US-12624043-B2 - Compositions useful for treating disorders related to kit

US12624043B2US 12624043 B2US12624043 B2US 12624043B2US-12624043-B2

Abstract

Compounds and compositions useful for treating disorders related to mutant KIT are described herein.

Inventors

Brian L. Hodous

Assignees

BLUEPRINT MEDICINES CORPORATION

Dates

Publication Date: 20260512
Application Date: 20231023

Claims (4)

1 . A compound having the structure: or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 ,
3 . A compound having the structure: or a pharmaceutically acceptable salt thereof or a tautomer thereof or a pharmaceutically acceptable salt of the tautomer thereof.
4 . The compound of claim 3 , or a tautomer thereof.

Description

CLAIM OF PRIORITY This application is a continuation of U.S. patent application Ser. No. 17/983,747, filed Nov. 9, 2022, which, in turn, is a continuation of U.S. patent application Ser. No. 17/070,556, filed Oct. 14, 2020, which is a continuation of U.S. patent application Ser. No. 15/973,378, filed May 7, 2018, now U.S. Pat. No. 10,807,985, which is a continuation of U.S. patent application Ser. No. 14/887,614, filed Oct. 20, 2015, now U.S. Pat. No. 9,994,575, which is a continuation of U.S. patent application Ser. No. 14/515,327, filed Oct. 15, 2014, now U.S. Pat. No. 9,200,002, which claims priority to U.S. Provisional Application No. 61/975,229, filed Apr. 4, 2014; U.S. Provisional Application No. 61/931,204, filed Jan. 24, 2014, and U.S. Provisional Application No. 61/892,086, filed Oct. 17, 2013, the contents of each of which are incorporated herein by reference in their entirety. BACKGROUND The invention relates to compounds and compositions useful for treating disorders related to KIT and PDGFR. The enzyme KIT (also called CD117) is a receptor tyrosine kinase expressed on a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain of KIT induces receptor dimerization and activation of downstream signaling pathways. KIT mutations generally occur in the DNA encoding the juxtumembrane domain (exon 11). They also occur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18. Mutations make KIT function independent of activation by SCF, leading to a high cell division rate and possibly genomic instability. Mutant KIT has been implicated in the pathogenesis of several disorders and conditions including systemic mastocytosis, GIST (gastrointestinal stromal tumors), AML (acute myeloid leukemia), melanoma, and seminoma. As such, there is a need for therapeutic agents that inhibit KIT, and especially agents that inhibit mutant KIT. Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. A PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance. As such, there is a need for agents that target this mutation. SUMMARY OF THE INVENTION The present invention features compounds and compositions for treating or preventing conditions such as mastocytosis and mast cell diseases by modulating the activity of KIT, such compounds having the structural Formula I or a pharmaceutically acceptable salt thereof, wherein: W is selected from hydrogen or wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, cycloalkyl or heterocyclyl; each X and Y is independently selected from CR1 or N;Z is C1-C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl; wherein each of C1-C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl is independently substituted with 0-5 occurrences of RC;L is selected from a bond, —(C(R2)(R2))m—, —(C2-C6 alkynylene)-, —(C2-C6 alkenylene)-, —(C1-C6 haloalkylene)-, —(C1-C6 heteroalkylene)-, —(C1-C6 hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —SO2—, —N(R2)—, —O—(C1-C6 alkylene)-, —(C1-C6 alkylene)-O—, —N(R2)—CO—, —CO—N(R2)_, —(C1-C6 alkylene)-N(R2)—, —N(R2)—(C1-C6 alkylene)-, —N(R2)—CO—(C1-C6 alkylene)-, —CO—N(R2)—(C1-C6 alkylene)-, —N(R2)—SO2—, —SO2—N(R2)—, —N(R2)—SO2—(C1-C6 alkylene)-, or —SO2—N(R2)—(C1-C6 alkylene)-;each RA and RB is independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 heterocyclyl, halo, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, monocyclic or bicyclic aralkyl, —N(R2)(R2), cyano, —OR2;each RC is independently selected from C1-C6 alkyl, C1-C6 alkynyl, halo, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano, —C(O)R2, —OC(O)R2, —C(O)OR2, —SR2, —S(O)2R2, —S(O)2—N(R2)(R2), —(C1-C6 alkylene)-S(O)2—N(R2)(R2), —N(R2)(R2), —C(O)—N(R2)(R2), —N(R2)(R2)—C(O)R2, —(C1-C6 alkylene)-N(R2)—C(O)R2, —NR2S(O)2R2, —P(O)(R2)(R2), and —OR2; wherein each of heteroalkyl, haloalkyl, haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl is independently substitu