Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
The present disclosure provides certain fused tricyclic ring 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.
1. A compound of formula (IIB)
or a pharmaceutically acceptable salt thereof, wherein:
Z is —Y-M, wherein Y is a bond and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are substituted with —O(alk)OR a , wherein R a is alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or Z is methoxymethyloxy, methoxyethyloxy, methoxymethyl, cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl;
R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl;
R 5 and R 6 are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl, or wherein one of R 5 and R 6 is optionally substituted heterocyclyl and the other R 5 and R 6 is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;
L is bond, O, S, S(O), S(O) 2 , or CR 7 R 8 where R 7 and R 8 are independently hydrogen or alkyl;
R 9 is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;
R 10 is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD 2 OH, alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl; and
R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is methoxymethyloxy, methoxyethyloxy, methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, or cyclopropylmethyloxymethyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, or methoxyethyloxymethyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, and amino.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 , R 2 , R 3 , and R 4 is hydrogen and the remaining three of R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, methyl, fluoro, methoxy, hydroxy, and amino.
8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein three of R 1 , R 2 , R 3 , and R 4 are hydrogen and the remaining one of R 1 , R 2 , R 3 , and R 4 is selected from hydrogen, methyl, fluoro, methoxy, hydroxy, and amino.
9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 3 , and R 4 are hydrogen.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is S, S(O) or S(O) 2 .
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein L is S.
12. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein L is S(O) 2 .
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen, amino, or alkyl.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydroxyalkyl.
16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydroxymethyl.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z is methoxymethyloxy, methoxyethyloxy, methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl;
R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, and amino;
L is S, S(O) or S(O) 2 ;
R 9 is hydrogen, amino, or alkyl; and R 10 is hydroxyalkyl.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected
20. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
21. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
23. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z is methoxymethyloxy, methoxyethyloxy, methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl;
R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, and amino;
L is S, S(O) or S(O) 2 ;
R 9 is hydrogen, amino, or alkyl;
R 10 is hydroxyalkyl; and
R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, or methoxyethyloxymethyl;
R 1 , R 2 , R 3 , and R 4 are hydrogen;
L is S, S(O) or S(O) 2 ;
R 9 is hydrogen;
R 10 is hydroxyalkyl; and
R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
26. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
27. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
28. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein L is S.
29. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
30. A compound of formula (IIB):
or a pharmaceutically acceptable salt thereof, wherein:
Z is —Y-M, wherein Y is a bond and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are substituted with alkoxy, —O(alk)OR a , wherein R a is alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or Z is alkoxy, cycloalkylmethyloxymethyl, heterocyclyloxy, heterocyclylmethyloxymethyl; wherein when Z is alkoxy, it is optionally substituted with methoxy;
R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl;
R 5 and R 6 are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl, or wherein one of R 5 and R 6 is optionally substituted heterocyclyl and the other R 5 and R 6 is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;
L is bond, O, S, S(O), S(O) 2 , or CR 7 R 8 where R 7 and R 8 are independently hydrogen or alkyl;
R 9 is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;
R 10 is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD 2 OH, alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl; and
R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
31. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein Z is methoxymethyloxy, methoxyethyloxy, methoxymethyl, methoxymethyloxymethyl, ethoxymetyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetan-3- ylmethyloxymethyl.
32. The compound of claim 31 , or pharmaceutically acceptable salt thereof, wherein Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl.
33. The compound of claim 32 , or a pharmaceutically acceptable salt thereof, wherein Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, or cyclopropylmethyloxymethyl.
34. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, or methoxyethymethyl.
35. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, and amino.
36. The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 , R 2 , R 3 , and R 4 is hydrogen and the remaining three of R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, methyl, fluoro, methoxy, hydroxy, and amino.
37. The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein three of R 1 , R 2 , R 3 , and R 4 are hydrogen and the remaining one of R 1 , R 2 , R 3 , and R 4 is selected form hydrogen, methyl, fluoro, methoxy, hydroxy, and amino.
38. The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 3 , and R 4 are hydrogen.
39. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein L is S, S(O) or S(O) 2 .
40. The compound of claim 39 , or a pharmaceutically acceptable salt thereof, wherein L is S.
41. The compound of claim 39 , or a pharmaceutically acceptable salt thereof, wherein L is S(O) 2 .
42. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen, amino or alkyl.
43. The compound of claim 42 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.
44. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydroxyalkyl.
45. The compound of claim 44 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydroxymethyl.
46. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein:
Z is methoxymethyloxy, methoxyethyloxy, methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetan-3- ylmethyloxymethyl;
R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, and amino;
L is S, S(O) or S(O) 2 ;
R 9 is hydrogen, amino, or alkyl; and R 10 is hydroxyalkyl.
47. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
48. The compound of claim 47 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
49. The compound of claim 47 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
50. The compound of claim 46 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
51. The compound of claim 50 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
52. The compound of claim 50 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
53. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein:
Z is methoxymethloxy, methoxyethyloxy, methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetan-3- ylmethyloxymethyl;
R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, and amino;
L is S, S(O) or S(O) 2 ;
R 9 is hydrogen, amino, or alkyl;
R 10 is hydroxyalkyl; and
R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
54. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein:
Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, or methoxyethyloxymethyl;
R 1 , R 2 , R 3 , and R 4 are hydrogen;
L is S, S(O) or S(O) 2 ;
R 9 is hydrogen;
R 10 is hydroxyalkyl; and
R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
55. The compound of claim 54 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
56. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 together with the carbon atom to which they are attached form a ring selected from
57. The compound of claim 54 , or a pharmaceutically acceptable salt thereof, wherein L is S.
58. A pharmaceutical composition comprising a compound of claim 30 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.