Organophosphorus-substituted compounds as c-MET inhibitors and therapeutic uses thereof
The present disclosure provides [1,2,4]triazolo[4,3-b][1,2,4]triazine, [1,2,4] triazolo[4,3-b]pyridazine, and [1,2,3]triazolo[4,5-b]pyrazine derivatives, and pharmaceutically acceptable salts, solvates or prodrugs thereof, as tyrosine kinase c-MET inhibitors, which are useful as novel anticancer and/or anti-inflammatory agents.
1. A compound of formula (I):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
A is absent, arylene or heteroarylene, each optionally substituted by one to four substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, C 1 -C 6 acyl, cyano, nitro, and NR c R d ;
L is absent, O, S, NR 1 , C(O), or C(R L ) 2 , wherein R L at each occurrence is independently hydrogen, halogen, or C 1 -C 4 alkyl;
Q is absent or C(R Q ) 2 , wherein R Q at each occurrence is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkoxy;
X and Y are each C or N;
Z is CR Z or N, wherein R Z is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkoxy;
when X is C and Y is N, then W is O, NR 1 , S, or CR 5 R 6 ;
when X is N, then W is CR 5 R 6 , provided that at least one of X and Y is N,
R 1 is H or C 1 -C 6 alkyl;
R 2 and R 3 are each independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR 4 , —NR 7 R 8 , or —OCH 2 (C═O)OR 9 , wherein said alkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl is each optionally substituted by one to five substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, halogen, cyano, nitro, —OR 9 , —SR 9 , —C(O)OR 9 , —C(O)R 10 , —NR a R b , and —C(O)NR c R d ; or alternatively R 2 and R 3 together with the phosphorus atom to which they are attached form a 4- to 8-membered ring optionally substituted with one to five substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, halogen, cyano, nitro, —OR 9 , —SR 9 , —C(O)OR 9 , —C(O)R 10 , —NR a R b , —C(O)NR c R d , and oxo;
R 4 at each occurrence is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or arylalkyl, each except hydrogen optionally substituted;
R 5 and R 6 are each independently selected from H, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; or R 5 and R 6 together form oxo (═O) or with the carbon atom to which they are attached form a 3- to 6-membered ring optionally substituted by one to five substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
R 7 and R 8 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; or alternatively, R 7 and R 8 together with the nitrogen atom to which they are attached, form a 4- to 6-membered ring, wherein said 4- to 6-membered ring optionally may contain one to five substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, and —OR 9 ;
B is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, CN, P(═O)(R 9 ) 2 , P(═O)(OR 9 ) 2 , —C(O)R 10 , —CO 2 R 9 , —OR 9 , —SR 9 , —NR a R b , —CONR a R b , —NR 12 C(O)R 10 , —NR 12 SO 2 R 11 , —NR 12 SO 2 NR a R b , —SO 2 R 11 , and —SO 2 NR a R b ;
R 9 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, or C 6 -C 10 aryl;
R 10 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, each except hydrogen optionally substituted;
R 11 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl, each optionally substituted;
R 12 each occurrence is independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;
wherein, unless specifically defined, cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one to five substituents independently selected from the group consisting of halogen, cyano, nitro, —OR 13 , —SR 13 , C 1 -C 6 alkyl, C 6 -C 10 aryl, —NR a R b , and —C(O)OR 14 ;
wherein, unless specifically defined, any said aryl and heteroaryl may optionally be substituted with one to five substituents independently selected from halogen, cyano, nitro, —OR 13 , —SR 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —C(O)OR 14 , —NR a R b , and —C(O)N c R d ;
R 13 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 14 at each occurrence is independently hydrogen or C 1 -C 6 alkyl;
R a and R b are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, and benzyl; and
R c and R d are independently hydrogen or C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein X is N, Y is C, and Z is N, having a structure of formula (II):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
3. The compound of claim 1 , wherein X is C, Y is N, and Z is CH, having a structure of formula (III):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
4. The compound of claim 1 , wherein X is C, Y is N, and Z is N, having a structure of formula (IV):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein A is arylene or heteroarylene each optionally substituted by one to four substituents independent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein A is selected from the group consisting of:
each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -C 4 haloalkoxy.
7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L is absent or NR 1 , and Q is absent or C(R Q ) 2 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L is absent, and Q is C(R Q ) 2 .
9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L is NR 1 , and Q is C(R Q ) 2 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L is NR 1 , and Q is absent.
11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L and Q are absent.
12. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein A, L, and Q are all absent.
13. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein B is heteroaryl or heterocyclyl, each optionally substituted with one to five substituents independently selected from the group consisting of halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O) R 10 , —CO 2 R 9 , —OR 9 , —NR a R b , —C(O) NR a R b , and —SO 2 NR a R b , wherein R 9 is hydrogen or C 1 -C 6 alkyl, R 10 is C 1 -C 4 alkyl, and R a and R b are each independently hydrogen or C 1 -C 4 alkyl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein B is selected from the group consisting of:
each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
15. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein W is C(R 5 R 6 ), wherein R 5 and R 6 are each independently H, halogen, or C 1 -C 4 alkyl.
16. The compound of claim 1 , wherein:
R 2 and R 3 are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —OR 4 , —NR 7 R 8 , and —OCH 2 (C═O)OR 9 , wherein said alkyl or cycloalkyl is optionally substituted by one to four substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, halogen, cyano, nitro, —OR 9 , —SR 9 , —C(O)OR 9 , —C(O) R 10 , —NR a R b , and —C(O) NR c R d ;
R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and benzyl;
R 7 and R 8 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 6 -C 10 aryl; or alternatively, R 7 and R 8 together with the nitrogen atom to which they are attached, form a 4- to 6-membered ring, wherein said 4- to 6-membered ring optionally may contain one to three substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, and —OR 9 ;
R 9 at each occurrence is independently H, C 1 -C 6 alkyl, or C 6 -C 10 aryl;
R 10 at each occurrence is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl;
R a and R b are each independently hydrogen or C 1 -C 6 alkyl; and
R c and R d are independently hydrogen or C 1 -C 4 alkyl.
17. The compound of claim 1 , having a structure of formula (V), (VI), (VII), or (VIII):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
i is 1, 2, 3, or 4;
j is 1 or 2; and
R A at each occurrence is independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, C 1 -C 6 acyl, cyano, nitro, and NR c R d ;
L 1 is a bond, O, S, NR 1 , or C(R L ) 2 , wherein R L at each occurrence is independently hydrogen, halogen, or C 1 -C 4 alkyl;
Q 1 is a bond or C(R Q ) 2 , wherein R Q at each occurrence is independently hydrogen, halogen, or C 1 -C 4 alkyl;
R 1 at each occurrence is independently H or C 1 -C 4 alkyl;
R 2 and R 3 are each independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —NR 7 R 8 , OR 4 , and —OCH 2 (C═O)OR 9 , wherein the alkyl is optionally substituted by one to three substituents independently selected from the group consisting of C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, halogen, cyano, nitro, —OR 9 , —SR 9 , —C(O)OR 9 , —C(O) R 10 , —NR a R b , and —C(O) NR c R d
R 4 at each occurrence is independently H, C 1 -C 4 alkyl, or phenyl;
W 1 is CR 5 R 6 , wherein R 5 and R 6 are each independently H, halogen, or C 1 -C 4 alkyl, or R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 6-membered ring optionally substituted;
R 7 and R 8 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; or alternatively, R 7 and R 8 together with the nitrogen atom to which they are attached, form a 4- to 6-membered ring, wherein said 4- to 6-membered ring optionally may contain one to three substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, and —OR 9 ;
“Het” is heteroaryl or heterocyclyl, each optionally substituted with one to four substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, and CN;
R 9 at each occurrence is independently H or C 1 -6 alkyl;
R 10 at each occurrence is independently H or C 1 -6 alkyl;
R 13 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 14 at each occurrence is independently hydrogen or C 1 -C 6 alkyl;
R a and R b are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, and benzyl; and
R c and R d are independently hydrogen or C 1 -C 6 alkyl.
18. The compound of claim 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is absent or NR 1 , and Q 1 is absent or C(R Q ) 2 .
19. The compound of claim 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is absent, and Q 1 is C(R Q ) 2 .
20. The compound of claim 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is NR 1 , and Q 1 is C(R Q ) 2 .
21. The compound of claim 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is NR 1 , and Q 1 is absent.
22. The compound of claim 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 and Q 1 are both absent.
23. The compound of claim 17 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the Het is selected from the group consisting of:
each optionally substituted by one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
24. The compound of claim 17 , wherein R 2 and R 3 are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —OR 4 , —NR 7 R 8 , and —OCH 2 (C═O)OR 9 , wherein said alkyl or cycloalkyl is optionally substituted by one to four substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, and C 3 -C 6 cycloalkyl; wherein R 4 is hydrogen or C 1 -C 6 alkyl, R 7 and R 8 are independently hydrogen or C 1 -C 4 alkyl, and R 9 is C 1 -C 4 alkyl.
25. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, selected from the Compound List 1
26. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, selected from the group consisting of:
27. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.
28. A method of treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the disease or disorder is associated with tyrosine kinase c-MET activity.
29. The method of claim 28 , wherein the disease or disorder is selected from the group consisting of gastric cancer, lung cancer, colon cancer, breast cancer, pancreatic cancer, esophageal cancer, colorectal cancers, ovarian cancers, glioblastomas, hepatocellular cancer, melanoma, sarcoma, fibrosarcoma, osteoma, neuroblastoma, teratocarcinoma, retinoblastoma, rhabdomyosarcoma, hematopoietic malignancy, malignant ascites, atherosclerosis, and fibrosis of the lung.
30. The method of claim 28 , wherein the disease or disorder is non-small cell lung cancer.