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
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11964968-B2
Publication Date
2024-04-23
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 (III) defined by a five- or six-member aryl or heteroaryl ring A, with substituent pattern A-(R1)n where n is 1, 2, or 3. The compounds define X1, X2, X3, and X4 so that exactly one of these positions is N, and the remaining positions are selected from CH, C—CH3, C—CH2—OH, C—OCH3, C—CH2—OCH3, or C-halogen. The scope also includes a restricted R2 substituent class and pharmaceutically acceptable salts.
Each R1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, and specified substituted groups, with optional substitution by halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, or mono-, di-, or tri-halomethyl. Two R1 groups can fuse to form a ring structure that includes a portion of A and is optionally aromatic. The disclosure also includes R-enantiomer and S-enantiomer forms, deuterated and fluorinated variants, and substituted pyrazole-4-carboxamide and related amide scaffolds.
The disclosed compounds include representative pyrazole-carboxamide scaffold embodiments and related amide compounds with substituted aryl or heteroaryl fragments. Example structures include halogenated aryl groups, oxazole and thiazole-linked variants, fluorinated and deuterated motifs, and aminocyano pyrazole-phenyl carboxamide structures. The document also references compound preparations, hydrolysis to carboxylic acids, and related intermediates and final compounds.
Claims Coverage
The provided claim coverage centers on structurally defined compound claims with ring A, R1 substitution and ring-fusion options, an X1-X4 pattern with exactly one N, and a limited R2 substituent class, together with pharmaceutically acceptable salts. The claim sets also include enantiomer-specific coverage and therapeutic method claims for treating RET-associated cancer, with refinements to specified cancer types.
Defined aryl or heteroaryl core with A-(R1)n substitution
A is a five- or six-member aryl or heteroaryl, n is 1, 2, or 3, and each R1 is independently selected from the listed substituents, with optional substitution and permitted ring fusion through two R1 groups that form a ring including a portion of A and optionally aromatic.
Exactly one N in X1-X4
X1, X2, X3, and X4 are each independently selected from N, CH, C—CH3, C—CH2—OH, C—OCH3, C—CH2—OCH3, or C-halogen, with one of X1-X4 required to be N.
Defined R2 substituent classes
R2 is C1-C4 alkyl, (C0-C4 alkyl)(C3-C7 cycloalkyl), (C0-C4 alkyl)(C4-C7 heterocycloalkyl), or (C0-C4 alkyl)(C4-C10 bicyclic), each optionally substituted with one or more groups independently selected from deuterium, halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl.
Pharmaceutically acceptable salts
The compound is covered as a pharmaceutically acceptable salt thereof.
Enantiomer-specific compound coverage
Dependent coverage includes a compound that is the R-enantiomer or the S-enantiomer, each as a pharmaceutically acceptable salt thereof.
RET-associated cancer treatment
A method for treating cancer in a patient by administering an effective amount of the compound, or a pharmaceutically acceptable salt, wherein the cancer is a RET-associated cancer.
Specified RET-associated cancer types
The treatment method is further limited to cancer selected from 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, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.
Overall, the claims define structurally constrained compounds based on an aryl or heteroaryl ring A, an optional ring-fused R1 framework, an X1-X4 pattern with exactly one N, and restricted R2 substituent classes, with coverage extended to pharmaceutically acceptable salts. The claim set also includes enantiomer-specific compounds and therapeutic method claims for treating RET-associated cancers, including methods limited to specified cancer types.
Stated Advantages
Low-nM potency is reported for multiple example compounds across wildtype RET and V804M/G810S mutant RET, with IC50 <100 nM and EC50 <100 nM.
Addresses the need for new inhibitors because RET genetic alterations may reduce efficacy of RET inhibitors.
Documented Applications
Treating cancer in a patient by administering an effective amount of the compound or a pharmaceutically acceptable salt where the cancer is a RET-associated cancer.
RET enzyme inhibition and RET cell autophosphorylation assay readouts, including autophosphorylation of RET at tyrosine 1062, for compounds described as RET kinase inhibitors.
Cancer treatment use-case refined to 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, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.
Interested in licensing this patent?