WO2018136663A1 - Ret inhibitors - Google Patents

Ret inhibitors Download PDF

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Publication number
WO2018136663A1
WO2018136663A1 PCT/US2018/014281 US2018014281W WO2018136663A1 WO 2018136663 A1 WO2018136663 A1 WO 2018136663A1 US 2018014281 W US2018014281 W US 2018014281W WO 2018136663 A1 WO2018136663 A1 WO 2018136663A1
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Prior art keywords
compound according
ret
alkyl
optionally substituted
methyl
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PCT/US2018/014281
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French (fr)
Inventor
Steven W. Andrews
James F. Blake
Julia Haas
Yutong Jiang
Original Assignee
Array Biopharma, Inc.
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Publication of WO2018136663A1 publication Critical patent/WO2018136663A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • 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 2-(pyridin-3-yl)-pyrimidine compounds useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.
  • RET Rearranged during Transfection
  • 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.
  • 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).
  • GDNF glial cell line-derived neurotrophic factor
  • NTRN neurturin
  • ARTN artemin
  • PSPN persephin
  • RET does not directly bind to GFLs and requires an additional co-receptor: that is, one of four GDNF receptor-a (GFRa) family members, which are tethered to the cell surface by a glycosylphosphatidylinositol linkage.
  • GFLs and GFRa family members form binary complexes that in turn bind to RET and recruit it into cholesterol- rich membrane subdomains, which
  • 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 PBK-Akt/mTOR signaling pathways or to recruitment of the CBL family of ubiquitin ligases that functions in RET downregulation of the RET-mediated functions.
  • composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
  • Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
  • Also provided herein is a method of treating a RET-associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
  • Also provided herein is a method of treating cancer and/or inhibiting metastasis associated with a particular cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.
  • Also provided herein is a method of treating irritable bowel syndrome (IBS) and/or pain associated with IBS in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.
  • IBS irritable bowel syndrome
  • 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.
  • 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.
  • IBS irritable bowel syndrome
  • a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment.
  • 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.
  • 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.
  • a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein in the manufacture of a medicament for the treatment of cancer and/or inhibiting metastasis associated with a particular cancer.
  • a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein in the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.
  • IBS irritable bowel syndrome
  • a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein in the manufacture of a medicament for providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment.
  • Also provided herein is a use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of RET kinase activity.
  • Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a RET-associated disease or disorder.
  • a pharmaceutical combination for treating cancer e.g., a
  • RET-associated cancer such as a RET-associated cancer having one or more RET inhibitor resistance mutations
  • 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.
  • a pharmaceutical composition comprising such a combination.
  • Also provided herein is a method for reversing or preventing acquired resistance to an anticancer drug, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, to a patient at risk for developing or having acquired resistance to an anticancer drug.
  • the patient is administered a dose of the anticancer drug (e.g., at substantially the same time as a dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the patient).
  • Also provided herein is a method of delaying and/or preventing development of cancer resistant to an anticancer drug in an individual, comprising administering to the individual an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of an effective amount of the anticancer drug.
  • Also provided herein is a method of treating an individual with cancer who has an increased likelihood of developing resistance to an anticancer drug, comprising administering to the individual (a) an effective amount of a compound of Formula I before, during, or after administration of (b) an effective amount of the anticancer drug.
  • Also provided are methods of treating an individual with a RET-associated cancer that has one or more RET inhibitor resistance mutations that increase resistance of the cancer to a first RET inhibitor e.g., one or more amino acid substitutions in the kinase domain (e.g., amino acid positions 723 to 1012 in a wildtype RET protein), a gatekeeper amino acid (e.g., amino acid position 804 in a wildtype RET protein), the P-loop (e.g., amino acid positions 730-737 in a wildtype RET protein), the DFG motif (e.g., amino acid positions 892-894 in a wildtype RET protein), ATP cleft solvent front amino acids (e.g., amino acid positions 758, 811, and 892 in a wildtype RET protein), the activation loop (e.g., amino acid positions 891-916 in a wildtype RET protein), the C-helix and loop preceeding the C-helix (e.g., amino acid positions 7
  • a wildtype RET protein is the exemplary wildtype RET protein described herein.
  • Also provided are methods of treating an individual with a RET-associated cancer that include administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anticancer drug (e.g., a first RET kinase inhibitor).
  • a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof before, during, or after administration of another anticancer drug (e.g., a first RET kinase inhibitor).
  • a method for treating irritable bowel syndrome (IBS) in a patient in need thereof comprising (a) determining if the IBS is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same; and (b) if the IBS is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • IBS irritable bowel syndrome
  • a pharmaceutical combination for treating irritable bowel syndrome which comprises administering (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use 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.
  • 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.
  • a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of the IBS a patient in need thereof.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
  • A is selected from:
  • R a is H or C 1 -C6 alkyl
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R k RTNT-, wherein R b and R c are independently H or Cl-C6 alkyl,
  • hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl-, hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R ⁇ 'TST-, wherein R b and R c are independently H or C1-C6 alkyl,
  • hetCyc 1 is a 4-6 membered saturated heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or C1-C6 alkyl;
  • B is selected from:
  • R a is H or C 1 -C6 alkyl
  • Ar 3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or Cl-C6 alkyl,
  • hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl-, hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R ⁇ 'TST-, wherein R b and R c are independently H or C1-C6 alkyl,
  • hetCyc 2 is a 4-6 membered saturated heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or C1-C6 alkyl;
  • X 1 , X 2 , X 3 and X 4 are independently CH, CF or N, wherein 0, 1 or 2 of X 1 , X 2 , X 3 and X 4 is N;
  • Y is a bond, - R d -, - R d (Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), or -(C1-C6 alkyl) R d - (optionally substituted with 1-3 fluoros), wherein R d is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
  • R 1 and R 2 at each occurrence are independently selected from the group consisting of halogen, OH, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyC2-C6 alkyl- (wherein the alkyl portion is optionally substituted with 1-3 fluoros), dihydroxyC3-C6 alkyl-, (Cl- C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), (R ⁇ Cl-Ce alkyl-, wherein R e and R f are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros), and (C3- C6 cycloalkyl)Cl-C3 alkyl-;
  • n 0, 1 or 2;
  • m is 0, 1 or 2.
  • A is selected from:
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), and oxo, and
  • hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), and oxo;
  • B is selected from:
  • Ar 3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and
  • hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C3-C6 cycloalkyl;
  • X 1 , X 2 , X 3 and X 4 are independently CH, CF or N, wherein 0, 1 or 2 of X 1 , X 2 , X 3 and X 4 is N;
  • Y is - R d - or - R d (C 1 -C6 alkyl)- (optionally substituted with 1 -3 fluoros), wherein
  • R d is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
  • R 1 and R 2 at each occurrence are independently selected from the group consisting of H, halogen, and C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • n 1 or 2;
  • m is 1 or 2.
  • A is Ar 1 , where Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, or CN. In certain embodiments of Formula I, A is Ar 1 , where Ar 1 is phenyl substituted with CN.
  • A is hetAr 2 , where hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of H, CN, C1-C6 alkyl, hydroxyCl-C6 alkyl, and oxo.
  • hetAr 2 is a 5 membered heteroaryl ring having 2 heteroatoms independently selected from N, O, and S.
  • hetAr 2 is a 5 membered heteroaryl ring having 3 heteroatoms independently selected from N, O, and S. In certain embodiments, hetAr 2 is a 6 membered heteroaryl ring having 1 heteroatom that is N. In certain embodiments, hetAr 2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr 2 is substituted with CN. In certain embodiments, hetAr 2 is 5-6 membered heteroaryl ring having 1- 3 heteroatoms independently selected from N, O and S, wherein hetAr 2 is substituted with oxo.
  • hetAr 2 is a 6 membered heteroaryl ring having 1 heteroatom that is N, wherein hetAr 2 is substituted with C1-C6 alkyl and oxo. In certain embodiments, hetAr 2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr 2 is substituted with C1-C3 alkyl. In certain embodiments, hetAr 2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr 2 is substituted with h droxyCl-C3 alkyl.
  • Non-limiting examples of hetAr 2 include the structures:
  • B is Ar , where Ar is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 alkoxy.
  • B is Ar 3 , where Ar 3 is phenyl substituted with H.
  • B is Ar 3 , where Ar 3 is phenyl substituted with halogen.
  • B is Ar 3 , where Ar 3 is phenyl substituted with F.
  • B is Ar 3 , where Ar 3 is phenyl substituted with C1-C6 alkyl.
  • B is Ar 3 , where Ar 3 is phenyl substituted with C1-C6 alkoxy. In certain embodiments of Formula I, B is Ar 3 , where Ar 3 is phenyl substituted with methoxy. In certain embodiments of Formula I, B is Ar 3 , where Ar 3 is phenyl substituted with methyl and F.
  • B is hetAr 4 , where hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 4 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
  • hetAr 4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N.
  • hetAr 4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr 4 is substituted with halogen. In certain embodiments, hetAr 4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr 4 is substituted with F. In certain embodiments, hetAr 4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr 4 is substituted with C1-C3 alkyl.
  • hetAr 4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr 4 is substituted with 1-2 methyls. In certain embodiments, hetAr 4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr 4 is substituted with C3-C6 cycloalkyl. In certain embodiments, hetAr 4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr 4 is substituted with cyclopropyl.
  • hetAr 4 is a 6 membered heteroaryl having 1 ring heteroatom that is N. In certain embodiments, hetAr 4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr 4 is substituted with C1-C6 alkoxy. In certain embodiments, hetAr 4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr 4 is substituted with C1-C6 alkyl. In certain embodiments, hetAr 4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr 4 is substituted with halogen. In certain embodiments, hetAr 4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein ctures:
  • X 1 , X 2 , X 3 and X 4 are independently CH or
  • each of X 1 , X 2 , X 3 and X 4 is CH.
  • X 1 , X 2 , X 3 and X 4 are independently CH or
  • X 1 , X 2 , X 3 and X 4 are N and the remainder are CH.
  • X 3 is N
  • X 1 , X 2 and X 4 are CH.
  • X 1 , X 2 , X 3 and X 4 are independently CH or
  • X 1 , X 2 , X 3 and X 4 are N.
  • X 1 and X 3 are N and X 2 and X 4 are CH.
  • Y is -NR d (Cl-C6 alkyl)-, wherein R d is H or
  • C1-C3 alkyl examples include methyl, ethyl, propyl, and isopropyl.
  • R 1 at each occurrence is independently Cl-
  • R 1 is C1-C3 alkyl. In certain embodiments of Formula I, R 1 is methyl.
  • R 2 at each occurrence is independently selected from the group consisting of H, halogen, and C1-C6 alkyl.
  • R 2 is H.
  • R 2 is halogen.
  • R 2 is F.
  • R 2 is C1-C6 alkyl.
  • R 2 is methyl.
  • the compound of Formula I is a compound of Formula la
  • B is selected from Ar 3 or hetAr 4 ,
  • Ar 3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R k RTNT-, wherein R b and R c are independently H or Cl-C6 alkyl,
  • hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or C1-C6 alkyl;
  • X 1 , X 2 , and X 4 are each CH and X 3 is N, or X 2 and X 4 are each CH and X 1 and X 3 are each N;
  • Y is -NR d (Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), wherein R d is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
  • Z 1 , Z 2 and Z 3 are each independently selected from CH, N, NH, O or S;
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros); and [00125] m is l .
  • B is Ar 3 .
  • B is hetAr 4 , substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3- C6 cycloalkyl, and C1-C3 alkyl.
  • X 1 , X 2 , and X 4 are each CH and X 3 is N.
  • X 2 and X 4 are each CH and X 1 and X 3 are each N.
  • Y is - R d (Cl-C6 alkyl)-, wherein R d is methyl.
  • Y is - R d (Cl-C6 alkyl)-, wherein R d is H.
  • Y is - HCH2-.
  • Y is - HCH(CH3)-.
  • R 1 is C1-C3 alkyl.
  • R 1 is methyl
  • R 2 is halogen
  • R 2 is F.
  • R 2 is C1-C3 alkyl.
  • R 2 is methyl
  • R 3 is CN
  • R 3 is hydroxyCl-C6 alkyl.
  • R 3 is C1-C3 alkyl.
  • R 3 is methyl
  • R 3 is ethyl
  • Z 1 is N or NH.
  • Z 1 is CH.
  • Z 2 is N or NH.
  • Z 2 is O.
  • Z 2 is S.
  • Z 3 is CH.
  • Z 3 is N or NH.
  • Z 1 is NH
  • Z 2 is N
  • Z 3 is CH.
  • Z 1 is N
  • Z 2 is O
  • Z 3 is CH
  • Z 1 is N
  • Z 2 is O
  • Z 3 is N
  • Z 1 is N
  • Z 2 is S
  • Z 3 is CH
  • Z 1 is N
  • Z 2 is S
  • Z 3 is N
  • Z 1 is CH
  • Z 2 is NH
  • Z 3 is N.
  • Z 1 is N
  • Z 2 is NH
  • Z 3 is CH.
  • R 1 is methyl
  • R 3 is CN
  • Z 1 is NH
  • Z 2 is N
  • Z 3 is CH.
  • R 1 is methyl
  • R 3 is CN
  • Z 1 is N
  • Z 2 is O
  • Z 3 is CH.
  • R 1 is methyl
  • R 3 is CN
  • Z 1 is N
  • Z 2 is O
  • Z 3 is N.
  • R 1 is methyl
  • R 3 is CN
  • Z 1 is N
  • Z 2 is S
  • Z 3 is CH.
  • R 1 is methyl
  • R 3 is CN
  • Z 1 is N
  • Z 2 is S
  • Z 3 is N.
  • R 1 is methyl
  • R 3 is CN
  • Z 1 is CH
  • Z 2 is NH
  • Z 3 is N.
  • R 1 is methyl
  • R 3 is CN
  • Z 1 is N
  • Z 2 is NH
  • Z 3 is CH.
  • R 1 is methyl
  • R 3 is hydroxyCl-C6 alkyl
  • Z 1 is N
  • Z 2 is NH
  • Z 3 is CH.
  • R 1 is methyl
  • R 3 is C1-C3 alkyl
  • Z 1 is N
  • Z 2 is NH
  • Z 3 is CH.
  • the compound of Formula I is a compound of Formula lb
  • [00170] B is selected from Ar 3 or hetAr 4 ,
  • Ar 2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or Cl-C6 alkyl,
  • hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or C1-C6 alkyl;
  • X 1 , X 2 , and X 4 are each CH and X 3 is N, or X 2 and X 4 are each CH and X 1 and X 3 are each N;
  • Y is -NR d (Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), wherein R d is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
  • Z 4 is CH or N
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 4 is CN
  • m is l .
  • B is Ar 3 .
  • B is hetAr 4 , substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3- C6 cycloalkyl, and C1-C3 alkyl.
  • n some embodiments of Formula lb, X 1 , X 2 , and X 4 are each CH and X 3 is N.
  • n some embodiments of Formula lb, X 2 and X 4 are each CH and X 1 and X 3 are each N.
  • Y is - R d (Cl-C6 alkyl)-, wherein R d is methyl.
  • the compound of Formula I is a compound of Formula Ic
  • Ar 3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or Cl-C6 alkyl,
  • hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or C1-C6 alkyl;
  • X 1 , X 2 , and X 4 are each CH and X 3 is N, or X 2 and X 4 are each CH and X 1 and X 3 are each N;
  • Y is -NR d (C 1 -C6 alkyl)- (optionally substituted with 1 -3 fluoros), wherein R d is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 5 is H or C 1 -C6 alkyl-
  • m is l .
  • B is Ar 3 .
  • B is hetAr 4 , substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3- C6 cycloalkyl, and C1-C3 alkyl.
  • X 1 , X 2 , and X 4 are each CH and X 3 is N.
  • X 2 and X 4 are each CH and X 1 and X 3 are each N.
  • Y is -NR d (Cl-C6 alkyl)-, wherein R d is methyl.
  • Y is -NR d (Cl-C6 alkyl)-, wherein R d is H.
  • R d is H.
  • Y is - HCH2-.
  • Y is - HCH(CH3)-.
  • R 1 is C1-C3 alkyl-.
  • R 1 is methyl
  • R 2 is halogen
  • R 2 is F.
  • R 2 is C1-C3 alkyl.
  • R 2 is methyl
  • R 5 is H.
  • R 5 is C1-C6 alkyl-.
  • R 5 is methyl
  • R 1 is methyl and R 5 is H.
  • R 1 is methyl and R 5 is methyl.
  • the compound of Formula I is a compound of Formula Id
  • A is selected from Ar 1 or hetAr 2 ,
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or Cl-C6 alkyl,
  • hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R k RTNT-, wherein R b and R c are independently H or C1-C6 alkyl;
  • X 2 is CH or N
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 6 is H or Cl-C6 alkyl
  • R 7 , R 8 , and R 9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl;
  • n is i .
  • A is Ar 1 , substituted with CN.
  • A is hetAr 2 , substituted with one or more substituents independently selected from the group consisting of CN, oxo, hydroxyCl-C3 alkyl, and C1-C3 alkyl.
  • X 2 is CH.
  • X 2 is N.
  • R 1 is methyl
  • R 2 is H.
  • R 2 is halogen
  • R 2 is F.
  • R 2 is C1-C6 alkyl
  • R 2 is Cl-C3 alkyl
  • R 2 is methyl
  • R 6 is H.
  • R 6 is C1-C6 alkyl
  • R 6 is Cl-C3 alkyl
  • R 6 is methyl
  • R 7 is H.
  • R 7 is C1-C6 alkyl
  • R 7 is Cl-C3 alkyl
  • R 7 is methyl.
  • R 8 is H.
  • R 8 is halogen
  • R 8 is F.
  • R 8 is C1-C6 alkyl.
  • R 8 is C1-C3 alkyl.
  • R 8 is methyl
  • R 9 is H.
  • R 9 is C1-C6 alkyl.
  • R 9 is C1-C3 alkyl.
  • R 9 is methyl
  • R 9 is C3-C6 cycloalkyl.
  • R 9 is cyclopropane.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is H
  • R 8 is H
  • R 9 is H
  • X 2 is CH.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is H
  • R 8 is H
  • R 9 is H
  • X 2 is N.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is H
  • R 8 is F
  • R 9 is H
  • X 2 is CH.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is H
  • R 8 is F
  • R 9 is H
  • X 2 is N.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is H
  • R 8 is methyl
  • R 9 is H
  • X 2 is CH.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is H
  • R 8 is methyl
  • R 9 is H
  • X 2 is N.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is methyl
  • R 8 is H
  • R 9 is methyl
  • X 2 is CH.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is methyl
  • R 8 is H
  • R 9 is methyl
  • X 2 is N.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is H
  • R 8 is H
  • R 9 is cyclopropyl
  • X 2 is CH.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is H
  • R 8 is H
  • R 9 is cyclopropyl
  • X 2 is N.
  • the compound of Formula I is a compound of Formula le
  • A is selected from Ar 1 or hetAr 2 ,
  • Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or Cl-C6 alkyl,
  • hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R b R c N-, wherein R b and R c are independently H or C1-C6 alkyl;
  • X 2 is CH or N
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 6 is H or Cl-C6 alkyl
  • R 10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy;
  • n is i ;
  • p is 1 or 2.
  • X 2 is CH.
  • X 2 is N.
  • A is Ar 1 , substituted with CN.
  • A is hetAr 2 , substituted with one or more substituents independently selected from the group consisting of CN, oxo, hydroxyCl-C3 alkyl, and C1-C3 alkyl.
  • R 1 is methyl
  • R 2 is H.
  • R 2 is halogen
  • R 2 is F.
  • R 2 is C1-C6 alkyl.
  • R 2 is C1-C3 alkyl.
  • R 2 is methyl
  • R 6 is H.
  • R 6 is C1-C6 alkyl.
  • R 6 is C1-C3 alkyl.
  • R 6 is methyl
  • R 10 is halogen
  • R 10 is F.
  • R 10 is C1-C6 alkyl.
  • R 10 is Cl-C3 alkyl.
  • R 10 is methyl
  • R 10 is Cl-C6 alkoxy.
  • R 10 is Cl-C3 alkoxy.
  • R 10 is methoxy
  • p is 1.
  • p is 2.
  • p is 2 and R 10 is F and methyl.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R 10 is methoxy
  • X 2 is CH
  • p is 1.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R 10 is methoxy
  • X 2 is N
  • p is 1.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is methyl and F
  • X 2 is CH
  • p is 2.
  • R 2 is H, F, or methyl
  • R 6 is H or methyl
  • R is methyl and F
  • X 2 is N
  • p is 2.
  • the compound of Formula I is a compound of Formula If
  • X 2 is CH or N
  • Z 1 , Z 2 and Z 3 are each independently selected from CH, N, NH, O or S;
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros); and
  • R 6 is H or Cl-C6 alkyl
  • R 7 , R 8 , and R 9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl.
  • X 2 is CH.
  • z 1 is N or NH.
  • z 1 is CH.
  • z 2 is N or NH.
  • z 2 is S.
  • z 3 is CH.
  • z 3 is N or H.
  • R 1 is C1-C3 alkyl.
  • R 1 is methyl
  • R 3 is CN
  • R 3 is hydroxyCl-C6 alkyl.
  • R 3 is C1-C3 alkyl.
  • R 3 is methyl
  • R 3 is ethyl
  • R 6 is H.
  • R 6 is C1-C6 alkyl.
  • R 6 is C1-C3 alkyl.
  • R 6 is methyl
  • R 7 is H.
  • R 7 is C1-C6 alkyl.
  • R 7 is C1-C3 alkyl.
  • R 7 is methyl
  • R 8 is H.
  • R 8 is halogen
  • R 8 is F.
  • R 8 is C1-C6 alkyl.
  • R 8 is C1-C3 alkyl.
  • R 8 is methyl
  • R 9 is H.
  • R 9 is C1-C6 alkyl.
  • R 9 is C1-C3 alkyl.
  • R 9 is methyl
  • R 9 is C3-C6 cycloalkyl.
  • R 9 is cyclopropane.
  • the compound of Formula I is a compound of Formula Ig
  • X 2 is CH or N
  • Z 1 , Z 2 and Z 3 are each independently selected from CH, N, NH, O or S;
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros);
  • R 6 is H or Cl-C6 alkyl
  • R 10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy;
  • p is 1 or 2.
  • X 2 is CH.
  • X 2 is N.
  • Z 1 is N or NH.
  • Z 1 is CH.
  • Z 2 is N or NH.
  • Z 2 is O.
  • Z 2 is S.
  • Z 3 is CH.
  • Z 3 is N or H.
  • Z 1 is H
  • Z 2 is N
  • Z 3 is CH
  • Z 1 is N
  • Z 2 is O
  • Z 3 is CH
  • Z 1 is N
  • Z 2 is O
  • Z 3 is N
  • Z 1 is N
  • Z 2 is S
  • Z 3 is CH
  • Z 1 is N
  • Z 2 is S
  • Z 3 is N
  • Z 1 is CH
  • Z 2 is NH
  • Z 3 is N.
  • Z 1 is N
  • Z 2 is NH
  • Z 3 is CH.
  • R 1 is methyl
  • R 3 is CN
  • R 3 is hydroxyCl-C6 alkyl.
  • R 3 is Cl-C3 alkyl.
  • R 3 is methyl
  • R 3 is ethyl
  • R 6 is H.
  • R 6 is C1-C6 alkyl.
  • R 6 is Cl-C3 alkyl.
  • R 6 is methyl
  • R 10 is halogen
  • R 10 is F.
  • R 10 is C1-C6 alkyl.
  • R 10 is Cl-C3 alkyl.
  • R 10 is methyl
  • R 10 is Cl-C6 alkoxy.
  • R 10 is Cl-C3 alkoxy.
  • R 10 is methoxy
  • p is 2 and R 10 is F and methyl.
  • the compound of Formula I is a compound of Formula Ih
  • X 2 is CH or N
  • Z 4 is CH or N
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 4 is CN
  • R 6 is H or C1-C6 alkyl
  • R 7 , R 8 , and R 9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl.
  • R 1 is Cl-C3 alkyl
  • R 1 is methyl
  • R 4 is CN
  • R 6 is H.
  • R 6 is C1-C6 alkyl
  • R 6 is Cl-C3 alkyl
  • R 6 is methyl
  • R 7 is H.
  • R 7 is C1-C6 alkyl
  • R 7 is Cl-C3 alkyl
  • R 7 is methyl
  • R 8 is H.
  • R 8 is halogen
  • R 8 is F.
  • R 8 is C 1-C6 alkyl.
  • R 8 is C 1-C3 alkyl.
  • R 8 is methyl
  • R 9 is H.
  • R 9 is C 1-C6 alkyl.
  • R 9 is C 1-C3 alkyl.
  • R 9 is methyl
  • R 9 is C3-C6 cycloalkyl.
  • R 9 is cyclopropane.
  • Z 4 is CH.
  • Z 4 is N.
  • R 1 is methyl
  • R 4 is CN
  • Z 4 is CH.
  • R 1 is methyl
  • R 4 is CN
  • Z 4 is N.
  • X 2 is CH.
  • X 2 is N.
  • the compound of Formula I is a compound of Formula
  • X 2 is CH or N
  • R 1 is C 1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 5 is H or C 1 -C6 alkyl-
  • R 6 is H or C 1-C6 alkyl
  • R 7 , R 8 , and R 9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl.
  • R 1 is C1-C3 alkyl-.
  • R 1 is methyl
  • R 5 is H.
  • R 5 is C1-C6 alkyl-.
  • R 5 is methyl
  • R 6 is H.
  • R 6 is C1-C6 alkyl.
  • R 6 is C1-C3 alkyl.
  • R 6 is methyl
  • R 7 is H.
  • R 7 is C1-C6 alkyl.
  • R 7 is C1-C3 alkyl.
  • R 7 is methyl
  • R 8 is H.
  • R 8 is halogen
  • R 8 is F.
  • R 8 is C1-C6 alkyl.
  • R 8 is C1-C3 alkyl.
  • R 8 is methyl
  • R 9 is H.
  • R 9 is C1-C6 alkyl.
  • R 9 is C1-C3 alkyl.
  • R 9 is methyl
  • R 9 is C3-C6 cycloalkyl.
  • R 9 is cyclopropane.
  • X 2 is CH.
  • X 2 is N.
  • the compound of Formula I is a compound of Formula Ij
  • R 1 is C1-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 4 is CN
  • R 6 isHorCl-C6alkyl
  • R 10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy;
  • p is 1 or 2.
  • R 1 is C1-C3 alkyl-.
  • R 1 is methyl
  • R 4 is CN
  • R 6 is H.
  • R 6 is C1-C6 alkyl.
  • R 6 isCl-C3 alkyl.
  • R 6 is methyl
  • R 10 is halogen
  • R 10 isF.
  • R 10 isCl-C6 alkyl.
  • R 10 isCl-C3 alkyl.
  • R 10 is methyl
  • R 10 isCl-C6 alkoxy
  • R 10 is Cl-C3 alkoxy.
  • R 10 is methoxy
  • p is 1.
  • p is 2.
  • p is 2 and R 10 is F and methyl.
  • Z 4 is CH.
  • Z 4 is N.
  • R 1 is methyl
  • R 4 is CN
  • Z 4 is CH.
  • R 1 is methyl
  • R 4 is CN
  • Z 4 is N.
  • X 2 is CH.
  • X 2 is N.
  • the compound of Formula I is a compound of Form
  • X 2 is CH or N
  • R 1 is Cl-C6 alkyl-
  • R 2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
  • R 5 is H or C 1 -C6 alkyl-
  • R 6 is H or Cl-C6 alkyl
  • R 10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy;
  • p is 1 or 2.
  • R 1 is C1-C3 alkyl-.
  • R 1 is methyl.
  • R 5 is H.
  • R 5 is C1-C6 alkyl-.
  • R 5 is methyl
  • R 6 is H.
  • R 6 is C1-C6 alkyl.
  • R 6 is Cl-C3 alkyl.
  • R 6 is methyl
  • R 10 is halogen
  • R 10 is F.
  • R 10 is C1-C6 alkyl.
  • R 10 is Cl-C3 alkyl.
  • R 10 is methyl
  • R 10 is Cl-C6 alkoxy.
  • R 10 is Cl-C3 alkoxy.
  • R 10 is methoxy
  • p is 1.
  • p is 2.
  • p is 2 and R 10 is F and methyl
  • X 2 is CH.
  • X 2 is N.
  • methoxyethyl comprises an ethyl backbone with a methoxy substituent.
  • halogen means -F (sometimes referred to herein as "fluoro" or
  • C1-C3 alkyl saturated linear or branched-chain monovalent hydrocarbon radicals of one to three, one to six, two to six, or three to six carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl- 2-propyl, pentyl, neopentyl, and hexyl.
  • C1-C6 alkoxy refers to a saturated linear or branched- chain monovalent alkoxy radical of one to six carbon atoms, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
  • (C1-C6 alkoxy)Cl-C6 alkyl- 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 (CH3OCH2-) and methoxyethyl (CH3OCH2CH2-).
  • hydroxyC 1 -C6 alkyl- and "hydroxyC2-C6 alkyl-” as used herein refer to a saturated linear or branched-chain monovalent alkyl radicals of one to six or two to six carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy group.
  • dihydroxyC3-C6 alkyl- refers to a saturated linear or branched-chain monovalent alkyl radical of three to six carbon atoms, wherein two of the carbon atoms are substituted with a hydroxy group.
  • ( ⁇ ⁇ - ⁇ alkyl-) as used herein refers to a C1-C6 alkyl as defined herein, wherein one of the carbon atoms is substituted with a R ⁇ R ⁇ - group, wherein R e and R f are as defined herein.
  • C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Ar l C 1 -C6 alkyl- and " Ar*C 1 -C3 alkyl-" as used herein refer to a C 1 -
  • hetAr 2 Cl-C6 alkyl- and “hetAr 2 Cl-C3 alkyl-” as used herein refer to a C1-C6 alkyl radical or C1-C3 alkyl radical, respectively, as defined herein, wherein one of the carbon atoms is substituted with an hetAr 2 group, wherein hetAr 2 is as defined herein.
  • hetCy ⁇ C 1 -C6 alkyl- and "hetCy ⁇ C 1 -C3 alkyl-” as used herein refer to a C1-C6 alkyl radical or a C1-C3 radical, respectively as defined herein, wherein one of the carbon atoms is substituted with a hetCyc 1 group, wherein hetCyc 1 is as defined herein.
  • tautomer 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.
  • the compounds of Formula I include pharmaceutically acceptable salts thereof.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable.
  • the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include monohydrochloride, dihydrochloride, trifluoroacetic acid, and di-trifluoroacetic acid salts.
  • compounds of Formula I include trifluoroacetic acid and dihydrochloride salts.
  • 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.
  • the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.
  • compounds of Formula I and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • 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.
  • 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.
  • 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.
  • the compounds of Formula I provided herein can be prepared according to methods known in to those of skill in the art.
  • the compounds of Formula I can be prepared according to the methods disclosed and described in WO 2016/127074, which is herein incorporated by reference in its entirety.
  • WO 2016/127074 which is herein incorporated by reference in its entirety.
  • Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds provided herein.
  • the compounds of Formula I provided herein can act as RET inhibitors.
  • the ability of the compounds of Formula I provided herein to act as RET inhibitors can be demonstrated by assays known to those of skill in the art. For example, assays such as those described in WO 2016/127074 and PCT Application No. PCT/US16/42576, both of which are herein incorporated by reference, can be used.
  • the compounds provided herein exhibit potent and selective RET inhibition.
  • the compounds provided herein exhibit nanomolar potency against wild type RET and select RET mutants, including, for example, the KIF5B-RET fusion, G810R and G810S ATP cleft front or linker mutations, M918T kinase domain, and V804M, V804L, and V804E gatekeeper mutations, with minimal activity against related kinases.
  • the compounds of Formula I or a pharmaceutically acceptable salt or solvate thereof selectively target a RET kinase.
  • 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.
  • 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.
  • 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.
  • selectivity for a RET kinas exhibits at least a 30-fold selectivity for a RET
  • the compounds provided herein can exhibit selectivity for a
  • the selectivity for a RET kinase over a KDR kinase is observed without loss of potency for a RET kinase encoded by a RET gene including an activating mutation or a RET kinase inhibitor resistance mutation (e.g., a gatekeeper mutant).
  • 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).
  • 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.
  • 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.
  • MKIs multikinase inhibitors
  • inhibition of V804M was similar to that observed for wild- type RET.
  • 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).
  • 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).
  • the compounds provided herein exhibit selective cytotoxicity to RET-mutant cells.
  • 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.
  • treatment of a patient with cancer e.g., a RET-associated cancer such as a RET-associated brain or CNS cancer
  • administration e.g., oral administration
  • the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.
  • 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.
  • Compounds of Formula I are useful for treating diseases and disorders which can be treated with a RET kinase inhibitor, such as RET-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors, and gastrointestinal disorders such as IBS.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the terms "subject,” “individual,” or “patient,” are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the patient is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • 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).
  • 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).
  • the subject is suspected of having a RET-associated cancer.
  • 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).
  • the patient is a pediatric patient.
  • 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.
  • 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).
  • 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.
  • compounds of Formula I are useful for preventing diseases and disorders as defined herein (for example, autoimmune diseases, inflammatory diseases, and cancer).
  • preventing 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.
  • RET-associated disease or disorder 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).
  • Non-limiting examples of a RET-associated disease or disorder include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).
  • RET-associated cancer 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.
  • RET-associated cancer is described herein.
  • 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 chromosomal translocation that results in the expression of a fusion protein including a RET kinase domain and a fusion partner, a mutation 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 a wildtype RET protein, a mutation in a RET gene that results in the expression of a RET protein with one or more point mutations as compared to a wildtype RET protein, a mutation in a RET gene that results in the expression of a RET protein with at least one inserted amino acid as compared to a wildtype RET protein, a gene duplication that results in an increased level of RET protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and
  • 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.
  • 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).
  • 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.
  • Non-limiting examples of fusion proteins are described in Table 1.
  • Non-limiting examples of RET kinase protein point mutations/insertions/deletions are described in Tables 2 and 2a.
  • Additional examples of RET kinase protein mutations are RET inhibitor resistance mutations.
  • Non-limiting examples of RET inhibitor resistance mutations are described in Tables 3 and 4.
  • dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be caused by an activating mutation in a RET gene (see, e.g., chromosome translocations that result in the expression of any of the fusion proteins listed in Table 1).
  • dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be caused by a genetic mutation that results in the expression of a RET kinase that has increased resistance to inhibition by a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype RET kinase (see, e.g., the amino acid substitutions in Tables 3 and 4).
  • MKI multi-kinase inhibitor
  • the exemplary RET kinase point mutations, insertions, and deletions shown in Tables 2 and 2a can be caused by an activating mutation and/or can result in the expression of a RET kinase that has increased resistance to inhibition by a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI).
  • MKI multi-kinase inhibitor
  • activating mutation describes a mutation in a RET kinase gene that results in the expression of a RET kinase that has an increased kinase activity, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions.
  • an activating mutation can result in the expression of a fusion protein that includes a RET kinase domain and a fusion partner.
  • an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions.
  • one or more amino acid substitutions e.g., any combination of any of the amino acid substitutions described herein
  • an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions.
  • an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted as compared to a wildtype RET kinase, e.g., the exemplary wildtype RET kinase described herein, e.g., when assayed under identical conditions. Additional examples of activating mtuations are known in the art.
  • 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).
  • a RET-associated disease e.g., a RET-associated cancer
  • regulatory agency refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country.
  • FDA U.S. Food and Drug Administration
  • a method of treating cancer e.g., a RET-associated cancer
  • 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.
  • methods for treating a RET-associated cancer in a patient in need of such treatment 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.
  • 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.
  • RET gene fusion proteins are described in Table 1.
  • the fusion protein is KIF5B-RET.
  • 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.
  • Non-limiting examples of RET kinase protein point mutations/insertions/deletions are described in Tables 2 and 2a.
  • the RET kinase protein point mutations/insertions/deletions are selected from the group consisting of M918T, M918V, C634W, V804L, and V804M.
  • the cancer in some embodiments of any of the methods or uses described herein, the cancer
  • the cancer (e.g., RET-associated cancer) is a hematological cancer.
  • the cancer e.g., RET-associated cancer
  • the cancer is a solid tumor.
  • the cancer e.g., RET- associated cancer
  • the cancer is a solid tumor.
  • the cancer e.g., RET-associated cancer
  • lung cancer e.g., small cell lung carcinoma or non-small cell lung carcinoma
  • thyroid cancer e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer
  • thyroid ademona endocrine gland neoplasms
  • lung adenocarcinoma bronchioles lung cell carcinoma
  • multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively)
  • pheochromocytoma parathyroid hyperplasia
  • breast cancer mammary cancer
  • mammary carcinoma mammary neoplasm
  • colorectal cancer e.g., metastatic colorectal cancer
  • papillary renal cell carcinoma ganglioneuromatosis of the gastroenteric mucosa
  • inflammatory myofibroblastic tumor or cervical cancer
  • the cancer e.g., RET-associated cancer
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • 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
  • CML chronic myelogenous leukemia
  • chronic myeloproliferative neoplasms neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T
  • a hematological cancer 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 (C L), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, A hematological cancers that are RET-associated cancers
  • ALL acute lymphocytic leukemia
  • AML
  • hematological cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF/IPF/PMF).
  • MPD myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocytopenia
  • IMF/IPF/PMF idiopathic primary myelofibrosis
  • the hematological cancer e.g., the hematological cancer that is a RET-associated cancer
  • AML or CMML.
  • the cancer is a solid tumor.
  • solid tumors e.g., solid tumors that are RET-associated cancers
  • 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.
  • the patient is a human.
  • a method for treating a patient diagnosed with or identified as having a RET-associated cancer comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
  • 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.
  • 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 a gene translocation resulting in the expression of a fusion protein that includes a RET kinase domain and a fusion partner.
  • a fusion protein can have increased kinase activity as compared to a wildtype RET protein.
  • a mutation in a RET gene can involve mutations in the RET ligand-binding site, extracellular domains, kinase domain, and in regions involved in protein: protein interactions and downstream signaling.
  • a mutation (e.g., an activating mutation) in a RET gene can result in the expression of a RET kinase having one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., one or more amino acid substitutions in the kinase domain (e.g., amino acid positions 723 to 1012 in a wildtype RET protein), a gatekeeper amino acid (e.g., amino acid position 804 in a wildtype RET protein), the P-loop (e.g., amino acid positions 730-737 in a wildtype RET protein), the DFG motif (e.g., amino acid positions 892-894 in a wildtype RET protein), ATP cleft solvent front amino acids (e.g., amino acid positions 758, 811, and 892 in a wildtype RET protein), the activation loop (e.g., amino acid positions 891-916 in a wildtype
  • a mutation can be a gene amplification of a RET gene.
  • a mutation (e.g., an activating mutation) in a RET gene can result in the expression of a RET kinase that lacks at least one amino acid (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids) as compared to a wildtype RET protein.
  • at least one amino acid e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids
  • dyregulation of a RET kinase can be increased expression (e.g., increased levels) of a wildtype RET kinase in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell).
  • a mutation (e.g., an activating mutation) in a RET gene can result in the expression of a RET kinase that has at least one amino acid (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids) inserted as compared to a wildtype RET protein.
  • at least one amino acid e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids
  • dyregulation of a RET kinase can be increased expression (e.g., increased levels) of a wildtype RET kinase in a mammalian cell (e.g., as compared to a control non-cancerous cell), e.g., due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling.
  • Other dysregulations can include RET mRNA splice variants.
  • the wildtype RET protein is the exemplary wildtype RET protein described herein.
  • 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).
  • 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.
  • 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.
  • 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.
  • Non-limiting examples of RET fusion proteins are shown in Table 1.
  • NCOA4 also Papillary Thyroid Cancer 21 , called PTC3, NSCLC, Colon Cancer
  • Adenocarcinoma 15 Adenocarcinoma 15 ;
  • TRIM33 also NSCLC, Papillary Thyroid called PTC7 and Cancer
  • ERC1 also called Papillary Thyroid Cancer
  • MBDl also known Papillary Thyroid Cancer as PCM1
  • PCM1 Papillary Thyroid Cancer
  • PRKAR1 A also Papillary Thyroid Cancer called PTC2
  • TRIM24 also Papillary Thyroid Cancer called PTC6
  • KTN1 also called Papillary Thyroid Cancer PTC8 .
  • GOLGA5 also Papillary Thyroid Cancer, called PTC5
  • PTC5 Papillary Thyroid Cancer
  • KIAA1468 also Papillary Thyroid Cancer, called PTC9 and Lung Adenocarcinoma 8 ' 12 RFG9
  • TRIM27 also Papillary Thyroid Cancer called RFP
  • KIAA1217 also Papillary Thyroid Cancer 10, called SKT 13
  • 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.
  • 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.
  • 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).
  • Amino acid position 32 (e.g., S32L)
  • Amino acid position 34 e.g., D34S
  • Amino acid position 40 (e.g., L40P)
  • Amino acid position 56 (e.g., L56M) 30
  • Amino acid position 64 (e.g., P64L)
  • Amino acid position 67 (e.g., R67H)
  • Amino acid position 114 (e.g., Rl 14H)
  • Amino acid position 136 (e.g., glutamic acid to stop codon)
  • Amino acid position 145 (e.g., V145G)
  • Amino acid position 180 (e.g., arginine to stop codon)
  • Amino acid position 292 e.g., V292M
  • Amino acid position 321 e.g., G321R
  • Amino acid position 330 (e.g., R330Q)
  • Amino acid position 338 e.g., T338I
  • Amino acid position 360 e.g., R360W
  • Amino acid position 373 (e.g., alanine to frameshift)
  • Amino acid position 423 (e.g., G423R) 27
  • Amino acid position 446 (e.g., G446R) 28
  • Amino acid position 510 e.g., A510V
  • Amino acid position 511 e.g., E51 IK
  • Amino acid position 513 e.g., G513D 7*
  • Amino acid position 515 (e.g., C515S, 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., 1602 V) 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,
  • Amino acid position 611 e.g., C611R, C611 S, C611G,
  • Amino acid position 616 (e.g., E616Q) 23
  • Amino acid position 618 e.g., C618S, C618Y, C618R,
  • Amino acid position 619 e.g., F619F
  • Amino acid position 620 (e.g., C620S, C620W,
  • Amino acid position 623 (e.g., E623K)
  • Amino acid position 624 e.g., D624N
  • Amino acid position 630 (e.g., C630A, C630R, C630S,
  • Amino acid position 631 e.g., D631N, D631Y,
  • Amino acid position 632 (e.g., E632K, E632G 5 ' u )
  • Amino acid position 633 (e.g., 9 base pair duplication 2 )
  • Amino acid position 634 (e.g., C634W, C634Y,
  • 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., A641 S, 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,
  • Amino acid position 686 e.g. S686N
  • Amino acid position 689 (e.g. S689T) 18
  • Amino acid position 691 e.g. G691 S
  • 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 804 (e.g., V804L 15 ' 16 , V804M 15 '
  • Amino acid position 805 e.g., E805K
  • Amino acid position 806 (e.g., Y806F, Y806S 12 ,
  • Amino acid position 810 e.g., G810R 12 , G810S 12 ,
  • 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,
  • 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 866 (e.g. A866W) 33
  • 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 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, S891 S 32 )
  • 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)
  • Amino acid position 1109 (e.g., Ml 109T) 34
  • Amino acid positions 791 and 852 e.g., Y791F +
  • Amino acid positions 634 and 852 e.g., C634R +
  • the RET kinase mutations shown may be activating mutations and/or confer increased resistance of the RET kinase to a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype RET kinase.
  • MKI multi-kinase inhibitor

Abstract

Provided herein are compounds of the Formula (I): and pharmaceutically acceptable salts or solvates thereof, where A, B, Y, X1, X2, X3, X4, R1, R2, n and m are as defined in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Description

RET INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Serial No. 62/447,858, filed on January 18, 2017, which is incorporated by reference in its entirety herein.
BACKGROUND
[0002] The present disclosure relates to novel compounds which exhibit Rearranged during Transfection (RET) kinase inhibition, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use of the compounds in therapy. More particularly, it relates to substituted 2-(pyridin-3-yl)-pyrimidine compounds useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.
[0003] RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is required for normal development, maturation, and maintenance of several tissues and cell types (Mulligan, L. M., Nature Reviews Cancer, 2014, 14, 173-186). The extracellular portion of the RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and a juxtamembrane cysteine-rich region necessary for the correct folding of the RET extracellular domain, while the cytoplasmic portion of the receptor includes two tyrosine kinase subdomains.
[0004] RET signaling is mediated by the binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN) and persephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev., 2005, 16, 441-67). Unlike other receptor tyrosine kinases, RET does not directly bind to GFLs and requires an additional co-receptor: that is, one of four GDNF receptor-a (GFRa) family members, which are tethered to the cell surface by a glycosylphosphatidylinositol linkage. GFLs and GFRa family members form binary complexes that in turn bind to RET and recruit it into cholesterol- rich membrane subdomains, which are known as lipid rafts, where RET signaling occurs.
[0005] Upon binding of the ligand-co-receptor complex, RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adaptor and signaling proteins to stimulate multiple downstream pathways. Adaptor protein binding to these docking sites leads to activation of Ras-MAPK and PBK-Akt/mTOR signaling pathways or to recruitment of the CBL family of ubiquitin ligases that functions in RET downregulation of the RET-mediated functions.
[0006] Aberrant RET expression and/or activity have been demonstrated in different cancers and in gastrointestinal disorders such as irritable bowel syndrome (IBS).
SUMMARY OF THE INVENTION
Provided herein are com ounds of the Formula I:
Figure imgf000003_0001
I
[0008] or pharmaceutically acceptable salt or solvate thereof, wherein A, B, Y, X1, X2, X3, X4, R1, R2, n, and m are as defined herein.
[0009] 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.
[0010] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
[0011] Also provided herein is a method of treating a RET-associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
[0012] Also provided herein is a method of treating cancer and/or inhibiting metastasis associated with a particular cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.
[0013] Also provided herein is a method of treating irritable bowel syndrome (IBS) and/or pain associated with IBS in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.
[0014] Also provided is a method of providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.
[0015] 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.
[0016] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer and/or inhibiting metastasis associated with a particular cancer.
[0017] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.
[0018] Also provided is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment.
[0019] 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.
[0020] 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.
[0021] Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer and/or inhibiting metastasis associated with a particular cancer. [0022] Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.
[0023] Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment.
[0024] Also provided herein is a use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of RET kinase activity.
[0025] Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a RET-associated disease or disorder.
[0026] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining if the cancer is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same (e.g., a RET-associated cancer); and (b) if the cancer is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same (e.g., a RET-associated cancer), administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
[0027] Also provided herein is a pharmaceutical combination for treating cancer (e.g., a
RET-associated cancer, such as a RET-associated cancer having one or more RET inhibitor resistance mutations) in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, wherein the compound of Formula I or the pharmaceutically acceptable salt or solvate thereof and the additional therapeutic are formulated as separate compositions or dosages for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the cancer. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of cancer. Also provided herein is a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer a patient in need thereof.
[0028] Also provided herein is a method for reversing or preventing acquired resistance to an anticancer drug, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, to a patient at risk for developing or having acquired resistance to an anticancer drug. In some embodiments, the patient is administered a dose of the anticancer drug (e.g., at substantially the same time as a dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the patient).
[0029] Also provided herein is a method of delaying and/or preventing development of cancer resistant to an anticancer drug in an individual, comprising administering to the individual an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of an effective amount of the anticancer drug.
[0030] Also provided herein is a method of treating an individual with cancer who has an increased likelihood of developing resistance to an anticancer drug, comprising administering to the individual (a) an effective amount of a compound of Formula I before, during, or after administration of (b) an effective amount of the anticancer drug.
[0031] Also provided are methods of treating an individual with a RET-associated cancer that has one or more RET inhibitor resistance mutations that increase resistance of the cancer to a first RET inhibitor (e.g., one or more amino acid substitutions in the kinase domain (e.g., amino acid positions 723 to 1012 in a wildtype RET protein), a gatekeeper amino acid (e.g., amino acid position 804 in a wildtype RET protein), the P-loop (e.g., amino acid positions 730-737 in a wildtype RET protein), the DFG motif (e.g., amino acid positions 892-894 in a wildtype RET protein), ATP cleft solvent front amino acids (e.g., amino acid positions 758, 811, and 892 in a wildtype RET protein), the activation loop (e.g., amino acid positions 891-916 in a wildtype RET protein), the C-helix and loop preceeding the C-helix (e.g., amino acid positions 768-788 in a wildtype RET protein), and/or the ATP binding site (e.g., amino acid positions 730-733, 738, 756, 758, 804, 805, 807, 811, 881, and 892 in a wildtype RET protein) (e.g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E, and/or one or more RET inhibitor resistance mutations listed in Tables 3 and 4), that include administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anticancer drug (e.g., a second RET kinase inhibitor). See also J. Kooistra, G. K. Kanev, O. P. J. Van Linden, R. Leurs, I. J. P. De Esch, and C. De Graaf, "KLIFS: A structural kinase- ligand interaction database," Nucleic Acids Res., vol. 44, no. Dl, pp. D365-D371, 2016; and O. P. J. Van Linden, A. J. Kooistra, R. Leurs, I. J. P. De Esch, and C. De Graaf, "KLIFS: A knowledge- based structural database to navigate kinase-ligand interaction space," J. Med. Chem., vol. 57, no. 2, pp. 249-277, 2014, both of which are incorporated by reference in their entirey herein. In some embodiments, a wildtype RET protein is the exemplary wildtype RET protein described herein.
[0032] Also provided are methods of treating an individual with a RET-associated cancer that include administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anticancer drug (e.g., a first RET kinase inhibitor).
[0033] Also provided herein is a method for treating irritable bowel syndrome (IBS) in a patient in need thereof, the method comprising (a) determining if the IBS is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same; and (b) if the IBS is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
[0034] 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 Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of IBS, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the IBS. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of the IBS. Also provided herein is a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of the IBS a patient in need thereof. [0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
DETAILED DESCRIPTION OF THE INVENTION
[0036] Provided herein are com ounds of the Formula I:
Figure imgf000008_0001
I
[0037] and pharmaceutically acceptable salts and solvates thereof, wherein:
[0038] A is selected from:
[0039] (a) Ar1,
[0040] (b) ArlC 1 -C6 alkyl-,
[0041] (c) Ar^Cl-CS alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
[0042] (d) Ar1C(=0)-,
[0043] (e) Ar1N(Ra)C(=0)-,
[0044] (f) hetAr2,
[0045] (g) hetAr2C 1 -C6 alkyl-,
[0046] (h) hetAr^Cl-CS alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
[0047] (i) hetAr2C(=0)-,
[0048] (j) hetAr2N(Ra)C(=0)-, [0049] (k) hetCyc1,
[0050] (1) hetCy^Cl-Ce alkyl-,
[0051] (m) hetCyc^Cl-CS alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
[0052] (n) hetCyc1C(=0)-, and
[0053] (o) hetCyc1N(Ra)C(=0)-,
[0054] Ra is H or C 1 -C6 alkyl,
[0055] Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RkRTNT-, wherein Rb and Rc are independently H or Cl-C6 alkyl,
[0056] hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl-, hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^'TST-, wherein Rb and Rc are independently H or C1-C6 alkyl,
[0057] hetCyc1 is a 4-6 membered saturated heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl;
[0058] B is selected from:
[0059] (a) Ar3,
[0060] (b) Ar3C 1 -C6 alkyl-,
[0061] (c) Ar3(Cl-C3 alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
[0062] (d) Ar3C(=0)-,
[0063] (e) Ar3N(Ra)C(=0)-, [0064] (f) hetAr4,
[0065] (g) hetAr4C 1 -C6 alkyl-,
[0066] (h) hetAr4(Cl-C3 alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
[0067] (i) hetAr4C(=0)-,
[0068] (j) hetAr4N(Ra)C(=0)-,
[0069] (k) hetCyc2,
[0070] (1) hetCyc2C 1 -C6 alkyl-,
[0071] (m) hetCyc2(Cl-C3 alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
[0072] (n) hetCyc2C(=0)-, and
[0073] (o) hetCyc2N(Ra)C(=0)-,
[0074] Ra is H or C 1 -C6 alkyl,
[0075] Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or Cl-C6 alkyl,
[0076] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl-, hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^'TST-, wherein Rb and Rc are independently H or C1-C6 alkyl,
[0077] hetCyc2 is a 4-6 membered saturated heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl;
[0078] X1, X2, X3 and X4 are independently CH, CF or N, wherein 0, 1 or 2 of X1, X2, X3 and X4 is N;
[0079] Y is a bond, - Rd-, - Rd(Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), or -(C1-C6 alkyl) Rd- (optionally substituted with 1-3 fluoros), wherein Rd is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
[0080] R1 and R2 at each occurrence are independently selected from the group consisting of halogen, OH, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyC2-C6 alkyl- (wherein the alkyl portion is optionally substituted with 1-3 fluoros), dihydroxyC3-C6 alkyl-, (Cl- C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), (R^^Cl-Ce alkyl-, wherein Re and Rf are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros), and (C3- C6 cycloalkyl)Cl-C3 alkyl-;
[0081] n is 0, 1 or 2; and
[0082] m is 0, 1 or 2.
[0083] In some embodiments of the com ounds of Formula I
Figure imgf000011_0001
I
[0084] and pharmaceutically acceptable salts and solvates thereof,
[0085] A is selected from:
[0086] (a) Ar1,
[0087] (b) ArlC 1 -C6 alkyl-,
[0088] (f) hetAr2, and
[0089] (g) hetAr2C 1 -C6 alkyl-,
[0090] Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), and oxo, and
[0091] hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), and oxo;
[0092] B is selected from:
[0093] (a) Ar3,
[0094] (b) Ar3C 1 -C6 alkyl-,
[0095] (f) hetAr4, and
[0096] (g) hetAr4C 1 -C6 alkyl-,
[0097] Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and
[0098] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C3-C6 cycloalkyl;
[0099] X1, X2, X3 and X4 are independently CH, CF or N, wherein 0, 1 or 2 of X1, X2, X3 and X4 is N;
[00100] Y is - Rd- or - Rd(C 1 -C6 alkyl)- (optionally substituted with 1 -3 fluoros), wherein
Rd is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
[00101] R1 and R2 at each occurrence are independently selected from the group consisting of H, halogen, and C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00102] n is 1 or 2; and
[00103] m is 1 or 2.
[00104] In certain embodiments of Formula I, A is Ar1, where Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, or CN. In certain embodiments of Formula I, A is Ar1, where Ar1 is phenyl substituted with CN.
[00105] In certain embodiments of Formula I, A is hetAr2, where hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, CN, C1-C6 alkyl, hydroxyCl-C6 alkyl, and oxo. In certain embodiments, hetAr2 is a 5 membered heteroaryl ring having 2 heteroatoms independently selected from N, O, and S. In certain embodiments, hetAr2 is a 5 membered heteroaryl ring having 3 heteroatoms independently selected from N, O, and S. In certain embodiments, hetAr2 is a 6 membered heteroaryl ring having 1 heteroatom that is N. In certain embodiments, hetAr2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr2 is substituted with CN. In certain embodiments, hetAr2 is 5-6 membered heteroaryl ring having 1- 3 heteroatoms independently selected from N, O and S, wherein hetAr2 is substituted with oxo. In certain embodiments, hetAr2 is a 6 membered heteroaryl ring having 1 heteroatom that is N, wherein hetAr2 is substituted with C1-C6 alkyl and oxo. In certain embodiments, hetAr2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr2 is substituted with C1-C3 alkyl. In certain embodiments, hetAr2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr2 is substituted with h droxyCl-C3 alkyl. Non-limiting examples of hetAr2 include the structures:
Figure imgf000013_0001
Figure imgf000014_0001
[00106] In certain embodiments of Formula I, B is Ar , where Ar is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 alkoxy. In certain embodiments of Formula I, B is Ar3, where Ar3 is phenyl substituted with H. In certain embodiments of Formula I, B is Ar3, where Ar3 is phenyl substituted with halogen. In certain embodiments of Formula I, B is Ar3, where Ar3 is phenyl substituted with F. In certain embodiments of Formula I, B is Ar3, where Ar3 is phenyl substituted with C1-C6 alkyl. In certain embodiments of Formula I, B is Ar3, where Ar3 is phenyl substituted with C1-C6 alkoxy. In certain embodiments of Formula I, B is Ar3, where Ar3 is phenyl substituted with methoxy. In certain embodiments of Formula I, B is Ar3, where Ar3 is phenyl substituted with methyl and F.
[00107] In certain embodiments of Formula I, B is hetAr4, where hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr4 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl. In certain embodiments, hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N. In certain embodiments, hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with halogen. In certain embodiments, hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with F. In certain embodiments, hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with C1-C3 alkyl. In certain embodiments, hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with 1-2 methyls. In certain embodiments, hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with C3-C6 cycloalkyl. In certain embodiments, hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with cyclopropyl. In certain embodiments, hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N. In certain embodiments, hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr4 is substituted with C1-C6 alkoxy. In certain embodiments, hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr4 is substituted with C1-C6 alkyl. In certain embodiments, hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr4 is substituted with halogen. In certain embodiments, hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein ctures:
Figure imgf000015_0001
[00108] In certain embodiments of Formula I, X1, X2, X3 and X4 are independently CH or
N. In certain embodiments, each of X1, X2, X3 and X4 is CH.
[00109] In certain embodiments of Formula I, X1, X2, X3 and X4 are independently CH or
N, wherein one of X1, X2, X3 and X4 is N and the remainder are CH. In certain embodiments of Formula I, X3 is N, and X1, X2 and X4 are CH.
[00110] In certain embodiments of Formula I, X1, X2, X3 and X4 are independently CH or
N, wherein two of X1, X2, X3 and X4 are N. In certain embodiments of Formula I, X1 and X3 are N and X2 and X4 are CH.
[00111] In certain embodiments of Formula I, Y is -NRd(Cl-C6 alkyl)-, wherein Rd is H or
C1-C3 alkyl. Examples of C1-C3 alkyl include methyl, ethyl, propyl, and isopropyl.
[00112] In certain embodiments of Formula I, R1 at each occurrence is independently Cl-
C6 alkyl. In certain embodiments of Formula I, R1 is C1-C3 alkyl. In certain embodiments of Formula I, R1 is methyl.
[00113] In certain embodiments of Formula I, R2 at each occurrence is independently selected from the group consisting of H, halogen, and C1-C6 alkyl. In certain embodiments of Formula I, R2 is H. In certain embodiments of Formula I, R2 is halogen. In certain embodiments of Formula I, R2 is F. In certain embodiments of Formula I, R2 is C1-C6 alkyl. In certain embodiments of Formula I, R2 is methyl. [00114] In some embodiments the compound of Formula I is a compound of Formula la
Figure imgf000016_0001
la
[00115] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00116] B is selected from Ar3 or hetAr4,
[00117] Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RkRTNT-, wherein Rb and Rc are independently H or Cl-C6 alkyl,
[00118] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl;
[00119] X1, X2, and X4 are each CH and X3 is N, or X2 and X4 are each CH and X1 and X3 are each N;
[00120] Y is -NRd(Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), wherein Rd is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
[00121] Z1, Z2 and Z3 are each independently selected from CH, N, NH, O or S;
[00122] R1 is C1-C6 alkyl-;
[00123] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00124] R3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros); and [00125] m is l .
[00126] In some embodiments of Formula la, B is Ar3.
[00127] In some embodiments of Formula la, B is hetAr4, substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3- C6 cycloalkyl, and C1-C3 alkyl.
[00128] In some embodiments of Formula la, X1, X2, and X4 are each CH and X3 is N.
[00129] In some embodiments of Formula la, X2 and X4 are each CH and X1 and X3 are each N.
[00130] In some embodiments of Formula la, Y is - Rd(Cl-C6 alkyl)-, wherein Rd is methyl.
[00131] In some embodiments of Formula la, Y is - Rd(Cl-C6 alkyl)-, wherein Rd is H.
[00132] In some embodiments of Formula la, Y is - HCH2-.
[00133] In some embodiments of Formula la, Y is - HCH(CH3)-.
[00134] In some embodiments of Formula la, R1 is C1-C3 alkyl.
[00135] In some embodiments of Formula la, R1 is methyl.
[00136] In some embodiments of Formula la, R2 is halogen.
[00137] In some embodiments of Formula la, R2 is F.
[00138] In some embodiments of Formula la, R2 is C1-C3 alkyl.
[00139] In some embodiments of Formula la, R2 is methyl.
[00140] In some embodiments of Formula la, R3 is CN.
[00141] In some embodiments of Formula la, R3 is hydroxyCl-C6 alkyl.
[00142] In some embodiments of Formula la, R3 is C1-C3 alkyl.
[00143] In some embodiments of Formula la, R3 is methyl.
[00144] In some embodiments of Formula la, R3 is ethyl.
[00145] In some embodiments of Formula la, Z1 is N or NH.
[00146] In some embodiments of Formula la, Z1 is CH.
[00147] In some embodiments of Formula la, Z2 is N or NH.
[00148] In some embodiments of Formula la, Z2 is O.
[00149] In some embodiments of Formula la, Z2 is S.
[00150] In some embodiments of Formula la, Z3 is CH.
[00151] In some embodiments of Formula la, Z3 is N or NH. [00152] In some embodiments of Formula la, Z1 is NH, Z2 is N, and Z3 is CH.
[00153] In some embodiments of Formula la, Z1 is N, Z2 is O, and Z3 is CH.
[00154] In some embodiments of Formula la, Z1 is N, Z2 is O, and Z3 is N.
[00155] In some embodiments of Formula la, Z1 is N, Z2 is S, and Z3 is CH.
[00156] In some embodiments of Formula la, Z1 is N, Z2 is S, and Z3 is N.
[00157] In some embodiments of Formula la, Z1 is CH, Z2 is NH, and Z3 is N.
[00158] In some embodiments of Formula la, Z1 is N, Z2 is NH, and Z3 is CH.
[00159] In some embodiments of Formula la, R1 is methyl, R3 is CN, Z1 is NH, Z2 is N, and
Z3 is CH.
[00160] In some embodiments of Formula la, R1 is methyl, R3 is CN, Z1 is N, Z2 is O, and Z3 is CH.
[00161] In some embodiments of Formula la, R1 is methyl, R3 is CN, Z1 is N, Z2 is O, and Z3 is N.
[00162] In some embodiments of Formula la, R1 is methyl, R3 is CN, Z1 is N, Z2 is S, and Z3 is CH.
[00163] In some embodiments of Formula la, R1 is methyl, R3 is CN, Z1 is N, Z2 is S, and Z3 is N.
[00164] In some embodiments of Formula la, R1 is methyl, R3 is CN, Z1 is CH, Z2 is NH, and Z3 is N.
[00165] In some embodiments of Formula la, R1 is methyl, R3 is CN, Z1 is N, Z2 is NH, and Z3 is CH.
[00166] In some embodiments of Formula la, R1 is methyl, R3 is hydroxyCl-C6 alkyl, Z1 is N, Z2 is NH, and Z3 is CH.
[00167] In some embodiments of Formula la, R1 is methyl, R3 is C1-C3 alkyl, Z1 is N, Z2 is NH, and Z3 is CH.
[00168] In some embodiments, the compound of Formula I is a compound of Formula lb
Figure imgf000019_0001
lb
[00169] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00170] B is selected from Ar3 or hetAr4,
[00171] Ar2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or Cl-C6 alkyl,
[00172] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl;
[00173] X1, X2, and X4 are each CH and X3 is N, or X2 and X4 are each CH and X1 and X3 are each N;
[00174] Y is -NRd(Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), wherein Rd is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
[00175] Z4 is CH or N;
[00176] R1 is C1-C6 alkyl-;
[00177] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00178] R4 is CN; and
[00179] m is l .
[00180] In some embodiments of Formula lb, B is Ar3. [00181] In some embodiments of Formula lb, B is hetAr4, substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3- C6 cycloalkyl, and C1-C3 alkyl.
[00182] n some embodiments of Formula lb, X1, X2, and X4 are each CH and X3 is N.
[00183] n some embodiments of Formula lb, X2 and X4 are each CH and X1 and X3 are each N.
[00184] n some embodiments of Formula lb, Y is - Rd(Cl-C6 alkyl)-, wherein Rd is methyl.
[00185] embodiments of Formula lb,
[00186] embodiments of Formula lb,
[00187] embodiments of Formula lb,
[00188] embodiments of Formula lb,
[00189] embodiments of Formula lb,
[00190] embodiments of Formula lb,
[00191] embodiments of Formula lb,
[00192] embodiments of Formula lb,
[00193] embodiments of Formula lb,
[00194] embodiments of Formula lb,
[00195] embodiments of Formula lb,
[00196] embodiments of Formula lb,
[00197] embodiments of Formula lb,
[00198] embodiments of Formula lb,
[00199] n some embodiments, the compound of Formula I is a compound of Formula Ic
Figure imgf000020_0001
Ic
[00200] harmaceutically acceptable salts and solvates thereof, wherein: [00201] B is selected from Ar3 or hetAr4,
[00202] Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or Cl-C6 alkyl,
[00203] hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl;
[00204] X1, X2, and X4 are each CH and X3 is N, or X2 and X4 are each CH and X1 and X3 are each N;
[00205] Y is -NRd(C 1 -C6 alkyl)- (optionally substituted with 1 -3 fluoros), wherein Rd is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
[00206] R1 is C1-C6 alkyl-;
[00207] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00208] R5 is H or C 1 -C6 alkyl-; and
[00209] m is l .
[00210] In some embodiments of Formula Ic, B is Ar3.
[00211] In some embodiments of Formula Ic, B is hetAr4, substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3- C6 cycloalkyl, and C1-C3 alkyl.
[00212] In some embodiments of Formula Ic, X1, X2, and X4 are each CH and X3 is N.
[00213] In some embodiments of Formula Ic, X2 and X4 are each CH and X1 and X3 are each N.
[00214] In some embodiments of Formula Ic, Y is -NRd(Cl-C6 alkyl)-, wherein Rd is methyl.
[00215] In some embodiments of Formula Ic, Y is -NRd(Cl-C6 alkyl)-, wherein Rd is H. [00216] In some embodiments of Formula Ic, Y is - HCH2-.
[00217] In some embodiments of Formula Ic, Y is - HCH(CH3)-.In some embodiments of
Formula Ic, R1 is C1-C3 alkyl-.
[00218] In some embodiments of Formula Ic, R1 is methyl.
[00219] In some embodiments of Formula Ic, R2 is halogen.
[00220] In some embodiments of Formula Ic, R2 is F.
[00221] In some embodiments of Formula Ic, R2 is C1-C3 alkyl.
[00222] In some embodiments of Formula Ic, R2 is methyl.
[00223] In some embodiments of Formula Ic, R5 is H.
[00224] In some embodiments of Formula Ic, R5 is C1-C6 alkyl-.
[00225] In some embodiments of Formula Ic, R5 is methyl.
[00226] In some embodiments of Formula Ic, R1 is methyl and R5 is H.
[00227] In some embodiments of Formula Ic, R1 is methyl and R5 is methyl.
[00228] In some embodiments, the compound of Formula I is a compound of Formula Id
Figure imgf000022_0001
Id
[00229] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00230] A is selected from Ar1 or hetAr2,
[00231] Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or Cl-C6 alkyl,
[00232] hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RkRTNT-, wherein Rb and Rc are independently H or C1-C6 alkyl;
[00233] X2 is CH or N;
[00234] R1 is C1-C6 alkyl-;
[00235] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00236] R6 is H or Cl-C6 alkyl;
[00237] R7, R8, and R9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl; and
[00238] n is i .
[00239] In some embodiments of Formula Id, A is Ar1, substituted with CN.
[00240] In some embodiments of Formula Id, A is hetAr2, substituted with one or more substituents independently selected from the group consisting of CN, oxo, hydroxyCl-C3 alkyl, and C1-C3 alkyl.
[00241] In some embodiments of Formula Id, X2 is CH.
[00242] In some embodiments of Formula Id, X2 is N.
[00243] In some embodiments of Formula Id, R1 is methyl.
[00244] In some embodiments of Formula Id, R2 is H.
[00245] In some embodiments of Formula Id, R2 is halogen.
[00246] In some embodiments of Formula Id, R2 is F.
[00247] In some embodiments of Formula Id, R2 is C1-C6 alkyl
[00248] In some embodiments of Formula Id, R2 is Cl-C3 alkyl
[00249] In some embodiments of Formula Id, R2 is methyl.
[00250] In some embodiments of Formula Id, R6 is H.
[00251] In some embodiments of Formula Id, R6 is C1-C6 alkyl
[00252] In some embodiments of Formula Id, R6 is Cl-C3 alkyl
[00253] In some embodiments of Formula Id, R6 is methyl.
[00254] In some embodiments of Formula Id, R7 is H.
[00255] In some embodiments of Formula Id, R7 is C1-C6 alkyl
[00256] In some embodiments of Formula Id, R7 is Cl-C3 alkyl
[00257] In some embodiments of Formula Id, R7 is methyl. [00258] In some embodiments of Formula Id, R8 is H.
[00259] In some embodiments of Formula Id, R8 is halogen.
[00260] In some embodiments of Formula Id, R8 is F.
[00261] In some embodiments of Formula Id, R8 is C1-C6 alkyl.
[00262] In some embodiments of Formula Id, R8 is C1-C3 alkyl.
[00263] In some embodiments of Formula Id, R8 is methyl.
[00264] In some embodiments of Formula Id, R9 is H.
[00265] In some embodiments of Formula Id, R9 is C1-C6 alkyl.
[00266] In some embodiments of Formula Id, R9 is C1-C3 alkyl.
[00267] In some embodiments of Formula Id, R9 is methyl.
[00268] In some embodiments of Formula Id, R9 is C3-C6 cycloalkyl.
[00269] In some embodiments of Formula Id, R9 is cyclopropane.
[00270] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is H, R8 is H, R9 is H, and X2 is CH.
[00271] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is H, R8 is H, R9 is H, and X2 is N.
[00272] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is H, R8 is F, R9 is H, and X2 is CH.
[00273] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is H, R8 is F, R9 is H, and X2 is N.
[00274] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is H, R8 is methyl, R9 is H, and X2 is CH.
[00275] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is H, R8 is methyl, R9 is H, and X2 is N.
[00276] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is methyl, R8 is H, R9 is methyl, and X2 is CH.
[00277] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is methyl, R8 is H, R9 is methyl, and X2 is N.
[00278] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is H, R8 is H, R9 is cyclopropyl, and X2 is CH.
[00279] In some embodiments of Formula Id, R2 is H, F, or methyl, R6 is H or methyl, R is H, R8 is H, R9 is cyclopropyl, and X2 is N.
[00280] In some embodiments, the compound of Formula I is a compound of Formula le
Figure imgf000025_0001
le
[00281] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00282] A is selected from Ar1 or hetAr2,
[00283] Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or Cl-C6 alkyl,
[00284] hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl;
[00285] X2 is CH or N;
[00286] R1 is C1-C6 alkyl-;
[00287] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00288] R6 is H or Cl-C6 alkyl;
[00289] R10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy;
[00290] n is i ; and
[00291] p is 1 or 2.
[00292] In some embodiments of Formula le, X2 is CH. [00293] In some embodiments of Formula le, X2 is N.
[00294] In some embodiments of Formula le, A is Ar1, substituted with CN.
[00295] In some embodiments of Formula le, A is hetAr2, substituted with one or more substituents independently selected from the group consisting of CN, oxo, hydroxyCl-C3 alkyl, and C1-C3 alkyl.
[00296] In some embodiments of Formula le, R1 is methyl.
[00297] In some embodiments of Formula le, R2 is H.
[00298] In some embodiments of Formula le, R2 is halogen.
[00299] In some embodiments of Formula le, R2 is F.
[00300] In some embodiments of Formula le, R2 is C1-C6 alkyl.
[00301] In some embodiments of Formula le, R2 is C1-C3 alkyl.
[00302] In some embodiments of Formula le, R2 is methyl.
[00303] In some embodiments of Formula le, R6 is H.
[00304] In some embodiments of Formula le, R6 is C1-C6 alkyl.
[00305] In some embodiments of Formula le, R6 is C1-C3 alkyl.
[00306] In some embodiments of Formula le, R6 is methyl.
[00307] In some embodiments of Formula le, R10 is halogen.
[00308] In some embodiments of Formula le, R10 is F.
[00309] In some embodiments of Formula le, R10 is C1-C6 alkyl.
[00310] In some embodiments of Formula le, R10 is Cl-C3 alkyl.
[00311] In some embodiments of Formula le, R10 is methyl.
[00312] In some embodiments of Formula le, R10 is Cl-C6 alkoxy.
[00313] In some embodiments of Formula le, R10 is Cl-C3 alkoxy.
[00314] In some embodiments of Formula le, R10 is methoxy.
[00315] In some embodiments of Formula le, p is 1.
[00316] In some embodiments of Formula le, p is 2.
[00317] In some embodiments of Formula le, p is 2 and R10 is F and methyl.
[00318] In some embodiments of Formula le, R2 is H, F, or methyl, R6 is H or methyl, R10 is methoxy, X2 is CH, and p is 1.
[00319] In some embodiments of Formula le, R2 is H, F, or methyl, R6 is H or methyl, R10 is methoxy, X2 is N, and p is 1. [00320] In some embodiments of Formula Ie, R2 is H, F, or methyl, R6 is H or methyl, R is methyl and F, X2 is CH, and p is 2.
[00321] In some embodiments of Formula Ie, R2 is H, F, or methyl, R6 is H or methyl, R is methyl and F, X2 is N, and p is 2.
[00322] In some embodiments, the compound of Formula I is a compound of Formula If
Figure imgf000027_0001
If
[00323] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00324] X2 is CH or N;
[00325] Z1, Z2 and Z3 are each independently selected from CH, N, NH, O or S;
[00326] R1 is C1-C6 alkyl-;
[00327] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00328] R3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros); and
[00329] R6 is H or Cl-C6 alkyl;
[00330] R7, R8, and R9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl.
[00331] In some embodiments of Formula If, X2 is CH.
[00332] In some embodiments of Formula If, X2 is N.
[00333] In some embodiments of Formula If, z1 is N or NH.
[00334] In some embodiments of Formula If, z1 is CH.
[00335] In some embodiments of Formula If, z2 is N or NH.
[00336] In some embodiments of Formula If, z2 is O.
[00337] In some embodiments of Formula If, z2 is S.
[00338] In some embodiments of Formula If, z3 is CH. [00339] In some embodiments of Formula if, z3 is N or H.
[00340] In some embodiments of Formula if, z1 is H, Z2 is N, and Z3 is CH.
[00341] In some embodiments of Formula if, z1 is N, Z2 is O, and Z3 is CH.
[00342] In some embodiments of Formula if, z1 is N, Z2 is O, and Z3 is N.
[00343] In some embodiments of Formula if, z1 is N, Z2 is S, and Z3 is CH.
[00344] In some embodiments of Formula if, z1 is N, Z2 is S, and Z3 is N.
[00345] In some embodiments of Formula if, z1 is CH, Z2 is NH, and Z3 is N.
[00346] In some embodiments of Formula if, z1 is N, Z2 is NH, and Z3 is CH.
[00347] In some embodiments of Formula if, R1 is C1-C3 alkyl.
[00348] In some embodiments of Formula if, R1 is methyl.
[00349] In some embodiments of Formula if, R3 is CN.
[00350] In some embodiments of Formula if, R3 is hydroxyCl-C6 alkyl.
[00351] In some embodiments of Formula if, R3 is C1-C3 alkyl.
[00352] In some embodiments of Formula if, R3 is methyl.
[00353] In some embodiments of Formula if, R3 is ethyl.
[00354] In some embodiments of Formula if, R6 is H.
[00355] In some embodiments of Formula if, R6 is C1-C6 alkyl.
[00356] In some embodiments of Formula if, R6 is C1-C3 alkyl.
[00357] In some embodiments of Formula if, R6 is methyl.
[00358] In some embodiments of Formula if, R7 is H.
[00359] In some embodiments of Formula if, R7 is C1-C6 alkyl.
[00360] In some embodiments of Formula if, R7 is C1-C3 alkyl.
[00361] In some embodiments of Formula if, R7 is methyl.
[00362] In some embodiments of Formula if, R8 is H.
[00363] In some embodiments of Formula if, R8 is halogen.
[00364] In some embodiments of Formula if, R8 is F.
[00365] In some embodiments of Formula if, R8 is C1-C6 alkyl.
[00366] In some embodiments of Formula if, R8 is C1-C3 alkyl.
[00367] In some embodiments of Formula if, R8 is methyl.
[00368] In some embodiments of Formula if, R9 is H.
[00369] In some embodiments of Formula if, R9 is C1-C6 alkyl. [00370] In some embodiments of Formula If, R9 is C1-C3 alkyl.
[00371] In some embodiments of Formula If, R9 is methyl.
[00372] In some embodiments of Formula If, R9 is C3-C6 cycloalkyl.
[00373] In some embodiments of Formula If, R9 is cyclopropane.
[00374] In some embodiments, the compound of Formula I is a compound of Formula Ig
Figure imgf000029_0001
[00375] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00376] X2 is CH or N;
[00377] Z1, Z2 and Z3 are each independently selected from CH, N, NH, O or S;
[00378] R1 is C1-C6 alkyl-;
[00379] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00380] R3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros);
[00381] R6 is H or Cl-C6 alkyl;
[00382] R10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy; and
[00383] p is 1 or 2.
[00384] In some embodiments of Formula Ig, X2 is CH.
[00385] In some embodiments of Formula Ig, X2 is N.
[00386] In some embodiments of Formula Ig, Z1 is N or NH.
[00387] In some embodiments of Formula Ig, Z1 is CH.
[00388] In some embodiments of Formula Ig, Z2 is N or NH.
[00389] In some embodiments of Formula Ig, Z2 is O.
[00390] In some embodiments of Formula Ig, Z2 is S.
[00391] In some embodiments of Formula Ig, Z3 is CH. [00392] In some embodiments of Formula Ig> Z3 is N or H.
[00393] In some embodiments of Formula Ig> Z1 is H, Z2 is N, and Z3 is CH.
[00394] In some embodiments of Formula Ig> Z1 is N, Z2 is O, and Z3 is CH.
[00395] In some embodiments of Formula Ig> Z1 is N, Z2 is O, and Z3 is N.
[00396] In some embodiments of Formula Ig> Z1 is N, Z2 is S, and Z3 is CH.
[00397] In some embodiments of Formula Ig> Z1 is N, Z2 is S, and Z3 is N.
[00398] In some embodiments of Formula Ig> Z1 is CH, Z2 is NH, and Z3 is N.
[00399] In some embodiments of Formula Ig> Z1 is N, Z2 is NH, and Z3 is CH.
[00400] In some embodiments of Formula Ig> R s Cl-CS alkyl.
[00401] In some embodiments of Formula Ig> R1 is methyl.
[00402] In some embodiments of Formula Ig> R3 is CN.
[00403] In some embodiments of Formula Ig> R3 is hydroxyCl-C6 alkyl.
[00404] In some embodiments of Formula Ig> R3 is Cl-C3 alkyl.
[00405] In some embodiments of Formula Ig> R3 is methyl.
[00406] In some embodiments of Formula Ig> R3 is ethyl.
[00407] In some embodiments of Formula Ig> R6 is H.
[00408] In some embodiments of Formula Ig> R6 is C1-C6 alkyl.
[00409] In some embodiments of Formula Ig> R6 is Cl-C3 alkyl.
[00410] In some embodiments of Formula Ig> R6 is methyl.
[00411] In some embodiments of Formula Ig, R10 is halogen.
[00412] In some embodiments of Formula Ig, R10 is F.
[00413] In some embodiments of Formula Ig, R10 is C1-C6 alkyl.
[00414] In some embodiments of Formula Ig, R10 is Cl-C3 alkyl.
[00415] In some embodiments of Formula Ig, R10 is methyl.
[00416] In some embodiments of Formula Ig, R10 is Cl-C6 alkoxy.
[00417] In some embodiments of Formula Ig, R10 is Cl-C3 alkoxy.
[00418] In some embodiments of Formula ig> R10 is methoxy.
[00419] In some embodiments of Formula ig, p is 1.
[00420] In some embodiments of Formula ig, p is 2.
[00421] In some embodiments of Formula ig, p is 2 and R10 is F and methyl.
[00422] In some embodiments, the compound of Formula I is a compound of Formula Ih
Figure imgf000031_0001
Ih
[00423] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00424] X2 is CH or N;
[00425] Z4 is CH or N;
[00426] R1 is C1-C6 alkyl-;
[00427] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00428] R4 is CN;
[00429] R6 is H or C1-C6 alkyl; and
[00430] R7, R8, and R9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl.
[00431] In some embodiments of Formula Ih, R1 is Cl-C3 alkyl
[00432] In some embodiments of Formula Ih, R1 is methyl.
[00433] In some embodiments of Formula Ih, R4 is CN.
[00434] In some embodiments of Formula Ih, R6 is H.
[00435] In some embodiments of Formula Ih, R6 is C1-C6 alkyl
[00436] In some embodiments of Formula Ih, R6 is Cl-C3 alkyl
[00437] In some embodiments of Formula Ih, R6 is methyl.
[00438] In some embodiments of Formula Ih, R7 is H.
[00439] In some embodiments of Formula Ih, R7 is C1-C6 alkyl
[00440] In some embodiments of Formula Ih, R7 is Cl-C3 alkyl
[00441] In some embodiments of Formula Ih, R7 is methyl.
[00442] In some embodiments of Formula Ih, R8 is H.
[00443] In some embodiments of Formula Ih, R8 is halogen.
[00444] In some embodiments of Formula Ih, R8 is F. [00445] In some embodiments of Formula Ih, R8 is C 1-C6 alkyl.
[00446] In some embodiments of Formula Ih, R8 is C 1-C3 alkyl.
[00447] In some embodiments of Formula Ih, R8 is methyl.
[00448] In some embodiments of Formula Ih, R9 is H.
[00449] In some embodiments of Formula Ih, R9 is C 1-C6 alkyl.
[00450] In some embodiments of Formula Ih, R9 is C 1-C3 alkyl.
[00451] In some embodiments of Formula Ih, R9 is methyl.
[00452] In some embodiments of Formula Ih, R9 is C3-C6 cycloalkyl.
[00453] In some embodiments of Formula Ih, R9 is cyclopropane.
[00454] In some embodiments of Formula Ih, Z4 is CH.
[00455] In some embodiments of Formula Ih, Z4 is N.
[00456] In some embodiments of Formula Ih, R1 is methyl, R4 is CN, and Z4 is CH.
[00457] In some embodiments of Formula Ih, R1 is methyl, R4 is CN, and Z4 is N.
[00458] In some embodiments of Formula Ih, X2 is CH.
[00459] In some embodiments of Formula Ih, X2 is N.
[00460] In some embodiments the compound of Formula I is a compound of Formula
Figure imgf000032_0001
[00461] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00462] X2 is CH or N;
[00463] R1 is C 1-C6 alkyl-;
[00464] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00465] R5 is H or C 1 -C6 alkyl-;
[00466] R6 is H or C 1-C6 alkyl; and
[00467] R7, R8, and R9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl.
[00468] In some embodiments of Formula I i, R1 is C1-C3 alkyl-.
[00469] In some embodiments of Formula I i, R1 is methyl.
[00470] In some embodiments of Formula I L, R5 is H.
[00471] In some embodiments of Formula I i, R5 is C1-C6 alkyl-.
[00472] In some embodiments of Formula I i, R5 is methyl.
[00473] In some embodiments of Formula I L, R6 is H.
[00474] In some embodiments of Formula I L, R6 is C1-C6 alkyl.
[00475] In some embodiments of Formula I L, R6 is C1-C3 alkyl.
[00476] In some embodiments of Formula I L, R6 is methyl.
[00477] In some embodiments of Formula I L, R7 is H.
[00478] In some embodiments of Formula I L, R7 is C1-C6 alkyl.
[00479] In some embodiments of Formula I L, R7 is C1-C3 alkyl.
[00480] In some embodiments of Formula I L, R7 is methyl.
[00481] In some embodiments of Formula I i, R8 is H.
[00482] In some embodiments of Formula I L, R8 is halogen.
[00483] In some embodiments of Formula I L, R8 is F.
[00484] In some embodiments of Formula I (, R8 is C1-C6 alkyl.
[00485] In some embodiments of Formula I (, R8 is C1-C3 alkyl.
[00486] In some embodiments of Formula I (, R8 is methyl.
[00487] In some embodiments of Formula I i, R9 is H.
[00488] In some embodiments of Formula I L, R9 is C1-C6 alkyl.
[00489] In some embodiments of Formula I i, R9 is C1-C3 alkyl.
[00490] In some embodiments of Formula I i, R9 is methyl.
[00491] In some embodiments of Formula I i, R9 is C3-C6 cycloalkyl.
[00492] In some embodiments of Formula I L, R9 is cyclopropane.
[00493] In some embodiments of Formula I L, X2 is CH.
[00494] In some embodiments of Formula I L, X2 is N.
[00495] In some embodiments, the compound of Formula I is a compound of Formula Ij
Figure imgf000034_0001
[00496] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00497] X2isCHorN;
[00498] Z4isCHorN;
[00499] R1 is C1-C6 alkyl-;
[00500] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00501] R4 is CN;
[00502] R6isHorCl-C6alkyl;
[00503] R10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy; and
[00504] p is 1 or 2.
[00505] In some embodiments of Formula I , R1 is C1-C3 alkyl-.
[00506] In some embodiments of Formula I , R1 is methyl.
[00507] In some embodiments of Formula I , R4 is CN.
[00508] In some embodiments of Formula I , R6 is H.
[00509] In some embodiments of Formula I ,R6 is C1-C6 alkyl.
[00510] In some embodiments of Formula I ,R6isCl-C3 alkyl.
[00511] In some embodiments of Formula I , R6 is methyl.
[00512] In some embodiments of Formula I , R10 is halogen.
[00513] In some embodiments of Formula I ,R10isF.
[00514] In some embodiments of Formula I ,R10isCl-C6 alkyl.
[00515] In some embodiments of Formula I ,R10isCl-C3 alkyl.
[00516] In some embodiments of Formula I , R10 is methyl.
[00517] In some embodiments of Formula I ,R10isCl-C6 alkoxy [00518] In some embodiments of Formula I , R10 is Cl-C3 alkoxy.
[00519] In some embodiments of Formula I , R10 is methoxy.
[00520] In some embodiments of Formula I , p is 1.
[00521] In some embodiments of Formula I , p is 2.
[00522] In some embodiments of Formula I , p is 2 and R10 is F and methyl.
[00523] In some embodiments of Formula I , Z4 is CH.
[00524] In some embodiments of Formula I , Z4 is N.
[00525] In some embodiments of Formula I , R1 is methyl, R4 is CN, and Z4 is CH.
[00526] In some embodiments of Formula I , R1 is methyl, R4 is CN, and Z4 is N.
[00527] In some embodiments of Formula I , X2 is CH.
[00528] In some embodiments of Formula I , X2 is N.
[00529] In some embodiments the compound of Formula I is a compound of Form
Figure imgf000035_0001
Ik
[00530] and pharmaceutically acceptable salts and solvates thereof, wherein:
[00531] X2 is CH or N;
[00532] R1 is Cl-C6 alkyl-;
[00533] R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
[00534] R5 is H or C 1 -C6 alkyl-;
[00535] R6 is H or Cl-C6 alkyl;
[00536] R10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy; and
[00537] p is 1 or 2.
[00538] In some embodiments of Formula Ik, R1 is C1-C3 alkyl-.
[00539] In some embodiments of Formula Ik, R1 is methyl. [00540] In some embodiments of Formula Ik, R5 is H.
[00541] In some embodiments of Formula Ik, R5 is C1-C6 alkyl-.
[00542] In some embodiments of Formula Ik, R5 is methyl.
[00543] In some embodiments of Formula Ik, R6 is H.
[00544] In some embodiments of Formula Ik, R6 is C1-C6 alkyl.
[00545] In some embodiments of Formula Ik, R6 is Cl-C3 alkyl.
[00546] In some embodiments of Formula Ik, R6 is methyl.
[00547] In some embodiments of Formula Ik, R10 is halogen.
[00548] In some embodiments of Formula Ik, R10 is F.
[00549] In some embodiments of Formula Ik, R10 is C1-C6 alkyl.
[00550] In some embodiments of Formula Ik, R10 is Cl-C3 alkyl.
[00551] In some embodiments of Formula Ik, R10 is methyl.
[00552] In some embodiments of Formula Ik, R10 is Cl-C6 alkoxy.
[00553] In some embodiments of Formula Ik, R10 is Cl-C3 alkoxy.
[00554] In some embodiments of Formula Ik, R10 is methoxy.
[00555] In some embodiments of Formula Ik, p is 1.
[00556] In some embodiments of Formula Ik, p is 2.
[00557] In some embodiments of Formula Ik, p is 2 and R10 is F and methyl
[00558] In some embodiments of Formula Ik, X2 is CH.
[00559] In some embodiments of Formula Ik, X2 is N.
[00560] Exemplary compounds of Formula I are shown in the table below.
Figure imgf000036_0001
105 106
Figure imgf000037_0001
107 108
109 110
0
111 112
0
113 114
115 116 H rNAVi
Figure imgf000038_0001
117 118
119 120
O
122
121
123 124
O
126
125
O
127 128
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
52
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
[00561] For complex chemical names employed herein, the substituent group is named before the group to which it attaches. For example, methoxyethyl comprises an ethyl backbone with a methoxy substituent.
[00562] The term "halogen" means -F (sometimes referred to herein as "fluoro" or
"fluoros"), -CI, -Br, and -I.
[00563] The terms "C1-C3 alkyl," "C1-C6 alkyl," "C2-C6 alkyl," and "C3-C6 alkyl" as used herein refer to saturated linear or branched-chain monovalent hydrocarbon radicals of one to three, one to six, two to six, or three to six carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl- 2-propyl, pentyl, neopentyl, and hexyl.
[00564] The term "C1-C6 alkoxy" as used herein refers to a saturated linear or branched- chain monovalent alkoxy radical of one to six carbon atoms, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
[00565] The term "(C1-C6 alkoxy)Cl-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 (CH3OCH2-) and methoxyethyl (CH3OCH2CH2-).
[00566] The terms "hydroxyC 1 -C6 alkyl-" and "hydroxyC2-C6 alkyl-" as used herein refer to a saturated linear or branched-chain monovalent alkyl radicals of one to six or two to six carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy group.
[00567] The term "dihydroxyC3-C6 alkyl-" as used herein refers to a saturated linear or branched-chain monovalent alkyl radical of three to six carbon atoms, wherein two of the carbon atoms are substituted with a hydroxy group.
[00568] The term "(Κ ^ΟΙ-ϋό alkyl-" as used herein refers to a C1-C6 alkyl as defined herein, wherein one of the carbon atoms is substituted with a R^R^- group, wherein Re and Rf are as defined herein.
[00569] The term "C3-C6 cycloalkyl" as used herein refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[00570] The terms " ArlC 1 -C6 alkyl-" and " Ar*C 1 -C3 alkyl-" as used herein refer to a C 1 -
C6 alkyl radical or C1-C3 alkyl radical, respectively, as defined herein, wherein one of the carbon atoms is substituted with an Ar1 group, wherein Ar1 is as defined herein.
[00571] The terms "hetAr2Cl-C6 alkyl-" and "hetAr2Cl-C3 alkyl-" as used herein refer to a C1-C6 alkyl radical or C1-C3 alkyl radical, respectively, as defined herein, wherein one of the carbon atoms is substituted with an hetAr2 group, wherein hetAr2 is as defined herein.
[00572] The terms "hetCy^C 1 -C6 alkyl-" and "hetCy^C 1 -C3 alkyl-" as used herein refer to a C1-C6 alkyl radical or a C1-C3 radical, respectively as defined herein, wherein one of the carbon atoms is substituted with a hetCyc1 group, wherein hetCyc1 is as defined herein.
[00573] The term "oxo" as used herein refers to =0.
[00574] 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.
[00575] 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.
[00576] It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
[00577] The compounds of Formula I include pharmaceutically acceptable salts thereof. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Many such salts are known in the art, for example, as described in WO 87/05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include monohydrochloride, dihydrochloride, trifluoroacetic acid, and di-trifluoroacetic acid salts. In one embodiment, compounds of Formula I include trifluoroacetic acid and dihydrochloride salts.
[00578] 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.
[00579] It will further be appreciated that the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention. For example, compounds of Formula I and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
[00580] 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.
[00581] Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula I, comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to ¾, 2H, 3H or mixtures thereof; when carbon is mentioned, it is understood to refer to UC, 12C, 13C, 14C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to 13N, 14N, 15N or mixtures thereof; when oxygen is mentioned, it is understood to refer to 140, 150, 160, 170, 180 or mixtures thereof; and when fluoro is mentioned, it is understood to refer to 18F, 19F or mixtures thereof. The compounds provided herein therefore also 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.
[00582] The compounds of Formula I provided herein can be prepared according to methods known in to those of skill in the art. For example, the compounds of Formula I can be prepared according to the methods disclosed and described in WO 2016/127074, which is herein incorporated by reference in its entirety. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds provided herein.
[00583] The compounds of Formula I provided herein can act as RET inhibitors. The ability of the compounds of Formula I provided herein to act as RET inhibitors can be demonstrated by assays known to those of skill in the art. For example, assays such as those described in WO 2016/127074 and PCT Application No. PCT/US16/42576, both of which are herein incorporated by reference, can be used.
[00584] 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, for example, the KIF5B-RET fusion, G810R and G810S ATP cleft front or linker mutations, M918T kinase domain, and V804M, V804L, and V804E gatekeeper mutations, with minimal activity against related kinases.
[00585] 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.
[00586] 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).
[00587] 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 potency for a RET kinase encoded by a RET gene including an activating mutation or a RET kinase inhibitor resistance mutation (e.g., a gatekeeper mutant). 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.
[00588] 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.
[00589] In some embodiments, the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting a RET kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treatment of a patient with cancer (e.g., a RET-associated cancer such as a RET-associated brain or CNS cancer) can include administration (e.g., oral administration) of the compound to the patient. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.
[00590] 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. [00591] Compounds of Formula I are useful for treating diseases and disorders which can be treated with a RET kinase inhibitor, such as RET-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors, and gastrointestinal disorders such as IBS.
[00592] As used herein, the terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.
[00593] As used herein, the terms "subject," "individual," or "patient," are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (a RET-associated cancer) (e.g., as determined using a regulatory agency -approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a RET gene, a RET protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency -approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a RET-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (and 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.
[00594] 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.
[00595] 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.
[00596] 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). Non-limiting examples of a RET-associated disease or disorder include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS). [00597] 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. Non-limiting examples of a RET-associated cancer are described herein.
[00598] 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 chromosomal translocation that results in the expression of a fusion protein including a RET kinase domain and a fusion partner, a mutation 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 a wildtype RET protein, a mutation in a RET gene that results in the expression of a RET protein with one or more point mutations as compared to a wildtype RET protein, a mutation in a RET gene that results in the expression of a RET protein with at least one inserted amino acid as compared to a wildtype RET protein, a gene duplication that results in an increased level of RET protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of RET protein in a cell), 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 increased expression (e.g., increased levels) of a wildtype RET kinase in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous 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. Non-limiting examples of fusion proteins are described in Table 1. Non-limiting examples of RET kinase protein point mutations/insertions/deletions are described in Tables 2 and 2a. Additional examples of RET kinase protein mutations (e.g., point mutations) are RET inhibitor resistance mutations. Non-limiting examples of RET inhibitor resistance mutations are described in Tables 3 and 4.
[00599] In some embodiments, dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be caused by an activating mutation in a RET gene (see, e.g., chromosome translocations that result in the expression of any of the fusion proteins listed in Table 1). In some embodiments, dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be caused by a genetic mutation that results in the expression of a RET kinase that has increased resistance to inhibition by a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype RET kinase (see, e.g., the amino acid substitutions in Tables 3 and 4). The exemplary RET kinase point mutations, insertions, and deletions shown in Tables 2 and 2a can be caused by an activating mutation and/or can result in the expression of a RET kinase that has increased resistance to inhibition by a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI).
[00600] The term "activating mutation" describes a mutation in a RET kinase gene that results in the expression of a RET kinase that has an increased kinase activity, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions. For example, an activating mutation can result in the expression of a fusion protein that includes a RET kinase domain and a fusion partner. In another example, an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted as compared to a wildtype RET kinase, e.g., the exemplary wildtype RET kinase described herein, e.g., when assayed under identical conditions. Additional examples of activating mtuations are known in the art.
[00601] 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).
[00602] 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).
[00603] 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. Non-limiting examples of RET gene fusion proteins are described in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, the 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. Non-limiting examples of RET kinase protein point mutations/insertions/deletions are described in Tables 2 and 2a. In some embodiments, the RET kinase protein point mutations/insertions/deletions are selected from the group consisting of M918T, M918V, C634W, V804L, and V804M.
[00604] In some embodiments of any of the methods or uses described herein, the cancer
(e.g., RET-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET- associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-associated cancer) is lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid ademona, endocrine gland neoplasms, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, mammary neoplasm, colorectal cancer (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 methods or uses described herein, the 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, neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct cancer, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasms, head and neck neoplasms, CNS tumor, primary CNS tumor, heart cancer, hepatocellular cancer, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, 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, neoplasms by site, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non- small cell lung cancer, lung neoplasm, pulmonary cancer, pulmonary neoplasms, respiratory tract neoplasms, bronchogenic carcinoma, bronchial neoplasms, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromosytoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colonic neoplasms, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, 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.
[00605] 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 (C L), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM). Additional examples of hematological cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF/IPF/PMF). In one embodiment, the hematological cancer (e.g., the hematological cancer that is a RET-associated cancer) is AML or CMML.
[00606] 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.
[00607] 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.
[00608] In some embodiments, the patient is a human.
[00609] Compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are also useful for treating a RET-associated cancer.
[00610] Accordingly, also provided herein is a method for treating a patient diagnosed with or identified as having a RET-associated cancer, e.g., any of the exemplary RET-associated cancers disclosed herein, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
[00611] 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 a gene translocation resulting in the expression of a fusion protein that includes a RET kinase domain and a fusion partner. For example, a fusion protein can have increased kinase activity as compared to a wildtype RET protein. In some embodiments, a mutation in a RET gene can involve mutations in the RET ligand-binding site, extracellular domains, kinase domain, and in regions involved in protein: protein interactions and downstream signaling. In some embodiments, a mutation (e.g., an activating mutation) in a RET gene can result in the expression of a RET kinase having one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., one or more amino acid substitutions in the kinase domain (e.g., amino acid positions 723 to 1012 in a wildtype RET protein), a gatekeeper amino acid (e.g., amino acid position 804 in a wildtype RET protein), the P-loop (e.g., amino acid positions 730-737 in a wildtype RET protein), the DFG motif (e.g., amino acid positions 892-894 in a wildtype RET protein), ATP cleft solvent front amino acids (e.g., amino acid positions 758, 811, and 892 in a wildtype RET protein), the activation loop (e.g., amino acid positions 891-916 in a wildtype RET protein), the C-helix and loop preceeding the C-helix (e.g., amino acid positions 768-788 in a wildtype RET protein), and/or the ATP binding site (e.g., amino acid positions 730-733, 738, 756, 758, 804, 805, 807, 811, 881, and 892 in a wildtype RET protein). In some embodiments, a mutation can be a gene amplification of a RET gene. In some embodiments, a mutation (e.g., an activating mutation) in a RET gene can result in the expression of a RET kinase that lacks at least one amino acid (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids) as compared to a wildtype RET protein. In some embodiments, dyregulation of a RET kinase can be increased expression (e.g., increased levels) of a wildtype RET kinase in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). In some embodiments, a mutation (e.g., an activating mutation) in a RET gene can result in the expression of a RET kinase that has at least one amino acid (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids) inserted as compared to a wildtype RET protein. In some embodiments, dyregulation of a RET kinase can be increased expression (e.g., increased levels) of a wildtype RET kinase in a mammalian cell (e.g., as compared to a control non-cancerous cell), e.g., due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling. Other dysregulations can include RET mRNA splice variants. In some embodiments, the wildtype RET protein is the exemplary wildtype RET protein described herein.
[00612] 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.
[00613] 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.
[00614] Non-limiting examples of RET fusion proteins are shown in Table 1.
[00615] Table 1. Exemplary RET Fusion Partners and Cancers
Figure imgf000073_0001
Fusion Partner Non-limiting Exemplary
RET-
Associated Cancer(s)
PTClex9 (a novel Metastatic papillary thyroid
CCDC6 cancer2
rearrangement)
NCOA4 (also Papillary Thyroid Cancer21, called PTC3, NSCLC, Colon Cancer,
ELE1, and RFG) Salivary Gland Cancer,
Metastatic Colorectal
Cancer5; Lung
Adenocarcinoma15;
Adenosquamous
Carcinomas15 Diffuse
Sclerosing Variant of
Papillary Thyroid Cancer16,
Breast Cancer30, Acinic
Cell Carcinoma32,
Mammary Analog
Secretory Carcinoma33
TRIM33 (also NSCLC, Papillary Thyroid called PTC7 and Cancer
RFG7)
ERC1 (also called Papillary Thyroid Cancer,
ELKS) Breast Cancer
FGFRIOP CMML, Primary
Myelofibrosis with secondary Acute Myeloid
Leukemia
MBDl(also known Papillary Thyroid Cancer as PCM1) Fusion Partner Non-limiting Exemplary RET- Associated Cancer(s)
RAB61P2 Papillary Thyroid Cancer
PRKAR1 A (also Papillary Thyroid Cancer called PTC2)
TRIM24 (also Papillary Thyroid Cancer called PTC6)
KTN1 (also called Papillary Thyroid Cancer PTC8 )
GOLGA5 (also Papillary Thyroid Cancer, called PTC5) Spitzoid Neoplasms
HOOK3 Papillary Thyroid Cancer
KIAA1468 (also Papillary Thyroid Cancer, called PTC9 and Lung Adenocarcinoma8' 12 RFG9)
TRIM27 (also Papillary Thyroid Cancer called RFP)
AKAP13 Papillary Thyroid Cancer
FKBP15 Papillary Thyroid Cancer
SPECC1L Papillary Thyroid Cancer;
Thyroid Gland Carcinoma
TBL1XR1 Papillary Thyroid Cancer;
Thyroid Gland Carcinoma
CEP 55 Diffuse Gastric Cancer7
CUX1 Lung Adenocarcinoma
ACBD5 Papillary Thyroid
Carcinoma Fusion Partner Non-limiting Exemplary RET- Associated Cancer(s)
MYH13 Medullary Thyroid
Carcinoma1
Uncharacterized Inflammatory
Myofibroblastic Tumor6
PIBF1 Bronchiolus Lung Cell
Carcinoma9
KIAA1217 (also Papillary Thyroid Cancer10, called SKT) 13
Lung Adenocarcinoma14 NSCLC14
MPRIP NSCLC11
HRH4-RET Thyroid Cancer and/or
Paillary Thyroid
Carcinoma17
Ria-RET Thyroid Cancer and/or
Papillary Thyroid
Carcinoma17
RFG8 Papillary Thyroid
Carcinoma18
FOXP4 Lung Adenocarcinoma19
MYH10 Infantile Myofibromatosis20
HTIF1 Various22
TIF1G Various22
H4L Various22
PTC4 (a novel Papillary Thyroid Cancer23
NC04/ELE1
rearrangement) Fusion Partner Non-limiting Exemplary
RET- Associated Cancer(s)
FRMD4A NSCLC24
SQSTM1 Papillary Thyroid
Carcinoma25
AFAP1L2 Papillary Thyroid
Carcinoma25
AFAPl NSCLC31
PPFIBP2 Papillary Thyroid
Carcinoma25
EML4 Papillary Thyroid Cancer26
PARD3 NSCLC27
UVELD Papillary Thyroid Cancer29
RASGEF1A Breast Cancer30
TEL In vitro34
RUFY1 Colorectal Cancer35
OLFM4 Small-Bowel Cancer36
UEVLD Papillary Thyroid
Carcinoma29
DLG5 Non-Anaplastic Thyroid
(NAT) Cancer37
RRBP1 Colon Cancer38
ETV6 Secretory Carcinoma39 Grubbs et al., J. Clin. Endocrinol. Metab. 100:788-793, 2015.
Halkova et al., Human Pathology 46: 1962-1969, 2015.
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[00616] 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.
[00617] 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).
[00618] Table 2. Activating RET Kinase Protein Amino Acid Substitutions/Insertions/
Deletions
Exemplary RET Amino Acid SubstitutionsA
Amino acid position 2
Amino acid position 3 Exemplary RET Amino Acid SubstitutionsA
Amino acid position 4
Amino acid position 5
Amino acid position 6
Amino acid position 7
Amino acid position 8
Amino acid position 11
Amino acid position 12
Amino acid position 13
Amino acid position 20
Amino acid position 32 (e.g., S32L)
Amino acid position 34 (e.g., D34S)
Amino acid position 40 (e.g., L40P)
Amino acid position 56 (e.g., L56M)30
Amino acid position 64 (e.g., P64L)
Amino acid position 67 (e.g., R67H)
Amino acid position 114 (e.g., Rl 14H)
Amino acid position 136 (e.g., glutamic acid to stop codon)
Amino acid position 145 (e.g., V145G)
Amino acid position 180 (e.g., arginine to stop codon)
Amino acid position 200
Amino acid position 292 (e.g., V292M)
Amino acid position 294
Amino acid position 321 (e.g., G321R)
Amino acid position 330 (e.g., R330Q)
Amino acid position 338 (e.g., T338I)
Amino acid position 360 (e.g., R360W)
Amino acid position 373 (e.g., alanine to frameshift)
Amino acid position 393 (e.g., F393L) Exemplary RET Amino Acid SubstitutionsA
Amino acid position 423 (e.g., G423R)27
Amino acid position 432
Amino acid position 446 (e.g., G446R)28
Δ Amino acid residues 505-506 (6-Base Pair In-Frame
Germline Deletion in Exon 7)3
Amino acid position 510 (e.g., A510V)
Amino acid position 511 (e.g., E51 IK)
Amino acid position 513 (e.g., G513D)7*
Amino acid position 515 (e.g., C515S, C515W4)
Amino acid position 525 (e.g., R525W)7*
Amino acid position 531 (e.g., C531R, or 9 base pair duplication2)
Amino acid position 532 (e.g., duplication)2
Amino acid position 533 (e.g., G533C, G533S)
Amino acid position 550 (e.g., 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., 1602 V)6
Amino acid position 603 (e.g., K603Q, K603E2)
Amino acid position 606 (e.g., Y606C)
Amino acid position 609 (e.g., C609Y, C609S, C609G,
C609R, C609F, C609W, C690C32)
Amino acid position 611 (e.g., C611R, C611 S, C611G,
C611Y, C61 1F, C611W)
Amino acid position 616 (e.g., E616Q)23
Amino acid position 618 (e.g., C618S, C618Y, C618R,
C618Y, C618G, C618F, C618W) Exemplary RET Amino Acid SubstitutionsA
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,
D631 A, D631G, D63 IV, D63 IE, )
Amino acid position 632 (e.g., E632K, E632G5' u)
Δ Amino acid residues 632-633 (6-Base Pair In-Frame
Germline Deletion in Exon l l)9
Amino acid position 633 (e.g., 9 base pair duplication2)
Amino acid position 634 (e.g., C634W, C634Y,
C634S, C634R, C634F, C634G, C634L, C634A, or
C634T, or an insertion ELCR2, or a 12 base pair duplication2) (e.g., causing MTC)
Amino acid position 635 (e.g., R635G)
Amino acid position 636 (e.g., T636P2, T636M4)
Amino acid position 640 (e.g., A640G)
Amino acid position 641 (e.g., A641 S, A641T8)
Amino acid position 648 (e.g., V648I)
Amino acid position 649 (e.g., S649L)28
Amino acid position 664 (e.g., A664D)
Amino acid position 665 (e.g., H665Q)
Amino acid position 666 (e.g., K666E, K666M,
K666N, K666R)
Amino acid position 675 (T675T, silent nucleotide change)18 Exemplary RET Amino Acid SubstitutionsA
Amino acid position 686 (e.g. S686N)
Amino acid position 689 (e.g. S689T)18
Amino acid position 691 (e.g. G691 S)
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, P766M6)
Amino acid position 768 (e.g. E768Q, E768D)
Amino acid position 769 (e.g. L769L)
Amino acid position 770 (e.g. R770Q)
Amino acid position 771 (e.g. D771N)
Amino acid position 777 (e.g. N777S)
Amino acid position 778 (e.g. V778I)
Amino acid position 781 (e.g. Q781R)
Amino acid position 788 (e.g. I788I32)
Amino acid position 790 (e.g. L790F)
Amino acid position 791 (e.g. Y791F, Y791N24)
Amino acid position 802
Amino acid position 804 (e.g., V804L15' 16, V804M15'
16, V804E12) (e.g., causing MTC)
Amino acid position 805 (e.g., E805K)
Amino acid position 804/805 (e.g., V804M/E805K)17 Exemplary RET Amino Acid SubstitutionsA
Amino acid position 806 (e.g., Y806F, Y806S12,
Y806G, Y806C2' 12> 14, Y806E 14, Y806H12, Y806N12*
Y806Y32)
Amino acid position 810 (e.g., G810R12, G810S12,
G810A13)
Amino acid position 818 (e.g. E818K)
Amino acid position 819 (e.g. S819I)
Amino acid position 823 (e.g. G823E)
Amino acid position 826 (e.g. Y826M, Y826S)10
Amino acid position 833 (e.g. R833C)
Amino acid position 836 (e.g. S836S)19
Amino acid position 841 (e.g. P841L, P841P)
Amino acid position 843 (e.g. E843D)
Amino acid position 844 (e.g. R844W, R844Q,
R844L)
Amino acid position 848 (e.g. M848T)
Amino acid position 852 (e.g. I852M)
Amino acid position 865 (e.g. L865V)12
Amino acid position 866 (e.g. A866W)33
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 882
Amino acid position 883 (e.g. A883F, A883S, A883T)
Amino acid position 884 (e.g. E884K)
Amino acid position 886 (e.g. R886W)
Amino acid position 891 (e.g. S891A, S891 S32)
Amino acid position 897 (e.g. R897Q) Exemplary RET Amino Acid SubstitutionsA
Amino acid position 898 (e.g., D898V)
Amino acid position 900 (e.g. Y900F) 22
Amino acid position 901 (e.g. E901K)
Amino acid position 904 (e.g. S904F, S904S, S904C2)
Amino acid position 905 (e.g. Y905F) 22
Amino acid position 907 (e.g. K907E, K907M)
Amino acid position 908 (e.g. R908K)
Amino acid position 911 (e.g. G911D)
Amino acid position 912 (e.g. R912P, R912Q)
Amino acid position 918 (e.g M918T2, M918V, M918L6) (e g., causing MTC)
Amino acid position 919 (e.g. A919V)
Amino acid position 921 (e.g. E921K)
Amino acid position 922 (e.g. S922P, S922Y)
Amino acid position 930 (e.g. T930M)
Amino acid position 961 (e.g. F961L)
Amino acid position 972 (e.g. R972G)
Amino acid position 981 (e.g. Y981F) 22
Amino acid position 982 (e.g., R982C)
Amino acid position 1009 (e.g., 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)
Amino acid position 1109 (e.g., Ml 109T) 34
RET+31
(In-Frame Deletion in Exons 6 and 11) 25 Exemplary RET Amino Acid SubstitutionsA
(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
A The RET kinase mutations shown may be activating mutations and/or confer increased resistance of the RET kinase to a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype RET kinase.
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34 Davila et. al., Rare Tumors, 2017; 9(2): 6834. doi: 10.4081/rt.2017.6834. [00619] 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).
[00620] Table 2a. Exemplary activating RET Kinase Protein Point
Mutations Insertions Deletions
Exemplary RET Point MutationsA
Amino acid position 20
Amino acid position 32 (e.g., S32L)
Amino acid position 34 (e.g., D34S)
Amino acid position 40 (e.g., L40P)
Amino acid position 64 (e.g., P64L)
Amino acid position 67 (e.g., R67H)
Amino acid position 114 (e.g., Rl 14H)
Amino acid position 145 (e.g., V145G)
Amino acid position 200
Amino acid position 292 (e.g., V292M)
Amino acid position 294
Amino acid position 321 (e.g., G321R)
Amino acid position 330 (e.g., R330Q)
Amino acid position 338 (e.g., T338I)
Amino acid position 360 (e.g., R360W)
Amino acid position 393 (e.g., F393L)
Amino acid position 432
Δ Amino acid residues 505-506 (6-Base Pair In-Frame
Germline Deletion in Exon 7)
Amino acid position 510 (e.g., A510V)
Amino acid position 511 (e.g., E51 IK) Exemplary RET Point MutationsA
Amino acid position 513 (e.g., G513D)
Amino acid position 515 (e.g., C515S, C515W4)
Amino acid position 525 (e.g., R525W)
Amino acid position 531 (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., 1602 V)
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, C611 S, C611G,
C611Y, C61 1F, 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) Exemplary RET Point MutationsA
Amino acid position 631 (e.g., D631N, D631Y,
D631 A, D631G, D63 IV, D63 IE, )
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., A641 S, 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., G691 S)
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) Exemplary RET Point MutationsA
Amino acid position 748 (e.g., G748C)
Amino acid position 750 (e.g., A750P)
Amino acid position 765 (e.g., S765P)
Amino acid position 766 (e.g., P766S, P766M)
Amino acid position 768 (e.g., E768Q, E768D)
Amino acid position 769 (e.g., L769L)
Amino acid position 770 (e.g., R770Q)
Amino acid position 771 (e.g., D771N)
Amino acid position 777 (e.g., N777S)
Amino acid position 778 (e.g., V778I)
Amino acid position 781 (e.g., Q781R)
Amino acid position 790 (e.g., L790F)
Amino acid position 791 (e.g., Y791F, Y791N)
Amino acid position 802
Amino acid position 804 (e.g., V804L, V804M,
V804E) (e.g., causing MTC)
Amino acid position 805 (e.g., E805K)
Amino acid position 804/805 (e.g., V804M/E805K)
Amino acid position 806 (e.g., Y806F, Y806S, Y806G,
Y806C, Y806E, Y806H, Y806N)
Amino acid position 810 (e.g., G810R, G810S,
G810A)
Amino acid position 818 (e.g., E818K)
Amino acid position 819 (e.g., S819I)
Amino acid position 823 (e.g., G823E)
Amino acid position 826 (e.g., Y826M, Y826S) Amino acid position 833 (e.g., R833C)
Amino acid position 836 (e.g., S836S)
Amino acid position 841 (e.g., P841L, P841P) Exemplary RET Point MutationsA
Amino acid position 843 (e.g. E843D)
Amino acid position 844 (e.g. R844W, R844Q,
R844L)
Amino acid position 848 (e.g. M848T)
Amino acid position 852 (e.g. I852M)
Amino acid position 865 (e.g. L865V)
Amino acid position 870 (e.g. L870F)
Amino acid position 873 (e.g. R873W)
Amino acid position 876 (e.g. A876V)
Amino acid position 881 (e.g. L881V)
Amino acid position 882
Amino acid position 883 (e.g. A883F, A883S, A883T)
Amino acid position 884 (e.g. E884K)
Amino acid position 886 (e.g. R886W)
Amino acid position 891 (e.g. 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) Exemplary RET Point MutationsA
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)
A The RET kinase mutations shown above may be activating mutations and/or may confer increased resistance of the RET kinase to a RET inhibitor and/or a multi -kinase inhibitor (MKI), e.g., as compared to a wildtype RET kinase.
[00621] 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.
[00622] A "RET kinase inhibitor" as defined herein includes any compound exhibiting RET inhibition activity. In some embodiments, a RET kinase inhibitor is selective for a RET kinase. Exemplary RET kinase inhibitors can exhibit inhibition activity (ICso) against a RET kinase of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein. In some embodiments, a RET kinase inhibitor can exhibit inhibition activity (ICso) against a RET kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein. [00623] 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.
[00624] 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 Vmax, a decreased Km for ATP, and an increased KD for a first RET kinase inhibitor, when in the presence of a first RET kinase inhibitor, as compared to a wildtype RET kinase or a RET kinase not having the same mutation in the presence of the same first RET kinase inhibitor.
[00625] 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 Vmax, a decreased Km, and a decreased KD in the presence of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as compared to a wildtype RET kinase or a RET kinase not having the same mutation in the presence of the same compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
[00626] 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 (e.g., amino acid positions 730-733, 738, 756, 758, 804. 805, 807, 811, 881, and 892 of a wildtype RET kinase, e.g., the exemplary wildtype RET kinase described herein), including but not limited to a gatekeeper residue (e.g., amino acid position 804 in a wildtype RET kinase), P-loop residues (e.g., amino acid positions 730-737 in a wildtype RET kinase), residues in or near the DFG motif (e.g., amino acid positions 888-898 in a wildtype RET kinase), and ATP cleft solvent front amino acid residues (e.g., amino acid positions 758, 811, and 892 of a wildtype RET kinase). Additional examples of these types of mutations include changes in residues that may affect enzyme activity and/or drug binding including but are not limited to residues in the activation loop (e.g., amino acid positions 891-916 of a wildtype RET kinase), 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 (e.g., amino acid positions 768-788 in a wildtype RET protein). In some embodiments, the wildtype RET protein is the exemplary wildtype RET kinase described herein. Specific residues or residue regions that may be changed (and are RET inhibitor resistance mutations) include but are not limited to those listed in Table 3, with numbering based on the human wildtype RET protein sequence (e.g., SEQ ID NO: 1). As can be appreciated by those skilled in the art, an amino acid position in a reference protein sequence that corresponds to a specific amino acid position in SEQ ID NO: 1 can be determined by aligning the reference protein sequence with SEQ ID NO: 1 (e.g., using a software program, such as ClustalW2). 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. See also J. Kooistra, G. K. Kanev, O. P. J. Van Linden, R. Leurs, I. J. P. De Esch, and C. De Graaf, "KLIFS: A structural kinase-ligand interaction database," Nucleic Acids Res., vol. 44, no. Dl, pp. D365-D371, 2016, which is incorporated by reference in its entirety herein.
[00627] Exemplary Sequence of Mature Human RET Protein (SEQ ID NO: 1)
MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYWEKL YVDQAAGTPL LYVHALRDAP EEVPSFRLGQ HLYGTYRTRL HENNWICIQE DTGLLYLNRS LDHSSWEKLS VRNRGFPLLT VYLKVFLSPT SLREGECQWP GCARVYFSFF NTSFPACSSL KPRELCFPET RPSFRIRENR PPGTFHQFRL LPVQFLCPNI SVAYRLLEGE GLPFRCAPDS LEVSTRWALD REQREKYELV AVCTVHAGAR EEWMVPFPV TVYDEDDSAP TFPAGVDTAS
AWEFKRKED TWATLRVFD ADWPASGEL VRRYTSTLLP GDTWAQQTFR VEHWPNETSV QANGS FVRAT
VHDYRLVLNR NLS I SENRTM QLAVL DSD FQGPGAGVLL LHFNVSVLPV SLHLPSTYSL SVSRRARRFA
QI GKVCVENC QAFSGINVQY KLHS SGANCS TLGWTSAED TSGI LF DT KALRRPKCAE LHYMWATDQ
QTSRQAQAQL LVTVEGSYVA EEAGCPLSCA VSKRRLECEE CGGLGS PTGR CEWRQGDGKG ITRNFSTCS P
STKTCPDGHC DWETQDINI CPQDCLRGS I VGGHEPGEPR GI KAGYGTCN CFPEEEKCFC EPEDIQDPLC
DELCRTVIAA AVLFS FIVSV LLSAFCIHCY HKFAHKPPI S SAEMTFRRPA QAFPVSYS S S GARRPSLDSM
ENQVSVDAFK I LEDPKWEFP RKNLVLGKTL GEGEFGKWK ATAFHLKGRA GYTTVAVKML KENAS PSELR
DLLSEFNVLK Q HPHVI KL YGACSQDGPL LLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNS S SLDH
PDERALTMGD LI S FAWQI SQ GMQYLAEMKL VHRDLAARNI LVAEGRKMKI SDFGLSRDVY EEDSYVKRSQ
GRI PVKWMAI ESLFDHIYTT QSDVWS FGVL LWEIVTLGGN PYPGI PPERL FNLLKTGHRM ERPDNCSEEM
YRLMLQCWKQ EPDKRPVFAD I SKDLEKMMV KRRDYLDLAA STPSDSLIYD DGLSEEETPL VDCNNAPLPR
ALPSTWI ENK LYGMSDPNWP GES PVPLTRA DGTNTGFPRY PNDSVYANWM LS PSAAKLMD TFDS
[00628] In some embodiments, compounds of Formula I and pharmaceutically acceptable salts and solvates are useful in treating patients that develop cancers with RET inhibitor resistance mutations (e.g., that result in an increased resistance to a first RET inhibitor, e.g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E, and/or one or more RET inhibitor resistance mutations listed in Tables 3 and 4) by either dosing in combination or as a subsequent or additional (e.g., 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, apatinib, sitravatinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, LOXO-292, BLU667, and BLU6864.
[00629] In some embodiments, compounds of Formula I or pharmaceutically acceptable salts and solvates thereof are useful for treating a cancer that has been identified as having one or more RET inhibitor resistance mutations (that result in an increased resistance to a first or second RET inhibitor, e.g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E). Non- limiting examples of RET inhibitor resistance mutations are listed in Tables 3 and 4. Table 3. RET Inhibitor Resistance Mutations
Exemplary RET Resistance Mutations
Amino acid position 732 (e.g., E732K)
Amino acid position 788 (e.g., I788N)'
Amino acid position 790 (e.g., L790F)9
Amino acid position 804 (e.g., V804M1' 2, V804L1' 2, V804E6)
Amino acid position 804/805 (e.g., V804M/E805K)3
Amino acid position 806 (e.g., Y806C4' 6, Y806E4, Y806S6, Y806H6, Y806N6)
Amino acid position 810 (e.g., G810A5, G810R6, G810S6)
Amino acid position 865 (e.g., L865V6)
Amino acid position 870 (e.g., L870F6)
1 Yoon et al., J. Med. Chem. 59(l):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 Mamedova et al., Summer Undergraduate Research Programs (SURP) Student Abstracts, University of Oklahoma Health Sciences Center, 2016.
8 Plenker et al., Set Transl. Med, 9(394), doi: 10.1126/scitranslmed.aah6144, 2017.
9 Kraft et al, Cancer Research, 2017, Vol. 77, No. 13, Supp. Supplement 1. Abstract Number: 4882; American Association for Cancer Research Annual Meeting 2017. Washington, DC, United States. 01 Apr 2017-05 Apr 2017.
Table 4. Additional Exemplary Amino Acid Positions of RET Inhibitor Resistance Mutations
Figure imgf000097_0001
L730 P Steric hindrance and/or active conformational effect
G731 V Steric hindrance and/or active conformational effect
E732 K Steric hindrance and/or active conformational effect
G733 V Steric hindrance and/or active conformational effect
E734 K Steric hindrance and/or active conformational effect
L760 M Active conformational effect
K761 E Active conformational effect
E762 K Active conformational effect
N763 D Active conformational effect
A764 V Active conformational effect
S765 N Active conformational effect
P766 A Active conformational effect
S767 C Active conformational effect
E768 K Active conformational effect
L779 M Steric hindrance and/or active conformational effect
1788 M Steric hindrance and/or active conformational effect
M868 R Steric hindrance and/or active conformational effect
K869 E Steric hindrance and/or active conformational effect
L870 Q Steric hindrance and/or active conformational effect
V871 M Steric hindrance and/or active conformational effect
H872 R Steric hindrance and/or active conformational effect
R873 P Steric hindrance and/or active conformational effect
D874 Y Steric hindrance and/or active conformational effect
L881 R Steric hindrance and/or active conformational effect
L895 M Active conformational effect
S896 N Active conformational effect
R897 C Active conformational effect
D898 Y Active conformational effect
V899 G Active conformational effect
Y900 D Active conformational effect E901 K Active conformational effect
E902 K Active conformational effect
D903 Υ Active conformational effect
S904 C Active conformational effect
Y905 D Active conformational effect
V906 Μ Active conformational effect
K907 Ε Active conformational effect
R908 Ρ Active conformational effect
S909 C Active conformational effect
Q910 R Active conformational effect
G911 C Active conformational effect
R912 Ρ Active conformational effect
[00630] The oncogenic role of RET was firstly described in papillary thyroid carcinoma (PTC) (Grieco et al., Cell, 1990, 60, 557-63), which arises from follicular thyroid cells and is the most common thyroid malignancy. Approximately 20-30% of PTC harbor somatic chromosomal rearrangements (translocations or inversions) linking the promoter and the 5' portions of constitutively expressed, unrelated genes to the RET tyrosine kinase domain (Greco et al., Q. J. Nucl. Med. Mol. Imaging, 2009, 53, 440-54), therefore driving its ectopic expression in thyroid cells. Fusion proteins generated by such rearrangements are termed "RET/PTC" proteins. For example, RET/PTC 1 is a fusion between CCDD6 and RET that is commonly found in papillary thyroid carcinomas. Similarly, both RET/PTC3 and RET/PTC4 are fusions of ELEl and RET that are commonly found in papillary thyroid carcinomas, although the fusion events resulting RET/PTC3 and RET/PTC4 lead to different proteins with different molecular weights (see e.g., Fugazzola et al., Oncogene, 13(5): 1093-7, 1996). Some RET fusions associated with PTC are not referred to as "RET/PTC", but instead are referred to as the the fusion protein inself. For example, fusion between RET and both ELKS and PCMl are found in PTCs, but the fusion proteins are referred to as ELKS-RET and PCMl-RET (see e.g., Romei and Elisei, Front. Endocrinol. (Lausanne), 3 :54, doi: 10.3389/fendo.2012.00054, 2012). The role of RET -PTC rearrangements in the pathogenesis of PTC has been confirmed in transgenic mice (Santoro et al., Oncogene, 1996, 12, 1821-6). To date, a variety of fusion partners have been identified, from PTC and other cancer types, all providing a protein/protein interaction domain that induces ligand-independent RET dimerization and constitutive kinase activity (see, e.g., Table 1). Recently, a 10.6 Mb pericentric inversion in chromosome 10, where RET gene maps, has been identified in about 2% of lung adenocarcinoma patients, generating different variants of the chimeric gene 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, such as the CCDC6- RET fusion protein, which has been found to play a key role in the proliferation of the human lung adenocarcinoma cell line LC-2/ad {Journal of Thoracic Oncology, 2012, 7(12): 1872-1876). RET inhibitors have been shown to be useful in treating lung cancers involving RET rearrangements (Drilon, 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).
[00631] 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 other tumors such as colorectal cancer (Wood et al., Science, 2007, 318, 1108-13) and small cell lung carcinoma (Jpn. J. Cancer Res., 1995, 86, 1127-30).
[00632] 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 GD F 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).
[00633] RET is also expressed in 30-70% of invasive breast cancers, with expression being relatively more frequent in estrogen receptor-positive tumors (Plaza-Menacho, L, 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).
[00634] 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). [00635] 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).
[00636] 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 (FGFRIOP-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).
[00637] 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).
[00638] 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).
[00639] 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). Such multitargeted inhibitors (or multikinase inhibitors or MKIs) can also be associated with development of RET inhibitor resistance mutations. See, for example, Q. Huang et al., "Preclinical Modeling of KIF5B-RET Fusion Lung Adenocarcinoma.," Mol. Cancer Ther., no. 18, pp. 2521-2529, 2016; Yasuyuki Kaneta et al., Abstract B 173 : Preclinical characterization and antitumor efficacy of DS-5010, a highly potent and selective RET inhibitor, Mol Cancer Ther January 1 2018 (17) (1 Supplement) B173; DOL 10.1158/1535-7163.TARG-17-B173, both of which are incorporated by reference in their entirety herein.
[00640] Accordingly, provided herein are methods for treating a patient diagnosed with (or identified as having) a cancer that include administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided herein are methods for treating a patient identified or diagnosed as having a RET- associated cancer that include administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof. In some embodiments, the patient that has been identified or diagnosed as having a RET-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying 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 patient or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a RET- associated cancer. For example, the RET-associated cancer can be a cancer that includes one or more RET inhibitor resistance mutations.
[00641] Also provided are methods for treating cancer in a patient in need thereof, the method comprising: (a) detecting a RET-associated cancer in the patient; and (b) administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or an immunotherapy). In some embodiments, the subject was previously treated with a first RET inhibitor or previously treated with another anticancer treatment, e.g., resection of the tumor or radiation therapy. In some embodiments, the patient is determined to have a RET- associated cancer through the use of a regulatory agency -approved, e.g., FDA-approved test or assay for identifying 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 patient or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a RET-associated cancer. For example, the RET-associated cancer can be a cancer that includes one or more RET inhibitor resistance mutations.
[00642] Also provided are methods of treating a patient that include performing an assay on a sample obtained from the patient to determine whether the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof to the patient determined to have a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments of these methods, the subject was previously treated with a first RET inhibitor or previously treated with another anticancer treatment, e.g., resection of a tumor or radiation therapy. In some embodiments, the patient is a patient suspected of having a RET-associated cancer, a patient presenting with one or more symptoms of a RET-associated cancer, or a patient having an elevated risk of developing a RET-associated cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency -approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the 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.
[00643] 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 methods or uses described herein further include recording in the patient's clinical record (e.g., a computer readable medium) that the patient is determined to have a 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 assay is a liquid biopsy. 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.
[00644] Also provided is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a cancer in a patient in need thereof or a patient identified or diagnosed as having a RET-associated cancer. Also provided is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a cancer in a patient identified or diagnosed as having a RET-associated cancer. In some embodiments, the cancer is a RET-associated cancer, for example, a 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. [00645] In some embodiments of any of the methods or uses described herein, the patient has been identified or diagnosed as having a cancer with a 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 methods or 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 methods or 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 methods or 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. Non-limiting examples of RET gene fusion proteins are described in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, the 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. Non-limiting examples of RET kinase protein point mutations/insertions/deletions are described in Tables 2 and 2a. 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. Non-limiting examples of RET inhibitor resistance mutations are described in Tables 3 and 4. In some embodiments, the RET inhibitor resistance mutation is V804M. In some embodiments, the cancer with a 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.
[00646] In some embodiments of any of the methods or uses described herein, the patient has a clinical record indicating that the patient has a tumor that has a 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 or solvates 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.
[00647] Also provided are methods of treating a patient that include administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to a patient having a clinical record that indicates that the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. Also provided is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a RET-associated cancer in a patient having a clinical record that indicates that the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. Some embodiments of these methods and uses can further include: a step of performing an 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, 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 assay is a liquid biopsy. 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.
[00648] Also provided herein is a method of treating a subject. In some embodiments, the method includes performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a RET gene, a RET protein, or expression or level of any of the same. In some such embodiments, the method also includes administering to a subject determined to have a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method includes determining that a subject has a dysregulation of a RET gene, a RET protein, or expression or level of any of the same via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering to a subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the dysregulation in a RET gene, a RET kinase protein, or expression or activity of the same is a gene or chromosome translocation that results in the expression of a RET fusion protein (e.g., any of the RET fusion proteins described herein). In some embodiments, the RET fusion can be selected from a KIF5B-RET fusion and a CCDC6-RET fusion. In some embodiments, the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutation in the RET gene (e.g., any of the one or more of the RET point mutations described herein). The one or more point mutations in a RET gene can result, e.g., in the translation of a RET protein having one or more of the following amino acid substitutions: M918T, M918V, C634W, V804L, and V804M. In some embodiments, the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more RET inhibitor resistance mutations (e.g., any combination of the one or more RET inhibitor resistance mutations described herein). Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second RET inhibitor a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy).
[00649] In some embodiments, the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting a RET kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treatment of a patient with cancer (e.g., a RET-associated cancer such as a RET-associated brain or CNS cancer) can include administration (e.g., oral administration) of the compound to the patient. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor. For example, the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, the tumors listed in Louis, D.N. et al. 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.
[00650] Also provided are methods (e.g., in vitro methods) of selecting a treatment for a patient identified or diagnosed as having a RET-associated cancer. Some embodiments can further include administering the selected treatment to the patient identified or diagnosed as having a RET- associated cancer. For example, the selected treatment can include administration of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Some embodiments can further include a step of performing an assay on a sample obtained from the patient to determine whether the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, and identifying and diagnosing a patient determined to have a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, as having a RET-associated cancer. In some embodiments, the cancer is a RET-associated cancer having one or more RET inhibitor resistance mutations. In some embodiments, the patient has been identified or diagnosed as having a 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 patient. In some embodiments, the RET- associated cancers is a cancer described herein or known in the art. In some embodiments, the assay is an in vitro assay. For example, an assay that utilizes the next generation sequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved, kit. In some embodiments, the assay is a liquid biopsy.
[00651] Also provided herein are methods of selecting a treatment for a patient, wherein the methods include a step of performing an assay on a sample obtained from the patient to determine whether the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same (e.g., one or more RET inhibitor resistance mutations), and identifying or diagnosing a patient determined to have a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, as having a RET-associated cancer. Some embodiments further include administering the selected treatment to the patient identified or diagnosed as having a RET-associated cancer. For example, the selected treatment can include administration of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to the patient identified or diagnosed as having a RET-associated cancer. In some embodiments, the assay is an in vitro assay. For example, an assay that utilizes the next generation sequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved, kit. In some embodiments, the assay is a liquid biopsy.
[00652] Also provided are methods of selecting a patient for treatment, wherein the methods include selecting, identifying, or diagnosing a patient having a RET-associated cancer, and selecting the patient for treatment including administration of a therapeutically-effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, identifying or diagnosing a patient as having a RET-associated cancer can include a step of performing an assay on a sample obtained from the patient to determine whether the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, and identifying or diagnosing a patient determined to have a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, as having a RET- associated cancer. In some embodiments, the method of selecting a patient for treatment can be used as a part of a clinical study that includes administration of various treatments of a RET- associated cancer. In some embodiments, a RET-associated cancer is a cancer having one or more RET inhibitor resistance mutations. In some embodiments, the assay is an in vitro assay. For example, an assay that utilizes the next generation sequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency -approved, e.g., FDA- approved, kit. In some embodiments, the assay is a liquid biopsy. 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.
[00653] In some embodiments of any of the methods or 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)
[00654] In some embodiments, dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., "Real-time liquid biopsies become a reality in cancer treatment", Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and/or the dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same. Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and/or dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same at an earlier stage than traditional methods. In some embodiments, the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same.
[00655] In some embodiments, ctDNA derived from a single gene can be detected using a liquid biopsy. In some embodiments, ctDNA derived from a plurality of genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more, or any number of genes in between these numbers) can be detected using a liquid biopsy. In some embodiments, ctDNA derived from a plurality of genes can be detected using any of a variety of commercially- available testing panels (e.g., commercially-available testing panels designed to detect dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same ). Liquid biopsies can be used to detect dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same including, without limitation, point mutations or single nucleotide variants (SNVs), copy number variants (CNVs), genetic fusions (e.g., translocations or rearrangements), insertions, deletions, or any combination thereof. In some embodiments, a liquid biopsy can be used to detect a germline mutation. In some embodiments, a liquid biopsy can be used to detect a somatic mutation. In some embodiments, a liquid biopsy can be used to detect a primary genetic mutation (e.g., a primary mutation or a primary fusion that is associated with initial development of a disease, e.g., cancer). In some embodiments, a liquid biopsy can be used to detect a genetic mutation that develops after development of the primary genetic mutation (e.g., a resistance mutation that arises in response to a treatment administered to a subject). In some embodiments, a dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same identified using a liquid biopsy is also present in a cancer cell that is present in the subject (e.g., in a tumor). In some embodiments, any of the types of dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same described herein can be detected using a liquid biopsy. In some embodiments, a genetic mutation identified via a liquid biopsy can be used to identify the subject as a candidate for a particular treatment. For example, detection of dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same in the subject can indicate that the subject will be responsive to a treatment that includes administration of a compound of Formula I or a pharmaceutically acceptable salt thereof.
[00656] Liquid biopsies can be performed at multiple times during a course of diagnosis, a course of monitoring, and/or a course of treatment to determine one or more clinically relevant parameters including, without limitation, progression of the disease, efficacy of a treatment, or development of resistance mutations after administering a treatment to the subject. For example, a first liquid biopsy can be performed at a first time point and a second liquid biopsy can be performed at a second time point during a course of diagnosis, a course of monitoring, and/or a course of treatment. In some embodiments, the first time point can be a time point prior to diagnosing a subject with a disease (e.g., when the subject is healthy), and the second time point can be a time point after subject has developed the disease (e.g., the second time point can be used to diagnose the subject with the disease). In some embodiments, the first time point can be a time point prior to diagnosing a subject with a disease (e.g., when the subject is healthy), after which the subject is monitored, and the second time point can be a time point after monitoring the subject. In some embodiments, the first time point can be a time point after diagnosing a subject with a disease, after which a treatment is administered to the subject, and the second time point can be a time point after the treatment is administered; in such cases, the second time point can be used to assess the efficacy of the treatment (e.g., if the genetic mutation(s) detected at the first time point are reduced in abundance or are undetectable) or to determine the presence of a resistance mutation that has arisen as a result of the treatment. In some embodiments, a treatment to be administered to a subject can include a compound of Formula I or a pharmaceutically acceptable salt thereof.
[00657] In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies. For example, a surgery may be open surgery or minimally invasive surgery. 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.
[00658] In some embodiments of any the methods described herein, the compound of
Formula I (or a pharmaceutically acceptable salt or solvate thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.
[00659] Non-limiting 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. In some embodiments, the other RET -targeted therapeutic is a multikinase inhibitor exhibiting RET inhibition activity. In some embodiments, the other RET-targeted therapeutic inhibitor is selective for a RET kinase. Exemplary RET kinase inhibitors can exhibit inhibition activity (ICso) against a RET kinase of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein. In some embodiments, a RET kinase inhibitors can exhibit inhibition activity (ICso) against a RET kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.
[00660] Non-limiting examples of RET-targeted therapeutic agents (e.g., a first RET inhibitor or a second RET inhibitor) include alectinib (9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4- yl)piperidin-l-yl]-l l-oxo-6, 1 l-dihydro-5H-benzo[b]carbazole-3-carbonitrile); amuvatinib (MP470, HPK56) (N-(l,3-benzodioxol-5-ylmethyl)-4-([l]benzofuro[3,2-d]pyrimidin-4- yl)piperazine-l-carbothioamide); apatinib (YN968D1) (N-[4-(l-cyanocyclopentyl) phenyl-2-(4- picolyl)amino-3 -Nicotinamide methanesulphonate); cabozantinib (Cometriq XL- 184) (N-(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide); dovitinib (TKI258; GFKI-258; CHIR-258) ((3Z)-4-amino-5-fluoro-3-[5-(4- methylpiperazin-l-yl)-l,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one); famitinib (5-[2- (diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-lH-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro- lH-pyrrolo[3,2-c]pyridin-4-one); fedratinib (SAR302503, TG101348) (N-(2-Methyl-2-propanyl)- 3-{[5-methyl-2-({4-[2-(l-pyrrolidinyl)ethoxy]phenyl}amino)-4- pyrimidinyl]amino}benzenesulfonamide); foretinib (XL880, EXEL-2880, GSK1363089, GSK089) (N -[3-fluoro-4-[[6-methoxy-7-(3-mo holinopropoxy)-4-quinolyl]oxy]phenyl]-Nl- (4-fluorophenyl)cyclopropane-l,l-dicarboxamide); fostamantinib (R788) (2H-Pyrido[3,2-b]-l,4- oxazin-3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2- dimethyl-4-[(phosphonooxy)methyl]-, sodium salt (1 :2)); ilorasertib (ABT-348) (l-(4-(4-amino- 7-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3- fluorophenyl)urea); lenvatinib (E7080, Lenvima) (4-[3-chloro-4- ( cyclopropylaminocarbonyl)aminophenoxy ]-7-methoxy-6-quinolinecarboxamide); motesanib (AMG 706) (N-(3,3-Dimethyl-2,3-dihydro-lH-indol-6-yl)-2-[(pyridin-4- ylmethyl)amino]pyridine-3-carboxamide); nintedanib (3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)- methylcarbonyl)-N-methyl-amino)-anilino)-l-phenyl-methylene]-6-methyoxycarbonyl-2- indolinone); ponatinib (AP24534) (3-(2-Imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methylpiperazin-l-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide); PP242 (a TORKinib) (2-[4-Amino-l-(l-methylethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl]-lH-indol-5-ol); quizartinib (l-(5-(tert-Butyl)isoxazol-3-yl)-3-(4-(7-(2-mo holinoethoxy)benzo[d]imidazo[2, l-b]thiazol-2- yl)phenyl)urea); regorfenib (BAY 73-4506, stivarga) (4-[4-({[4-Chloro-3- (trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate); RXDX-105 (CEP-32496, agerafenib) (l-(3-((6,7-dimethoxyquinazolin-4- yl)oxy)phenyl)-3-(5-(l, l,l-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea); semaxanib (SU5416) ((3Z)-3-[(3,5-dimethyl-lH-pyrrol-2-yl)methylidene]-l,3-dihydro-2H-indol-2-one); sitravatinib (MGCD516, MG516) (N-(3-Fluoro-4-{[2-(5-{[(2-methoxyethyl)amino]methyl}-2- pyridinyl)thieno[3,2-b]pyridin-7-yl]oxy}phenyl)-N?-(4-fluorophenyl)-l, l- cyclopropanedicarboxamide); sorafenib (BAY 43-9006) (4-[4-[[[[4-chloro-3- (trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide); vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(l-methylpiperidin-4- yl)methoxy]quinazolin-4-amine); vatalanib (PTK787, PTK/ZK, ZK222584) (N-(4-chlorophenyl)- 4-(pyridin-4-ylmethyl)phthalazin- 1 -amine); AD-57 (N-[4-[4-amino-l-(l-methylethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-N'-[3-(trifluoromethyl)phenyl]-urea); AD-80 (l-[4-(4- amino-l-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-3-[2-fluoro-5- (trifluoromethyl)phenyl]urea); AD-81 (l-(4-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin- 3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea); ALW-II-41-27 (N-(5-((4-((4- ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen- 2-yl)nicotinamide); BPR1K871 (l-(3-chlorophenyl)-3-(5-(2-((7-(3-
(dimethylamino)propoxy)quinazolin-4-yl)amino)ethyl)thiazol-2-yl)urea); CLM3 (1-phenethyl-N- (l-phenylethyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine); EBI-907 (N-(2-chloro-3-(l-cyclopropyl- 8-methoxy-3H-pyrazolo[3,4-c]isoquinolin-7-yl)-4-fluorophenyl)-3-fluoropropane-l- sulfonamide); NVP-AST-487 (N-[4-[(4-ethyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]- N'-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]-urea); NVP-BBT594 (BBT594) (5-((6- acetamidopyrimidin-4-yl)oxy)-N-(4-((4-methylpiperazin-l-yl)methyl)-3-
(trifluoromethyl)phenyl)indoline-l-carboxamide); PD 173955 (6-(2,6-dichlorophenyl)-8-methyl-
2- (3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one); PP2 (4-amino-5-(4-chlorophenyl)-7- (dimethylethyl)pyrazolo[3,4-d]pyrimidine); PZ-1 (N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(5-(l- methyl-lH-pyrazol-4-yl)-lHbenzo[d]imidazol-l-yl)phenyl)acetamide); RPI-1 (l,3-dihydro-5,6- dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one; (3E)-3-[(4- hydroxyphenyl)methylidene]-5,6-dimethoxy-lH-indol-2-one); SGI-7079 (3-[2-[[3-fluoro-4-(4- methyl-l-piperazinyl)phenyl]amino]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- benzeneacetonitrile); SPP86 (l-Isopropyl-3-(phenylethynyl)-lH-pyrazolo[3,4-d]pyrimidin-4- amine); SU4984 (4-[4-[(E)-(2-oxo-lH-indol-3-ylidene)methyl]phenyl]piperazine-l- carbaldehyde); sunitinb (SU11248) (N-(2-Diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-lH-indol-
3- ylidene)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide); TG101209 (N-tert-butyl-3-(5- methyl-2-(4-(4-methylpiperazin-l-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide); Withaferin A ((4p,5p,6p,22R)-4,27-Dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-l,26- dione); XL-999 ((Z)-5-((l-ethylpiperidin-4-yl)amino)-3-((3-fluorophenyl)(5-methyl-lH- imidazol-2-yl)methylene)indolin-2-one); BPR1J373 (a 5-phenylthiazol-2-ylamine-pyriminide derivative); CG-806 (CG806); DCC-2157; GTX-186; HG-6-63-01 ((E)-3-(2-(4-chloro-lH- pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-l-yl)methyl)-3-
(trifluoromethyl)phenyl)-4-methylbenzamide); SW-01 (Cyclobenzaprine hydrochloride);
XMD15-44 (TST-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-
(pyridin-3-ylethynyl)benzamide (generated from structure)); Y078-DM1 (an antibody drug conjugate composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine); Y078-DM4 (an antibody drug conjugate composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine); ITRI-305 (D0N5TB, DIB003599); BLU-667; BLU6864; DS-5010; GSK3179106; GSK3352589; and NMS-E668.
[00661] Further examples of RET -targeted therapeutics (e.g., a first RET kinase inhibitor aor a second RET kinase inhibitor) include 5-amino-3-(5-cyclopropylisoxazol-3-yl)-l-isopropyl- lH-pyrazole-4-carboxamide; 3-(5-cyclopropylisoxazol-3-yl)-l-isopropyl-lH-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[l,2-a]pyridin-6-yl)phenyl)acetamide; N-(5-(tert- butyl)isoxazol-3-yl)-2-(3-(imidazo[l,2-b]pyridazin-6-yloxy)phenyl)acetamide; N-(2-fluoro-5- trifluoromethylphenyl)-N'-{4'-[(2"-benzamido)pyridin-4"-ylamino]phenyl}urea; 2-amino-6-{[2- (4-chlorophenyl)-2-oxoethyl]sulfanyl}-4-(3-thienyl)pyridine-3,5-dicarbonitrile; and 3- arylureidobenzylidene-indolin-2-ones.
[00662] 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, all of which are hereby incorporated by reference. For example, in some embodiments the other RET inhibitor is a compound of formula I:
Figure imgf000117_0001
wherein Ri is C6-C24alkyl or polyethylene glycol; or a pharmaceutically acceptable salt form thereof. In some embodiments, the other RET inhibitor is 4-{5-[bis-(chloroethyl)-amino]-l- methyl-lH-benzimidazol-2-yl}butyric acid dodecyl ester. [00663] Additional examples of other RET kinase inhibitors include those described in
International Publication No. WO 2016127074, which is hereby incorporated by reference. For example, in some embodiments, the other RET inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000118_0001
(I)
wherein Rings A and B are each independently selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;
each L1 and L2 is independently selected from a bond, -(C1-C6 alkylene)-, -(C2- C6alkenylene)-, -(C2-C6 alkynylene)-, -(C1-C6 haloalkylene)-, -(C1-C6 heteroalkylene)-, -C(0)- , -0-, -S-, -S(O), -S(0)2-, -NCR1)-, -0-(Cl-C6 alkylene)-, -(C1-C6 alkylene)-0-, -Ν(^)-0(0)-, - C(0)N(R1)-, -(C1-C6 alkylene)-N(R1)-, -Ν(^)-(Ό1-06 alkylene)-, -N(R1)-C(0)-(C1-C6 alkylene)-, -(C1-C6 alkylene)-N(R1)-C(0)-, -C(0)-N(R1)-(C1-C6 alkylene)-, -(C1-C6 alkylene)- C(0)-N(R1)-, -Ν(^)-8(0)2-, -S(0)2-N(R1)-, -N(R1)-S(0)2-(C1-C6 alkylene)-, and-S(0)2-N(R1)- (C1-C6 alkylene)-; wherein each alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene is independently substituted with 0-5 occurrences of R;
each RA and RB is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, and -N(R1)(R1); wherein each alkyl, alkoxy, haloalkyl, hydroxyalkyl, and hydroxyalkyl is independently substituted with 0-5 occurrences of Ra;
each Rc and RD 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(0)R1, -OC(0)R1, -C(0)OR1, -(C1-C6 alkylene)-C(0)R1, -SR1,-S(0)2R1, -S(0)2- N(R1)(R1), -(C1-C6 alkylene)-S(0)2R1, -(C1-C6 alkylene)-S(0)2-N(R1)(R1), -N(R1)(R1) -C(O)- N(R1)(R1)-N(R1)-C(0)R1, -N(R1)-C(0)OR1, -(C1-C6 alkylene)-N(R1)-C(0)R1, -N^S^R1, and -P(0)(R1)(R1); 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 Ra; or 2 Rc or 2 RD together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Ra;
each R1 is independently selected from hydrogen, hydroxyl, halo, thiol, C1-C6 alkyl, Cl- 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 Rb, or 2 R1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Rb;
each Ra and Rb 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:
Figure imgf000119_0001
Figure imgf000120_0001
119
Figure imgf000121_0001
120
Figure imgf000122_0001
Figure imgf000123_0001
ı22
Figure imgf000124_0001
, or a pharmaceutically acceptable salt thereof.
[00664] Additional examples of other RET kinase inhibitors include those described in International Publication No. WO 2016075224, which is hereby incorporated by reference. For example, in some embodiments, the other RET inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000125_0001
(Π)
Rl and R2 are independently hydrogen or an optionally substituted group selected from straight or branched (Ci-C6) alkyl, (C3-C6) cycloalkyl and COR', wherein R is an optionally substituted group selected from straight or branched (Ci-C6) alkyl and (C3-C6) cycloalkyl;
R3 is hydrogen or an optionally substituted group selected from straight or branched (Ci- C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, aryl, heteroaryl and a 3- to 7- membered heterocyclyl ring;
R4 is hydrogen or an optionally substituted group selected from straight or branched (Ci- C6) alkyl, (C2-C6) alkenyl, aryl, heteroaryl or heterocyclyl;
A is a 5- or 6-membered heteroaryl ring or a phenyl ring;
B is a 5- or 6-membered ring selected from heteroaryl, (C5-C6) cycloalkyl and heterocyclyl ring or a phenyl ring; wherein ring A and ring B are fused together to form a bicyclic system comprising a 6-membered aromatic or 5- to 6-membered heteroaromatic ring fused with a 6- membered aromatic or 5- to 6-membered heteroaromatic, (C5-C6) cycloalkyl or heterocyclyl ring;
Y is carbon or nitrogen;
X is hydrogen, halogen, hydroxyl, cyano or an optionally substituted group selected from straight or branched (Ci-C6) alkyl and (Ci-C6) alkoxyl; and
R5 and R6 are independently hydrogen or an optionally substituted group selected from straight or branched (Ci-C6) alkyl, (C3-C6) cycloalkyl, heterocyclyl, aryl and heteroaryl.
[00665] Additional examples of other RET kinase inhibitors include those described in International Publication No. WO 2015079251, which is hereby incorporated by reference. For example, in some embodiments, the other RET inhibitor is a compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein:
Figure imgf000126_0001
(III)
X is H, Rx, 0 or S, wherein Rx is (l-3C)alkyl;
Ri is selected from halo (e.g., fluoro, chloro, or bromo), trifluoromethyl, (l-4C)alkyl (e.g., methyl), (l-4C)alkoxy or (3-6C)cycloalkyl, wherein an alkyl, alkoxy or cycloalkyl group is optionally substituted with one or more fluoro;
R2 is selected from hydrogen, halo (e.g., fluoro, chloro or bromo), hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, (l-6C)alkyl (e.g., methyl), (3-8C)cycloalkyl, or (l-4C)alkoxy (e.g., OMe), wherein an alkyl, cycloalkyl or alkoxy group is optionally substituted with one or more fluoro;
R3 is selected from hydrogen, halo (e.g. fluoro, chloro or bromo), hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, (l-6C)alkyl (e.g., methyl), (3-8C)cycloalkyl, or (l-4C)alkoxy (e.g., OMe), wherein an alkyl, cycloalkyl or alkoxy group is optionally substituted with one or more fluoro;
R4 is selected from hydrogen, halo (e.g., fluoro, chloro or bromo), hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, (l-6C)alkyl (e.g., methyl), (3-8C)cycloalkyl, or (l-4C)alkoxy (e.g., OMe), wherein an alkyl, cycloalkyl or alkoxy group is optionally substituted with one or more fluoro;
R5 is selected from hydrogen or a group defined by the formula:
Figure imgf000126_0002
wherein
L5 is absent or a linear or branched (l-4C)alkylene;
Xs is absent or -C(0)0-, -0-, -C(O)-, -OC(O)-, -CH(QRSL)-, -N(Rj)-, -N(RSL)- C(O)-, -N(R5L)-C(0)0-, -C(0)-N(R5L)-, -S-, -SO-, -SO2-, -S(0)2N(R5L)-, or -N(R5L)S02- wherein RSL is selected from hydrogen or methyl; and Qs is (l -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl-(l-4C)alkyl, aryl, aryl-(l-4C)alkyl, heteroaryl, heteroaryl-(l-4C)alkyl, heterocyclyl or heterocyclyl-(l-4C)alkyl;
R6 is selected from hydrogen, or a group defined by the formula:
-O-Le-Xe-Qe
wherein
L6 is absent or a linear or branched (l -4C)alkylene;
Xe is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6L)-, -N(R6L), -N(R6L)-C(0)-, -N(R6L)-C(0)0-, -C(0)-N(R6L)-, -S-, -SO-, -SO2-, -S(0)2N(R6L)-, or - N(R6L)S02- wherein R6L is selected from hydrogen or (l -3C)alkyl;
Qe is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl-(l-6C)alkyl, aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l- 6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl,
or Q6 and RL6 are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein R6 is optionally substituted (e.g. substituted on L6 and/or Q6) with one or more (l-6C)alkyl, (l-6C)alkanoyl, ORex, SRex, S(0)Rex, S(0)2R6x, C(0)ORex or C(0) R6xR'6x, wherein R6x and R6x are independently hydrogen, (l-8C)alkyl, or R6x and R'6x are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; and
R7 is selected from hydrogen, (l-6C)alkoxy, or a group defined by the formula:
Figure imgf000127_0001
wherein
L7 is absent or a linear or branched (l -4C)alkylene;
X? is absent or selected from -0-, -C(0)-, -C(0)0-, -0C(0)-, -CH(OR6L)-, -N(RTL)- , -N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -SO2-, -S(0)2N(R7L)-, or - N(R7L)S02- wherein R7L is selected from hydrogen or (l -3C)alkyl;
Q7 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl-(l-6C)alkyl, aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, or Q7 and RJL are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein Rj is optionally substituted (e.g., substituted on L7 and/or Qi) with one or more halo, hydroxyl, nitro, cyano, (l-8C)alkyl, (l-8C)alkanoyl, ORJX, SR X, S(0)R7x, S(0)2R7x, C(0)OR7x or C(0)NR7xR'7x, wherein R7X and R x are independently hydrogen, (l-8C)alkyl, or R7X and R x are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; or
R7 is optionally substituted with one or more groups selected from oxo, (1 - 4C)haloalkyl, (l-4C)hydroxyalkyl, C(0)R7y or NR7yR'7y, wherein R7y and R'7y are independently hydrogen or (l-8C)alkyl.
[00666] Additional examples of other RET kinase inhibitors include those described in International Publication No. WO2017178845, which is hereby incorporated by reference. For example, in some embodiments, the other RET inhibitor is a compound of Formula (IV) or a pharmaceutically acceptable salt thereof wherein:
Figure imgf000128_0001
(IV)
HET is selected from one of the following:
Figure imgf000129_0001
Figure imgf000129_0002
wherein ' denotes the point of attachment;
Ri is selected from hydrogen, (l-4C)haloalkyl, (l-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (l-5C)alkylene optionally substituted by one or more substituents selected from (l-2C)alkyl or oxo;
Y is absent or O, S, SO, SO2, N(Ra), C(O), C(0)0, OC(O), C(0)N(Ra), N(Ra)C(0), N(Ra)C(0)N(Rb), N(Ra)C(0)0, OC(0)N(Ra), S(0)2N(Ra), or N(Ra)S02, wherein Ra and Rb are each independently selected from hydrogen or (l-4C)alkyl; and
Q is hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (l-4C)alkyl, halo, (l-4C)haloalkyl, (l-4C)haloalkoxy, amino, (l-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, RcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)PRc(where p is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Re)(Rd)Rc or (CH2)q RcRd (where q is 1, 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (l-6C)alkyl or (3-6C)cycloalkyl; or Rc and Rd are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (l-4C)alkyl, halo, (l-4C)haloalkyl, (l-4C)haloalkoxy, (1- 4C)alkoxy, (l-4C)alkylamino, amino, cyano or hydroxy; or
Q is optionally substituted by a group of the formula:
Figure imgf000130_0001
wherein:
Li is absent or (l-3C)alkylene optionally substituted by one or more substituents selected from (l-2C)alkyl or oxo;
LQI is absent or selected from O, S, SO, S02, N(Rf), C(O), C(0)0, OC(O), C(0)N(Rf), N(Rf)C(0), N(Rf)C(0)N(Rg), N(Rf)C(0)0, OC(0)N(Rf), S(0)2N(Rf), or N(Rf)S02, wherein Rf and Rg are each independently selected from hydrogen or (l-2C)alkyl; and
Wi is hydrogen, (l-6C)alkyl, aryl, aryl(l-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Wi is optionally substituted by one or more substituents selected from (l-4C)alkyl, halo, (l-4C)haloalkyl, (1- 4C)haloalkoxy, (l-4C)alkoxy, (l-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3- 6C)cycloalkyl, NRhRi, ORh, C(0)Rh, C(0)ORh, OC(0)Rh, C(0)N(Ri)Rh, N(Ri)C(0)Rh, S(0)rRh (where r is 0, 1 or 2), S02N(Ri)Rh, N(Ri)S02Rh or (CH2)s RiRh (where s is 1, 2 or 3); wherein Rh and Ri are each independently selected from hydrogen, (l-4C)alkyl or (3-6C)cycloalkyl;
Ria and Rib are each selected from H, (l-4C)alkyl, halo, (l-4C)haloalkyl, (1- 4C)haloalkoxy, (l-4C)alkoxy, (l-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl or mercapto;
W is selected from 0, S or Rwi, wherein Rwi is selected from H or (l-2C)alkyl; Xi, X2, X3 and X4 are independently selected from CH, CR2 or N;
R2 is selected from hydrogen, halo, (l -4C)alkyl, (l-4C)alkoxy, (l-4C)haloalkyl, (1 - 4C)haloalkoxy, amino, cyano, nitro, aryl, heteroaryl, heterocyclyl, cycloalkyl, (2-4C)alkynyl, NRjRk, ORj, C(0)Rj, C(0)ORj, OC(0)Rj, C(0)N(Rk)Rj, N(Rk)C(0)Rj, N(Rk)C(0)N(Rj), S(0)nRk (where π is 0, 1 or 2), S02N(Rj)Rk, N(Rj)S02Rk or (CH2)vNRjRk (where v is 1, 2 or 3); wherein Rj and Rk are each independently selected from hydrogen or (l-4C)alkyl; and wherein said (1 - 4C)alkyl, aryl, heteroaryl, heterocycyl or cycloalkyl is optionally substituted by one or more substituents selected from halo, (l -4C)alkyl, (l-4C)alkoxy, (l -4C)haloalkyl, (l-4C)haloalkoxy, amino, cyano, nitro, phenyl, (2-4C)alkynyl, NRjiRki, ORji, C(0)Rji, C(0)ORji, OC(0)Rji, C(0)N(Rki)Rj i, N(Rki)C(0)Rj i, S(0 2Rh (where r2 is 0, 1 or 2), S02N(Rj i)Rki, N(Rj i)S02Rki or (CH2)viNRj iRki (where vi is 1, 2 or 3); and wherein Rj i and Rki are each independently selected from hydrogen or (l-4C)alkyl; and
R3 is selected from halo, (l -4C)alkyl, (l-4C)alkoxy, (l-4C)haloalkyl, (l-4C)haloalkoxy, amino, cyano, nitro, (2-4C)alkynyl, NRiRm, ORi, C(0)Ri, C(0)ORi, OC(0)Ri, C(0)N(Rm)Ri, N(Rm)C(0)Ri, or (CH2)yNRiRm (where y is 1, 2 or 3); wherein said (l-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (l -2C)alkoxy or halo; and wherein Ri and Rm are each independently selected from hydrogen or (l-4C)alkyl.
[00667] Additional examples of other RET kinase inhibitors include those described in International Publication No. WO2017178844, which is hereby incorporated by reference. For example, in some embodiments, the other RET inhibitor is a compound of Formula (V) or a pharmaceutically acceptable salt thereof wherein:
Figure imgf000131_0001
(V)
HET is selected from one of the following:
Figure imgf000132_0001
wherein ' denotes the point of attachment;
Ri is selected from hydrogen, (l-4C)haloalkyl, (l-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (l-5C)alkylene optionally substituted by one or more substituents selected from (l-2C)alkyl or oxo;
Y is absent or O, S, SO, SO2, N(Ra), C(O), C(0)0, OC(O), C(0)N(Ra), N(Ra)C(0), N(Ra)C(0)N(Rb), N(Ra)C(0)0, OC(0)N(Ra), S(0)2N(Ra), or N(Ra)S02, wherein Ra and Rb are each independently selected from hydrogen or (l-4C)alkyl; and
Q is hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (l-4C)alkyl, halo, (l-4C)haloalkyl, (l-4C)haloalkoxy, amino, (l-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, RcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)z RcRd (where z is 1, 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (l-6C)alkyl or (3-6C)cycloalkyl; or Rc and Rd can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (l-4C)alkyl, halo, (l-4C)haloalkyl, (l-4C)haloalkoxy, (1- 4C)alkoxy, (l-4C)alkylamino, amino, cyano or hydroxyl; or
Q is optionally substituted by a group of the formula:
-LI-LQI-ZI
wherein:
Li is absent or (l-3C)alkylene optionally substituted by one or more substituents selected from (l-2C)alkyl or oxo;
LQI is absent or selected from O, S, SO, S02, N(Rf), C(O), C(0)0, OC(O), C(0)N(Rf), N(Rf)C(0), N(Rg)C(0)N(Rf), N(Rf)C(0)0, OC(0)N(Rf), S(0)2N(Rf), or N(Rf)S02, wherein Rf and Rg are each independently selected from hydrogen or (l-2C)alkyl; and
Zi is hydrogen, (l-6C)alkyl, aryl, aryl(l-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Zi is optionally substituted by one or more substituents selected from (l-4C)alkyl, halo, (l-4C)haloalkyl, (1- 4C)haloalkoxy, (l-4C)alkoxy, (l-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3- 6C)cycloalkyl, NRhRi, ORh, C(0)Rh, C(0)ORh, OC(0)Rh, C(0)N(Ri)Rh, N(Ri)C(0)Rh, S(0)yaRh (where ya is 0, 1 or 2), S02N(Ri)Rh, N(Ri)S02Rh or (CH2)za RiRh (where za is 1, 2 or 3); wherein Rh and Ri are each independently selected from hydrogen, (l-4C)alkyl or (3-6C)cycloalkyl;
Ria and Rib are each selected from hydrogen, (l-4C)alkyl, halo, (l-4C)haloalkyl, (1- 4C)haloalkoxy, (l-4C)alkoxy, (l-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl or mercapto;
W is selected from O, So r Rj, wherein Rj is selected from H or (l-2C)alkyl; Xi and X2 are each independently selected from N or CRk;
wherein
Rk is selected from hydrogen, halo, (l-4C)alkyl, (l-4C)alkoxy, amino, (1- 4C)alkylamino, (l-4C)dialkylamino, cyano, (2C)alkynyl, C(0)Rki, C(0)ORki, OC(0)Rki, C(0)N(Rk2)Rki, N(Rk2)C(0)Rki, S(0)ybRki (where yb is 0, 1 or 2), S02N(Rk2)Rki, N(Rk2)S02Rki or (CH2)zb RkiRk2 (where zb is 1, 2 or 3); wherein said (l-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1- 2C)alkoxy or halo; and
Rki and Rk2 are each independently selected from hydrogen or (l-4C)alkyl;
X3 is selected from N or CRm;
wherein
Rm is selected from hydrogen, halo, (l-4C)alkyl, (l-4C)alkoxy, amino, (1- 4C)alkylamino, (l-4C)dialkylamino, cyano, (2C)alkynyl, C(0)Rmi, C(0)ORmi, OC(0)Rmi, C(0)N(Rm2)Rmi, N(Rm2)C(0)Rmi, S(0)ycRmi (where yc is 0, 1 or 2), S02N(Rm2)Rmi, N(Rm2)SC>2Rmi or (CH2)zc Rmi Rm2 (where zc is 1, 2 or 3); wherein said (l-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (l-2C)alkoxy or halo; and
Rmi and Rm2 are each independently selected from hydrogen or (l-4C)alkyl;
Ro is selected from halo, (l-4C)alkyl, (l-4C)alkoxy, amino, (l-4C)alkylamino, (1- 4C)dialkylamino, cyano, (2C)alkynyl, C(0)R0i, C(0)OR0i, OC(0)R0i, C(0)N(R02)Roi, N(Ro2)C(0)Roi, S(0)ydRoi (where yd is 0, 1 or 2), S02N(R02)Roi, N(R02)S02Roi or (CH2)zd R0iRo2 (where zd is 1, 2 or 3); wherein said (l-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (l-2C)alkoxy or halo; and
Roi and R02 are each independently selected from hydrogen or (l-4C)alkyl;
R2 is selected from hydrogen, (l-4C)alkyl or a group of the formula:
Figure imgf000134_0001
wherein:
L2 is absent or (l-3C)alkylene optionally substituted by one or more substituents selected from (l-2C)alkyl or oxo;
Y2 is absent or C(O), C(0)0, C(0)N(RP), wherein Rp is selected from hydrogen or (l-4C)alkyl; and Q2 is hydrogen, (l-6C)alkyl, aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (l-4C)alkyl, halo, (l-4C)haloalkyl, (l-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, RqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen, (l-4C)alkyl or (3-6C)cycloalkyl; R3 is selected from a group of the formula:
Figure imgf000135_0001
wherein:
Y3 is C(O), C(0)N(Ry), C(0)N(Ry)0, N(Ry)(0)C, C(0)0, OC(O), N(Ry)C(0)N(Ryi), S02N(Ry), N(Ry)S02, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridinyl, pyrazolyl, pyrrolyl or tetrazolyl, wherein Ry and Ryi are independently selected from hydrogen or (l-2C)alkyl; and
Q3 is hydrogen, (l-6C)alkyl, aryl, aryl(l-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (l-4C)alkyl, halo, (1- 4C)haloalkyl, (l-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, RzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1- 4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
-L4-LQ4-Z4
wherein:
L4 is absent or (l-3C)alkylene optionally substituted by one or more substituents selected from (l-2C)alkyl or oxo;
LQ4 is absent or selected from or O, S, SO, SO2, N(Rab), C(O), C(0)0, OC(O), C(0)N(Rab), N(Rab)C(0), N(Rac)C(0)N(Rab), N(Rab)C(0)0, OC(0)N(Rab), S(0)2N(Rab), or N(Rab)S02, wherein Rab and Rac are each independently selected from hydrogen or (l-2C)alkyl; and
Z4 is hydrogen, (l-6C)alkyl, aryl, aryl(l-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (l-4C)alkyl, halo, (l-4C)haloalkyl, (1- 4C)haloalkoxy, (l-4C)alkoxy, (l-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3- 6C)cycloalkyl, NRadRae, ORad, C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad,
N(Rae)C(0)Rad, S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad or (CH2)zeNRadRae (where ze is 1, 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (l-4C)alkyl or (3-6C)cycloalkyl; or
Q3 and Ry are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (l-4C)alkyl, halo, (1- 4C)haloalkyl, (l-4C)haloalkoxy, (l-4C)alkoxy, (l-4C)alkylamino, amino, cyano or hydroxyl;
with the proviso that only one or two of Xi, X2 or X3 can be N.
[00668] Additional examples of other RET kinase inhibitors include those described in International Publication No. WO 2017145050, which is hereby incorporated by reference. For example, in some embodiments, the other RET has the Formula (VI) or is a pharmaceutically acceptable salt thereof.
Figure imgf000136_0001
(VI)
[00669] Additional examples of other RET kinase inhibitors include those described in International Publication No. WO 2016038552 is hereby incorporated by reference. For example, in some embodiments, the other RET has the Formula (VII), or the Formula (VIII), or is a pharmaceutically acceptable salt thereof.
Figure imgf000136_0002
(VII)
Figure imgf000137_0001
(VIII)
[00670] Yet other therapeutic agents include RET inhibitors such as those described, for example, in U.S. Patent Nos. 9,738,660; 9,801,880; 9,682,083; 9,789, 100; 9,550,772; 9,493,455; 9,758,508; 9,604,980; 9,321,772; 9,522,910; 9,669,028; 9,186,318; 8,933,230; 9,505,784; 8,754,209; 8,895,744; 8,629, 135; 8,815,906; 8,354,526; 8,741,849; 8,461, 161; 8,524,709; 8, 129,374; 8,686,005; 9,006,256; 8,399,442; 7,795,273; 7,863,288; 7,465,726; 8,552,002; 8,067,434; 8,198,298; 8, 106,069; 6,861,509; 8,299,057; 9, 150,517; 9,149,464; 8,299,057; and 7,863,288;; U.S. Publication Nos. 2018/0009817; 2018/0009818; 2017/0283404; 2017/0267661; 2017/0298074; 2017/0114032; 2016/0009709; 2015/0272958; 2015/0238477; 2015/0099721;
2014/0371219 2014/0137274 2013/0079343 2012/0283261 2012/0225057 2012/0065233; 2013/0053370 2012/0302567 2011/0189167 2016/0046636 2013/0012703 2011/0281841; 2011/0269739 2012/0271048 2012/0277424 2011/0053934 2011/0046370 2010/0280012; 2012/0070410 2010/0081675 2010/0075916 2011/0212053 2009/0227556 2009/0209496; 2009/0099167 2010/0209488 2009/0012045 2013/0303518 2008/0234267 2008/0199426; 2010/0069395 2009/0312321 2010/0173954 2011/0195072 2010/0004239 2007/0149523; 2017/0281632 2017/0226100 2017/0121312 2017/0096425 2017/0044106 2015/0065468; 2009/0069360 2008/0275054 2007/0117800 2008/0234284 2008/0234276 2009/0048249; 2010/0048540 2008/0319005 2009/0215761 2008/0287427 2006/0183900 2005/0222171; 2005/0209195 2008/0262021 2008/0312192 2009/0143399 2009/0130229 2007/0265274; 2004/0185547 and 2016/0176865; and International Publication Nos. WO 2017/145050; WO 2017/097697; WO 2017/049462; WO 2017/043550; WO 2017/027883; WO 2017/013160; WO 2017/009644; WO 2016/168992; WO 2016/137060; WO 2016/127074; WO 2016/075224; WO 2016/038552; WO 2015/079251; WO 2014/086284; WO 2013/042137; WO 2013/036232; WO 2013/016720; WO 2012/053606; WO 2012/047017; WO 2007/109045; WO 2009/042646; WO 2009/023978; WO 2009/017838; WO 2017/178845; WO 2017/178844; WO 2017/146116; WO 2017/026718; WO 2016/096709; WO 2007/057397; WO 2007/057399; WO 2007/054357; WO 2006/130613; WO 2006/089298; WO 2005/070431; WO 2003/020698; WO 2001/062273; WO 2001/016169; WO 1997/044356; WO 2007/087245; WO 2005/044835; WO 2014/075035; and WO 2016/038519; and J. MedChem. 2012, 55 (10), 4872-4876, all of which are hereby incorporated by reference in their entireties.
[00671] In some embodiments, a RET inhibitor (e.g., a first RET inhibitor or a second RET inhibitor) is a compound of the Formula II:
Figure imgf000138_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X1 is CH, CCH3, CF, CC1 or N;
X2 is CH, CF or N;
X3 is CH, CF or N;
X4 is CH, CF or N;
wherein zero, one or two of X1, X2, X3 and X4 is N;
A is H, CI, CN, Br, CH3, CH2CH3 or cyclopropyl;
B is hetAr1;
hetAr1 is a 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, hydroxyCl-C6 alkyl, fluoroCl-C6 alkyl, difluoroCl-C6 alkyl, trifluoroCl-C6 alkyl, cyanoCl-C6 alkyl, (C1-C6 alkoxy)Cl-C6 alkyl, (C1-C4 alkoxy)CH2C(=0)-, (C1-C4 alkoxy)C(=0)Cl-C3 alkyl, C3-C6 cycloalkyl, (RaRbN)Cl-C6 alkyl, (RaRbN)C(=0)Cl-C6 alkyl, (C1-C6 alkyl S02)C1- C6 alkyl, hetCyc3, and 4-methoxybenzyl;
Ra and Rb are independently H or C1-C6 alkyl;
hetCyc3 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O, wherein said heterocyclic ring is optionally substituted with halogen, C1-C6 alkyl, fluoroCl-C6 alkyl, difluoroCl -C6 alkyl, trifluoroCl-C6 alkyl, (C1-C6 alkoxy)Cl-C6 alkyl, di(Cl-C3 alkyl)NCH2C(=0), (C1-C6 alkoxy)C(=0) or (C1-C6 alkoxy)CH2C(=0);
D is hetCyc1, hetCyc2, hetCyc3 or hetCyc9;
hetCyc1 is a 4-6 membered heterocyclic ring having 1-2 ring atoms selected from N and O, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, fluoroCl-C3 alkyl, difluoroCl - C3 alkyl, trifluoroCl-C3 alkyl and OH, or said heterocyclic ring is substituted with a C3-C6 cycloalkylidene ring, or said heterocyclic ring is substituted with an oxo group;
hetCyc2 is a 7-8 membered bridged heterocyclic ring having 1-3 ring heteroatoms independently selected from N and O, wherein said heterocyclic ring is optionally substituted with C1-C3 alkyl;
hetCyc3 is a 7-11 membered heterospirocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein said ring is optionally substituted with C1-C3 alkyl;
hetCyc9 is a fused 9-10 membered heterocyclic ring having 1-3 ring nitrogen atoms and optionally substituted with oxo;
E is
(a) hydrogen,
(b) OH,
(c) RaRbN-, wherein Ra is H or C1-C6 alkyl and Rb is H, C1-C6 alkyl or phenyl;
(d) C1-C6 alkyl optionally substituted with one to three fluoros,
(e) hydroxyCl-C6 alkyl- optionally substituted with one to three fluoros,
(f) C1-C6 alkoxy optionally substituted with one to three fluoros,
(g) hydroxy(Cl-C6 alkoxy) optionally substituted with one to three fluoros,
(h) (C1-C6 alkoxy)hydroxy C1-C6 alkyl- optionally substituted with one to three fluoros,
(i) (C1-C6 alkyl)C(=0)- optionally substituted with one to three fluoros,
(j) (hydroxy C1-C6 alkyl)C(=0)- optionally substituted with one to three fluoros,
(k) (Cl-C6 alkoxy)C(=0)-,
(1) (C1-C6 alkoxy)(Cl-C6 alkyl)C(O)-,
(m) HC(=0)-,
(n) Cyc1, (o) Cyc^O)-,
(p) Cyc^Cl-Ce alkyl)C(=0)- wherein said alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, fluoro, C1-C3 alkoxy and RcRdN-, where Rc and Rd are independently H or C1-C6 alkyl,
(q) hetCyc4,
(r) hetCyc4C(=0)-,
(s) hetCyc4(Cl-C3 alkyl)C(=0)-,
(t) (hetCyc4)C(=0)Cl-C2 alkyl-,
(u) hetCyc4C(=0) H-,
(v) Ar2,
(w) Αι¾(=0)-,
(x) Ar2Cl-C6 alkyl-,
(y) (Ar2)hydroxy C2-C6 alkyl-,
(z) Ar2(Cl-C3 alkyl)C(=0)- wherein said alkyl portion is optionally substituted with one or two groups independently selected from the group consisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, C1-C6 alkoxy and R^R^ f- , where Re and Rf are independently H or C1-C6 alkyl, or Re and Rf together with the nitrogen to which they are attached form a 5-6 membered azacyclic ring optionally having an additional ring heteroatom selected from N and O,
(aa) hetAr2C(=0)-,
(bb) (hetAr2)hydroxyC2-C6 alkyl-,
(cc) hetAr2(Cl-C3 alkyl)C(=0)-, wherein said alkyl portion is optionally substituted with one or two groups independently selected from the group consisting of OH, C1-C6 alkyl, hydroxyCl-C6 alkyl, C1-C6 alkoxy and R'T^ -, wherein Re and Rf are independently H or C1-C6 alkyl or Re and Rf together with the nitrogen to which they are attached form a 5-6 membered azacyclic ring optionally having an additional ring heteroatom selected from N and O,
(dd) R1R2NC(=0)-,
(ee) R1R2N(C1-C3 alkyl)C(=0)-, wherein said alkyl portion is optionally substituted with phenyl,
(ff) R1R2NC(=0)C1-C2 alkyl-, (gg) R1R2NC(=0) H-,
(hh) CH3S02(C1-C6 alkyl)C(=0)-,
(ii) (Cl-C6 alkyl)S02-,
Gj) (C3-C6 cycloalkyl)CH2S02-,
(kk) hetCyc5-S02-,
(11) R4R5NS02-,
(mm) R6C(=0) H-,
(nn) hetCyc6,
(oo) hetAr2Cl-C6 alkyl-,
(pp) (hetCyc4)Cl-C6 alkyl-,
(qq) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,
(rr) (C3-C6 cycloalkoxy)Cl-C6 alkyl-,
(ss) (C3-C6 cycloalkyl)Cl-C6 alkyl-, wherein said cycloalkyl is optionally substituted with 1 -2 fluoros,
(tt) (RgR^Cl-Ce alkyl-, wherein Rg and Rh are independently H or C1-C6 alkyl, (uu) Ar2-0-,
(vv) (C1-C6 alkyl S02)C1-C6 alkyl-,
(ww) (C1-C6 alkoxy)C(=0) HCl-C6 alkyl-,
(xx) (C3-C6 cycloalkoxy)C(=0)-,
(yy) (C3-C6 cycloalkyl)S02-, wherein said cycloalkyl is optionally substituted with Cl- C6 alkyl,
(zz) Ar4CH2OC(=0)-,
(aaa) (N-(C1-C3 alkyl)pyridinonyl)Cl-C3 alkyl-, and
(bbb) (Ar4S02)Cl-C6 alkyl-;
Cyc s a C3-C6 cycloalkyl, wherein (a) said cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, halogen, C1-C6 alkoxy, CN, hydroxyCl-C6 alkyl, (C1-C6 alkoxy)Cl-C6 alkyl, and C1-C6 alkyl optionally substituted with 1-3 fluoros, or (b) said cycloalkyl is substituted with phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy and CF, or (c) said cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy and CF3;
Ar2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), fluoroCl-C6 alkyl, difluoroCl-C6 alkyl, trifluoroCl-C6 alkyl, CN, a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and R^N- wherein R1 and R> are 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 and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy (optionally substituted with 1- 3 fluoros), fluoroCl-C6 alkyl, difluoroCl-C6 alkyl, trifluoroCl-C6 alkyl, hydroxyCl-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6 alkoxy)Cl-C6 alkyl, CN, OH, and R'R'N-, wherein R and R" are independently H or C1-C3 alkyl;
hetCyc4 is (a) a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said S is optionally oxidized to SO2, (b) a 7-8 membered bridged heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, (c) a 6-12 membered fused bicyclic heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally independently substituted with 1-2 C1-C6 alkyl subsitutents, or (d) a 7-10 membered spirocyclic heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein each of said heterocyclic rings is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, (C1-C6 alkoxy)Cl-C6 alkyl, (C3- C6)cycloalkyl, (C1-C6 alkyl)C(=0)-, a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and phenyl wherein said phenyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl and C1-C6 alkoxy; hetCyc5 is a 5-6 membered heterocyclic ring having a ring heteroatom selected from O and N; hetCyc6 is a 5 membered heterocyclic ring having one or two ring heteroatoms independently selected from N and O, wherein said ring is substituted with oxo and wherein said ring is further optionally substituted with one or more substituents independently selected from the group consisting of OH and C1-C6 alkyl;
R1 is H, C1-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl; R2 is H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl (optionally substituted with 1-3 fluoros), Cyc3, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0), hetCyc7, Ar3, Ar3Cl-C3 alkyl-, hydroxyCl-C6 alkoxy or (3-6C cycloalkyl)CH20-;
Cyc3 is a 3-6 membered carbocyclic ring optionally substituted with 1-2 groups independently selected from the group consisting of C1-C6 alkoxy, OH and halogen;
hetCyc7 is a 5-6 membered heterocyclic ring having a ring heteroatom selected from O and N wherein said ring is optionally substituted with C1-C6 alkyl;
Ar3 is phenyl optionally substituted with one or more substituents independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, fluoroCl-C3 alkyl, difluoroCl-C3 alkyl and trifluoroCl-C3 alkyl;
R4 and R5 are independently H or C1-C6 alkyl;
R6 is C1-C6 alkyl, hydroxyCl-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkoxy)Cl-C6 alkyl, phenyl or hetCyc8;
hetCyc8 is a 5-6 membered heterocyclic ring having a ring heteroatom selected from O and N, wherein said heterocyclic ring is optionally substituted with C1-C6 alkyl; and
Ar4 is phenyl optionally substituted with one or more halogens.
[00672] In some embodiments, a RET inhibitor (e.g., a first RET inhibitor or a second RET inhibitor) is a compound of the Formula III:
Figure imgf000143_0001
III
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X s CH or N;
X2 is CH or N;
X3 is CH or N;
X4 is CH or N; wherein one or two of X1, X2, X3 and X4 is N;
A is CN;
B is hetAr1;
hetAr1 is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, hydroxyCl-C6 alkyl, fluoroCl-C6 alkyl, difluoroCl-C6 alkyl, trifluoroCl -C6 alkyl, cyanoCl-C6 alkyl, (C1-C6 alkoxy)Cl-C6 alkyl, (C1-C4 alkoxy)CH2C(=0)-, (C1-C4 alkoxy)C(=0)Cl-C3 alkyl, C3-C6 cycloalkyl, (RaRbN)Cl-C6 alkyl, (RaRbN)C(=0)Cl-C6 alkyl, (C1-C6 alkyl S02)C1-C6 alkyl, and 4-methoxybenzyl;
Ra and Rb are independently H or C1-C6 alkyl;
D is hetCyc1;
hetCyc1 is a 4-6 membered heterocyclic ring having 1-2 ring nitrogen atoms, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, fluoroCl-C3 alkyl, difluoroCl-C3 alkyl, trifluoroCl - C3 alkyl and OH, or said heterocyclic ring is substituted with a C3-C6 cycloalkylidene ring, or said heterocyclic ring is substituted with an oxo group;
E is
(w) Αι¾(=0)-,
(x) Ar2Cl-C6 alkyl-,
(z) Ar2(Cl-C3 alkyl)C(=0)- wherein said alkyl portion is optionally substituted with one or two groups independently selected from the group consisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, C1-C6 alkoxy and R'R^- , where Re and Rf are independently H or C1-C6 alkyl, or Re and Rf together with the nitrogen to which they are attached form a 5-6 membered azacyclic ring optionally having an additional ring heteroatom selected from N and O,
(cc) hetAr2(Cl-C3 alkyl)C(=0)-, wherein said alkyl portion is optionally substituted with one or two groups independently selected from the group consisting of OH, C1-C6 alkyl, hydroxyCl-C6 alkyl, C1-C6 alkoxy and R'T^ -, wherein Re and Rf are independently H or C1-C6 alkyl or Re and Rf together with the nitrogen to which they are attached form a 5-6 membered azacyclic ring optionally having an additional ring heteroatom selected from N and O, (dd) R1R2NC(=0)-,
(oo) hetA^Cl-Ce alkyl-,
Ar2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), fluoroCl-C6 alkyl, difluoroCl-C6 alkyl, trifluoroCl-C6 alkyl, CN, a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and RT^N- wherein R1 and R> are 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 and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy (optionally substituted with 1- 3 fluoros), fluoroCl-C6 alkyl, difluoroCl-C6 alkyl, trifluoroCl-C6 alkyl, hydroxyCl-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6 alkoxy)Cl-C6 alkyl, CN, OH, and R'R'N-, wherein R and R" are independently H or C1-C3 alkyl;
R1 is H, C1-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl; and
R2 is H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0), hydroxyCl-C6 alkoxy or (3-6C cycloalkyl)CH20.
[00673] In some embodiments, a RET inhibitor (e.g., a first RET inhibitor or a second RET inhibitor) is selected from the group consisting of: ((S)-4-(6-(4-(2-hydroxy-3- phenylpropanoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile; 6-(l -methyl- lH-pyrazol -4-yl)-4-(6-(4-(2-(pyri din-2- yl)acetyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2,6- difluorobenzoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate; 4-(5-(3-cyano-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-l-carboxamide; l-(5-(3- cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3- methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-l-yl)pyridine-3-yl)-6-(l-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l- methyl-lH-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)- 6-(l -methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof.
[00674] In some embodiments, a RET inhibitor (e.g., a first RET inhibitor or a second RET inhibitor) is a compound of the Formula IV:
Figure imgf000146_0001
IV
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X1, X2, X3 and X4 are independently CH, CF, CCH3 or N, wherein zero, one or two of X1, X2, X3 and X4 is N;
A is H, CN, CI, CH3-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH3;
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 1-3 fluoros or a C3-C6 cycloalkylidene ring,
(d) dihydroxyC3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3- C6 cycloalkylidene ring,
(e) (C 1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,
(f) ^¾2Ν)01-06 alkyl- wherein said alkyl portion is optionally substituted with OH and wherein R1 and R2 are independently H or C 1-C6 alkyl (optionally substituted with 1-3 fluoros);
(g) hetA^Cl-CS alkyl-, wherein hetAr1 is a 5-6 membered heteroaryl ring having 1 -3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents;
(h) (C3-C6 cycloalkyl)Cl-C3 alkyl-, wherein said cycloalkyl is optionally substituted with OH,
(i) (hetCyca)Cl-C3 alkyl-,
G) hetCyc3-,
(k) C3-C6 cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH, (1) (C1-C4 alkyl)C(=0)0-Cl-C6 alkyl-, wherein each of the C1-C4 alkyl and C1-C6 alkyl portions is optionally and independently substituted with 1-3 fluoros, or
(m) (R1R2N)C(=0)C1-C6 alkyl-, wherein R1 and R2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);
hetCyc3- is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=0)-, (C1-C6 alkoxy)Cl-C6 alkyl-, and fluoro, or wherein hetCyc3 is substituted with oxo;
Ring D is (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, (ii) a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein each of said rings is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group;
E is
(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(c) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,
(d) (C1-C6 alkyl)C(=0)-, wherein said alkyl portion is optionally substituted with 1-3 fluoros or with a R^ 'TST- substituent wherein Rg and Rh are independently H or C1-C6 alkyl, (e) (hydroxyC2-C6 alkyl)C(=0)- optionally substituted with 1-3 fluoros,
(f) (C1-C6 alkoxy)C(=0)-,
(g) (C3-C6 cycloalkyl)C(=0)-, wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)Cl-C6 alkyl-, or said cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O,
(h) ΑΓ^Ι-Οό alkyl-,
(i) Ar^Cl-Ce alkyl)C(=0)-, wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl-, C1-C6 alkoxy, RmRnN- or RmRnN-CH2-, wherein each Rm and Rn is independently H or C1-C6 alkyl,
(j) hetAr2Cl-C6 alkyl-, wherein said alkyl portion is optionally substituted with 1-3 fluoros,
(k) hetAr2(Cl-C6 alkyl)C(=0)- wherein said alkyl portion is optionally substituted with
OH, hydroxyCl-C6 alkyl- or C1-C6 alkoxy,
(1) hetAr2C(=0)-,
(m) hetCyc1C(=0)-,
(n) hetCy^Cl-Ce alkyl-,
(o) R3R4NC(=0)-,
(p) Ar1N(R3)C(=0)-,
(q) hetAr2N(R3)C(=0)-,
(r) (C1-C6 alkyl)S02-, wherein the alkyl portion is optionally substituted with 1-3 fluoros, (s) Ar1S02-,
Figure imgf000148_0001
(u ) N-(C1-C6 alkyl)pyridinonyl,
(v) Ar1C(=0)-;
(w) Ar10-C(=0)-,
(x) (C3-C6 cycloalkyl)(Cl-C6 alkyl)C(=0)-,
(y) (C3-C6 cycloalkyl)(Cl-C6 alkyl)S02-, wherein the alkyl portion is optionally substituted with 1-3 fluoros,
(z) Ar^Cl-C^ alkyl)S02-,
(aa) hetCyc1-0-C(=0)-, (bb) hetCyc1CH2C(=0)-,
(cc) hetAr2, or
(dd) C3-C6 cycloalkyl;
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), ReRfN- wherein Re and Rf are independently H, C1-C6 alkyl, (RpRqN)Cl-C6 alkoxy- wherein Rp and Rq are independently H or C1-C6 alkyl, and (hetAra)Cl-C6 alkyl- wherein hetAr3 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar1 is a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S or a 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), Cl- C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), R'T^ - wherein Re and Rf are independently H or C1-C6 alkyl, OH, (C1-C6 alkoxy)Cl-C6 alkoxy- and C3-C6 cycloalkyl;
hetCyc1 is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and halogen;
R3 is H or Cl-C6 alkyl; and
R4 is Cl-C6 alkyl.
[00675] In some embodiments, a RET inhibitor (e.g., a first RET inhibitor or a second RET inhibitor) is a compound of the Formula V:
Figure imgf000150_0001
V
or a pharmaceutically acceptable salt and solvate thereof, wherein:
X1, X2, X3 and X4 are independently CH or N, wherein zero, one or two of X1, X2, X3 and X4 is N;
A is CN;
B is
(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(c) hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros or a C3-C6 cycloalkylidene ring,
(e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,
(f) (Κ¾2Ν)01-06 alkyl-, wherein said alkyl portion is optionally substituted with OH and wherein R1 and R2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);
(g) hetA^Cl-CS alkyl-, wherein hetAr1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents; or
(i) (hetCyca)Cl-C3 alkyl-,
hetCyc3- is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=0)-, (C1-C6 alkoxy)Cl-C6 alkyl- and fluoro, or wherein hetCyc3 is substituted with oxo;
Ring D is (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, or (ii) a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein each of said rings is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group;
E is
(h) Ατΐΐ-ϋό alkyl-,
(j)
Figure imgf000151_0001
alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros, or
(1) hetAr2C(=0)-,
Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), R'T^ - wherein Re and Rf are independently H or C1-C6 alkyl, (RpRqN)Cl-C6 alkoxy- wherein Rp and Rq are independently H or C1-C6 alkyl, and (hetAra)Cl-C6 alkyl- wherein hetAr3 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar1 is a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O; and
hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S or a 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), Cl- C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), Κ¾¾- wherein Re and Rf are independently H or C1-C6 alkyl, OH, (C1-C6 alkoxy)Cl-C6 alkoxy- and C3-C6 cycloalkyl.
[00676] In some embodiments, a RET inhibitor which is not a compound of Formula I is selected from the group consisting of: 4-(6-(4-benzylpiperazin-l-yl)pyridin-3-yl)-6-(2- mo holinoethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6- methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2 -hydroxy -2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3. l . l]heptan-3-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)-6-((l-methyl-lH-imidazol-4-yl)methoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan- 3-yl)pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof.
[00677] In some embodiments, a RET inhibitor (e.g., a first RET inhibitor or a second RET inhibitor) is a compound of Formula VI:
Figure imgf000152_0001
VI
or a pharmaceutically acceptable salt or solvate 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, CI, methyl, ethyl or cyclopropyl;
B is:
(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with 1 -3 fluoros,
(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,
(d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3- C6 cycloalkylidene ring,
(e) (C 1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros, (f) (Κ¾2Ν)01-06 alkyl- where R1 and R2 are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-;
(g) hetA^Cl-CS alkyl-, where 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)Cl-C3 alkyl-, wherein said cycloalkyl is optionally substituted with OH,
(i) (hetCyca)Cl-C3 alkyl-,
G) hetCyc3,
(k) (R1R2N)C(=0)C1-C6 alkyl-, where R1 and R2 are independently selected from H and C1-C6 alkyl;
(1) (R1R2N)C(=0)-, where R1 and R2 are independently selected from H and C1-C6 alkyl, or
(m) hetCycaC(=0)Cl-C6 alkyl-;
hetCyc3 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-;
Ring D is (i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, (ii) a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, or (iii) a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen;
each Ra is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-;
Rb is (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1 and Rj are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (Cl- C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0) H- or (1) hetAraC(=0) H-;
hetCycb is a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycb is optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (Cl- C6 alkoxy)C(=0)-, C1-C6 alkoxy, and R'R"N- where R and R" are independently hydrogen or C1-C6 alkyl;
hetAr3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S wherein hetAr3 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), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros),
Rc is hydrogen or C1-C6 alkyl;
Rd is hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)- , hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rk and R1 are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rn are independently H or C1-C6 alkyl, PhCH2- wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (C1-C6 alkyl)S02-, ReR¾- and (R^^Cl-Ce alkyl- where each Re and Rf is independently H or C1-C6 alkyl, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCycc where hetCycc is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl;
n is 0, 1, 2, 3, 4, 5 or 6;
m is 0 or 1;
E is:
(a) hydrogen,
(b) hydroxy,
(c) C1-C6 alkyl optionally substituted with 1-3 fluoros, (d) alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros,
(e) hetAr2Cl-C6 alkyl-,
(f) (C 1 -C6 alkoxy)C 1 -C6 alkoxy-,
(g) Α^Ο-,
(h) hetAr2-0-,
(i) Ar1 Rg- where Rg is H or C1-C6 alkyl,
(j) hetAi^ RS- where Rg is H or C1-C6 alkyl,
(k) R3C(=0) Rg- where R is H or C1-C6 alkyl;
(1) Ar1C(=0) R - where R is H or C1-C6 alkyl,
(m) hetAr2C(=0) R (CH2)P- where p is 0 or 1 and R is H or C1-C6 alkyl,
(n) R4R5NC(=0)-,
(o) A^ ^C^O)-, where R is H or C1-C6 alkyl,
(p) hetAr2 RgC(=0)-, where Rg is H or C1-C6 alkyl,
(q) Ar^Cl-Ce alkyl)C(=0)- wherein said alkyl portion is optionally substituted with OH, hydroxy(Cl-C6 alkyl), C1-C6 alkoxy or NH2,
(r) hetCyc5C(=0)-,
(s) R4R5NC(=0) R - where R is H or C1-C6 alkyl, or
(t) (C1-C6 alkyl)S02-;
(u) Ar^Cl-Ce alkyl)C(=0) R - where R is H or C1-C6 alkyl,
(v) hetAr4C(=0) R - where R is H or C1-C6 alkyl,
(w) hetAr2-S(=0)-,
(x) (C3-C6 cycloalkyl)CH2S02-,
(y) Ar1(Cl-C6 alkyl)S02-,
(z) hetAr2S02-,
(aa) Ar1,
(bb) hetAr2,
(cc) hetCyc5,
(dd) C1-C6 alkoxy,
(ee) Ar^Cl-C^ alkyl)-0-,
(ff) hetAr2(Cl-C6 alkyl)-0-,
(gg)
Figure imgf000155_0001
alkyl-, (hh) Ar^Cl-Ce alkyl)NR - where R is H or C1-C6 alkyl,
(ii) hetAi^-S-,
Oj) Ar2S02NR (CH2)P- where p is 0 or 1 and Rg is H or C1-C6 alkyl,
(kk) (Cl-C6 alkoxy)C(=0)-,
(11) (C1-C6 alkyl) RgC(=0)0- where Rg is H or C1-C6 alkyl,
(mm) (C1-C6 alkyl) R S02- where R is H or C1-C6 alkyl,
(nn) hetCyc5C(=0) R - where R is H or C1-C6 alkyl,
(oo) Q- Rh(C 1 -C3 alkyl)C(=0)NR - where R and Rh are independently H or C 1 -C6 alkyl and -C6 alkyl or (C1-C6 alkyl)OC(=0)-,
(pp)
Figure imgf000156_0001
where Rg and Rh are independently H or C 1 -C6 alkyl, Q is H, C 1 -
C6 alk l or (C1-C6 alkyl)OC(=0)- and r is 1, 2, 3 or 4,
(qq)
Figure imgf000156_0002
where Rg and Rh are independently H or C1-C6 alkyl and Q is H, -C6 alkyl or (C1-C6 alkyl)OC(=0)-,
Figure imgf000156_0003
where R is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)-, or
(ss) R¾hN- where R and Rh are independently H or C1-C6 alkyl,
(tt) (C3-C6 cycloalkyl)C(=0) Rg- where the cycloalkyl is optionally and independently substituted with one or more halogens,
(uu) (C1-C6 alkyl)C(=0) R CH2- where R is H or C1-C6 alkyl, or
(vv) C1-C6 alkyl)S02 Rg- where Rg is H or C1-C6 alkyl;
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)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (C1-C6 alkyl)S02-, R^- and (R^^Cl-Ce alkyl- where each 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)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-;
hetCyc5 is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;
R3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH20-, hetCyc70-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3- C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;
R4 is H or Cl-C6 alkyl;
R5 is Ar2, hetAr3, Ar2CH2-, hetCyc6-CH2-, hydroxyCl-C6 alkyl-, (C3-C6 cycloalkyl)CH2-, or C1-C6 alkyl optionally substituted with 1-3 fluoros;
Ar2 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)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R¾hN- where Rg and Rh are independently H or C1-C6 alkyl, or Ar2 is phenyl fused to a 6 membered heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;
hetAr3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros);
hetAr4 is pyridin-4(lH)-onyl or pyridin-2(lH)-onyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;
hetCyc6 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S; and
hetCyc7 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.
[00678] In some embodiments, a RET inhibitor (e.g., a first RET inhibitor or a second RET inhibitor) is a compound of the Formula VII:
Figure imgf000158_0001
VII
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X1, X2, X3 and X4 are independently CH or N, wherein zero, one or two of X1, X2, X3 and X4 is N;
A is CN;
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, or
(i) (hetCyca)Cl-C3 alkyl-;
hetCyc3 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo, and (C1-C6 alkoxy)C(=0)-;
Ring D is 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); Rb is (a) hydroxy;
n is 0 or 1;
m is 0 or 1;
E is:
(e) hetAr2Cl-C6 alkyl-,
(h) hetAi^-O-,
(k) R3C(=0)NR - where Rg is H or C1-C6 alkyl,
(1) Ar1C(=0)NRg- where R is H or C1-C6 alkyl, or
(m) hetAr2C(=0)NRg(CH2)P- where p is 0 or 1 and Rg is H or C1-C6 alkyl;
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)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (C1-C6 alkyl)S02-, ReR¾- and (R^^Cl-Ce 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)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-; and
R3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH20-, hetCyc70-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3- C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH, or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl.
[00679] In some embodiments, a RET inhibitor which is not a compound of Formula I is selected from the group consisting of: N-(l-(5-(3-cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide; 6- ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-l- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4- ((6-methoxypyridazin-3-yl)oxy)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3- carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-l- yl)pyridin-3 -yl)pyrazolo[ 1 , 5-a]pyridine-3 -carbonitrile; N-( 1 -(5-(3 -cyano-6-((3 -fluoro- 1 - methylazetidin-3-yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)- 5-fluoro-2-methylbenzamide; 3-chloro-N-(l-(5-(3-cyano-6-((3-fluoro-l-methylazetidin-3- yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide; N- ((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4- yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 3-chloro-N- ((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin- 4-yl)picolinamide; or a pharmaceutically acceptable salt or solvate thereof.
[00680] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeted therapeutic agents, include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, l-((3 S,4R)-4-(3-fluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4- methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Go 6976, GNF-5837, GTx-186, GW 441756, LOXO- 101, MGCD516, PLX7486, VM-902A, 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 2015/1 12806; WO 2013/183578; and WO 2013/074518, all of which are hereby incorporated by reference in their entireties.
[00681] 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, all of which are incorporated by reference in their entireties herein. 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-(lH-pyrrol-2-ylmethylene)-lH-indol-6-yl]amino]-4-methylphenyl]-N'-[2- fluoro-5-(trifluoromethyl)phenyl]-urea), described in ACS Med. Chem. Lett. 3(2): 140-145, 2012, each of which is incorporated by reference in its entirety herein.
[00682] 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, all of which are incorporated by reference in their entireties herein. 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-(l-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy- lH-pyrazol-3-yl)pyrimidine-2,4-diamine), described in Mol. Cancer Ther. 8: 1818-1827, 2009; and AZD7451; each of which is incorporated by reference in its entirety.
[00683] 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, each of which is incorporated by reference in its entirety.
[00684] 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-lH-indol-3- ylidene)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide), as described in PLoS One 9:e95628, 2014; compounds described in International Publication No. WO 2011/133637; compounds described in U.S. Patent No. 8,637,256; compounds described in Expert. Opin. Ther. Pat. 24(7):731-744, 2014; compounds described in Expert Opin. Ther. Pat. 19(3):305-319, 2009; (R)- 2-phenylpyrrolidine substituted imidazopyridazines, e.g., GNF-8625, (R)-l-(6-(6-(2-(3- fluorophenyl)pyrrolidin- 1 -yl)imidazo[ 1 ,2-b]pyri
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-(9a,10p,12a))-2,3,9, 10,l l, 12-hexahydro-10-hydroxy- 10-(methoxycarbonyl)-9-methyl-9,12-epoxy-lH-diindolo[l,2,3-fg:3',2',r-kl]pyrrolo[3,4- i][l,6]benzodiazocin-l-one), as described in Mol. Cell Biochem. 339(1-2):201-213, 2010; 4- aminopyrazolylpyrimidines, e.g., AZ-23 (((S)-5-chloro-N2-(l-(5-fluoropyridin-2-yl)ethyl)-N4- (5-isopropoxy-lH-pyrazol-3-yl)pyrimidine-2,4-diamine)), as described in J. Med. Chem. 51(15):4672-4684, 2008; PHA-739358 (danusertib), as described in Mol. Cancer Ther. 6:3158, 2007; Go 6976 (5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole- 12-propanenitrile), as described in J. Neurochem. 72:919-924, 1999; GW441756 ((3Z)-3-[(l- methylindol-3-yl)methylidene]-lH-pyrrolo[3,2-b]pyridin-2-one), as described in IJAE 115: 117, 2010; milciclib (PHA-848125AC), described in J. Carcinog. 12:22, 2013; AG-879 ((2E)-3-[3,5- Bis(l, 1 -dimethyl ethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide); altiratinib (N-(4-((2- (cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4- fluorophenyl)cyclopropane-l, 1-dicarboxamide); cabozantinib (N-(4-((6,7-Dimethoxyquinolin-4- yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide); lestaurtinib ((5 S,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-l-yl)-lH-benzimidazol-2-yl]quinolin-2(lH)-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-l, 1-dicarboxamide); ONO-5390556; regorafenib (4-[4-({[4-Chloro- 3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2- carboxamide hydrate); and VSR-902A; all of the references above are incorporated by reference in their entireties herein.
[00685] 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, which is incorporated herein by reference.
[00686] 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, such as baricitinib, brigatinib, capmatinib, danusertib, ibrutinib, milciclib, quercetin, regorafenib, ruxolitinib, semaxanib, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, MS-088, MS-1286937, PF 477736 ((R)-amino-N-[5,6-dihydro-2-(l-methyl-lH- pyrazol-4-yl)-6-oxo-lHpyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106, RXDX108, and TG101209 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-l- yl)phenylamino)pyrimidin-4- ylamino)benzenesulfonamide).
[00687] Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS- 936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.
[00688] 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.
[00689] Non-limiting examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.
[00690] 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.
[00691] 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™).
[00692] 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.
[00693] 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
[00694] In some embodiments, the immunotherapy includes blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).
[00695] In some embodiments, the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).
[00696] In some embodiments, the immunotherapy is a cytokine therapy. In some embodiments, the cytokine therapy is an interleukin 2 (IL-2) therapy, an interferon alpha (IFNa) therapy, a granulocyte colony stimulating factor (G-CSF) therapy, an interleukin 12 (IL-12) therapy, an interleukin 15 (IL-15) therapy, an interleukin 7 (IL-7) therapy or an erythropoietin- alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNa therapy is IntronA® (Roferon-A®). In some embodiments, the G- CSF therapy is filgrastim (Neupogen®).
[00697] 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- Ll 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™).
[00698] 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).
[00699] In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG) therapy.
[00700] In some embodiments, the immunotherapy is an oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC; Imlygic®).
[00701] 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®, SCIB 1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac, or viagenpumatucel-L (HS-110).
[00702] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax™), IMA901, or SurVaxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic personal neoantigen vaccine (see, e.g., Ott et al. (2017) Nature 547: 217-221; Sahin et al. (2017) Nature 547: 222-226). In some embodiments, the cancer vaccine is RGSH4K, or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA-based vaccine is a mammaglobin-A DNA vaccine (see, e.g., Kim et al. (2016) Oncolmmunology 5(2): el069940).
[00703] In some embodiments, immune-targeted agents are selected from aldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.
[00704] Non-limiting examples of radiotherapy include radioiodide therapy, external-beam radiation, and radium 223 therapy..
[00705] Additional kinase inhibitors include those described in, for example, U.S. Patent
No. 7,514,446; 7,863,289; 8,026,247; 8,501,756; 8,552,002; 8,815,901; 8,912,204; 9,260,437; 9,273,051; U.S. Publication No. US 2015/0018336; International Publication No. WO 2007/002325; WO 2007/002433; WO 2008/080001; WO 2008/079906; WO 2008/079903; WO 2008/079909; WO 2008/080015; WO 2009/007748; WO 2009/012283; WO 2009/143018; WO 2009/143024; WO WO 2009/014637; 2009/152083; WO 2010/111527; WO 2012/109075; WO 2014/194127; WO 2015/112806; WO 2007/110344; WO 2009/071480; WO 2009/1 18411; WO 2010/031816; WO 2010/145998; WO 2011/092120; WO 2012/101032; WO 2012/139930; WO 2012/143248; WO 2012/152763; WO 2013/014039; WO 2013/102059; WO 2013/050448; WO 2013/050446; WO 2014/019908; WO 2014/072220; WO 2014/184069; and WO 2016/075224 all of which are hereby incorporated by reference in their entireties.
[00706] 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, each of which is hereby incorporated by reference in its entirety.
[00707] Further examples of kinase inhibitors include luminespib (AUY-922, NVP-AUY922) (5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(mo holinomethyl)phenyl)isoxazole-3- carboxamide) and doramapimod (BIRB-796) (l-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3- [4-(2-morpholin-4-ylethoxy)naphthalen-l-yl]urea).
[00708] Accordingly, also provided herein is a method of treating cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are together effective in treating the cancer.
[00709] In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same.
[00710] These additional therapeutic agents may be administered with one or more doses of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and/or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.
[00711] 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.
[00712] 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
[00713] Accordingly, also provided herein is a method of treating a cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are together effective in treating the cancer. In one embodiment, the compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In one embodiment, the compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g. in daily or intermittently dosages. In one embodiment, the compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer having one or more RET inhibitor resistance mutations.
[00714] Also provided herein is a method of treating a disease or disorder mediated by RET in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof. In some embodiments, the disease or disorder mediated by RET is a dysregulation of RET gene, a RET kinase, or expression or activity or level of any of the same. For example 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. A disease or disorder mediated by RET can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of RET, including overexpression and/or abnormal activity levels. In one embodiment, the disease is cancer (e.g., a RET-associated cancer). In one embodiment, the cancer is any of the cancers or RET-associated cancers described herein.
[00715] 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.
[00716] Accordingly, also provided herein are methods for inhibiting, preventing, aiding in the prevention, or decreasing the symptoms of metastasis of a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof. Such methods can be used in the treatment of one or more of the cancers described herein. See, e.g., US Publication No. 2013/0029925; International Publication No. WO 2014/083567; and US Patent No. 8,568,998. See also, e.g., Hezam K et al., Rev Neurosci 2018 Jan 26;29:93-98; Gao L, et al., Pancreas 2015 Jan;44: 134-143; Ding K et al., J Biol Chem 2014 Jun 6; 289: 16057-71; and Amit M et al., Oncogene 2017 Jun 8; 36:3232-3239. In some embodiments, the cancer is a RET-associated cancer. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is used in combination with an additional therapy or another therapeutic agent, including a chemotherapeutic agent, such as a kinase inhibitor. For example, a first or second RET kinase inhibitor.
[00717] 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.
[00718] Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a patient having a RET-associated cancer that include: selecting, identifying, or diagnosing a patient as having a RET-associated cancer, and administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to the patient selected, identified, or diagnosed as having a RET-associated cancer. Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a patient having a RET-associated cancer that includes administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvent thereof to a patient having a RET-associated cancer. The decrease in the risk of developing a metastasis or an additional metastasis in a patient having a RET-associated cancer can be compared to the risk of developing a metastasis or an additional metastasis in the patient prior to treatment, or as compared to a patient or a population of patients having a similar or the same RET-associated cancer that has received no treatment or a different treatment. In some embodiments, the RET-associated cancer is a RET-associated cancer having one or more RET inhibitor resistance mutations.
[00719] The phrase "risk of developing a metastasis" means the risk that a subject or patient having a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject or patient over a set period of time, where the additional tumor includes the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing a metastasis in a subject or patient having a cancer are described herein.
[00720] The phrase "risk of developing additional metastases" means the risk that a subject or patient having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors include the same or similar cancer cells as the primary tumor) will develop one or more further tumors distant from the primary tumor, where the further tumors include the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastasis are described herein.
[00721] In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a first RET inhibitor. Methods useful when a RET inhibitor resistance mutation causes the tumor to be more resistant to treatment with a first RET inhibitor are described below. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the identified subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. Also provided are methods of treating a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations that include administering to the subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00722] For example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00723] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorfenib, sorafenib, sunitinib, vandetanib, RXDX-105 (agerafenib), LOXO-292, BLU-667, BLU6864, DS-5010, GSK3179106, GSK3352589, and MS-E668. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00724] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorfenib, sorafenib, sunitinib, vandetanib, RXDX-105 (agerafenib), LOXO-292, BLU-667, BLU6864, DS-5010, GSK3179106, GSK3352589, and MS-E668. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00725] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorfenib, sorafenib, sunitinib, vandetanib, RXDX-105 (agerafenib), LOXO-292, BLU-667, BLU6864, DS- 5010, GSK3179106, GSK3352589, and MS-E668. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00726] As another example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting 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 subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorfenib, sorafenib, sunitinib, vandetanib, RXDX-105 (agerafenib), LOXO-292, BLU-667, BLU6864, DS- 5010, GSK3179106, GSK3352589, and NMS-E668, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorfenib, sorafenib, sunitinib, vandetanib, RXDX-105 (agerafenib), LOXO-292, BLU-667, BLU6864, DS- 5010, GSK3179106, GSK3352589, and NMS-E668, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorfenib, sorafenib, sunitinib, vandetanib, RXDX-105 (agerafenib), LOXO-292, BLU-667, BLU6864, DS-5010, GSK3179106, GSK3352589, and MS-E668, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00727] In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a first RET inhibitor. Methods useful when a RET inhibitor resistance mutation causes the tumor to be more resistant to treatment with a first RET inhibitor are described below. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the identified subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. Also provided are methods of treating a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations that include administering to the subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00728] For example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: ((S)-4-(6-(4-(2- hydroxy-3-phenylpropanoyl)piperazin-l-yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l-methyl-lH-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2- yl)acetyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2,6- difluorobenzoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate; 4-(5-(3-cyano-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-l-carboxamide; l-(5-(3- cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3- methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-l-yl)pyridine-3-yl)-6-(l-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l- methyl-lH-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)- 6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00729] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: ((S)-4-(6-(4-(2-hydroxy-3- phenylpropanoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile; 6-(l -methyl- lH-pyrazol -4-yl)-4-(6-(4-(2-(pyri din-2- yl)acetyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2,6- difluorobenzoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate; 4-(5-(3-cyano-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-l-carboxamide; l-(5-(3- cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3- methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-l-yl)pyridine-3-yl)-6-(l-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l- methyl-lH-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)- 6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00730] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of ((S)-4-(6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-l-yl)pyridin- 3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l-methyl-lH- pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl)acetyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(4-(2,6-difluorobenzoyl)piperazin-l-yl)pyridin-3-yl)-6-(l-methyl- lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate; 4-(5-(3-cyano-6- ( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1 ,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine- 1 - carboxamide; l-(5-(3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2- yl)-N-(2-methoxy-3-methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2- yl)acetyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1 ,5-a]pyridine-3 - carbonitrile bis(2,2,2-trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-l-yl)pyridine-3-yl)- 6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2- methoxybenzyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3 -carbonitrile; 6-(l -methyl- lH-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin- l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin-l-yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3- carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00731] As another example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: ((S)-4- (6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-l-yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l-methyl-lH-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2- yl)acetyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2,6- difluorobenzoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate; 4-(5-(3-cyano-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-l-carboxamide; l-(5-(3- cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3- methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-l-yl)pyridine-3-yl)-6-(l-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l- methyl-lH-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)- 6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: ((S)-4- (6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-l-yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l-methyl-lH-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2- yl)acetyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2,6- difluorobenzoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate; 4-(5-(3-cyano-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-l-carboxamide; l-(5-(3- cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3- methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-l-yl)pyridine-3-yl)-6-(l-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l- methyl-lH-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)- 6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: ((S)-4-(6-(4-(2-hydroxy-3- phenylpropanoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile; 6-(l -methyl- lH-pyrazol -4-yl)-4-(6-(4-(2-(pyri din-2- yl)acetyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2,6- difluorobenzoyl)piperazin- 1 -yl)pyridin-3 -yl)-6-( 1 -methyl- lH-pyrazol-4-yl)pyrazolo[ 1,5- a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate; 4-(5-(3-cyano-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-l-carboxamide; l-(5-(3- cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3- methylbutyl)piperidine-4-carboxamide; 4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate); 4-(6-(4-(2,6-difluorobenzyl)piperazin-l-yl)pyridine-3-yl)-6-(l-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(4-(2-methoxybenzyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(l- methyl-lH-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)- 6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00732] In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a first RET inhibitor. Methods useful when a RET inhibitor resistance mutation causes the tumor to be more resistant to treatment with a first RET inhibitor are described below. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the identified subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. Also provided are methods of treating a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations that include administering to the subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00733] For example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: 4-(6-(4- benzylpiperazin-l-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; (R)-6-(2- hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)-6-((l-methyl-lH midazol-4-yl)methoxy)pyrazolo[l,5-a]pyridine-3-carbonitrik and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan- 3-yl)pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00734] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: 4-(6-(4-benzylpiperazin-l- yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2- hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6- methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2 -hydroxy -2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3, 6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2- methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6- methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3- carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2- mo holinoethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3- yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-((l-methyl-lH-imidazol-4- yl)methoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00735] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of4-(6-(4-benzylpiperazin-l-yl)pyridin-3-yl)-6-(2- mo holinoethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6- methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2 -hydroxy -2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)-6-((l-methyl-lH-imidazol-4-yl)methoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan- 3-yl)pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00736] As another example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: 4-(6-(4- benzylpiperazin-l-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; (R)-6-(2- hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)-6-((l-methyl-lH-imidazol-4-yl)methoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan- 3-yl)pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: 4-(6-(4- benzylpiperazin-l-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; (R)-6-(2- hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)-6-((l-methyl-lH-imidazol-4-yl)methoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan- 3-yl)pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: 4-(6-(4-benzylpiperazin-l-yl)pyridin-3-yl)- 6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6- methoxypyridin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2 -hydroxy -2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-mo holinoethoxy)pyrazolo[l,5-a]pyridine-3- carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)-6-((l-methyl-lH-imidazol-4-yl)methoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan- 3-yl)pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00737] In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a first RET inhibitor. Methods useful when a RET inhibitor resistance mutation causes the tumor to be more resistant to treatment with a first RET inhibitor are described below. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the identified subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. Also provided are methods of treating a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations that include administering to the subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00738] For example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: N-(l-(5-(3- cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3- (pyridin-2-yloxy)azetidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2- hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin- 2-yloxy)pyrrolidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; N-(l-(5-(3-cyano-6- ((3 -fluoro- 1 -methylazetidin-3 -yl)methoxy)pyrazolo[ 1 ,5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide; 3-chloro-N-(l-(5-(3-cyano-6-((3-fluoro-l- methylazetidin-3-yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4- yl)picolinamide; N-((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-3- hydroxypiperidin-4-yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy- 4-(pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 3- chloro-N-((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyrazin-2-yl)-3- hydroxypiperidin-4-yl)picolinamide; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00739] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: N-(l-(5-(3-cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide; 6- ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-l- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4- ((6-methoxypyridazin-3-yl)oxy)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3- carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-l- yl)pyridin-3 -yl)pyrazolo[ 1 , 5-a]pyridine-3 -carbonitrile; N-( 1 -(5-(3 -cyano-6-((3 -fluoro- 1 - methylazetidin-3-yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)- 5-fluoro-2-methylbenzamide; 3-chloro-N-(l-(5-(3-cyano-6-((3-fluoro-l-methylazetidin-3- yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide; N- ((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4- yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 3-chloro-N- ((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin- 4-yl)picolinamide; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00740] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of: N-(l-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[l,5- a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4- (pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2- hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3- yl)oxy)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2- methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine- 3-carbonitrile; N-(l-(5-(3-cyano-6-((3-fluoro-l-methylazetidin-3-yl)methoxy)pyrazolo[l,5- a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide; 3-chloro-N- (l-(5-(3-cyano-6-((3-fluoro-l-methylazetidin-3-yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)picolinamide; N-((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5- a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-l-(5-(3-cyano-6- ethoxypyrazolo[l,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00741] As another example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: N-(l- (5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3- (pyridin-2-yloxy)azetidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2- hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin- 2-yloxy)pyrrolidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; N-(l-(5-(3-cyano-6- ((3 -fluoro- 1 -methylazetidin-3 -yl)methoxy)pyrazolo[ 1 ,5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide; 3-chloro-N-(l-(5-(3-cyano-6-((3-fluoro-l- methylazetidin-3-yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4- yl)picolinamide; N-((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-3- hydroxypiperidin-4-yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy- 4- (pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 3- chloro-N-((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyrazin-2-yl)-3- hydroxypiperidin-4-yl)picolinamide; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: N-(l-(5-(3-cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide; 6- ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-l- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4- ((6-methoxypyridazin-3-yl)oxy)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3- carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-l- yl)pyridin-3 -yl)pyrazolo[ 1 , 5-a]pyridine-3 -carbonitrile; N-( 1 -(5-(3 -cyano-6-((3 -fluoro- 1 - methylazetidin-3-yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-
5- fluoro-2-methylbenzamide; 3-chloro-N-(l-(5-(3-cyano-6-((3-fluoro-l-methylazetidin-3- yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide; N- ((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4- yl)-3-methylbutanamide; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 3-chloro-N- ((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin- 4-yl)picolinamide; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of: N-(l-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridin-4- yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide; 6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3- carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin- l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; (S)-6-(2-hydroxy-2-methylpropoxy)-4- (6-(3-(pyridin-2-yloxy)pyrrolidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; N-(l- (5-(3-cyano-6-((3-fluoro-l-methylazetidin-3-yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide; 3-chloro-N-(l-(5-(3-cyano-6-((3- fluoro-l-methylazetidin-3-yl)methoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4-yl)picolinamide; N-((3S,4S)-l-(5-(3-cyano-6-ethoxypyrazolo[l,5-a]pyridin-4- yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide; 6-(2-hydroxy-2- methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile; and 3-chloro-N-((3S,4S)-l-(5-(3-cyano-6- ethoxypyrazolo[l,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide; or a pharmaceutically acceptable salt or solvate thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. [00742] In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a multikinase inhibitor. Methods useful when a RET inhibitor resistance mutation causes the tumor to be more resistant to treatment with a multikinase inhibitor are described below. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the identified subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the multikinase inhibitor. Also provided are methods of treating a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations that include administering to the subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the multikinase inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the multikinase inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00743] For example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a multikinase inhibitor, wherein the multikinase inhibitor is selected from vandetanib or cabozantinib; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the multikinase inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00744] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a multikinase inhibitor, wherein the multikinase inhibitor is selected from the group consisting of: vandetanib or cabozantinib; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the multikinase inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00745] In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a multikinase inhibitor, wherein the multikinase inhibitor is selected from the group consisting of vandetanib or cabozantinib; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the multikinase inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00746] As another example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a multikinase inhibitor (e.g., vandetanib or cabozantinib), as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables 2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a multikinase inhibitor (e.g., vandetanib or cabozantinib), as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a multikinase inhibitor (e.g., vandetanib or cabozantinib) as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.
[00747] Also, provided herein are methods for treating a RET-associated cancer in a subj ect 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 subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula
1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject as a monotherapy or in conjunction with another anticancer agent (e.g., a second RET inhibitor, a second compound of another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (e.g., surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a 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 subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject as a monotherapy or in with another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (e.g., surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Tables
2 and 2a in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject as a monotherapy or in conjunction with another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (e.g., surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, a second RET inhibitor selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864 is administered in step (d). In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject as a monotherapy or in conjunction with another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (e.g., surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, a second RET inhibitor selected from the group consisting of alectinib, cabozantinib, lenvatinib, nintedanib, ponatinib, regorfenib, sorafenib, sunitinib, vandetanib, RXDX-105 (agerafenib), LOXO-292, BLU-667, BLU6864, DS-5010, GSK3179106, GSK3352589, and MS-E668 is administered in step (d).
[00748] Also provided are methods of selecting a treatment for a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting a treatment that includes administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. Also provided are methods of selecting a treatment for a subject having a cancer that include: selecting a treatment that includes administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations. Also provided are methods of selecting a subject having a cancer for a treatment that does not include a first RET inhibitor as a monotherapy that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting the identified subject for a treatment that includes a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of selecting a subject having a cancer for a treatment that does not include a first RET inhibitor as a monotherapy that include: selecting a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations for a treatment that includes administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. In some embodiments, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00749] Also provided are methods of determining the likelihood that a subject having a cancer (e.g., a RET-associated cancer) will have a positive response to treatment with a first RET inhibitor as a monotherapy that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations has a decreased likelihood of having a positive response (i.e. an increased likelihood of having a negative response) to treatment with a first RET inhibitor as a monotherapy. Also provided are methods of determining the likelihood that a subject having a cancer (e.g., a RET-associated cancer) will have a positive response to treatment with a first RET inhibitor as a monotherapy that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that a subject not having a cancer cell that has one or more RET inhibitor resistance mutations has an increased likelihood of having a positive response to treatment with a first RET inhibitor as a monotherapy as compared to a subject having a cancer cell that has one or more RET inhibitor resistance mutations. Also provided are methods of predicting the efficacy of treatment with a first RET inhibitor as a monotherapy in a subject having cancer that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that treatment with a first RET inhibitor as a monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has one or more RET inhibitor resistance mutations. Also provided are methods of predicting the efficacy of treatment with a first RET inhibitor as a monotherapy in a subject having cancer that include: determining that treatment with a first RET inhibitor as a monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has one or more RET inhibitor resistance mutations. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00750] Also provided are methods of treating a subject having a cancer that include: (a) administering one or more doses of a first RET inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (d) administering additional doses of the first RET inhibitor of step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the first RET inhibitor of step (a), the subject can also be administered another anticancer agent (e.g., a second RET inhibitor or a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of step (c), another RET inhibitor can be the first RET inhibitor administered in step (a). In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00751] Also provided are methods of treating a subject having a cancer that include: (a) administering one or more doses of a first RET inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) administering a second RET inhibitor as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (d) administering additional doses of the first RET inhibitor step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the first RET inhibitor of step (a), the subject can also be administered another anticancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anticancer agent is an immunotherapy.
[00752] Also provided are methods of treating a subject having a cancer (e.g., a RET-associated cancer) that include: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor, has one or more RET inhibitor resistance mutations; and (b) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) administering additional doses of the first RET inhibitor previously administered to the subject if the subject has cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the first RET inhibitor previously administered to the subject, the subject can also be administered another anticancer agent (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of step (b), another anticancer agent can be the first RET inhibitor administered in step (a).
[00753] Also provided are methods of treating a subject having a cancer that include: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations; and (b) administering a second RET inhibitor as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) administering additional doses of the first RET inhibitor previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the first RET inhibitor previously administered to the subject, the subject can also be administered another anticancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of (b), another anticancer agent can be the first RET inhibitor administered in step (a).
[00754] Treatment of a patient having a cancer with a multi-kinase inhibitor (MKI) or target-specific kinase inhibitor (e.g., a BRAF inhibitor, a EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROSl inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, or a RAS inhibitor) can result in dysregulation of a RET gene, a RET kinase, or the expression or activity or level of the same in the cancer, and/or resistance to a RET inhibitor. See, e.g., Bhinge et al., Oncotarget 8:27155-27165, 2017; Chang et al., Yonsei Med. J. 58:9-18, 2017; and Lopez- Delisle et al., doi: 10.1038/s41388-017-0039-5, Oncogene 2018.
[00755] Treatment of a patient having a cancer with a RET inhibitor in combination with a multi-kinase inhibitor or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, a EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROSl inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, or a RAS inhibitor) can have increased therapeutic efficacy as compared to treatment of the same patient or a similar patient with the RET inhibitor as a monotherapy, or the multi-kinase inhibitor or the target-specific kinase inhibitor as a monotherapy. See, e.g., Tang et al., doi: 10.1038/modpathol.2017.109, Mod. Pathol. 2017; Andreucci et al., Oncotarget 7:80543-80553, 2017; Nelson-Taylor et al., Mol. Cancer Ther. 16: 1623-1633, 2017; and Kato et al., Clin. Cancer Res. 23 : 1988-1997, 2017.
[00756] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) and previously administered a multi-kinase inhibitor (MKI) or a target- specific kinase inhibitor (e.g., a BRAF inhibitor, a EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROSl inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, or a RAS inhibitor) (e.g., as a monotherapy) that include: administering to the patient (i) a therapeutically effective dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy, or (ii) a therapeutically effective dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective dose of the previously administered MKI or the previously administered target-specific kinase inhibitor.
[00757] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) previously administered a MKI or a target specific kinase inhibitor (e.g., a BRAF inhibitor, a EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROS 1 inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, or a RAS inhibitor) (e.g., as a monotherapy) that include: identifying a patient having a cancer cell that has a dysregulation of a RET gene, a RET kinase, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy, or (ii) a therapeutically effective dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective dose of the previously administered MKI or the previously administered target-specific kinase inhibitor.
[00758] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: administering to a patient a therapeutically effective amount of a MKI or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, a EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROS1 inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, or a RAS inhibitor) (e.g., as a monotherapy) for a first period of time; after the period of time, identifying a patient having a cancer cell that has a dysregulation of a RET gene, a RET kinase, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy, or (ii) a therapeutically effective dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective dose of the previously administered MKI or the previously administered target-specific kinase inhibitor.
[00759] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of a BRAF gene, a BRAF kinase, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of a BRAF inhibitor (e.g., any of the BRAF inhibitors described herein or known in the art).
[00760] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of a BRAF gene, a BRAF kinase, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of a BRAF inhibitor (e.g., any of the BRAF inhibitors described herein or known in the art).
[00761] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of an EGFR inhibitor (e.g., any of the EGFR inhibitors described herein or known in the art).
[00762] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of an EGFR inhibitor (e.g., any of the EGFR inhibitors described herein or known in the art).
[00763] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of a MEK gene, a MEK protein, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of a MEK inhibitor (e.g., any of the MEK inhibitors described herein or known in the art).
[00764] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of a MEK gene, a MEK protein, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of a MEK inhibitor (e.g., any of the MEK inhibitors described herein or known in the art).
[00765] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of an ALK gene, an ALK protein, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of an ALK inhibitor (e.g., any of the ALK inhibitors described herein or known in the art).
[00766] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of an ALK gene, an ALK protein, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount an ALK inhibitor (e.g., any of the ALK inhibitors described herein or known in the art).
[00767] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of a ROS gene, a ROS protein, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of a ROS inhibitor (e.g., any of the ROS inhibitors described herein or known in the art).
[00768] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of a ROS gene, a ROS protein, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount a ROS inhibitor (e.g., any of the ROS inhibitors described herein or known in the art).
[00769] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of a MET gene, a MET protein, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of a MET inhibitor (e.g., any of the MET inhibitors described herein or known in the art).
[00770] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of a MET gene, a MET protein, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount a MET inhibitor (e.g., any of the MET inhibitors described herein or known in the art).
[00771] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of an aromatase gene, an aromatase protein, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of an aromatase inhibitor (e.g., any of the aromatase inhibitors described herein or known in the art).
[00772] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of an aromatase gene, an aromatase protein, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount an aromatase inhibitor (e.g., any of the aromatase inhibitors described herein or known in the art).
[00773] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of a RAF gene, a RAF protein, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of a RAF inhibitor (e.g., any of the RAF inhibitors described herein or known in the art).
[00774] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of a RAF gene, a RAF protein, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount a RAF inhibitor (e.g., any of the RAF inhibitors described herein or known in the art). [00775] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that has dysregulation of a RAS gene, a RAS protein, or the expression or activity or level of the same that include administering to the patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount of a RAS inhibitor (e.g., any of the RAS inhibitors described herein or known in the art).
[00776] Provided herein are methods of treating a patient having a cancer (e.g., any of the cancers described herein) that include: identifying a patient having a cancer cell that has dysregulation of a RAS gene, a RAS protein, or the expression or activity or level of the same; and administering to the identified patient (i) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and (ii) a therapeutically effective amount a RAS inhibitor (e.g., any of the RAS inhibitors described herein or known in the art).
[00777] The phrase "dysregulation of a BRAF gene, a BRAF protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a BRAF kinase domain and a fusion partner, a mutation in a BRAF gene that results in the expression of a BRAF protein that includes a deletion of at least one amino acid as compared to a wildtype BRAF protein, a mutation in a BRAF gene that results in the expression of a BRAF protein with one or more point mutations as compared to a wildtype BRAF protein, a mutation in a BRAF gene that results in the expression of a BRAF protein with at least one inserted amino acid as compared to a wildtype BRAF protein, a gene duplication that results in an increased level of BRAF protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of BRAF protein in a cell), an alternative spliced version of a BRAF mRNA that results in a BRAF protein having a deletion of at least one amino acid in the BRAF protein as compared to the wild-type BRAF protein), or increased expression (e.g., increased levels) of a wildtype BRAF protein in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a BRAF gene, a BRAF protein, or expression or activity, or level of any of the same, can be a mutation in a BRAF gene that encodes a BRAF protein that is constitutively active or has increased activity as compared to a protein encoded by a BRAF gene that does not include the mutation. For example, a dysregulation of a BRAF gene, a BRAF 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 a BRAF protein that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not BRAF). In some examples, dysregulation of a BRAF gene, a BRAF protein, or expression or activity or level of any of the same can be a result of a gene translocation of one BRAF gene with another non- BRAF gene.
[00778] Non-limiting examples of a BRAF inhibitor include dabrafenib, vemurafenib (also called RG7204 or PLX4032), sorafenib tosylate, PLX-4720, GDC-0879, BMS-908662 (Bristol- Meyers Squibb), LGX818 (Novartis), PLX3603 (Hofmann-LaRoche), RAF265 (Novartis), R05185426 (Hofmann-LaRoche), and GSK2118436 (GlaxoSmithKline). Additional examples of a BRAF inhibitor are known in the art.
[00779] The phrase "dysregulation of an EGFR gene, an EGFR protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including an EGFR kinase domain and a fusion partner, a mutation in an EGFR gene that results in the expression of an EGFR protein that includes a deletion of at least one amino acid as compared to a wildtype EGFR protein, a mutation in an EGFR gene that results in the expression of an EGFR protein with one or more point mutations as compared to a wildtype EGFR protein, a mutation in an EGFR gene that results in the expression of an EGFR protein with at least one inserted amino acid as compared to a wildtype EGFR protein, a gene duplication that results in an increased level of EGFR protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of EGFR protein in a cell), an alternative spliced version of a EGFR mRNA that results in an EGFR protein having a deletion of at least one amino acid in the EGFR protein as compared to the wild-type EGFR protein), or increased expression (e.g., increased levels) of a wildtype EGFR protein in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same, can be a mutation in an EGFR gene that encodes an EGFR protein that is constitutively active or has increased activity as compared to a protein encoded by an EGFR gene that does not include the mutation. For example, a dysregulation of an EGFR gene, an EGFR 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 a EGFR protein that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not EGFR). In some examples, dysregulation of an EGFR gene, an EGFR protein, or expression or activity or level of any of the same can be a result of a gene translocation of one EGFR gene with another non-EGFR gene.
[00780] Non-limiting examples of an EGFR inhibitor include gefitinib, erlotinib, brigatinib, lapatinib, neratinib, icotinib, afatinib, dacomitinib, poziotinib, vandetanib, afatinib, AZD9291, CO-1686, HM61713, AP26113, CI-1033, PKI-166, GW-2016, EKB-569, PDI-168393, AG-1478, CGP-59326A. Additional examples of an EGFR inhibitor are known in the art.
[00781] The phrase "dysregulation of a MEK gene, a MEK protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a MEK kinase domain and a fusion partner, a mutation in a MEK gene that results in the expression of a MEK protein that includes a deletion of at least one amino acid as compared to a wildtype MEK protein, a mutation in a MEK gene that results in the expression of a MEK protein with one or more point mutations as compared to a wildtype MEK protein, a mutation in a MEK gene that results in the expression of a MEK protein with at least one inserted amino acid as compared to a wildtype MEK protein, a gene duplication that results in an increased level of MEK protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of MEK protein in a cell), an alternative spliced version of a MEK mRNA that results in a MEK protein having a deletion of at least one amino acid in the MEK protein as compared to the wild-type MEK protein), or increased expression (e.g., increased levels) of a wildtype MEK protein in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a MEK gene, a MEK protein, or expression or activity, or level of any of the same, can be a mutation in a MEK gene that encodes a MEK protein that is constitutively active or has increased activity as compared to a protein encoded by a MEK gene that does not include the mutation. For example, a dysregulation of a MEK gene, a MEK 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 a MEK protein that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not MEK). In some examples, dysregulation of a MEK gene, a MEK protein, or expression or activity or level of any of the same can be a result of a gene translocation of one MEK gene with another non-MEK gene.
[00782] Non-limiting examples of a MEK inhibitor include mekinist, trametinib
(GSK1120212), cobimetinib (XL518), binimetinib (MEK162), selumetinib, PD-325901, CI-1040, PD035901, TAK-733, PD098059, U0126, AS703026/MSC1935369, XL-518/GDC-0973, BAY869766/RDEA119, and GSK1120212. Additional examples of a MEK inhibitor are known in the art.
[00783] The phrase "dysregulation of an ALK gene, an ALK protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including an ALK kinase domain and a fusion partner, a mutation in an ALK gene that results in the expression an ALK protein that includes a deletion of at least one amino acid as compared to a wildtype ALK protein, a mutation in an ALK gene that results in the expression of an ALK protein with one or more point mutations as compared to a wildtype ALK protein, a mutation in an ALK gene that results in the expression of an ALK protein with at least one inserted amino acid as compared to a wildtype ALK protein, a gene duplication that results in an increased level of ALK protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of ALK protein in a cell), an alternative spliced version of an ALK mRNA that results in an ALK protein having a deletion of at least one amino acid in the ALK protein as compared to the wild-type ALK protein), or increased expression (e.g., increased levels) of a wildtype ALK protein in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of an ALK gene, an ALK protein, or expression or activity, or level of any of the same, can be a mutation in an ALK gene that encodes an ALK protein that is constitutively active or has increased activity as compared to a protein encoded by an ALK gene that does not include the mutation. For example, a dysregulation of an ALK gene, an ALK 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 an ALK protein that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not ALK). In some examples, dysregulation of an ALK gene, an ALK protein, or expression or activity or level of any of the same can be a result of a gene translocation of one ALK gene with another non-ALK gene.
[00784] Non-limiting examples of an ALK inhibitor include crizotinib (Xalkori), ceritinib
(Zykadia), alectinib (Alecensa), dalantercept, ACE-041 (Brigatinib) (AP26113), entrectinib (NMS-E628), PF-06463922 (Pfizer), TSR-011 (Tesaro), CEP-37440 (Teva), CEP-37440 (Teva), X-396 (Xcovery), and ASP-3026 (Astellas). Additional examples of an ALK inhibitor are known in the art.
[00785] The phrase "dysregulation of a ROSl gene, a ROSl protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a ROSl kinase domain and a fusion partner, a mutation in a ROSl gene that results in the expression a ROSl protein that includes a deletion of at least one amino acid as compared to a wildtype ROSl protein, a mutation in a ROSl gene that results in the expression of a ROS 1 protein with one or more point mutations as compared to a wildtype ROSl protein, a mutation in a ROSl gene that results in the expression of a ROSl protein with at least one inserted amino acid as compared to a wildtype ROSl protein, a gene duplication that results in an increased level of ROSl protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of ROSl protein in a cell), an alternative spliced version of a ROSl mRNA that results in a ROSl protein having a deletion of at least one amino acid in the ROSl protein as compared to the wild-type ROSl protein), or increased expression (e.g., increased levels) of a wildtype ROSl protein in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a ROSl gene, a ROSl protein, or expression or activity, or level of any of the same, can be a mutation in a ROSl gene that encodes a ROSl protein that is constitutively active or has increased activity as compared to a protein encoded by a ROSl gene that does not include the mutation. For example, a dysregulation of a ROSl gene, a ROSl 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 a ROSl protein that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not ROSl). In some examples, dysregulation of a ROSl gene, a ROSl protein, or expression or activity or level of any of the same can be a result of a gene translocation of one ROSl gene with another non- ROS1 gene. [00786] Non-limiting examples of a ROS1 inhibitor include crizotinib, entrectinib (RXDX-
101), lorlatinib (PF-06463922), certinib, TPX-0005, DS-605, and cabozantinib. Additional examples of a ROS1 inhibitor are known in the art.
[00787] The phrase "dysregulation of a MET gene, a MET protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a MET kinase domain and a fusion partner, a mutation in a MET gene that results in the expression a MET protein that includes a deletion of at least one amino acid as compared to a wildtype MET protein, a mutation in a MET gene that results in the expression of a MET protein with one or more point mutations as compared to a wildtype MET protein, a mutation in a MET gene that results in the expression of a MET protein with at least one inserted amino acid as compared to a wildtype MET protein, a gene duplication that results in an increased level of MET protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of MET protein in a cell), an alternative spliced version of a MET mRNA that results in a MET protein having a deletion of at least one amino acid in the MET protein as compared to the wild-type MET protein), or increased expression (e.g., increased levels) of a wildtype MET protein in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a MET gene, a MET protein, or expression or activity, or level of any of the same, can be a mutation in a MET gene that encodes a MET protein that is constitutively active or has increased activity as compared to a protein encoded by a MET gene that does not include the mutation. For example, a dysregulation of a MET gene, a MET 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 a MET protein that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not MET). In some examples, dysregulation of a MET gene, a MET protein, or expression or activity or level of any of the same can be a result of a gene translocation of one MET gene with another non-MET gene.
[00788] Non-limiting examples of a MET inhibitor include crizotinib, cabozantinib, JNJ-
38877605, PF-04217903 (Pfizer), MK-2461, GSK 1363089, AMG 458 (Amgen), tivantinib, INCB28060 (Incyte), PF-02341066 (Pfizer), E7050 (Eisai), BMS-777607 (Bristol-Meyers Squibb), JNJ-38877605 (Johnson & Johnson), ARQ197 (ArQule), GSK/1363089/XL880 (GSK/Exeilixis), and XL 174 (BMS/Exelixis). Additional examples of a MET inhibitor are known in the art.
[00789] The phrase "dysregulation of a aromatase gene, an aromatase protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a mutation in an aromatase gene that results in the expression an aromatase protein that includes a deletion of at least one amino acid as compared to a wildtype aromatase protein, a mutation in an aromatase gene that results in the expression of an aromatase protein with one or more point mutations as compared to a wildtype aromatase protein, a mutation in an aromatase gene that results in the expression of an aromatase protein with at least one inserted amino acid as compared to a wildtype aromatase protein, a gene duplication that results in an increased level of aromatase protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of aromatase protein in a cell), an alternative spliced version of an aromatase mRNA that results in an aromatase protein having a deletion of at least one amino acid in the aromatase protein as compared to the wild-type aromatase protein), or increased expression (e.g., increased levels) of a wildtype aromatase in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of an aromatase gene, an aromatase protein, or expression or activity, or level of any of the same, can be a mutation in an aromatase gene that encodes an aromatase protein that is constitutively active or has increased activity as compared to a protein encoded by an aromatase gene that does not include the mutation.
[00790] Non-limiting examples of an aromatase inhibitor include Arimidex (anastrozole),
Aromasin (exemestane), Femara (letrozole), Teslac (testolactone), and formestane. Additional examples of an aromatase inhibitor are known in the art.
[00791] The phrase "dysregulation of a RAF gene, a RAF protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a RAF kinase domain and a fusion partner, a mutation in a RAF gene that results in the expression a RAF protein that includes a deletion of at least one amino acid as compared to a wildtype RAF protein, a mutation in a RAF gene that results in the expression of a RAF protein with one or more point mutations as compared to a wildtype RAF protein, a mutation in a RAF gene that results in the expression of a RAF protein with at least one inserted amino acid as compared to a wildtype RAF protein, a gene duplication that results in an increased level of RAF protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of RAF protein in a cell), an alternative spliced version of a RAF mRNA that results in a RAF protein having a deletion of at least one amino acid in the RAF protein as compared to the wild-type RAF protein), or increased expression (e.g., increased levels) of a wildtype RAF protein in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a RAF gene, a RAF protein, or expression or activity, or level of any of the same, can be a mutation in a RAF gene that encodes a RAF protein that is constitutively active or has increased activity as compared to a protein encoded by a RAF gene that does not include the mutation. For example, a dysregulation of a RAF gene, a RAF 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 a RAF protein that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not RAF). In some examples, dysregulation of a RAF gene, a RAF protein, or expression or activity or level of any of the same can be a result of a gene translocation of one RAF gene with another non-RAF gene.
[00792] Non-limiting examples of a RAF inhibitor include sorafenib, vemurafenib, dabrafenib, BMS-908662/XL281, GSK2118436, RAF265, R05126766, and R04987655. Additional examples of a RAF inhibitor are known in the art.
[00793] The phrase "dysregulation of a RAS gene, a RAS protein, or the expression or activity or level of any of the same" refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a RAS kinase domain and a fusion partner, a mutation in a RAS gene that results in the expression a RAS protein that includes a deletion of at least one amino acid as compared to a wildtype RAS protein, a mutation in a RAS gene that results in the expression of a RAS protein with one or more point mutations as compared to a wildtype RAS protein, a mutation in a RAS gene that results in the expression of a RAS protein with at least one inserted amino acid as compared to a wildtype RAS protein, a gene duplication that results in an increased level of RAS protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of RAS protein in a cell), an alternative spliced version of a RAS mRNA that results in a RAS protein having a deletion of at least one amino acid in the RAS protein as compared to the wild-type RAS protein), or increased expression (e.g., increased levels) of a wildtype RAS protein in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a RAS gene, a RAS protein, or expression or activity, or level of any of the same, can be a mutation in a RAS gene that encodes a RAS protein that is constitutively active or has increased activity as compared to a protein encoded by a RAS gene that does not include the mutation. For example, a dysregulation of a RAS gene, a RAS 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 a RAS protein that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not RAS). In some examples, dysregulation of a RAS gene, a RAS protein, or expression or activity or level of any of the same can be a result of a gene translocation of one RAS gene with another non-RAS gene.
[00794] Non-limiting examples of a RAS inhibitor include Kobe0065 and Kobe2602.
Additional examples of a RAS inhibitor are known in the art.
[00795] Non-limiting examples of multi-kinase inhibitors (MKIs) include dasatinib and sunitinib.
[00796] Also provided are methods of selecting a treatment for a subject having a cancer that include (a) administering one or more doses of a first RET inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) selecting a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has one or more RET inhibitor resistance mutations; or (d) selecting additional doses of the first RET inhibitor of step (a) for the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, when additional doses of the first RET inhibitor of step (a) are selected for the subject, the method can further include selecting doses of another anticancer agent for the subject. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of step (c), another RET inhibitor can be the first RET inhibitor administered in step (a).
[00797] Also provided are methods of selecting a treatment for a subject having a cancer that include (a) administering one or more doses of a first RET inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) selecting a second RET inhibitor as a monotherapy or in conjunction with another anticancer agent if the subject has a cancer cell that has one or more RET inhibitor resistance mutations; or (d) selecting additional doses of the first RET inhibitor of step (a) for the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, when additional doses of the first RET inhibitor of step (a) are selected for the subject, the method can further include selecting doses of another anticancer agent for the subject. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the first RET inhibitor administered in step (a).
[00798] Also provided are methods of selecting a treatment for a subject having a cancer that include (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations; (b) selecting a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) selecting additional doses of the first RET inhibitor previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, when additional doses of the first RET inhibitor previously administered to the subject are selected for the subject, the method can further include selecting doses of another anticancer agent (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or an immunotherapy) for the subject. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of step (c), another RET inhibitor can be the first RET inhibitor administered in step (a).
[00799] Also provided are methods of selecting a treatment for a subject having a cancer that include (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations; (b) selecting a second RET inhibitor as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) selecting additional doses of the first RET inhibitor previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, when additional doses of the first RET inhibitor previously administered to the subject are selected for the subject, the method can further include selecting doses of another anticancer agent (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or an immunotherapy) for the subject. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the first RET inhibitor administered in step (a).
[00800] Also provided are methods of determining a subject's risk for developing a cancer that has some resistance to a first RET inhibitor that include: determining whether a cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and identifying a subject having a cell that has one or more RET inhibitor resistance mutations, as having an increased likelihood of developing a cancer that has some resistance to the first RET inhibitor. Also provided are methods of determining a subject's risk for developing a cancer that has some resistance to a first RET inhibitor that include: identifying a subject having a cell that has one or more RET inhibitor resistance mutations, as having an increased likelihood of developing a cancer that has some resistance to the first RET inhibitor. Also provided are methods of determining the presence of a cancer that has some resistance to a first RET inhibitor that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that the subject having a cancer cell that has one or more RET inhibitor resistance mutations has a cancer that has some resistance to the first RET inhibitor. Also provided are methods of determining the presence of a cancer that has some resistance to a first RET inhibitor in a subject that include: determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations, has a cancer that has some resistance to the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
[00801] In some embodiments of any of the methods described herein, a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with a first RET inhibitor can be any of the RET inhibitor resistance mutations listed in Table 3 or 4 (e.g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E).
[00802] In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Methods useful when a RET inhibitor resistance mutation causes the tumor to be more resistant to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof are described below. For example, provided herein are methods of treating a subj ect having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the identified subject a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second RET kinase inhibitor). Also provided are methods of treating a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations that include administering to the subject a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second RET kinase inhibitor). In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
[00803] Also provided are methods of selecting a treatment for a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy for the identified subject (e.g., a second RET kinase inhibitor). Also provided are methods of selecting a treatment for a subject having a cancer that include: selecting a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second RET kinase inhibitor) for a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations. Also provided are methods of selecting a subject having a cancer for a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second RET kinase inhibitor) that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting the identified subject for a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second RET kinase inhibitor). Also provided are methods of selecting a subject having a cancer for a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second RET kinase inhibitor) that include: selecting a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations for a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
[00804] Also provided are methods of determining the likelihood that a subject having a cancer will have a positive response to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that the subject having the cancer cell that has one or more RET inhibitor resistance mutations has a decreased likelihood of having a positive response to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy. Also provided are methods of determining the likelihood that a subject having cancer will have a positive response to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy that include: determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations has a decreased likelihood of having a positive response to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy. Also provided are methods of predicting the efficacy of treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy in a subject having cancer that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has one or more RET inhibitor resistance mutations. Also provided are methods of predicting the efficacy of treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy in a subject having cancer that include: determining that treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has one or more RET inhibitor resistance mutations. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
[00805] Also provided are methods of treating a subject having a cancer that include: (a) administering one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and (c) administering a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to a subject having a cancer cell that has one or more RET inhibitor resistance mutations; or (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a) to a subject having a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a), the subject can also be administered another anticancer agent or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof administered in step (a).
[00806] Also provided are methods of treating a subject having a cancer that include: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, has one or more RET inhibitor resistance mutations; (b) administering a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to a subject having a cancer cell that has one or more RET inhibitor resistance mutations; or (c) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof previously administered to a subject having a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a), the subject can also be administered another anticancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof administered in step (a).
[00807] Also provided are methods of selecting a treatment for a subject having a cancer that include: (a) administering one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and (c) selecting a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has a RET inhibitor resistance mutation; or (d) selecting additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a) for the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where additional doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a) are selected for the subject, the method can also include further selecting another anticancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof administered in step (a).
[00808] Also provided are methods of selecting a treatment for a subject having a cancer that include: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, has one or more RET inhibitor resistance mutations; (b) selecting a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has a RET inhibitor resistance mutation; or (c) selecting additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a) are selected for the subject, the method can also include further selecting another anticancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof administered in step (a).
[00809] Also provided are methods of determining a subject's risk for developing a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof that include: determining whether a cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and identifying the subject if the subject has a cell that has one or more RET inhibitor resistance mutations as having an increased likelihood of developing a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of determining a subject's risk for developing a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof that include: identifying a subject having a cell that has one or more RET inhibitor resistance mutations as having an increased likelihood of developing a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of determining the presence of a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof that includes: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that the subject having the cancer cell that has one or more RET inhibitor resistance mutations has a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of determining the presence of a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in a subject that include: determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations has a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
[00810] In some embodiments of any of the methods described herein, a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, can be any of the RET inhibitor resistance mutations listed in Table 3 or 4.
[00811] Methods of determining the level of resistance of a cancer cell or a tumor to a RET inhibitor (e.g., any of the RET inhibitors described herein or known in the art) can be determined using methods known in the art. For example, the level of resistance of a cancer cell to a RET inhibitor can be assessed by determining the ICso of a RET inhibitor (e.g., any of the RET inhibitors described herein or known in the art) on the viability of a cancer cell. In other examples, the level of resistance of a cancer cell to a RET inhibitor can be assessed by determining the growth rate of the cancer cell in the presence of a RET inhibitor (e.g., any of the RET inhibitors described herein). In other examples, the level of resistance of a tumor to a RET inhibitor can be assessed by determining the mass or size of one or more tumors in a subject over time during treatment with a RET inhibitor (e.g., any of the RET inhibitors described herein). In other examples, the level of resistance of a cancer cell or a tumor to a RET inhibitor can be indirectly assessed by determining the activity of a RET kinase including one or more of the RET inhibitor resistance mutations (i.e., the same RET kinase expressed in a cancer cell or a tumor in a subject). The level of resistance of a cancer cell or tumor having one or more RET inhibitor resistance mutations to a RET inhibitor is relative to the level of resistance in a cancer cell or tumor that does not have a RET inhibitor resistance mutation (e.g., a cancer cell or tumor that does not have the same RET inhibitor resistance mutations, a cancer cell or a tumor that does not have any RET inhibitor resistance mutations, or a cancer cell or a tumor that expresses a wildtype RET protein). For example, the determined level of resistance of a cancer cell or a tumor having one or more RET inhibitor resistance mutations can be greater than about 1%, greater than about 2%, greater than about 3% , greater than about 4%, greater than about 5%, greater than about 6%, greater than about 7%, greater than about 8%, greater than about 9%, greater than about 10%, greater than about 11%, greater than about 12%, greater than about 13%, greater than about 14%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%), greater than about 150%, greater than about 160%, greater than about 170%, greater than about 180%), greater than about 190%, greater than about 200%, greater than about 210%, greater than about 220%, greater than about 230%, greater than about 240%, greater than about 250%, greater than about 260%, greater than about 270%, greater than about 280%, greater than about 290%), or greater than about 300% of the level of resistance in a cancer cell or tumor that does not have a RET inhibitor resistance mutation (e.g., a cancer cell or tumor that does not have the same RET inhibitor resistance mutations, a cancer cell or a tumor that does not have any RET inhibitor resistance mutations, or a cancer cell or a tumor that expresses a wildtype RET protein).
[00812] RET is thought to play an important role in the development and survival of afferent nociceptors in the skin and gut. RET kinase knock-out mice lack enteric neurons and have other nervous system anomalies suggesting that a functional RET kinase protein product is necessary during development (Taraviras, S. et al., Development, 1999, 126:2785-2797). Moreover population studies of patients with Hirschsprung's disease characterized by colonic obstruction due to lack of normal colonic enervation have a higher proportion of both familial and sporadic loss of function RET mutations (Butler Tjaden N., et al., Transl. Res., 2013, 162: 1-15). Irritable bowel syndrome (IBS) is a common illness affecting 10-20%) of individuals in developed countries and is characterized by abnormal bowel habits, bloating and visceral hypersensitivity (Camilleri, M., N. Engl. J. Med, 2012, 367: 1626-1635). While the etiology of IBS is unknown it is thought to result from either a disorder between the brain and gastrointestinal tract, a disturbance in the gut microbiome or increased inflammation. The resulting gastrointestinal changes affect normal bowel transit resulting in either diarrhea or constipation. Furthermore in many IBS patients the sensitization of the peripheral nervous system results in visceral hypersensitivity or allodynia (Keszthelyi, D., Eur. J. Pain, 2012, 16: 1444-1454). See, e.g., U.S. Publication No. 2015/0099762.
[00813] Accordingly, provided herein are methods for treating a patient diagnosed with (or identified as having) an irritable bowel syndrome (IBS) including diarrhea-predominant, constipation- predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, and inflammatory bowel disease that include administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
[00814] Also provided herein are methods for treating a patient identified or diagnosed as having a RET-associated irritable bowel syndrome (IBS) (e.g., a patient that has been identified or diagnosed as having a RET-associated irritable bowel syndrome (IBS) through the use of a regulatory agency-approved, 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 patient) that include administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
[00815] Also provided herein are methods for treating pain associated with IBS that include administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with another therapeutic agent useful for treating one or more symptoms of IBS.
[00816] Also provided are methods for treating an irritable bowel syndrome (IBS) in a patient in need thereof, the method comprising: (a) determining if the irritable bowel syndrome (IBS) in the patient is a RET-associated IBS (e.g., using a regulatory-agency approved, e.g., 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 patient, or by performing any of the non-limiting examples of assays described herein); and (b) if the IBS is determined to be a RET-associated IBS, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
[00817] In some embodiments, the compounds of the present invention are useful for treating irritable bowel syndrome (IBS) in combination with one or more additional therapeutic agents or therapies effective in treating the irritable bowel syndrome that work by the same or a different mechanism of action. The at least one additional therapeutic agent may be administered with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.
[00818] Non-limiting examples of additional therapeutics for the treatment of irritable bowel syndrome (IBS) include probiotics, fiber supplements (e.g., psyllium, methylcellulose), anti-diarrheal medications (e.g., loperamide), bile acid binders (e.g., cholestyramine, colestipol, colesevelam), anticholinergic and antispasmodic medications (e.g., hyoscyamine, dicyclomine), antidepressant medications (e.g., tricyclic antidepressant such as imipramine or notriptyline or a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine), antibiotics (e.g., rifaximin), alosetron, and lubiprostone.
[00819] Accordingly, also provided herein are methods of treating irritable bowel syndrome
(IBS), comprising administering to a patient in need thereof a pharmaceutical combination for treating IBS which comprises (a) a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of IBS, wherein the amounts of the compound of Formula I or pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are together effective in treating the IBS. In one embodiment, the compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In one embodiment, the compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g. in daily or intermittently dosages. In one embodiment, compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.
[00820] Also provided herein is (i) a pharmaceutical combination for treating irritable bowel syndrome in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein for treating irritable bowel syndrome or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of irritable bowel syndrome, wherein the amounts of the compound of Formula I or pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the irritable bowel syndrome; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of irritable bowel syndrome; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of irritable bowel syndrome in a patient in need thereof. In one embodiment the patient is a human.
[00821] The term "pharmaceutical combination", as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent (e.g., an agent effective in treating irritable bowel syndrome), are both administered to a patient simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent (e.g., an agent effective in treating irritable bowel syndrome) are formulated as separate compositions or dosages, such that they may be administered to a patient in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient. In one embodiment, the compound of Formula I and the additional therapeutic agent are formulated as separate unit dosage forms, wherein the separate dosages forms are suitable for either sequential or simultaneous administration. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.
[00822] In some embodiments, a compound provided herein can be used as an agent for supportive care for a patient undergoing cancer treatment. For example, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, can be useful to reduce one or more symptoms associated with treatment with one or more cancer therapies such as diarrheal or constipations complications and/or abdominal pain. See, for example, U.S. Publication No. 2015/0099762 and Hoffman, J.M. et al. Gastroenterology (2012) 142:844-854. Accordingly, a compound, or a pharmaceutically acceptable salt thereof, or composition provided herein can be administered to a patient to address one or more complications associated with cancer treatment (e.g., gastrointestinal complications such as diarrhea, constipation, or abdominal pain).
[00823] In some embodiments, a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, can be administered to a patient undergoing cancer treatment (e.g., a patient experiencing an adverse event associated with cancer treatment such as an immune-related adverse event or a gastrointestinal complication including diarrhea, constipation, and abdominal pain). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used in the treatment of colitis or IBS associated with administration of a checkpoint inhibitor; see, e.g., Postow, M.A. et al. Journal of Clinical Oncology (2015) 33 : 1974-1982. In some such embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be formulated to exhibit low bioavailability and/or be targeted for delivery in the gastrointestinal tract. See, for example, US Patent No. 6,531,152.
[00824] Also provided is a method for inhibiting RET kinase activity in a cell, comprising contacting the cell with a compound of Formula I. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to a subject having a cell having RET kinase activity. In some embodiments, the cell is a cancer cell. In one embodiment, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a RET-associated cancer cell. In some embodiments, the cell is a gastrointestinal cell.
[00825] Also provided is a method for inhibiting RET kinase activity in a mammalian cell, comprising contacting the cell with a compound of Formula I. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to a mammal having a cell having RET kinase activity. In some embodiments, the mammalian cell is a mammalian cancer cell. In one embodiment, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a RET-associated cancer cell. In some embodiments, the mammalian cell is a gastrointestinal cell.
[00826] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a RET kinase with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having a RET kinase, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the RET kinase.
[00827] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
[00828] 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 factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
[00829] 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, thickeners and the like may be necessary or desirable.
[00830] Also provided herein are pharmaceutical compositions which contain, as the active ingredient, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.
[00831] 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.
[00832] 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. [00833] 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.
[00834] 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.
[00835] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
[00836] 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.
[00837] Provided herein are pharmaceutical kits useful, for example, in the treatment of RET-associated diseases or disorders, such as cancer or irritable bowel syndrome (IBS), which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
[00838] 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.
[00839] 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.
OTHER EMBODIMENTS
[00840] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

What is claimed is:
1. A compound of the Formula I:
Figure imgf000234_0001
and pharmaceutically acceptable salts and solvates thereof, wherein:
A is:
(a) Ar1,
(b) Ατΐΐ-ϋό alkyl-,
(c) Ar^Cl-CS alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
(d) Ar1C(=0)-,
(e) Ar1N(Ra)C(=0)-,
(f) hetAr2,
(g) hetAr2Cl-C6 alkyl-,
(h) hetAr2(Cl-C3 alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
(i) hetAr2C(=0)-,
0) hetAr2N(Ra)C(=0)-,
(k) hetCyc1,
(1) hetCy^C l -Ce alkyl-,
(m) hetCyc^Cl-CS alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
(n) hetCyc1C(=0)-, and
(o) hetCyc1N(Ra)C(=0)-,
Ra is H or Cl-C6 alkyl,
Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RkRTNT-, wherein Rb and Rc are 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, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl-, hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbR°N-, wherein Rb and Rc are independently H or C1-C6 alkyl,
hetCyc1 is a 4-6 membered saturated heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl;
B is:
(a) Ar3,
(b) Ar3Cl-C6 alkyl-,
(c) Ar3(Cl-C3 alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
(d) Ar3C(=0)-,
(e) Ar3N(Ra)C(=0)-,
(f) hetAr4,
(g) hetAr4Cl-C6 alkyl-,
(h) hetAr4(Cl-C3 alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
(i) hetAr4C(=0)-,
0) hetAr4N(Ra)C(=0)-,
(k) hetCyc2,
(1) hetCyc2Cl-C6 alkyl-, (m) hetCyc2(Cl-C3 alkyl)C(=0)-, wherein the alkyl portion is optionally substituted with halogen, OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy,
(n) hetCyc2C(=0)-, and
(o) hetCyc2N(Ra)C(=0)-,
Ra is H or Cl-C6 alkyl,
Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl,
hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl-, hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^t^N-, wherein Rb and Rc are independently H or C1-C6 alkyl,
hetCyc2 is a 4-6 membered saturated heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl;
X1, X2, X3 and X4 are independently CH, CF or N, wherein 0, 1 or 2 of X1, X2, X3 and X4 is N;
Y is a bond, -NRd-, -NRd(Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), or -(Cl- C6 alkyl)NRd- (optionally substituted with 1-3 fluoros), wherein Rd is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
R1 and R2 at each occurrence are independently selected from the group consisting of halogen, OH, C1-C6 alkyl- (optionally substituted with 1-3 fluoros), hydroxyC2-C6 alkyl- (wherein the alkyl portion is optionally substituted with 1-3 fluoros), dihydroxyC3-C6 alkyl-, (Cl- C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), (R^^Cl-Ce alkyl-, wherein Re and Rf are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros), and (C3- C6 cycloalkyl)Cl-C3 alkyl-;
n is 0, 1 or 2; and
m is 0, 1 or 2.
2. A compound according to claim 1, wherein:
A is:
(a) Ar1,
(b) ΑΓ^1 6 alkyl-,
(f) hetAr2, and
(g) hetAr2Cl-C6 alkyl-,
Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), and oxo, and
hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), and oxo;
B is:
(a) Ar3,
(b) Ar3Cl-C6 alkyl-,
(f) hetAr4, and
(g) hetAr4Cl-C6 alkyl-,
Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and
hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C3-C6 cycloalkyl;
X1, X2, X3 and X4 are independently CH, CF or N, wherein 0, 1 or 2 of X1, X2, X3 and X4 is N;
Y is - Rd- or - Rd(Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), wherein Rd is H or C1-C3 alkyl (optionally substituted with 1-3 fluoros);
R1 and R2 at each occurrence are independently selected from the group consisting of H, halogen, and C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
n is 1 or 2; and
m is 1 or 2.
3. A compound according to claim 1 or claim 2, wherein A is Ar1.
4. A compound according to claim 3, wherein Ar1 is phenyl optionally substituted with CN.
5. A compound according to claim 1 or claim 2, wherein A is hetAr2.
6. A compound according to claim 5, wherein hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, CN, C1-C6 alkyl, hydroxyCl-C6 alkyl, and oxo.
7. A compound according to claim 5, wherein hetAr2 is a 5 membered heteroaryl ring having 2 heteroatoms independently selected from N, O, and S.
8. A compound according to claim 5, wherein hetAr2 is a 5 membered heteroaryl ring having 3 heteroatoms independently selected from N, O, and S.
9. A compound according to claim 5, wherein hetAr2 is a 6 membered heteroaryl ring having 1 heteroatom that is N.
10. A compound according to claim 5, wherein hetAr2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr2 is substituted with CN.
11. A compound according to claim 5, wherein hetAr2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr2 is substituted with oxo.
12. A compound according to claim 5, wherein hetAr2 is a 6 membered heteroaryl ring having 1 heteroatom that is N, wherein hetAr2 is substituted with C1-C6 alkyl and oxo.
13. A compound according to claim 5, wherein hetAr2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr2 is substituted with CI -C3 alkyl.
14. A compound according to claim 5, wherein hetAr2 is 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, wherein hetAr2 is substituted with hydroxy CI -C3 alkyl.
15. A com ound according to claim 1 or 2, wherein hetAr2 is:
Figure imgf000239_0001
Figure imgf000240_0001
16. A compound according to any one of claims 1-15, wherein B is Ar.
17. A compound according to claim 16, wherein Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, Cl- C6 alkyl, and Cl-C6 alkoxy.
18. A compound according to claim 17, wherein Ar3 is substituted with H.
19. A compound according to claim 17, wherein Ar3 is substituted with halogen.
20 A compound according to claim 19, wherein Ar3 is substituted with F.
21. A compound according to claim 17, wherein Ar3 is substituted with C1-C6 alkyl.
22. A compound according to claim 17, wherein Ar3 is substituted with C1-C6 alkoxy.
23. A compound according to claim 22, wherein Ar3 is substituted with methoxy.
24. A compound according to claim 17, wherein Ar3 is substituted with methyl and F.
25. A compound according to any one of claims 1-15, wherein B is hetAr4.
26. A compound according to claim 25, wherein hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr4 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
27. A compound according to claim 25, wherein hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N.
28. A compound according to claim 25, wherein hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with halogen.
29. A compound according to claim 25, wherein hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with F.
30. A compound according to claim 25, wherein hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with C1-C3 alkyl.
31. A compound according to claim 25, wherein hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with 1-2 methyls.
32. A compound according to claim 25, wherein hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with C3-C6 cycloalkyl.
33. A compound according to claim 25, wherein hetAr4 is a 5 membered heteroaryl ring having 2 ring heteroatoms that are both N, wherein hetAr4 is substituted with cyclopropyl.
34. A compound according to claim 25, wherein hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N.
35. A compound according to claim 25, wherein hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr4 is substituted with C1-C6 alkoxy.
36. A compound according to claim 25, wherein hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr4 is substituted with C1-C6 alkyl.
37. A compound according to claim 25, wherein hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr4 is substituted with halogen.
38. A compound according to claim 25, wherein hetAr4 is a 6 membered heteroaryl having 1 ring heteroatom that is N, wherein hetAr4 is substituted with methyl and F.
39. A compound according to any one of claims 1-25, wherein hetAr4 is:
Figure imgf000242_0001
40. A compound according to any one of the previous claims, wherein X1, X2, X3 and X4 are independently CH or N.
41. A compound according to any one of the previous claims, wherein each of X1, X2, X3 and X4 is CH.
42. A compound according to any one of claims 1-40, wherein one of X1, X2, X3 and X4 is N and the remainder are CH.
43. A compound according to claim 42, wherein X3 is N, and X1, X2 and X4 are CH.
44. A compound according to any one of claims 1-40, wherein two of X1, X2, X3 and X4 are N.
45. A compound according to claim 44, wherein X1 and X3 are N and X2 and X4 are
CH.
46. A compound according to any one of the previous claims, wherein Y is - Rd(Cl- C6 alkyl)-.
47. A compound according to any one of the previous claims, wherein Rd is H or Cl- C3 alkyl.
48. A compound according to claim 47, wherein C1-C3 alkyl is selected from the group consisting of methyl, ethyl, propyl, and isopropyl.
49. A compound according to any one of the previous claims, wherein R1 at each occurrence is independently C1-C6 alkyl.
50. A compound according to any one of the previous claims, wherein R1 is C1-C3 alkyl.
51. A compound according to claim 50, wherein R1 is methyl.
52. A compound according to any one of the previous claims, wherein R2 at each occurrence is independently selected from the group consisting of H, halogen, and C1-C6 alkyl.
53. A compound according to any one of the previous claims, wherein R2 is H.
54. A compound according to any one of claims 1-52, wherein R2 is halogen.
55. A compound according to any one of claims 1-52, R2 is F.
56. A compound according to any one of claims 1-52, R2 is C1-C6 alkyl.
57. A compound according to claim 56, wherein R2 is methyl.
58. A compound according to any one of the previous claims, wherein the compound of Formula I is a compound of Formula la
Figure imgf000244_0001
and pharmaceutically acceptable salts and solvates thereof, wherein:
B is Ar3 or hetAr4,
Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^'TST-, wherein Rb and Rc are independently H or C1-C6 alkyl,
hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^t^N-, wherein Rb and Rc are independently H or C1-C6 alkyl;
X1, X2, and X4 are each CH and X3 is N, or X2 and X4 are each CH and X1 and X3 are each N;
Y is - Rd(Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), wherein Rd is H or Cl- C3 alkyl (optionally substituted with 1-3 fluoros);
Z1, Z2 and Z3 are each independently selected from CH, N, NH, O or S;
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros); and
m is 1.
59. A compound according to claim 58, wherein B is Ar3.
60. A compound according to claim 58, wherein B is hetAr4, substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3-C6 cycloalkyl, and C1-C3 alkyl.
61. A compound according to any one of claims 58-60, wherein X1, X2, and X4 are each CH and X3 is N.
62. A compound according to any one of claims 58-60, wherein X2 and X4 are each CH and X1 and X3 are each N.
63. A compound according to any one of claims 58-62, wherein Y is -NRd(Cl-C6 alkyl)-, wherein Rd is methyl.
64. A compound according to any one of claims 58-62, wherein Y is -NRd(Cl-C6 alkyl)-, wherein Rd is H.
65. A compound according to claim 64, wherein Y is -NHCH2-
66. A compound according to claim 64, wherein Y is - HCH(CH3)-.
67. A compound according to any one of claims 58-66, wherein R1 is C1-C3 alkyl.
68. A compound according to any one of claims 58-66, wherein R1 is methyl.
69. A compound according to any one of claims 58-68, wherein R2 is halogen.
70. A compound according to any one of claims 58-69, wherein R2 is F.
71. A compound according to any one of claims 58-68, wherein R2 is C1-C3 alkyl.
72. A compound according to claim 71, wherein R2 is methyl.
73. A compound according to any one of claims 58-72, wherein R3 is CN.
74. A compound according to any one of claims 58-72, wherein R3 is hydroxyCl-C6 alkyl.
75. A compound according to any one of claims 58-72, wherein R3 is C1-C3 alkyl.
76. A compound according to claim 75, wherein R3 is methyl.
77. A compound according to claim 75, wherein R3 is ethyl.
78. A compound according to any one of claims 58-77, wherein Z1 is N or NH.
79. A compound according to any one of claims 58-77, wherein Z1 is CH.
80. A compound according to any one of claims 58-79, wherein Z2 is N or NH.
81. A compound according to any one of claims 58-79, wherein Z2 is O.
82. A compound according to any one of claims 58-79, wherein Z2 is S.
83. A compound according to any one of claims 58-82, wherein Z3 is CH.
84. A compound according to any one of claims 58-82, wherein Z3 is N or NH.
85. A compound according to any one of claims 58-77, wherein Z1 is NH, Z2 is N, and Z3 is CH.
86. A compound according to any one of claims 58-77, wherein Z1 is N, Z2 is O, and Z3 is CH.
87. A compound according to any one of claims 58-77, wherein Z1 is N, Z2 is O, and
Z3 is N.
88. A compound according to any one of claims 58-77, wherein Z1 is N, Z2 is S, and Z3 is CH.
89. A compound according to any one of claims 58-77, wherein Z1 is N, Z2 is S, and
Z3 is N.
90. A compound according to any one of claims 58-77, wherein Z1 is CH, Z2 is NH, and Z3 is N.
91. A compound according to any one of claims 58-77, wherein Z1 is N, Z2 is NH, and Z3 is CH.
92. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is CN, Z1 is NH, Z2 is N, and Z3 is CH.
93. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is CN, Z s N, Z2 is O, and Z3 is CH.
94. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is CN, Z s N, Z2 is O, and Z3 is N.
95. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is CN, Z s N, Z2 is S, and Z3 is CH.
96. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is CN, Z s N, Z2 is S, and Z3 is N.
97. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is CN, Z1 is CH, Z2 is NH, and Z3 is N.
98. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is CN, Z1 is N, Z2 is NH, and Z3 is CH.
99. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is hydroxyCl-C6 alkyl, Z1 is N, Z2 is NH, and Z3 is CH.
100. A compound according to any one of claims 58-66, wherein R1 is methyl, R3 is Cl- C3 alkyl, Z1 is N, Z2 is NH, and Z3 is CH.
101. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula lb
Figure imgf000249_0001
lb
and pharmaceutically acceptable salts and solvates thereof, wherein:
B is selected from Ar3 or hetAr4,
Ar2 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are independently H or C1-C6 alkyl,
hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^t^N-, wherein Rb and Rc are independently H or C1-C6 alkyl;
X1, X2, and X4 are each CH and X3 is N, or X2 and X4 are each CH and X1 and X3 are each
N;
Y is -NRd(Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), wherein Rd is H or Cl- C3 alkyl (optionally substituted with 1-3 fluoros);
Z4 is CH or N;
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R4 is CN; and
m is 1.
102. A compound according to claim 101, wherein B is Ar3.
103. A compound according to claim 101, wherein B is hetAr4, substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3-C6 cycloalkyl, and C1-C3 alkyl.
104. A compound according to any one of claims 101-103, wherein X1, X2, and X4 are each CH and X3 is N.
105. A compound according to any one of claims 101-103, wherein X2 and X4 are each CH and X1 and X3 are each N.
106. A compound according to any one of claims 101-105, wherein Y is - Rd(Cl-C6 alkyl)-, wherein Rd is methyl.
107. A compound according to any one of claims 101-105, wherein Y is - Rd(Cl-C6 alkyl)-, wherein Rd is H.
108. A compound according to claim 107, wherein Y is - HCH2-.
109. A compound according to claim 107, wherein Y is - HCH(CH3)-.
110. A compound according to any one of claims 101-109, wherein R1 is C1-C3 alkyl-.
111. A compound according to claim 110, wherein R1 is methyl.
112. A compound according to any one of claims 101-111, wherein R2 is halogen.
113. A compound according to claim 112, wherein R2 is F.
114. A compound according to any one of claims 101-111, wherein R2 is C1-C3 alkyl.
115. A compound according to claim 114, wherein R2 is methyl.
116. A compound according to any one of claims 101-115, wherein R4 is CN.
117. A compound according to any one of claims 101-116, wherein Z4 is CH.
118. A compound according to any one of claims 101-116, wherein Z4 is N.
119. A compound according to any one of claims 101-109, wherein R1 is methyl, R4 is CN, and Z4 is CH.
120. A compound according to any one of claims 101-109, wherein R1 is methyl, R4 is CN, and Z4 is N.
121. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula Ic
Figure imgf000251_0001
Ic
and pharmaceutically acceptable salts and solvates thereof, wherein:
B is selected from Ar3 or hetAr4,
Ar3 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^'TST-, wherein Rb and Rc are independently H or C1-C6 alkyl, hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbR°N-, wherein Rb and Rc are independently H or C1-C6 alkyl;
X1, X2, and X4 are each CH and X3 is N, or X2 and X4 are each CH and X1 and X3 are each
N;
Y is -NRd(Cl-C6 alkyl)- (optionally substituted with 1-3 fluoros), wherein Rd is H or Cl- C3 alkyl (optionally substituted with 1-3 fluoros);
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R5 is H or Cl-C6 alkyl-; and
m is 1.
122. A compound according to claim 121, wherein B is Ar3.
123. A compound according to claim 121, wherein B is hetAr4, substituted with one or more substituents independently selected from the group consisting of halogen, alkoxyCl-C3 alkyl, C3-C6 cycloalkyl, and C1-C3 alkyl.
124. A compound according to any one of claims 121-123, wherein X1, X2, and X4 are each CH and X3 is N.
125. A compound according to any one of claims 121-123, wherein X2 and X4 are each CH and X1 and X3 are each N.
126. A compound according to any one of claims 121-125, wherein Y is -NRd(Cl-C6 alkyl)-, wherein Rd is methyl.
127. A compound according to any one of claims 121-125, wherein Y is - Rd(Cl-C6 alkyl)-, wherein Rd is H.
128. A compound according to claims 127, wherein Y is - HCH2-.
129. A compound according to claim 127, wherein Y is - HCH(CH3)-.
130. A compound according to any one of claims 121-129, wherein R1 is C1-C3 alkyl-.
131. A compound according to claim 130, wherein R1 is methyl.
132. A compound according to any one of claims 121-131, wherein R2 is halogen.
133. A compound according to claim 132, wherein R2 is F.
134. A compound according to any one of claims 121-131, wherein R2 is C1-C3 alkyl.
135. A compound according to claim 134, wherein R2 is methyl.
136. A compound according to any one of claims 121-135, wherein R5 is H.
137. A compound according to any one of claims 121-135, wherein R5 is C1-C6 alkyl-.
138. A compound according to claim 137, wherein R5 is methyl.
139. A compound according to any one of claims 121-138, wherein R1 is methyl and R5 is H.
140. A compound according to any one of claims 121-138, wherein R1 is methyl and R5 is methyl.
141. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula Id
Figure imgf000254_0001
and pharmaceutically acceptable salts and solvates thereof, wherein:
A is selected from Ar1 or hetAr2,
Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are 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, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^t^N-, wherein Rb and Rc are independently H or C1-C6 alkyl;
X2 is CH or N;
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R6 is H or Cl-C6 alkyl;
R7, R8, and R9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl; and
n is 1.
142. A compound according to claim 141, wherein A is Ar1.
143. A compound according to claim 142, wherein Ar1 is substituted with CN.
144. A compound according to claim 141, wherein A is hetAr2.
145. A compound according to claim 144, wherein hetAr2 is substituted with one or more substituents independently selected from the group consisting of CN, oxo, hydroxyC l-C3 alkyl, and C1-C3 alkyl.
146. A compound according to any one of claims 141-145, wherein X2 is CH.
147. A compound according to any one of claims 141-145, wherein X2 is N.
148. A compound according to any one of claims 141-147, wherein R1 is methyl.
149. A compound according to any one of claims 141-148, wherein R2 is H.
150. A compound according to any one of claims 141-148, wherein R2 is halogen.
151. A compound according to claim 150, wherein R2 is F.
152. A compound according to any one of claims 141-148, wherein R2 is C1-C6 alkyl.
153. A compound according to claim 152, wherein R2 is C1-C3 alkyl.
154. A compound according to claim 153, wherein R2 is methyl.
155. A compound according to any one of claims 141-154, wherein R6 is H.
156. A compound according to any one of claims 141-154, wherein R6 is C1-C6 alkyl.
157. A compound according to claim 156, wherein R6 is C1-C3 alkyl.
158. A compound according to claim 157, wherein R6 is methyl.
159. A compound according to any one of claims 141-158, wherein R7 is H.
160. A compound according to any one of claims 141-158, wherein R7 is C1-C6 alkyl.
161. A compound according to claim 160, wherein R7 is C1-C3 alkyl.
162. A compound according to claim 160, wherein R7 is methyl.
163. A compound according to any one of claims 141-162, wherein R8 is H.
164. A compound according to any one of claims 141-162, wherein R8 is halogen.
165. A compound according to claim 164, wherein R8 is F.
166. A compound according to any one of claims 141-162, wherein R8 is C1-C6 alkyl.
167. A compound according to claim 166, wherein R8 is C1-C3 alkyl.
168. A compound according to claim 167, wherein R8 is methyl.
169. A compound according to any one of claims 141-168, wherein R9 is H.
170. A compound according to any one of claims 141-168, wherein R9 is C1-C6 alkyl.
171. A compound according to claim 170, wherein R9 is C1-C3 alkyl.
172. A compound according to claim 171, wherein R9 is methyl.
173. A compound according to any one of claims 141-168, wherein R9 is C3-C6 cycloalkyl.
174. A compound according to claim 173, wherein R9 is cyclopropane.
175. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is H, R8 is H, R9 is H, and X2 is CH.
176. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is H, R8 is H, R9 is H, and X2 is N.
177. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is H, R8 is F, R9 is H, and X2 is CH.
178. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is H, R8 is F, R9 is H, and X2 is N.
179. A compound according to any one of claims 141- 145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is H, R8 is methyl, R9 is H, and X2 is CH.
180. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is H, R8 is methyl, R9 is H, and X2 is N.
181. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is methyl, R8 is H, R9 is methyl, and X2 is CH.
182. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is methyl, R8 is H, R9 is methyl, and X2 is N.
183. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is H, R8 is H, R9 is cyclopropyl, and X2 is CH.
184. A compound according to any one of claims 141-145, wherein R2 is H, F, or methyl, R6 is H or methyl, R7 is H, R8 is H, R9 is cyclopropyl, and X2 is N.
185. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula Ie
Figure imgf000258_0001
and pharmaceutically acceptable salts and solvates thereof, wherein:
A is Ar1 or hetAr2,
Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and RbRcN-, wherein Rb and Rc are 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, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), oxo, and R^t^N-, wherein Rb and Rc are independently H or C1-C6 alkyl;
X2 is CH or N;
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R6 is H or Cl-C6 alkyl; R10 at each occurrence is independently selected from the group consisting of halogen, Cl- C6 alkyl-, and C1-C6 alkoxy;
n is i ; and
p is 1 or 2.
186. A compound according to claim 185, wherein A is Ar1.
187. A compound according to claim 186, wherein Ar1 is substituted with CN.
188. A compound according to claim 185, wherein A is hetAr2.
189. A compound according to claim 188, wherein hetAr2 is substituted with one or more substituents independently selected from the group consisting of CN, oxo, hydroxyCl-C3 alkyl, and C1-C3 alkyl.
190. A compound according to any one of claims 185-189, wherein R1 is methyl.
191. A compound according to any one of claims 185-190, wherein R2 is H.
192. A compound according to any one of claims 185-190, wherein R2 is halogen.
193. A compound according to claim 192, wherein R2 is F.
194. A compound according to any one of claims 185-190, wherein R2 is C1-C6 alkyl.
195. A compound according claim 194, wherein R2 is C1-C3 alkyl.
196. A compound according to claim 195, wherein R2 is methyl.
197. A compound according to any one of claims 185-196, wherein R6 is H.
198. A compound according to any one of claims 185-196, wherein R6 is C1-C6 alkyl.
199. A compound according to claim 198, wherein R6 is C1-C3 alkyl.
200. A compound according to claim 199, wherein R6 is methyl.
201. A compound according to any one of claims 185-200, wherein R10 is halogen.
202. A compound according to claim 201, wherein R10 is F.
203. A compound according to any one of claims 185-200, wherein R10 is C 1-C6 alkyl.
204. A compound according to claim 203, wherein R10 is C1-C3 alkyl.
205. A compound according to claim 204, wherein R10 is methyl.
206. A compound according to any one of claims 185-200, wherein R10 is C 1-C6 alkoxy.
207. A compound according to claim 206, wherein R10 is C1-C3 alkoxy.
208. A compound according to claim 207, wherein R10 is methoxy.
209. A compound according to any one of claims 185-208, wherein p is 1.
210. A compound according to any one of claims 185-208, wherein p is 2.
21 1. A compound according to claim 210, wherein p is 2 and R10 is F and methyl.
212. A compound according to any one of claims 185-211, wherein X2 is CH.
213. A compound according to any one of claims 185-21 1, wherein X2 is N.
214. A compound according to any one of claims 185-190, wherein R2 is H, F, or methyl, R6 is H or methyl, R10 is methoxy, X2 is CH, and p is 1.
215. A compound according to any one of claims 185-190, wherein R2 is H, F, or methyl, R6 is H or methyl, R10 is methoxy, X2 is N, and p is 1.
216. A compound according to any one of claims 185-190, wherein R2 is H, F, or methyl, R6 is H or methyl, R10 is methyl and F, X2 is CH, and p is 2.
217. A compound according to any one of claims 185-190, wherein R2 is H, F, or methyl, R6 is H or methyl, R10 is methyl and F, X2 is N, and p is 2.
218. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula If
Figure imgf000261_0001
If
and pharmaceutically acceptable salts and solvates thereof, wherein:
X2 is CH or N;
Z1, Z2 and Z3 are each independently selected from CH, N, NH, O or S;
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros); and
R6 is H or Cl-C6 alkyl; R7, R8, and R9 are each independently selected from the group consisting of H, halogen,
C1-C6 alkyl-, and C3-C6 cycloalkyl.
219. A compound according to claim 218, wherein X2 is CH.
220. A compound according to claim 218, wherein X2 is N.
221. A compound according to any one of claims 218-220, wherein Z1 is N or NH.
222. A compound according to any one of claims 218-220, wherein Z1 is CH.
223. A compound according to any one of claims 218-222, wherein Z2 is N or NH.
224. A compound according to any one of claims 218-222, wherein Z2 is O.
225. A compound according to any one of claims 218-222, wherein Z2 is S.
226. A compound according to any one of claims 218-225, wherein Z3 is CH.
227. A compound according to any one of claims 218-225, wherein Z3 is N or NH.
228. A compound according to any one of claims 218-220, wherein Z1 is NH, Z2 is N, and Z3 is CH.
229. A compound according to any one of claims 218-220, wherein Z1 is N, Z2 is O, and Z3 is CH.
230. A compound according to any one of claims 218-220, wherein Z1 is N, Z2 is O, and
Z3 is N.
231. A compound according to any one of claims 218-220, wherein Z1 is N, Z2 is S, and Z3 is CH.
232. A compound according to any one of claims 218-220, wherein Z1 is N, Z2 is S, and
Z3 is N.
233. A compound according to any one of claims 218-220, wherein Z1 is CH, Z2 is NH, and Z3 is N.
234. A compound according to any one of claims 218-220, wherein Z1 is N, Z2 is NH, and Z3 is CH.
235. A compound according to any one of claims 218-234, wherein R1 is C1-C3 alkyl.
236. A compound according to any one of claims 218-234, wherein R1 is methyl.
237. A compound according to any one of claims 218-236, wherein R3 is CN.
238. A compound according to any one of claims 218-236, wherein R3 is hydroxyCl- C6 alkyl.
239. A compound according to any one of claims 218-236, wherein R3 is C1-C3 alkyl.
240. A compound according to claim 239, wherein R3 is methyl.
241. A compound according to claim 239, wherein R3 is ethyl.
242. A compound according to any one of claims 218-241, wherein R6 is H.
243. A compound according to any one of claims 218-241, wherein R6 is C1-C6 alkyl.
244. A compound according to claim 243, wherein R6 is C1-C3 alkyl.
245. A compound according to claim 244, wherein R6 is methyl.
246. A compound according to any one of claims 218-245, wherein R7 is H.
247. A compound according to any one of claims 218-245, wherein R7 is C1-C6 alkyl.
248. A compound according to claim 247, wherein R7 is C1-C3 alkyl.
249. A compound according to claim 248, wherein R7 is methyl.
250. A compound according to any one of claims 218-249, wherein R8 is H.
251. A compound according to any one of claims 218-249, wherein R8 is halogen.
252. A compound according to claim 251, wherein R8 is F.
253. A compound according to any one of claims 218-249, wherein R8 is C1-C6 alkyl.
254. A compound according to claim 253, wherein R8 is C1-C3 alkyl.
255. A compound according to claim 254, wherein R8 is methyl.
256. A compound according to any one of claims 218-255, wherein R9 is H.
257. A compound according to any one of claims 218-255, wherein R9 is C1-C6 alkyl.
258. A compound according to claim 257, wherein R9 is C 1-C3 alkyl.
259. A compound according to claim 258, wherein R9 is methyl.
260. A compound according to any one of claims 218-255, wherein R9 is C3-C6 cycloalkyl.
261. A compound according to claim 260, wherein R9 is cyclopropane.
262. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula Ig
Figure imgf000265_0001
Ig
and pharmaceutically acceptable salts and solvates thereof, wherein:
X2 is CH or N;
Z1, Z2 and Z3 are each independently selected from CH, N, NH, O or S;
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R3 is selected from the group consisting of CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros);
R6 is H or Cl-C6 alkyl;
R10 at each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl-, and C1-C6 alkoxy; and
p is 1 or 2.
263. A compound according to claim 262, wherein X2 is CH.
264. A compound according to claim 262, wherein X2 is N.
265. A compound according to any one of claims 262-264, wherein is ZXN or NH.
266. A compound according to any one of claims 262-265, wherein Z1 is CH.
267. A compound according to any one of claims 262-266, wherein Z2 is N or NH.
268. A compound according to any one of claims 262-266, wherein Z2 is O.
269. A compound according to any one of claims 262-266, wherein Z2 is S.
270. A compound according to any one of claims 262-269, wherein Z3 is CH.
271. A compound according to any one of claims 262-269, wherein Z3 is N or NH.
272. A compound according to any one of claims 262-264, wherein Z1 is NH, Z2 is N, and Z3 is CH.
273. A compound according to any one of claims 262-264, wherein is N, Z2 is O, and Z3 is CH.
274. A compound according to any one of claims 262-264, wherein Z1 is N, Z2 is O, and
Z3 is N.
275. A compound according to any one of claims 262-264, wherein Z1 is N, Z2 is S, and Z3 is CH.
276. A compound according to any one of claims 262-264, wherein Z1 is N, Z2 is S, and
Z3 is N.
277. A compound according to any one of claims 262-264, wherein Z1 is CH, Z2 is NH, and Z3 is N.
278. A compound according to any one of claims 262-264, wherein Z1 is N, Z2 is NH, and Z3 is CH.
279. A compound according to any one of claims 262-278, wherein R1 is C1-C3 alkyl.
280. A compound according to claim 279, wherein R1 is methyl.
281. A compound according to any one of claims 262-280, wherein R3 is CN.
282. A compound according to any one of claims 262-280, wherein R3 is hydroxyCl- C6 alkyl.
283. A compound according to claim 282, wherein R3 is C1-C3 alkyl.
284. A compound according to claim 283, wherein R3 is methyl.
285. A compound according to claim 283, wherein R3 is ethyl.
286. A compound according to any one of claims 262-285, wherein R6 is H.
287. A compound according to any one of claims 262-285, wherein R6 is C1-C6 alkyl.
288. A compound according to claim 287, wherein R6 is C1-C3 alkyl.
289. A compound according to claim 288, wherein R6 is methyl.
290. A compound according to any one of claims 262-289, wherein R10 is halogen.
291. A compound according to any claim 290, wherein R10 is F.
292. A compound according to any one of claims 262-289, wherein R is C1-C6 alkyl.
293. A compound according to claim 292, wherein R10 is C1-C3 alkyl.
294. A compound according to claim 293, wherein R10 is methyl.
295. A compound according to any one of claims 262-289, wherein, R10 is C1-C6 alkoxy.
296. A compound according to claim 295, wherein R10 is C1-C3 alkoxy.
297. A compound according to claim 296, wherein R10 is methoxy.
298. A compound according to any one of claims 262-297, wherein p is 1.
299. A compound according to any one of claims 262-297, wherein p is 2.
300. A compound according to claim 299, wherein p is 2 and R10 is F and methyl.
301. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula Ih
Figure imgf000268_0001
Ih
pharmaceutically acceptable salts and solvates thereof, wherein:
X2 is CH or N;
Z4 is CH or N; R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R4 is CN;
R6 is H or Cl-C6 alkyl; and
R7, R8, and R9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl.
302. A compound according to claim 301, wherein R1 is C1-C3 alkyl-.
303. A compound according to any one of claims 301-302, wherein R1 is methyl.
304. A compound according to any one of claims 301-303, wherein R4 is CN.
305. A compound according to any one of claims 301-304, wherein R6 is H.
306. A compound according to any one of claims 301-304, wherein R6 is C1-C6 alkyl.
307. A compound according to claim 306, wherein R6 is C1-C3 alkyl.
308. A compound according to claim 307, wherein R6 is methyl.
309. A compound according to any one of claims 301-308, wherein R7 is H.
310. A compound according to any one of claims 301-308, wherein R7 is C1-C6 alkyl.
311. A compound according to claim 310, wherein R7 is C1-C3 alkyl.
312. A compound according to claim 311, wherein R7 is methyl.
313. A compound according to any one of claims 301-312, wherein R8 is H.
314. A compound according to any one of claims 301-312, wherein R is halogen.
315. A compound according to claim 314, wherein R8 is F.
316. A compound according to any one of claims 301-312, wherein R8 is C1-C6 alkyl.
317. A compound according to claim 316, wherein R8 is C1-C3 alkyl.
318. A compound according to claim 317, wherein R8 is methyl.
319. A compound according to any one of claims 301-318, wherein R9 is H.
320. A compound according to any one of claims 301-318, wherein R9 is C1-C6 alkyl.
321. A compound according to claim 320, wherein R9 is C1-C3 alkyl.
322. A compound according to claim 321, wherein R9 is methyl.
323. A compound according to any one of claims 301-318, wherein R9 is C3-C6 cycloalkyl.
324. A compound according to claim 323, wherein R9 is cyclopropane.
325. A compound according to any one of claims 301-324, wherein Z4 is CH.
326. A compound according to any one of claims 301-324, wherein Z4 is N.
327. A compound according to any one of claims 301-326, wherein R1 is methyl, R4 is CN, and Z4 is CH.
328. A compound according to any one of claims 301-326, wherein R1 is methyl, R4 is CN, and Z4 is N.
329. A compound according to any one of claims 301-328, wherein X2 is CH.
330. A compound according to any one of claims 301-328, wherein X2 is N.
331. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula Ii
Figure imgf000271_0001
and pharmaceutically acceptable salts and solvates thereof, wherein:
X2 is CH or N;
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R5 is H or Cl-C6 alkyl-;
R6 is H or Cl-C6 alkyl; and
R7, R8, and R9 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl-, and C3-C6 cycloalkyl.
332. A compound according to claim 331, wherein R1 is C1-C3 alkyl-.
333. A compound according to claim 332, wherein R1 is methyl.
334. A compound according to any one of claims 331-333, wherein R5 is H.
335. A compound according to any one of claims 331-333, wherein R5 is C1-C6 alkyl-.
336. A compound according to claim 335, wherein R5 is methyl.
337. A compound according to any one of claims 331-336, wherein R6 is H.
338. A compound according to any one of claims 331-336, wherein R6 is C1-C6 alkyl.
339. A compound according to claim 338, wherein R6 is C 1-C3 alkyl.
340. A compound according to claim 339, wherein R6 is methyl.
341. A compound according to any one of claims 331-340, wherein R7 is H.
342. A compound according to any one of claims 331-340, wherein R7 is C1-C6 alkyl.
343. A compound according to claim 342, wherein R7 is C1-C3 alkyl.
344. A compound according to claim 343, wherein R7 is methyl.
345. A compound according to any one of claims 331-344, wherein R8 is H.
346. A compound according to any one of claims 331-344, wherein R8 is halogen.
347. A compound according to claim 346, wherein R8 is F.
348. A compound according to any one of claims 331-344, wherein R8 is C1-C6 alkyl.
349. A compound according to claim 348, wherein R8 is C1-C3 alkyl.
350. A compound according to claim 349, wherein R8 is methyl.
351. A compound according to any one of claims 331-350, wherein R9 is H.
352. A compound according to any one of claims 331-350, wherein R9 is C1-C6 alkyl.
353. A compound according to claim 352, wherein R9 is C1-C3 alkyl.
354. A compound according to claim 353, wherein R9 is methyl.
355. A compound according to any one of claims 331-350, wherein R9 is C3-C6 cycloalkyl.
356. A compound according to claim 355, wherein R9 is cyclopropane.
357. A compound according to any one of claims 331-356, wherein X2 is CH.
358. A compound according to any one of claims 331-356, wherein X2 is N.
359. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula Ij
Figure imgf000273_0001
Ij
and pharmaceutically acceptable salts and solvates thereof, wherein:
X2 is CH or N;
Z4 is CH or N; R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R4 is CN;
R6 is H or Cl-C6 alkyl;
R10 at each occurrence is independently selected from the group consisting of halogen, Cl- C6 alkyl-, and C1-C6 alkoxy; and
p is 1 or 2.
360. A compound according to claim 359, wherein R1 is C1-C3 alkyl-.
361. A compound according to claim 360, wherein R1 is methyl.
362. A compound according to any one of claims 359-361, wherein R4 is CN.
363. A compound according to any one of claims 359-362, wherein R6 is H.
364. A compound according to any one of claims 359-362, wherein R6 is C1-C6 alkyl.
365. A compound according to claim 364, wherein R6 is C1-C3 alkyl.
366. A compound according to claim 365, wherein R6 is methyl.
367. A compound according to any one of claims 359-366, wherein R10 is halogen.
368. A compound according to claim 367, wherein R10 is F.
369. A compound according to any one of claims 359-366, wherein R10 is C1-C6 alkyl.
370. A compound according to claim 369, wherein R10 is C1-C3 alkyl.
371. A compound according to claim 370, wherein R10 is methyl.
372. A compound according to any one of claims 359-366, wherein R10 is C1-C6 alkoxy.
373. A compound according to claim 372, wherein R10 is C1-C3 alkoxy.
374. A compound according to claim 373, wherein R10 is methoxy.
375. A compound according to any one of claims 359-374, wherein p is 1.
376. A compound according to any one of claims 359-374, wherein p is 2.
377. A compound according to claim 376, wherein p is 2 and R10 is F and methyl.
378. A compound according to any one of claims 359-377, wherein Z4 is CH.
379. A compound according to any one of claims 359-377, wherein Z4 is N.
380. A compound according to any one of claims 359-379, wherein R1 is methyl, R4 is CN, and Z4 is CH.
381. A compound according to any one of claims 359-379, wherein R1 is methyl, R4 is CN, and Z4 is N.
382. A compound according to any one of claims 359-381, wherein X2 is CH.
383. A compound according to any one of claims 359-381, wherein X2 is N.
384. A compound according to any one of claims 1-57, wherein the compound of Formula I is a compound of Formula Ik
Figure imgf000276_0001
Ik
and pharmaceutically acceptable salts and solvates thereof, wherein:
X2 is CH or N;
R1 is Cl-C6 alkyl-;
R2 is selected from the group consisting of H, halogen, or C1-C6 alkyl- (optionally substituted with 1-3 fluoros);
R5 is H or Cl-C6 alkyl-;
R6 is H or Cl-C6 alkyl;
R10 at each occurrence is independently selected from the group consisting of halogen, Cl- C6 alkyl-, and C1-C6 alkoxy; and
p is 1 or 2.
385. A compound according to claim 384, wherein R1 is C1-C3 alkyl-.
386. A compound according to claim 385, wherein R1 is methyl.
387. A compound according to any one of claims 384-386, wherein R5 is H.
388. A compound according to any one of claims 384-386, wherein R5 is C1-C6 alkyl-.
389. A compound according to claim 388, wherein R5 is methyl.
390. A compound according to any one of claims 384-389, wherein R6 is H.
391. A compound according to any one of claims 384-389, wherein R6 is C1-C6 alkyl.
392. A compound according to claim 391, wherein R6 is C1-C3 alkyl.
393. A compound according to claim 392, wherein R6 is methyl.
394. A compound according to any one of claims 384-393, wherein R10 is halogen.
395. A compound according to claim 394, wherein R10 is F.
396. A compound according to any one of claims 384-393, wherein R10 is C1-C6 alkyl.
397. A compound according to claim 396, wherein R10 is C1-C3 alkyl.
398. A compound according to claim 397, wherein R10 is methyl.
399. A compound according to any one of claims 384-393, wherein R10 is C 1-C6 alkoxy.
400. A compound according to claim 399, wherein R10 is C1-C3 alkoxy.
401. A compound according to claim 400, wherein R10 is methoxy.
402. A compound according to any one of claims 384-401, wherein p is 1.
403. A compound according to any one of claims 384-401, wherein p is 2.
404. A compound according to claim 403, wherein p is 2 and R10 is F and methyl.
405. A compound according to any one of claims 384-404, wherein X2 is CH.
406. A compound according to any one of claims 384-404, wherein X2 is N.
407. A compound according to any one of the previous claims selected from the group consisting of:
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
283
Figure imgf000285_0001
Figure imgf000286_0001
285
Figure imgf000287_0001
Figure imgf000288_0001
287
Figure imgf000289_0001
Figure imgf000290_0001
289
Figure imgf000291_0001
Figure imgf000292_0001
291
Figure imgf000293_0001
292
Figure imgf000294_0001
293
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
298
Figure imgf000300_0001
408. A pharmaceutical composition comprising a compound according to any one of claims 1-407, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
409. A method for treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of any one of claims 1-407, or a pharmaceutical composition according to claim 408.
410. A method for treating cancer in a patient in need thereof, the method comprising (a) determining if the cancer is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same; and (b) if the cancer is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, administering to the patient a therapeutically effective amount of a compound of any one of claims 1-407, or a pharmaceutical composition according to claim 408.
411. A method of treating a RET-associated cancer in a patient, the method comprising administering to a patient identified or diagnosed as having a RET-associated cancer a therapeutically effective amount of a compound of any one of claims 1-407 or a
pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408.
412. A method of treating a RET-associated cancer in a patient, the method
comprising:
determining if the cancer in the patient is a RET-associated cancer; and
administering to a patient determined to have a RET-associated cancer a therapeutically effective amount of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408.
413. A method of treating a patient, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-407 or a
pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408, to a patient having a clinical record that indicates that the patient has a
dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same.
414. A method of selecting a treatment for a patient, the method comprising selecting a treatment comprising administration of a therapeutically effective amount of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408, for a patient identified or diagnosed as having a RET- associated cancer.
415. A method of selecting a treatment for a patient having a cancer, the method comprising:
determining if the cancer in the patient is a RET-associated cancer; and
selecting a treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408, for a patient determined to have a RET- associated cancer.
416. A method of selecting a patient for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-407 or a
pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408, the method comprising:
identifying a patient having a RET-associated cancer; and
selecting the patient for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408.
417. A method of selecting a patient having cancer for treatment including
administration of a therapeutically effective amount of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408, the method comprising:
determining if the cancer in the patient is a RET-associated cancer; and
selecting a patient determined to have a RET-associated cancer for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408.
418. The method of any one of claims 412, 415, and 417, wherein the step of determining if the cancer in the patient is a RET-associated cancer includes performing an assay to detect dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same in a sample from the patient.
419. The method of claim 418, further comprising:
obtaining a sample from the patient.
420. The method of claim 419, wherein the sample is a biopsy sample.
421. The method of any one of claims 418-420, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).
422. The method of claim 421, wherein the FISH is break apart FISH analysis.
423. The method of claim 421, wherein the sequencing is pyrosequencing or next generation sequencing.
424. The method of any one of claims 418-423, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.
425. The method of claim 424, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 432, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 901, 904, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 982, 1009, 1017, 1041, 1062, and 1064.
426. The method of claim 425, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 510, 511, 515, 531, 532, 533, 550, 591, 593, 600, 602, 603, 606, 609, 611, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 686, 691, 694, 700, 706, 713, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 790, 791, 804, 805, 806, 818, 819, 823, 826, 833, 841, 843, 844, 848, 852, 873, 876, 881, 883, 884, 886, 891, 897, 898, 901, 904, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 982, 1009, 1017, 1041, and 1064.
427. The method of claim 426, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, A510V, E51 1K, C515S, C531R, G533C, G533S, G550E, V591I, G593E, R600Q, I602V, K603Q, K603E, Y606C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611 S, C611G, C611Y, C611F, C611W, C618S, C618Y, C618R, C618Y, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641 S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, S686N, G691 S, R694Q, M700L, V706M, V706A, E713K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, L790F, Y791F, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, E818K, S819I, G823E, Y826M, R833C, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, R897Q, D898V, E901K, S904F, S904S, S904C, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, R982C, M1009V, D1017N, V1041G, and M1064T.
428. The method of claim 424, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.
429. The method of any one of claims 418-423, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.
430. The method of claim 429, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIPl-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33- RET, ERCl-RET, ELKS-RET, RET-ELKS, FGFRl OP-RET, RET-MBDl, RET-RAB61P2, RET-PCMl, RET-PPK AR 1 A, RET-TRIM24, RET-RFG9, RFP-RET, RET-GOLGA5, HOOK3- RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET,
TBLIXRI/RET, CEP55-RET, CUXl-RET, KIAA1468-RET, RFG8/RET, RET/RFG8, H4-RET, ACBD5-RET, PTCex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, and Ria-RET.
431. The method of any one of claims 411, 412, and 415-430, 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.
432. The method of claim 431, wherein the lung cancer is RET fusion lung cancer or the cancer is medullary thyroid cancer.
433. The method of claim 431, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronchioles lung cell carcinoma, or lung adenocarcinoma.
434. The method of any one of claims 409-433, wherein the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is orally administered.
435. The method of any one of claims 409-434, further comprising administering an additional therapy or therapeutic agent to the patient.
436. The method according to claim 435, wherein said additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase targeted- therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies and angiogene sis-targeted therapies.
437. The method according to claim 436, wherein said additional therapeutic agent is selected from one or more kinase targeted therapeutics.
438. The method according to any one of claims 435-437, wherein the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a
pharmaceutical composition according to claim 408, and the additional therapeutic agent are administered simultaneously as separate dosages.
439. The method according to any one of claims 435-437, wherein the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a
pharmaceutical composition according to claim 408, and the additional therapeutic agent are administered as separate dosages sequentially in any order.
440. Use of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a RET-associated cancer in a patient.
441. The use of claim 440, 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.
442. The use of claim 441, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.
443. The use of claim 442, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 432, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 901, 904, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 982, 1009, 1017, 1041, 1062, and 1064.
444. The use of claim 443, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 510, 511, 515, 531, 532, 533, 550, 591, 593, 600, 602, 603, 606, 609, 611, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 686, 691, 694, 700, 706, 713, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 790, 791, 804, 805, 806, 818, 819, 823, 826, 833, 841, 843, 844, 848, 852, 873, 876, 881, 883, 884, 886, 891, 897, 898, 901, 904, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 982, 1009, 1017, 1041, and 1064.
445. The use of claim 444, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, A510V, E51 1K, C515S, C531R, G533C, G533S, G550E, V591I, G593E, R600Q, I602V, K603Q, K603E, Y606C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611 S, C611G, C611Y, C611F, C611W, C618S, C618Y, C618R, C618Y, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641 S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, S686N, G691 S, R694Q, M700L, V706M, V706A, E713K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, L790F, Y791F, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, E818K, S819I, G823E, Y826M, R833C, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, R897Q, D898V, E901K, S904F, S904S, S904C, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, R982C, M1009V, D1017N, V1041G, and M1064T.
446. The use of claim 442, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.
447. The use of claim 441, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.
448. The use of claim 447, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIPl-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33- RET, ERC1-RET, ELKS-RET, RET-ELKS, FGFR1 OP-RET, RET-MBD1, RET-RAB61P2, RET-PCMl, RET-PPKARIA, RET-TRIM24, RET-RFG9, RFP-RET, RET-GOLGA5, HOOK3- RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET,
TBLIXRI/RET, CEP55-RET, CUXl-RET, KIAA1468-RET, RFG8/RET, RET/RFG8, H4-RET, ACBD5-RET, PTCex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, and Ria-RET.
449. The use of any one of claims 440-448, 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.
450. The use of claim 449, wherein the lung cancer is RET fusion lung cancer or the cancer is medullary thyroid cancer.
451. The use of claim 449, wherein the lung cancer is small cell lung carcinoma, non- small cell lung cancer, bronchioles lung cell carcinoma, or lung adenocarcinoma.
452. The use of any one of claims 440-451, wherein the medicament is formulated for oral administration.
453. A compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceuticial composition according to claim 408 for use in treating a patient identified or diagnosed as having a RET-associated cancer.
454. The compound of claim 453, 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.
455. The compound of claim 454, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.
456. The compound of claim 455, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 432, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 901, 904, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 982, 1009, 1017, 1041, 1062, and 1064.
457. The compound of claim 456, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 510, 511, 515, 531, 532, 533, 550, 591, 593, 600, 602, 603, 606, 609, 611, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 686, 691, 694, 700, 706, 713, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 790, 791, 804, 805, 806, 818, 819, 823, 826, 833, 841, 843, 844, 848, 852, 873, 876, 881, 883, 884, 886, 891, 897, 898, 901, 904, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 982, 1009, 1017, 1041, and 1064.
458. The compound of claim 457, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, A510V, E51 1K, C515S, C531R, G533C, G533S, G550E, V591I, G593E, R600Q, I602V, K603Q, K603E, Y606C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611 S, C611G, C611Y, C611F, C611W, C618S, C618Y, C618R, C618Y, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641 S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, S686N, G691 S, R694Q, M700L, V706M, V706A, E713K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, L790F, Y791F, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, E818K, S819I, G823E, Y826M, R833C, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, R897Q, D898V, E901K, S904F, S904S, S904C, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, R982C, M1009V, D1017N, V1041G, and M1064T.
459. The compound of claim 455, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.
460. The compound of claim 454, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.
461. The compound of claim 460, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIP 1 -RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, ELKS-RET, RET-ELKS, FGFR1 OP-RET, RET-MBD1, RET- RAB61P2, RET-PCM1, RET-PPK AR 1 A, RET-TRFM24, RET-RFG9, RFP-RET, RET- GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET,
SPECC1L-RET, TBL1XR1/RET, CEP 55 -RET, CUX1-RET, KIAA1468-RET, RFG8/RET, RET/RFG8, H4-RET, ACBD5-RET, PTCex9-RET, MYH13-RET, PIBF1-RET, KIAA1217- RET, MPRIP-RET, HRH4-RET, and Ria-RET.
462. The compound of any one of claims 453-461, 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.
463. The compound of claim 462, wherein the lung cancer is RET fusion lung cancer or the cancer is medullary thyroid cancer.
464. The compound of claim 462, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronciolus lung cell carcinoma, or lung adenocarcinoma.
465. A method for inhibiting RET kinase activity in a mammalian cell, the method comprising contacting the mammalian cell with a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof.
466. The method of claim 465, wherein the contacting occurs in vivo.
467. The method of claim 465, wherein the contacting occurs in vitro.
468. The method of any one of claims 465-467, wherein the mammalian cell is a mammalian cancer cell.
469. The method of claim 468, wherein the mammalian cancer cell is a mammalian RET-associated cancer cell.
470. The method of any one of claims 465-469, wherein the cell has a dysregulation of a RET gene, a RET kinase protein, or expression or activity or level of any of the same.
471. The method of claim 470, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.
472. The method of claim 471, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 432, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 901, 904, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 982, 1009, 1017, 1041, 1062, and 1064.
473. The method of claim 472, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 510, 511, 515, 531, 532, 533, 550, 591, 593, 600, 602, 603, 606, 609, 611, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 686, 691, 694, 700, 706, 713, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 790, 791, 804, 805, 806, 818, 819, 823, 826, 833, 841, 843, 844, 848, 852, 873, 876, 881, 883, 884, 886, 891, 897, 898, 901, 904, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 982, 1009, 1017, 1041, and 1064.
474. The method of claim 473, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, A510V, E511K, C515S, C531R, G533C, G533S, G550E, V591I, G593E, R600Q, I602V, K603Q, K603E, Y606C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611 S, C611G, C611Y, C611F, C611W, C618S, C618Y, C618R, C618Y, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641 S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, S686N, G691 S, R694Q, M700L, V706M, V706A, E713K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, L790F, Y791F, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, E818K, S819I, G823E, Y826M, R833C, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, R897Q, D898V, E901K, S904F, S904S, S904C, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, R982C, M1009V, D1017N, V1041G, and M1064T.
475. The method of claim 471, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.
476. The method of claim 470, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.
477. The method of claim 476, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIPl-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33- RET, ERC1-RET, ELKS-RET, RET-ELKS, FGFR1 OP-RET, RET-MBD1, RET-RAB61P2, RET-PCMl, RET-PPK AR 1 A, RET-TRIM24, RET-RFG9, RFP-RET, RET-GOLGA5, HOOK3- RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET,
TBLIXRI/RET, CEP55-RET, CUXl-RET, KIAA1468-RET, RFG8/RET, RET/RFG8, H4-RET, ACBD5-RET, PTCex9-RET, MYH13-RET, PIBR1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, and Ria-RET.
478. A method of treating irritable bowel syndrome in a patient, the method
comprising administering to a patient identified or diagnosed as having irritable bowel syndrome a therapeutically effective amount of a compound of any one of claims 1-407 or a
pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408.
479. A method for reducing pain associated with irritable bowel syndrome in a patient in need thereof, the method comprising administering to a patient identified or diagnosed as having irritable bowel syndrome a therapeutically effective amount of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 408.
480. A method for inhibiting metastasis of a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-407, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to claim 408.
481. The method of claim 480, wherein the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof is used in combination with another chemotherapeutic agent.
482. A method of treating a subject having a cancer, wherein the method comprises:
(a) administering one or more doses of a first RET inhibitor to the subject for a period of time;
(b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); and
(c) administering a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); or
(d) administering additional doses of the first RET inhibitor of step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a).
483. The method of claim 482, wherein the anticancer agent in step (c) is a second RET inhibitor.
484. The method of claim 482, wherein the anticancer agent in step (c) is the first RET inhibitor administered in step (a).
485. The method of claim 482, wherein the subject is administered additional doses of the first RET inhibitor of step (a), and the method further comprises (e) administering another anticancer agent to the subject.
486. The method of claim 485, wherein the anticancer agent of step (e) is a second RET inhibitor.
487. The method of claim 486, wherein the anticancer agent of step (e) is a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof.
488. A method of treating a subject having a cancer, wherein the method comprises:
(a) administering one or more doses of a first RET inhibitor to the subject for a period of time;
(b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); and
(c) administering a second RET inhibitor as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); or
(d) administering additional doses of the first RET inhibitor of step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); wherein the mutation is a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.
489. The method of claim 488, wherein the anticancer agent of step (c) is the first RET inhibitor administered in step (a).
490. The method of claim 488, wherein the subject is administered additional doses of the first RET inhibitor of step (a), and the method further comprises (e) administering another anticancer agent.
491. The method of claim 490, wherein the anticancer agent of step (e) is a second RET inhibitor.
492. The method of claim 490, wherein the anticancer agent of step (e) is a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof.
493. A method of treating a subject having a cancer, wherein the method comprises:
(a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; and
(b) administering a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; or
(c) administering additional doses of the first RET inhibitor to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor previously administered to the subject.
494. The method of claim 493, wherein the anticancer agent of step (b) is a second RET inhibitor.
495. The method of claim 493, wherein the anticancer agent of step (b) is the first RET inhibitor previously administered to the subject.
496. The method of claim 495, wherein the subject is administered additional doses of the first RET inhibitor previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.
497. The method of claim 496, wherein the anticancer agent of step (d) is a second RET inhibitor.
498. The method of claim 496, wherein the anticancer agent of step (d) is a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof.
499. A method of treating a subject having a cancer, wherein the method comprises:
(a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor previously administered to the subject; and
(b) administering a second RET inhibitor to the subject as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; or
(c) administering additional doses of the first RET inhibitor that was previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject.
500. The method of claim 499, wherein the anticancer agent of step (b) is the first RET inhibitor previously administered to the subject.
501. The method of claim 499, wherein the subject is administered additional doses of the first RET inhibitor previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.
502. The method of claim 501, wherein the anticancer agent of step (d) is a second RET inhibitor.
503. The method of claim 501, wherein the anticancer agent of step (d) is a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof.
504. A method of treating a subject having a cancer, wherein the method comprises:
(a) administering one or more doses of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof for a period of time;
(b) after (a), determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1 -407 or a pharmaceutically acceptable salt or solvate thereof of step (a); and
(c) administering a second RET inhibitor or a second compound of any one of claims 1- 407 or a pharmaceutically acceptable salt or solvate therof as a monotherapy or in conjunction with another anticancer agent to a subject determined to have one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof of step (a); or
(d) administering additional doses of the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof of step (a) to a subject having a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof of step (a).
505. The method of claim 504, wherein the second RET inhibitor is administered in step (c).
506. The method of claim 504, wherein the second compound of any one of claims 1- 407 or a pharmaceutically acceptable salt or solvate thereof is administered in step (c).
507. The method of claim 504, wherein the anticancer agent of step (c) is a first RET inhibitor.
508. The method of claim 504, wherein the anticancer agent of step (c) is a second compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof that is different from that administered in step (a).
509. The method of claim 504, wherein the anticancer agent of step (c) is the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof administered in step (a).
510. The method of claim 504, wherein the subject is administered additional doses of the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof of step (a), and the method further comprises (e) administering another anticancer agent to the subject.
511. The method of claim 510, wherein the anticancer agent of step (e) is a second RET inhibitor.
512. The method of claim 510, wherein the anticancer agent of step (e) is a second compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof that is different from the compound of step (a).
513. A method of treating a subject having a cancer, wherein the method comprises: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject; and
(b) administering a second RET inhibitor or a second compound of any one of claims 1- 407 or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to a subject determined to have a cancer cell that has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject; or
(c) administering additional doses of the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof previously administered to the subject having a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject.
514. The method of claim 513, wherein the second RET inhibitor is administered in step
(b).
515. The method of claim 513, wherein the second compound of any one of claims 1- 407 or a pharmaceutically acceptable salt or solvate thereof is administered in step (b).
516. The method of claim 513, wherein the anticancer agent of step (b) is a second RET inhibitor.
517. The method of claim 513, wherein the anticancer agent of step (b) is a second compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof.
518. The method of claim 513, wherein the anticancer agent of step (b) is the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject.
519. The method of claim 513, wherein the subject is administered additional doses of the compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.
520. The method of claim 519, wherein the anticancer agent of step (d) is a second RET inhibitor.
521. The method of claim 520, wherein the anticancer agent of step (d) is a second compound of any one of claims 1-407 or a pharmaceutically acceptable salt or solvate thereof.
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