Inhibitors of phosphoglycerate dehydrogenase (PHGDH) and uses thereof
The present invention provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, pro-drugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I), (II) or (III) for treating diseases associated with the over-expression of phosphoglycerate dehydrogenase (PHGDH) in a subject, such as proliferative diseases (e.g., cancers (e.g., breast cancer, ER negative breast cancer, melanoma, cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases). Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the activity of PHGDH or inhibit the serine biosynthetic pathway, or both.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
W 2 is of formula:
L 2 is —CH 2 —;
L is —CH 2 —;
A 2 is of the formula:
R A is halogen, nitrile, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
j is 0 or 1;
R 1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 4 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , or —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 5 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each R 6 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , or —C(═O)NR c R d ;
each R a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
each R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
each of R c and R d is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R c and R d are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
each R e is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a sulfur protecting group;
each R f is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
k6 is 0, 1, 2, 3, or 4; and
z is 1 or 2.
2. The compound of claim 1 , wherein R 5 is hydrogen.
3. The compound of claim 1 , wherein k6 is 0.
4. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein W 2 is:
7. The compound of claim 1 , wherein W 2 is:
8. The compound according to claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
10. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
W 2 is of formula:
L 2 is —CH 2 —;
L 4 is —CH 2 —;
A 2 is of the formula:
R A is halogen, nitrile, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
j is 0 or 1;
R 1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 4 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , or —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 5 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each R 6 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , or —C(═O)NR c R d ;
each R a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
each R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
each of R c and R d is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R c and R d are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
each R e is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a sulfur protecting group;
each R f is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
k6 is 0, 1, 2, 3, or 4; and
z is 1 or 2;
provided that the compound is not N-(4,6-dimethylpyridin-2-yl)-4-(3-(trifluoromethyl)benzyl)piperazine-1-carbothioamide; wherein the disease is pulmonary fibrosis, renal cell carcinoma, or breast cancer.
11. The method of claim 10 , wherein the disease is pulmonary fibrosis or renal cell carcinoma.
12. The method of claim 10 , wherein the disease is breast cancer.
13. A method of inhibiting the activity of a phosphoglycerate dehydrogenase (PHGDH) in a subject or biological sample, the method comprising administering to the subject or contacting the biological sample with an effective amount of a compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
W 2 is of formula:
L 2 is —CH 2 —;
L 4 is —CH 2 —;
A 2 is of the formula:
R A is halogen, nitrile, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
j is 0 or 1;
R 1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 4 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , or —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 5 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each R 6 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , or —C(═O)NR c R d ;
each R a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
each R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
each of R c and R d is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R c and R d are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
each R e is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a sulfur protecting group;
each R f is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
k6 is 0, 1, 2, 3, or 4; and
z is 1 or 2;
provided that the compound is not N-(4,6-dimethylpyridin-2-yl)-4-(3-(trifluoromethyl)benzyl)piperazine-1-carbothioamide.
14. A method of inducing cell death in PHGDH-dependent cells in a subject or biological sample, the method comprising administering to the subject or contacting the biological sample with an effective amount of a compound Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
W 2 is of formula:
L 2 is —CH 2 —;
L 4 is —CH 2 —;
A 2 is of the formula:
R A is halogen, nitrile, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
j is 0 or 1;
R 1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 4 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , or —C(═O)R f , —C(═O)OR b , —C(═O)NR c R d , —S(═O)R f , —S(═O)OR b , —S(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 OR b , or —S(═O) 2 NR c R d ;
R 5 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each R 6 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —NR c R d , —SR e , —C(═O)R f , —C(═O)OR b , or —C(═O)NR c R d ;
each R a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
each R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
each of R c and R d is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or R c and R d are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
each R e is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a sulfur protecting group;
each R f is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
k6 is 0, 1, 2, 3, or 4; and
z is 1 or 2;
provided that the compound is not N-(4,6-dimethylpyridin-2-yl)-4-(3-(trifluoromethyl)benzyl)piperazine-1-carbothioamide.
15. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof; wherein the disease is pulmonary fibrosis, renal cell carcinoma, or breast cancer.
16. The method of claim 15 , wherein the disease is pulmonary fibrosis or renal cell carcinoma.
17. The method of claim 15 , wherein the disease is breast cancer.
18. A method of inhibiting the activity of a phosphoglycerate dehydrogenase (PHGDH) in a subject or biological sample, the method comprising administering to the subject or contacting the biological sample with a compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
19. A method of inducing cell death in PHGDH-dependent cells in a subject or biological sample, the method comprising administering to the subject or contacting the biological sample with a selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
20. The method of claim 13 , wherein the method is for inhibiting the activity of a phosphoglycerate dehydrogenase (PHGDH) in a biological sample.
21. The method of claim 14 wherein the method is for inducing cell death in PHGDH-dependent cells in a biological sample.
22. The method of claim 18 , wherein the method is for inhibiting the activity of a phosphoglycerate dehydrogenase (PHGDH) in a biological sample.
23. The method of claim 19 , wherein the method is for inducing cell death in PHGDH-dependent cells in a biological sample.
24. The method of claim 10 wherein the compound is the following:
or a pharmaceutically acceptable salt thereof.
25. The method of claim 15 , wherein the compound is the following:
or a pharmaceutically acceptable salt thereof.