Inhibitors of nedd8-activating enzyme

Abstract

Disclosed are chemical entities which are inhibitors of Nedd8-activating enzyme (NAE), namely, the compound {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate and pharmaceutically acceptable salts thereof; solid state forms thereof; and prodrugs thereof. Also disclosed are methods of using the chemical entities to treat disorders such as cancer.

1 - 22 . (canceled) 
     
     
         23 . A method of treating cancer comprising administering to a subject in need of such treatment a chemical entity comprising compound {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate. 
     
     
         24 . The method of  claim 23 , wherein said chemical entity is a hydrochloride salt of the compound or a pharmaceutically acceptable solvate thereof. 
     
     
         25 . The method of  claim 24 , wherein said chemical entity is substantially Form I. 
     
     
         26 . The method of  claim 25 , wherein Form I is characterized by an x-ray powder diffraction (XRPD) pattern having peaks at 2θ angles of 4.5°, 15.2°, 21.3°, 21.8° and 24.0°. 
     
     
         27 . The method of  claim 25 , wherein Form I is characterized by an XRPD pattern having peaks at 2θ angles of 4.5°, 7.5°, 14.4°, 14.6°, 15.2°, 15.9°, 19.5°, 21.3°, 21.8°, 22.4°, 22.7°, 24.0° and 24.8°. 
     
     
         28 . The method of  claim 25 , wherein Form I is characterized by an XRPD pattern having peaks at 2θ angles of 4.5°, 7.5°, 8.9°, 9.8°, 13.3°, 14.4°, 14.6°, 15.2°, 15.9°, 17.2°, 19.5°, 20.0°, 21.3°, 21.8°, 22.4°, 22.7°, 24.0°, 24.8°, 25.7° and 26.4°. 
     
     
         29 . The method of  claim 25 , wherein Form I is characterized by an x-ray powder diffraction (XRPD) pattern having a reference peak with a 2θ angle of 4.5±0.3°, and having peaks at 2θ angles of 10.7°, 16.8°, 17.3° and 19.5° relative to the reference peak. 
     
     
         30 . The method of  claim 25 , wherein Form I is characterized by an XRPD pattern substantially as shown in  FIG. 4 . 
     
     
         31 . The method of  claim 25 , wherein Form I is characterized by a DSC thermogram substantially as shown in  FIG. 5 . 
     
     
         32 . The method of  claim 25 , wherein Form I is characterized by a TGA thermogram substantially as shown in  FIG. 6 . 
     
     
         33 . The method of  claim 25 , wherein said chemical entity is administered in solid dosage form. 
     
     
         34 . The method of  claim 24 , wherein said chemical entity is substantially Form II. 
     
     
         35 . The method of  claim 34 , wherein Form II is characterized by an x-ray powder diffraction (XRPD) pattern having peaks at 2θ angles of 8.7°, 15.2°, 15.7°, 19.6°, and 24.2°, wherein each 2θ angle value is ±0.2°. 
     
     
         36 . The method of  claim 34 , wherein Form II is characterized by an x-ray powder diffraction (XRPD) pattern substantially as shown in  FIG. 10 . 
     
     
         37 . The method of  claim 34 , wherein said chemical entity is administered in solid dosage form. 
     
     
         38 . A method of treating cancer comprising administering to a subject in need of such treatment a prodrug of a chemical entity, wherein:
 the chemical entity is compound {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate or a pharmaceutically acceptable salt thereof; and the prodrug is a carbamate or amide of the —NH— group of the chemical entity, or an ether or ester of the —OH group of the chemical entity.   
     
     
         39 . The method of  claim 38 , wherein the cancer is a hematological malignancy selected from acute myeloid leukemia (AML); chronic myelogenous leukemia (CML); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL); B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS); and myeloproliferative syndrome. 
     
     
         40 . The method of  claim 38 , wherein the cancer is a solid tumor selected from pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; melanoma; neuroendocrine cancer; brain tumors; bone cancer; and soft tissue sarcoma. 
     
     
         41 . The method of  claim 23 , wherein the cancer is a hematological malignancy selected from acute myeloid leukemia (AML); chronic myelogenous leukemia (CML); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL); B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS); and myeloproliferative syndrome. 
     
     
         42 . The method of  claim 23 , wherein the cancer is a solid tumor selected from pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; melanoma; neuroendocrine cancer; brain tumors; bone cancer; and soft tissue sarcoma.