WO2018136663A1 - Inhibiteurs de ret - Google Patents

Inhibiteurs de ret 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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English (en)
Inventor
Steven W. Andrews
James F. Blake
Julia Haas
Yutong Jiang
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Array Biopharma, Inc.
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Publication of WO2018136663A1 publication Critical patent/WO2018136663A1/fr

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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

L'invention concerne des composés de formule (I) : et des sels ou solvates pharmaceutiquement acceptables de ceux-ci. Dans la formule, A, B, Y, X1, X2, X3, X4, R1, R2, n et m sont tels que définis dans la description. Les composés de l'invention sont des inhibiteurs de la kinase RET et sont utiles dans le traitement et la prévention de maladies qui peuvent être traitées avec un inhibiteur de la kinase RET, y compris des maladies et des troubles associés à RET.
PCT/US2018/014281 2017-01-18 2018-01-18 Inhibiteurs de ret WO2018136663A1 (fr)

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WO2020083332A1 (fr) * 2018-10-24 2020-04-30 南京明德新药研发有限公司 Dérivé de pyrimidine tenant lieu d'inhibiteur ret
CN111285882A (zh) * 2018-12-07 2020-06-16 四川科伦博泰生物医药股份有限公司 稠环化合物、包含其的药物组合物及其制备方法和用途
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2020200314A1 (fr) * 2019-04-03 2020-10-08 南京明德新药研发有限公司 Dérivé spiro contenant de l'azote utilisé en tant qu'inhibiteur de ret
WO2020207419A1 (fr) 2019-04-12 2020-10-15 浙江海正药业股份有限公司 Dérivé de pipérazine amide, son procédé de préparation et son utilisation en médecine
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
CN113784963A (zh) * 2019-05-20 2021-12-10 浙江同源康医药股份有限公司 用作ret激酶抑制剂的化合物及其应用
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CN113853375B (zh) * 2019-05-21 2024-03-08 株式会社沃若诺伊 含n杂芳基衍生物及包含其作为活性成分的用于预防或治疗癌症的药物组合物
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
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WO2023239422A2 (fr) 2021-10-22 2023-12-14 University Of Houston System Méthodes et compositions pour traiter une lésion inflammatoire chronique, une métaplasie, une dysplasie et des cancers des tissus épithéliaux

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