Amido spirocyclic amide and sulfonamide derivatives

Abstract

Provided are amido spirocyclic amide and sulfonamide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein: 
       R is (a) an 8-, 9-, or 10-membered bicyclic heteroaryl comprising one heteroatom selected from N, S, and O, and one, two, or three additional N atoms, wherein said bicyclic heteroaryl is unsubstituted or is substituted with one or more substituents selected from the group consisting of deuterium, amino, alkylamino, dialkylamino, alkyl, halo, cyano, haloalkyl, hydroxy, hydroxyalkyl, and alkoxy, and wherein one or more N atoms of said bicyclic heteroaryl is optionally an N-oxide; or
 (b) a five- or six-membered nitrogen-linked heterocycloalkyl ring fused to a phenyl or monocyclic five- or six-membered heteroaryl, wherein said phenyl or heteroaryl is unsubstituted or is substituted with one or more substituents selected from the group consisting of deuterium, amino, alkylamino, dialkylamino, alkyl, halo, cyano, haloalkyl, hydroxy, hydroxyalkyl, and alkoxy; and 
 
       R 1  is H, —(C 1-4 alkylene) 0-1 C(O)R a , —(C 1-4 alkylene) 0-1 CO 2 R a , —(C 1-4 alkylene) 0-1 S(O)R a , —(C 1-4 alkylene) 0-1 SO 2 R a , —C(O)NH(R a ), —C(O)N(R a ) 2 , or —C(O)C(O)NH(R a );
 wherein each R a  is independently 
 (1) alkyl, unsubstituted or substituted with one or more R m  substituents,
 wherein each R m  is independently selected from the group consisting of deuterium, hydroxy, —NR b R c , alkoxy, cyano, halo, —C(O)alkyl, —CO 2 alkyl, —CONR b R c , —S(O)alkyl, —SO 2 alkyl, —SO 2 NR b R c , aryl, heteroaryl, cycloalkyl, heterocycloalkyl, phenoxy, and —O-alkyl-OH; wherein R b  is H or alkyl;
 R c  is H, alkyl, alkoxyalkyl, haloalkyl, —C(O)alkyl, —CO 2 alkyl, —SO 2 alkyl, —C(O)NH 2 , or C(O)H; and 
 each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group within R m  is unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, hydroxy, —NR b R c , alkoxy, haloalkoxy, cyano, halo, oxo, —C(O)alkyl, —CO 2 alkyl, —C(O)-heterocycloalkyl, —CONR b R c , —S(O)alkyl, —SO 2 alkyl, —SO 2 -haloalkyl, —SO 2 NR b R c , aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or two substituents taken together form a fused heteroaryl, cycloalkyl, or heterocycloalkyl ring;
 wherein each alkyl or alkoxy is unsubstituted or substituted with phenyl, —NR b R c , heterocycloalkyl, heteroaryl, or —C(O)alkyl; and 
 each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is unsubstituted or substituted with alkyl, halo, or C(O)alkyl, 
 
 
 
 (2) phenyl, cycloalkyl, heteroaryl, or heterocycloalkyl, each unsubstituted or substituted with one or more R g  substituents;
 wherein each R g  is independently selected from the group consisting of alkyl, haloalkyl, hydroxy, —NR b R c , alkoxy, haloalkoxy, cyano, halo, oxo, —C(O)alkyl, —CO 2 alkyl, —C(O)-heterocycloalkyl, —CONR b R c , —S(O)alkyl, —SO 2 alkyl, —SO 2 -haloalkyl, —SO 2 NR b R c , aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or two R g  substituents taken together form a fused phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl ring;
 wherein each alkyl or alkoxy is unsubstituted or substituted with —NR b R c , heterocycloalkyl, heteroaryl, or —C(O)alkyl; and 
 each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is unsubstituted or substituted with alkyl, halo, —CO 2 alkyl, or —C(O)alkyl; or 
 
 
 (3) —NR x R y ,
 where R x  is H or alkyl; and 
 R y  is H, alkyl, alkoxyalkyl, haloalkyl, —C(O)alkyl, —CO 2 alkyl, or —SO 2 alkyl; 
 
 
       R 2  and R 3  are each independently H or deuterium; and 
       n is 1 or 2; 
       or a stereoisomer thereof, or a pharmaceutically acceptable salt of such a compound or stereoisomer. 
     
     
         2 . The compound of  claim 1 , wherein R is an 8- or 9-membered heteroaryl, unsubstituted or substituted as described for  claim 1 . 
     
     
         3 . The compound of  claim 1 , wherein R is: 
       
         
           
           
               
               
           
         
         each unsubstituted or substituted as described for  claim 1 . 
       
     
     
         4 . The compound of  claim 1 , wherein, R is a five- or six-membered nitrogen-linked heterocycloalkyl ring fused to an unsubstituted or substituted phenyl or monocyclic heteroaryl, as defined in  claim 1 . 
     
     
         5 . The compound of  claim 1 , wherein R is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein R 1  is H. 
     
     
         7 . The compound of  claim 1 , wherein R 1  is —C(O)R a , —CO 2 R a , —S(O)R a , or —SO 2 R a . 
     
     
         8 . The compound of  claim 1 , wherein R a  is alkyl, unsubstituted or substituted as described for  claim 1 . 
     
     
         9 . The compound of  claim 1 , wherein R a  is methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, isopentyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazoyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, or tetrahydrothiophenyl, each unsubstituted or substituted. 
     
     
         10 . The compound of  claim 1 , wherein R a  is phenyl, cycloalkyl, heteroaryl, or heterocycloalkyl, each unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, oxo, methyl, —CONH 2 , acetyl, —SO 2 methyl, —C(O)-isopropyl, pyridazinyl, triazolyl, dimethylaminomethyl, cyano, methyl-triazolyl-methoxy, trifluoromethoxy, pyrrolidinylmethyl, acetylamino, tetrazolylmethyl, methyl-tetrazolyl-methyl, methyl-imidazolyl-methyl, —NHSO 2 methyl, 1,1-dioxothiomorpholinyl, 4-methyl-piperazinylmethyl, —NHCONH 2 , —SO 2 CF 3 , morpholinylmethyl, imidazolyl, —SO 2 NH 2 , methylpiperidinyl, methyl-piperazinyl, —C(O)(4-methyl-piperazinyl), morpholinyl, trifluoromethyl, cyclopropyl, ethyl, isoxazolyl, tetrazolyl, isopropyl, phenyl, fluoro-phenyl, tert-butyl, benzyl, N-methylpyrrolidinyl, N-acetyl-pyrrolidinyl, isobutyl, propyl, methylpyrazolyl, trifluoroethyl, pyrimidinyl, oxo, acetyl, cyano, —CO 2 -tert-butyl, and amino. 
     
     
         11 . The compound of  claim 1 , wherein R a  is alkyl, unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, tert-butoxy, —C(O)NMe 2 , —NHCHO, methoxy, phenoxy, cyano, acetyl, hydroxy, —OCH 2 C(CH 3 )═OH, —NH(acetyl), and —N(Me)(acetyl). 
     
     
         12 . The compound of  claim 1 , wherein R 1  is —SO 2 R a , where R a  is methyl, ethyl, phenyl, benzyl, or 2,2-dimethylpropyl. 
     
     
         13 . The compound of  claim 1 , wherein R 1  is —C(O)NHR a , wherein R a  is methyl, ethyl, propyl, isopropyl, tertobutyl, cyclohexyl, —CH 2 -cyclohexyl, oxetanyl, or methyloxetanyl, or R a  is a phenyl or benzyl group, each optionally substituted with one or more substituents selected from the group consisting of cyano, methyl, fluoro, methoxy, and chloro. 
     
     
         14 . The compound of  claim 1 , wherein both R 2  and R 3  are H. 
     
     
         15 . The compound of  claim 1 , which is a compound of Formula I-a: 
       
         
           
           
               
               
           
         
         wherein R, R 1 , R 2 , and R 3  are as defined for Formula I; 
         or a stereoisomer thereof, or a pharmaceutically acceptable salt of such a compound or stereoisomer. 
       
     
     
         16 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and stereoisomers thereof, and pharmaceutically acceptable salts of such compounds and stereoisomers. 
       
     
     
         17 . A pharmaceutical composition comprising: (a) an effective amount of at least one compound of  claim 1 ; and (b) a pharmaceutically acceptable carrier. 
     
     
         18 . The pharmaceutical composition of  claim 17 , further comprising therapeutically effective amounts of one or more additional adjunctive active agents. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein said one or more additional adjunctive active agents are selected from the group consisting of cytotoxic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, Intron®, Peg-Intron®, aromatase combinations, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATIN®), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, Campath, leucovorin, and dexamethasone, bicalutamide, carboplatin, chlorambucil, cisplatin, letrozole, megestrol, valrubicin, vinblastine and NIASPAN®. 
     
     
         20 . The pharmaceutical composition of  claim 17  further comprising a rescuing agent. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the rescuing agent is selected from the group consisting of nicotinamide, nicotinic acid, and nicotinamide mononucleotide (NMN). 
     
     
         22 . A method of treating a subject suffering from or diagnosed with a disease or medical condition mediated by NAMPT activity, comprising administering to the subject in need of such treatment an effective amount of at least one compound of  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the disease or medical condition is a solid or liquid tumor, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer, CNS cancer, bladder cancer, pancreatic cancer, Hodgkin's disease, rheumatoid arthritis, diabetes, atherosclerosis, sepsis, aging or inflammation. 
     
     
         24 . The method of  claim 22 , further comprising administering to the subject an effective amount of at least one compound selected from the group consisting of: a cytotoxic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, Intron®, Peg-Intron®, aromatase combinations, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, leucovirin, oxaliplatin (ELOXATIN®), Pentostatine, vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, Campath, leucovorin, dexamethasone, bicalutamide, chlorambucil, letrozole, megestrol, valrubicin, vinblastine, and NIASPAN®. 
     
     
         25 . The method of  claim 22  further comprising administering an effective amount of a rescuing agent. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the rescuing agent is selected from the group consisting of nicotinamide, nicotinic acid, and nicotinamide mononucleotide (NMN).