MAP4K1 inhibitors
One embodiment of the disclosure is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The variables in Formula I are defined herein. Compounds of Formula I are selective MAP4K1 inhibitors, which can be used to treat a diseases or disorders in a subject that benefits from control of MAP4K1 activity.
1. A method for treating a MAP4K1-dependent disorder or disease that is a cancer or a viral infection, comprising administering to a subject in need thereof an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
A 1 and A 2 are selected from N and CH;
A 3 is selected from CH and N;
X is selected from C 1-3 alkyl, OR 6 , NHR 7 and halogen;
B is selected from CR 11 and N, Y is selected from N and CR 12 , and the bond between Y and B is a double bond; or
B is C(O), Y is NR 14 , and the bond between Y and B is a single bond; or Y and B taken together form a 5 to 7-membered heterocycle or C 5-6 cycloalkyl, and the bond between Y and B is a double bond, wherein said heterocycle or cycloalkyl is optionally substituted with 1-6 R 8 ;
each R 8 is independently selected from C 1-3 alkyl and OH, or
two R 8 attached to the same carbon form an oxo, or
two R 8 attached to the same carbon atom taken together with the carbon atom to which they are attached form a C 3-5 cycloalkyl, or
two R 8 attached to two adjacent carbon atoms taken together with the two adjacent carbon atoms to which they are attached form a C 3-6 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with 1-6 halogen;
R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, and 3 to 5-membered heterocycle, wherein said alkyl and cycloalkyl are optionally substituted with OH, C 1-6 alkoxy or 1-6 halogen; or
R 1 and R 2 , taken together with the atoms to which they are attached, form a 4 to 6-membered heterocycle or C 3-6 cycloalkyl;
R 3 and R 4 are each independently selected from hydrogen, C 1-6 alkyl substituted with OR 16 , C 1-6 alkyl, C 3-6 cycloalkyl and 4 to 6-membered heterocycle; or
R 3 and R 4 , taken together with the atoms to which they are attached, form a C 3-6 cycloalkyl or 4 to 6-membered heterocycle; or
R 1 and R 3 , taken together with the atoms to which they are attached, form a 3 to 6-membered heterocycle;
R 6 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4 to 6-membered heterocycle, wherein said alkyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 R 9 ;
R 7 is selected from hydrogen, C 1-3 alkyl, C 3-5 cycloalkyl and 4 to 6-membered heterocycle, wherein said alkyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 R 9 ;
R 9 is selected from C 1-3 alkyl, C 3-6 cycloalkyl substituted with halogen, halogen, C 1-3 alkoxy, and OH;
R 11 is selected from hydrogen, COOH, CN, halogen, and C 1-3 alkoxy;
R 12 is selected from C 1-5 alkyl, C 4-6 cycloalkyl, 3 to 6-membered heterocycle, NH R 13 ,
NR 13 R 13 and OR 13 , wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with OH, NH 2 , 1-4 halogen or R 16 ;
each R 13 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with halogen;
R 14 is selected from C 1-6 alkyl, C 3-6 cycloalkyl and 4 to 6-membered heterocycle, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-6 halogen;
R 15 is OH, C 1-3 alkyl or C 3-5 cycloalkyl; and
R 16 is H or C 1-3 alkyl, and
wherein the cancer comprises at least one cancer selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, bladder cancer, stomach cancer, liver cancer, cancer of the head and neck, lymphoma, leukemia, melanoma, urothelial carcinoma, merkel cell carcinoma, gastroesophageal junction carcinoma, esophageal squamous cell carcinoma, skin squamous cell carcinoma, endometrial cancer, thyroid cancer, brain cancer, multiple myeloma, myeloproliferative diseases, and sarcoma.
2. The method of claim 1 , wherein the cancer comprises at least one cancer selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, bladder cancer, stomach cancer, liver cancer, cancer of the head and neck, lymphoma, leukemia, melanoma, urothelial carcinoma, merkel cell carcinoma, gastroesophageal junction carcinoma, esophageal squamous cell carcinoma, skin squamous cell carcinoma, endometrial cancer, thyroid cancer, brain cancer, multiple myeloma, myeloproliferative diseases, and sarcoma.
3. The method of claim 1 , wherein the MAP4K1-dependent disorder or disease is a viral infection.
4. The method of claim 1 , wherein:
X is selected from OR 6 , NHR 7 and halogen; and
R 3 and R 4 are each independently selected from hydrogen, C 1-6 alkyl substituted with OH, C 1-6 alkyl, C 3-6 cycloalkyl and 4 to 6-membered heterocycle; or
R 3 and R 4 , taken together with the atoms to which they are attached, form a C 3-6 cycloalkyl or 4 to 6-membered heterocycle; or
R 1 and R 3 , taken together with the atoms to which they are attached, form a 3 to 6-membered heterocycle.
5. The method of claim 4 , wherein the compound is represented by Formula II, Formula III or Formula IV:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , wherein the compound is represented by Formula V or VI:
or a pharmaceutically acceptable salt thereof,
wherein E is CH 2 , NH, or O; R 8 is C 1-3 alkyl, and n is 0 to 4; two R 8 groups attached to the same carbon atom taken together with the carbon atom to which they attach form a C 3-5 cycloalkyl; or two R 8 groups attached to two adjacent carbon atoms taken together with the two adjacent carbon atoms to which they are attached form a C 4-6 cycloalkyl.
7. The method of claim 6 , wherein the compound is represented by Formula V(B) or VI(B):
or a pharmaceutically acceptable salt thereof.
8. The method of claim 7 , wherein R 8 is methyl and n is 0, 1, 2, 3, or 4.
9. The method of claim 7 , wherein two R 8 attached to the same carbon atom taken together with the carbon atom to which they are attached form a cyclopropyl; or two R 8 attached to two adjacent carbon atoms taken together with the two adjacent carbon atoms to which they are attached form a cyclopentyl.
10. The method of claim 5 , wherein the compound is represented by Formula VII, VIII or IX:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 , wherein:
R 11 is CN; and
R 12 is selected from isopropyl, fluoropropyl, trifluoroisopropyl, isobutyl, tert-butyl, isopropyloxy, methylpyrrolidine, methylazetidine, and hydroxycyclohexyl.
12. The method of claim 5 , wherein the compound is represented by Formula X:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 , wherein R 14 is isobutyl.
14. The method of claim 5 , wherein X is OR 6 and R 6 is selected from methyl, ethyl, propyl, isopropyl, trifluoroethyl, trifluoroisopropyl, difluoroethyl, difluoropropyl, difluoroisopropyl, oxetanyl, tetrahydrofuranyl, cyclobutyl, and cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or one or two fluoro, wherein cyclobutyl is optionally substituted with OH, and wherein oxetanyl is optionally substituted with methyl.
15. The method of claim 5 , wherein X is NEM 7 and R 7 is selected from methyl, ethyl, cyclopropyl and cyclobutyl.
16. The method of claim 5 , wherein X is methyl.
17. The method of claim 5 , wherein R 3 and R 4 are each independently selected from hydrogen, methyl, methyl substituted with OCH 3 , ethyl, hydroxymethyl, cyclopropyl and cyclobutyl.
18. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.