Polymorphic compounds and uses thereof

Abstract

The present invention provides co-crystal and salt forms, and compositions and methods thereof, useful for treating various diseases, disorders or conditions in which EP4 prostaglandin receptors are implicated in the mediation of a proliferative disorder, by the administration of small molecule therapeutics acting as inhibitors of prostaglandin EP4 receptor activity.

We claim: 
     
         1 . Compound 4: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound according to  claim 1 , wherein said compound is crystalline. 
     
     
         3 . The compound according to  claim 1 , wherein said compound is a crystalline solid substantially free of amorphous compound 4. 
     
     
         4 . The compound according to  claim 1 , wherein said compound is substantially free of impurities. 
     
     
         5 . The compound according to  claim 1 , having one or more peaks in its XRPD selected from those at about 14.9, about 16.8 and about 24.5 degrees 2-theta. 
     
     
         6 . The compound according to  claim 5 , having at least two peaks in its XRPD selected from those at about 14.9, about 16.8 and about 24.5 degrees 2-theta. 
     
     
         7 . The compound according to  claim 6 , wherein said compound is of Form A. 
     
     
         8 . The compound according to  claim 1 , having an XRPD substantially similar to that depicted in  FIG. 7 . 
     
     
         9 . A composition comprising the compound according to  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         10 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 1  or composition thereof. 
     
     
         11 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 1  or composition thereof. 
     
     
         12 . The method according to  claim 11 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         13 . The method according to  claim 11 , wherein the method comprises administration of compound 4 in combination with an additional therapeutic agent. 
     
     
         14 . Compound 1: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 14 , wherein said compound is crystalline. 
     
     
         16 . The compound according to  claim 14 , wherein said compound is a crystalline solid substantially free of amorphous compound 1. 
     
     
         17 . The compound according to  claim 14 , wherein said compound is substantially free of impurities. 
     
     
         18 . The compound according to  claim 14 , having one or more peaks in its XRPD selected from those at about 13.0, about 15.2 and about 22.0 degrees 2-theta. 
     
     
         19 . The compound according to  claim 18 , having at least two peaks in its XRPD selected from those at about 13.0, about 15.2 and about 22.0 degrees 2-theta. 
     
     
         20 . The compound according to  claim 19 , wherein said compound is of Form A. 
     
     
         21 . The compound according to  claim 14 , having an XRPD substantially similar to that depicted in  FIG. 1 . 
     
     
         22 . A composition comprising the compound according to  claim 14  and a pharmaceutically acceptable carrier or excipient. 
     
     
         23 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 14  or composition thereof. 
     
     
         24 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 14  or composition thereof. 
     
     
         25 . The method according to  claim 24 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         26 . The method according to  claim 24 , wherein the method comprises administration of compound 1 in combination with an additional therapeutic agent. 
     
     
         27 . Compound 2: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound according to  claim 27 , wherein said compound is crystalline. 
     
     
         29 . The compound according to  claim 27 , wherein said compound is a crystalline solid substantially free of amorphous compound 2. 
     
     
         30 . The compound according to  claim 27 , wherein said compound is substantially free of impurities. 
     
     
         31 . The compound according to  claim 27 , having one or more peaks in its XRPD selected from those at about 10.6, about 19.4 and about 22.4 degrees 2-theta. 
     
     
         32 . The compound according to  claim 31 , having at least two peaks in its XRPD selected from those at about 10.6, about 19.4 and about 22.4 degrees 2-theta. 
     
     
         33 . The compound according to  claim 32 , wherein said compound is of Form A. 
     
     
         34 . The compound according to  claim 27 , having an XRPD substantially similar to that depicted in  FIG. 3 . 
     
     
         35 . A composition comprising the compound according to  claim 27  and a pharmaceutically acceptable carrier or excipient. 
     
     
         36 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 27  or composition thereof. 
     
     
         37 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 27  or composition thereof. 
     
     
         38 . The method according to  claim 37 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         39 . The method according to  claim 27 , wherein the method comprises administration of compound 2 in combination with an additional therapeutic agent. 
     
     
         40 . Compound 3: 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound according to  claim 40 , wherein said compound is crystalline. 
     
     
         42 . The compound according to  claim 40 , wherein said compound is a crystalline solid substantially free of amorphous compound 3. 
     
     
         43 . The compound according to  claim 40 , wherein said compound is substantially free of impurities. 
     
     
         44 . The compound according to  claim 40 , having one or more peaks in its XRPD selected from those at about 8.2, about 9.5 and about 12.4 degrees 2-theta. 
     
     
         45 . The compound according to  claim 44 , having at least two peaks in its XRPD selected from those at about 8.2, about 9.5 and about 12.4 degrees 2-theta. 
     
     
         46 . The compound according to  claim 45 , wherein said compound is of Form A. 
     
     
         47 . The compound according to  claim 40 , having an XRPD substantially similar to that depicted in  FIG. 5 . 
     
     
         48 . A composition comprising the compound according to  claim 40  and a pharmaceutically acceptable carrier or excipient. 
     
     
         49 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 40  or composition thereof. 
     
     
         50 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 40  or composition thereof. 
     
     
         51 . The method according to  claim 50 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         52 . The method according to  claim 40 , wherein the method comprises administration of compound 3 in combination with an additional therapeutic agent. 
     
     
         53 . Compound 5: 
       
         
           
           
               
               
           
         
       
     
     
         54 . The compound according to  claim 53 , wherein said compound is crystalline. 
     
     
         55 . The compound according to  claim 53 , wherein said compound is a crystalline solid substantially free of amorphous compound 5. 
     
     
         56 . The compound according to  claim 53 , wherein said compound is substantially free of impurities. 
     
     
         57 . The compound according to  claim 53 , having one or more peaks in its XRPD selected from those at about 4.9, about 15.8 and about 25.2 degrees 2-theta. 
     
     
         58 . The compound according to  claim 57 , having at least two peaks in its XRPD selected from those at about 4.9, about 15.8 and about 25.2 degrees 2-theta. 
     
     
         59 . The compound according to  claim 58 , wherein said compound is of Form A. 
     
     
         60 . The compound according to  claim 53 , having an XRPD substantially similar to that depicted in  FIG. 9 . 
     
     
         61 . A composition comprising the compound according to  claim 53  and a pharmaceutically acceptable carrier or excipient. 
     
     
         62 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 53  or composition thereof. 
     
     
         63 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 53  or composition thereof. 
     
     
         64 . The method according to  claim 63 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         65 . The method according to  claim 53 , wherein the method comprises administration of compound 5 in combination with an additional therapeutic agent. 
     
     
         66 . Compound 6: 
       
         
           
           
               
               
           
         
       
     
     
         67 . The compound according to  claim 66 , wherein said compound is crystalline. 
     
     
         68 . The compound according to  claim 66 , wherein said compound is a crystalline solid substantially free of amorphous compound 6. 
     
     
         69 . The compound according to  claim 66 , wherein said compound is substantially free of impurities. 
     
     
         70 . The compound according to  claim 66 , having one or more peaks in its XRPD selected from those at about 5.8, about 15.2 and about 22.1 degrees 2-theta. 
     
     
         71 . The compound according to  claim 70 , having at least two peaks in its XRPD selected from those at about 5.8, about 15.2 and about 22.1 degrees 2-theta. 
     
     
         72 . The compound according to  claim 71 , wherein said compound is of Form A. 
     
     
         73 . The compound according to  claim 66 , having an XRPD substantially similar to that depicted in  FIG. 11 . 
     
     
         74 . A composition comprising the compound according to  claim 66  and a pharmaceutically acceptable carrier or excipient. 
     
     
         75 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 66  or composition thereof. 
     
     
         76 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 66  or composition thereof. 
     
     
         77 . The method according to  claim 76 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         78 . The method according to  claim 66 , wherein the method comprises administration of compound 6 in combination with an additional therapeutic agent. 
     
     
         79 . Compound 7: 
       
         
           
           
               
               
           
         
       
     
     
         80 . The compound according to  claim 79 , wherein said compound is crystalline. 
     
     
         81 . The compound according to  claim 79 , wherein said compound is a crystalline solid substantially free of amorphous compound 7. 
     
     
         82 . The compound according to  claim 79 , wherein said compound is substantially free of impurities. 
     
     
         83 . The compound according to  claim 79 , having one or more peaks in its XRPD selected from those at about 15.6, about 19.1 and about 22.5 degrees 2-theta. 
     
     
         84 . The compound according to  claim 83 , having at least two peaks in its XRPD selected from those at about 15.6, about 19.1 and about 22.5 degrees 2-theta. 
     
     
         85 . The compound according to  claim 84 , wherein said compound is of Form A. 
     
     
         86 . The compound according to  claim 79 , having an XRPD substantially similar to that depicted in  FIG. 13 . 
     
     
         87 . A composition comprising the compound according to  claim 79  and a pharmaceutically acceptable carrier or excipient. 
     
     
         88 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 79  or composition thereof. 
     
     
         89 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 79  or composition thereof. 
     
     
         90 . The method according to  claim 89 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         91 . The method according to  claim 79 , wherein the method comprises administration of compound 7 in combination with an additional therapeutic agent. 
     
     
         92 . Compound 8: 
       
         
           
           
               
               
           
         
       
     
     
         93 . The compound according to  claim 92 , wherein said compound is crystalline. 
     
     
         94 . The compound according to  claim 92 , wherein said compound is a crystalline solid substantially free of amorphous compound 8. 
     
     
         95 . The compound according to  claim 92 , wherein said compound is substantially free of impurities. 
     
     
         96 . The compound according to  claim 92 , having one or more peaks in its XRPD selected from those at about 13.5, about 14.0 and about 21.7 degrees 2-theta. 
     
     
         97 . The compound according to  claim 96 , having at least two peaks in its XRPD selected from those at about 13.5, about 14.0 and about 21.7 degrees 2-theta. 
     
     
         98 . The compound according to  claim 97 , wherein said compound is of Form A. 
     
     
         99 . The compound according to  claim 92 , having an XRPD substantially similar to that depicted in  FIG. 15 . 
     
     
         100 . A composition comprising the compound according to  claim 92  and a pharmaceutically acceptable carrier or excipient. 
     
     
         101 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 92  or composition thereof. 
     
     
         102 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 92  or composition thereof. 
     
     
         103 . The method according to  claim 102 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         104 . The method according to  claim 92 , wherein the method comprises administration of compound 8 in combination with an additional therapeutic agent. 
     
     
         105 . Compound 9: 
       
         
           
           
               
               
           
         
       
     
     
         106 . The compound according to  claim 105 , wherein said compound is crystalline. 
     
     
         107 . The compound according to  claim 105 , wherein said compound is a crystalline solid substantially free of amorphous compound 9. 
     
     
         108 . The compound according to  claim 105 , wherein said compound is substantially free of impurities. 
     
     
         109 . The compound according to  claim 105 , having one or more peaks in its XRPD selected from those at about 16.6, about 17.5 and about 23.2 degrees 2-theta. 
     
     
         110 . The compound according to  claim 109 , having at least two peaks in its XRPD selected from those at about 16.6, about 17.5 and about 23.2 degrees 2-theta. 
     
     
         111 . The compound according to  claim 110 , wherein said compound is of Form A. 
     
     
         112 . The compound according to  claim 105 , having an XRPD substantially similar to that depicted in  FIG. 17 . 
     
     
         113 . A composition comprising the compound according to  claim 105  and a pharmaceutically acceptable carrier or excipient. 
     
     
         114 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 105  or composition thereof. 
     
     
         115 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 105  or composition thereof. 
     
     
         116 . The method according to  claim 115 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         117 . The method according to  claim 105 , wherein the method comprises administration of compound 9 in combination with an additional therapeutic agent. 
     
     
         118 . Compound 10: 
       
         
           
           
               
               
           
         
       
     
     
         119 . The compound according to  claim 118 , wherein said compound is crystalline. 
     
     
         120 . The compound according to  claim 118 , wherein said compound is a crystalline solid substantially free of amorphous compound 10. 
     
     
         121 . The compound according to  claim 118 , wherein said compound is substantially free of impurities. 
     
     
         122 . The compound according to  claim 118 , having one or more peaks in its XRPD selected from those at about 3.6, about 9.4 and about 17.3 degrees 2-theta. 
     
     
         123 . The compound according to  claim 122 , having at least two peaks in its XRPD selected from those at about 3.6, about 9.4 and about 17.3 degrees 2-theta. 
     
     
         124 . The compound according to  claim 123 , wherein said compound is of Form A. 
     
     
         125 . The compound according to  claim 118 , having an XRPD substantially similar to that depicted in  FIG. 19 . 
     
     
         126 . A composition comprising the compound according to  claim 118  and a pharmaceutically acceptable carrier or excipient. 
     
     
         127 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 118  or composition thereof. 
     
     
         128 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 118  or composition thereof. 
     
     
         129 . The method according to  claim 128 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         130 . The method according to  claim 118 , wherein the method comprises administration of compound 10 in combination with an additional therapeutic agent. 
     
     
         131 . Compound 11: 
       
         
           
           
               
               
           
         
       
     
     
         132 . The compound according to  claim 131 , wherein said compound is crystalline. 
     
     
         133 . The compound according to  claim 131 , wherein said compound is a crystalline solid substantially free of amorphous compound 11. 
     
     
         134 . The compound according to  claim 131 , wherein said compound is substantially free of impurities. 
     
     
         135 . The compound according to  claim 131 , having one or more peaks in its XRPD selected from those at about 9.6, about 15.1 and about 15.7 degrees 2-theta. 
     
     
         136 . The compound according to  claim 134 , having at least two peaks in its XRPD selected from those at about 9.6, about 15.1 and about 15.7 degrees 2-theta. 
     
     
         137 . The compound according to  claim 136 , wherein said compound is of Form A. 
     
     
         138 . The compound according to  claim 131 , having an XRPD substantially similar to that depicted in  FIG. 21 . 
     
     
         139 . A composition comprising the compound according to  claim 131  and a pharmaceutically acceptable carrier or excipient. 
     
     
         140 . A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient a compound according to  claim 131  or composition thereof. 
     
     
         141 . A method for treating a cancer in a patient comprising administering to the patient a compound according to  claim 131  or composition thereof. 
     
     
         142 . The method according to  claim 141 , wherein the cancer is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         143 . The method according to  claim 131 , wherein the method comprises administration of compound 11 in combination with an additional therapeutic agent.