Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
Inventors
Fu, Jiping • Lou, Yan • HE, Yigang
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11459340-B2
Publication Date
2022-10-04
Expiration Date
Abstract
The present disclosure provides certain tri-substituted heteroaryl derivatives that are Src Homology-2 phosphatase (SHP2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of SHP2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
Core Innovation
The invention is directed to compounds of Formula (I′/I) defined by a multi-ring heteroaryl framework. Ring A is a heteroaryl of formula (d), ring E is a 4 to 7 membered heterocycle containing 1 or 2 heteroatoms independently selected from O, N, S, and SO2, and W is O, CH2, or N. The structure further includes Q1, Q2, R2, and a linkage L, with isotopic options including hydrogen or deuterium and CD or deuterated variants.
The compound definition also includes a ring of formula (a) and a ring D. Ring of formula (a) is characterized by m and n, with an allowance for replacement of one CH2 with O, S, or SO2 when n is 2, and ring D is phenyl or a 5 or 6 membered heteroaryl ring containing one to three heteroatoms independently selected from N, O, and S. Ring D can be optionally substituted with one or two groups selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, cycloalkyl, heterocyclyl, heteroaryl, and acylamino.
The disclosed embodiments also include narrowed structural subsets in which Ra, Rb, and Rc are constrained and Ra and Rc can, when attached to the same carbon atom, together with that carbon atom form cycloalkylene or heterocyclylene. The structural scope further includes enumerated embodiments corresponding to formulas (III) to (VI), together with pharmaceutical composition scope including a pharmaceutically acceptable excipient.
Claims Coverage
One independent claim is present, covering a compound of Formula (I′/I) with five main inventive features centered on defined ring systems, substituent patterns, isotopic variants, linkage options, and a ring D/ring of formula (a) framework. Dependent claims further narrow L, R2, and enumerated formula representations, and add pharmaceutical composition scope.
Formula (I′/I) compound with defined ring A and ring E
A compound of Formula (I′/I) wherein ring A is a heteroaryl of formula (d), ring E is a 4 to 7 membered heterocycle containing 1 or 2 heteroatoms selected from O, N, S, and SO2, and W is O, CH2, or N substituted with Ra, Rb, and/or Rc.
Defined substituent sets for Ra, Rb, and Rc
Ra and Rb are independently selected from hydrogen, amino, alkyl, alkenyl, halo, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, and alkoxycarbonyl, and Rc is hydrogen, alkyl, halo, hydroxy, or alkoxy, with the proviso that when Ra and Rc are attached to the same carbon atom they together with that carbon atom can form cycloalkylene or heterocyclylene.
Isotopic and deuterium-defined groups
Q1 is N or CR1 where R1 is hydrogen or deuterium, and Q2 is N or CH or CD.
Defined R2 substituent and linkage L
R2 is alkyl, halo, hydroxy, hydroxyalkyl, —CD2OH, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl, and L is bond, O, S, S(O), S(O)2, or CR5R6 where R5 and R6 are independently hydrogen or alkyl.
Ring of formula (a) and ring D with X/X1 constraint
The compound includes a ring of formula (a) defined by m and n with the stated CH2 replacement option when n is 2 and m+n is 1, 2, or 3, and ring D is phenyl or a 5 or 6 membered heteroaryl ring containing one to three heteroatoms selected from N, O, and S, with X and X1 independently N or C but only one of X and X1 being N.
Pharmaceutically acceptable salts and composition scope
The claimed subject matter includes pharmaceutically acceptable salts thereof and a pharmaceutical composition including the compound and a pharmaceutically acceptable excipient.
Specific linkage and R2 refinements
Dependent claims further limit L to S, S(O), or S(O)2, and limit R2 to hydroxyalkyl, alkyl, or halo, or to hydroxymethyl or —CD2OH.
Enumerated formulas (III) to (VI)
The compound is limited to a structure defined by one of formulas (III) to (VI).
Overall, the claims center on a single Formula (I′/I) compound architecture with defined ring A, ring E, ring of formula (a), and ring D elements, together with specified substituent, isotopic, and linkage options. Dependent claims refine these features, including specific sulfur-based L options, restricted R2 selections, enumerated structures (III) to (VI), and pharmaceutical composition scope.
Stated Advantages
Inhibition of SHP2 by contacting SHP2.
Therapeutic use for disease treatment including cancer and Noonan syndrome and Leopard syndrome.
Use as a medicament.
Documented Applications
Therapeutic use for SHP2 inhibition in cancer, including specific cancer types, as well as Noonan syndrome and Leopard syndrome.
Use as a medicament for SHP2 inhibition.
Use in a pharmaceutical composition including a pharmaceutically acceptable excipient.
Interested in licensing this patent?