a solution of (R)-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate (1.05 g, 2.07 mmol) in 3 mL DCM was treated with TFA (3 mL, 39 mmol). The reaction mixture was stirred for 4 h at ambient temperature, and then concentrated in vacuo. The residue was diluted with DCM (4 mL) and toluene (1 mL) and stirred at ambient temperature for 15 min. The mixture was concentrated in vacuo and dried under vacuum for 2 days to afford the title compound with quantitative yield. MS (apci) m / z = 407.3 (M+H). (S)-4-(6-(3 -amino-3 -methylpyrrolidin-1 -yl)pyridin-3 -yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate)

[0327] Step 1: Preparation of tert-butyl (S)-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate. To a mixture of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P42; 700 mg, 2.15 mmol) and (S)-(3-Methyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester HCl (601 mg, 3.0 mmol) in DMSO (4.3 mL) was added DIEA (1.1 mL, 6.44 mmol). The reaction mixture was stirred 12 h at 90°C. After cooling to ambient temperature, the reaction mixture was diluted into cold water and stirred for 2 h at ambient temperature. The suspension was filtered and the solids were rinsed with water. The isolated solids were dried under vacuum for 48 h to afford the title compound (950 mg, 87% yield) in sufficient purity for step 2. MS (apci) m / z = 507.3 (M+H)

[0328] Step 2: Preparation of (S)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate). To a solution of tert-butyl (S)-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate (950 mg, 1.88 mmol) in 3 mL DCM was treated with TFA (3 mL, 39 mmol). The reaction mixture was stirred for 4 h at ambient temperature, and then concentrated in vacuo. The residue was diluted with DCM (4 mL) and toluene (1 mL) and stirred at ambient temperature for 15 min. The mixture was concentrated in vacuo and dried under vacuum for 2 days afford the title compound with quantitive yield. MS (apci) m / z = 407.2 (M+H). 4-(6-(3 -aminopyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate)

[0329] Step 1:Preparation of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate. To a mixture of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P42; 850 mg, 2.60 mmol) and 3-(tert-butoxycarbonylamino)pyrrolidine (679 mg, 3.65 mmol) in DMSO (5.2 mL) was added DIEA (1.36 mL, 7.81 mmol). The reaction mixture was stirred 12 h at 90°C. After cooling to ambient temperature, the reaction mixture was diluted into cold water and stirred for 2 h at ambient temperature. The suspension was filtered and the solids were rinsed with water. The isolated solids were dried under vacuum for 48 h to afford the title compound (1.26 g, 98% yield) in sufficient purity for step 2. MS (apci) m / z = 493.3 (M+H)

[0330] Step 2: Preparation of 4-(6-(3-aminopyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate). To a solution of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (950 mg, 1.88 mmol) in 3 mL DCM was treated with TFA (3 mL, 39 mmol). The reaction mixture was stirred for 4 h at ambient temperature, and then concentrated in vacuo. The residue was diluted with DCM (4 mL) and toluene (1 mL) and stirred at ambient temperature for 15 min. The mixture was concentrated in vacuo and dried under vacuum for 2 days afford the title compound with quantative yield. MS (apci) m / z = 393.2 (M+H). 6-ethoxy-4-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0331] To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 0.500 g, 1.77 mmol) inDMSO (3.5 mL) was added TEA (0.741 mL, 5.31 mmol) and piperidin-4-ol (269 mg, 2.66 mmol). The reaction mixture was stirred at 70°C for 5 h. After cooling to ambient temperature, the reaction mixture was poured into ice water. The resultant solids were isolated by vacuum filtration to afford the title compound (501 mg, 1.38 mmol, 77.8 % yield). MS (apci) m / z = 364.2 (M+H). 4-(6-(4-benzyl-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0332] To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 30 mg, 0.106 mmol) in DMA (0.5 mL) was added TEA (0.044 mL, 0.319 mmol) and 4-benzylpiperidin-4-ol (40.7 mg, 0.213 mmol) The reaction mixture was stirred at 90°C for 24 h. After cooling to ambient temperature, the reaction mixture was diluted with DCM and washed with saturated NH 4 Cl (aq) then water. The combined aqueous washes were further extracted with DCM, and the combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (30-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (39 mg, 0.0860 mmol, 80.9 % yield). MS (apci) m / z = 454.2 (M+H). 4-(6-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0333] To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 100.5 mg, 0.3560 mmol) in DMSO (3 ml) was added (4-benzylpiperidin-4-yl)methanol hydrochloride (151.5 mg, 0.6267 mmol) and cesium carbonate (812.0 mg, 2.492 mmol). The reaction mixture was stirred at 60°C for 24 h. After cooling to ambient temperature, the reaction mixture was diluted with DCM and washed with water and saturated NH 4 Cl (aq) . The combined aqueous layers were extracted with DCM, and the combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated. The residue was purified by silica chromatography (0-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (118.2 mg, 0.2528 mmol, 71.00 % yield). MS (apci) m / z = 468.2 (M+H). 4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3 -yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0334] Step 1: Preparation of methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate. To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 303.4 mg, 1.075 mmol) in DMSO (21.50 mL) was added 4-N-Boc-amino-piperidine-4-carboxylic acid methyl ester (416.5 mg, 1.612 mmol) and potassium carbonate (297.1 mg, 2.150 mmol). The reaction mixture was stirred at 110°C for 72 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous MgSO 4(s) and concentrated in vacuo. The resultant crude residue was purified by silica chromatography (0-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (76.7 mg, 13.7% yield) in sufficient purity for step 2. MS (apci) m / z = 521.2 (M+H).

[0335] Step 2: Preparation of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate. To a solution of lithium borohydride (0.0120 mL, 0.365 mmol) in THF (0.912 mL) was added methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate (47.5 mg, 0.0912 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with EtOAc and washed with brine. The organic extract was dried over anhydrous MgSO 4(s) and concentrated in vacuo to afford the title compound as crude product (65.9 mg), which was used in the next step without further purifications. MS (apci) m / z = 493.2 (M+H).

[0336] Step 3: Preparation of 4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile. A solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate (65.9 mg, 0.134 mmol) in DCM (1 mL) was treated with TFA (0.2 mL, 2.68 mmol). The reaction mixture was stirred at rt 30 min then concentrated in vacuo. The residue was taken up in DCM and washed with saturated Na 2 CO 3 . The aqueous fraction was extracted with DCM, and the combined organic extracts were dried over anhydrous MgSO 4(s) and concentrated in vacuo to afford the title compound (35.6 mg, 68% yield). MS (apci) m / z = 393.2 (M+H). tert-butyl (R)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate

[0337] To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 0.147 g, 0.521 mmol) in DMSO (1 mL) was added tert-butyl (R)-piperidin-3-ylcarbamate (209 mg, 1.04 mmol) and potassium carbonate (216 mg, 1.56 mmol). The reaction mixture was heated to 110°C for 72 h. After cooling to ambient temperature, the reaction mixture was diluted with DCM and quenched with saturated NH 4 Cl and extracted into additional DCM. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (0-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (100 mg, 0.216 mmol, 41.5 % yield). MS (apci) m / z = 463.2 (M+H). 4-(6-((3 S,4S)-3 -azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0338] Step 1: Preparation of (3S,4S)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate. A solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (15.42 g, 83.25 mmol), (R)-N,N'-Bis(3,5-Di-tert-butylsalicylidene)-1,2-cyclohexanediaminochromium(III) chloride (0.5904 g, 0.8325 mmol), potassium carbonate (13.81 g, 99.90 mmol), and azidotrimethylsilane (12.79 ml, 91.58 mmol) was sparged with nitrogen and stirred at rt for 24 h. The reaction mixture was treated with silica gel (30 g) and water (2 mL) and stirred at rt for an additional 72 h. The solution was filtered through a pad of Celite ®< and concentrated in vacuo. The residue was purified by silica chromatography (20-50% EtOAc in hexanes as the gradient eluent) to afford the title compound (18.5 g, 81.05 mmol, 97.36 % yield) in sufficient purity for step 2.

[0339] Step 2: Preparation of (3S,4S)-4-azidopyrrolidin-3-ol dihydrochloride. A solution of tert-butyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate (0.500 g, 2.19 mmol) in DCM (2.19 mL) was treated with 6M HCl in IPA (4.5 mL, 27 mmol). The reaction mixure was stirred at rt for 4 h, at which time the reaction mixture was concentrated in vacuo to afford the title compound (assumed theoretical yield, 0.440 g, 2.19 mmol) in sufficient purity for step 3. MS (apci) m / z = 129.1 (M+H).

[0340] Step 3: Preparation of 4-(6-((3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1.5-a]pyridine-3-carbonitrile. To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 0.300 g, 1.06 mmol) in DMSO (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.70 mL, 21.3 mmol) and (3S,4S)-4-azidopyrrolidin-3-ol dihydrochloride (0.427 g, 2.13 mmol) The reaction mixture was stirred 100°C for 24 h. After cooling to ambient temperature, the reaction mixture was quenched with saturated NH 4 Cl (aq) and extracted into DCM. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (20-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.220 g, 0.564 mmol, 53.0 % yield over two steps). MS (apci) m / z = 391.15 (M+H). 4-(6-((3R,4R)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0341] Step 1: Preparation of (3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate. A solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (15.42 g, 83.25 mmol), (1S,2S)-(-)- [1,2-Cyclohexanediammo-N,N'-bis(3,5-di-t-butylsalicylidene)]chromium (III) chloride (1.181 g, 1.665 mmol), and azidotrimethylsilane (12.79 ml, 91.58 mmol) was sparged with nitrogen and stirred at rt for 24 h. To this was added potassium carbonate (13.81 g, 99.90 mmol) in MeOH (100 mL), and the reaction mixture was stirred an additional 5 h at rt. The solution was filtered through a pad of Celite ®< and concentrated in vacuo. The residue was taken up in EtOAc and water. The aqueous fraction was extracted with EtOAc, and the combined organic extracts were washed successively with saturated NaHCO 3(aq) , water, and brine. They were dried over anhydrous MgSO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (20% EtOAc in hexanes as the eluent) to afford the title compound (18.5 g, 81.05 mmol, 97.36 % yield) in sufficient purity for step 2.

[0342] Step 2: Preparation of (3R,4R)-4-azidopyrrolidin-3-ol dihydrochloride. A solution of tert-butyl (3R,4R)-3-azido-4-hydroxypyrrolidine-1-carboxylate (0.500 g, 2.19 mmol) in DCM (2.19 mL) was treated with 6M HCl in IPA (4.5 mL, 27 mmol). The reaction mixure was stirred at rt for 4 h, at which time the reaction mixture was concentrated in vacuo to afford the title compound (assumed theoretical yield, 0.440 g, 2.19 mmol) in sufficient purity for step 3. MS (apci) m / z = 129.1 (M+H).

[0343] Step 3: Preparation of 4-(6-((3R,4R)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3 -carbonitrile. To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 0.300 g, 1.06 mmol) in DMSO (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.70 mL, 21.3 mmol) and (3R,4R)-4-azidopyrrolidin-3-ol dihydrochloride (0.427 g, 2.13 mmol) The reaction mixture was stirred 100°C for 24 h. After cooling to ambient temperature, the reaction mixture was quenched with saturated NH 4 Cl (aq) and extracted into DCM. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (20-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.205 g, 0.525 mmol, 49.4 % yield over two steps). MS (apci) m / z = 391.2 (M+H). tert-butyl ((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate

[0344] To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 0.215 g, 0.762 mmol) in DMSO (1.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.663 ml, 3.81 mmol) and tert-butyl ((3R,4S)-4-hydroxypyrrolidin-3-yl)carbamate (0.231 g, 1.14 mmol). The reaction mixture was stirred 100°C for 24 h. After cooling to ambient temperature, the reaction mixture was quenched with saturated NH 4 Cl (aq) and extracted into DCM. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (20-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.347 g, 0.747 mmol, 98.1 % yield). MS (apci) m / z = 465.3 (M+H). tert-butyl ((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate

[0345] To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 0.215 g, 0.762 mmol) in DMSO (1.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.663 ml, 3.81 mmol) and tert-butyl ((3S,4R)-4-hydroxypyrrolidin-3-yl)carbamate (0.231 g, 1.14 mmol). The reaction mixture was stirred 100°C for 24 h. After cooling to ambient temperature, the reaction mixture was quenched with saturated NH 4 Cl (aq) and extracted into DCM. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (0-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.284 g, 0.611 mmol, 80.3 % yield). MS (apci) m / z = 465.2 (M+H). tert-butyl ((3R, 5 S)-1 -(5 -(3 -cyano-6-ethoxypyrazolo [1,5 -a]pyridin-4-yl)pyridin-2-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate

[0346] To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 0.060 g, 0.21 mmol) in DMSO (0.4 mL) was added potassium carbonate (0.15 g, 1.1 mmol) and tert-butyl ((3R,5S)-5-(trifluoromethyl)piperidin-3-yl)carbamate (0.171 g, 0.638 mmol). The reaction mixture was stirred at 110°C for 24 h. After cooling to ambient temperature, the reaction mixture was quenched with saturated NH 4 Cl (aq) and extracted into DCM. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (0-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.0538 g47.7 % yield) in sufficient purity for step 2. MS (apci) m / z = 531.2 (M+H). 4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0347] Step 1: Preparation of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate. To a solution of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P42; 205 mg, 0.628 mmol) and tert-butyl piperidin-4-ylcarbamate (252 mg, 1.26 mmol) in DMA (2.09 mL) was added DIEA (549 µL, 3.14 mmol). The reaction was stirred 2 h at 95°C. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with water and brine. The organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered and concentrated in vacuo to afford the title compound (assumed quantative yield, 319 mg) in sufficient purity for step 2. MS (apci) m / z= 507.20 (M+H)

[0348] Step 2: Preparation of 4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile. To a solution of tert-butyl (1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate (319 mg, 0.63 mmol) in DCM (3.15 mL) was added TFA (3.14 mL, 40.9 mmol). The reaction was stirred for 30 min at ambient temperature. The reaction was concentrated in vacuo. The residue was resuspended in DCM and purified using silica chromatography (1-9% MeOH in DCM with 0.1-0.9% NH 4 OH as the gradient eluent) to cleanly provide the title compound (37 mg, 53% yield) MS (apci) m / z = 407.2 (M+H). 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0349] In a pressure vessel, a solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P1; 15.4 g, 64.7 mmol) in dioxane (320 mL) was treated sequentially with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15.2 g, 67.9 mmol), Pd(PPh 3 ) 4 (3.74 g, 3.23 mmol) and 2 M Na 2 CO 3(aq) (97 mL, 194 mmol). The resulting mixture was sparged with Ar (g) and then the vessel was sealed. The mixture was stirred 16 h at 80°C. After cooling to ambient temperature, the reaction mixture was diluted with MTBE and extracted with 1 M NaOH. The combined aqueous layers were extracted with MTBE. The combined aqueous layers were acidified to pH 4 with 4 M HCl. The suspension was filtered and washed with water to cleanly provide the title compound (14.8 g, 72% yield). MS (apci) m / z = 253.1 (M-H) 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.48-8.47 (d, 1H), 8.41-8.40 (d, 1H), 8.26-8.21 (m, 1H), 7.38-7.36 (m, 1H), 7.31-7.30 (d, 1H). 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride

[0350] Step 1: Preparation of tert-butyl (1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate. To a solution of 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P66; 3.0 g, 9.44 mmol) and tert-butyl 4-methylpiperidin-4-ylcarbamate (2.83 mg, 13.2 mmol) in DMSO (12 mL) was added DIEA (4.93 mL, 28.3 mmol). The reaction was stirred 16 h at 90°C. After cooling to ambient temperature, the reaction mixture was diluted into water and acidified to pH 5 using a 10% citric acid solution and stirred for 15 min at ambient temperature. The suspension was filtered and the precipitate was rinsed with water. The isolated solids were dissolved in 4:1 DCM:IPA and dried over anhydrous Na 2 SO 4(s) , filtered and concentrated in vacuo. The residue was purified using silica chromatography (5-75% EtOAc in DCM) to afford the title compound (assumed theoretical yield, 4.23 g) in sufficient purity for step 2. MS (apci) m / z= 449.3 (M+H)

[0351] Step 2: Preparation of 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride To a solution of tert-butyl (1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (assumed 4.23 g, 9.44 mmol) in MeOH (30 mL) was added HCl (5-6 N solution in 2-propanol, 28.3 mL, 142 mmol). The reaction was stirred for 2.5 h at ambient temperature. The reaction was diluted with MTBE (30 mL) and stirred for 30 min at ambient temperature. The suspension was filtered and washed with MTBE (50 mL) to cleanly provide the title compound (2.18 g, 55% yield over two steps) MS (apci) m / z = 349.2 (M+H). N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

[0352] To a solution of 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride (Intermediate P67; 503 mg, 1.19 mmol), 5-fluoro-2-methylbenzoic acid (552 mg, 3.58 mmol), and HATU (1.36g, 3.58 mmol) in DMSO (5 mL) was added DIEA (1.7 mL, 9.55 mmol). The reaction was stirred 16 h at ambient temperature. The reaction mixture was diluted with THF (4 mL) and treated with NaOH (5.97 mL, 11.9 mmol) and stirred for 4 h at ambient temperature. The reaction was concentrated in vacuo. The residue was diluted with EtOAc and washed with water. The pH was adjusted to pH 5 with AcOH and then extracted with EtOAc. The organic extracts were washed with brine. The organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered and concentrated in vacuo. The residue was purified using silica chromatography (50-100% Hexanes to EtOAc) to afford the title compound (534 mg, 92% yield) in sufficient purity for step 2. MS (apci) m / z= 485.2 (M+H). methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate

[0353] To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 0.700 g, 2.480 mmol) in DMSO (4.96 mL) was added DIEA (1.296 mL, 7.439 mmol) and methyl 4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (0.8968 g, 3.472 mmol). The reaction mixture was stirred 90°C for 24 h. After cooling to ambient temperature, the reaction mixture was quenched water and extracted into EtOAc. The combined organic extracts were washed with saturated NaCl (aq) , dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (10-90% EtOAc in hexanes as the gradient eluent) to afford the title compound (1.003 g, 1.927 mmol, 77.69 % yield). MS (apci) m / z = 521.3 (M+H). N-(1-(5 -(3 -cyano-6-ethoxypyrazolo [1,5 -a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

[0354] Step 1: Preparation of methyl 4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate. A solution of methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate (Intermediate P69, 0.8 g, 1.5 mmol) in DCM was treated with TFA. The reaction mixture was stirred at rt for 24 h, then concentrated in vacuo. HCl in iPrOH (6N) was added to the mixture to precipitate product. The suspension was stirred at RT for 1h then concentrated, affording the title compound (assumed theoretical yield, 0.65 g, 1.5 mmol) in sufficient purity for step 2. MS (apci) m / z = 421.25 (M+H).

[0355] Step 2: Preparation of methyl 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(5-fluoro-2-methylbenzamido)piperidine-4-carboxylate. To a solution of methyl 4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate (0.65 g, 1.5 mmol) in DCM (31 mL) was added 5-fluoro-2-methylbenzoic acid (0.36 g, 2.3 mmol) and HATU (0.88 g, 2.3 mmol). The reaction mixture was stirred at rt for 1 h, at which time a catalytic amount of DMAP was added. The reaction mixture was stirred at 50°C for 1 h, then cooled to RT and purified directly by silica chromatography (0-100% EtOAc in Hexanes then 1-10% MeOH in CHCl 3 as the gradient eluent) to afford the title compound (0.8g, 1.4 mmol, 93% yield over two steps) in sufficient purity for step 3. MS (apci) m / z = 557.2 (M+H).

[0356] Step 3: Preparation of N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide. To a solution of methyl 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(5-fluoro-2-methylbenzamido)piperidine-4-carboxylate (750 mg, 1.35 mmol) in THF (26.949 mL) at 0°C was added lithium borohydride (117 mg, 5.39 mmol). The reaction mixture was stirred at 0°C for 1h. The reaction mixture was diluted with EtOAc and washed with a 10% aqueous citric acid solution. The organic extract was dried and concentrated in vacuo. The residue was purified by silica chromatography (0-100% EtOAc in Hexanes then 1-10% MeOH in EtOAc as the gradient eluent) to afford the title compound (700 mg, 1.32 mmol, 98.3% yield) in sufficient purity for step 4. MS (apci) m / z = 529.1 (M+H).

[0357] Step 4: Preparation of N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-5-fluoro-2-methylbenzamide. To a solution of N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide (100 mg, 0.189 mmol) in DCM (0.946 mL) at 0°C was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyltriacetate (201 mg, 0.473 mmol). The reaction mixture was warmed to rt and stirred at that temperature for 1 h, at which time additional 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (201 mg, 0.473 mmol) was added. The reaction mixture was stirred at rt an additional 15 min, then quenched with EtOAc and saturated NaHCO 3(aq) The organic extract was washed with Na 2 S 2 O 3(aq) , dried, and concentrated in vacuo. The residue was purified by silica chromatography (0-100% EtOAc in Hexanes then 1-10% MeOH in EtOAc as the gradient eluent) to afford the title compound (358 mg, 55.3% yield). MS (apci) m / z = 527.15 (M+H).Intermediate P71 tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo [1,5 -a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate

[0358]

[0359] Step 1: Preparation of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate. To a solution of methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate (Intermediate P69, 1.00 g, 1.92 mmol) in THF (12.8 mL) at 0°C was added lithium borohydride (0.167 g, 7.68 mmol). The reaction mixture was allowed to reach rt and stirred at this temperature for 24 h. The reaction mixture was quenched with water, and the residual solids were removed by filtration. The filtrate was extracted with EtOAc, and the combined organic extracts were washed with saturated NaCl (aq) . The organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was purified by silica chromatography (10-90% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.832 g, 1.69 mmol, 87.9 % yield) in sufficient purity for step 2. MS (apci) m / z = 493.3 (M+H).

[0360] Step 2: Preparation of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate. To a solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate (0.832 g, 1.69 mmol) in THF (16.9 mL) was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (0.832 g, 1.69 mmol). The reaction mixture was stirred at rt for 24 h then quenched with water. The mixture was extracted with EtOAc, and the combined organic extracts were washed with saturated NaCl (aq) . The organic extracts were concentrated in vacuo, and the residue was purified by silica chromatography (10-90% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.594 g, 1.21 mmol, 71.7 % yield). MS (apci) m / z = 491.2 (M+H). 4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3 -yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0361] Step 1: Preparation of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate. To a mixture of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate (0.594 g, 1.21 mmol) in DCM (0.077 mL) was added dimethylamine hydrochloride (0.197 g, 2.42 mmol) and DIEA (0.443 mL, 2.54 mmol). This mixture was stirred at rt for 15 min, then sodium triacetoxyborohydride (0.385 g, 1.82 mmol) was slowly added. The reaction mixture was stirred at rt for 24 h then quenched with water. The solution was extracted with EtOAc, and the combined organic extracts were washed with saturated NaCl (aq) . The organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo, and the residue was purified by silica chromatography (10-90% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.181 g, 0.348 mmol, 28.8 % yield) in sufficient purity for step 2. MS (apci) m / z = 520.3 (M+H).

[0362] Step 2: Preparation of 4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile. A mixture of tert-butyl (1-(5-(3 -cyano-6-ethoxypyrazolo [1,5 -a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate (0.181 g, 0.348 mmol) in DCM (0.02 mL) was treated with TFA (0.0268 mL). The reaction mixture was stirred at rt. The reaction mixture was concentrated in vacuo, resuspended in DCM, and washed successively with saturated NaHCO 3(aq) and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo to afford the title compound (0.145 g, 0.346 mmol, 99.2 % yield). MS (apci) m / z = 420.3 (M+H). 4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0363] Step 1: Preparation of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)carbamate. To a solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate (Intermediate P71, 400 mg, 0.815 mmol) in DCM (4.077 mL) was added morpholine (0.07703 mL, 0.815 mmol) and sodium triacetoxyborohydride (346 mg, 1.63 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was concentrated in vacuo, and the residue was purified by C-18 reverse phase chromatography (5-95% ACN in water [+ 0.1% TFA] as the gradient eluent). The fractions containing the desired product were diluted with 4:1 DCM / IPA and washed successively with saturated NaHCO 3(aq) and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (assumed theoretical yield, 458 mg, 0.815 mmol) in sufficient purity for step 2. MS (apci) m / z = 562.4 (M+H).

[0364] Step 2: Preparation of 4-(6-(4-amino-4-(morr)holinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile. A solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)carbamate (458 mg, 0.815 mmol) in DCM (0.815 mL) was treated with TFA (0.0628 mL, 0.815 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with 4:1 DCM / IPA and water. The mixture was washed washed successively with saturated NaHCO 3(aq) and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (135 mg, 0.292 mmol, 35.9 % yield over two steps). MS (apci) m / z = 462.3 (M+H). 4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0365] A solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate (Example 379, 0.149 g, 0.253 mmol) in DCM (0.0163 mL) was treated with HCl in IPA (0.00769 mL, 0.253 mmol). The reaction mixture was stirred at rt then quenched with DCM and saturated Na 2 CO 3(aq) . The organic extract was dried over anhydrous MgSO 4(s) , filtered, then concentrated in vacuo to afford the title compound (assumed theoretical yield, 0.124 g, 0.253 mmol). MS (apci) m / z = 489.3 (M+H). 3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

[0366] To a solution of 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride (Intermediate P67; 256 mg, 0.608 mmol), 3-Chloropicolinic acid (287 mg, 1.82 mmol), and HATU (294 mg, 1.82 mmol) in DMSO (3 mL) was added DIEA (0.74 mL, 4.25 mmol). The reaction was stirred overnight at ambient temperature. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL) and 4:1AcOH:water (10 mL) and then extracted with EtOAc. The organic extracts were washed with 4:1 AcOH:Water and then brine. The organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered and concentrated in vacuo. The residue was diluted with THF (4 mL) and 2M NaOH (6 mL). The solution was concentrated in vacuo. The residue was resuspended in DCM (2mL) and purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford the title compound as the TFA salt. The TFA salt was resuspended in DCM and passed through a Pl-HCO 3 resin to elute the free-based product. The organic eluents were concentrated in vacuo and recrystallized using DCM / Hexanes to afford the title compound (226 mg, 76% yield). MS (apci) m / z = 488.2 (M+H). 4-(6-(4-benzyl-4-formylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3 -carbonitrile

[0367] Step 1: Preparation of 4-(6-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile. To a solution of 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 100.5 mg, 0.3560 mmol) in DMSO (3 mL) was added (4-benzylpiperidin-4-yl)methanol hydrochloride (151.5 mg, 0.6267 mmol), and cesium carbonate (812.0 mg, 2.492 mmol). The reaction mixture was stirred at 60°C for 24 h. After cooling to ambient temperature, the reaction mixture was diluted with DCM and washed successively with water and saturated NH 4 Cl (aq) . The aqueous fractions were extracted with DCM, and the combined organic extracts were dried over anhydrous Na 2 SO 4(s) then purified by silica chromatography (0-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (118.2 mg, 0.2528 mmol, 71.00 % yield) in sufficient purity for step 2. MS (apci) m / z = 468.2 (M+H).

[0368] Step 2: Preparation of 4-(6-(4-benzyl-4-formylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile. A solution of 4-(6-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile (51.3 mg, 0.110 mmol) in DCM (1.5 mL) was treated with 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (93.1 mg, 0.219 mmol). The reaction mixture was stirred at rt for 1.5 h. The reaction mixture was quenched with saturated NaHCO 3(aq) and extracted with DCM. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) and purified by silica chromatography (0-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (46.7 mg, 0.100 mmol, 91.4 % yield) in sufficient purity for step 2. MS (apci) m / z = 466.3 (M+H). 6-hydroxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3 -carbonitrile

[0369] Step 1: Preparation of 2-(4-(pyridin-2-yloxy)piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. To a solution of 2-Chloropyridine-5-boronic acid, pinacol ester (1.18 g, 4.93 mmol) in DMSO (5.0 mL) was added DIEA (4.29 mL, 24.6 mmol) and 2-(piperidin-4-yloxy)pyridine dihydrochloride (1.55 g, 6.16 mmol). The reaction mixture was stirred at 90°C for 72 h. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were successively washed with water and saturated NaCl (aq) then dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (1.19 g, 3.12 mmol, 63.3 % yield) in sufficient purity for step 2.

[0370] Step 2: Preparation of 6-hydroxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. A solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P1, 800.5 mg, 3.363 mmol) in 4:1 dioxane:water (30 mL) was treated with 2-(4-(pyridin-2-yloxy)piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1410.406 mg, 3.699 mmol), tetrakis(triphenylphosphine)palladium (0) (388.6035 mg, 0.3363 mmol), and aqueous potassium carbonate (1394.277 mg, 10.088 mmol). The reaction mixture was sparged with argon and stirred at 90°C for 16 h. After cooling to ambient temperature, the reaction mixture was quenched with water and adjusted to pH 7 with 4N HCl. The mixture was extracted with 4:1 DCM:IPA, and the combined organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo. The residue was purified by silica chromatography (5-95% acetone in hexanes as the gradient eluent) to afford the title compound (475.3 mg, 1.152 mmol, 34.3% yield). MS (apci) m / z = 413.2 (M+H). 4-(6-fluoropyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0371] Step 1: Preparation of 4-bromo-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile. A solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P1, 1000 mg, 4.201 mmol) in DMA (21.005 L) was treated with potassium carbonate (1742 mg, 12.60 mmol) and 4-(2-chloroethyl)morpholine (1.132 mL, 8.402 mmol). The reaction mixture was stirred at 50°C for 72 h. After cooling to ambient temperature, the reaction mixture was quenched with saturated NaCl (aq) . The resultant precipitate was isolated by filtration to afford the title compound (1475 mg, 4.200 mmol, 99% yield) in sufficient purity for step 2. MS (apci) m / z = 351 (M +< ).

[0372] Step 2: Preparation of 4-(6-fluoropyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile. A solution of 4-bromo-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.83 g, 1.394 mmol) in 1,4-dioxane (1000 mL) was treated with 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (373.2181 mg, 1.673 mmol), tetrakis(triphenylphosphine)palladium (0) (32.22577 mg, 0.0279 mmol), and aqueous potassium carbonate (2.092 mL, 4.183 mmol). The reaction mixture was sparged with argon and stirred at 90°C for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with MTBE and washed with 1N NaOH. The aqueous fractions were extracted with MTBE then adjusted to pH 4 with 4N HCl. Saturated NaCl (aq) was added and the aqueous mixture was extracted with 4:1 DCM / IPA. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered and concentrated in vacuo to afford the title compound (0.341 g, 0.928 mmol, 66.6 % yield). MS (apci) m / z = 368.1 (M+H). (R)-4-(6-fluoropyridin-3 -yl)-6-(2-hydroxypropoxy)pyrazolo [1,5 -a]pyridine-3 - carbonitrile

[0373] To a solution of 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P66, 0.2027 g, 0.78935 mmol) in THF (3.16 mL) was added aqueous sodium hydroxide (2M, 0.40257 mL, 0.80514 mmol) dropwise. The mixture was stirred at rt for 1 h, at which time (R)-2-methyloxirane (0.33181 mL, 4.7361 mmol) was added. The reaction mixture was stirred at 80°C for 16 h. After cooling to ambient temperature, the pH was adjusted to 5 by addition of a 10% aqueous citric acid solution. The mixture was extracted with EtOAc, then the combined organic extracts were washed successively with water and saturated NaCl (aq) then dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo. The residue was purified by silica chromatography (10-90% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.084 g, 0.26897 mmol, 34.074 % yield. MS (apci) m / z = 313.1 (M+H). tert-butyl (1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0374] Step 1: Preparation of 4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine. To a solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (5.122 g, 22.56 mmol) in 1,4-dioxane (45.12 mL) was added 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.038 g, 27.07 mmol), tetrakis(triphenylphosphine)palladium (0) (1.043 g, 0.9023 mmol), and aqueous sodium carbonate (2M, 23.69 mL, 47.37 mmol). The reaction mixture was stirred at 80°C for 16 h. After cooling to ambient temperature, the reaction mixture was poured onto water and stirred for 4 h. The resultant precipitate was isolated by vacuum filtration then taken up in MTBE and stirred an additional 30 min. The precipitate was isolated by vacuum filtration to afford the title compound (4.616 g, 18.98 mmol, 84.13 % yield) in sufficient purity for step 2. MS (apci) m / z = 244.1 (M+H).

[0375] Step 2: Preparation of tert-butyl (1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate. To a solution of 4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine (2.25 g, 9.25 mmol) in DMSO (18.5 mL) was added tert-butyl (4-methylpiperidin-4-yl)carbamate (2.97 g, 13.9 mmol) and DIEA (4.83 mL, 27.8 mmol). The reaction mixture was stirred at 90°C for 16 h. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with saturated NaCl (aq , dried over anhydrous Na 2 SO 4(s) , and concentrated in vacuo. The residue was purified by silica chromatography (10-90% EtOAc in hexanes as the gradient eluent) to afford the title compound (3.8 g, 8.68 mmol, 93.9 % yield). MS (apci) m / z = 438.3 (M+H). 1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine

[0376] A solution of tert-butyl (1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate P81, 0.500 g, 1.14 mmol) in DCM (5 mL) was treated with TFA (5 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with EtOAc and washed successively with saturated NaHCO 3(aq) and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , and concentrated in vacuo to afford the title compound (0.38 g, 1.13 mmol, 98.5 % yield). MS (apci) m / z = 338.2 (M+H). 1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine

[0377] Step 1: Preparation of tert-butyl (1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-vl)-4-methylpyperidin-4-yl)carbamate. To a solution of tert-butyl (1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate P81, 0.800 g, 1.83 mmol) in DCM (12.2 mL) was added NCS (0.293 g, 2.19 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and washed successively with water and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , and concentrated in vacuo. The residue was purified by silica chromatography (10-90% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.765 g, 1.62 mmol, 88.6 % yield) in sufficient purity for step 2. MS (apci) m / z = 472.2 (M+H).

[0378] Step 2: Preparation of 1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine. A solution of tert-butyl (1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (0.765 g, 1.62 mmol) in DCM (12 mL) was treated with TFA (12 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and washed successively with saturated NaHCO 3(aq) and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , and concentrated in vacuo to afford the title compound (0.548 g, 1.47 mmol, 90.9 % yield). MS (apci) m / z = 372.2 (M+H). 4-bromo-3 -chloropyrazolo [1,5-a]pyridin-6-ol

[0379] Step 1: Preparation of 4-bromo-3-chloro-6-methoxypyrazolorI .5-a l py< ridine. To a solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (15 g, 66.06 mmol) in DCM (100 mL) was added NCS (8.821 g, 66.06 mmol). The reaction mixture was sonicated for 5 min then stirred at rt for 24 h. The reaction mixture was diluted with Et 2 O, in which it was stirred for 10 min then sonicated for 2 min. The solid precipitate was isolated by vacuum filtration to afford the title compound (18.69 g, 71.47 mmol, 108.2% yield) in sufficient purity for step 2. MS (apci) m / z = 263.1 (M+H).

[0380] Step 2: Preparation of 4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-ol. A solution of 4-bromo-3-chloro-6-methoxypyrazolo[1,5-a]pyridine (7.59 g, 29.0 mmol) in DCE (290 mL) was sparged with N 2 and treated with aluminum trichloride (11.6 g, 87.1 mmol) over the course of 5 min. The reaction mixture was stirred at 76°C for 16 h. After cooling to ambient temperature, the reaction mixture was quenched with DMA then concentrated in vacuo. The residue was taken up in water and cooled on ice for 30 min. The resultant precipitate was isolated by vacuum filtration then taken up in DMA. The solution was filtered through a plug of silica to afford the title compound as a solution in DMA (assumed quantitative yield, 7.00g, 28.3 mmol).Intermediate P85 1-((3-chloro-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol

[0381]

[0382] Step 1: Preparation of 1-((4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol. To a solution of 4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-ol (Intermediate P84 , 4.2 g, 17.0 mmol) in DMA (300 mL) was added potassium carbonate (23.5 g, 170 mmol) and 2,2-dimethyloxirane (14.9 mL, 169.8 mmol). The reaction mixture was stirred at 85°C for 2 h. After cooling to ambient temperature, the reaction mixture was quenched with 1:1 saturated NH 4 Cl (aq) / water. The solution was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo to afford the title compound (2.62 g, 5.74 mmol, 33.8% yield) in sufficient purity for step 2. MS (apci) m / z = 321.0 (M+H).

[0383] Step 2: Preparation of 1-((3-chloro-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol. To a solution of 1-((4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol (1.44 g, 4.51 mmol) in 1,4-dioxane was added 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.51 g, 6.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.260 g, 0.225 mmol), and aqueous sodium carbonate (2M, 50 mL, 100 mmol). The reaction mixture was sparged with N 2 and stirred at 90°C for 16 h. After cooling to ambient temperature, the reaction mixture was quenched with water. The solution was extracted with MTBE, and the combined organic extracts were dried over anhydrous Na 2 SO 4(s) , and concentrated in vacuo. The residue was purified by silica chromatography (0-100% EtOAc in hexanes as the gradient eluent) to afford the title compound (0.37 g, 1.10 mmol, 24.5 % yield). MS (apci) m / z = 336.1 (M+H). 3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide

[0384] To a solution of 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride (Intermediate P67, 0.253 g, 0.600 mmol) in DCM (3 mL) was added 3-chloro-5-fluoropicolinic acid (0.232 g, 1.32 mmol), HATU (0.502 g, 1.32 mmol), and DIEA (0.524 mL, 3.00 mmol). The reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted with DCM and washed with aqueous citric acid (adjusted to pH 5). The aqueous mixture was extracted with DCM, and the combined organic extracts were washed successively with water and saturated NaCl (aq) then dried over anhydrous Na 2 SO 4(s) and concentrated in vacuo. The residue was taken up in THF and 2M NaOH and stirred at rt for 5 min. The mixture was diluted with DCM, washed with aqueous citric acid (adjusted to pH 5), and extracted with 4:1 DCM / IPA. The combined organic extracts were washed with saturated NaCl (aq) , dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase chromatography (5-95% ACN in water [+ 0.1% TFA] as the gradient eluent). The fractions containing the desired product were diluted with 4:1 DCM / IPA and washed successively with saturated NaHCO 3(aq) and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (0.325 g, 0.578 mmol, 96.3 % yield). MS (apci) m / z = 506.2 (M+H). N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

[0385] To a solution of 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride (Intermediate P67, 255.4 mg, 0.606 mmol) in DCM (6 mL) was added benzoic acid (185.072 mg, 1.51545 mmol), HATU (576.228 mg, 1.515 mmol), and DIEA (1.056 mL, 6.06 mmol). The reaction mixture was stirred at rt for 16 h then concentrated in vacuo. The residue was taken up in THF and treated with 2M KOH (aq) . The mixture was stirred at rt for 1 h then adjusted to pH 4 by addition of 2M HCl. The mixture was diluted with water and extracted with 4:1 DCM / IPA. The combined organic extracts were washed with water then dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase chromatography (5-95% ACN in water [+ 0.1% TFA] as the gradient eluent). The fractions containing the desired product were washed with saturated NaHCO 3(aq) and extracted with 4:1 DCM / IPA. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (172.5 mg, 0.381 mmol, 62.9% yield). MS (apci) m / z = 453.2 (M+H). N-(1-(5 -(3 -cyano-6-(2-(piperazin-1 -yl)ethoxy)pyrazolo [1,5 -a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

[0386] Step 1: Preparation of tert-butyl 4-(2-((4-(6-(4-benzamido-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate. To a solution of N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide (Intermediate P87, 157.2 mg, 0.3474 mmol) in DMA (3.5 mL) was added tert-Butyl 4-(2-chloroethyl)tetrahydro-1(2H)-pyrazinecarboxylate (172.8 mg, 0.6948 mmol) and cesium carbonate (565.9 mg, 1.737 mmol). The reaction mixture was stirred at 60°C for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed successively with water and saturated NaCl (aq) . The combined organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (assumed theoretical yield, 231 mg, 0.3474 mmol) in sufficient purity for step 2. MS (apci) m / z = 665.4 (M+H).

[0387] Step 2: Preparation of N-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide. A solution of tert-butyl 4-(2-((4-(6-(4-benzamido-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate in DCM (1.75 mL) was treated with TFA (1.75 mL, 22.9 mmol). The reaction mixture was stirred at rt for 30 min then concentrated in vacuo. The residue was directly purified by C-18 reverse phase chromatography (5-95% ACN in water (+ 0.1% TFA) as the gradient eluent). The fractions containing the desired product were washed with saturated NaHCO 3(aq) and extracted with 4:1 DCM / IPA. The combined organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (111.8 mg, 0.1980 mmol, 56.99% yield over two steps). MS (apci) m / z = 565.3 (M+H). 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3 -yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0388] A solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (Example 469 , 100 mg, 0.210 mmol) in DCM (2 mL) was treated with TFA (2 mL). The reaction mixture was stirred at rt for 1 h. The crude reaction mixture was directly purified by silica chromatography (5-50% [MeOH + 2% NH 4 OH] in DCM as the gradient eluent) to afford the title compound (20 mg, 0.0531 mmol, 25.3% yield). MS (apci) m / z = 377.2 (M+H). N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

[0389] To a solution of 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride (Intermediate P67 , 1.38 g, 3.2754 mmol) in DCM (6.5507 mL) was added 2-Picolinic acid (1.0081 g, 8.1884 mmol), HATU (3.1135 g, 8.1884 mmol), and DIEA (5.7207 mL, 32.754 mmol). The reaction mixture was stirred at rt for 1 h then concentrated in vacuo. The residue was taken up in THF and 2M aqueous KOH and stirred at rt for 30 min. The mixture was adjusted to pH 4 by addition of 1M HCl and extracted with 4:1 DCM / IPA. The combined organic extracts were washed successively with water and saturated NaCl (aq) then dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase chromatography (5-95% ACN in water (+ 0.1% TFA) as the gradient eluent). The fractions containing the desired product were diluted with 4:1 DCM / IPA and washed successively with saturated NaHCO 3(aq) and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (737 mg, 1.6251 mmol, 49.616% yield). MS (apci) m / z = 454.2 (M+H). N-(1-(5 -(3 -cyano-6-(2-(piperazin-1 -yl)ethoxy)pyrazolo [1,5 -a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

[0390] Step 1: Preparation of tert-butyl 4-(2-((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate. To a solution of N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide (Intermediate P90, 120 mg, 0.265 mmol) in DMA (2.646 mL) was added tert-Butyl 4-(2-chloroethyl)tetrahydro-1(2H)-pyrazinecarboxylate (65.8 mg, 0.265 mmol) and cesium carbonate (431 mg, 1.32 mmol). The reaction mixture was stirred at 60°C for 48 h. After cooling to ambient temperature, the reaction mixture was diluted with 4:1 DCM / IPA and washed successively with saturated NaHCO 3(aq) and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (176 mg, 0.264 mmol, 99.9 % yield) in sufficient purity for step 2. MS (apci) m / z = 666.4 (M+H).

[0391] Step 2: Preparation ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide. A solution of tert-butyl 4-(2-((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate (176 mg, 0.264 mmol) in DCM (2.643 mL) was treated with TFA (0.2 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with 4:1 DCM / IPA and washed successively with saturated NaHCO 3(aq) , water, and saturated NaCl (aq) . The organic extract was dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to afford the title compound (assumed theoretical yield, 150 mg, 0.264 mmol). MS (apci) m / z = 566.4 (M+H). 4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0392] In a pressure tube, a mixture of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P1, Step 6 ; 1.1854 g, 4.7026 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2587 g, 5.6432 mmol), Pd(PPh 3 ) 4 (0.1087 g, 0.094 mmol) and 2 M Na 2 CO 3(aq) (15 mL, 30 mmol) in dioxane (15 mL) was sparged with N 2(g) . The vessel was sealed, and the sparged mixture was stirred for 4 d at 60 °C. After cooling to ambient temperature, the reaction mixture was quenched with water. The resultant precipitate was filtered, washed with water, and then purified by silica chromatography (0-25% MeOH in DCM) to afford the title compound (734.6 mg, 58% yield). MS (apci), m / z = 269.1 (M+H). 4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride

[0393] A solution of tert-butyl ((3S,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate (Example 514 , 274.5 mg, 0.5909 mmol) in dioxane (3 mL) was treated with 37% HCl (97 µL, 1.18 mmol), then stirred overnight at ambient temperature. The resulting mixture was concentrated in vacuo to afford the title compound (258 mg, 100% yield). MS (apci) m / z = 365.2 (M+H). 4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride

[0394] A stirring, ambient temperature, solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (Example 469, 807 mg, 1.69 mmol) in MeOH (3387 µL) was treated dropwise with 12 M HCl (aq) (1.41 mL, 16.9 mmol). The resulting mixture was stirred overnight at ambient temperature. The resulting thick slurry was diluted with MeOH (ca. 1 mL), and vacuum filtered. The solids were rinsed with MeOH (3 × 1 mL) and MTBE (3 × 10 mL), then dried in vacuo to afford the title compound (690 mg, 91% yield). MS (apci) m / z = 377.2 (M+H). Tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-yl)carbamate

[0395] Tert-Butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate (Intermediate P71, 100 mg, 0.2038 mmol) was added to solution of pyrrolidine (681 µL, 0.82 mmol) and TEA (142 µL, 1.0 mmol) in DCM (1.0 mL), and the mixture was stirred for 1 h at ambient temperature. Subsequently, NaBH(AcO) 3 (86.4 mg, 0.41 mmol) was added, and the resulting mixture was stirred for 2.5 h at ambient temperature then concentrated in vacuo. The residue was purified by C18 reverse phase chromatography (5-95% ACN:water with 0.1% TFA). Fractions containing the desired product were combined, diluted with 4:1 DCM:iPrOH, then sequentially extracted with saturated NaHCO 3(aq) , water and brine. The organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to cleanly afford the title compound (40 mg, 36% yield). MS (apci) m / z = 546.3 (M+H). 4-(6-(4-amino-4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0396] A solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-yl)carbamate (Intermediate P96; 40 mg, 0.073 mmol) in DCE (4.7 µL) and TFA (5.6 µE , 0.073 mmol) was stirred for 90 min at ambient temperature. The resulting mixture was diluted with 4:1 DCM:iPrOH, then sequentially extracted with saturated NaHCO 3(aq) , water and brine. The organic extracts were dried over anhydrous Na 2 SO 4(s) , filtered, and concentrated in vacuo to cleanly afford the title compound (30 mg, 92% yield). MS (apci) m / z = 446.3 (M+H). 4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo [1,5 -a]pyridine-3 -carbonitrile dihydrochloride

[0397] A solution of tert-butyl (1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate (Example 379, 171.2 mg, 0.2908 mmol) in dioxane (5.0 mL) was treated with 12 M HCl (aq) (23.88 µL, 0.2908 mmol). The resulting mixture was stirred for 45 min at ambient temperature before concentrating the mixture in vacuo to cleanly afford the title compound (205.5 mg, quantitative yield). MS (apci) m / z = 489.3 (M+H). 4-(6-(4-amino-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3 -yl)-6-ethoxypyrazolo [1,5-a]pyridine-3 -carbonitrile

[0398] A solution of 4-(pyridin-2-ylmethyl)piperidin-4-amine bis(2,2,2-trifluoroacetate) (Intermediate R41; 287.5 mg, 0.6856 mmol) in DMF (2 mL) was treated with 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P6, 176 mg, 0.624 mmol), K 2 CO 3(s) (431 mg, 3.12 mmol) was stirred overnight at 70 °C. The mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with DCM (3 × 20 mL). The organic extra...

Claims

1. A compound of the Formula I: and pharmaceutically acceptable salts thereof, wherein: X1, X2, X3 and X4 are independently CH, CCH3, CF or N, wherein zero, one or two of X1, X2, X3 and X4 is N; A is H, CN, Cl, methyl, ethyl or cyclopropyl; B is: (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, (f) (R1R2N)C1-C6 alkyl- where R1 and R2 are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(=O)-; (g) hetAr1C1-C3 alkyl-, where 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; (h) (C3-C6 cycloalkyl)C1-C3 alkyl-, (i) (hetCyca)C1-C3 alkyl-, (j) hetCyca, (k) (R1R2N)C(=O)C1-C6 alkyl- where R1 and R2 are independently selected from H and C1-C6 alkyl, (l) (R1R2N)C(=O)-, where R1 and R2 are independently selected from H and C1-C6 alkyl, or (m) hetCycaC(=O)C1-C6 alkyl-; hetCyca 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), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl)C(=O)-, C1-C6 alkoxy, oxo, and (C1-C6 alkoxy)C(=O)-; Ring D is (i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, each Ra is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; Rb is (a) hydroxy, (c) hetCycbCH2- wherein hetCycb is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and wherein hetCycb is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), (e) RcRdN- or (f) RcRdNCH2-; Rc is hydrogen or C1-C6 alkyl; and Rd is hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros); n is 0, or 1; m is 0 or 1; E is: (d) Ar1C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2C1-C6 alkyl-, (g) Ar1O-, (h) hetAr2O-, (l) Ar1C(=O)NRg- where Rg is H or C1-C6 alkyl, or (m) hetAr2C(=O)NRg(CH2)p- where p is 0 or 1; 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), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO2-, ReRfN- and (ReRfN)C1-C6 alkyl- where each Re and Rf is independently H or C1-C6 alkyl; 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 having 1-2 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)C1-C6 alkyl- (optionally substituted with 1-3 fluoros) andhydroxyC1-C6 alkoxy.

2. A compound according to claim 1, wherein each Ra is an independently selected C1-C6 alkyl group.

3. A compound according to claim 2, wherein D is 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 of Ring D to the E group.

4. A compound according to claim 1, wherein D is 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 the E group.

5. A compound according to claim 4, wherein E is (d) Ar1C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2C1-C6 alkyl-, (g) Ar1O-, (h) hetAr2O-, (1) Ar1C(=O)NRg- where Rg is H or C1-C6 alkyl, or (m) hetAr2C(=O)NRg(CH2)p- where p is 0 or 1.

6. A compound according to any one of claims 1-5, wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros.

7. A compound according to any one of claims 1-6, wherein X1 is N, and X2, X3 and X4 are CH.

8. A compound according to any one of claims 1-7, wherein A is CN.

9. A compound according to claim 1 which is or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 which is: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition, comprising a compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

12. A compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

13. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 12 wherein the cancer is a RET-associated cancer.

14. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 13, wherein the RET-associated cancer is a cancer having a dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same caused by one or more point mutations in the RET gene.

15. The compound, or pharmaceutically acceptable salt thereof, for use according to either claim 13 or 14, wherein the RET-associated cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

16. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 12-15, wherein the medicament is formulated for oral administration.