Compounds for targeted degradation of interleukin-2-inducible T-cell kinase and methods of use

1 . A compound of formula (I),

wherein

R 1 represents

 and

R 2 represents O or

wherein the degron has a structure represented by any one of formulas D1a-j:

 wherein X 1 is independently absent, CH 2 , NH, or O; and X 2 is alkyl, halo, CN, CF 3 , OCHF 2 or OCF 3 , or has a structure represented by any one of formulas D2-a-f:

 wherein Y′ is a bond, NH, O or CH 2 ;

 wherein Z is a C 5 -C 6 carbocyclic or a 5-6 membered heterocyclic group;

 wherein R′ is H, F or CN, and Y′ is a bond, NH, O or CH 2 , or a stereoisomer thereof, or

has a structure represented by any one of formulas D3-a-c:

 or a stereoisomer thereof, or has a structure represented by any one of formulas D4-a-b:

 and

the linker comprises an alkylene chain or a polyethylene glycol chain, either of which may be interrupted by and/or terminate at either or both termini in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different,

or a pharmaceutically acceptable salt or stereoisomer thereof.

2 . The compound of claim 1 , wherein R 1 represents

and the compound is represented by formula Ia:

 or a pharmaceutically acceptable salt or stereoisomer thereof.

3 . The compound of claim 2 , wherein R 2 represents O and the compound is represented by formula Ia1:

 or a pharmaceutically acceptable salt or stereoisomer thereof, or

wherein R 2 represents

 and the compound is represented by formula Ia2:

 or a pharmaceutically acceptable salt or stereoisomer thereof.

4 . The compound of claim 1 , wherein R 1 represents

 and the compound is represented by formula Ib:

 or a pharmaceutically acceptable salt or stereoisomer thereof.

5 . The compound of claim 4 , wherein R 2 represents O and the compound is represented by formula Ib1:

 or a pharmaceutically acceptable salt or stereoisomer thereof, or

wherein R 2 represents

 and the compound is represented by formula Ib2:

 or a pharmaceutically acceptable salt or stereoisomer thereof.

6 . The compound of claim 1 , wherein the linker comprises an alkylene chain which may be interrupted by and/or terminate at either or both termini in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different.

7 . The compound of claim 1 , wherein the linker comprises a polyethylene glycol chain which may terminate at either or both termini in at least one of —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —S—CR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the one or both terminating groups may be the same or different.

8 . The compound of claim 1 , wherein the linker is represented by any one of the following structures:

9 . The compound of claim 1 , which is represented by any one of the following structures:

 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each “n” may be the same or different.

10 . The compound of claim 1 , wherein the degron has a structure represented by any one of formulas D1a-j:

 wherein X 1 is independently absent, CH 2 , NH, or O; and X 2 is alkyl, halo, CN, CF 3 , OCHF 2 or OCF 3 .

11 . The compound of claim 10 , which is represented by any one of the following structures:

 or a pharmaceutically acceptable salt or stereoisomer thereof.

12 . The compound of claim 1 , wherein the degron has a structure represented by any one of formulas D2-a-f:

 wherein Y′ is a bond, NH, O or CH 2 ;

 wherein Z is a C 5 -C 6 carbocyclic or a 5-6 membered heterocyclic group;

 wherein R′ is H, F or CN, and Y′ is a bond, NH, O or CH 2 , or a stereoisomer thereof.

13 . The compound of claim 12 , which is represented by any one of the following structures:

 or a pharmaceutically acceptable salt or stereoisomer thereof.

14 . The compound of claim 1 , wherein the degron has a structure represented by any one of formulas D3-a-c:

 or a stereoisomer thereof.

15 . The compound of claim 14 , which is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

16 . The compound of claim 1 , wherein the degron has a structure represented by any one of formulas D4-a-b:

17 . The compound of claim 16 , which is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

18 . The compound of claim 1 , which is represented by any one of the following structures:

 or a pharmaceutically acceptable salt or stereoisomer thereof.

19 . The compound of claim 18 , which is:

or a pharmaceutically acceptable salt thereof.

20 . A pharmaceutical composition, comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of claim 1 , and a pharmaceutically acceptable carrier.

21 . The pharmaceutical composition of claim 20 , which is in the form of a tablet, a capsule, or a liquid suitable for oral or parenteral administration.

22 . A method of treating a disease or disorder, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of claim 1 to a subject in need thereof, wherein the disease or disorder is inflammatory myofibroblastic tumor (IMT), breast cancer, colorectal cancer, esophageal squamous cell cancer (ESCC), renal cell cancer (RCC), colorectal cancer, melanoma, non-small cell lung cancer (NSCLC), cutaneous T-cell lymphoma, peripheral T-cell lymphoma, multiple myeloma, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, T-cell prolymphocytic leukemia, or T-cell large granular lymphocyte leukemia.

23 . The method of claim 22 , wherein the disease or disorder is inflammatory myofibroblastic tumor (IMT), breast cancer, colorectal cancer, esophageal squamous cell cancer (ESCC), renal cell cancer (RCC), colorectal cancer, melanoma, non-small cell lung cancer (NSCLC), cutaneous T-cell lymphoma, or peripheral T-cell lymphoma.

24 . The method of claim 22 , wherein the disease or disorder is multiple myeloma, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, cutaneous T-cell lymphoma, T-cell prolymphocytic leukemia, T-cell large granular lymphocyte leukemia, or peripheral T-cell lymphoma.

25 . The method of claim 22 , wherein the subject is administered an additional therapeutic agent.

26 . The method of claim 25 , wherein the additional therapeutic agent is an immune effector cell that expresses a chimeric antigen receptor.

27 . The method of claim 22 , wherein the disease or disorder is cutaneous T-cell lymphoma, peripheral T-cell lymphoma, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, T-cell prolymphocytic leukemia, or T-cell large granular lymphocyte leukemia.