Fatty acid analogues and methods of use
Provided herein are compounds, pharmaceutical compositions, and methods of treatment for various diseases or conditions, such as cancer. In one aspect, the method comprises the treatment of metastatic cancers. Compounds and methods provided herein are also used for the treatment of diseases such as inflammatory disease, cardiovascular disease, autoimmune disease, and dry eye syndrome. Further provided herein are dietary supplement formulations and methods for supporting a healthy lifestyle.
1. A compound of Formula (Ia-1) or (Ia-2), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
D is —CO 2 H or —C(═O) NR 7 R 9 ;
W is —(CH 2 ) p -(L) n -(CH 2 ) q ;
tis 0-2;
each L is independently —(CR 1 R 2 )—, —O-alkylene-, —NR 7 -alkylene-, —S-alkylene-, —S(═O)-alkylene, or —S(═O) 2 -alkylene wherein R 1 and R 2 are not both alkyl when the compound is of the Formula (Ia-1);
Ring A is substituted aryl, substituted heteroaryl, or substituted C 2 -C 8 heterocycloalkyl wherein each of the substituents of the substituted aryl, substituted heteroaryl, or substituted C 2 -C 8 heterocycloakyl is itself unsubstituted; wherein if Ring A is heteroaryl or C 2 -C 8 heterocycloakyl then at least one substituent of the substituted heteroaryl or the substituted C 2 -C 8 heterocycloakyl is CF 3 ; and wherein if Ring A is substituted aryl then at least two substituent of the substituted aryl is each CF 3 ;
each R 1 or R 2 is independently hydrogen, halogen, —CN, —OR a , —SR a , —S(═O)R b , —NO 2 , —NR c R d , —S(═O) 2 R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O) NR c R d , —OC(═O) NR c R d , —NR a C(═O) NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d ;
R a is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OMe, or —NH 2 ;
R b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OMe, or —NH 2 ;
each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —OMe, or —NH 2 ;
R 3 is hydrogen, —S(═O)R b , —S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —CO 2 R a , —C(═O) NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d ;
R 4 is hydrogen, —S(═O)R b , —S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —CO 2 R a , —C(═O) NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR a , or —NR c R d ;
R 7 and R 9 are independently hydrogen;
each R 8 is independently hydrogen, —S(═O)R b , —S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —CO 2 R a , —C(═O) NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl;
wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d , wherein R a , R b , R c and R d each is not C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl;
m is 1-5;
n is 0-3;
p is 0-9;
q is 0-5; and
the atom chain connecting D and —NR 3 C (—O) NR 4 — or —NR 3 C(═O)— is 11, 12, 13, or 14 atoms.
2. The compound of claim 1 , wherein D is —CO 2 H.
3. The compound of claim 1 , wherein D is —C(═O)NR 7 R 9 .
4. The compound of claim 1 , wherein R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 haloalkyl.
5. The compound of claim 1 , wherein R 1 and R 2 are independently hydrogen.
6. The compound of claim 1 , wherein R 1 and R 2 are hydrogen.
7. The compound of claim 1 , wherein R 3 and R 4 are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 haloalkyl.
8. The compound of claim 1 , wherein R 3 and R 4 are independently hydrogen.
9. The compound of claim 1 , wherein R 3 and R 4 are H.
10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is selected from:
11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated as a capsule.
13. A method of treating a proliferative disease, wherein the method comprises administering the compound or pharmaceutical composition of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to a subject in need thereof.
14. The method of claim 13 , wherein the proliferative disease is cancer.
15. The method of claim 14 , wherein the cancer is non-melanoma skin cancer, lung cancer, brain cancer, breast cancer, prostate cancer, colorectal cancer, bladder cancer, melanoma, non-Hodgkin lymphoma, kidney cancer, leukemia, pancreatic cancer, mesothelioma, head and neck cancer, gastric cancer, small cell lung cancer, or eye cancer.