Heterogeneous Algebras and Their Uses

Abstract

The present disclosure provides compounds and pharma- ceutically acceptable salts thereof, as well as methods of use thereof.The compounds and methods have a wide range of applications as therapeutic, diagnostic, and research tools.In particular, the subject compositions and methods are useful for reducing the signaling output of oncogenic proteins.

Claims

1. Compounds of formula (Ia-3), or their pharmaceutically acceptable salts or solvates: 【Chemical 901】 (In the formula, W １ N is, W ２ C(R) ２ ) and W ３ C(R) ３ ) and W ４ C(R) ４ ) and R² is hydrogen, halogen, -CN, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ２－９ heterocycloalkyl, C ６－１０ aryl, C １－９ heteroaryl, -OR １２ , -SR １２ , -N(R １２ )(R １３ ), -C(O)OR １２ , -OC(O)N(R １２ )(R １３ ), -N(R １４ )(O)N(R １２ )(R １３ ), -N(R １４ )(O)OR １２ , -N(R １４ )(O)S ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ )(R １３ ), -C(O)C(O)N(R １２ )(R １３ ), -N(R １４ )(O)C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N(R １２ )(R １３ )-, S(=O)(=NH)N(R １２ )(R １３ ), -CH ２ C(O)N(R １２ )(R １３ ), -CH ２ N(R １４ )(O)C(O)R １５ , -CH ２ S(O) ２ R １５ , and -CH ２ S(O) ２ N(R １２ )(R １３ ), selected from, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryls have 1, 2, or 3 R's. ２０ｂ Replaced by optional selection, R3 is hydrogen, R4 is hydrogen, R ５ It is selected from hydrogen and halogens. R ６ It is -OH, R ７ It is hydrogen, R ９ and R ９ａ It is hydrogen, R10 is hydrogen, R １２ is selected from hydrogen, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, -CH ２ -C ３－６ cycloalkyl, C ２－９ heterocycloalkyl, -CH ２ -C ２－９ heterocycloalkyl, C ６－１０ aryl, -CH ２ -C ６－１０ aryl, and C １－９ heteroaryl, where C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, -CH ２ -C ３－６ cycloalkyl, C ２－９ heterocycloalkyl, -CH ２ -C ２－９ heterocycloalkyl, C ６－１０ aryl, -CH ２ -C ６－１０ aryl, and C １－９ heteroaryl may be optionally substituted with one, two, or three Rs ２０ｋ and, R １３ is hydrogen, C １－６ Alkyl and C １－６ Selected from haloalkyls, or R １２ and R １３ Together with the nitrogen atoms to which they are bonded, they form 1, 2, or 3 R atoms. ２０ｋ C replaced by arbitrary selection ２－９ Forming a heterocycloalkyl ring, R １４ is hydrogen, C １－６ Alkyl and C １－６ Selected from haloalkyl groups, R １５ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Selected from heteroaryls, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryls have 1, 2, or 3 R's. ２０ｋ Replaced by optional selection, Each R ２０ｂ And R20k is oxo, -CN, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Ariel, -CH ２ -C ６－１０ Ariel, C １－９ heteroaryl, -OR ２１ , -SR ２１ , -N(R ２２ ) (Caution ２３ ), -C(O)OR ２２ , -C(O)N(R ２２ ) (Caution ２３ ), -C(O)C(O)N(R ２２ ) (Caution ２３ ), -OC(O)N(R ２２ ) (Caution ２３ ), -N(R ２４ ) C(O)N(R ２２ ) (Caution ２３ ), -N(R ２４ ) C(O)OR ２２ , -N(R ２４ ) C(O)R ２５ , -N(R ２４ ) S(O) ２ R ２５ , -C(O)R ２５ , -S(O) ２ R ２５ , -S(O) ２ N(R) ２２ ) (Caution ２３ ), -OCH ２ C(O)OR ２２ , and -OC(O)R ２５ Selected independently from, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Ariel, -CH ２ -C ６－１０ Aryl, and C １－９ Heteroaryls include halogens, oxo, -CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ２１ , -SR ２１ , -N(R ２２ ) (Caution ２３ ), -C(O)OR ２２ , -C(O)N(R ２２ ) (Caution ２３ ), -C(O)C(O)N(R ２２ ) (Caution ２３ ), -OC(O)N(R ２２ ) (Caution ２３ ), -N(R ２４ ) C(O)N(R ２２ ) (Caution ２３ ), -N(R ２４ ) C(O)OR ２５ , -N(R ２４ ) C(O)R ２５ , -N(R ２４ ) S(O) ２ R ２５ , -C(O)R ２５ , -S(O) ２ R ２５ , -S(O) ２ N(R) ２２ ) (Caution ２３ ), and -OC(O)R ２５ It is optionally replaced by one, two, or three elements that are independently selected from the above. Each R ２１ H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Selected independently from heteroaryls, Each R ２２ H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Selected independently from heteroaryls, Each R ２３ H and C １－６ Selected independently of alkyl, Each R ２４ H and C １－６ Selected independently of alkyl, Each R ２５ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ (Selected from heteroaryls).

2. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is hydrogen.

3. R ５ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is hydrogen.

4. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is a halogen.

5. R ２ However, -OR １２ And, R １２ However, C １－６ Alkyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl and -CH ２ -C ２－９ Selected independently from heterocycloalkyl groups, where C １－６ Alkyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl and -CH ２ -C ２－９ Heterocycloalkyls have 1, 2, or 3 R ２０ｋ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is optionally substituted.

6. R ２ but, 【Chemistry 891】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the above.

7. R ２ However, -N(R １２ ) (Caution １３ ) and R １３ However, independently, it is hydrogen, R １２ However, C １－６ Alkyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Ariel, -CH ２ -C ６－１０ Ariel, C １－９ Heteroaryls and -CH ２ -C １－９ Selected independently from heteroaryls, where C １－６ Alkyl, C ３－６ Cycloalkyl, -CH ２ -C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -CH ２ -C ２－９ Heterocycloalkyl, C ６－１０ Ariel, -CH ２ -C ６－１０ Ariel, C １－９ Heteroaryls and -CH ２ -C １－９ Heteroaryls have 1, 2, or 3 R's. ２０ｋ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is optionally substituted.

8. R ２ but, 【Chemical Figure 892】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the above.

9. R ２ However, C １－６ Alkyl, C ２－９ Heterocycloalkyl, C １－９ heteroaryl, -OR １２ , -N(R １２ ) (Caution １３ ), -C(O)R １５ , -C(O)N(R １２ ) (Caution １３ ) is selected, where C １－６ Alkyl, C ２－９ Heterocycloalkyl and C １－９ Heteroaryls have 1, 2, or 3 R's. ２０ｂ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is optionally substituted.

10. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the following: 【Chemical Engineering 902-1】 【Chemical Engineering 902-2】 【Chemical Engineering 902-3】 。

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

12. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a drug for enhancing immunity in a subject that requires such enhancement, (a) Select the subject that shows expression or activity of PTPN2, (b) The use comprising downregulating the expression or activity of PTPN2.

13. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a drug for treating cancer in combination with cell therapy to a subject in need thereof.

14. A composition for use in a method of enhancing immunity in a subject requiring such enhancement, wherein the composition comprises a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, and the method is (a) Select the subject that shows expression or activity of PTPN2, (b) The composition comprising downregulating the expression or activity of PTPN2.

15. A composition for treating cancer in combination with cell therapy to a subject in need thereof, comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof.

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