Heterocyclic compounds and uses thereof
The present invention relates to pharmaceutical compounds, compositions and methods, especially as they are related to compositions and methods for the treatment and/or prevention of a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye or an immunologically related disease, and in some embodiments diseases or disorders related to the dysregulation of kinase such as, but not limited to, EGFR (including HER), Alk, PDGFR, BLK, BMX/ETK, FLT3(D835Y), ITK, TEC, TXK, BTK, or JAK, and the respective pathways.
1. A method for treating and/or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye or an immunologically related disease, or lupus, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (Ia)
wherein
R 1 is
NR c R d wherein
R c is H, C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring, said C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring being optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic ring being optionally substituted with C 1-4 alkyl that is further optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic ring being optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4, or said 3-7 member cyclic ring being optionally substituted with C 1-4 alkyl that is further optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4, or said 3-7 member cyclic ring being optionally substituted with R 8 CO, wherein R 8 is C 1-4 alkyl, and
R d is H, C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring, said C 1-4 alkyl, C 1-4 alkenyl or 3-7 member cyclic ring being optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl; or
3-7 member cyclic ring substituted with R a wherein R a is C 2-8 alkyl optionally substituted with halo, C 1-4 alkoxy or SO 2 (CH 2 ) q H, wherein q is 1-4; or
O(CH 2 ) m SO 2 (CH 2 ) n H, wherein m is 1-4 and n is 1-4;
R 2 is absent, H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 3 is hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 5 is absent, H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 6 is H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 7 is H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 9 is H, hydroxyl, halo, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 10 is H, hydroxyl, halo, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl; or
R 1 and R 5 are part of 3-7 member cyclic ring, said 3-7 member cyclic being optionally substituted with C 1-4 alkyl optionally substituted with OZ or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic being optionally substituted with R 8 CO, wherein R 8 is C 1-4 alkyl, or said 3-7 member cyclic being optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4; or
R 1 and R 2 are part of 3-7 member cyclic ring, optionally substituted with C 1-4 alkyl, said C 1-4 alkyl further optionally substituted with halo, OZ, or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl, or one or more members of said 3-7 member cyclic ring is optionally part of a carbonyl group or a sulfonyl group; or
R 2 and R 6 are part of 3-7 member cyclic ring, optionally substituted with C 1-4 alkyl optionally substituted with OZ or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl;
R 4 is C 2 alkenyl optionally substituted with C 1-4 alkyl, —CH 2 OCH 3 , or —CH 2 N(CH 3 ) 2 ;
X is O, C 1-4 alkyl optionally substituted with halo, or NR b , wherein R b is H, or C 1-8 alkyl optionally substituted with halo;
Y is C, CH optionally substituted with halo, or N;
A is C, CH optionally substituted with halo or N; and
wherein at least one of R 2 , R 3 , R 5 and R 6 is not H;
or a pharmaceutically acceptable salt thereof.
2. A combination for treating and/or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye or an immunologically related disease or lupus in a subject, which combination comprises an effective amount of a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and/or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye or an immunologically related disease or lupus in a subject; wherein the compound of Formula (Ia) is:
wherein
R 1 is
NR c R d wherein
R c is H, C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring, said C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring being optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic ring being optionally substituted with C 1-4 alkyl that is further optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic ring being optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4, or said 3-7 member cyclic ring being optionally substituted with C 1-4 alkyl that is further optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4, or said 3-7 member cyclic ring being optionally substituted with R 8 CO, wherein R 8 is C 1-4 alkyl, and
R d is H, C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring, said C 1-4 alkyl, C 1-4 alkenyl or 3-7 member cyclic ring being optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl; or
3-7 member cyclic ring substituted with R a wherein R a is C 2-8 alkyl optionally substituted with halo, C 1-4 alkoxy or SO 2 (CH 2 ) q H, wherein q is 1-4; or
O(CH 2 ) m SO 2 (CH 2 ) n H, wherein m is 1-4 and n is 1-4;
R 2 is absent, H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 3 is hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 5 is absent, H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 6 is H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 7 is H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 9 is H, hydroxyl, halo, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 10 is H, hydroxyl, halo, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl; or
R 1 and R 5 are part of 3-7 member cyclic ring, said 3-7 member cyclic being optionally substituted with C 1-4 alkyl optionally substituted with OZ or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic being optionally substituted with R 8 CO, wherein R 8 is C 1-4 alkyl, or said 3-7 member cyclic being optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4; or
R 1 and R 2 are part of 3-7 member cyclic ring, optionally substituted with C 1-4 alkyl, said C 1-4 alkyl further optionally substituted with halo, OZ, or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl, or one or more members of said 3-7 member cyclic ring is optionally part of a carbonyl group or a sulfonyl group; or
R 2 and R 6 are part of 3-7 member cyclic ring, optionally substituted with C 1-4 alkyl optionally substituted with OZ or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl;
R 4 is C 2 alkenyl optionally substituted with C 1-4 alkyl, —CH 2 OCH 3 , or —CH 2 N(CH 3 ) 2 ;
X is O, C 1-4 alkyl optionally substituted with halo, or NR b , wherein R b is H, or C 1-8 alkyl optionally substituted with halo;
Y is C, CH optionally substituted with halo, or N;
A is C, CH optionally substituted with halo or N; and
wherein at least one of R 2 , R 3 , R 5 and R 6 is not H;
or a pharmaceutically acceptable salt thereof.
3. A method for treating and/or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye or an immunologically related disease or lupus in a subject, which methods comprises administering to a subject in need thereof an effective amount of the combination of claim 2 .
4. A method for inhibiting an activity of a Bruton's tyrosine kinase (Btk or BTK) or a Janus kinase (JAK), EGFR (including HER), Alk, PDGFR, BLK, BMX/ETK, FLT3(D835Y), ITK, TEC, TXK, and the respective pathways, in a cell or subject, which methods comprises administering to a cell or subject in need thereof an effective amount of a compound of Formula (Ia)
wherein
R 1 is
NR c R d wherein
R c is H, C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring, said C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring being optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic ring being optionally substituted with C 1-4 alkyl that is further optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic ring being optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4, or said 3-7 member cyclic ring being optionally substituted with C 1-4 alkyl that is further optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4, or said 3-7 member cyclic ring being optionally substituted with R 8 CO, wherein R 8 is C 1-4 alkyl, and
R d is H, C 1-4 alkyl, C 1-4 alkenyl, or 3-7 member cyclic ring, said C 1-4 alkyl, C 1-4 alkenyl or 3-7 member cyclic ring being optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl; or
3-7 member cyclic ring substituted with R a wherein R a is C 2-8 alkyl optionally substituted with halo, C 1-4 alkoxy or SO 2 (CH 2 ) q H, wherein q is 1-4; or
O(CH 2 ) m SO 2 (CH 2 ) n H, wherein m is 1-4 and n is 1-4;
R 2 is absent, H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 3 is hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 5 is absent, H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 6 is H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 7 is H, halo, C 1-4 alkyl, C 2-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 9 is H, hydroxyl, halo, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl;
R 10 is H, hydroxyl, halo, C 1-4 alkyl, C 1-4 alkoxy, or alkylamine (NR 11 R 12 ), wherein R 11 and R 12 are independently H or C 1-4 alkyl; or
R 1 and R 5 are part of 3-7 member cyclic ring, said 3-7 member cyclic being optionally substituted with C 1-4 alkyl optionally substituted with OZ or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl, or said 3-7 member cyclic being optionally substituted with R 8 CO, wherein R 8 is C 1-4 alkyl, or said 3-7 member cyclic being optionally substituted with SO 2 (CH 2 ) q H, wherein q is 1-4; or
R 1 and R 2 are part of 3-7 member cyclic ring, optionally substituted with C 1-4 alkyl, said C 1-4 alkyl further optionally substituted with halo, OZ, or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl, or one or more members of said 3-7 member cyclic ring is optionally part of a carbonyl group or a sulfonyl group; or
R 2 and R 6 are part of 3-7 member cyclic ring, optionally substituted with C 1-4 alkyl optionally substituted with OZ or NR 11 R 12 wherein Z, R 11 and R 12 are independently H or C 1-4 alkyl;
R 4 is C 2 alkenyl optionally substituted with C 1-4 alkyl, —CH 2 OCH 3 , or —CH 2 N(CH 3 ) 2 ;
X is O, C 1-4 alkyl optionally substituted with halo, or NR b , wherein R b is C 1-8 alkyl optionally substituted with halo;
Y is C, CH optionally substituted with halo, or N;
A is C, CH optionally substituted with halo or N; and
wherein at least one of R 2 , R 3 , R 5 and R 6 is not H;
or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 , which is used for treating and/or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye or an immunologically related disease or lupus in the subject.
6. The method of claim 5 , wherein the proliferation disorder is selected from the group consisting of sarcoma, epidermoid cancer, fibrosarcoma, cervical cancer, gastric carcinoma, skin cancer, leukemia, lymphoma, lung cancer, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, liver cancer, head and neck cancers, and pancreatic cancer.
7. The method of claim 1 , wherein the compound is selected from the group consisting of compounds I-3, I-5, I-7, I-9, I-13, I-14, I-16, I-17, I-25a, I-28a, I-29a, I-30a, I-31a, I-32a, I-33a, I-34a, I-35a, I-38a, I-39a, I-42a, I-43a, I-44a, I-45a, I-50a, I-51a, I-52a, I-53a, I-54a, I-55a, I-56a, I-57a, I-58a, I-59a, I-60a, I-66a, I-70a, and I-72a.
8. The method of claim 1 , wherein R 4 is C 2 alkenyl.
9. The method of claim 8 , wherein R 9 is H.
10. The method of claim 9 , wherein R 10 is H.
11. The method of claim 10 , wherein A and Y are each independently C or CH.
12. The method of claim 11 , wherein R 2 and R 5 are each independently absent or H.
13. The method of claim 12 , wherein R 6 and R 7 are each H.
14. The method of claim 13 , wherein R 1 is NR c R d and R c is 3-7 member cyclic ring.
15. The method of claim 14 , wherein the 3-7 member cyclic ring is optionally substituted with R 8 CO, wherein R 8 is C 1-4 alkyl.
16. The method of claim 15 , wherein R d is C 1-4 alkyl, optionally substituted with OZ or NR 11 R 12 , wherein Z, R 11 , R 12 are independently H or C 1-4 alkyl.
17. The method of claim 16 , wherein R 1 is NR c R d and R c is a 5 member cyclic ring that comprises a N atom, and the H linked to the N atom is substituted with R 8 CO, wherein R 8 is C 1-4 alkyl.
18. The method of claim 17 , wherein the H linked to the N atom is substituted with CH 3 CO.
19. The method of claim 18 , wherein R d is methyl.
20. The method of claim 19 , wherein R 3 is methoxy.
21. The method of claim 20 , wherein X is O.