Compounds useful for inhibiting RET kinase
Inventors
ANDERSON, Erin D. • Andrews, Steven W. • Condroski, Kevin R. • IRVIN, Thomas C. • Kolakowski, Gabrielle R. • Kumar, Manoj • McFaddin, Elizabeth A. • MCKENNEY, Megan • Munchhof, Michael J. • WELCH, Michael B.
Assignees
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Publication Number
US-11613533-B2
Publication Date
2023-03-28
Expiration Date
Abstract
Provided herein are RET kinase inhibitors according to the formula: pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods for their use in the treatment of diseases that can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders. A, R1, n, X1, X2, X3, X4, and R2 have the meanings given in the specification.
Core Innovation
The invention relates to compounds of formulas (I), (II), and/or (III) defined by a five- or six-member aryl or heteroaryl unit A, with X1, X2, X3, and X4 independently selected from N, CH, C—CH3, C—CH2—OH, C—OCH3, C—CH2—OCH3, or C-halogen. The compounds further define R1 as hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, or multiple substituted alkyl, cycloalkyl, heterocycloalkyl, bicyclic, aryl, heteroaryl, heterobicyclic, spirane, heterospirane, adamantane, difluoromethylsulfane, or pentafluorosulfane groups, with each R1 optionally substituted and two R1 groups able to fuse to form a ring structure including a portion of A, and n being 1, 2, or 3.
The compounds also specify R2 as C1-C4 alkyl or selected (alkyl)(cycloalkyl), (alkyl)(heterocycloalkyl), or (alkyl)(bicyclic) variants, each optionally substituted with deuterium, halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl. The disclosure includes deuterated and fluorinated analogs, isomeric and stereochemical variants, and pharmaceutically acceptable salts. The partial content also describes substituted pyrazole-4-carboxamide and related heteroaryl-containing scaffold examples, including oxazole, isoxazole, and pyridine-containing embodiments.
The invention is also framed as including compounds and pharmaceutically acceptable salts for treating cancer. A method scope is explicitly directed to treating RET-associated cancers by administering an effective amount of a compound of the described formula, and the disclosure further references RET-associated disease/cancer, RET dysregulation or mutations, and RET inhibitor resistance mutations.
Claims Coverage
The consolidated claim coverage includes broad compound-formula claims and a treatment method directed to RET-associated cancers. Across the independent claim families, the inventive features center on the defined A scaffold, the X1–X4 position set, the fusion-capable and optionally substituted R1 pattern, the defined R2 substituent class, optional pharmaceutically acceptable salts, and R/S enantiomeric chirality at the δ (5) position. A total of six inventive features are identified.
Formula-defined aryl or heteroaryl scaffold with fused R1 ring formation
A is a five- or six-member aryl or heteroaryl; each R1 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, and multiple specified substituted ring-containing groups; each R1 is optionally substituted with halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, or mono-, di-, or tri-halomethyl; and two R1 groups can fuse to form a ring structure including a portion of A, with n being 1, 2, or 3.
Defined heteroatom, alkyl, alkoxy, and halogen pattern at X1-X4
X1, X2, X3, and X4 are each independently N, CH, C—CH3, C—CH2—OH, C—OCH3, C—CH2—OCH3, or C-halogen.
Constrained R2 substituent set with optional deuterium substitution
R2 is C1-C4 alkyl or selected (alkyl)(cycloalkyl), (alkyl)(heterocycloalkyl), or (alkyl)(bicyclic) groups, each optionally substituted with deuterium and the listed halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl groups.
Pharmaceutically acceptable salts
The compounds are covered as pharmaceutically acceptable salts thereof.
RET-associated cancer treatment by administering the compounds
A method of treating cancer in a patient by administering an effective amount of the compound or pharmaceutically acceptable salt, where the cancer is a RET-associated cancer.
Stereochemical selection at the δ (5) position
A compound of the formula is characterized by R-enantiomeric chirality at the δ (5) position or by S-enantiomeric chirality at the δ (5) position, with pharmaceutically acceptable salts included.
Overall, the claims cover a structurally defined compound class built on a five- or six-member aryl or heteroaryl core A with fusion-capable R1 substitution, defined X1-X4 and R2 options, and pharmaceutically acceptable salts. Additional claim coverage includes stereochemical embodiments at the δ (5) position and a method of treating RET-associated cancers by administering the compounds.
Stated Advantages
The document states the compounds are RET kinase inhibitors, confirmed by RET enzyme and RET cell autophosphorylation assays with reported IC50/EC50 thresholds.
Documented Applications
Treating RET-associated cancers by administering an effective amount of the compound or a pharmaceutically acceptable salt.
RET-associated cancer indications include medullary thyroid cancer, RET fusion lung cancer, thyroid and lung cancers, multiple endocrine neoplasia type 2A/2B related conditions, small cell lung carcinoma, non-small cell lung carcinoma, papillary thyroid cancer, differentiated thyroid cancer, recurrent/refractory differentiated thyroid cancer, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, inflammatory myofibroblastic tumor, and cervical cancer.
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