Isoxazole carboxamide compounds

Abstract

The present disclosure provides substituted isoxazole carboxamide compounds having Formula (1) and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , A, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2 Compounds of the present disclosure are especially useful for treating cancer.

1 . A compound having Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, 
         wherein: 
         R 1  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-4  alkenyl, C 1-4  haloalkyl, C 3-6  cycloalkyl, and hydroxyalkyl; 
         R 2  is selected from the group consisting of hydrogen, halo, and carboxamido; 
         A is selected from the group consisting of C 1-10  alkylenyl, (cycloalkylenyl)alkyl, optionally substituted C 3-12  cycloalkylenyl, optionally substituted C 6-14  arylenyl, optionally substituted 5- to 14-membered heteroarylenyl, and —C(H)R 3 R 4 ; 
         with the provisos:
 a) when R 1  is ethyl or cyclopropyl; R 2  is hydrogen; and X is —N(R 7 )S(═O) 2 —N(R 7 )C(═O)—, or —N(R 7 )C(═O)C(R 8 )(H)—, then A is not optionally substituted 1,4-cyclohexylenyl; and 
 b) when R 1  is ethyl or cyclopropyl; R 2  is hydrogen; X is absent; and Z is amino, alkylamino, dialkylamino, or heterocycloamino, then A is not optionally substituted 1,4-cyclohexylenyl; 
 
         R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl, (hydroxy)(aryl)alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, optionally substituted C 3-12  cycloalkyl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted C 6-14  aryl, aralkyl, alkoxycarbonyl, and —C(═O)N(R 5 )(R 6 ); 
         R 4  is selected from the group consisting of C 1-6  alkyl, hydroxyalkyl, optionally substituted C 3-12  cycloalkyl, optionally substituted C 6-14  aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, and (heteroaryl)alkyl; 
         R 5  is selected from the from the group consisting of hydrogen and C 1-4  alkyl; 
         R 6  is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(carboxamido)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (amino)(heteroaryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C 6-14  aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C 3-12  cycloalkyl, aralkyl, and (heteroaryl)alkyl; 
         X is selected from the group consisting of —S(═O) 2 —, —S(═O) 2 N(R 7 )—, —N(R 7 )S(═O) 2 —,—S(═O) 2 C(R 8 )(H)—, —C(═O)—, —C(═O)N(R 7 )—, —N(R 7 )C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)C(R 8 )(H)N(R 7 )—, —N(R 7 )C(═O)C(R 8 )(H)—, —C(R 8 )(H)C(═O)N(R 7 )—, —C(R 8 )(H)N(R 7 )C(═O)—, and —C(═O)C(R 8 )(H)—; or X is absent; 
         Z is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, fluoroalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, heterocycloamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (amino)(heteroaryl)alkyl (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C 6-14  aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C 3-12  cycloalkyl, aralkyl, and (heteroaryl)alkyl; 
         wherein —X—Z is attached to any available carbon or nitrogen atom of A, R 3 , R 4 , or R 6 ; 
         R 7  is selected from the group consisting of hydrogen and C 1-4  alkyl; and 
         R 8  is selected from the group consisting of hydrogen, C 1-4  alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and hydroxyalkyl. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein A is C 1-10  alkylenyl. 
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R 9a  and R 9b  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         R 9c  and R 9d  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; or 
         R 9c  and R 9d  taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; 
         R 9  is selected from the group consisting of hydrogen and C 1-4  alkyl; 
         m is 0 or 1; 
         X is selected from the group consisting of —N(R 7 )C(═O)—, —N(R 7 )C(═O)C(R 8 )(H)—, and —N(R 7 )S(═O) 2 —; 
         R 8  is selected from the group consisting of C 1-4  alkyl, amino, alkylamino, and dialkylamino; and 
         Z is selected from the group consisting of C 1-6  alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12  cycloalkyl. 
       
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein A is optionally substituted C 6-14  arylenyl. 
     
     
         5 . The compound of  claim 4 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula III: 
       
         
           
           
               
               
           
         
         wherein: 
         R 10a  is selected from the group consisting of hydrogen, halo, C 1-6  alkyl, alkoxy, hydroxyalkyl, and alkoxycarbonyl; 
         X is selected from the group consisting of —C(═O)N(R 7 )—, —N(R 7 )C(═O)—, —C(═O)C(R 8 )(H)N(R 7 )—, —C(R 8 )(H)C(═O)N(R 7 )— and —S(═O) 2 N(R 7 )—; or X is absent; 
         R 8  is selected from the group consisting of C 1-4  alkyl, amino, alkylamino, and dialkylamino; and 
         Z is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, heteroalkyl, (amino)(hydroxy)alkyl, (heterocyclo)alkyl, optionally substituted C 3-12  cycloalkyl, and optionally substituted 4- to 14-membered heterocyclo. 
       
     
     
         6 . The compound of  claim 5 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula IV: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein A is optionally substituted C 3-12  cycloalkylenyl. 
     
     
         8 . The compound of  claim 7 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula V: 
       
         
           
           
               
               
           
         
         wherein: 
         R 10a  and R 10b  are independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         X is selected from the group consisting of —S(═O) 2 —, —S(═O) 2 N(R 7 )—, —N(R 7 )C(═O)—, —C(═O)N(R 7 )—, —N(R 7 )S(═O)—, and —OC(═O)—; or X is absent; 
         Z is selected from the group consisting of amino, alkylamino, dialkylamino, heterocycloamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and (hydroxyalkylamino)alkyl; 
         n is 0 or 1; and 
         p is 0 or 1. 
       
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein A is —C(H)R 3 R 4 . 
     
     
         12 - 14 . (canceled) 
     
     
         15 . The compound of  claim 11 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula VII, Formula VIII, or Formula IX: 
       
         
           
           
               
               
           
         
         wherein: 
         R 3  is selected from the group consisting of hydrogen, C 1-4  alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted C 6-14  aryl, aryloxyalkyl, and aralkyl 
         X is selected from the group consisting of —S(═O) 2 —, —S(═O) 2 N(R 7 )—, —S(═O) 2 C(R 8 )(H)—, —C(═O)—, —C(═O)N(R 7 )—, —C(═O)O—, —OC(═O)—, and —C(═O)C(R 8 )(H)—; or X is absent; 
         R 8  is selected from the group consisting of C 1-4  alkyl, amino, alkylamino, and dialkylamino; and 
         Z is selected from the group consisting of C 1-6  alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, hydroxyalkyl, optionally substituted C 3-12  cycloalkyl, aralkyl, and (heteroaryl)alkyl. 
       
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 11 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula X, Formula XI, or Formula XII: 
       
         
           
           
               
               
           
         
         wherein R 12  is selected from the group consisting of hydrogen, halo, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, (aralkyloxy)alkyl, alkoxyalkyl, heteroalkyl, (hydroxyalkylamino)alkyl, (heterocycloamino)alkyl, and carboxamido. 
       
     
     
         18 . The compound of  claim 17 , or a pharmaceutically acceptable salt or hydrate thereof, wherein:
 X is selected from the group consisting of —C(═O)N(R 7 )— and —S(═O) 2 N(R 7 )—;   Z is optionally substituted C 1-6  alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted C 6-14  aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12  cycloalkyl, aralkyl, and (heteroaryl)alkyl; and   R 12  is hydrogen.   
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 11 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula XIII, Formula XIV, or Formula XV: 
       
         
           
           
               
               
           
         
         wherein: 
         R 6  is selected from the group consisting of optionally substituted C 1-6  alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted C 6-14  aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12  cycloalkyl, aralkyl, and (heteroaryl)alkyl; 
         X is selected from the group consisting of —C(═O)N(R 7 )—, —C(═O)C(R 8 )(H)—, and —S(═O) 2 N(R 7 )—; or 
         X is absent; 
         R 8  is selected from the group consisting of C 1-4  alkyl, amino, alkylamino, and dialkylamino; 
         Z is selected from the group consisting of C 1-4  alkyl, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, and (amino)(hydroxy)alkyl. 
       
     
     
         21 - 24 . (canceled) 
     
     
         25 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is selected from the group consisting of C 1-4  alkyl and C 3-6  cycloalkyl. 
     
     
         26 . The compound of  claim 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is cyclopropyl. 
     
     
         27 . The compound of  claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         28 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         29 . A method of treating a patient comprising administering to the patient a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein the patient has cancer. 
     
     
         30 . The method of  claim 29 , wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor. 
     
     
         31 - 38 . (canceled) 
     
     
         39 . A method of treating a SMYD protein mediated disorder comprising administering to a subject in need thereof a compound of  claim 1 , or a pharmaceutically acceptable salt or hydrate thereof in an effective amount to treat the SMYD protein mediated disorder.