Carbazole compounds and therapeutic uses of the compounds
Compounds of the general structural formula (I) and (II) and use of the compounds and salts and hydrates thereof, as therapeutic agents are disclosed. Treatable diseases and conditions include cancers, inflammatory diseases and conditions, and immunodeficiency diseases. (I), (II).
1. A method for treating a hematopoietic cancer, comprising administering to a patient in need thereof an effective amount of a compound of a structural formula:
wherein R a is selected from the group consisting of C 1 - 6 alkyl, C 1 - 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 , and SR e ; alternatively, either R a and R 1 or NR e and R 1 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic or heterocyclic ring;
R b is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 , and SR e , alternatively, either R b and R 6 or NR e and R 6 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring or a five or six-membered aliphatic carbocyclic or heterocyclic ring;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e , or R c and R d are taken together to form a five, six, or seven-membered aliphatic ring, optionally containing an oxygen atom;
R d is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e , or R d and R 7 together with the atoms to which they are attached form a five or six-membered aliphatic ring;
R e , independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two R e groups taken together with a nitrogen to which they are attached to form a five or six-membered aliphatic ring;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, OR e , C(═O)R e , C(═O)OR e , OC(═O)R e , C(═O)N(R e ) 2 , C(═O)NR e SO 2 R e , N(R e ) 2 , NR e C(═O)R e , NR e C(═O)N(R e ) 2 , CN, NO 2 , CF 3 , OCF 3 , SR e , SOR e , SO 2 N(Re) 2 , and OSO 2 CF 3 ;
R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
n is 1, 2, 3, 4, or 5,
or a pharmaceutically acceptable salt or hydrate thereof.
2. The method of claim 1 , wherein the hematopoietic cancer is a leukemia or a lymphoma.
3. The method of claim 2 , wherein the leukemia or a lymphoma is one of acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burkett's lymphoma.
4. The method of claim 1 , wherein the compound is
5. A method for treating a tumor of the central and peripheral nervous system, comprising administering to a patient in need thereof an effective amount of a compound of a structural formula:
wherein R a is selected from the group consisting of C 1 - 6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 , and SR e ; alternatively, either R a and R 1 or NR e and R 1 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic or heterocyclic ring;
R b is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 , and SR e , alternatively, either R b and R 6 or NR e and R 6 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring or a five or six-membered aliphatic carbocyclic or heterocyclic ring;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e , or R c and R d are taken together to form a five, six, or seven-membered aliphatic ring, optionally containing an oxygen atom;
R d is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e , or R d and R 7 together with the atoms to which they are attached form a five or six-membered aliphatic ring;
R e , independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two R e groups taken together with a nitrogen to which they are attached to form a five or six-membered aliphatic ring;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, OR e , C(═O)R e , C(═O)OR e , OC(═O)R e , C(═O)N(R e ) 2 , C(═O)NR e SO 2 R e , N(R e ) 2 , NR e C(═O)R e , NR e C(═O)N(R e ) 2 , CN, NO 2 , CF 3 , OCF 3 , SR e , SOR e , SO 2 N(Re) 2 , and OSO 2 CF 3 ;
R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
n is 1, 2, 3, 4, or 5,
or a pharmaceutically acceptable salt or hydrate thereof.
6. The method of claim 5 , wherein tumor of the central and peripheral nervous system is a glioblastoma or a neuroblastoma.
7. The method of claim 5 , wherein the compound is
8. A method for treating a solid tumor, comprising administering to a patient in need thereof an effective amount of a compound of a structural formula:
wherein R a is selected from the group consisting of C 1 - 6 alkyl, C 1 - 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 , and SR e ; alternatively, either R a and R 1 or NR e and R 1 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic or heterocyclic ring;
R b is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 , and SR e , alternatively, either R b and R 6 or NR e and R 6 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring or a five or six-membered aliphatic carbocyclic or heterocyclic ring;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e , or R c and R d are taken together to form a five, six, or seven-membered aliphatic ring, optionally containing an oxygen atom;
R d is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e , or R d and R 7 together with the atoms to which they are attached form a five or six-membered aliphatic ring;
R e , independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two R e groups taken together with a nitrogen to which they are attached to form a five or six-membered aliphatic ring;
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, OR e , C(═O)R e , C(═O)OR e , OC(═O)R e , C(═O)N(R e ) 2 , C(═O)NR e SO 2 R e , N(R e ) 2 , NR e C(═O)R e , NR e C(═O)N(R e ) 2 , CN, NO 2 , CF 3 , OCF 3 , SR e , SOR e , SO 2 N(Re) 2 , and OSO 2 CF 3 ;
R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
n is 1, 2, 3, 4, or 5,
or a pharmaceutically acceptable salt or hydrate thereof.
9. The method of claim 5 , wherein the solid tumor is one or more of a colorectal cancer, renal cancer, pancreatic cancer, head and neck cancer, prostate cancer, melanoma, and a lung cancer.
10. The method of claim 8 , wherein the compound is