สารประกอบเฮเทอโรเอริลที่ใช้ประโยชน์ในฐานะเป็นสารยับยั้งของเอนไซม์ที่กระตุ้น SUMO

Abstract

แก้ไข21 / 02 / 2560สิ่งที่เปิดเผยเอาไว้คือเอนทิตีทางเคมีซึ่งเป็นสารประกอบที่มีสูตร(I):                        (สูตรเคมี)                            (I);หรือเกลือที่ยอมรับได้ทางเภสัชกรรมของสารนั้นที่ซึ่งY,Ra,Ra',Rb,Rc,X1,X2,X3,Rd,Z1และZ2มีค่าตามที่อธิบายเอาไว้ในคำขอนี้และโครงร่างทางสเตอริโอเคมีที่แสดงที่ตำแหน่งที่มีเครื่องหมายดอกจันบ่งชี้สเตอริโอเคมีสัมบูรณ์เอนทิตีทางเคมีตามสิ่งที่เปิดเผยเอาไว้สามารถถูกใช้ประโยชน์ในฐานะเป็นสารยับยั้งของเอนไซม์ที่กระตุ้นSUMO(SAE)สิ่งที่จัดให้มีเอาไว้เพิ่มเติมคือองค์ประกอบทางเภสัชกรรมซึ่งประกอบรวมด้วยสารประกอบของสิ่งที่เปิดเผยเอาไว้และวิธีการใช้องค์ประกอบต่างๆในการรักษาโรคหรือความผิดปกติที่มีการเพิ่มจำนวนของเซลล์,ที่มีการอักเสบ,หัวใจร่วมหลอดเลือดและโรคทางระบบประสาท-------สิ่งที่เปิดเผยเอาไว้คือเอนทิตีทางเคมีซึ่งเป็นสารประกอบที่มีสูตร(I):          (สูตรเคมี)              (I);หรือเกลือที่ยอมรับได้ทางเภสัชกรรมของสารนั้นที่ซึ่งY,Ra,Ra1,Rb,Rc,X1,X2,X3,Rd,Z1และZ2มีด่าตามที่อธิบายเอาไว้ในคำขอนี้และโครงร่างทางสเตอริโอเคมีที่แสดงที่ตำแหน่งที่มีเครื่องหมายดอกจันบ่งชี้สเตอริโอเคมสัมบูรณ์เอนทิตีทางเคมีตามสิ่งที่เปิดเผยเอาไว้สามารถถูกใช้ประโยชน์ในฐานะเป็นสารยับยั้งของเอนไซม์ที่กระตุ้นSUMO(SAE)สิ่งที่จัดให้มีเอาไว้เพิ่มเติมคือองค์ประกอบทางเภสัชกรรมซึ่งประกอบรวมด้วยสารประกอบของสิ่งที่เปิดเผยเอาไว้และวิธีการใช้องค์ประกอบต่างๆในการรักษาโรคหรือความผิดปกติที่มีการเพิ่มจำนวนของเซลล์,ที่มีการอักเสบ,หัวใจร่วมหลอดเลือดและโรคทางระบบประสาท;

Description

HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYMEINTRODUCTION

[0001] This application claims the benefit of United States Provisional Patent Application No. 62 / 019,756, filed July 1 , 2014, and United States Provisional Patent Application No. 62 / 185,678, filed June 28, 2015, all of which are incorporated by reference in their entirety.

[0002] Small ubiquitin-like modifier (SUMO) is a member of the ubiquitin-like protein (Ubl) family that is covalently conjugated to cellular proteins in a manner similar to Ub-conjugation (Kerscher, O., Felberbaum, R., and Hochstrasser, M. 2006. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol. 22: 159-80). Mammalian cells express three major isoforms: SUMO l , SUM02 and SUM03. SUM02 and SUM03 share -95% amino acid sequence homology but have -45% sequence homology with SUMO l (Kamitani, T., Kito, K., Nguyen, H. P., Fukuda-Kamitani, T., and Yeh, E. T. 1998. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem. 273( 18): 1 1349-53). SUMO proteins can be conjugated to a single lysine residue of a protein (monosumoylation) or to a second SUMO protein that is already conjugated to a protein forming a SUMO chain (polysumoylation). Only SUM02 / 3 can form such chains because they possess internal consensus SUMO modification sites (Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Naismith, J. H., Hay, R. T. 2001. Polymeric chains of SUMO-2 and SUM 0-3 are conjugated to protein substrates by SAE1 / SAE2 and Ubc9. J Biol Chem. 276(38):35368-74). An additional isoform, SUM04, is found in kidney, lymph node and spleen cells, but it is not known whether SUM04 can be conjugated to cellular proteins.

[0003] SUMO l , SUM02 and SUM03 are activated in an ATP-dependent manner by the SUMO-activating enzyme (SAE). SAE is a heterodimer that consists of SAE 1 (SUMO-activating enzyme subunit 1) and SAE2 (UBA2). SAE, like other El activating enzymes, uses ATP to adenylate the C-terminal glycine residue of SUMO. In a second step, a thioester intermediate is then formed between the C-terminal glycine of SUMO and a cysteine residue in SAE2. Next, SUMO is transferred from the El to the cysteine residue of the SUMO conjugating enzyme (E2), UBC9. Unlike the Ub pathway that contains many E2 enzymes, Ubc9 is currently the only known conjugating enzyme for SUMO and functions with SUMOl , SUM02 and SUM03 proteins. SUMO proteins are then conjugated to the target protein, either directly or in conjunction with an E3 ligase, through isopeptide bond formation with the epsilon amino group of a lysine side chain on a target protein. Several SUMO E3 ligases, including PIAS (protein inhibitor of activated signal transducer and activator of transcription protein) proteins and Ran-binding protein 2 (RanBP2), and polycomb 2 (Pc2), have been identified (Johnson, E. S., and Gupta, A. A. 2001. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell. 106(6):735-44; Pichler, A., Gast, A., Seeler, J. S., Dejean, A.; Melchior, F. 2002. The nucleoporin RanBP2 has SUMOl E3 ligase activity. Cell. 108(1): 109-20; Kagey, M. H.,Melhuish, T. A., and Wotton, D. 2003. The polycomb protein Pc2 is a SUMO E3. Cell. 1 13(1): 127- 37). Once attached to cellular targets, SUMO modulates the function, subcellular localization, complex formation and / or stability of substrate proteins (Miiller, S., Hoege, C, Pyrowolakis, G., and Jentsch, S. 2001. SUMO, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol. 2(3):202-10). SUMO- conjugation is reversible through the action of de-sumoylating enzymes called SENPs (Hay, R. T. 2007. SUMO-specific proteases: a twist in the tail. Trends Cell Biol. 17(8):370-6) and the SUMO proteins can then participate in additional conjugation cycles.

[0004] SAE-initiated SUMO-conjugation plays a major role in regulating diverse cellular processes, including cell cycle regulation, transcriptional regulation, cellular protein targeting, maintenance of genome integrity, chromosome segregation, and protein stability (Hay, R. T. 2005. SUMO: a history of modification. Mol Cell. 18( 1): 1 -12; Gill, G. 2004. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev. 18(17):2046-59). For example, SUMO- conjugation causes changes in the subcellular localization of RanGAPl by targeting it to the nuclear pore complex (Mahajan, R., Delphin, C., Guan, T., Gerace, L., and Melchior, F. 1997. A small ubiquitin-related polypeptide involved in targeting RanGAPl to nuclear pore complex protein RanBP2. Cell. 88(1):97- 1070). Sumoylation counteracts ubiquitination and subsequently blocks the degradation of Ι Β, thereby negatively regulating NF-κΒ activation (Desterro, J. M., Rodriguez, M. S., Hay, R. T. 1998. SUMO- 1 modification of IkappaB alpha inhibits NF-kappaB activation. Mol Cell. 2(2):233-9). Sumoylation has been reported to play an important role in transcription exhibiting both repressive and stimulatory effects. Many of the transcriptional nodes that are modulated play important roles in cancer. For example, sumoylation stimulates the transcriptional activities of transcription factors such as p53 and HSF2 (Rodriguez, M. S., Desterro, J. M., Lain, S., Midgley, C. A., Lane, D. P., and Hay, R. T. 1999. SUMO- 1 modification activates the transcriptional response of p53. EMBO J. 18(22):6455-61 ; Goodson, M. L., Hong, Y., Rogers, R., Matunis, M. J., Park-Sarge, O. K., Sarge, K. D. 2001. Sumo- 1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor. J Biol Chem. 276(21 ): 18513-8). In contrast, SUMO-conjugation represses the transcriptional activities of transcription factors such as LEF (Sachdev, S., Bruhn, L., Sieber, H., Pichler, A., Melchior, F., Grosschedl, R. 2001. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15(23):3088- 103) and c-Myb (Bies, J., Markus, J., and Wolff, L. 2002. Covalent attachment of the SUMO- 1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity. / Biol Chem. 277( 1 1):8999-9009). Thus, SUMO-conjugation controls gene expression and growth control pathways that are important for cancer cell survival.

[0005] Altered expression of SAE pathway components have been noted in a variety of cancer types: (Moschos, S. J., Jukic, D. M., Athanassiou, C., Bhargava, R., Dacic, S., Wang, X., Kuan, S. F., Fayewicz, S. L., Galambos, C., Acquafondata, M., Dhir, R., and Becker, D. 2010. Expression analysisof Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. Hum Pathol. 41(9): 1286-980); including multiple myeloma (Driscoll, J. J., Pelluru, D., Lefkimmiatis, K., Fulciniti, M., Prabhala, R. H., Greipp, P. R., Barlogie, B., Tai, Y. T., Anderson, K. C, Shaughnessy, J. D. Jr., Annunziata, C. M., and Munshi, N. C. 2010. The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. Blood. 1 15(14):2827-34); and breast cancer (Chen, S. F., Gong, C, Luo, M., Yao, H. R., Zeng, Y. J., and Su, F. X. 201 1. Ubc9 expression predicts chemoresistance in breast cancer. Chin J Cancer. 30(9):638-44), In addition, preclinical studies indicate that Myc-driven cancers may be especially sensitive to SAE inhibition (Kessler, J. D., Kahle, K. T., Sun, T., Meerbrey, K. L., Schlabach, M. R., Schmitt, E. M., Skinner, S. O., Xu, Q., Li, M. Z., Hartman, Z. C, Rao, M., Yu, P., Dominguez-Vidana, R., Liang, A. C, Solimini, N. L., Bernardi, R. J., Yu, B., Hsu, T., Golding, I., Luo, J., Osborne, C. K., Creighton, C. J., Hilsenbeck, S. G., Schiff, R., Shaw, C. A., Elledge, S. J., and Westbrook, T. F. 2012. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 335(6066):348-53; Hoellein, A., Fallahi, M., Schoeffmann, S., Steidle, S., Schaub, F. X., Rudelius, M., Laitinen, I., Nilsson, L., Goga, A., Peschel, C, Nilsson, J. A., Cleveland, J. L., and Keller, U. 2014. Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. Blood. 124( 13):2081 -90). Since SUMO-conjugation regulates essential cellular functions that contribute to the growth and survival of tumor cells, targeting SAE could represent an approach to treat proliferative disorders such as cancer.

[0006] SAE inhibitors may also be applicable for the treatment of other diseases and conditions outside of oncology. For example, SUMO modifies proteins that play important roles in neurodegenerative diseases (Steffan, J. S., Agrawal, N., Pallos, J., Rockabrand, E., Trotman, L. C, Slepko, N., Hies, K., Lukacsovich, T., Zhu, Y. Z., Cattaneo, E., Pandolfi, P. P., Thompson, L. M., Marsh, J. L. 2004. SUMO modification of Huntington and Huntington's disease pathology. Science. 304(5667): 100-4); Dorval, V., and Fraser, P. E. 2006. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J Biol Chem. 281 ( 15):9919-24; Ballatore, C, Lee, V. M., and Trojanowski, J. Q. 2007. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci. 8(9):663-72). Sumoylation also has been reported to play important role in pathogenic viral infection, inflammation and cardiac function (Lee, H. R., Kim, D. J., Lee, J. M., Choi, C. Y., Ahn, B. Y., Hayward, G. S., and Ahn, J. H. 2004. Ability of the human cytomegalovirus ΓΕ1 protein to modulate sumoylation of PML correlates with its functional activities in transcriptional regulation and infectivity in cultured fibroblast cells. / Virol. 78(12):6527-42; Liu, B., and Shuai, K. 2009. Summon SUMO to wrestle with inflammation. Mol Cell. 35(6):731-2; Wang, J., and Schwartz, R. J. 2010. Sumoylation and regulation of cardiac gene expression. Circ Rei. l07( l): 19-29).

[0007] It would be beneficial therefore to provide new SAE inhibitors that possess good therapeutic properties, especially for the treatment of proliferative, inflammatory, cardiovascular and neurodegenerative disorders.

[0008] This application provides chemical entities which are inhibitors of SAE and accordingly are useful for the treatment of proliferative, inflammatory, cardiovascular and neurodegenerative disorders. The chemical entities of the present disclosure are represented by Formula ( / ):( )or a pharmaceutically acceptable salt thereof;wherein:stereochemical configurations depicted at asterisked positions indicate absolutestereochemistry;Y is -O-, -CH , or -N(H)-;RAis hydrogen, fluoro, -NH2, or hydroxyl;RA' is hydrogen or fluoro, provided that when R is -NH2or hydroxyl, RA' is hydrogen;RBis hydrogen or, together with the oxygen to which it is attached, forms a prodrug;RCis hydrogen or C alkyl;RDis hydrogen, halogen, -CF3, or C,.4alkyl;X, is C(H), C(F), or N;X2is S or O;X3is C(RX3) or N;Rxis hydrogen, methyl, or halogen;Zxis hydrogen, halogen, cyano, Rz3, -S-Rz3, -S(0)-Rz3, or -S(0)2-Rz3;Rz3is an optionally substituted phenyl, an optionally substituted 5- to 7-membered cycloaliphatic, an optionally substituted 5- to 7-membered heterocyclyl, or an optionally substituted Ci-4 aliphatic;wherein Z] is not hydrogen, halogen, methyl, or cyano if ¾ is hydrogen or methyl; and(a) ¾ is a ring system having an optionally substituted 5- to 7-membered heterocyclyl with 1 -2 heteroatoms or an optionally substituted 5- to 7-membered cycloaliphatic fused to(i) an optionally substituted 5-membered heteroaryl or an optionally substituted 6- membered aryl or heteroaryl to form a bicyclic group; or(ii) an optionally substituted 9-membered heteroaryl or an optionally substituted 10- membered aryl or heteroaryl to form a tricyclic group;OR(b) ¾ is L-Rewherein L is -Lr, -VrL2-, or -L|-VrL2-;L, is a C] -3 alkylene chain wherein 1 or 2 saturated carbon atoms are optionally substituted by (Rf)(Rfl) and in which there are optionally one or two degrees of unsaturation;each Rfis independently hydrogen; hydroxyl; -N(Rh)(Rh'); d.4aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl ; -0-C|„4aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl ; or, together with Rfland the carbon atom to which they are attached, form =CH2, or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C,. alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle;each Rflis independently hydrogen; Ci-4aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl; -0-Ci_4aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl; or, together with Rfand the carbon atom to which they are attached, form =CH2, or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or Q_ alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle; wherein if Rfis hydroxyl, Rflis not -0-Ci. aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl;Rhand Rh' are each independently hydrogen or Q.4 alkyl;V, is -S-, -0-, -S(O)-, -S(0)2-, -C(O)- or -N(Rg)-;L2 is a Co-2 alkylene chain wherein one saturated carbon atom is optionally substituted by (Rf)(Rf');Rgis hydrogen or C4alkyl; andeither (i) Reis hydrogen, hydroxyl, halogen, -CF3, or an optionally substituted C,.4aliphatic,with the proviso that Reis not hydrogen if Rfand Rf' are present and formOR (ii) Reis a ring chosen from optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl, which is optionally fused to a second optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl;ORZj is hydrogen.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 is an XRPD pattern of compound I-257b Form 1 .

[0010] FIG. 2 is an XRPD pattern of compound I-263a Form 1.

[0011] FIG. 3 is an XRPD pattern of compound I-256b Form 1 .

[0012] FIG. 4 shows a differential scanning calorimetry (DSC) thermogram for I-263a Form 1 .

[0013] FIG. 5 shows a thermogravimetric analysis (TGA) thermogram for I-263a Form 1 .

[0014] FIG. 6 shows a raman pattern for I-263a Form 1 including data in the region of 500 cm"' to 3000 cm"' .

[0015] FIG. 7 shows a raman pattern for I-263a Form 1 including data in the region of 200 cm"' to 1600 cm" 1.

[0016] FIG. 8 shows a differential scanning calorimetry (DSC) thermogram for I-257b Form 1 .

[0017] FIG. 9 shows a thermogravimetric analysis (TGA) thermogram for I-257b Form 1 .

[0018] FIG. 10 shows a raman pattern for I-257b Form 1 including data in the region of 500 cm"' to 3000 cm"' .

[0019] FIG. 1 1 shows a raman pattern for I-257b Form 1 including data in the region of 200 cm"1to 1600 cm"' .

[0020] FIG. 12 shows a differential scanning calorimetry (DSC) thermogram for I-256b Form 1 .

[0021] FIG. 13 shows a thermogravimetric analysis (TGA) thermogram for I-256b Form 1 .

[0022] FIG. 14 is an XRPD pattern of compound I-263a Form 2.

[0023] FIG. 15 is an XRPD pattern of compound I-263a Form 3.

[0024] FIG. 16 shows a thermogravimetric analysis (TGA) thermogram for I-263a Form 3.

[0025] FIG. 17 shows a differential scanning calorimetry (DSC) thermogram for I-263a Form 3.DETAILED DESCRIPTION

[0026] Chemical entities of the present disclosure include those described generally for formula ( / ), above, and are further illustrated by the classes, subclasses, and species disclosed herein. It will be appreciated that preferred subsets described for each variable herein can be used for any of the structural subsets as well. As used herein, the following definitions shall apply unless otherwise indicated.

[0027] As described herein, chemical entities of the present disclosure may be optionally substituted with one or more substituents, such as are disclosed generally above, or as exemplified by particular classes, subclasses, and species disclosed herein. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally" or not, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible chemical entity. The term "substitutable," when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which hydrogen atom can be replaced with the radical of a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are, for instance, those that result in the formation of stable or chemically feasible chemical entities.

[0028] A stable chemical entity or chemically feasible chemical entity is one in which the chemical structure is not substantially altered when kept at a temperature from about -80°C to about +40°C, in the absence of moisture or other chemically reactive conditions, for at least a week, or a chemical entity which maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a patient.

[0029] The phrase "one or more substituents," as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met.

[0030] As used herein, the term "independently selected" means that the same or different values may be selected for multiple instances of a given variable in a single chemical entity.

[0031] As used herein, "a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10- membered partially unsaturated, or aromatic bicyclic ring system having 0-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur" includes cycloaliphatic, heterocyclic, aryl and heteroaryl rings.

[0032] As used herein, the term "aromatic" includes aryl and heteroaryl groups as described generally below and herein.

[0033] The term "aliphatic" or "aliphatic group," as used herein, means an optionally substituted straight-chain or branched CM2hydrocarbon, or a cyclic Ci_12hydrocarbon which is completely saturated or which contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic," "cycloalkyl," or "cycloalkenyl"). For example, suitable aliphatic groups include optionally substituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise specified, in various embodiments, aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-5, 1-4, 1-3, or 1-2 carbon atoms.

[0034] The term "alkyl," used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain saturated hydrocarbon group having 1 -12, 1-10, 1-8, 1-6, 1-5,1- 4, 1-3, or 1 -2 carbon atoms.

[0035] The term "alkenyl," used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one double bond and having2- 12, 2- 10, 2-8, 2-6, 2-5, 2-4, or 2-3 carbon atoms.

[0036] The term "alkynyl," used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having 2- 12, 2- 10, 2-8, 2-6, 2-5, 2-4, or 2-3 carbon atoms.

[0037] The terms "cycloaliphatic," "carbocycle," "carbocyclyl," "carbocyclo," or "carbocyclic," used alone or as part of a larger moiety, refer to an optionally substituted saturated or partially unsaturated cyclic aliphatic ring system having from 3 to about 14 ring carbon atoms. In some embodiments, the cycloaliphatic group is an optionally substituted monocyclic hydrocarbon having 3- 8 or 3-6 ring carbon atoms. Cycloaliphatic groups include, without limitation, optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, or cyclooctadienyl. The terms "cycloaliphatic," "carbocycle," "carbocyclyl," "carbocyclo," or "carbocyclic" also include optionally substituted bridged or fused bicyclic rings having 6- 12, 6-10, or 6-8 ring carbon atoms, wherein any individual ring in the bicyclic system has 3-8 ring carbon atoms.

[0038] The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0039] The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 toabout 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0040] The terms "haloaliphatic," "haloalkyl," "haloalkenyl" and "haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms. As used herein, the term "halogen" or "halo" means F, CI, Br, or I. The term "fluoroaliphatic" refers to a haloaliphatic wherein the halogen is fluoro, including perfluorinated aliphatic groups. Examples of fluoroaliphatic groups include, without limitation, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1 , 1 ,2-trifluoroethyl, 1 ,2,2- trifluoroethyl, and pentafluoroethyl.

[0041] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0042] The terms "aryl" and "ar-," used alone or as part of a larger moiety, e.g., "aralkyl," "aralkoxy," or "aryloxyalkyl," refer to an optionally substituted C^u aromatic hydrocarbon moiety comprising one to three aromatic rings. In at least one embodiment, the aryl group is a C6_|0aryl group. Aryl groups include, without limitation, optionally substituted phenyl, naphthyl, or anthracenyl. The terms "aryl" and "ar-," as used herein, also include groups in which an aryl ring is fused to one or more cycloaliphatic rings to form an optionally substituted cyclic structure such as a tetrahydronaphthyl, indenyl, or indanyl ring. The term "aryl" may be used interchangeably with the terms "aryl group," "aryl ring," and "aromatic ring."

[0043] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently attached to an alkyl group, either of which independently is optionally substituted. In at least one embodiment, the aralkyl group is C6_io aryl Ci_6alkyl, including, without limitation, benzyl, phenethyl, and naphfhylmethyl.

[0044] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, e.g., "heteroaralkyl," or "heteroaralkoxy," refer to groups having 5 to 14 ring atoms, such as 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. A heteroaryl group may be mono-, bi-, tri-, or polycyclic, for instance mono-, bi-, or tricyclic, such as mono- or bicyclic. In the context of "heteroar" entities, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. For example, a nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide. When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloaliphatic rings. Nonlimiting examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]- l ,4-oxazin-3(4H)-one. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0045] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, for instance one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl).

[0046] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, for instanct mono-, bi-, or tricyclic, and such as mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. Additionally, a heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.

[0047] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0048] The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, such as from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, twosubstituents can be taken together to form a 3-7-membered ring. The substituents can be on the same or different atoms.

[0049] An alkylene chain also can be optionally interrupted by a functional group. An alkylene chain is "interrupted" by a functional group when an internal methylene unit is interrupted by the functional group. Examples of suitable "interrupting functional groups" are described in the specification and claims herein, and include double and / or triple bonds between carbons in the alkylene chain.

[0050] For purposes of clarity, all bivalent groups described herein, including, e.g., the alkylene chain linkers described above, are intended to be read from left to right, with a corresponding left-to- right reading of the formula or structure in which the variable appears.

[0051] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents and thus may be "optionally substituted." In addition to the substituents defined above and herein, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group also include and are generally selected from -halo, -N02, -CN, -R+, -C(R+)=C(R+)2, -C≡C-R+, -OR+, -SR°, -S(0)R°, -S02R°, -S03R+, -S02N(R+)2, -N(R+)2, -NR+C(0)R+, -NR+C(S)R+, -NR+C(0)N(R+)2, -NR+C(S)N(R+)-N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-R°, -NR+C02R+, -NR+S02R°, -NR+S02N(R+)2, -0-C(0)R+, -0-C02R+, -OC(0)N(R+)2, -C(0)R+, -C(S)R°, -C02R+, -C(0)-C(0)R+, -C(0)N(R+)2, -C(S)N(R+)2,-C(0)N(R+)-OR+, -C(0)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(0)R+, -C(=NR+)-N(R+)2, -C(=NR+)-OR+, -N(R+)-N(R+)2, -C(=NR+)-N(R+)-OR+, -C(R°)=N-OR+, -P(0)(R+)2, -P(0)(OR+)2, -0-P(0)-OR+, and -P(0)(NR+)-N(R+)2, wherein R+, independently, is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclyl group, or two independent occurrences of R+are taken together with their intervening atom(s) to form an optionally substituted 5-7-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl. Each R° is, independently, an optionally substituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclyl group.

[0052] An aliphatic or heteroaliphatic group, or a non-aromatic carbocyclic or heterocyclic ring may contain one or more substituents and thus may be "optionally substituted." Unless otherwise defined above and herein, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic carbocyclic or heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: =0, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(0)R*, =N-NHC02R° =N-NHS02R° or =N-R* where R° is defined above, and each R* is independently selected from hydrogen or an optionally substituted Ci_6aliphatic group.

[0053] In addition to the substituents defined above and herein, optional substituents on the nitrogen of a non-aromatic heterocyclic ring also include and are generally selected from -R+, -N(R+)2, -C(0)R+, -C(0)OR+, -C(0)C(0)R+, -C(0)CH2C(0)R+, -S(0)2R+,-S(0)2N(R+)2, -C(S)N(R+)2, -C(=NH)-N(R+)2, or -N(R+)S(0)2R+; wherein each R+is defined above. A ring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ring also may be oxidized to form the corresponding N-hydroxy or N-oxide chemical entity. A nonlimiting example of such a heteroaryl having an oxidized ring nitrogen atom is N-oxidopyridyl.

[0054] As detailed above, in some embodiments, two independent occurrences of R+(or any other variable similarly defined in the specification and claims herein), are taken together with their intervening atom(s) to form a monocyclic or bicyclic ring selected from 3-13-membered cycloaliphatic,3-12-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5- 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0055] Exemplary rings that are formed when two independent occurrences of R+(or any other variable similarly defined in the specification and claims herein), are taken together with their intervening atom(s) include, but are not limited to the following: a) two independent occurrences of R+(or any other variable similarly defined in the specification or claims herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R+)2, where both occurrences of R+are taken together with the nitrogen atom to form a piperidin- l -yl, piperazin- l -yl, or morpholin-4-yl group; and b) two independent occurrences of R+(or any other variable similarly defined in the specification or claims herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two, these two occurrences of R+are taken together with the oxygenatoms to which they are bound to form a fused 6-membered oxygen containing ring:.It will be appreciated that a variety of other rings (e.g., spiro and bridged rings) can be formed when two independent occurrences of R+(or any other variable similarly defined in the specification and claims herein) are taken together with their intervening atom(s) and that the examples detailed above are not intended to be limiting.

[0056] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present chemical entities are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the chemical entities disclosed herein are within the scope of the present disclosure. Additionally,unless otherwise stated, structures depicted herein are also meant to include chemical entities that differ only in the presence of one or more isotopically enriched atoms. For example, chemical entities having the present structures where there is a replacement of hydrogen by deuterium or tritium, or a replacement of a carbon by al3C- or14C-enriched carbon are within the scope of this disclosure. Such chemical entities are useful, as a nonlimiting example, as analytical tools or probes in biological assays.

[0057] It is to be understood that, when a disclosed chemical entity has at least one chiral center, the present disclosure encompasses one enantiomer of inhibitor free from the corresponding optical isomer, a racemic mixture of the inhibitor, and mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a mixture is enriched in one enantiomer relative to its optical isomers, the mixture contains, for example, an enantiomeric excess of at least 50%, 75%, 90%, 95%, 99%, or 99.5%.

[0058] The enantiomers of the present disclosure may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. Where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0059] When a disclosed chemical entity has at least two chiral centers, the present disclosure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diasteromeric pairs, mixtures of diasteromers, mixtures of diasteromeric pairs, mixtures of diasteromers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diasteromeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s). When a mixture is enriched in one diastereomer or diastereomeric pair(s) relative to the other diastereomers or diastereomeric pair(s), the mixture is enriched with the depicted or referenced diastereomer or diastereomeric pair(s) relative to other diastereomers or diastereomeric pair(s) for the chemical entity, for example, by a molar excess of at least 50%, 75%, 90%, 95%, 99% or 99.5%.

[0060] The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Specific procedures for chromatographically separating diastereomeric pairs of precursors used in the preparation of chemical entities disclosed herein are provided the examples herein.

[0061] For the avoidance of doubt, for chemical entities described herein, where the chemical entity is a single diastereomer and the absolute configuration of the chiral centers is known the name of the chemical entity reflects the assigned configuration at each stereochemical center; for example chemical entity 1-43: { ( lR,2S,4R)-4-[(5-{ [4-(3-chlorobenzyl)-2-thienyl]carbonyl }pyrimidin-4- yl)amino]-2-hydroxycyclopentyl }rnethyl sulfamate. Where the chemical entity is a single diastereomer and the absolute configuration is known at some of the chiral centers but is unknown at one chiral center, the name reflects the two possibilities separated by an "or"; for example chemical entity I-la: [( lR,2R,3S,4R)-4- { [5-( { 4-[( 1 S)- 1 -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate or[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 R)- 1 -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate. Where the chemical entity is a mixture of two or more diastereomers the name reflects the two or more possibilities by using "and" between the names of the individual diastereomers that make up the mixture; for example chemical entity I-l: [( l R,2R,3S,4R)-4-{ [5-( {4-[( l S)- l -(6-bromopyridin-2-yl)- l - hydroxyethyl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino} -2, 3-dihydroxycyclopentyl] methyl sulfamate and [(lR,2R,3S,4R)-4-{ [5-( {4-[( l R)- l -(6-bromopyridin-2-yl)- ] -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate.

[0062] In some embodiments, the chemical entity of formula (Γ) is represented by formula (I-a):(I-a)or a pharmaceutically acceptable salt thereof;wherein Ra, Ra', Rb, XbX2, X3, Rd, Z and ¾ have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0063] In some embodiments, the chemical entity of formula (I) is represented by formula (II):Wwherein R , R ', R , Xi , X2, X3, Z{, and Z2have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0064] In some embodiments, the chemical entity of formula ( / ) is represented by formula (H-a) or (II-b)ill-b)or a pharmaceutically acceptable salt thereof;wherein Ra, Ra', Rb, X2, X3, Zl sand Z? have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (I) is represented by formula (II-a) wherein Ra, Ra', Rb, X2, X3, Zi, and Z2have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula ( / ) is represented by formula (Il-b) wherein R\ R ', Rb, X2, X3, Z, , and Z2have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0065] In some embodiments, the chemical entity of formula (7) is represented by formula (IH-a) or (Ill-b(Ill-b)or a pharmaceutically acceptable salt thereof;wherein Ra, Ra', Rb, Z\, and Z2have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemicalentity of formula (I) is represented by formula (III-a) wherein Ra, Ra', Rb, Zj , and Z2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (I) is represented by formula (IH-b) wherein Ra, Ra', Rb, Z and Z? have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0066] In some embodiments, the chemical entity of formula (I) is represented by formula (IV-a) or (IV-b):(IV-b)or a pharmaceutically acceptable salt thereof;wherein Rb, Z1 ;and Z2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (I) is represented by formula (IV-a) wherein Rb, Z1 ;and Z? have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (I) is represented by formula (IV-b) wherein Rb,Z) , and have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0067] In some embodiments, the chemical entity of formula (I) is represented by formula (V):X5, m, and Ring A have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0068] In some embodiments, the chemical entity of formula ( / ) is represented by formula (V-a) or (V-b):(V-b)or a pharmaceutically acceptable salt thereof;wherein dashed lines indicate single or double bonds and Rb, Z Rk, ¾, X5, m, and Ring A have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (7) is represented by formula V-a) wherein Rb, Z,, Rk, X4, X5, m, and Ring A have the values described herein andstereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (I) is represented by formula (V-b) wherein Rb, Z, R , X4, X5, m, and Ring A have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0069] In some embodiments, the chemical entity of formula ( / ) is represented by formula (VI):(VI)or a pharmaceutically acceptable salt thereof;wherein Y, Ra, Ra', Rb, Rc, X, , X2, X3, Rd, Z, , Rk, X4, X_, m, X6, Rj, and Rmhave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0070] In some embodiments, the chemical entity of formula (Γ) is represented by formula (Vl-a) or (VI-b):(Vl-b)or a pharmaceutically acceptable salt thereof;wherein Ra, Ra', R , X Z, , Rk, X4, X5, m, X6, X6', Rj, and Rmhave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula ( / ) is represented by formula (VI-α) wherein Ra, Ra', Rb, Xi, Zj, Rk, X4, X5, m, X6, X6', R and Rmhave the values described herein and stereochemicalconfigurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula ( / ) is represented by formula (Vl-b) wherein Ra, Ra', Rb, Xi, Zi , Rk, X4, X5, m, X6, X6\ RJ, and Rmhave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0071] (VII):(VII)wherein R\ Ra', R , Rc, Xi , Rd, Zt, Xi, X3, L, and Rehave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0072] In some embodiments, the chemical entity of formula (I) is represented by formula (VII- a) or (VH-b):(Vll-a)(Vll-b)or a pharmaceutically acceptable salt thereof;wherein Rb, Z, , L, and Rehave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (7) is represented by formula (VH-a) wherein Rb, Z, , L, and Rehave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (Γ) is represented by formula (VH-b) wherein Rb, Z L, and Rehave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0073] In some embodiments, the chemical entity of formula ( / ) is represented by formula (VHI).(VIII)harmaceutically acceptable salt thereof;wherein Y, Ra, Ra', Rb, Rc, XbX2, X3, Rd, Z,, Rf, Rf', and Rehave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0074] In some embodiments, the chemical entity of formula (I) is represented by formula (VIII- d) or (Vlll-b):(Vlll-b)or a pharmaceutically acceptable salt thereof;wherein Y, Ra, Ra', Rb, X, , Rc, Rd, Z, , Rf, Rf*, E5, E6, Re6, Re7, and Re8have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (I) is represented by formula (VIII-a) wherein Y, Ra, Ra', Rb, Xi, Rc, Rd, Z, , Rf, Rf', E5, E6, Re6, Re7, and Re8have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. Insome embodiments, the chemical entity of formula (I) is represented by formula VlH-b) wherein Y, R\ Ra', Rb, X Rc, Rd, Z, , Rf, Rf', E5)E6, Re6, Re7, and ReShave the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.(IX)or a pharmaceutically acceptable salt thereof;wherein Ra, Ra', Rb, X2, X3, Z, , Rf, Rf', Re5, E6, Re6, Re7, and Re8have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

[0076] In some embodiments, the chemical entity of formula ( / ) is represented by formula (IX-a) -b):(IX-a)(IX-b)or a pharmaceutically acceptable salt thereof;wherein R\ Ra', Rb, Z, , Rf, Rf', Re5, E6, Re6, Re7, and Re8have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (I) is represented by formula (IX-a) wherein Ra, Ra', Rb, Z, , Rr, Rf', Re5, E6, Re6, Re7, and Re8have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. In some embodiments, the chemical entity of formula (I) is represented by formula {IX-b) wherein Ra, Ra', Rb, Z| , Rf, Rf*, Re5, E6, Re6, Re7, and ReShave the val ues described herein and stereochemicalconfigurations depicted at asterisked positions indicate absolute stereochemistry.

[0077] The following values are described for any of formulas (I), (I-a), (II), (Il-a), (Il-b), (III- a), (Ill-b), (IV-a), (IV-b), (V), (V-a), (V-b), (VI), (VI-α), (Vl-b), (VII), (VH-a), (Vll-b), (VIII), (VIII-a), (VUI-b), (IX), (IX-a), or (IX-b).

[0078] In some embodiments, Y is -0-, -CH2-, or -N(H)-. In some embodiments, Y is -0-. In some embodiments, Y is -CH2-. In some embodiments, Y is -N(H)-.

[0079] In some embodiments, Rais hydrogen, fluoro, -NH2, or -OH. In some embodiments, Rais hydrogen, fluoro or -OH. In some embodiments, Rais hydrogen or -OH. In some embodiments, Rais hydrogen. In some embodiments, Rais -OH.

[0080] In some embodiments, Ra' is hydrogen or fluoro; provided that when Rais -NH2or -OH, Ra' is hydrogen. In some embodiments, Ra' is hydrogen.

[0081] In some embodiments, Rais hydrogen and Ra' is hydrogen. In some embodiments, Rais fluoro and Ra' is fluoro. In some embodiments, Rais -NH2and Ra' is hydrogen. In some embodiments, Rais hydrogen and Ra' is fluoro. In some embodiments, Rais -OH and Ra' is hydrogen. In some embodiments, Rais fluoro or hydrogen and Ra' is fluoro.

[0082] In some embodiments, Rcis hydrogen or C]_4alkyl. In some embodiments, Rcis hydrogen or methyl. In some embodiments, Rcis hydrogen.

[0083] In some embodiments, RDis hydrogen, halogen, -CF3, or Ci_4alkyl. In some embodiments, RDis hydrogen, fluoro, chloro, or methyl. In some embodiments, RDis hydrogen.

[0084] In some embodiments, Xi is C(H), C(F) or N. In some embodiments, Xi is C(H) or N. In some embodiments, X] is C(H). In some embodiments, Xj is N.

[0085] In some embodiments, X2is S or O. In some embodiments, X2is S. In some embodiments, X2is O.

[0086] In some embodiments, X3is C(RX3) or N, wherein RX3has the values described herein. In some embodiments, X3is C(R3), wherein R3has the values described herein. In some embodiments, X3is N. In some embodiments, X3is C(H).

[0087] In some embodiments, R" is hydrogen, methyl, or halogen. In some embodiments, RX3is hydrogen, methyl, fluoro, or chloro. In some embodiments, RX3is hydrogen or methyl. In some embodiments, RXJis hydrogen.

[0088] In some embodiments, Z, is hydrogen, halogen, cyano, RZ3, -S-RZ3, -S(0)-RZ3, or -S(0)2- RZ3, wherein RZ3has the values described herein, and wherein Zj is not hydrogen, halogen, methyl, or cyano if Z2is hydrogen or methyl.

[0089] In some embodiments, Z, is hydrogen; halogen; cyano; phenyl optionally substituted with one or more independently selected halogens; 5- to 7-membered cycloaliphatic or heterocyclyl optionally fused to a 6-membered aryl, wherein the 5- to 7-membered cycloaliphatic or heterocyclyl optionally fused to a 6-membered aryl is optionally substituted with one or more independently selected halogens; C fluoroaliphatic; or a Q.4aliphatic group optionally substituted with one or more hydroxyl, Q_4alkoxy, phenyl optionally substituted with one more independently selected halogens, 5- or 6-membered cycloaliphatic, 5- or 6-membered heterocyclyl, or -N(RZ:>)2; wherein each RZ3independently has the values described herein; and wherein Zi is not hydrogen, halogen, methyl, or cyano if Z> is hydrogen or methyl. In some embodiments, Z, is phenyl, halophenyl, or 5- to 7- membered cycloaliphatic or heterocyclyl optionally fused to a 6-membered aryl, wherein the 5- to 7- membered cycloaliphatic or heterocyclyl optionally fused to a 6-membered aryl is optionally substituted with one or more halogen. In some embodiments, Zi is a C aliphatic group (i) substituted with one or more phenyl, halophenyl, 5- or 6-membered cycloaliphatic or heterocyclyl, and (ii) optionally substituted with one or more hydroxyl, -OCM aliphatic, halogen, C aliphatic, acetyl, -OCH3, -CH2OCH3, cyano, -N(RZ5)2, -CH2NH2, -C02H, or -CF3, wherein each RZ5independently has the values described herein.

[0090] In some embodiments, Zi is hydrogen; halogen; cyano; or C aliphatic optionally substituted with one or more hydroxyl, CM alkoxy, -N(RZ5)2, or phenyl optionally substituted with one more independently selected halogens wherein each R" independently has the values described herein; wherein Zi is not hydrogen, halogen, methyl, or cyano if Z? is hydrogen or methyl. In some embodiments, Zi is hydrogen, chloro, or methyl, and Z2is not hydrogen or methyl. In some embodiments, Z\is hydrogen, and ¾ is not hydrogen or methyl. In some embodiments, Z:is chloro,and ¾ is not hydrogen or methyl. In some embodiments, Zj is methyl, and ¾ is not hydrogen or methyl.

[0091] In some embodiments, Rz3is an optionally substituted phenyl, an optionally substituted 5- to 7-membered cycloaliphatic, an optionally substituted 5- to 7-membered heterocyclyl, or an optionally substituted C,_4aliphatic. In some embodiments, Rz3is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or Ci_4aliphatic, any of which are optionally substituted with n occurrences of R2, wherein n and R2have the values described herein. In some embodiments, Rz3is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or C,_ 4 aliphatic, any of which may be substituted with one or more independently selected Rz4, wherein each R24independently has the values described herein. In some embodiments, Rz3is a phenyl, 5- to 7- membered cycloaliphatic, 5- to 7-membered heterocyclyl, or Ci_4aliphatic, any of which are optionally substituted with one to three independently selected Rz4, wherein each Rz4independently has the values described herein. In some embodiments, Rz3is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or C)_ aliphatic, any of which may be substituted with one to two independently selected Rz4, wherein each R7'4independently has the values described herein. In some embodiments, Rz3is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or C,_4aliphatic, any of which may be substituted with one Rz4, wherein Rz4has the values described herein. In some embodiments, Rz3is a phenyl, 5- to 7-membered cycloaliphatic, or Ci.4 aliphatic, any of which may be substituted with one to three Rz4, wherein each Rz4independently has the values described herein. In some embodiments, Rz3is a phenyl, 5- to 7-membered cycloaliphatic, or C1.4 aliphatic, any of which may be substituted with one Rz4, wherein Rz4has the values described herein.

[0092] In some embodiments, each occurrence of Rz4is independently hydroxyl, halogen, cyano, C,„4 aliphatic, C,.4fluoroaliphatic, C,.4alkoxy, C fluoroalkoxy, -N(Rz5)2, -C(0)Rz6, -C(0)2Rz5, 5- or 6-membered cycloaliphatic or heterocyclyl, or a phenyl optionally substituted with one or more independently selected halogens, wherein each R" independently has the values described herein and Rz6has the values described herein. In some embodiments, each occurrence of Rz4is independently halogen, cyano, C1.4 aliphatic, or C,_4fluoroaliphatic. In some embodiments, each occurence of Rz4is independently chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, cyclopropyl, or phenyl. In some embodiments, each occurrence of Rz4is independently chloro, bromo, fluoro, iodo, methyl, ethyl, difluoromethoxy, trifluoromethoxy, ethyne, cyclopropyl, or phenyl. In some embodiments, each occurence of Rz4is independently chloro, bromo, fluoro, methyl, ethyl, or trifluoromethyl. In some embodiments, each occurrence of Rz4is independently chloro, bromo, iodo, or methyl.

[0093] In some embodiments, each Rz5is independently hydrogen or Q_4alkyl. In some embodiments, each Rz5is independently hydrogen or methyl. In some embodiments, Rz5is hydrogen.In some embodiments, R" is methyl. In some embodiments, each R" is independently methyl or ethyl.

[0094] In some embodiments, Rz6is C,.4alkyl. In some embodiments, Rz6is methyl. In some embodiments, Rz6is methyl or ethyl.

[0095] In some embodiments, (a) ¾ is a ring system having an optionally substituted 5- to 7- membered heterocyclyl with 1-2 heteroatoms or an optionally substituted 5- to 7-membered cycloaliphatic fused to(i) an optionally substituted 5-membered heteroaryl or an optionally substituted 6- membered aryl or heteroaryl to form a bicyclic group; or(ii) an optionally substituted 9-membered heteroaryl or an optionally substituted 10- membered aryl or heteroaryl to form a tricyclic group;OR (b) ¾ is L-Rewherein L and Rehave the values described herein;OR (c) ¾ is hydrogen.

[0096] In some embodiments, (a) ¾ is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to(i) a 5-membered heteroaryl or a 6-membered aryl or heteroaryl to form a bicyclicgroup; or(ii) a 9-membered heteroaryl or a 10-membered aryl or heteroaryl to form a tricyclic group;wherein the ring system is optionally substituted by n occurrences of R2, wherein n and R2have the values described herein;OR(b)*∑n is L-Rewherein L is -Lr, -VrL2-, or -Li-VrL2-;Reis either:(i) hydrogen, hydroxyl, halogen, -CF3, or C,.4aliphatic optionally substituted with one or more hydroxyl, halogen, or C|_4aliphatic,with the proviso that Reis not hydrogen if Rfand Rflare present and form a ring;OR (ii) a ring chosen from 3- to 7-membered cycloaliphatic or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the Rering or rings are optionally substituted by n occurrences of R2, wherein n and R2have the values described herein;Lj is a Ci_3 alkylene chain wherein 1 or 2 saturated carbon atoms are optionally substituted by (Rf)(Rf') and in which there are optionally one or two degrees of unsaturation;V, is -S-, -0-, -S(O)-, -S(0)2-, -C(O)- or -N(RS)-, wherein Rshas the values described herein; L2 is a Co-2alkylene chain wherein one saturated carbon atom is optionally substituted by(Rf)(Rf');wherein Rfand Rflhave the values described herein.

[0097] In some embodiments, (a) ¾ is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to(i) a 5-membered heteroaryl or a 6-membered aryl or heteroaryl to form a bicyclicgroup; or(ii) a 9-membered heteroaryl or a 10-membered aryl or heteroaryl to form a tricyclic group;wherein the ring system is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, Ci_ aliphatic, Cj.4fluoroaliphatic, Ci_4alkoxy, fluoroalkoxy, -S-Ci. aliphatic, -S-C1.4 fluoroaliphatic, -N(Rz7)2, -C(0)Rz8,-S(0)Rz8, -S(0)2Rz8, -C(0)2Rz7, - C(0)N(Rz7)2, -S(0)2N(Rz7)2, -OC(0)N(Rz7)2, -N(Rz7)C(0)Rz8, -N(Rz7)S02Rz8, - N(Rz7)C(0)ORz8, T2-Rz9, a 5- to 6-membered heteroaryl, a 6-membered aryl, a 3- to 6- membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and the ring system is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or 4- to 6-membered heterocycle;each occurrence of R7is independently hydrogen or Ci_4alkyl;each occurrence of RzSis independently Ci_4alkyl;T2is a Ci_C2alkylene chain; andRz9is cyano, -N02, -N(Rz7)2, -ORz7, -C(0)Rz8, -C(0)2Rz7, or -C(0)N(Rz7)2;OR(b) Z? is L-Rewherein either:(i) Reis hydrogen, hydroxyl, halogen, -CF3, or Ci_4aliphatic optionally substituted with one or more hydroxyl, halogen, or C\_4aliphatic,with the proviso that Reis not hydrogen if Rfand Rf' are present and form a ring;OR (ii) Reis a ring chosen from 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, Rebeing optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, C,_4aliphatic, Q.4fluoroaliphatic, C,.4alkoxy, C|_4fluoroalkoxy,S-Ci-4 aliphatic, S-C fluoroaliphatic, -N(Rz7)2, -C(0)Rz8,-S(0)Rz8, -S(0)2RzS, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -OC(0)N(Rz7)2, -N(Rz7)C(0)Rz8, -N(Rz7)S02Rz8, - N(Rz7)C(0)ORz8, T2-Rz9, a 5- to 6-membered heteroaryl, a 6-membered aryl, a 3- to 6- membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and which is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or a spirocyclic 4- to 6-membered heterocycle;each occurrence of Rz7is independently hydrogen or C]_4alkyl;each occurrence of Rzis independently C,_4alkyl;T2is a C I.CT alkylene chain; andRz9is cyano, -N02, -N(Rz7)2, -ORz7, -C(0)Rz8, -C(0)2Rz7, or -C(0)N(Rz7)2.

[0098] In some embodiments, (a) Z2is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to(i) a 5-membered heteroaryl or a 6-membered aryl or heteroaryl to form a bicyclicgroup; or(ii) a 9-membered heteroaryl or a 10-membered aryl or heteroaryl to form a tricyclic group;wherein the ring system is optionally substituted by n occurrences of R2, wherein n and R2have the values described herein.

[0099] In some embodiments, ¾ is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to(i) a 5-membered heteroaryl or a 6-membered aryl or heteroaryl to form a bicyclicgroup; or(ii) a 9-membered heteroaryl or a 10-membered aryl or heteroaryl to form a tricyclic group;wherein the ring system is optionally substituted by 1 -3 independent occurrences of halogen, hydroxyl, cyano, Ci_4aliphatic, Ci_4fluoroaliphatic, Ci.4alkoxy, C,4fluoroalkoxy, -S-C|.4aliphatic, - S-C fluoroaliphatic, -N(Rz7)2, -C(0)Rz8. -S(0)RzS, -S(0)2Rz8, -C(0)2Rz7, -C(0)N(Rz7)2, - S(0)2N(Rz7)2, -OC(0)N(Rz7)2, -N(Rz7)C(0)RzS, -N(Rz7)S02Rz8, -N(Rz7)C(0)ORzS, T2-Rz9, a 5- to 6- membered heteroaryl, a 6-membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and the ring system is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or 4- to 6-membered heterocycle;wherein each Rz7independently has the values described herein and Rz8, T2, and Rz9have the values described herein.

[0100] In some embodiments, ¾ is a ring system having a 5- to 7-membered heterocyclyl with 1 -2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to a 5-membered heteroaryl or a 6- membered aryl or heteroaryl to form a bicyclic group; wherein the ring system is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, Ci_4aliphatic, Ci_4fluoroaliphatic, C,_4alkoxy, C fluoroalkoxy, -S-Ci_4aliphatic, -S-Ci_4fluoroaliphatic, -N(Rz7)2, - C(0)Rz8,-S(0)RzS, -S(0)2Rz8, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -OC(0)N(Rz7)2, - N(Rz7)C(0)RzS, -N(Rz7)S02Rz8, -N(Rz7)C(0)ORzS, T2-Rz9, a 5- to 6-membered heteroaryl, a 6- membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and the ring system is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or a spirocyclic 4- to 6-membered heterocycle;wherein each Rzindependently has the values described herein and Rz, T2, Rzhave the values described herein.

[0101] In some embodiments, ¾ is a 6-membered heterocyclyl, the heterocyclyl containing 1 N or O atom, fused to a 6-membered aryl or heteroaryl ring to form a bicyclic group, wherein the ring system is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, Ci_4aliphatic, Ci_4fluoroaliphatic, CMalkoxy, Ci_4fluoroalkoxy, -S-C,_4aliphatic, -S-C,.4fluoroaliphatic, -N(Rz7)2, -C(0)RzS,-S(0)Rz8, -S(0)2Rz8, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -OC(0)N(Rz7)2, - N(Rz7)C(0)Rz8, -N(Rz7)S02RzS, -N(Rz7)C(0)ORz8, T2-Rz9, a 5- to 6-membered heteroaryl, a 6- membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and the ring system is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or 4- to 6-membered heterocycle; wherein each Rz7independently has the values described herein and RzS, T2, and Rz9have the values described herein.

[0102] In some embodiments, Rz7is hydrogen or Ci- alkyl. In some embodiments, Rz7is hydrogen or methyl. In some embodiments, Rz7is hydrogen. In some embodiments, Rz7is methyl. In some embodiments, Rz7is methyl or ethyl.

[0103] In some embodiments, Rz8is Ci_4alkyl. In some embodiments, Rz8is methyl. In some embodiments, RzSis methyl or ethyl.

[0104] In some embodiments, T2is an optionally substituted C|_2alkylene chain. In some embodiments, T2is a Ci_C2alkylene chain optionally substituted with 0-3 independent occurrences of Rt2, wherein R'2has the values described herein. In some embodiments, T2is a Q.2alkylene chain. In some embodiments, T2is -CH2-CH2-. In some embodiments, T2is -C(CH3)2-. In some embodiments, T2is -CH2-.

[0105] In some embodiments, each occurrence of Rt2is independently C,_4alkyl. In some embodiments, each occurrence of R12is independently methyl or ethyl. In some embodiments, R12is methyl.

[0106] In some embodiments, Rz9is cyano, -N(Rz7)2, -ORz7, -C(0)Rz8, -C(0)2Rz7, or - C(0)N(Rz7)2, wherein Rz7and Rz8have the values described herein.[ diments, ¾ is(α-ι)wherein X4, X5, Rk, m, and Ring A have the values described herein.

[0108] In some embodiments, Rkis hydrogen or methyl. In some embodiments, Rkis deuterium. In some embodiments, Rkis hydrogen.

[0109] In some embodiments, X4is S, O, or N(Rn4), wherein R"4has the values described herein. In some embodiments, X4 is O or N(R"4), wherein Rn4has the values described herein. In some embodiments, X4is N(Rn4), wherein R"4has the values described herein. In some embodiments, X4is O or N(H). In some embodiments, X4is O. In some embodiments, X4is N(H).

[0110] In some embodiments, R"4is hydrogen or C|_4alkyl. In some embodiments, R"4is hydrogen or methyl. In some embodiments, R"4is hydrogen.

[0111] In some embodiments, X5is O, C(O), or C(Rx5)(Rx5'), wherein Rx5and Rx5,have the values described herein. In some embodiments, X5is O. In some embodiments, X5is C(R:,)(R:"). In some embodiments, X5is CD2. In some embodiments, X5is O, C(O), or C(Rx3)(Rx5'), wherein X5is not O iftis N(R"4) or S. In some embodiments, X5is CH2.

[0112] In some embodiments, R" is hydrogen, halogen, hydroxyl, or C,.4alkyl, or R" and Rx5', taken together with the carbon atom to which they are attached, form a spirocychc 3-6 membered carbocycle or a spirocychc 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S. In some embodiments, Rx5is hydrogen, fluoro, hydroxyl, or Ci_4alkyl, or Rx5and Rx:", taken together with the carbon atom to which they are attached, form a spirocychc 3-6 membered carbocycle or a spirocyclic 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S. In some embodiments, Rx5is hydrogen, fluoro, hydroxyl, or d-4alkyl. In some embodiments, Rx5is hydrogen, fluoro, chloro, hydroxyl, or methyl. In some embodiments, R"5is hydrogen or methyl. In some embodiments, RxSis hydrogen.

[0113] In some embodiments, Rx5,is hydrogen, halogen or C1-4 alkyl, or R° and Rx5', taken together with the carbon atom to which they are attached, form a spirocyclic 3-6 membered carbocycle or a spirocyclic 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S, wherein Rx5' is not halogen if Rnis hydroxyl. In some embodiments, Rx5' is hydrogen, fluoro, or Ci_4 alkyl, or Rx5and Rx5', taken together with the carbon atom to which they are attached, form a spirocyclic 3-6 membered carbocycle or a spirocyclic 4-6 membered heterocycle comprising oneheteroatom chosen from O, N, or S, wherein Rx3' is not halogen if Rx5is hydroxyl. In some embodiments, R5,is hydrogen, fluoro, or CMalky], wherein R5' is not fluoro if R" is hydroxyl. In some embodiments, R"' is hydrogen, fluoro, chloro, or methyl, wherein Rx3' is not fluoro if Rx5is hydroxyl. In some embodiments, Rx5' is hydrogen.

[0114] In some embodiments, Rx5is hydrogen, halogen, hydroxy], or Q.4alkyl and Rx5' is hydrogen. In some embodiments, R3is hydrogen, fluoro, chloro, hydroxyl, or methyl and Rx5' is hydrogen. In some embodiments, R3is hydrogen or methyl and R"' is hydrogen. In some embodiments, R3is hydrogen and R3' is hydrogen. In some embodiments, Rx5is fluoro and Rx5' is fluoro. In some embodiments, R'° is methyl and R"' is methyl. In some embodiments, Rx1and R"', taken together with the carbon atom to which they are attached, a spirocyclic 3-6 membered carbocycle or a spirocyclic 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S. In some embodiments, Rx5and R°', taken together with the carbon atom to which they are attached, form a spirocyclic 3-6 membered carbocycle. In some embodiments, Rx5and R5', taken together with the carbon atom to which they are attached, form a cyclopropyl ring. In some embodiments, Rx5and Rx5' are independently hydrogen or fluoro; or, together with the carbon to which they are attached, form a cyclopropyl ring.

[0115] In some embodiments, Ring A is a fused 5-membered heteroaryl or 6-membered aryl or heteroary], and is optionally substituted with 1-3 independent occurrences of halogen, hydroxy], cyano, CM aliphatic, C fluoroaliphatic, C M alkoxy, C fluoroalkoxy, -S-CM aliphatic, -S-C fluoroaliphatic, -N(Rz7)2, -C(0)Rz8, -S(0)RzS, -S(0)2Rz8, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, - OC(0)N(Rz7)2, -N(Rz7)C(0)RzS, -N(Rz7)S02RzS, -N(Rz7)C(0)ORz8, T2-Rz9, a 5- to 6-membered heteroaryl, a 6-membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein Rz7, RzS, T2, and Rz9have the values described herein. In some embodiments, Ring A is a fused 6-membered aryl or heteroaryl having one heteroatom and is optionally substituted with 1 -3 independent occurrences of halogen, hydroxyl, cyano, Q _4aliphatic, CMfluoroaliphatic, C alkoxy, CMfluoroalkoxy, -S-CMaliphatic, -S-C,.4fluoroaliphatic, -N(Rz7)2, -C(0)Rz8. -S(0)Rz8, - S(0)2Rz8, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -OC(0)N(Rz7)2, -N(Rz7)C(0)RzS, -N(Rz7)S02Rz8, - N(Rz7)C(0)ORz8, T2-Rz9, a 5- to 6-membered heteroaryl, a 6-membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein Rz7, Rz8, T2, and Rz9have the values described herein.

[0116] In some embodiments, Ring A is a fused 5-membered heteroaryl or 6-membered aryl or heteroaryl, and is optionally substituted with 1 -3 independent occurrences of chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, cyano, ethyne, cyclopropyl, or phenyl. In some embodiments, Ring A is a fused 6-membered aryl or heteroaryl, and is optionally substituted with 1-3 independent occurrences of chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy,ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, cyano,ethyne, cyclopropyl, or phenyl.

[0117] In some embodiments, Ring A is a fused phenyl or pyridyl, and is optionally substituted with 1-3 independent occurrences of chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, cyano, ethyne, cyclopropyl, or phenyl. In some embodiments, Ring A is a fused 6-membered aryl or heteroaryl, and is optionally substituted with 1-3 independent occurrences of chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, cyano, diethylamino, ethyne, cyclopropyl, or phenyl.ts, ¾ is(a-ii)wherein X4, X5, X6, X6', Rm, and RJhave the values described herein.

[0119] In some embodiments, Z2is(a-iii) (a-iv)wherein X4, X5, X6, X6', Rm, and RJhave the values described herein. In some embodiments, ¾ is (a- iii), wherein X4, X5, X6, X6', Rm, and Rjhave the values described herein. In some embodiments, ¾ is (a-iv), wherein X4, X5, X¾, X(,', Rm, and RJhave the values described herein.

[0120] In some embodiments, Z2(a-v) (a-vi)wherein ¾, X5, X6, X7, X8, and R1have the values described herein. In some embodiments, ¾> is (a- v), wherein X4, X5, X6, X7, X8, and Rjhave the values described herein. In some embodiments, ¾ is (a-vi), wherein X4, X5, X6, X7, Xg, and Rshave the values described herein. In some embodiments, X7is O or S. In some embodiments, X8is S or N(H).

[0121] In some embodiments, ¾ is(a-x) (a-xi) (a-xii)wherein X4, X5, Rm, and Rjhave the values described herein. In some embodiments, ¾ is (a-vii), wherein X4, X5, Rm, and RJhave the values described herein. In some embodiments, ¾ is (a-viii), wherein X5and Rjhave the values described herein. In some embodiments, ¾ is (a-ix), wherein X5and RJhave the values described herein. In some embodiments, Z2is (a-x), wherein X5and RJhavethe values described herein. In some embodiments, ¾ is (a-xi), wherein X5and Rjhave the values described herein. In some embodiments, ¾ is (a-xii), wherein X4, Rm, and RJhave the values described herein. In some embodiments, ¾ is(a-xiii)wherein X4, X6, X^, and RJhave the values described herein.

[0122] In some embodiments, X6is N or C(R6), wherein Rx6has the values described herein. In some embodiments, X6is N or C(H). In some embodiments, X6is N. In some embodiments, X6is C(R6), wherein Rx6has the values described herein. In some embodiments, X6is C(H).

[0123] In some embodiments, R6is hydrogen, halogen, hydroxyl, cyano, C aliphatic, C,_4fluoroaliphatic, C,.4alkoxy, C4fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, - CH2-ORz7, -CH2NRz7, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each Rz7independently has the values described herein. In some embodiments, Rx6is hydrogen, chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, or cyclopropyl. In some embodiments, R6is hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF3, -OCH3, -OCH2CH3, or - C≡CH. In some embodiments, Rx6is hydrogen, fluoro, chloro, bromo, iodo, or methyl. In some embodiments, R6is hydrogen, fluoro, chloro, or methyl. In some embodiments, Rx6is hydrogen, fluoro, or chloro. In some embodiments, Rx6is hydrogen.

[0124] In some embodiments, X6' is N or C(Rx6'), wherein Rx6' has the values described herein. In some embodiments, X6' is N or C(R6), wherein Rx6has the values described herein. In some embodiments, X6' is N or C(H). In some embodiments, X6' is N. In some embodiments, X6' is C(Rx6'), wherein Rx6' has the values described herein. In some embodiments, X6' is C(H).

[0125] In some embodiments, Rx6' is hydrogen, halogen, hydroxyl, cyano, Ci_4aliphatic, C|. fluoroaliphatic, C,_4alkoxy, C,.4fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, - CH2-ORz7, -CH2NRz7, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each Rz?independently has the values described herein. In some embodiments, Rx6is hydrogen, chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio,dimethylamino, diethylamino, ethyne, or cyclopropyl. In some embodiments, Rx' is hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF3, -OCH3, -OCH2CH3, or - C≡CH. In some embodiments, Rx6is hydrogen, fluoro, chloro, bromo, iodo, or methyl. In some embodiments, Rx6' is hydrogen, fluoro, chloro, bromo, iodo, or methyl. In some embodiments, Rx6' is hydrogen, fluoro, chloro, or methyl. In some embodiments, Rx6' is hydrogen, fluoro, or chloro. In some embodiments, Rx6,is hydrogen.

[0126] In some embodiments, Rjis hydrogen, halogen, hydroxyl, cyano, Cj.4aliphatic, CMfluoroaliphatic, C,.4alkoxy, C fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, - CH2-ORz7, -CH2NRZ?, a 3- to 6-membered cycloaliphatic, or a 4- to 6-menibered heterocyclyl, wherein each Rz7independently has the values described herein. In some embodiments, Rjis hydrogen, chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, or cyclopropyl. In some embodiments, RJis hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF3, -OCH3, -OCH2CH3, or - C≡CH. In some embodiments, RJis methyl, ethyl, isopropyl, hydrogen, fluoro, chloro, bromo, cyclopropyl, -C≡CH or -CF3. In some embodiments, RJis hydrogen, fluoro, chloro, bromo, iodo, or methyl. In some embodiments, Rjis hydrogen, fluoro, chloro, or methyl. In some embodiments, R' is fluoro, chloro, or methyl. In some embodiments, RJis hydrogen, fluoro, or chloro. In some embodiments, Rjis hydrogen. In some embodiments, Rjis fluoro or chloro. In some embodiments, Rjis methyl. In some embodiments, RJis fluoro. In some embodiments, RJis chloro.

[0127] In some embodiments, Rmis hydrogen, halogen, hydroxyl, cyano, Ci_4aliphatic, Ci_4fluoroaliphatic, C,.4alkoxy, C fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, - CH2-ORz7, -CH2NRz7, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each Rz7independently has the values described herein. In some embodiments, Rmis hydrogen, chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, or cyclopropyl. In some embodiments, Rmis hydrogen, fluoro, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF3, -OCH3, -OCH2CH , or -C≡CH. In some embodiments, Rmis hydrogen, fluoro, chloro, bromo, iodo, or methyl. In some embodiments, Rmis hydrogen, fluoro, chloro, or methyl. In some embodiments, Rmis hydrogen, fluoro, or chloro. In some embodiments, Rmis hydrogen.

[0128] In some embodiments, each Rx6, Rx6', Rsand Rmis independently hydrogen, halogen, hydroxyl, cyano, aliphatic, C,_4fluoroaliphatic, C].4alkoxy, Ci- fluoroalkoxy, -N(Rz7)2, - C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -CH2-ORz7, -CH2NRz7, 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each Rz?independently has the values described herein and at least one of Rx6, Rx6', Rjand Rmis hydrogen. In some embodiments, each of Rx6, Rx6', Rj, and Rmis independently hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl,CF3, -OCH3, -OCH2CH3, or -C≡CH; wherein at least one of Rx6, Rx7, Rjand Rmis hydrogen. In some embodiments, each R6, Rx6', R' and Rmis independently hydrogen, halogen, hydroxyl, cyano, Ci_4aliphatic, C,.4fluoroaliphatic, C alkoxy, C fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, - S(0)2N(Rz7)2, -CH2-ORz7, -CH2NRz7, 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each Rz7independently has the values described herein and at least one of Rx6, Rx6', Rjand Rmis hydrogen. In some embodiments, each of Rx6, Rx6', RJ, and Rmis independently hydrogen, chloro, iluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF3, -OCH3, - OCH2CH3, or -OCH; wherein at least two of Rx6, Rx7, Rjand Rmare hydrogen. In some embodiments, each Rx6, Rx6', R1and Rmis independently hydrogen, halogen, hydroxyl, cyano, C)_ aliphatic, C fluoroaliphatic, C alkoxy, C fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, - S(0)2N(Rz7)2, -CH2-ORz7, -CH2NRz7, 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each Rz7independently has the values described herein and at least one of R6, Rx6', Rjand Rmis hydrogen. In some embodiments, each of R6, Rx6', R and Rmis independently hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF3, -OCH3, - OCH2CH3, or -C≡CH; wherein at least two of Rx6, Rx7, Rjand Rmare hydrogen.

[0129] In some embodiments, R6is hydrogen; R6' is hydrogen; and Rjand Rmare independently hydrogen, halogen, hydroxyl, cyano, C1.4 aliphatic, C^4fluoroaliphatic, C1.4 alkoxy, C1.4 fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -CH2-ORz7, -CH2NRz7, 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each Rz7independently has the values described herein. In some embodiments, R6is hydrogen; R6' is hydrogen; and Rjand Rmare independently hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF3, -OCH3, -OCH2CH3, or -C≡CH. In some embodiments, Rx6is hydrogen; Rx6' is hydrogen; Rmis hydrogen; and Rjis methyl, ethyl, isopropyl, hydrogen, fluoro, chloro, bromo, cyclopropyl, -C≡CH or -CF3. In some embodiments, R6is hydrogen; R6' is hydrogen; Rmis hydrogen; and Rjis hydrogen, fluoro, chloro, or methyl.

[0130] In some embodiments, m is 0-2. In some embodiments, m is 1 -2. In some embodiments, m is 0- 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0131] In some embodiments, ¾ is L-Re.

[0132] In some embodiments, L is -Lr, -V,-L2-, orwherein L, , VI ;and L2 have the values described herein. In some embodiments, L is -C(Rf)(Rf')-, -S-, -S(O)-, -S(0)2-, -C(O)-, - C(=CH2)-, -C(Rf)(Rf,)-C(=CH2)-, -C(Rf)(Rf')-C≡C-, -C(Rf)(Rf')-0-, -C(Rf)(Rf')-S-, -C(Rf)(Rf')-N(R8)-, -C(Rf)(Rf')-N(Rg)-CH2-, -C(Rf)(Rf,)-CH2-, -C(Rf)(Rf')-CH2-CH2-, or -C(0)-C(Rf)(Rf')-, wherein Rf, Rf', and Rshave the values described herein. In some embodiments, L is -C(Rf)(Rf')-, -S-, -C(=0)-, - C(Rf)(Rf,)-0-, -C(Rf)(Rf')-S-, -C(Rf)(Rf')-N(Rs)-, -C(Rf)(Rf')-CH2- or -C(Rf)(Rf')-C≡C-, wherein Rf, Rf', and Rshave the values described herein.

[0133] In some embodiments, L is -CH2-, -CH(OH)-, -C(OH)(CH3)-, -CH(NH2)-, -C(CH3)(NH2)-, -CH2-CH2-, -S(O)-,, or Λ- «** . In some embodiments, L is -CH(OH)- or - C(OH)(CH3)-. In some embodiments, L is -CH(NH2)- or -C(CH3)(NH2)-. In some embodiments, L is - CH(OH)- or -CH(NH2)-. In some embodiments, L is -C(CH3)(OH)- or -C(CH3)(NH2)-. In someembodiments, L is «* Λ. ΛorΛ. Λ τη someembodiments, L is -CH2-. In some embodiments, L is -CH(OH)-. In some embodiments, L is -C(OH)(CH3)-. In some embodiments, L is -CH(NH2)-. In some embodiments, L is -C(CH3)(NH2)-. In some embodiments, L is -CH2-CH2-. Inembodiments, L isΛ. In some embodiments, L is

[0134] In some embodiments, L, is a C|.3alkylene chain wherein 1 or 2 saturated carbon atoms are optionally substituted by (Rf)(Rfl) and in which there are optionally one or two degrees of unsaturation, wherein Rfand Rf' have the values described herein. In some embodiments, L, is - C(Rf)(Rf')-, wherein Rfand Rf' have the values described herein. In some embodiments, L| is -CH?-. In some embodiments, Li is * ,

[0135] In some embodiments, each Rfis independently hydrogen; hydroxyl; -N(Rh)(Rh'); d.4aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl; -O-C1.4aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl; or, together with Rf' and the carbon atom to which they are attached, form C=CH2, a 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or Ci_4alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle. In some embodiments, each Rfis independently hydrogen, hydroxyl, N(Rh)(Rh'), -OCH3, cyclopropyl, or C aliphatic optionally substituted with hydroxyl or -OCH3, wherein Rhand Rh' have the values described herein, or, together with the carbon atom to which they are attached, Rfand Rflform a 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C]_4alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle. In some embodiments, each Rfis independently hydrogen, hydroxyl, N(Rh)(Rhl), -OCH3, cyclopropyl, or C aliphatic optionally substit together withirbon atom to which they are attached, Rfand Rflwherein Xi has the values described herein. In some embodiments, each Rfis independently hydrogen, hydroxyl,N(Rh)(Rh'), C1.4alkoxy, cyclopropyl, or C alkyl optionally substituted with hydroxyl or -OCH3. In some embodiments, each Rfis independently hydrogen, C|_4alkyl, or cyclopropyl. In some embodiments, each Rfis independently hydrogen, methyl, ethyl, or isopropyl. In some embodiments, each Rfis independently hydrogen or methyl. In some embodiments, each Rfis hydrogen.

[0136] In some embodiments, each Rf' is independently hydrogen; C1.4 aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl; -O-C1.4aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl; or, together with Rfand the carbon atom to which they are attached, form C=CH2, a 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or Ci_4alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle; wherein if Rfis hydroxyl, Rf' is not -0-C| _4aliphatic optionally substituted with hydroxyl, -OCH3, or cyclopropyl. In some embodiments, each Rflis independently hydrogen, cyclopropyl, or Q. aliphatic optionally substituted with hydroxyl or -OCH3, or, together with the carbon atom to which they are attached, Rfand Rf' form a 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle; or, together with the carbon atom to which they are attached, Rfand RF' formwherein X9has the values described herein. In some embodiments, each RFLis independently hydrogen, cyclopropyl, or C,.4alkyl optionally substituted with hydroxyl or -OCH3. In some embodiments, each RF' is independently hydrogen, CM alkyl, or cyclopropyl. In some embodiments, each RFLis independently hydrogen, methyl, ethyl, or isopropyl. In some embodiments, each RF' is independently hydrogen or methyl. In some embodiments, each RF' is independently hydrogen or methyl. In some embodiments, each RF' is hydrogen.

[0137] In some embodiments, each RFis independently hydrogen, hydroxyl, N(RH)(RH'), -OCH3, cyclopropyl, or .4aliphatic optionally substituted with hydroxyl or -OCH3; and each RF' is independently hydrogen, cyclopropyl, or CM aliphatic optionally substituted with hydroxyl or -OCH3, wherein at least one of RFand RF' comprises at least one heteroatom; or, together with the carbon atom to which they are attached, RFand RF' form a 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C,.4alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle. In some emdodiments, togetherwith the carbon atom to which they are attached, Rfand Rf' form, ,or ¾· ΛfwhereinX9has the values described herein. In some emdodiments, together with the carbon atom to whichthey are attached, R and R ' formsome emdodiments, together with the carbon atom to which they are attached, Rfand Rf' form , wherein X9has the values described herein. In some emdodiments, each Rfis independently hydrogen, hydroxyl, N(Rh)(Rh'), C|_4alkoxy, cyclopropyl, or Ci_4alkyl optionally substituted with hydroxyl or -OCH3; and each Rf' is independently hydrogen, cyclopropyl, or Ci_ alkyl optionally substituted with hydroxyl or -OCH3. In some embodiments, each Rfand Rf' is independently hydrogen, C1.4 alkyl, or cyclopropyl; or are taken together to form =CH2. In some embodiments, each Rfand Rf' is independently hydrogen, methyl, ethyl, or isopropyl. In some embodiments, each Rfand Rf' is independently hydrogen or methyl.

[0138] In some embodiments, Rhand Rh' are each independently hydrogen or C,4alkyl. In some embodiments, Rhand Rh' are each independently hydrogen or methyl. In some embodiments, Rhand Rhlare each hydrogen. In some embodiments, Rhis hydrogen or Ci_ alkyl. In some embodiments, Rhis hydrogen or methyl. In some embodiments, Rhis hydrogen. In some embodiments, Rbis hydrogen or Ci_ alkyl and R1" is hydrogen. In some embodiments, Rhis hydrogen or methyl and Rh' is hydrogen. In some embodiments, Rhis methyl and Rhlis methyl.

[0139] In some embodiments, X9is O, N(Rh), or S, wherein Rhhas the values described herein. In some embodiments, X9is O, N(H), N(CH3), or S. In some embodiments, X9is O. In some embodiments, X9is N(H). In some embodiments, X9is N(CH3). In some embodiments, X9is S.

[0140] In some embodiments, V, is -S-, -0-, -S(O)-, -S(0)2-, -C(O)- or -N(R )-, wherein Rshas the values described herein. In some embodiments, V, is -C(O)- or -N(RS)-, wherein Rshas the values described herein. In some embodiments, V{is -S-, -S(O)-, or -S(0)2-. In some embodiments, V| is -O-

[0141] In some embodiments, Rgis hydrogen or Ci_ alkyl. In some embodiments, Rsis hydrogen, methyl, ethyl, or isopropyl. In some embodiments, Rsis hydrogen or methyl. In some embodiments, Rgis hydrogen. In some embodiments, Rsis methyl.

[0142] In some embodiments, > is a C0.2 alkylene chain wherein one saturated carbon atom is optionally substituted by (Rf)(Rf'), wherein Rfand Rf' have the values described herein. In someembodiments, L2is -C(Rf)(Rf')-. In some embodiments, L> is -CH2-. In some embodiments, L? is - CH2-CH2-. In some embodiments, L2is absent.

[0143] In some embodiments, Reis either (i) hydrogen, hydroxyl, halogen, -CF3, or an optionally substituted C(_4aliphatic, with the proviso that Reis not hydrogen if Rfand Rf' are present and form a ring; OR (ii) Reis a ring chosen from optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl, which is optionally fused to a second optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl. In some embodiments, Reis hydrogen, hydroxyl, halogen, -CF3, or C|.4alkyl optionally substituted with one or more hydroxyl, halogen, or Ci_4alkyl, with the proviso that Reis not hydrogen if Rfand Rf' are present and form a ring. In some embodiments, Reis hydroxyl, halogen, -CF3, or Ci_4alkyl optionally substituted with one or more hydroxyl, halogen, or d.4alkyl.

[0144] In some embodiments, Reis an optionally substituted ring chosen from 3- to 7-membered cycloaliphatic or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, which is optionally substituted. In some embodiments, Reis a ring chosen from 3- to 7- membered cycloaliphatic or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6- membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the Rering or rings are optionally substituted by n occurrences of R2, wherein n and R2have the values described herein.

[0145] In some embodiments, R is a ring chosen from 3- to 7-membered cycloaliphatic or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the Rering or rings are optionally substituted by 1 -3 independent occurrences of halogen, hydroxyl, cyano, C|.4aliphatic, fluoroaliphatic, Ci_4alkoxy, Q_ fluoroalkoxy, S-C, _4aliphatic, S-Ci_4fluoroaliphatic, - N(Rz7)2, -C(0)Rz8,-S(0)Rz8, -S(0)2RzS, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -OC(0)N(Rz7)2, - N(Rz7)C(0)Rz8, -N(Rz7)S02Rz8, -N(Rz7)C(0)ORz8, T2-Rz9, a 5- to 6-membered heteroaryl, a 6- membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and which is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle, wherein each Rz7independently has the values described herein and Rz8, T2, and Rz9have the values described herein. In some embodiments, Reis RRwhich is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, Q- aliphatic, Ci_fluoroaliphatic, Q.4alkoxy, Ci_4fluoroalkoxy, S-Q.4aliphatic, S-Ci_4fluoroaliphatic, -N(Rz7)2, - C(0)Rz8,-S(0)Rz8, -S(0)2RzS, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -OC(0)N(Rz7)2, - N(Rz7)C(0)Rz8, -N(Rz7)S02Rz8, -N(Rz7)C(0)ORz8, T2-Rz9, a 5- to 6-membered heteroaryl, a 6- membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and which isoptionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle, wherein each Rz7independently has the values described herein and RR, Rz8, T2, and Rz9have the values described herein.

[0146] In some embodiments, Reis a 5- to 7-membered cycloaliphatic ring or a 5- to 7- membered heterocyclyl having only one heteroatom, wherein the ring is optionally substituted. In some embodiments, Reis a 5- to 7-membered cycloaliphatic ring or a 5- to 7-membered heterocyclyl having only one heteroatom, wherein the ring is optionally substituted by n occurrences of R2, wherein n and R2have the values described herein. In some embodiments, Reis a 5- to 7-membered cycloaliphatic ring or a 5- to 7-membered heterocyclyl having only one heteroatom, wherein the ring is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, C,_4aliphatic, C| .4fluoroaliphatic, C| _4alkoxy, C fluoroalkoxy, S-C aliphatic, S-C) .4fluoroaliphatic, -N(Rz7)2, - C(0)Rz8,-S(0)RzS, -S(0)2RzS, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -OC(0)N(Rz7)2, - N(Rz7)C(0)Rz8, -N(Rz7)S02Rz8, -N(Rz7)C(0)ORz8, T2-Rz9, a 5- to 6-membered heteroaryl, a 6- membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and which is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle, wherein each Rz7independently has the values described herein and Rz8, T2, and Rz9have the values described herein.47] In some embodiments, Reis-i) (b-ii) (b-iii) (b-iv)(b-v) (b-vi)wherein E, , ¾, E3, E3', Rel, Rel', and Re2have the values described herein and dashes indicate single or double bonds. In some embodiments, Reis (b-i) wherein Ej , Rel, and Rel' have the values described herein. In some embodiments, Reis (b-ii) wherein E] has the values described herein. In some embodiments, Reis (b-iii) wherein E2has the values described herein and dashes indicate single ordouble bonds. In some embodiments, Reis (b-iv) wherein E3, Rel, Rel', and Re2have the values described herein and dashes indicate single or double bonds. In some embodiments, Reis (b-v) wherein E3', Rel, Rl', and Re2have the values described herein. In some embodiments, Reis (b-vi) wherein Rel, Rel', and Re2have the values described herein. In some embodiments, E, is N or C(H). In some embodiments, E2is O, S, or CH2. In some embodiments, E3is O, S, N(Re3), or C(H)(Re3), wherein Re3has the values described herein. In some embodiments, E3' is O, N(Re3) or C(H)(Re3), wherein Re3has the values described herein. In some embodiments, Rland Rel' are eachindependently hydrogen or fluoro. In some embodiments, Re2is hydrogen or methyl. In some embodiments, Re3is hydrogen or methyl.

[0148] In some embodiments, Reis a 6-membered aryl or 5-to 6-membered heteroaryl, which is optionally fused to a second 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the Rering or rings are optionally substituted. In some embodiments, Reis a 6-membered aryl or 5-to 6-membered heteroaryl, which is optionally fused to a second 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the Rering or rings are optionally substituted with n occurrences of R2, wherein n and R2have the values described herein. In some embodiments, Reis a 6-membered aryl or 5-to 6-membered heteroaryl, which is optionally fused to a second 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7- membered heterocyclyl, wherein the Rering or rings are optionally substituted with 1 -3 independent occurrences of halogen, hydroxy!, cyano, C1.4 aliphatic, Ci_4fluoroaliphatic, CM alkoxy, Cfluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -CH2-ORz7, -CH2NRz7or a 3- to 6- membered cycloaliphatic or 4- to 6-membered heterocyclyl, wherein each Rz7independently has the values described herein. In some embodiments, Reis a 6-membered aryl or 5-to 6-membered heteroaryl, which is optionally substituted with 1 -3 independent occurrences of chloro, fluoro, bromo, iodo, methyl, ethyl, cyano, cyclopropyl, CF3, -OCH3, -OCH2CH3, or -C≡CH.

[0149] In some embodiments, Reis(b-vii) (b-viii)wherein E4, E5, E6, and Rehave the values described herein. In some embodiments, Reis (b-vii), wherein E4and Re4have the values described herein. In some embodiments, Reis (b-viii), wherein E5, E6, and Re4have the values described herein. In some embodiments, Reis(b-ix)wherein E5, E6, Re6, R7, and Re8have the values described herein.

[0150] In some embodiments, E4is S, O, or N(Rn4), wherein R"4has the values described herein. In some embodiments, E4is S or O. In some embodiments, E4is S. In some embodiments, E4is O.

[0151] In some embodiments, Re4is hydrogen, methyl, chloro, fluoro, bromo, iodo, cyano, or - CF3. In some embodiments, Re4is hydrogen, methyl, chloro, fluoro, cyano, or -CF3. In some embodiments, Re4is hydrogen, methyl, chloro, or fluoro. In some embodiments, Re4is hydrogen or methyl. In some embodiments, Re4is hydrogen.

[0152] In some embodiments, E5is N or C(R"), wherein Re:>has the values described herein. In some embodiments, E5is C(Re:>), wherein R" has the values described herein. In some embodiments, E5is N or C(H). In some embodiments, E5is C(H). In some embodiments, E5is N.

[0153] In some embodiments, Re5is hydrogen, halogen, methyl, -SCH3, -OCH3, -CF3, -OCF3, - OCF2H, or -C≡CH. In some embodiments, R" is hydrogen, halogen, methyl, -OCH3, -CF3, or -C≡CH. In some embodiments, R" is hydrogen or halogen. In some embodiments, R" is hydrogen, fluoro, or chloro. In some embodiments, Re5is hydrogen, methyl, fluoro, or chloro. In some embodiments, Re5is hydrogen.

[0154] In some embodiments, E6is N or C(H). In some embodiments, E6is N. In some embodiments, E6is C(H).

[0155] In some embodiments, Re6is hydrogen, halogen, methyl, -SCH3, -OCH3, -CF3, -OCF3, - OCF2H, or -C≡CH. In some embodiments, Re6is hydrogen, halogen, methyl, -OCH3, -CF3, or -C≡CH. In some embodiments, Re6is hydrogen or halogen. In some embodiments, Re6is hydrogen, fluoro, or chloro. In some embodiments, Re6is hydrogen, methyl, fluoro, or chloro. In some embodiments, Re6is hydrogen.

[0156] In some embodiments, Re7is hydrogen, halogen, methyl, -SCH3, -OCH3, -CF3, -OCF3, - OCF2H, or -C≡CH. In some embodiments, Re7is hydrogen, halogen, methyl, -OCH3, -CF3, or -C≡CH. In some embodiments, Re7is hydrogen or halogen. In some embodiments, Re7is hydrogen, fluoro, or chloro. In some embodiments, Re7is hydrogen, methyl, fluoro, or chloro. In some embodiments, Re7is hydrogen.

[0157] In some embodiments, ReSis hydrogen, halogen, methyl, -SCH3, -OCH3, -CF3, -OCF3, - OCF2H, or -C≡CH. In some embodiments, Re8is hydrogen, halogen, methyl, -OCH3, -CF3, or -C≡CH. In some embodiments, Re8is hydrogen or halogen. In some embodiments, Re8is hydrogen, fluoro, orchloro. In some embodiments, Reis hydrogen, methyl, fluoro, or chloro. In some embodiments, Reis hydrogen.

[0158] In some embodiments, each of Re5, Re6, Re7, and Re8is independently hydrogen, halogen, methyl, -OCH3, -CF3, or -C≡CH; wherein at least one of R", Re6, Re7, and ReSis hydrogen. In some embodiments, each of Re5, Re6, Re7, and Re8is independently hydrogen, halogen, methyl, -OCH3, -CF3, or -C≡CH; wherein at least two of Re5, Re6, Re7, and ReSare hydrogen.

[0159] In some embodiments, Re6is hydrogen, fluoro, or chloro; Re7is hydrogen, fluoro, or chloro; and ReSis hydrogen, halogen, methyl, -OCH3, or cyano; wherein at least one of Re6, Re7, and ReSis hydrogen. In some embodiments, Re6is hydrogen, fluoro, or chloro; Re7is hydrogen, fluoro, or chloro; and Re8is hydrogen, halogen, methyl, -OCH3, or cyano; wherein at least two of Re6, Re7, and Re8are hydrogen.

[0160] In some embodiments, RRis furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl, tetrahydronaphthyridinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, indanyl, tetrahydroindazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, oxodihydropyridyl, indolinyl, benzodioxanyl, chromanyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicycloheptanyl, azabicyclooctanyl, oxabicyclooctanyl, bicyclononyl, bicyclooctanyl, or adamantyl. In some embodiments, RRis furanyl, thienyl, phenyl, naphthyl, pyridyl, benzothienyl, benzofuranyl, cyclohexyl, or cyclohexenyl.

[0161] In some embodiments, ¾ is hydrogen. In some embodiments, ¾ is chloro and Z\is not hydrogen, halogen, methyl, or cyano.

[0162] In some embodiments, Rbis hydrogen or, together with the oxygen to which it is attached, forms a prodrug. In some embodiments, Rbis hydrogen or -C(0)-Rbx, wherein Rbhas the values described herein. In some embodiments, Rbis hydrogen. In some embodiments, Rbis -C(0)-Rbx, wherein Rbhas the values described herein.

[0163] In some embodiments, Rbxis C,_4alkyl, -CH(Ry)-NH2, pyrrolidinyl, or -Lb-OP03H2, wherein Lband Rbyhave the values described herein. In some embodiments, Rbxis -CH(Rby)-NH2wherein Rbyhas the values described herein. In some embodiments, Rxis -Lb-OP03H2, wherein Lbhas the values described herein. In some embodiments, Rbxis C1.4 alkyl.

[0164] In some embodiments, Ryis C|_4alkyl optionally substituted with hydroxyl, phenyl, phenolyl, imidazolyl, carboxyl, amino, guanidino, -SCH3, -C(0)NH2, or indolyl. In some embodiments, Rbyis C].4alkyl optionally substituted with hydroxyl, phenyl, carboxyl, amino, or - C(0)NH2. In some embodiments, Rbyis Ci-4alkyl. In some embodiments, Rbyis methyl, ethyl, isopropyl, propyl, butyl, or isobutyl. In some embodiments, Rbyis methyl, ethyl, isopropyl, or isobutyl. In some embodiments, Rbyis methyl. In some embodiments, Rbyis ethyl. In some embodiments, Ryis isopropyl. In some embodiments, Rbyis isobutyl.

[0165] In some embodiments, Lbis a bivalent linker chosen from Clalkylene or -(CH2)„r phenylene-(CH2)n2- where n l is 0 or 1 and n2 is 1 or 2. In some embodiments, Lbis C:.4alkylene. In some embodiments, Lbis C].4methylene. In some embodiments, Lbis ethylene. In some embodiments, Lbis -(CH2)ni -phenyl ene-(CH2)n2- where n l is 0 or 1 and n2 is 1 or 2. In some embodiments, L is -phenylene-(CH2)n2- where n2 is 1 or 2. In some embodiments, Lbis -CH2- phenylene-(CH2)n2- where n2 is 1 or 2. In some embodiments, Lbis -(CH2)ni-phenylene-CH2- where n l is 0 or 1. In some embodiments, Lbis -(CH2)„rphenylene-(CH2)n2- where n l is 0 or 1 and n2 is 2.

[0166] In some embodiments, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following is / are true: Y is -0-; Rais hydroxyl; Ra' is hydrogen; Rcis hydrogen; Xi is N; Rdis hydrogen; or X3is C(H). In some embodiments, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following is / are true: Y is -0-; Rais hydrogen; Ra' is hydrogen; Rcis hydrogen; Xi is N; Rdis hydrogen; or X3is C(H).

[0167] In some embodiments, n is 1 -5. In some embodiments, n is 1 -4. In some embodiments, n is 1-3. In some embodiments, n is 1 -2. In some embodiments, n is 1.

[0168] In some embodiments, each occurrence of R2is independently -R2\ -T3-R2d, -T3-R2a, or - V2-T3-R2d, wherein R2a, T3, R2d, V2and T3have the values described herein. In some embodiments, each occurrence of R2is independently -R2aor T3-Ra, wherein R2aand T3have the values described herein. In some embodiments, each occurrence of R2is independently -R2, wherein R2ahas the values described herein. In some embodiments, each occurrence of R2is independently halogen, -R2c, -N(R2b)2, -OR2b, -SR2c, d-6 aliphatic or C,.6fluoroaliphatic, wherein R2band R2chave the values described herein.

[0169] In some embodiments, each occurrence of R2ais independently halogen, -CN, -N02, -R2c, -N(R2b)2, -OR2b, -SR2c, -S(0)R2c, -S(0)2R2c, -C(0)Rb, -C(0)ORb, -C(0)N(R2b)2, -S(0)2N(R2b)2, -OC(0)N(R2b)2, -N(R2e)C(0)R2b, -N(R2e)S02R2c, -N(R2e)C(0)OR2b, -N(R2e)C(0)N(R2b)2, - N(R2e)S02N(R2b)2, or -Si(R2c)3, or a C,.6aliphatic or C,.6haloaliphatic, wherein R2b, R2c, and R2ehave the values described herein.

[0170] In some embodiments, each occurrence of R2bis independently hydrogen or a group selected from C,_6aliphatic, Ci_6haloaliphatic, 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or two occurrences of R2b, taken together with a nitrogen atom to which they are bound, form a 4- to -7-membered heterocyclyl having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

[0171] In some embodiments, each occurrence of R2cis independently a group selected from C,_ C6aliphatic, Q.Q haloaliphatic, 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0172] In some embodiments, each occurrence of R2dis independently hydrogen or a group selected from 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0173] In some embodiments, each occurrence of R2eis independently hydrogen or a Ci_6aliphatic group.

[0174] In some embodiments, each occurrence of V2is independently -N(R )-, -0-, -S-, -S(O)-, -S(0)2-, -C(O)-, -C(0)0-, -C(0)N(R2e)-, -S(0)2N(R2e)-, -OC(0)N(R2e)-, -N(R2e)C(0)-, -N(R2e)S02-, - N(R2e)C(0)0-, -N(R2e)C(0)N(Re)-, -N(R2e)S02N(R2e)-, -OC(O)-, or -C(0)N(R2e)-0-, wherein R2ehas the values described herein.

[0175] In some embodiments, each occurrence of T3is a C^6alkylene chain wherein the alkylene chain optionally is interrupted by -N(R4)-, -0-, -S-, -S(O)-, -S(0)2-, -C(O)-, -C(0)0-, -C(0)N(R4)-, - S(0)2N(R4)-, -OC(0)N(R4)-, -N(R4)C(0)-, -N(R4)SOr, -N(R4)C(0)0-, -N(R4)C(0)N(R4)-, - N(R4)S(0)2N(R4)-, -OC(O)-, or -C(0)N(R4)-0- or wherein T3or a portion thereof optionally forms part of a 3- to 7-membered cycloaliphatic or 4- to 7-membered heterocyclyl, wherein R4is hydrogen or a C aliphatic group.

[0176] In some embodiments, the chemical entity of formula (7) is represented by formula (X-a):(X-a)or a pharmaceutically acceptable salt thereof;wherein:stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry; Rais hydrogen and Ra' is hydrogen; Rais hydrogen and Ra' is fluoro; Rais fluoro and Ra' is fluoro; or Rais OH and Ra' is hydrogen;Z, is hydrogen, halogen, cyano, Rz3, -S-Rz3, -S(0)-Rz3, or -S(0)2-Rz3;Rz3is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or Ci_4aliphatic, any of which may be substituted with one or more independently selected Rz4;Rz4is hydroxyl, halogen, cyano, CM aliphatic, C fluoroaliphatic, d_4alkoxy, Q_4fluoroalkoxy, -N(R")2, -C(0)Rz6. -C(0)2Rz5. 5- or 6-membered cycloaliphatic or heterocyclyl, or a phenyl optionally substituted with one or more independently selected halogens;each R" is independently hydrogen or C4alkyl ;Rz6is C,.4alkyl;X4is O or N(Rn4);Rn4is hydrogen or CM alkyl;X6is N or C(Rx6);each of Rx6, Rx6', Rjand Rmis independently hydrogen, halogen, hydroxyl, cyano, C aliphatic, C fluoroaliphatic, CMalkoxy, C,.4fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, - CH2-ORz7, -CH2NRz7,a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein at least one of Rx6, Rx6', Rjand Rmis hydrogen; andeach Rz7is independently hydrogen or C alkyl.

[0177] In some such embodiments described directly above:Z| is hydrogen, halogen, cyano, or Ci_4aliphatic optionally substituted with one or more hydroxyl, Q. 4 alkoxy, -N(Rz5)2, or phenyl optionally substituted with one more independently selected halogens; X4is O or N(H);X6is N or C(H);Rx6' is hydrogen;Rmis hydrogen, fluoro or chloro; andRjis methyl, ethyl, isopropyl, hydrogen, fluoro, chloro, bromo, cyclopropyl, -C≡CH or -CF3.

[0178] In some embodiments, the chemical entity of formula ( / ) is:[( l R,2S,4R)-4-{ [5-( {4-[7-chloro-] ,2,3,4-tetrahydroisoquinolin- l -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate;[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[7-chloro- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl] methyl sulfamate;[( l R,2S,4R)-4H [5-({4 7-chloro- l ,2,3,4-tetrahydroisoquinolin- l -yl]-2-thienyl }carbonyl)pyrimidin-4- yl]amino }-2-hydroxycyclopentyl]methyl sulfamate;[( 1 R,2R,3S,4R)-4- { [5-( { 5-chloro-4-[7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl ]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate;[( 1 R,2S,4R)-4- { [5-( { 4-[7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydiOxycyclopentyl]methyl sulfamate;[( 1 R,2S,4R)-4- { [5-( { 4-[3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2-thienyl } carbonyl)pyrimidin-4- yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[(1 R,2S,4R)-4- { [5-( { 5-chloro-4-[7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate;[( l R,2S,4R)-4-{ [5-({4-[7-chloro-3,4-dihydro- l H-isochromen- l -yl]-2-thienyl }carbonyl)pyrimidin-4- yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the chemical entity of formula ( / ) is:[( 1 R,2S,4R)-4- { [5-( {4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[( l R,2S,4R)-4-{ [5-( {4-[7-chloro- l ,2,3,4-tetrahydroisoquinolin-l-yl]-2-thienyl }carbonyl)pyrimidin-4- yl]amino }-2-hydroxycyclopentyl]methyl sulfamate;[( 1 R,2R,3S,4R)-4- { [5-( { 5-chloro-4-[7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate;[( 1 R,2S,4R)-4- { [5-( {4-[( lR)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl } carbony l)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate;[(lR,2S,4R)-4-{ [5-({4-[(lR)-3,4-dihydro-lH-isochromen-l-yl]-5-methyl-2- thieny] }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopenty]]methyl sulfamate;[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({4-[7-chloro-3,4-dihydro-l H-isochromen-l -yl]-2 hienyl }carbonyl)pyrimidin-4- yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, a chemical entity is provided which is[(lR,2S,4R)-4-{ [5-({4-[(S)-(3-bromophenyl)(hydroxy)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI- 16aor [(lR,2S,4R)-4-{ [5-({4-[(R)-(3-bromophenyl)(hydroxy)methyl]-5-chloro-2- thienyl }carbonyl)pyrirnidin-4-yl]amino }-2-hydroxycyclopentyl]rriethyl sulfamate;[(lR,2S,4R)-4-{ [5-({4-[(R)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI- 18bor [( lR,2S,4R)-4-{ [5-({4-[(S)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({4-[(R)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateI-22bor [(lR,2S,4R)-4-{ [5-({4-[(S)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate;[(l R,2S,4R)-4-{ [5-({4-[(l S)-7-bromo-l ,2,3,4-tetrahydroisoquinolin- l -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl I-248a sulfamate or [( lR,2S,4R)-4-{ [5-({4-[(l R)-7-bromo- l ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyl-2-thienyl } carbonyl)pyrimidin-4-yl] amino } -2- hydroxycyclopentyl]methyl sulfamate;[(lR,2R,3S,4R)-4-{ [5-({4-[(R)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl I-24a sulfamate or [(lR,2R,3S,4R)-4-{ [5-({4-[(S)-amino(3-bromophenyl)methyl]-5- chloro-2-thienyl }carbonyl)pyrimidin-4-yl] amino } -2,3- dihydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({ 4-[(lR)-7-bromo-l ,2,3,4-tetrahydroisoquinolin- l -yl]-5- chloro-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl 1-25 la sulfamate or [(lR,2S,4R)-4-{ [5-({4-[(lS)-7-bromo-l ,2,3,4-tetrahydroisoquinolin- l-yl]-5-chloro-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2- hydroxycyclopentyl]mefhyl sulfamate;[(lR,2S,4R)-4-{ [5-({4-[(lR)-7-ethynyl-3,4-dihydro-lH-isochromen-l-yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl I-252b sulfamate or [(lR,2S,4R)-4-{ [5-({4-[(lS)-7-ethynyl-3,4-dihydro-lH-isochromen- 1 -y 1] -5-methyl-2-thienyl } carbonyl)pyrimidin-4-yl] amino } -2- hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({5-chloro-4-[(8S)-2-chloro-5,6,7,8-tetrahydro-l,7- 1-253a naphthyridin-8-yl] -2-thienyl } carbonyl)pyrimidin-4-yl] amino } -2- hydroxycyclopentyl] methyl sulfamate or [(lR,2S,4R)-4-{ [5-({5-chloro-4-[(8R)-2- chloro-5,6,7,8-tetrahydro-l,7-naphthyridin-8-yl]-2-thienyl }carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate ;[(lR,2S,4R)-4-{[5-({4-[(lR)-3,4-dihydro-lH-isochromen-l-yl]-2-Tthienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or [(lR,2S,4R)-4-{[5-({4-[(lS)-3,4-dihydro-m-isochromen-l-yl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hy droxycyclopentyljmethyl sulfamate ;[( 1 R,2S ,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-7-chloro- 1 ,2,3 ,4-tetrahydroi soquinolin- 1 -yl] -2-Tthienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateor [( 1 R,2S,4R)-4-{ [5-({ 5-chloro-4-[( 1 S)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl}carbony])pyrimidin-4-y]]amino}-2-hydroxycyclopenty]]rnethyl sulfamate;[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-3,4-Dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2-I-256bthienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-Chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- I-257b methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(lR)-7-(trifluoromethyl)-3,4-dihydro- 1 H-isochromen- l-yl]-2-thienyl }carbonyl)pyrimidin-4- I-258a yl]amino}cyclopentyl]methy] sulfamate or [(lR,2S,4R)-2-hydroxy-4-{[5-({5- methyl-4-[(l S)-7-(trifluoromethyl)-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate;[(lR,2R,3S,4R)-4-{[5-({4-[(lR)-7-bromo-l,2,3,4-tetrahydroisoquinolin-l-yl]-5- chloro-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3- I-259a dihydroxycyclopentyl]methyl sulfamate or [(lR,2R,3S,4R)-4-{[5-({4-[(lS)-7- bromo-l,2,3,4-tetrahydroisoquinolin-l-yl]-5-chloro-2-thienyl}carbonyl)pyrimidin- 4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate;[( 1 R,2S,4R)-4- { [5-( { 4-[(l R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- ίςι, thienyl }carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate or [(lR,2S,4R)-4-{[5-({4-[(lS)-7-chloro-3,4-dihydro-lH-isochromen-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-l,2,3,4-tetrahydroisoquinolin-l-yl]-5- I-263a methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[( 1 R,2R,3R,4R)-4- { [5-({ 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl] -5- methyl-2-thienyl } carbonyl)pyrimidin-4-yl] amino } -3-fluoro-2- I-264b hydroxycyclopentyl]methyl sulfamate or [(lR,2R,3R,4R)-4-{ [5-({4-[(lR)-7- chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2-thienyl }carbonyl)pyrimidin- 4-yl]amino}-3-fluoro-2-hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]- 2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2^hydroxycyclopentyl]methylI-266b sulfamate or [(lR,2S,4R)-4-{ [5-({5-chloro-4-[(8R)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl] -2-thienyl } carbonyl)pyrimidin-4-yl] amino } -2- hydroxycyclopentyl] methyl sulfamate;[( 1 R,2S,4R)-4- { [5-( { 4-[( lR)-7-bromo-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or [(lR,2S,4R)-4-{[5-({4-[(lS)-7-bromo-3,4-dihydro-lH-isochromen-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({4-[(7S)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate I-269a or [(lR,2S,4R)-4-{ [5-({4-[(7R)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate;{ (lR,2S,4R)-4-[(5-{4-[(lR)-7-chloro-3,4-dihydro- lH-isochromen-l-yl]-5-methyl- 7„, 2-furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methyl sulfamate or{ ( 1 R,2S,4R)-4-[(5-{ 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 2-furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamate;[(lR,2R,3R,4R)-4-{ [5-({4-[(lR)-3,4-dihydro-lH-isochromen-l -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-3-fluoro-2-hydroxycyclopentyl]methyl I-271 a sulfamate or [(lR,2R,3R,4R)-4-{ [5-({4-[(l S)-3,4-dihydro-lH-isochromen-l -yl]-5- methyl-2-thienyl } carbonyl)pyrimidin-4-yl] amino } -3-fluoro-2- hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({ 4-[(lR)-7-cyclopropyl-3,4-dihydro-l H-isochromen- l -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl I-277a sulfamate or [(lR,2S,4R)-4-{ [5-({4-[(l S)-7-cyclopropyl-3,4-dihydro- lH- isochromen- 1 -yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino } -2- hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(lR)-7-chloro-3,4-dihydro- l H-isochromen-l -yl]- 2-thienyl } carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl I-282b sulfamate or [(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(l S)-7-chloro-3,4-dihydro- l H- isochromen- 1 -yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino } -2- hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({4-[(8S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-y]]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methylI-285a sulfamate or [(lR,2S,4R)-4-{ [5-({4-[(8R)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8- yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({ 4-[(R)-amino(3-chlorophenyl)methyl]-5-methyl-2- , thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate or [(lR,2S,4R)-4-{ [5-({4-[(S)-amino(3-chlorophenyl)methyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;[(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2-T Qthienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or [(l R,2S,4R)-4-{ [5-({ 5-chloro-4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate; harmaceutically acceptable salt thereof.

[0181] In some embodiments, the chemical entity of formula (Γ) is represented by formula (X-b):(X-b)or a pharmaceutically acceptable salt thereof;wherein:stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry; Rais hydrogen and Ra' is hydrogen; Rais hydrogen and R ' is fluoro; Rais fluoro and Ra' is fluoro; or Rais OH and Ra' is hydrogen;Z, is hydrogen, halogen, cyano, Rz3, -S-Rz3, -S(0)-Rz3, or -S(0)2-Rz3;Rz3is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or CM aliphatic, any of which may be substituted with one or more independently selected Rz4;Rz4is hydroxyl, halogen, cyano, CM aliphatic, Ci_4fluoroaliphatic, C alkoxy, Ci_4fluoroalkoxy, -N(Rz:>)2, -C(0)Rz6i-C(0)2RZ:',5- or 6-membered cycloaliphatic or heterocyclyl, or a phenyl optionally substituted with one or more independently selected halogens;each Rz5is independently hydrogen or C alkyl;Rz6is CMalkyl;X4is O or N(R"4);R"4is hydrogen or Q.4alkyl;X6is N or C(Rx6);each of Rx6, Rx6', Rjand Rmis independently hydrogen, halogen, hydroxyl, cyano, CM aliphatic, CMfluoroaliphatic, C,.4alkoxy, C,.4fluoroalkoxy, -N(Rz7)2, -C(0)2Rz7, -C(0)N(Rz7)2, -S(0)2N(Rz7)2, -CH2-ORz, -CH2N(RZ)2, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein at least one of Rx6, Rx6', RJand Rmis hydrogen; andeach Rz7is independently hydrogen or C1.4 alkyl.

[0182] In some such embodiments described directly above:Zi is hydrogen, halogen, cyano, or C] -4aliphatic optionally substituted with one or more hydroxyl, Q. 4 alkoxy, -N(R")2, or phenyl optionally substituted with one more independently selected halogens; X4is O or N(H);X6is N or C(H);Rx6' is hydrogen;Rmis hydrogen, fluoro or chloro; andR* is methyl, ethyl, isopropyl, hydrogen, fluoro, chloro, bromo, cyclopropyl, -C≡CH or -CF3.

[0183] Representative examples of the chemical entities of formula ( / ) are shown below in Table 1.1-4I-4aI-4b1-11 1-12 I-lla I-12a I-llb I-12b1-18 I-18a1-17 I-18b1-19I-19a I-20a I-19b I-20bI-24a I-24b601-102 I-102a I-102b1-106I-106a1-105 I-106b1-111 1-1121-117I-117aI-117b1-119 1-1201-121 1-1221-123 1-1241-127 1-1281-131 1-1321-135I-135aI-135b1-139 1-140I-151aI-151bI-153aI-153b 1-1541-163 1-1641-175 1-1761-187 1-1881-189 1-1901-195 1-19680811-217 1-2181-2191-223 1-2241-225 1-2261-235 1-2361-241 1-2421-250 I-250a I-250b1-251 1-252 I-251a I-252a I-251b I-252b1-253 1-254 I-253a I-254a I-253b I-254b1-256I-255a I-256a I-255b I-256b1-257 1-258 I-257a I-258a I-257b I-258bI-259a I-260a I-259b I-260b1-261 1-262 I-261a I-262a I-261b I-262b1-265 1-266 I-265a I-266a I-265b I-266b1-267 1-268 I-267a I-268a I-267b I-268bI-269a I-270a I-269b I-270b1-276 I-276a1-275 I-276bI-277a I-278a I-277b I-278b1-281 1-282 I-281a I-282a I-281b I-282b1-283I-283a I-284a I-283b I-284b1-287I-287aI-287b 1-2881-289I-289a I-290a I-289b I-290b1-291I-291a I-292a I-291b I-292b1-293 1-294 I-293a I-294a I-293b I-294b1-295 1-2961-297 1-298 I-297a I-298a I-297b I-298b1-299I-299a I-300a I-299b I-300b1-303 1-3041-307I-307aI-307b 1-308I-311aI-311b1-314 I-314a I-314b1-320I-320aI-320b1-3251-331 1-332I-335a I-335b1-339 I-339a I-339b1-347 1-3481-349I-349aI-349b1-356I-356aI-356b1-362 1-3631-366

[0184] The chemical entities in Table 1 may also be identified by the following chemical names:Compound NameNo.[( 1 R,2R,3S,4R)-4-{ [5-( { 4-[( 1 S)-l -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate 1- 1 and[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 R)- 1 -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-4-{ [5-( {4-[( 1 S)- 1 -(6-bromopyridin-2-yl)- l-hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methy] sulfamate I-l a or[( lR,2R,3S,4R)-4- { [5-( { 4-[( 1 R)- 1 -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( lR,2R,3S,4R)-4- { [5-( { 4-[( 1 S)- 1 -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I-lb or[( 1 R,2R,3S,4R)-4- { [5-( { 4- [( 1 R)- 1 -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate l [(lR,2S,4R)-4-{ [5-({5-chloro-4-[(S)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateName and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(R)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({ 5-chloro-4-[(S)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or[( lR,2S,4R)-4-{ [5-( { 5-chloro-4-[(R)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4- { [5-({ 5-chloro-4-[(S)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyI)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate or[( lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(R)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[( 1R)- 1 -(3-bromophenyl)- 1 -hydroxyethyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)- 1 -(3-bromophenyl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[( lR)- l -(3-bromophenyl)- l -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or[( 1 R,2S,4R)-4-{ [5-( {4-[( 1 S)- 1 -(3-bromophenyl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)- 1 -(3-bromophenyl)- 1 -hydroxyethyI]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate or[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)- l-(3-bromophenyI)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl] methyl sulfamate and[( l R,2S,4R)-4-{ [5-( {4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydiOxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate or[( l R,2S,4R)-4-{ [5-( {4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or[( lR,2S,4R)-4-{ [5-({ 4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4- { [5-( { 4-[( 1 R)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- thienyl } carbony l)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate and[(1 R,2S,4R)-4- { [5-( { 4-[( 1 S)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.( 1 R,2S,4R)-4-{ [5-( {4-[( 1 R)- 1 -(3-chlorophenyl)- 1 -hydroxyefhyl]-2- hienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- hienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- hienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or( 1 R,2S ,4R)-4- { [5-( { 4-[( 1 S)- 1 -(3-chlorophenyl)- 1 -hydroxy ethyl] -2- :hienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate(lR,2S,4R)-4-{[5-({4-[(R)-amino(3-chlorophenyl)methyl]-5-methyl-2- hienyl}carbony])pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methy] sulfamate and( 1 R,2S,4R)-4- { [5-( { 4-[(S)-amino(3-chlorophenyl)methyl]-5-methyl-2- hienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate(lR,2S,4R)-4-{[5-({4-[(R)-amino(3-chlorophenyl)methyl]-5-methyl-2- hienyl}carbonyl)pyrimidin-4-yl]amino)-2-hydroxycyclopentyl]methyl sulfamate or( 1 R,2S,4R)-4- { [5-( { 4-[(S)-amino(3-chlorophenyl)methyl]-5-methyl-2- hienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate(lR,2S,4R)-4-{[5-({4-[(R)-amino(3-chlorophenyl)methyl]-5-methyl-2- hienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or(lR,2S,4R)-4-{[5-({4-[(S)- amino(3-chlorophenyl)methyl]-5-methyl-2- hienyl}carbonyl)pyrimidin -4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate(lR,2S,4R)-4-{[5-({4-[(R> (3-chlorophenyl)(hydi xy)methyl]-5-(methoxymethyl)-2- hienyl}carbonyl)pyrimidin- -4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate and(lR,2S,4R)-4-{[5-({4-[(S)- (3-chlorophenyl)(hydroxy)methyl]-5-(methoxymethyl)-2- hienyl }carbonyl)pyrimidin-■4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate(lR,2S,4R)-4-{[5-({4-[(R •(3-chlorophenyl)(hydroxy)methyl]-5-(methoxymethyl)-2- hienyl}carbonyl)pyrimidin- -4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or(lR,2S,4R)-4-{[5-({4-[(S)- (3-chlorophenyl)(hydroxy)methyl]-5-(methoxymethyl)-2- hienyl}carbonyl)pyrimidin-■4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate(lR,2S,4R)-4-{[5-({4-[(R> ■(3-chlorophenyl)(hydroxy)methyl]-5-(methoxymethyl)-2- hienyl}carbonyl)pyrimidin- 4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or(lR,2S,4R)-4-{[5-({4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-5-(methoxymethyl)-2- hienyl}cai-bonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate(lR,2R,3S,4R)-4-{[5-({4-[(lS)-l-amino-l-(3-chlorophenyl)ethyl]-2- hienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate and( lR,2R,3S,4R)-4- { [5-( { 4-[( 1 R)- 1 -amino- 1 -(3-chlorophenyl)ethyl]-2- hienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate( 1 R,2R,3S,4R)-4- { [5-({4-[( 1 S)- 1 -amino- 1 -(3-chlorophenyl)ethyl]-2- :hienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate orCompound NameNo.[( 1 R.2R.3S.4R 1-4- { [5-( { 4-[( 1R)- 1 -amino- 1 -(3-chlorophenyl)ethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 S)- 1 -amino- 1 -(3-chlorophenyl)ethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate I-8b or[(lR,2R,3S,4R)-4- { [5-({4-[( l R)- l-amino- l -(3-chlorophenyl)ethyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[(l R,2S,4R)-4-{ [5-({ 5-chloro-4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate 1-9 and[( l R,2S,4R)-4-{ [5-( { 5-chloro-4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({ 5-chloro-4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-9a or[(l R,2S,4R)-4-{ [5-({ 5-chloro-4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate I-9b or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-(3-chlorophenyI)(hydroxy)methyl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl]methyl sulfamate[( lR,2R,3S,4R)-4- { [5-({4-[(R)-amino(6-bromopyridin-2-y])methyl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I- 10 and[( l R,2R,3S,4R)-4-{ [5-({4-[(S)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( l R,2R,3S,4R)-4-{ [5-({4-[(R)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I- 10a or[(lR,2R,3S,4R)-4- { [5-( {4-[(S)-amino(6-bromopyridin-2-yl)methyl]-5-chloiO-2- thienyl ) carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[(l R,2R,3S,4R)-4-{ [5-({4-[(R)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I- 10b or[( 1 R,2R,3S,4R)-4- { [5-( { 4-[(S)-amino(6-bromopyridin-2-yl)rnethyl]-5-chloro-2- thienyl )carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{ [5-({4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I- 1 1 and[(lR,2S,4R)-4-{ [5-( {4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I- l la or[(lR,2S,4R)-4-{ [5-({4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI- 1 lb [( lR,2S,4R)-4- { [5-( { 4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl-2-Compound NameNo.thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyc]opentyl]methyl sulfamate or[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-({4-[( 1 S)-l -amino- 1 -(3-chlorophenyl)ethyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-12 and[( 1 R,2S,4R)-4- { [5-( {4-[( 1 R)- 1 -amino- 1 -(3-chlorophenyl)ethyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)- 1 -amino- 1 -(3-chlorophenyl)ethyl]-2- thienyl } carbonyl)pyri midin-4-yl] amino } -2-hydroxycy clopentyl] methyl sulfamate I- 12a or[(lR,2S,4R)-4-{[5-({4-[(lR)-l-amino-l-(3-chlorophenyl)ethyl]-2- thienyl)carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)- 1 -amino- 1 -(3-chlorophenyl)ethyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I- 12b or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)- 1 -amino- 1 -(3-chlorophenyl)ethyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-5-(hydroxymethyl)-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-13 and[(lR,2S,4R)-4-{[5-({4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-5-(hydroxymethyl)-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2R,3S,4R)-4-{[5-({4-[(R)-amino(3-chlorophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate I- 14a or[(lR,2R,3S,4R)-4-{[5-({4-[(S)-amino(3-chlorophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pynmidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[(lR,2R,3S,4R)-4-{[5-({4-[(R)-amino(3-chlorophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate I- 14b or[(lR,2R,3S,4R)-4-{[5-({4-[(S)-amino(3-chlorophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-amino(3-chlorophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-15 and[(lR,2S,4R)-4-{[5-({4-[(S)-amino(3-chlorophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[(R)-amino(3-chlorophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I- 15a or[(lR,2S,4R)-4-{[5-({4-[(S)-amino(3-chlorophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-amino(3-chlorophenyl)methyl]-5-chloro-2- j ^ thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or[(lR,2S,4R)-4-{[5-({4-[(S)-amino(3-chlorophenyl)methyl]-5-chloro-2-Compound NameNo.thienyl }carbonyl)pynmidin-4-yl]amino}-2-hydiOxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(3-bromophenyl)(hydroxy)methyl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I- 16a or[(lR,2S,4R)-4-{ [5-( {4-[(R)-(3-bromophenyl)(hydroxy)methyl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(3-bromophenyl)(hydroxy)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I- 16b or[( lR,2S,4R)-4-{ [5-({ 4-[(R)-(3-bromophenyl)(hydroxy)methyl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(R)-(3-bromophenyl)(hydroxy)methyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1- 17 and[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(3-bromophenyl)(hydroxy)methyl]-2- thieny] } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-18 and[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({4-[(R)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I- 18a or[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( { 4-[(R)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I- 18b or[( l R,2S,4R)-4-{ [5-({4-[(S)-amino(6-bromopyridin-2-yl)methyl]-5-chloro-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-(5-bromo-2-fluorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1- 19 and[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(5-bromo-2-fluorophenyl)(hydroxy)methyl]-2- thienyl )carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-(5-bromo-2-fluorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I- 19a or[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(5-bromo-2-fluorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(R)-(5-bromo-2-fluorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I- 19b or[( lR,2S,4R)-4- { [5-( { 4-[(S)-(5-bromo-2-fluorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamateI 20a [(lR,2S,4R)-4-{ [5-({4-[(2S)-2-(3-chlorophenyI)tetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.or[(lR,2S,4R)-4-{[5-({4-[(2R)-2-(3-chlorophenyl)tetrahydrofuran-2-yl]-2- thienyl}cai'bonyl)pyrirnidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(2S)-2-(3-chlorophenyl)tetrahydrofuran-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-20b or[(1 R,2S,4R)-4-{ [5-( { 4-[(2R)-2-(3-chlorophenyl)tetrahydrofuran-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(5-chloro-2-furyl)(hydroxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino)-2-hydroxycyclopentyl]methyl sulfamate 1-21 and[(lR,2S,4R)-4-{[5-({4-[(R)-(5-chloro-2-furyl)(hydroxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-22 and[(lR,2S,4R)-4-{[5-({4-[(S)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycycIopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-amino(3-bromophenyl)methyl]-5-chloi -2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-22a or[(lR,2S,4R)-4-{[5-({4-[(S)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-amino(3-bromophenyI)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-22b or[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2R,3S,4R)-4-{[5-({4-[(R)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate I-24a or[(lR,2R,3S,4R)-4-{[5-({4-[(S)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino)-2,3-dihydroxycyclopentyl]methyl sulfamate[(lR,2R,3S,4R)-4-{[5-({4-[(R)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate I-24b or[(lR,2R,3S,4R)-4-{[5-({4-[(S)-amino(3-bromophenyl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4- { [5-( { 4-[(S)-amino(6-chloropyridin-2-yl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-25 and[(lR,2S,4R)-4-{[5-({4-[(R)-amino(6-chloropyridin-2-yl)methyl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate ,4R)-4-{[5-({4-[(S)-amino(6-chloropyridin-2-yl)methyl]-5-chloro-2- carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-amino(6-chloropyridin-2-yl)methyl]-5-chloro-2-Compound NameNo.thieny] }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-amino(6-chloropyridin-2-yl)methyl]-5-chloro-2- thi enyl } carbonyl)pyri midin-4-yl] amino } -2-hydroxy cyclopen ty 1] methyl sulfamate I-25b or[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-amino(6-chloropyridin-2-yl)methyl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate6{ ( 1 R,2R,3S,4R)-4-[(5- { [4-(3-bromobenzyl)-2-thienyl]carbonyl }pyrimidin-4-yl)amino]2,3-dihydroxycyclopentyl } methyl sulfamate[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 S)- 1 -amino- 1 -(3-bromophenyl)ethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I-27a or[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 R)- 1 -amino- 1 -(3-bromophenyl)ethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-4- { [5-( {4-[( 1 S)- 1 -amino- 1 -(3-bromophenyl)ethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I-27b or[( 1 R,2R,3S,4R)-4- { [5-({4-[( l R)- l -amino- 1 -(3-bromophenyl)ethyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-(3-chlorophenyl)sulfinyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-28 and[(lR,2S,4R)-4-{ [5-({4-[(S)-(3-chlorophenyl)sulfinyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( {4-[(R)-(3-chlorophenyl)sulfinyl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-28a or[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(3-chlorophenyl)sulfinyl]-5-mefhyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4- { [5-( {4-[(R)-(3-chlorophenyl)sulfinyl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-28b or[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(3-chlorophenyl)sulfinyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydiOxycyclopentyl]methyl sulfamate[( l R,2Ss4R)-4-{ [5-({ 4-[(S)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-29 and[( lR,2S,4R)r4-{ [5-( {4-[(R)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4- { [5-( { 4-[(S)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-29a or[( lR,2S,4R)-4-{ [5-( { 4-[(R)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[(S)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-29b or[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-(6-chloropyridin-2-yl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.{ ( 1 R,2S ,4R)-4-[(5- { 4-[( l S)- l -(3-chlorophenyl)- 1 -hydroxyethyl] -2-furoyl } pyrimidin-4- yl)amino]-2-hydroxycyclopentyl } methyl sulfamate1-30 and{ ( 1 R,2S,4R)-4-[(5- { 4-[( 1 R)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2-furoyl } pyri midin-4- yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { 4-[( 1 S)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2-furoyl }pyrimidin-4- yl)amino]-2-hydroxycyclopentyl Jmethyl sulfamateI-30a or{ ( 1 R,2S,4R)-4-[(5- { 4-[( 1 R)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2-furoy 1 } pyrimidin-4- yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { 4-[( 1 S)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2-furoyl }pyrimidin-4- yl)amino]-2-hydroxycyclopentyl }methyl sulfamateI-30b or{ (lR,2S,4R)-4-[(5-{ 4-[( l R)- l -(3-chlorophenyl)- l -hydroxyethyl]-2-furoyl }pyrimidin-4- yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( l R,2R,3S,4R)-4-{ [5-({4-[(2S)-2-(3-chlorophenyl)pyiTolidin-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate 1-31 and[( l R,2R,3S,4R)-4- { [5-({ 4-[(2R)-2-(3-chlorophenyl)pyrrolidin-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({4-[(2S)-2-phenyltetrahydrofuran-2-yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate1-32 and[( l R,2S,4R)-2-hydroxy-4-{ [5-({4-[(2R)-2-phenyltetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino )cyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({4-[(2S)-2-phenyltetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino icyclopentyl]methyl sulfamateI-32a or[(l R,2S,4R)-2-hydroxy-4-{ [5-({4-[(2R)-2-phenyltetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({4-[(2S)-2-phenyltetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl] methyl sulfamateI-32b or[(1 R,2S,4R)-2-hydroxy-4- { [5-({ 4-[(2R)-2-phenyltetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[(lR,2S,4R)-4-({ 5-[4-(3-chlorobenzyl)-5-methyl-2-furoyl]pyrimidin-4-yl }amino)-2-1-33hydroxycyclopentyljmethyl sulfamate[( lR,2S,4R)-4-({5-[4-(3-bromobenzyl)-5-methyl-2-furoyl]pyrimidin-4-yl }amino)-2- 1-34hydroxycyclopentyl]methyl sulfamate{ ( lR,2S,4R)-4-[(5-{ [4-(3-chlorobenzyl)-5-(hydroxymethyl)-2- 1-35thienyl]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[(R)-amino(3-chlorophenyl)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-36 and[( 1 R,2S,4R)-4-{ [5-( { 4-[(S)-amino(3-chlorophenyl)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateI-36a [(lR,2S,4R)-4-{ [5-({ 4-[(R)-amino(3-chlorophenyl)methyl]-2-Compound NameNo.thienyl}carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate or[( l R,2S,4R)-4-{ [5-({4-[(S)-amino(3-chloropheny])methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[(R)-amino(3-chlorophenyl)methyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-36b or[(1 R,2S,4R)-4- { [5-( { 4-[(S)-amino(3-chlorophenyI)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino ) -2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{ [5-({4-[(4-iodo- lH-pyrazol- l -yl)methyl]-5-methyl-2-1-37thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methy] sulfamate[( lR,2S,4R)-4-{ [5-({4-[(2S)-2-(3-chlorophenyl)pynOlidin-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino ) -2-hydroxycyclopentyl]methyl sulfamate 1-38 and[( 1 R,2S,4R)-4- { [5-( { 4-[(2R)-2-(3-chlorophenyl)pyrrolidin-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(2S)-2-(3-chlorophenyl)pyrroIidin-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate 1-38a or[( 1 R,2S,4R)-4- { [5-( { 4-[(2R)-2-(3-chlorophenyl)pyrrolidin-2-yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({4-[(2S)-2-(3-chlorophenyl)pyrrolidin-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-38b or[( 1 R,2S,4R)-4- { [5-( { 4-[(2R)-2-(3-chlorophenyl)pyrrolidin-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(4-bromo- 1 H-pyrazol- 1 -yl)methyl]-5-methyl-2-1-39thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methy] sulfamate[( lR,2S,4R)-4- { [5-({ 5-chloro-4-[(R)-(3-chloro-2-fluorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-40 and[( lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(S)-(3-chloro-2-fluorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( {4-(3-chlorobenzyl)-5-[(2S)-tetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-41 and[(lR,2S,4R)-4-{ [5-({ 4-(3-chlorobenzyl)-5-[(2R)-tetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4- { [5-( { 4-(3-chlorobenzyl)-5-[(2S)-tetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-4 la or[( 1 R,2S,4R)-4- { [5-( { 4-(3-chlorobenzy l)-5-[(2R)-tetrahydrofuran-2-yl] -2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{ [5-({4-(3-chlorobenzyl)-5-[(2S)-tetrahydrofuran-2-y]]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-4 lb or[(lR,2S,4R)-4-{ [5-({4-(3-chlorobenzyl)-5-[(2R)-tetrahydrofuran-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methy] sulfamateCompound NameNo.{(lR,2S,4R)-4-[(5-{4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2-fuiOyl}pyrimidin-4- yl)amino]-2-hydroxycyclopentyl} methyl sulfamate1-42 and{(lR,2S,4R)-4-[(5-{4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2-furoyl}pyrimidin-4- yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{(lR,2S,4R)-4-[(5-{4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2-furoyl}pyrimidin-4- yl)amino]-2-hydroxycyclopentyl } methyl sulfamateI-42a or{(lR,2S,4R)-4-[(5-{4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2-furoyl}pyrimidin-4- yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{(lR,2S,4R)-4-[(5-{4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2-furoyl}pyrimidin-4- yl)amino]-2-hydroxycyclopentyl} methyl sulfamateI-42b or{(lR,2S,4R)-4-[(5-{4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2-fuiOyl}pyrimidin-4- yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3-chlorobenzyl)-2-thienyl]carbonyl}pyrimidin-4-yl)amino]-2-1-43hydroxycyclopentyl} methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3-chlorobenzyl)-5-(methoxymethyl)-2- 1-44thienyl]carbonyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methyl sulfamate j45{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [5-methyl-4-(3-methylbenzyl)-2- thienyl]carbonyl}pyrimidin-4-yl)amino]cyclopentyl} methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(6-bromopyridin-2-yl)methyl]-5-chloro-2-1-46thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-(3-chlorophenyl)(methylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-47 and[(lR,2S,4R)-4-{[5-({4-[(S)-(3-chlorophenyl)(methylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methy] sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[(R)-(3-chlorophenyl)(methylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-47a or[(lR,2S,4R)-4-{[5-({4-[(S)-(3-chlorophenyl)(methylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopenty]]methyl sulfamate[(1 R,2S,4R)-4- { [5-( { 4-[(R)-(3-chlorophenyl)(methylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-47b or[(lR,2S,4R)-4-{[5-({4-[(S)-(3-chlorophenyl)(methylamino)methyl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(R)-(5-chloro-2-fluorophenyl)(hydroxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-48 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-(5-chloro-2-fluorophenyl)(hydroxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-({ 5-chloro-4-[( 1 R)- 1 -(3-chlorophenyl)- 1 ,3-dihydroxypropyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate1-49and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)- 1 -(3-chlorophenyl)- 1 ,3-dihydroxypropyl] -2-Compound NameNo.thienyl }carbonyl)pyrimidin-4-yl]arnino }-2-hydiOxycyclopenty]]methyl sulfamate[( l R,2S,4R)-4-{ [5-({4-[(S)-(3-chlorophenyl)(cyclopropyl)hydroxymethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-50 and[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-(3-chlorophenyl)(cyclopiOpyl)hydroxymethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydiOxycyclopentyl]rnethyl sulfamate{ ( lR,2S,4R)-4-[(5-{ [4-(3-chlorobenzyl)-5-methyl-2-thienyl]carbonyl }pyrimidin-4-1-51yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{ ( l R,2S,4R)-4-[(5-{ [4-(3-bi mobenzyl)-5-methyl-2-thienyl]carbonyl }pyrimidin-4- 1-52yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(6-bromopyridin-2-yl)methyl]-2-thieny] } carbonyl)pyrimidin-4- 1-53yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)- 1 -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-54 and[( l R,2S,4R)-4- { [5-({4-[( lR)- l -(6-bromopyridin-2-yl)- l-hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(4-chloro- 1 H-pyrazol- 1 -yl)methyl]-5-methyl-2-1-55thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[(R)-hydroxy(phenyI)methy]]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-56 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-hydroxy(phenyl)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate j57[( l R,2S,4R)-2-hydroxy-4-({ 5-[4-(3-methylbenzyl)-2-furoyl]pyrimidin-4- yl } amino)cyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { 4-[( 1 S)- 1 -hydroxy- 1 -phenylethyl]-2-furoyl }pyrimidin-4- yI)amino]cyclopentyl } methyl sulfamate1-58 and{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { 4-[( 1 R)-l -hydroxy- 1 -phenylethyl]-2-furoyl Jpyrimidin- 4-yl)amino]cyclopentyl }methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { 4-[( 1 S)- 1 -hydroxy- 1 -phenylethyl]-2-furoyl }pyrimidin-4- yl)amino]cyclopentyl } methyl sulfamateI-58a or{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { 4-[( 1 R)- 1 -hydroxy- 1 -phenylethyl]-2-furoyl Ipyrimidin- 4-yl)amino]cyclopentyl Jmethyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- {4-[( 1 S)- 1 -hydroxy- 1 -phenylethyl]-2-furoyl }pyrimidin-4- yl)amino]cyclopentyl } methyl sulfamate1-58b or{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { 4-[( 1 R)- 1 -hydroxy- 1 -phenylethyl]-2-furoyl }pyrimidin- 4-yl)amino]cyclopentyl } methyl sulfamate{ (lR,2S,4R)-4-[(5-{ [4-(3-bromobenzyl)-2-thienyl]carbonyl }pyrimidin-4-yl)amino]-2-1-59hydroxycyclopentyl } methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [4-(3-methylbenzyl)-2-thienyl]carbonyl }pyrimidin-4- 1-60yl)amino]cyclopentyl } methyl sulfamate1-61 { ( 1 R,2S,4R)-4-[(5- { [4-(3-chloro-4-fluorobenzyl)-2-thienyl]carbonyl }pyrimidin-4-Compound NameNo.yl)amino]-2-hydroxycyclopentyl Jmethyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [4-(3-iodobenzyl)-2-thienyl]carbony 1 } pyrimidin-4-1-62yl)amino]cyclopentyl } methyl sulfamate[(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(R)-(5-chloro-2-methoxyphenyl)(hydroxy)methyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-63 and[( l R,2S,4R)-4-{ [5-({ 5-chloro-4-[(S)-(5-chloro-2-methoxyphenyl)(hydroxy)methyl]-2- thienyl }cai"bonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3R,4R)-4-( { 5-[4-(3-bromobenzyl)-5-methyl-2-furoyl]pyrimidin-4-yl } amino)-3-1-64fluoro-2-hydroxycyclopentyl]methyl sulfamate[( l R,2R,3R,4R)-3-fluoro-2-hydroxy-4-( { 5-[5-methyl-4-(3-methylbenzyl)-2- 1-65furoyl]pyrimidin-4-yl } amino)cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(5-chloro-2-furyl)methyl]-2-thienyl } carbonyl)pyrimidin-4- 1-66yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(2R)-2-(3-chlorophenyl)oxetan-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-67 and[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[(2S)-2-(3-chlorophenyl)oxetan-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({ 5-methyl-4-[(R)-phenylsulfinyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate1-68 and[( 1 R,2S,4R)-2-hydroxy-4- { [5-({ 5-methyl-4-[(S)-phenylsulfinyI]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( lR,2S,4R)-2-hydroxy-4-( { 5-[(5-methy]-4-{ (R)-[3-(trifluoromethyl)phenyl]sulfinyl }-2- thienyl)carbonyl]pyrimidin-4-yl }amino)cyclopentyl]methyl sulfamate1-69 and[( lR,2S,4R)-2-hydroxy-4-( { 5-[(5-methyl-4-{ (S)-[3-(trifluoromethyl)phenyl]sulfinyl }-2- thienyl)carbonyl]pyrimidin-4-yl j amino)cyclopentyl]methyl sulfamate{ ( l R,2S,4R)-4-[(5-{ [4-(3-ethynylbenzyl)-2-thienyl]carbonyl }pyrimidin-4-yl)amino]-2-1-70hydroxycyclopentyl Jmethyl sulfamate[( l R,2S,4R)-4-{ [5-({4-[(6-chloropyridin-2-yl)methyl]-2-thienyl }carbonyl)pyrimidin-4- 1-71yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-({ 5-[5-chloro-4-(3-chlorobenzyl)-2-furoyl]pyrimidin-4-yl }amino)-2- 1-72hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[(R)-(3-bromophenyl)(methoxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-73a or[( 1 R,2S,4R)-4-{ [5-( { 4-[(S)-(3-bromophenyl)(methoxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(lRi2S,4R)-4-{ [5-({4-[(R)-(3-bromophenyl)(methoxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-73b or[(lR,2S,4R)-4-{ [5-({4-[(S)-(3-bromophenyl)(methoxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate1-74 [( 1 R,2S ,4R)-2-hydroxy-4- { [5-( { 4-[(4-methyl- 1 H-pyrazol- 1 -yl)methyl]-2-Compound NameNo.thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2R,3R,4R)-4-( { 5-[4-(3-chlorobenzyl)-5-methyl-2-furoyl]pyrimidin-4-yl } amino)-3-1-75fluoro-2-hydroxycyclopentyl]methyl sulfamate{ (lR,2R,3S,4R)-4-[(5- { [4 3-bromobenzyl)-5-chloro-2-thienyl]carbonyl }pyrimidin-4- yl)amino]-2,3-dihydroxycyclopentyl }methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-(3-chlorobenzyl)-5-[(dimethylamino)methyl]-2-1-77thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(4-methyl- 1 H-pyrazol- 1 -yl)methyl]-2- 1-78thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[(lR,2S,4R)-4-( { 5-[4-(3-chlorobenzyl)-2-furoyl]pyrimidin-4-yl }amino)-2- 1-79hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({4-[(2-methoxyphenoxy)methyl]-2- 1-80thienyl }cai"bonyl)pyrimidin-4-yl]amino}cyclopenty]]methyl sulfamate[(l R,2S,4R)-2-hydroxy-4-{ [5-({4-[3-(methylsulfanyl)benzyl]-2- 1-81thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( l R,2S,4R)-4-({ 5-[5-(3-bromobenzyl)-2-furoyl]pyrimidin-4-yl }amino)-2- 1-82hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(6-chloro-2,3-dihydro- 1 H-indol- 1 -yl)mefhyl]-2- 1-83thienyl } carbonyl)pyri midin-4-yl] amino } -2-hydroxycy clopentyl] methyl sulfamate{ ( lR,2S,4R)-4-[(5-{ [4-(3-chloro-2-fluorobenzyl)-2-thienyl]carbonyl }pyrimidin-4- 1-84yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(R)-hydroxy(2-methoxyphenyl)methy]]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopenty]]methyl sulfamate 1-85 and[( l R,2S,4R)-4-{ [5-({ 5-chloro-4-[(S)-hydroxy(2-methoxyphenyl)methyI]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-(2-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-86 and[(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(R)-(2-chlorophenyl)(hydroxy)methyl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(lR,2R,3S,4R)-4-{ [5-(5-benzyl-2-furoyl)pyrimidin-4-yl]amino}-2,3-1-87dihydroxycyclopentyl] methyl sulfamate[( 1 R,2S,4R)-4-( { 5-[(4-benzyl-2-thienyl)carbonyl]pyrimidin-4-yl } amino)-2- 1-88hydroxycyclopentyl]methyl sulfamate{ (lR,2S,4R)-4-[(5-{ [4-(3-chlorobenzyl)-5-fluoro-2-thienyl]carbonyl }pyrimidin-4- 1-89yl)amino]-2-hydroxycyclopentyl }methyl sulfamate[(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(R)-(3-chlorophenyl)(methoxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-90 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-(3-chlorophenyl)(methoxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(R)-(3-chlorophenyl)(methoxy)methyl]-2- I-90a thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateorCompound NameNo.|(lR.2S.4K)-4-!|5-({5 chl(n -4-[(S)^(3-chloiOphenyl)(n)ellu)xy)inclhyl|-2 thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydiOxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(R)-(3-chlorophenyl)(methoxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-90b or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-(3-chlorophenyl)(methoxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate{(lR,2S,4R)-2-hydroxy-4-[(5-{[4-(phenoxymethyl)-2-thienyl]carbonyl}pyrimidin-4-1-91yl)amino]cyclopentyl } methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [4-( 1 H-pyrrolo[2,3-b]pyridin- 1 -ylmethyl)-2- 1-92thienyl]carbonyl}pyrimidin-4-yl)amino]cyclopentyl} methyl sulfamate[( 1 R,2S,4R)-4-( { 5-[5-(3-chloiObenzyl)-2-furoyl]pyrimidin-4-yl } amino)-2- 1-93hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(R)-(3-chlorophenyl)sulfinyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-94 and[(lR,2S,4R)-4-{[5-({5-chloro-4-[(S)-(3-chlorophenyl)sulfinyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(R)-(3-chlorophenyl)(methylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-95 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-(3-chlorophenyl)(methylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-({5-[(4-benzyl-5-chloiO-2-thienyl)carbonyl]pyrimidin-4-yl}amino)-2-1-96hydroxycyclopen tyl ] methyl sul famate{(lR,2S,4R)-4-[(5-{[4-(3-fluorobenzyl)-2-thienyl]carbony]}pyrimidin-4-yl)amino]-2-1-97hydroxycyclopen tyl } methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(2-bromophenoxy)methyl]-2-thieny 1 } carbonyl)pyrimidin-4-1-98yl]amino}-2-hydroxycyclopentyI]methyl sulfamate{ ( 1 R,2R,3R,4R)-3-fluoro-2-hydroxy-4-[(5- { [4-(3-iodobenzyl)-2-1-99thienyl]carbonyl}pyrimidin-4-yl)amino]cyclopentyl} methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[l-(3-chlorophenyl)vinyl]-5-methyl-2-I- 100thieny])carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopenty]]methyl sulfamate{(lR,2R,3R,4R)-4-[(5-{[4-(3-bromobenzyl)-2-thienyl]carbonyl}pyrimidin-4-yl)amino]-1-1013-fluoro-2-hydroxycyclopentyl } methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- thienyl}carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-102 and[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 R)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- thienyl)carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I- 102a or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI- 102b [( lR,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2-Compound NameNo.thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or[(lR,2S,4R)-4-{[5-({5-chloro-4-[(lS)-l-(3-chlorophenyl)-l-hydroxyethyl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(S)-(5-chloro-2-thienyl)(hydroxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-103 and[(lR,2S,4R)-4-{[5-({5-chloro-4-[(R)-(5-chloro-2-thienyl)(hydroxy)methyl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methy] sulfamate{(lR,2S,4R)-4-[(5-{[4-(3,4-dichlorobenzyl)-2-thienyl]carbonyl}pyrimidin-4-yl)amino]-1-1042-hydroxycyclopentyl } methyl sulfamatej [(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(3-methyl-lH-indol-l-yl)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S ,4R)-2-hydroxy-4- { [5-( { 4- [( 1 R)- 1 -phenylethyl] -2-thienyl } carbonyl)pyrimidin- 4-yl] amino } cyclopenty 1] methyl sulfamate1-106 and[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(lS)-l-phenylethyl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino}cyclopentyl]methy] sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(lR)-l-phenylethyl]-2-thienyl}carbonyl)pyrimidin- 4-yl]amino}cyclopentyl]methyl sulfamateI- 106a or[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(lS)-l-phenylethyl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino}cyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(lR)-l-phenylethyl]-2-thienyl}carbonyl)pyrimidin- 4-y]]amino) cyclopenty l]methyl sulfamateI- 106b or[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(lS)-l-phenylethyl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino}cyclopentyl]methyl sulfamate{(lR,2S,4R)-4-[(5-{[5-chloro-4-(3-chlorobenzyl)-2-thienyl]carbonyl}pyrimidin-4-1-107yl)amino]-2-hydroxycyclopentyl}methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [4-(2-phenylethyl)-2-thienyl]carbonyl }pyrimidin-4- yl)amino]cyclopentyl}methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [5-methyl-4-( 1 H-pyrazol- 1 -ylmethyl)-2-1-109thienyl]carbonyl}pyrimidin-4-yl)amino]cyclopentyl} methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3-chlorobenzyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-2- 1-110thienyl]carbonyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3-ethylbenzyl)-5-methyl-2-thienyl]carbonyl}pyrimidin-4- 1-111yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3-bromobenzyl)-5-chloro-2-thienyl]carbonyl}pyrirnidin-4- 1-112yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[3-(difluoromethoxy)benzyl]-2-thienyl } carbonyl)pyrimidin-4- 1-113yl]amino }-2-hydroxycyclopentyl]methyl sulfamate{(lR,2S,4R)-2-hydroxy-4-[(5-{[4-(lH-indol-l-ylmethyl)-2-thienyl]carbonyl}pyrimidin- 1-1144-yl)amino]cyclopentyl}methyl sulfamate[(lR,2R,3S,4R)-4-({5-[(5-benzy]-2-thienyl)carbonyl]pyrimidin-4-yl}amino)-2,3- 1-115dihydroxycyclopentyl] methyl sulfamateCompound NameNo.[( 1 R,2S ,4R)-4- { [5-( { 4-[(2S)-2-(cyclohex- 1 -en- 1 -yl)tetrahy drofuran-2-yl] -2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-116 and[( 1 R,2S,4R)-4-{ [5-( { 4-[(2R)-2-(cyclohex- 1 -en- 1 -yl)tetrahydrofuran-2-yl]-2- thieny]}carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)- 1 -(3-chlorophenyl)ethyl]-2-thienyl }carbonyl)pyrimidin-4- yl] amino } -2-hydroxycyclopentyl ] methyl sulfamate1-117 and[(lR,2S,4R)-4-{[5-({4-[(lR)-l-(3-chlorophenyl)ethyl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(1 R,2S,4R)-4- { [5-( { 4-[( 1 S)- 1 -(3-chlorophenyl)ethyl]-2-thienyl } carbony l)pyrimidin-4- yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI- 117a or[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 R)- 1 -(3-chlorophenyl)ethyl]-2-thienyl } carbonyl)pyrimidin-4- yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lS)-l-(3-chlorophenyl)ethyl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino)-2-hydroxycyclopenty]]methyl sulfamateI- 117b or[(lR,2S,4R)-4-{[5-({4-[(lR)-l-(3-chlorophenyl)ethyl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{(lR,2S,4R)-4-[(5-{[5-bromo-4-(3-chlorobenzyl)-2-thienyl]carbony]}pyrimidin-4-1-118yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-({5-[(4-{[5-(trifluoromethyl)-2-furyl]methyl}-2- 1-119thienyl)carbonyl]pyrimidin-4-yl}amino)cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(3-chlorophenoxy)methyl]-2-thienyl } carbonyl)pyri midin-4- 1-120yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(2S)-2-phenyltetrahydrofuran-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yI]amino}cyclopentyl]methyl sulfamate1-121 and[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(2R)-2-phenyltetrahydrofuran-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-( { -[(5-chloro-4- { (R)-[3-(trifluoromethyl)phenyl]sulfinyl } -2- thienyl)carbonyl]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methyl sulfamate 1-122 and[( 1 R,2S,4R)-4-( { 5-[(5-chloro-4- { (S)-[3-(trif]uoromethyl)phenyl] sulfinyl } -2- thienyl)carbonyl]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methyl sulfamate{ ( lR,2S,4R)-2-hydroxy-4-[(5- { [4-(3-methoxybenzyl)-2-thienyl]carbonyl } pyrimidin-4-1-123yl)amino]cyclopentyl ) methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(2-cyanophenoxy)methyl]-2-thienyl}carbonyl)pyrimidin-4- 1-124yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(6-chloro- 1 H-indol- 1 -yl)methyl]-2-thienyl }carbonyl)pyrimidin- 1-1254-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(6-methoxy-2,3-dihydro-lH-indol-l-yl)methyl]-5- 1-126methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-(5-benzyl-2-fuiOyl)pyrimidin-4-yl]amino}-2- 1-127hydroxycyclopentyljmethyl sulfamateCompound NameNo.[( 1 R,2S,4R)-4- { [5-({4-[(6-cyano-2,3-dihydro- 1 H-indol- 1 -yl)methyl]-5-methyl-2-1-128thienyl }carbonyl)pyrimidin-4-yl]arnino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({4 (2-chlorophenoxy)methyl]-2-thienyl }carbonyl)pyrimidin-4- 1-129yl] amino } -2-hydroxycyclopentyl ] methyl sulfamate[( 1 R,2S ,4R)-2-hydroxy-4-( { 5- [(4- { [4-(trifluoromethyl)- 1 H-pyrazol- 1 -yl] methyl } -2- thienyl)carbonyl]pyrimidin-4-yl } amino)cyclopentyl]methy 1 sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({4-[(2-methylphenoxy)methyl]-2-1- 131thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[(6-methyl- 1 H-indol- 1 -yl)methyl]-2- 1- 132thienyl } carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-2,3-dihydroxy-4- { [5-(5-phenyl-2-furoyl)pyrimidin-4-1-134yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)- 1 -(3-chlorophenyl)ethyl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl]methyl sulfamate 1-135 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)- 1 -(3-chlorophenyl)ethyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( {4-[( lR)- l-(3-chlorophenyl)ethyl]-5-methyl-2- thienyl ) carbonyl)pyrimidin-4-y]]amino }-2-hydroxycyclopentyl]methy] sulfamate I- 135a or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)- 1 -(3-chlorophenyl)ethyl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1R)- 1 -(3-chlorophenyl)ethyl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I- 135b or[( 1 R,2S,4R)-4-{ [5-( {4-[( IS)- 1 -(3-chlorophenyl)ethyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({ 5-chloro-4-[( l R)- l -hydroxy-2-phenylethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-136 and[( 1 R,2S ,4R)-4- { [5-( { 5-chloro-4-[( 1 S)- 1 -hydroxy-2-phenylethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{ (l R,2S,4R)-2-hydroxy-4-[(5-{ [5-methyl-4-(phenylsulfanyl)-2-1- 137thienyl]carbonyl }pyrimidin-4-yl)amino]cyclopentyl} methyl sulfamate[(lR,2S,4R)-4-({ 5-[(4-{ [(3-chlorophenyl)(methyl)amino]methyl }-2- 1- 138thienyl)carbonyl]pyrimidin-4-yl }amino)-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S!4R)-4-{ [5-(4,5-dibenzyl-2-furoyl)pyrimidin-4-yl]amino}-2- 1-139hydroxycyclopentyl]methyl sulfamate{ ( 1 R,2S ,4R)-4- [(5- { [4-(cyclohex- 1 -en- 1 -ylmethyl)-2-thienyl] carbonyl } pyri midin-4- 1- 140yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)- 1 -hydroxy-2-methylprop-2-en- l-yl]-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate 1- 141 and[( lR,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)- 1 -hydroxy-2-methylprop-2-en- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.{ ( 1 R,2S,4R)-4-[(5- { [5-(3-chlorobenzyl)-4-(hydroxymethyl)-2-1- 142thienyl]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamatel[( lR,2S,4R)-4-{ [5-({ 4-[(3-chlorophenyl)sulfanyl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino} -2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-( { 5-[(4,5-dibenzyl-2-thienyl)carbonyl]pyrimidin-4-yl } amino)-2-1- 144hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-2-hydroxy-4-({ 5-[(5-methyl-4-{ [3-(trifluoromethyl)phenyl]sulfanyl }-2- 1-145thienyl)carbonyl]pyrimidin-4-yl }amino)cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[2-(3-chlorophenyl)ethyl]-2-thienyl } carbonyl)pyrimidin-4- 1-146yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-( { 5-[(4- { [(2-chlorophenyl)sulfanyl]methyl } -2- 1- 147thienyl)carbonyl]pyrimidin-4-yl } amino)-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-({ 4-[(4-bromo-2-cyano- 1 H-pyrrol- 1 -yl)rnethyl]-5-methyl-2- 1- 148thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S?4R)-4-{ [5-( { 5-chloro-4-[(R)-(2,5-dichlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino )-2-hydroxycyclopentyl]methyl sulfamate 1- 149 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-(2,5-dichlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-3-cyclopropyl- 1 -hydroxyprop-2-yn- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate 1- 150 and[( 1 R,2S,4R)-4-{ [5-({ 5-chloro-4-[( 1 S)-3-cyclopropyl- 1 -hydroxyprop-2-yn- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( {4-chloro-5-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1- 151 and[( lR,2S,4R)-4-{ [5-({4-chloro-5-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methy] sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-chloro-5-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-151 a or[( lR,2S,4R)-4- { [5-({ 4-chloro-5-[(S)-(3-chlorophenyl)( ydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-chloro-5-[(R)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I- 151b or[( lR,2S,4R)-4-{ [5-({4-chloro-5-[(S)-(3-chlorophenyl)(hydroxy)methyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-( { 5-[( 1R)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1- 152 and[( 1 R,2S,4R)-4-{ [5-({ 5-[( 1 S)- 1 -(3-chlorophenyl)- 1 -hydroxyethyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{ [5-({4-[(R)-(3-chlorophenyl)(dimethylamino)methyl]-2- 1-153 thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate andCompound NameNo.[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(3-chlorophenyl)(dimemylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(R)-(3-chlorophenyl)(dimethylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-153a or[(lR>2S,4R)-4-{[5-({4-[(S)-(3-chlorophenyl)(dimethylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-(3-chlorophenyl)(dimethylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I- 153b or[(lR,2S,4R)-4-{[5-({4-[(S)-(3-chloropheny])(dimethylamino)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methy] sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(2R)-2-(3-chlorophenyl)tetrahydro-2H-pyran-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-154 and[(lR,2S,4R)-4-{[5-({4-[(2S)-2-(3-chlorophenyl)tetrahydro-2H-pyran-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(2,3-dichlorobenzyl)-2-thienyl]carbonyl}pyrimidin-4-yl)amino]-1-1552-hydroxycyclopentyl } methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(2-ethoxyphenoxy)methyl]-2-thienyl } carbonyl)pyrimidin-4- 1-156yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(4-chlorobenzyl)-2-thienyl]carbonyl}pyrimidin-4-yl)amino]-2- 1-157hydroxycyclopentyl } methyl sulfamate[(lR,2R,3S,4R)-4-({5-[5-(2-chlorophenyl)-2-furoyl]pyrimidin-4-yl}amino)-2,3- 1-158dihydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(5-chloro-2,3-dihydro- 1 H-indol- 1 -yl)mefhyl]-5-methyl-2- 1-159thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(3-methyl-lH-pyrazolo[3,4-c]pyridin-l-yl)methyl]- 1-1602- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[(2-iodophenoxy)methyl]-2- 1-161thienyl}carbonyl)pyrimidin-4-y]]amino}cyclopentyl]methyl sulfamate[( 1 R,2R,3R,4R)-4-( { 5-[(4-benzyl-5-chloro-2-thienyl)carbonyl]pyrimidin-4-yl } amino)- 1-1623- fluoro-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(4-chlorophenoxy)methyl]-2-thienyl}carbonyl)pyrimidin-4- 1-163y]]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[ 1 -(3-bromophenyl)vinyl]-2-thienyl } carbonyl)pyrimidin-4- 1-164yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { [4-(2-chlorobenzyl)-2-thienyl]carbonyl } pyrimidin-4-yl)amino]-2- 1-165hydroxycycl open tyl } methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(2S)-2-cyclohexyltetrahydrofuran-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-166 and[(lR,2S,4R)-4-{[5-({4-[(2R)-2-cyclohexyltetrahydrofuran-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { [4-(3,4-dihydroisoquinolin-2( 1 H)-ylmethyl)-2-1-167thienyl]carbonyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methyl sulfamateCompound NameNo.{(lR,2S,4R)-4-[(5-{[4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylmethyl)-2-1-168fhienyljcarbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamate j j69[(1 R,2S,4R)-4- { [5-( { 4-[(6-cyano- 1 H-indol- 1 -yl)methyl]-2-thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S ,4R)-2-hydroxy-4- { [5-( { 4- [(3-methyl- 1 H-pyrrol - 1 -yl)methyl] -2-1-170thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { [4-(2,3-dihydro- 1 H-pyrrolo[2,3-b]pyridin- 1 -ylmethyl)-5-methyl-2- 1-171thienyl]carbonyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl} methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(R)-cyclohexyl(hydroxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-172 and[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[(S)-cyclohexyl(hydroxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3,6-dihydro-2H-thiopyran-4-ylmethyl)-2-1-173thienyl]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopenty] } methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(R)-hydroxy(tetrahydro-2H-pyran-4-yl)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-174 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(S)-hydroxy(tetrahydro-2H-pyran-4-yl)methy l]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(3-chlorophenyl)sulfanyl]-2-1-175thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-({5-[(4-{[2-(trifluoromethoxy)phenoxy]methyl}-2- 1-176thienyl)carbonyl]pyrimidin-4-yl}amino)cyclopentyl]methyl sulfamatel [(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(phenylsulfanyl)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[2-(4-chlorophenyl)ethyl]-2-thienyl } carbonyl)pyrimidin-4-1-178yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3-chlorobenzyl)-5-cyano-2-thienyl]carbonyl}pyrimidin-4- 1-179yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(2,3-dichlorophenoxy)methyl]-2-thienyl)carbonyl)pyrimidin-4- 1-180yl]amino}-2-hydroxycyc]opentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(3-chlorophenyl)sulfonyl]-5-methyl-2- 1-181thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(1 R,2S,4R)-4- { [5-( { 4-[(2-ethylphenoxy)methyl]-2-thienyl } carbonyl)pyrimidin-4- 1-182yl]amino}-2-hydroxycyclopentyl]methy] sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[2-(2-methoxyphenyl)ethyl]-2- 1-183thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4-({ 5-[(4- { [6-(trifluoromethyl)- 1 H-indol- l-yl]methyl }-2- 1-184thienyl)carbonyl]pyrimidin-4-yl}amino)cyclopentyl]methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3-cyanobenzyl)-2-thienyl]carbonyl}pyrimidin-4-yl)amino]-2- 1-185hydroxycyclopentyl } methyl sulfamate{(lR,2S,4R)-2-hydroxy-4-[(5-{[4-(lH-pyrrolo[2,3-c]pyridin-l-ylmethyl)-2- 1-186thienyl]carbonyl}pyrimidin-4-yl)amino]cyclopenty]} methyl sulfamateI- 187 { ( 1 R,2S,4R)-4-[(5- { [4-( 1 ,3-dihydro-2H-i soindol-2-ylmethyl)-2-Compound NameNo.thienyl]carbonyl}pyrimidin-4-yl)amino]-2-hydroxycyc]opentyl}methyl sulfamate[( 1 R.2S ,4R)-2-hydroxy-4-( { 5- [(4- { [2-(trifluoromethyl)phenoxy]methyl } -2- l-Uthienyl)carbonyl]pyrimidin-4-yl}amino)cyclopentyl]methyl sulfamate[(lR,2S,4R)-4-({5-[(5-chloro-4-{[3-(trifluoromethyl)phenyl]sulfanyl}-2- thienyl)carbonyl]pyrimidin-4-yl}amino)-2-hydroxycyc]opentyl]methy] sulfamate{(lR,2S,4R)-4-[(5-{[4-(5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-ylmethyl)-2-1-190thienyl]carbonyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl} methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(2-isopropylphenoxy)methyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { [4-( 1 H-benzimidazol- 1 -ylmethyl)-2-thienyl]carbonyl Jpyrimidin-1-192yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(2,5-dihydrofuran-3-ylmethyl)-2-thienyl]carbonyl}pyrimidin^ yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( {4-[(3-cyano- 1 H-pyrrol- 1 -yl)methyl]-5-methyl-2-1-194thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)- 1 -hydroxy-2-methylpropyl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydiOxycyclopentyl]methyl sulfamate 1-195 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)- 1 -hydroxy-2-methylpropyl]-2- thienyl}carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(3,6-dihydro-2H-pyran-4-ylmethyl)-2-1-196thienyl]carbonyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { 4-[( 1 S)- 1 -hydroxy-2-methylprop-2-en- 1 -yI]-2- furoyl}pyrimidin-4-yl)amino]cyclopentyl} methyl sulfamate1-197 and{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { -[( 1 R)- 1 -hy droxy-2-methy lprop-2-en- 1 -yl]-2- furoyl}pyrimidin-4-yl)amino]cyclopentyl} methyl sulfamate{(lR,2S,4R)-4-[(5-{[4-(cyclohexylmethyl)-2-thienyl]carbonyl}pyrimidin-4-yl)amino]-1-1992-hydroxycyclopentyl } methyl sulfamate{(lR,2S,4R)-2-hydroxy-4-[(5-{[4-(phenylsulfonyl)-2-thienyl]carbonyl}pyri1-200yl)amino]cyclopentyl} methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(2-isopropoxyphenoxy)methyl]-2- 1-201thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate{ ( 1 R,2R,3S,4R)-2,3-dihydroxy-4-[(5- { [5-(2-hydroxypropan-2-yl)-2- thienyl]carbonyl}pyrimidin-4-yl)amino]cyclopentyl} methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[(3-chlorophenyl)sulfonyl]-2-1-203thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-4- [(5- { [4-(3 ,6-dihydropyri din- 1 (2H)-y lmethyl)-2- 1-204thienyl]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl Jmethyl sulfamate{(lR,2R,3R,4R)-4-[(5-{[5-(3-chlorobenzyl)-2-thienyl]carbonyl}pyrimidin-4-yl)amino]- 1-2053-fluoro-2-hydroxycyclopentyl } methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-({5-[5-(hydi xymethyl)-2-furoyl]pyrimidin-4- 1-206yl } amino)cyclopentyl]methyl sulfamateCompound NameNo.{ (lR,2S,4R)-4-[(5-{ [5-ch]oro-4-(3-chlorobenzoyl)-2-thienyl]carbonyl }pyrimidin-4-1-207yl)amino]-2-hydroxycyclopentyl } methyl sulfamate1 208 [(lR,2S,4R)-4-{ [5-(4-benzoyl-2-furoyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl]methy] sulfamate{ ( lR,2S,4R)-4-[(5-{ [(2S)-2-(3-chlorophenyl)-2,3,4,5-tetrahydro-2,3'-bithiophen-5'- yl]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methyl sulfamate 1-209 and{ ( lR,2S,4R)-4-[(5-{ [(2R)-2-(3-chlorophenyl)-2,3,4,5-tetrahydro-2,3'-bithiophen-5'- yljcarbonyl }pyrimidin-4-y])amino]-2-hydroxycyclopenty] }methy] sulfamate[( lR,2S,4R)-4-{ [5-({4-[(5-chloropyridin-3-yl)methyl]-2-thienyl }carbonyl)pyrimidin-4-1-210yl]amino }-2-hydroxycyclopentyl]methyl sulfamate{ ( l R,2S,4R)-4-[(5-{ [5-chloro-4-(hydroxymethyl)-2-thienyl]carbonyl }pyrimidin-4- 1-21 1yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( lR,2S,4R)-2-hydroxy-4-( { 5-[5-(methoxymethyl)-2-furoyl]pyrimidin-4- 1-212yl } amino)cyclopentyl]methyl sulfamate[(lR,2S,4R)-4-({ 5-[(4-benzoyl-5-chloro-2-thienyl)carbonyl]pyrimidin-4-yl } amino)-2- 1-215hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4-( { 5-[4-(hydroxymethyl)-2-furoyl]pyrimidin-4- 1-216yl }amino)cyclopentyl]methyl sulfamate{ ( l R,2S,4R)-2-hydroxy-4-[(5-{ [4-(methoxymethyl)-2-thienyl]carbonyl }pyrimidin-4- 1-217yl)amino]cyclopentyl } methyl sulfamate{ ( lR,2S,4R)-4-[(5-{ [5-chloro-4-(methoxymethyl)-2-thieny]]carbonyl }pyrimidin-4- 1-218yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{ ( 1 R,2S,4R)-4-[(5-{ [4-(2,5-dihydro- 1 Η-pyrrol· 1 -ylmethyl)-2- 1-219thieny]]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methyl sulfamate[( lR,2S,4R)-2-hydroxy-4-({ 5-[4-(2-hydroxypropan-2-yl)-2-furoyl]pyrimidin-4- 1-220yl } amino)cyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { [4-( { 3-[(dimethylamino)methyl]- 1 H-indol- 1 -yl } methyl)-2- 1-221thienyl]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methyl sulfamate[( l R,2S,4R)-4-{ [5-( {4-[(benzylamino)methyl]-2-thienyl }carbonyl)pyrimidin-4- 1-222yl]amino }-2-hydroxycyclopentyl]methy] sulfamate[( lR,2S,4R)-2-hydroxy-4-( { 5-[4-(methoxymethyl)-2-furoyl]pyrimidin-4- 1-223yl }amino)cyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(3,3-difluoropiperidin-l -yl)methyl]-2- 1-224thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4-( { 5-[(4- { [(3R)-3-methylpiperidin- 1 -yl]methyl } -2- thienyl)carbonyl]pyrimidin-4-yl } amino)cyclopentyl] methyl sulfamate1-225 and[( 1 R,2S,4R)-2-hydroxy-4-( { 5-[(4- { [(3S)-3-methylpiperidin- 1 -yl]methyl } -2- thienyl)carbonyl]pyrimidin-4-yl } amino)cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)- 1 -hydroxyethyl]-2-thienyl } carbonyl)pyrimidin-4- yl]amino }-2-hydroxycyclopentyl]methyl sulfamate1-226 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)- 1 -hydroxyethyl]-2-thienyl }carbonyl)pyrimidin-4- yl]amino }-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.[(lR,2S,4R)-4-{ [5-({4-[(2S)-2-(3-chlorophenyl)-l -methylpyrrolidin-2-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-227 and[( lR,2S,4R)-4-{ [5-({4-[(2R)-2-(3-chlorophenyl)- l-methylpyrrolidin-2-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(3,3-difluoropyrrolidin- 1 -yl)methyl]-2-1-228thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-({ 5-[(4-acetyl-2 hienyl)carbonyl]pyrimidin-4-yl }amino)-2- 1-229hydroxycyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [4-(hydroxymethyl)-2-thienyl]carbonyl }pyrimidin-4- 1-230yl)amino]cyclopentyl } methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [4-( 1 H-imidazol- 1 -ylmethyl)-2- 1-231thienyl]carbonyl } pyrimidin-4-yl)amino]cyclopentyl } methyl sulfamate{ ( l R,2S,4R)-4-[(5-{ [5-(3-chlorobenzyl)-3-methyl-2-thienyl]carbonyl }pyrimidin-4-1-233yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( l R,2S,4R)-4-{ [5-(4-acetyl-2-furoyl)pyrimidin-4-yl]amino }-2- 1-234hydroxycyclopentyl]methyl sulfamatej235{ ( lR,2S,4R)-2-hydroxy-4-[(5-{ [5-(2-hydroxypropan-2-yl)-2- thienyl]carbonyl }pyrimidin-4-yl)amino]cyclopentyl } methyl sulfamatej236[( l R,2R,3S,4R)-4-{ [2-chloro-5-(5-phenyl-2-furoyl)pyrimidin-4-yl]amino }-2,3- dihydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[(5-methyl-2-furyl)methyl]-2-1-237thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(2S)-2-cyclopropyltetrahydrofuran-2-yl]-2- thienyl } carbonyl)pyi"imidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate 1-238 and[( 1 R,2S,4R)-4-{ [5-( { 4-[(2R)-2-cyclopropyltetrahydrofuran-2-yI]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-({ 5-[5-(phenylsulfonyl)-2-furoyl]pyrimidin-4-1-239yl }amino)cyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [4-(2-hydroxypropan-2-yl)-2- 1-240thienyl]carbonyl }pyrimidin-4-yl)amino]cyclopentyl } methyl sulfamate[( lR,2S,4R)-2-hydroxy-4-{ [5-({4-[(4-phenylpiperazin- l-yl)methyl]-2- 1-241thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( lR,2S,4R)-4-({ 5-[(4-acetyl-5-chloro-2-thienyl)carbonyl]pyrimidin-4-yl }amino)-2- 1-242hydroxycyclopentyl] methyl sulfamate[(lR,2S,4R)-4-{ [5-({4-[(4-bromo-lH-imidazol-l-yl)methyl]-2- 1-243thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2R,3S,4R)-4-{ [5-({4-[(lR)-7-bromo- l ,2,3,4-tetrahydroisoquinolin-l-yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I-247a or[( lR,2R,3S,4R)-4-{ [5-({4-[( 1 S)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamateI-247b [(lR,2R,3S,4R)-4-{ [5-({4-[( lR)-7-bromo-l,2,3,4-tetrahydroisoquinolin-l-yl]-5-methyl-Compound NameNo.2-thienyl}carbonyl)pyrimidin-4-y]]arm sulfamate or[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 S)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-248a or[( 1 R,2S,4R)-4-{ [5-({4-[( lR)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-248b or[( 1 R,2S ,4R)-4- { [5-( { 4- [( 1 R)-7-bromo- 1 ,2,3 ,4-tetrahy droi soquinolin- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2R,3S,4R)-4- { [5-({5-chloro-4-[(l R)-7-chIoro- l ,2,3,4-tetrahydroisoquinolin- l-yl]- 2-thienyl }cai"bonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I-249a or[( 1 R,2R,3S,4R)-4-{ [5-({ 5-chloro-4-[( 1 S)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( l R,2R,3S,4R)-4-{ [5-({ 5-chloro-4-[( l R)-7-chloro- l ,2,3,4-tetrahydroisoquinolin- l-yl]- 2-thienyl }cai-bonyl)pyrimidin-4-y]]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I-249b or[( lR,2R,3S,4R)-4-{ [5-({ 5-chloro-4-[( l S)-7-chloro- l ,2,3,4-tetrahydroisoquinolin- l -yl]- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-4- { [5-({4-[( 1 R)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate 1-250 and[( 1 R,2R,3S,4R)-4-{ [5-({4-[( 1 S)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 R)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I-250a or[( 1 R,2R,3S,4R)-4- { [5-( {4-[( 1 S)-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( lR,2R,3S,4R)-4- { [5-({4-[( lR)-3,4-dihydro-lH-isochromen- l-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yI]amino } -2, 3-dihydroxycyclopentyl] methyl sulfamate I-250b or[( lR,2R,3S,4R)-4-{ [5-({4-[( lS)-3,4-dihydro- l H-isochromen-l -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[( lR)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-251 and[(1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-chloro-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl]methyl sulfamate R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-chloro-2- enyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-({ 4-[( lS)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- l-yl]-5-chloro-2-Compound NameNo.thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lR)-7-bromo-l,2,3,4-tetrahydroisoquinolin-l-yl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-25 lb or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-chloro-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R.2S ,4R)-4- { [5-( { 4-[( 1 R)-7-ethynyl-3 ,4-di hydro- 1 H-i sochromen- 1 -yl]-5-methy 1-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-252 and[( 1 R,2S,4R)-4-{ [5-( { 4-[(l S)-7-ethynyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[( 1 R)-7-ethynyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-252a or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-ethynyl-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-ethynyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]aminoj-2-hydroxycyclopentyl]methyl sulfamate I-252b or[( 1 R,2S,4R)-4-{ [5-( {4-[( 1 S)-7-ethynyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydi"oxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8S)-2-chloro-5,6,7,8-tetrahydro-l,7-naphthyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-253 and[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8R)-2-chloro-5,6,7,8-tetrahydro-l,7-naphthyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8S)-2-chloro-5,6,7,8-tetrahydro-l,7-naphthyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-253 a or[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8R)-2-chloro-5,6,7,8-tetrahydro-l,7-naphthyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8S)-2-chloro-5,6,7,8-tetrahydro-l,7-naphthyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-253b or[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8R)-2-chloro-5,6,7,8-tetrahydro-l,7-naphthyridin-8- yI]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[( 1 R)-3,4-dihydro- ΙΗ-i sochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-254 and[( lR,2S,4R)-4- { [5-( {4-[( 1 S)-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[( lR)-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate I-254a or[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lR)-3,4-dihydro-lH-isochromen-l-yl]-2-I-254bthienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-7-chloro- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate I-255a or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({ 5-chloro-4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbony])pyrimidin-4-yl]amino)-2-hydroxycyc]opentyl]methyl sulfamate I-255b or[( l R,2S,4R)-4-{ [5-({ 5-chloro-4-[( lS)-7-chloro-l ,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(l R,2S,4R)-4-{ [5-({ 4-[( l R)-3,4-dihydro-l H-isochromen- l -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate 1-256 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyI sulfamateI-256a [( 1 R,2S,4R)-4- { [5-( {4-[( 1 S)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2-I-256bthienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-({ 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-257 and[( 1 R,2S,4R)-4-{ [5-({4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino ) -2-hydroxycyclopentyl]methyl sulfamate j257a[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2-I-257bthienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[( 1 R)-7-(trifluoromethy l)-3,4-dihydro- 1 H- isochromen- l -yl]-2-thienyl }carbonyl)pyrimidin-4-yl]arnino}cyclopentyl]methyl sulfamate1-258 and[( 1 R,2S,4R)-2-hydroxy-4-{ [5-( { 5-methyl-4-[( 1 S)-7-(trifluoromethy])-3,4-dihydro- 1 H- isochromen- l -yl]-2-thieny] }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[( lR)-7-(trifluoromethyl)-3,4-dihydro- 1 H- isochromen- l -yl]-2-thienyl }cai-bonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamateI-258a or[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[( 1 S)-7-(trifluoromethyl)-3 ,4-dihydro- 1 H- isochromen- l -yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamateI-258b [( lR,2S,4R)-2-hydroxy-4- { [5-({ 5-methyl-4-[( 1 R)-7-(trifluoromethyl)-3 ,4-dihydro- 1 H-Compound NameNo.isochromen- 1 -yl]-2-thienyl } carbonyl)pyrimidin-4-yl]amino } cyclopentyljmethyl sulfamateor[( 1 R,2S ,4R)-2-hy droxy-4- { [5-( { 5-methyl-4- [( 1 S)-7-(trifluoromethyl)-3 ,4-dihydro- 1 H- isochromen- 1 -yl]-2-thienyl } carbonyl)pyrimidin-4-yl]amino } cyclopentyl] methyl sulfamate[(1 R,2R,3S,4R)-4- { [5-({4-[( 1 R)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-chloro- 2-thienyl }carbony])pyrimidin-4-y]]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate1-259 and[(lR,2R,3S,4R)-4- { [5-({4-[(l S)-7-bromo- l ,2,3,4-tetrahydroisoquinolin- l -yl]-5-chloro- 2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 R)-7-bromo- 1 ,2,3,4-tetrahydroisoquinolin- 1 -y l]-5-chloro- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamateI-259a or[( 1 R,2R,3S,4R)-4- ( [5-( {4-[( 1 S)-7-bromo- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl]-5-chloro- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( lR,2R,3S,4R)-4-{ [5-({4-[( l R)-7-bromo- l ,2,3,4-tetrahydroisoquinolin- l -yl]-5-chloro- 2-thienyl }carbonyl)pyrimidin-4-yl]amino } -2,3-dihydroxycyclopentyl]methyl sulfamateI-259b or[( l R,2R,3S,4R)-4-{ [5-({4-[( lS)-7-bromo- l ,2,3,4-tetrahydroisoquinolin- l -yl]-5-chloro- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({4-[(8R)-2-chloro-5,5-difluoro-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl]methyl sulfamate1-260 and[( l R,2S,4R)-4-{ [5-({ 4-[(8S)-2-chloro-5,5-difluoro-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( {4-[(8R)-2-chloro-5,5-difluoro-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl } carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyljmethyl sulfamateI-260a or[(lR,2S,4R)-4-{ [5-({4-[(8S)-2-chloro-5,5-difluoro-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyljmethyl sulfamate[(l R,2S,4R)-4-{ [5-({4-[(8R)-2-chloro-5,5-difluoro-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl } carbonyl)pyrimidin-4-yl]amino } -2- hydroxycyclopentyl]methyl sulfamateI-260b or[(lR,2S,4R)-4-{ [5-({ 4-[(8S)-2-chloro-5,5-dif]uoro-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyljmethyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( lR)-7-chloro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thieny] )carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate1-261 and[(lR,2S,4R)-4-{ [5-({4-[(lS)-7-chloro-3,4-dihydro-lH-isochromen-l -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-26 l a [(1 R,2S,4R)-4-{ [5-( { 4-[( lR)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2-Compound NameNo.thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[( l R)-7-chloro-3,4-dihydro- l H-isochromen- l -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino) -2-hydroxycyclopentyl]methyl sulfamate 1-26 lb or[(lR,2S,4R)-4-{ [5-({4-[( lS)-7-chloro-3,4-dihydro- l H-isochromen- l -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-6-chloro-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-262 and[( lR,2S,4R)-4-{ [5-({ 5-chloro-4-[( 1 S)-6-chloro-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thieny] } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-6-chloro-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-262a or[( 1 R,2S,4R)-4- ( [5-( { 5-chloro-4-[( 1 S)-6-chloro-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methy] sulfamate[( 1 R,2S,4R)-4-{ [5-({ 5-chloro-4-[( 1 R)-6-chloro-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-262b or[( 1 R,2S,4R)-4- { [5-({ 5-chloro-4-[( 1 S)-6-chloro-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino )-2-hydroxycyclopentyl]methy] sulfamateI-263a [( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyI-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopenty]]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-5-methyl-2-I-263bthieny] }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3R,4R)-4-{ [5-({ 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-3-f]uoro-2-hydroxycyclopentyl]methyl sulfamate1-264 and[( 1 R,2R,3R,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-3-fluoro-2-hydroxycyclopentyl]methyl sulfamate[(1 R,2R,3R,4R)-4-{ [5-( { 4-[( 1 S)-7-chloro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 2-thienyl )carbonyl)pyrimidin-4-yl]amino }-3-fluoro-2-hydroxycyclopentyl]methy] sulfamateI-264a or[(1 R,2R,3R,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino } -3-fluoro-2-hydroxycyclopentyl]methyl sulfamate[(1 R,2R,3R,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino}-3-fluoro-2-hydroxycyclopentyl]methyl I-264b sulfamateor[( 1 R,2R,3R,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-Compound NameNo.2-thienyl }carbonyl)pyrimidin-4-yl]amino }-3-fluoro-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-6-chloro-2-mefhy]-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl]methyl sulfamate 1-265 and[( 1 R,2S,4R)-4-{ [5-({4-[( 1 S)-6-chloro-2-methyl-2,3-dihydro- lH-isoindol- l-yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-({4-[( lR)-6-chloro-2-methyl-2,3-dihydro-l H-isoindol- l -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-265a or[(1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-6-chloro-2-methyl-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl] methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-6-chloro-2-methyl-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-265b or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-6-chloro-2-methyl-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate[( l R,2S,4R)-4-{ [5-( { 5-chloro-4-[(8S)-5,8-dihydro-6H-pyrano[3,4-b]pyndin-8-yl]-2- thienyl }carbony])pyrimidin-4-y]]amino }-2-hydroxycyclopenty]]methyl sulfamate 1-266 and[( l R,2S,4R)-4-{ [5-({ 5-chloro-4-[(8R)-5,8-dihydro-6H-pyrano[3>4-b]pyridin-8-yl]-2- thieny] }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( { 5-chloro-4-[(8S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-266a or[(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(8R)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( { 5-ch]oro-4-[(8S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-2- thienyl }carbony])pyrimidin-4-y]]amino }-2-hydroxycyclopentyl]methyI sulfamate I-266b or[( lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(8R)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate 1-267 and[(1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[( lR)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-267a or[( lR,2S,4R)-4- { [5-({ 4-[( 1 S)-7-fluoro-3 ,4-dihydro- 1 H-isochromen- l-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[( 1 R)-7-fluoro-3,4-dihydro- lH-isochromen- l-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-267b or[( lR,2S,4R)-4- { [5-( { 4-[( 1 S)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate1-268 [( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-bromo-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2-Compound NameNo.thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]rnethyl sulfamate and[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)-7-bromo-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thieny] } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopenty]]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-bromo-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-268a or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-bromo-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-bromo-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thieny] } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-268b or[(1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-bromo-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[(7S)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-269 and[( 1 R,2S,4R)-4- { [5-( { 4-[(7R)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( { 4-[(7S)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino )-2-hydroxycyclopenty]]methy] sulfamate I-269a or[( l R,2S,4R)-4-{ [5-( {4-[(7R)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-y]]amino }-2-hydroxycyclopentyl]methyl sulfamate[(l R,2S,4R)-4-{ [5-({4-[(7S)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl]-5-methyI-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycycIopentyl]methyl sulfamate I-269b or[(lR,2S,4R)-4-{ [5-({4-[(7R)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-4-[(5-{ 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamate 1-270 and{ ( l R,2S,4R)-4-[(5-{ 4-[( l S)-7-chloro-3,4-dihydro- lH-isochromen-l-yl]-5-methyl-2- furoy] }pyrimidin-4-y])amino]-2-hydroxycyclopentyl } methyl sulfamate{ ( 1 R,2S,4R)-4-[(5-{4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamate I-270a or{ ( 1 R,2S,4R)-4-[(5- { 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl} methyl sulfamate{ ( 1 R,2S,4R)-4-[(5-{ 4-[( 1 R)-7-chloro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl} methyl sulfamate I-270b or{ ( 1 R,2S,4R)-4-[(5-{ 4-[( 1 S)-7-chloro-3,4-dihydro- IH-isochromen- 1 -yl]-5-methyl-2- furoyl } pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( lR,2R,3R,4R)-4- { [5-( { 4-[( 1 R)-3,4-dih dro- IH-isochromen- 1 -yl]-5-methyl-2- I 271a thienyl }carbonyl)pyrimidin-4-yl]amino}-3-fluoro-2-hydroxycyclopentyl]methyl sulfamateorCompound NameNo.[(1 R,2R,3R,4R)-4- { [5-( { 4-[( 1 S)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-3-fluoro-2-hydiOxycyclopentyl]rnethyl sulfamate{ (1 R,2S,4R)-4-[(5-{ 4-[( lR)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- furoyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl} methyl sulfamateI-272a or{ ( 1 R,2S,4R)-4-[(5- { 4-[( 1 S)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- furoy]}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl} methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { 4-[( 1 R)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- furoyl } pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamateI-272b or{ ( 1 R,2S,4R)-4-[(5-{ 4-[( 1 S)-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- furoyl}pyrimidin-4-yl)amino]-2-hydroxycyc]opentyl (methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[ ( 1 R)-6,7-difluoro-3 ,4-dihydro- 1 H-i sochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-273 or[(lR,2S,4R)-4-{[5-({4-[(lS)-6,7-difluoro-3,4-dihydro-lH-isochromen-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate[(1 R,2S,4R)-4-{ [5-({ 4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-274 and[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)-7-chloro- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl)carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate I-274a or[(lR,2S,4R)-4-{[5-({4-[(lS)-7-chloro-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl } carbony] )pyri midin-4-yl] ami no } -2-hydroxycyclopentyl] methyl sul famate[(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-274b or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(4S)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-275 and[(lR,2S,4R)-4-{[5-({4-[(4R)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8S)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-276 and[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8R)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4- { [5-( { 5-chloro-4-[(8S)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycycIopentyl]methyl sulfamate I-276a or[(lR,2S,4R)-4-{[5-({5-chloro-4-[(8R)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8- yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.[(lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(8S)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridi yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-276b or[( l R,2S,4R)-4-{ [5-({ 5-ch]oro-4-[(8R)-2-ch]oro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8- yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methy] sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[( lR)-7-cyclopropyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate1-277and[( 1 R,2S,4R)-4-{ [5-({ 4-[( 1 S)-7-cyclopropyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyc]opentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[( lR)-7-cyclopropyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI-277aor[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-cyclopropyl-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyc]opentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-({ 4-[( 1 R)-7-cyclopropyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateI-277bor[( l R,2S,4R)-4-{ [5-({ 4-[( 1 S)-7-cyclopropy]-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2R,3S,4R)-4-{ [5-({4-[(lR)-7-chloro-3,4-dihydro- l H-isothiochromen- l -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate 1-278 and[( lR,2R,3S,4R)-4- { [5-( {4-[( l S)-7-chloro-3,4-dihydro-l H-isothiochromen- l -y]]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydiOxycyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isothiochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate I-278a or[(l R,2R,3S,4R)-4-{ [5-( {4-[( l S)-7-chloro-3,4-dihydro-l H-isothiochromen- l-yI]-2- thienyl } carbonyl)pyrimidin-4-yl]amino } -2,3-dihydroxycyclopentyl]methy] sulfamate[(lR,2R,3S,4R)-4-{ [5-( {4-[( lR)-7-chloro-3,4-dihydro- lH-isothiochromen- l -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyc]opentyl]methyl sulfamate I-278b or[( 1 R,2R,3S,4R)-4-{ [5-( {4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isothiochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-279 and[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 R)- 1 ,2,3,4-tetrahydroisoquinolin- l-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-279a or[( lR,2S,4R)-4- { [5-({ 5-chloro-4-[( 1R)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.[( 1 R,2S,4R)-i { [5-( { 5-chloro-4-[( 1 S)- 1 ,2,3 ,4-tetrahydroisoquinolin- l-yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-279b or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(4R)-4H- l ,3-benzodioxin-4-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-280 and[( 1 R,2S,4R)-4- { [5-( { 4-[(4S)-4H- 1 ,3-benzodioxin-4-yl]-5-methyl-2- thieny] }carbonyl)pyrimidin-4-yI]amino }-2-hydroxycyclopentyl]methy] sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[(4R)-4H- 1 ,3-benzodioxin-4-y l]-5-mefhyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl]methyl sulfamate I-280a or[( lR,2S,4R)-4-{ [5-( {4-[(4S)-4H- l ,3-benzodioxin-4-yl]-5-methyl-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-4-{ [5-( {4-[(4R)-4H- l ,3-benzodioxin-4-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino )-2-hydiOxycyclopentyl]methyl sulfamate I-280b or[( l R,2S,4R)-4-{ [5-({4-[(4S)-4H- l ,3-benzodioxin-4-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[( l 'R)- 1 'H-spiro[cyclopropane- 1 ,4'-isochromen]- 1 '- yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate 1-281 and[(1 R,2S,4R)-2-hydroxy-4- { [5-( {4-[( 1 'S)- 1 Ή-spirofcyclopropane- 1 ,4'-isochromen]- 1 '- yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4-{ [5-( { 4-[( 1 'R)- 1 'H-spiro[cyclopropane- 1 ,4'-i sochromen]- 1 '- yl]-2-thieny] }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate 1-28 l a or[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[( 1 'S)~ 1 'H-spiro[cycIopropane- 1 ,4'-isochromen]- 1 '- yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( lR,2S,4R)-2-hydroxy-4-{ [5-({4-[( 1 'R)- 1 'H-spiro[cyclopropane- 1 ,4'-isochromen]- 1 '- yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate 1-28 l b or[( 1 R,2S,4R)-2-hydroxy-4- { [5-({4-[( 1 'S)- 1 'H-spiro[cyclopropane- 1 ,4'-isochromen]- 1 '- y]]-2-thienyl }carbonyl)pyrimidin-4-y]]amino }cyclopenty]]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-282 and[( lR,2S,4R)-4-{ [5-({ 5-chloro-4-[(l S)-7-chloro-3,4-dihydro- lH-isochromen- l -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4- { [5-( { 5-chloro-4-[( lR)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-282a or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({ 5-chloro-4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- I-282b thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate orCompound NameNo.[( 1 R,2S,4R)-4- { [5-({ 5-chloro-4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[( 1R)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate1-283 and[( 1 R,2S,4R)-2-hydroxy-4- { [5-( {4-[( 1 S)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } cyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{ [5-({4-[(lR)- l ,2,3,4-tetrahydroisoquinolin- l-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamateI-283a or[( 1 R,2S,4R)-2-hydroxy-4-{ [5-( { 4-[( 1 S)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{ [5-({4-[( lR)- l ,2,3,4-tetrahydroisoquinolin- l -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamateI-283b or[( 1 R,2S,4R)-2-hydroxy-4-{ [5-({4-[( 1 S)- 1 ,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S ,4R)-4- { [5-( { 5-chIoro-4-[( 1 R)-6-chloro-2-methyl-2,3-dihydro- 1 H-isoindol- 1 - yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydi xycyclopentyl]methyl sulfamate I-284a or[(1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-6-chloro-2-methyl-2,3-dihydro- 1 H-isoindol- 1 -yl]- 2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 R)-6-chloro-2-methyl-2,3-dihydro- 1 H-isoindol- 1 - yl]-2-thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-284b or[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)-6-chloro-2-methyl-2,3-dihydro- 1 H-isoindol- 1 -yl]- 2-thienyl }cai-bonyl)pyrimidin-4-yl]amino }-2-hydiOxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{ [5-({4-[(8S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-285 and[(lR,2S,4R)-4-{ [5-({4-[(8R)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{ [5-({4-[(8S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino)-2-hydroxycyclopentyl]methyl sulfamate I-285a or[(lR,2S,4R)-4-{ [5-({4-[(8R)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{ [5-({4-[(8S)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-285b or[(lR,2S,4R)-4-{ [5-({4-[(8R)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(8S)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate1-286and[(lR,2S,4R)-4-{ [5-({4-[(8R)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methylCompound NameNo.sulfamate[( lR,2S,4R)-4-{ [5-({4-[(8S)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5- methyl-2 hienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateI-286a or[( l R,2S,4R)-4-{ [5-( {4-[(8R)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5- methyl-2 hienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(8S)-2-chloro-5,8-dihydro-6H-pyrano[3 ,4-b]pyridin-8-yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateI-286b or[( l R,2S,4R)-4-{ [5-({4-[(8R)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-8-yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-( { 5-methyl-4-[(4S)-2-methyl-6,7-dihydro-4H-pyrano[3,4- d] [ l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino )cyclopentyl]methyl sulfamate1-287 and[( l R,2S,4R)-2-hydroxy-4-{ [5-( {5-methyl-4-[(4R)-2-methyl-6,7-dihydro-4H-pyrano[3,4- d][ l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(4S)-2-methyl-6,7-dihydro-4H-pyrano[3,4- d][ l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamateI-287a or[( 1 R,2S,4R)-2-hydroxy-4-{ [5-( { 5-methyl-4-[(4R)-2-methyl-6,7-dihydro-4H-pyrano[3,4- d] [ l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({ 5-methyl-4-[(4S)-2-methyl-6,7-dihydro-4H-pyrano[3,4- d][ l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamateI-287b or[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(4R)-2-methyl-6,7-dihydro-4H-pyrano[3,4- d] [l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-4,4-difluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate1-288 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-4,4-difluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4- { [5-( { 4-[( lR)-7-chloro-4,4-difluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate 1-289 and[( 1 R,2S,4R)-4- { [5-({ 4-[( 1 S)-7-chloro-4,4-difluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.[( 1 R,2S,4R)-4-{ [5-( { 4-[( lR)-7-chloro-4,4-difluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrirnidin-4-yl]amino}-2-hydiOxycyclopentyl]methyl sulfamate I-289a or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-4,4-difluoro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-({ 4-[( 1 R)-7-chloro-4,4-difluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate I-289b or[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)-7-chloro-4,4-difluoro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino)-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-6,7-difluoro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-290a or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-6,7-difluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( lR)-6,7-difluoro-3,4-dihydro-l H-isochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycycIopentyl]methyl sulfamate I-290b or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-6,7-difluoro-3,4-dihydro- 1 H-i sochromen- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(8S)-2-methyl-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate 1-291 and[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(8R)-2-methyl-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(8S)-2-methyl-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate 1-29 la or[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(8R)-2-methyl-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(8S)-2-methyl-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate 1-29 lb or[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(8R)-2-methyl-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[( 1 S)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamateI-292a or[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(lR)-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methy] sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(lS)-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl] amino Jcyclopentyl] methyl sulfamateI-292b or[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(lR)-l,2,3,4-tetrahydroisoquinoIin-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-4,4-difluoro-3 ,4-dihydro- 1 H-i sochromen- 1 -yl]-2- 1-293 thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateandCompound NameNo.[(1 R,2S,4R)-4-{ [5-( { 4-[( 1 S)-4,4-difluoro-3,4-di ydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydiOxycyclopenty]]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( {4-[( lR)-4,4-difluoro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thieny] }carbonyl)pyrirnidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-293a or[( 1 R,2S,4R)-4-{ [5-( {4-[( 1 S)-4,4-difluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopenty]]methyl sulfamate[( 1 R,2S ,4R)-4- { [5-( { 4-[( 1 R)-4,4-difluoro-3 ,4-dihydro- 1 H-i sochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydiOxycyc]opentyl]methyl sulfamate I-293b or[( 1 R,2S,4R)-4-{ [5-({ 4-[( 1 S)-4,4-difluoro-3,4-dihydro- 1 H-isochromen- l-yl]-2- thienyl }carbonyl)pyrimidin-4-y]]amino }-2-hydiOxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-294 and[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-294a or[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-294b or[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)-7-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydiOxycyclopenty]]methyl sulfamate[( 1 R,2R,3S,4R)-2,3-dihydroxy-4- { [5-( { 4-[( 1 S)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate 1-295 and[( 1 R,2R,3S,4R)-2,3-dihy droxy-4- { [5-( { 4-[( 1 R)- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(8S)-3-methyl-5,6-dihydro-8H- imidazo[2, 1 -c][ 1 ,4]oxazin-8-yl]-2-thienyl }carbonyl)pyrimidin-4- yl]amino }cyclopentyl]methyl sulfamate1-296 and[( l R,2S,4R)-2-hydroxy-4-{ [5-({ 5-methyl-4-[(8R)-3-methyl-5,6-dihydro-8H- imidazo[2, 1 -c] [ 1 ,4]oxazin-8-yl]-2-thienyl } carbonyl)pyrimidin-4- yl]amino }cyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydi xy-4-{ [5-({5-methyl-4-[(8S)-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-8-yl]-2-thienyl } carbonyl)pyrimidin-4- y]]amino }cyclopentyl]methyl sulfamate1-297 and[( lR,2S,4R)-2-hydroxy-4-{ [5-({5-methyl-4-[(8R)-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-8-yl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(8S)-2-(trifluoromethyl)-5,8-dihydro-6H-I-297apyrano[3,4-b]pyridin-8-yl]-2-thienyl}carbonyl)pyrimidin-4-Compound NameNo.y]]amino}cyclopentyl]methyl sulfamateor[( lR,2S,4R)-2-hydroxy-4-{ [5-({ 5-methyl-4-[(8R)-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-8-yl]-2-thienyl }carbonyl)pyrimidin-4- yl]amino}cyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({ 5-methyl-4 (8S)-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-8-yl]-2-thienyl }carbonyl)pyrimidin-4- yl] amino } cyclopentyl] methyl sulfamateI-297b or[( l R,2S,4R)-2-hydroxy-4-{ [5-( { 5-rnethyl-4-[(8R)-2-(trifluorornethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-8-yl]-2-thienyl } carbonyl)pyrimidin-4- yl]amino }cyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(4R)-2-chloro-6,7-dihydro-4H-furo[3,2-c]pyran-4-yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-298 and[( l R,2S,4R)-4-{ [5-( {4-[(4S)-2-chloiO-6,7-dihydro-4H-furo[3,2-c]pyran-4-yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(4R)-2-chloro-6,7-dihydro-4H-furo[3,2-c]pyran-4-yl]-5-methyl- 2-thienyl } carbonyl)pyrimidi n-4-yl] ami no } -2-hy droxycy clopenty 1] methyl sulfamate I-298a or[( l R,2S,4R)-4-{ [5-({4-[(4S)-2-chloro-6>7-dihydro-4H-furo[3,2-c]pyran-4-yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-y]]amino}-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(4R)-2-chloro-6,7-dihydro-4H-furo[3,2-c]pyran-4-yl]-5-methyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycydopentyl]methyl sulfamate I-298b or[( l R,2S,4R)-4-{ [5-( {4-[(4S)-2-chloro-6J-dihydro-4H-furo[3,2-c]pyran-4-yl]-5-rnethyl- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { 5-chloro-4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamate1-299 and{ ( 1 R,2S,4R)-4-[(5- { 5-chloro-4-[( 1 S)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- l-yl]-2- furoyl }pyrimidin-4-yl)amino]-2-hydiOxycyclopentyl }methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { 5-chloro-4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methyl sulfamateI-299a or{ ( 1 R,2S,4R)-4-[(5- { 5-chloro-4-[( 1 S)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- furoyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { 5-chloro-4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methyl sulfamateI-299b or{ ( 1 R,2S,4R)-4-[(5- { 5-chloro-4-[( 1 S)-7-chloro- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- furoyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methy] sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 1 ,3- thiazol-2-yl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-300a or[( lR,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 1 ,3- thiazol-2-yl }carbony])pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI-300b [( 1 R,2S,4R)-4-{ [5-( {4-[( lR)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl- 1 ,3-Compound NameNo.thiazol-2-yl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or[( lR,2S,4R)-4-{ [5-({4-[( l S)-7-chloro-3,4-dihydiO-lH-isochromen- l -yl]-5-methyl- l ,3- thiazol-2-yl }carbonyl)pyrimidin-4-yl]arriino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( lR)-5-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate 1-301 and[( lR,2S,4R)-4- { [5-( { 4-[( 1 S)-5-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-({ 4-[( 1 R)-5-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycycIopentyl]methyl sulfamate 1-30 l a or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-5-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-5-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-30 l b or[( lR,2S,4R)-4-{ [5-({4-[( 1 S)-5-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2R,3S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)- 1 ,2,3,4-tetrahydroisoqui nolin- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino } -2,3-dihydroxycyclopentyl]methyl sulfamate 1-302 and[( lR,2R,3S,4R)-4-{ [5-({ 5-chloro-4-[(l R)- l ,2,3,4-tetrahydroisoquinolin-l -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2,3-dihydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-8-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate1-303 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-8-fluoro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-2-methyl-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-304 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-2-methyl-2,3-dihydro- 1 H-isoindol- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{ [5-({ 5-methyl-4-[(4S)-2-methyl-6,7-dihydro-4H-pyrano[4,3- d][ l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate1-305 and[(lR,2S,4R)-2-hydroxy-4-{ [5-({ 5-methyl-4-[(4R)-2-methyl-6,7-dihydro-4H-pyrano[4,3- d][l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( lR,2S,4R)-2-hydroxy-4-{ [5-({5-methyl-4-[(4S)-2-methyl-6,7-dihydro-4H-pyrano[4,3- d][l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl I-305a sulfamateor[(lR,2S,4R)-2-hydroxy-4-{ [5-({5-methyl-4-[(4R)-2-methyl-6,7-dihydro-4H-pyrano[4,3-Compound NameNo.d] [ 1 ,3]thiazol-4-yl]-2-thienyl } carbonyl)pyrimidin-4-yl]amino } cyclopentyljmethyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(4S)-2-methyl-6,7-dihydro-4H-pyrano[4,3- d]

[0001] thiazol-4-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamateI-305b or[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(4R)-2-methyl-6,7-dihydro-4H-pyrano[4,3- d] [ 1 ,3]thiazol-4-yl]-2-thienyl } carbonyl)pyrimidin-4-yl]amino } cyclopentyljmethyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lS)-7-chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl]-5- methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate1-306 and[(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl]-5- methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-2-rnethyl-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-307 and[(lR,2S,4R)-4-{[5-({4-[(lS)-7-ch]oro-2-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-307a or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-2-methyl- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-307b or[(lR,2S,4R)-4-{[5-({4-[(lS)-7-chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({4-[(lR)-2-methyl-2,3-dihydro-lH-isoindol-l-yl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino) cyclopentyljmethyl sulfamate1-308 and[(1 R,2S,4R)-2-hydroxy-4-{ [5-( {4-[( 1 S)-2-methyl-2,3-dihydro- lH-isoindol- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(8S)-2-methyl-5,6-dihydro-8H- imidazo[2,l-c][l,4]oxazin-8-yl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino}cyclopentyl]methyl sulfamate1-309 and[( 1 R,2S ,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[(8R)-2-methyl-5 ,6-dihydro-8H- imidazo[2, 1 -c] [ 1 ,4]oxazin-8-yl]-2-thienyl }carbonyI)pyrimidin-4- yl]amino}cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-6-chloro- 1 ,3-dihydro-2-benzofuran- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-310 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-6-chloro- 1 ,3-dihydro-2-benzof uran- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateCompound NameNo.[( IR.2S.4R) 4 { [5-( { 5-chloro-4- [( 1 R)-6-chloro- 1. diliydn) 2 ben / ol'uran- 1 -yI]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-310a or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-6-chloro- 1 ,3-dihydro-2-benzofuran- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]arnino}-2-hydroxycyclopentyl]methy] sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-6-chloro- 1 ,3-dihydro-2-benzofuran- 1 -yl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methy] sulfamate 1-310b or[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-6-chloro- 1 ,3-dihydro-2-benzofuran- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydiOxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(lR)-7-chloro-2-methy]-l,2,3,4-tetrahydroisoquino]in- l-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate1-31 la or[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)-7-chloro-2-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- l-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({5-chloro-4-[(lR)-7-chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin- l-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate1-31 lb or[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)-7-chloro-2-methyl- 1 ,2,3,4-tetrahydroisoquinolin- l-yl]-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[(lR,2S,4R)-4-{[5-({4-[(lR)-7-cyano-3,4-dihydi -lH-isochromen-l-yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydi xycyclopentyl]methyl sulfamate 1-313 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-cyano-3,4-dihydro- 1 H-i sochromen- 1 -yl]-5-methy]-2- thienyl}carbony])pyrimidin-4-yI]amino}-2-hydiOxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-8-chloro- 1 ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-314 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-8-chloro- 1 ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-8-chloro- 1 ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thienyl}carbony])pyrimidin-4-yl] amino} -2-hydroxycyclopentyl]methyl sulfamate 1-314a or[( lR,2S,4R)-4- { [5-( { 4-[( 1 S)-8-chloro- 1 ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( lR)-8-chloro-l ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thieny]}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methy] sulfamate 1-314b or[(lR,2S,4R)-4-{[5-({4-[(lS)-8-chloro-l,3,4,5-tetrahydro-2-benzoxepin-l-yl]-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydiOxycyclopentyl]methyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{[5-({5-methyl-4-[(4S)-2-(trifluoromethyl)-6,7-dihydro-4H- 1315 pyrano[3,4-d][l,3]thiazol-4-yl]-2-thienyl}carbonyl)pyrimidin-4- yl]amino}cyclopentyl]methyl sulfamateandCompound NameNo.[(lR,2S,4R)-2-hydroxy-4-{ [5-({5-methyl-4-[(4R)-2-(trifluoromethyl)-6J-dihydro-4H- pyrano[3,4-d][ l ,3]thiazol-4-yl]-2-thienyl }carbonyl)pyrimidin-4- yl] amino } cyclopentyl] methyl sulfamate[( 1 R,2S,4R)-4- { [5-({ 4-[( lR)-7-chloro-3,4-dihydro- 1 H-pyrano[4,3-c]pyridin- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate1-316 and[(lR,2S,4R)-4-{ [5-({4-[( l S)-7-chloro-3,4-dihydro- l H-pyrano[4,3-c]pyridin- l -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 R)-7-chloro- 1 -methyl-3 ,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-317 and[(1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro- 1 -methyl-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[(1 R,2S,4R)-2-hydroxy-4-{ [5-( (4-[(lR)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamate1-318 and[(lR,2S,4R)-2-hydroxy-4-{ [5-( { 4-[( 1 S)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 R)-2,3,4,5-tetrahydro- 1 H-2-benzazepin- 1 -yl]-2- thienyl }carbony])pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methy] sulfamate 1-319 and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-2,3,4,5-tetrahydro- 1 H-2-benzazepin- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isothiochromen- 1 -yl]-2- thienyl ) carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-320 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isothiochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isothiochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-320a or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-i sothiochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[( lR)-7-chloro-3,4-dihydro- 1 H-isothiochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate I-320b or[(1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isothiochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( lR)-7-chloro- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-321 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( lR)-5-chloro-2-methyl-2,3-dihydro- lH-isoindol- 1 -yl]-2- 1-322 thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateandName[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-5-chloro-2-methy]-2,3-dihydro- 1 H-isoindol- l-yl]-2- thienyl }carbony])pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-pyrano[4,3-c]pyridin- 1 yl]-2 hienyl }carbonyl)pynmidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate and[( 1 R,2S,4R)-4- { [5-( { 5-chloro-4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-pyrano[4,3-c]pyridin- 1 yl]-2-thieny] }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-cyano-4-[( 1 R)-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl] amino }-2-hydroxycyclopentyl]methyl sulfamate and[( 1 R,2S,4R)-4-{ [5-({ 5-cyano-4-[( 1 S)-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbony])pyrimidin-4-yl]amino }-2-hydiOxycyclopentyl]methyl sulfamate[(l R,2S,4R)-4-{ [5-({5-[( lR)-5-chloro-3,4-dihydro-l H-isochromen- l -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl] methyl sulfamate and[( 1 R,2S,4R)-4-{ [5-( { 5-[( 1 S)-5-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 R)-6-chloro-3-oxo- 1 ,3-dihydro-2-benzofuran- 1 -yl]- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate and[( 1 R,2S,4R)-4-{ [5-( { 5-chloro-4-[( 1 S)-6-chloro-3-oxo- 1 ,3-dihydro-2-benzofuran- 1 -yl]- 2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-( { 5-[(4- { ( 1 R)-7-[(dimethylamino)methyl]-3,4-dihydro- 1 H-isochromen- l -yl }-5-methyl-2-thienyl)carbonyl]pyrimidin-4-yl }amino)-2- hydroxycyclopentyl]methyl sulfamateand[( 1 R,2S,4R)-4-( { 5-[(4-{ ( 1 S)-7-[(dimethylamino)methyl]-3,4-dihydro- 1 H-isochromen- 1 yl } -5-methyl-2-thienyl)carbonyl]pyrimidin-4-yl } amino)-2-hydroxycyclopentyl]methyl sulfamate( 1 S,2R,4R)-4- { [5-( {4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- thienyl jcarbonyl)pyrimidin-4-yl]amino }-2-[(sulfamoyloxy)methyl]cyclopentyl aminoacetate[( l R,2S,4R)-4-{ [5-({4-[(5R)-8,8-difluoro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-yl]-5 methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamateand[( l R,2S,4R)-4-{ [5-( { 4-[(5S)-8,8-difluoro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-yl]-5 methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4- [(4S)-2-methyl-6,7-dihydro-4H-pyrazolo[5 , 1 - c][ l ,4]oxazin-4-yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamateand[(lR,2S,4R)-2-hydroxy-4-{ [5-({4-[(4R)-2-methyl-6,7-dihydro-4H-pyrazolo[5, l- c] [ 1 ,4]oxazin-4-yl]-2-thienyl } carbonyl)pyrimidin-4-yl] amino } cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4- { [5-( {4-[(4S)-3-methyl-6,7-dihydro-4H-pyrazolo[5, 1 - c][ l ,4]oxazin-4-yl]-2-thienyl)carbonyl)pyrimidin-4-yl]amino}cyclopenty]]methylCompound NameNo.sulfamateand[( lR,2S,4R)-2-hydroxy-4-{ [5-({4-[(4R)-3-methyl-6,7-dihydro-4H-pyrazolo[5, l- c] [ 1 ,4]oxazin-4-yl]-2-thienyl } carbonyl)pyrimidin-4-yl]amino } cyclopentyljmethyl sulfamatetert-butyl ( 1 R)-7-chl oro- 1 -(5- { [4-( { ( 1 R,3 S,4R)-3-hydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl }arnino)pyrimidin-5-yl]carbonyl }-3-thienyl)-3,4- dihydroi soquinoline-2( 1 H)-carboxylate1-334 andtert-butyl ( 1 S)-7-chloro- 1 -(5- { [4-( { ( 1 R,3S,4R)-3-hydroxy-4-[(sulfamoyloxy)methyl]cyclopenty] } amino)pyrimidin-5-yl]carbony] }-3-thienyl)-3,4- dihydroisoquinoline-2( lH)-carboxylate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate 1-335 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl]-2- thienyl }carbony])pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[( 1 R)-7-chloro- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl]-2- thieny] }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-335a or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[( lR)-7-chloro-l ,2,3,4-tetrahydronaphthalen- l -yl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate I-335b or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-7-chloro- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate tert-butyl ( 1 R)-7-chloro- 1 -(2-chloro-5- { [4-( { ( 1 R,3S,4R)-3-hydroxy-4- [(sulfamoyloxy)methyl]cyclopentyl } amino)pyrimidin-5-yl]carbonyl }-3-thienyl)-3,4- dihydroisoquinoIine-2(lH)-carboxylate1-336 andtert-butyl ( 1 S)-7-chloro- 1 -(2-chloro-5- { [4-( { ( 1 R,3S,4R)-3-hydroxy-4- [(sulfamoyloxy)methyl]cyclopentyl }amino)pyrimidin-5-yl]carbonyl }-3-thienyl)-3,4- dihydroisoquinoline-2( 1 H)-carboxylate[( l R,2S,4R)-2-hydroxy-4-{ [5-({5-methyl-4-[(8S)-2-(trifluoromethyl)-5,6-dihydro-8H- imidazo[2, 1 -c][ 1 ,4]oxazin-8-yl]-2-thienyl }carbonyl)pyrimidin-4- yl] amino } cyclopentyl] methyl sulfamate1-337 and[( l R,2S,4R)-2-hydroxy-4-{ [5-({5-methyl-4-[(8R)-2-(trifluoromethyl)-5,6-dihydro-8H- imidazo[2, l-c][l ,4]oxazin-8-yl]-2-thienyl }carbonyl)pyrimidin-4- yl]amino }cyclopentyl]methyl sulfamate( 1 S,2R,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- 1-338 thienyl}carbonyl)pyrimidin-4-yl]amino}-2-[(su]famoyloxy)methyl]cyclopentyl (2S)-2- amino-3-methylbutanoate[(lR,2S,4R)-2-hydroxy-4-{ [5-( {4-[(8S)-2-methoxy-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl1-339sulfamateandCompound NameNo.[(l R,2S,4R)-2-hydroxy-4-{ [5-({4-[(8R)-2-methoxy-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4-{ [5-( { 4-[(8S)-2-methoxy-5,8-dihydro-6H-pyrano[3 ,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamateI-339a or[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[(8R)-2-methoxy-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]rnethyl sulfamate[(lR,2S,4R)-2-hydroxy-4-{ [5-({ 4-[(8S)-2-methoxy-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamateI-339b or[( lR,2S,4R)-2-hydroxy-4-{ [5-({4-[(8R)-2-methoxy-5,8-dihydro-6H-pyrano[3,4- b]pyridin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4-{ [5-( { 4-[( lR)-7-methoxy-3,4-dihydro- 1 H-isochromen- 1 -yl]- 5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino } cyclopentyl]methyl sulfamate 1-341 and[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[( 1 S)-7-methoxy-3,4-dihydro- 1 H-isochromen- 1 -yl]- 5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( lR,2S,4R)-2-hydroxy-4-{ [5-({4-[( 1 R)-4-oxo-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl] methyl sulfamate1-342 and[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 4-[( 1 S)-4-oxo-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 5-[( lR)-8-chloro-l ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-343a or[( 1 R,2S,4R)-4-{ [5-( { 5-[( 1 S)-8-chloro- 1 ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 5-[( 1 R)-8-chloro- 1 ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl]methyl sulfamate I-343b or[( 1 R,2S,4R)-4- { [5-( { 5-[( 1 S)-8-chloro- 1 ,3,4,5-tetrahydro-2-benzoxepin- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-3,4-dihydro- 1 H-[ 1 ,4]oxazino[4,3-a]benzimidazol- 1 -yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyc]opentyl]methyl sulfamate1-344 and[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-3,4-dihydro- 1 H-[ 1 ,4]oxazino[4,3-a]benzimidazol- l-yl]-5- methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate( 1 S,2R,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- 1-345 thienyl} carbonyl)pyrimidin-4-yl]amino }-2-[(sulfamoyloxy)methyl]cyclopentyl 3-[(phosphonooxy)methyljbenzoate1-346 [(lR,2S,4R)-4-{ [5-({4-[( lR)-7-ethyl-3,4-dihydro- lH-isochromen- l-yl]-5-methyl-2-Name thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate and[( lR,2S,4R)-4-{ [5-({ 4-[( 1 S)-7-ethyl-3,4-dihydro- 1 H-isochromen-1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-2-hydroxy-4-{ [5-( { 5-methyl-4-[( 1 R)-7-methyl-3,4-dihydro- 1 H- isochromen- l -yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino}cyclopentyl]methyl sulfamateand[( 1 R,2S,4R)-2-hydroxy-4- { [5-( { 5-methyl-4-[( 1 S)-7-methyl-3,4-dihydro- 1 H- isochromen-l -yl]-2-thienyl }carbonyl)pyrimidin-4-yl]amino} cyclopentyl]methyl sulfamate[( l R,2S,4R)-2-hydroxy-4-{ [5-({ 5-methyl-4-[(8R)-2-(pyrrolidin- l -yl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-8-yl]-2-thienyl }carbonyl)pyrimidin-4- yl]amino}cyclopentyl]methyl sulfamateand[( 1 R,2S,4R)-2-hydroxy-4- { [5-({ 5-methyl-4-[(8S)-2-(pyrrolidin- 1 -yl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-8-yl]-2-thieny] } carbonyl)pyrimidin-4- yl]amino }cyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-({ 4-[( 1 R)-6-chloro-2,3-dihydro- 1 H-inden- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydiOxycyclopentyl]methyl sulfamate and[( 1 R,2S,4R)-4-{ [5-( {4-[( 1 S)-6-chloro-2,3-dihydro- 1 H-inden- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-y]]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-6-chloro-2,3-dihydro- 1 H-inden- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate or[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 S)-6-chloro-2,3-dihydro- 1 H-inden- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[( I R)-6-chloro-2,3-dihydro- 1 H-inden- 1 -y]]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate or[( 1 R,2S,4R)-4-{ [5-({4-[( 1 S)-6-chloro-2,3-dihydro- 1 H-inden- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( lR,2R,3S,4R)-4-({5-[(5-benzyl-l ,3-thiazol-2-yl)carbonyl]pyrimidin-4-yl }amino)-2,3--350dihydroxycyclopentyljmethyl sulfamate{ ( 1 R,2S,4R)-2-hydroxy-4-[(5- { [4-(3-methylbenzyl)- 1 ,3-thiazol-2--351yl]carbonyl }pyrimidin-4-yl)amino]cyclopentyl }methyl sulfamate{ ( 1 R,2R,3S,4R)-4-[(5- { [4-(3-chlorobenzyl)-5-methyl- 1 ,3-thiazol-2--352yl]carbonyl }pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl ) methyl sulfamate{ ( 1 R,2S,4R)-4-[(5- { [4-(3-chlorobenzyl)-5-methyl- 1 ,3-thiazol-2-yl]carbonyl } pyrimidin--3534-yl)amino]-2-hydroxycyclopentyl }methyl sulfamate{ ( lR,2R,3S,4R)-4-[(5- { [4-(3-bromobenzyl)-5-methyl- 1 ,3-thiazol-2--354yl]carbonyl }pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl} methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl-l ,3-thiazol-2- yl } carbonyl)pyri mi din-4-yl] amino } -2-hydroxycyclopentyl]methyl sulfamate and[( lR,2S,4R)-4-{ [5-({4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl-l ,3-thiazol-2-Compound NameNo.yl } carbonyl)pyrimidin-4-yl]amino } -2-hydroxycyclopentyl] methyl sulfamate[( lR,2S,4R)-4-{ [5-({4-[(R)-(3-chlorophenyl)(hy^yl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI-355a or[( 1 R,2S,4R)-4- { [5-( { 4-[(S)-(3-chloropheny])(hydroxy)methyl]-5-methyl- 1 ,3-thiazol-2- yl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[(R)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl- 1 ,3-thiazol-2- yl }carbonyl)pyrimidin-4-yl]amino )-2-hydi xycyclopentyl]methy] sulfamateI-355b or[( lR,2S,4R)-4-{ [5-({ 4-[(S)-(3-chlorophenyl)(hydroxy)methyl]-5-methyl- l ,3-thiazol-2- yl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4-{ [5-( { 4-[(8R)-2,3-dimethyl-5,6-dihydro-8H-imidazo[2, 1 -c] [ 1 ,4]oxazin- 8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl]methyl sulfamate1-356 and[( l R,2S,4R)-4-{ [5-({ 4-[(8R)-2,3-dimethyl-5,6-dihydro-8H-imidazo[2, l-c][ l ,4]oxazin-8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl] methyl sulfamate[( lR,2S,4R)-4-{ [5-( { 4-[(8R)-2,3-dimethyl-5,6-dihydro-8H-imidazo[2, l -c][ l ,4]oxazin- 8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyljmethyl sulfamateI-356a or[( lR,2S,4R)-4-{ [5-( { 4-[(8R)-2,3-dimethy]-5,6-dihydro-8H-imidazo[2, 1 -c] [ 1 ,4]oxazin- 8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl]methyl sulfamate[( lR,2S,4 )-4-{ [5-( {4-[(8R)-2,3-dimethyl-5,6-dihydro-8H-imidazo[2, l -c][ l ,4]oxazin- 8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino } -2- hydroxycyclopentyljmethyl sulfamateI-356b or[( 1 R,2S,4R)-4-{ [5-( { 4-[(8R)-2,3-dimethyl-5,6-dihydro-8H-imidazo[2, 1 -c][ 1 ,4]oxazin- 8-yl]-5-methyl-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-6-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-357 and[( lR,2S,4R)-4-{ [5-({4-[( 1 S)-6-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate{ ( lR,2S,4R)-4-[(5-{ [4-(7-chloroisoquinolin- 1 -yl)-5-methyl-2-1-358thienyl]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl } methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-6-chloro- 1 ,3-dihydro-2-benzothiophen- 1 -yl]-5-methyl-2- thienyl }carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate I-359a or[( 1 R,2S,4R)-4- { [5-( {4-[( 1 S)-6-chloro- 1 ,3-dihydro-2-benzothiophen- 1 -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-6-chloro-l ,3-dihydro-2-benzothiophen- 1 -yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamateI-359bor[( 1 R,2S,4R)-4- { [5-({ 4-[( 1 S)-6-chloro- 1 ,3-dihydro-2-benzothiophen- 1 -yl]-5-methyl-2-Compound NameNo.thienyl } carbonyl)pyrimidin-4-yl] amino } -2-hydroxycyclopentyl] methyl sulfamate j360{ ( 1 R,2S,4R)-4-[(5- { [4-(7-chloro-3,4-dihydroisoquinolin- 1 -yl)-5-methyl-2- thienyl]carbonyl }pyrimidin-4-yl)amino]-2-hydroxycyclopentyl }methyl sulfamate[(lR,2S,4R)-4-{ [5-({4-[( l R)-7-chloro-3,4-dihydro-l H-isochromen- l-yl]-5- (difluoromethyl)-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyl]methyl sulfamate1-361 and[( 1 R,2S,4R)-4- { [5-( {4-[( 1 S)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5- (difluoromethyl)-2-thienyl }carbonyl)pyrimidin-4-yl]amino }-2- hydroxycyclopentyljmethyl sulfamate( 1 S,2R,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- 1-362 thienyl } carbonyl)pyrimidin-4-yl]amino } -2-[(sulfamoyloxy)methyl]cyclopenty] (2S)-2- aminopropanoate( 1 S,2R,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- 1-363 thienyl } carbonyl)pyrimidin-4-yl]amino }-2-[(sulfamoyloxy)methyl]cyclopentyl (2S,3S)-2-amino-3-methylpentanoate( 1 S,2R,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-5-methyl-2- 1-364 thienyl }carbonyl)pyrimidin-4-yl]amino }-2-[(sulfamoyloxy)methyl]cyclopentyl [4-(phosphonooxy)phenyl]acetate[( 1 R,2S ,4R)-4- { [5-( { 4-[( 1 R)-8-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl }carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate 1-365 and[( 1 R,2S,4R)-4-{ [5-({4-[( lS)-8-chloro-3,4-dihydro- 1 H-isochromen- 1 -yl]-2- thienyl } carbonyl)pyrimidin-4-yl]amino }-2-hydroxycyclopentyl]methyl sulfamate[( 1 R,2S,4R)-4- { [5-( { 4-[( 1 R)-7-chloro-3,4-dihydro- 1 H-i sochromen- 1 -yl]-5- (hydroxymethyl)-2-thienyl }carbonyl)pyrimidin-4-yl](methyl)amino } -2- hydroxycyclopentyl]methyl sulfamate1-366 and[( l R,2S,4R)-4-{ [5-({4-[( l S)-7-chloro-3,4-dihydro- l H-isochromen- l -yl]-5- (hydroxymethyl)-2-thienyl }carbonyl)pyrimidin-4-yl](methyl)amino } -2- hydroxycyclopentyl]methyl sulfamate

[0185] It will be appreciated that the chemical entities of this disclosure may be derivatized at functional groups to provide prodrug derivatives which are capable of conversion back to the parent chemical entities in vivo. Examples of such prodrugs include the physiologically acceptable and metabolically labile derivatives. More specifically, the prodrug of the chemical entity of this disclosure is an ether or ester of the -OH group of the chemical entity. Prodrugs according to this disclosure include those in which Rbis -C(0)-Rbx, wherein Rbxhas the values described herein, as discussed above. Furthermore, various approaches for providing prodrugs are known to those skilled in the art, as described in, e.g., Li et al., "Prodrugs of Nucleoside Analogues for Improved Oral Absorption and Tissue Targeting," J. Phann. Sci. 97, 1 109-34 (2008); Rautio et al., "Prodrugs: designand clinical applications," Nat. Rev. Drug Discovery 7, 255-270 (2008); and Rautio, Prodrugs and Targeted Deliver}', Wiley- VCH (201 1) (ISBN- 10: 3527326030).

[0186] As used herein, "crystalline" refers to a solid in which the constituent atoms, molecules, or ions are packed in a regularly ordered, repeating three-dimensional pattern having a highly regular chemical structure. In particular, a crystalline compound or salt might be produced as one or more crystalline forms. For the purposes of this application, the terms "crystalline form" and "polymorph" are synonymous; the terms distinguish between crystals that have different properties (e.g., different XRPD patterns, different DSC scan results). Pseudopolymorphs are typically different solvates of a material, and thus the properties of pseudopolymorphs differ from one another. Thus, each distinct polymorph and pseudopolymorph is considered to be a distinct crystalline form herein.

[0187] "Substantially crystalline" refers to compounds or salts that are at least a particular weight percent crystalline. In some embodiments, the compound or salt is substantiallycrystalline. Examples of a crystalline form or substantially crystalline form include a single crystalline form or a mixture of different crystalline forms. Particular weight percentages include 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%. In some embodiments, substantially crystalline refers to compounds or salts that are at least 70% crystalline. In some embodiments, substantially crystalline refers to compounds or salts that are at least 80% crystalline. In some embodiments, substantially crystalline refers to compounds or salts that are at least 85% crystalline. In some embodiments, substantially crystalline refers to compounds or salts that are at least 90% crystalline. In some embodiments, substantially crystalline refers to compounds or salts that are at least 95% crystalline.

[0188] The term "hydrate" includes, for example, hemihydrates, monohydrates, sesquihydrates, dihydrates, and trihydrates. In some embodiments, a hydrate, such as a sesquihydrate, may be prepared by crystallization of a chemical entity disclosed herein from ethanol / distilled water. In some embodiments, a hydrate may be prepared by crystallization of a chemical entity disclosed herein from aqueous 50 mM citrate buffer at about pH 4.5.

[0189] The term "seeding" refers to the addition of crystalline material to a solution or mixture to initiate crystallization.

[0190] Some embodiments are directed to compounds or salts wherein at least a particular percentage by weight of the compound or salt is crystalline. Some embodiments are directed to a compound or salt wherein at least a particular percentage by weight of the compound or salt is crystalline. Particular weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%), 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and99.9%. When a particular percentage by weight of the compound or salt is crystalline, the remainder of the compound or salt is the amorphous form of the compound or salt. When a particular percentage by weight of the compound or salt is a designated crystalline form, the remainder of the compound orsalt is some combination of the amorphous form of the compound or salt, and one or more crystalline forms of the compound or salt excluding the designated crystalline form.

[0191] When a crystalline form of a compound or salt is identified using one or more temperatures from a DSC profile (e.g., onset of endothermic transition, melt, etc.), each of the temperature values is understood to mean the given value ± 2 °C.

[0192] When a crystalline form of a compound or salt is identified using one or more peaks from a raman pattern expressed as cm"1, it is understood to mean the given value ± 0.2 cm"1, unless otherwise expressed.

[0193] Solid state forms ofI-257b. Provided herein is an assortment of characterizing information, which is sufficient, but not all of which is necessary, to describe crystalline Form 1 anhydrous compound 1-257 ("I-257b Form 1").

[0194] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of Form 1 of compound I- 257b obtained using CuAOc radiation. Peaks identified in Figure 1 include those listed in the table below.

[0195] In some embodiments, I-257b Form 1 is characterized by an XRPD pattern having a peak at 2Θ angle 25.2°. In some embodiments, I-257b Form 1 is characterized by an XRPD pattern having peaks at 2Θ angles of 25.2° and 18.6°. In some embodiments, I-257b Form 1 is characterized by anXRPD pattern having peaks at 2Θ angles of 25.2°, 21.7°, 18.6°, and 14.5°. In some embodiments, I- 257b Form 1 is characterized by an XRPD pattern having peaks at 2Θ angles of 25.2°, 21.7°, 18.6°, 14.5°, 22.6°, 20.7° and 27.9°. In some embodiments, I-257b Form 1 is characterized by an XRPD pattern having peaks at 2Θ angles of 25.2°, 21.7°, 18.6°, 14.5°, 22.6°, 20.7°, 27.9°, 24.0°, 19.1 °, 25.8° and 21.4°. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.1 °. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.2°. In some embodiments, the 2Θ angles given above have an error tolerance of +0.3°. In some embodiments, I-257b Form 1 is characterized by an XRPD pattern substantially as shown in Figure 1.

[0196] In some embodiments, I-257b Form 1 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 14.5 ± 0.3°, and having peaks at 2Θ angles of 4. , 7.2°, and 10.7° relative to the reference peak. The term "reference peak" refers to a peak in the XRPD diffractogram that one skilled in the art considers as informing the polymorphic form of the material, i.e. , differentiated from instrument noise. By "relative" it is meant that the observed 2Θ angle of each peak will be the sum of the 2Θ angle of the reference peak and the relative 2Θ angle of that peak. For example, if the reference peak has a 2Θ angle of 14.2°, the relative peaks will have 2Θ angles of 18.3°, 21.4°, and 24.9°; if the reference peak has a 2Θ angle of 14.3°, the relative peaks will have 2Θ angles of 18.4°, 21.5°, and 25.0°; if the reference peak has a 2Θ angle of 14.4°, the relative peaks will have 2Θ angles of 18.5°, 21.6°, and 25.1 °; etc. In some embodiments, I-257b Form 1 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 14.5 ± 0.3°, and having peaks at 2Θ angles of 4. Γ, 6.2°, 7.2°, 8.1°, 10.7°, and 13.4° relative to the reference peak. In some embodiments, I-257b Form 1 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 14.5 ± 0.3°, and having peaks at 2Θ angles of 4. Γ, 4.6°, 6.2°, 6.9°, 7.2°, 8.1°, 9.5°, 10.7°, 1 1.3°, and 13.4° relative to the reference peak. Any of the peaks that one skilled in the art considers as informing the polymorphic form of the material can serve as the reference peak and the relative peaks can then be calculated. For example, if the reference peak has a 2Θ angle of 25.2°, then the relative peaks will have 2Θ angles of -3.5°, -6.6°, and - 10.7° relative to the reference peak.

[0197] In some embodiments, the chemical entity according to the disclosure is or comprises substantially crystalline I-257b Form 1. In some embodiments, the chemical entity according to the disclosure comprises at least 70% by weight crystalline I-257b Form 1. In some embodiments, the chemical entity according to the disclosure comprises at least 80% by weight crystalline I-257b Form 1. In some embodiments, the chemical entity according to the disclosure comprises at least 90% by weight crystalline I-257b Form 1. In some embodiments, the chemical entity according to the disclosure comprises at least 95% by weight crystalline I-257b Form 1 .

[0198] FIG. 8 shows a differential scanning calorimetry (DSC) profile of I-257b Form 1. The DSC thermogram plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C / min. In some embodiments, I-257b Form 1 is characterized by a DSC profile substantially as shown in FIG. 8. FIG. 8 shows an endotherm event with onset of about 57.8°C and peak at about 83.2 °C. FIG. 8 also shows an endotherm event with onset of about 135.0 °C and peak at about 143.8 °C. In some embodiments, I-257b Form 1 is characterized by a DSC profile having an endotherm event with onset of about 57.8 °C. In some embodiments, I-257b Form 1 is characterized by a DSC profile having an endotherm event with peak at about 83.2 °C. In some embodiments, I-257b Form 1 is characterized by a DSC profile having an endotherm event with onset of about 135.0 °C. In some embodiments, I-257b Form 1 is characterized by a DSC profile having an endotherm event with peak at about 143.8 °C.

[0199] FIG. 9 shows a thermal gravimetric analysis (TGA) profile of I-257b Form 1. The TGA thermogram plots the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C / min. FIG. 9 shows approximately 2.7 % weight loss to 79.5 °C. In some embodiments, I-257b Form 1 is characterized by a TGA profile substantially as shown in FIG. 9. In some embodiments, I-257b Form 1 is characterized by a TGA profile having about 2.7 % weight loss to 79.5°C.

[0200] FIG. 10 shows a raman pattern of I-257b Form 1 including data in the region of 500 cm" 1to 3000 cm"' . In some embodiments, I-257b Form 1 is characterized by a raman pattern substantially as shown in FIG. 10. FIG. 1 1 shows a raman pattern of I-257b Form 1 including data in the region of 200 cm" 1to 1600 cm"1. In some embodiments, I-257b Form 1 is characterized by a raman pattern substantially as shown in FIG. 1 1.

[0201] In some embodiments, I-257b Form 1 is characterized by a raman pattern with a peak at 1450 cm"1. In some embodiments, I-257b Form 1 is characterized by a raman pattern with a peak at 1572 cm"' . In some embodiments, I-257b Form 1 is characterized by a raman pattern with a peak at 1422 cm"' . In some embodiments, I-257b Form 1 is characterized by a raman pattern with a peak at 754 cm"1. In some embodiments, I-257b Form 1 is characterized by a raman pattern with a peaks at 1450, 1572, 1422, and 754 cm"1. In some embodiments, I-257b Form 1 is characterized by a raman pattern with a peaks at 1450, 1572, and 1422 cm"1. In some embodiments, I-257b Form 1 is characterized by a raman pattern with a peaks at 1450 and 1572 cm"' .

[0202] In some embodiments, I-257b Form 1 is characterized by at least one of the following features (I-i)-(I-v):(I-i) an XRPD pattern having peaks at 2Θ angles of 25.2°, 21.7°, 18.6°, and 14.5°;(I-ii) a DSC profile substantially as shown in FIG. 8;(I-iii) a TGA profile substantially as shown in FIG. 9;(I-iv) a raman pattern substantially as shown in FIG. 10;(I-v) a raman pattern substantially as shown in FIG. 1 1.

[0203] In some embodiments, I-257b Form 1 is characterized by at least two of the features (I-i)- (I-v). In some embodiments, I-257b Form 1 is characterized by at least three of the features (I-i)-(I-v). In some embodiments, I-257b Form 1 is characterized by at least four of the features (I-i)-(I-v). In some embodiments, I-257b Form 1 is characterized by all five of the features (I-i)-(I-v).

[0204] Solid state forms ofI-263a. Provided herein is an assortment of characterizing information, which is sufficient, but not all of which is necessary, to describe crystalline Form 1 anhydrous compound I-263a ("I-263a Form 1 ").

[0205] Figure 2 shows an X-ray powder diffraction (XRPD) pattern of Form 1 of compound I- 263a obtained using CuKa radiation. Peaks identified in Figure 2 include those listed in the table below.

[0206] In some embodiments, I-263a Form 1 is characterized by an XRPD pattern having a peak at 2Θ angle 21.6°. In some embodiments, I-263a Form 1 is characterized by an XRPD pattern having peaks at 2Θ angles of 21.6° and 19.5°. In some embodiments, I-263a Form 1 is characterized by an XRPD pattern having peaks at 2Θ angles of 21.6°, 19.5°, 18.9°, and 27.2°. In some embodiments, I- 263a Form 1 is characterized by an XRPD pattern having peaks at 2Θ angles of 21.6°, 19.5°, 18.9°, 27.2°, 26.3°, 15. , and 23.5°. In some embodiments, I-263a Form 1 is characterized by an XRPD pattern having peaks at 2Θ angles of 21.6°, 19.5°, 18.9°, 27.2°, 26.3°, 15.1 °, 23.5°, 16.3°, 17.0°, 28.8°,and 9.7°. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.1 °. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.2°. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.3°. In some embodiments, I-263a Form 1 is characterized by an XRPD pattern substantially as shown in Figure 2.

[0207] In some embodiments, I-263a Form 1 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 18.9 ± 0.3°, and having peaks at 2Θ angles of 0.6°, 2.7°, and 8.3° relative to the reference peak. The term "reference peak" refers to a peak in the XRPD diffractogram that one skilled in the art considers as informing the polymorphic form of the material, i.e., differentiated from instrument noise. By "relative" it is meant that the observed 2Θ angle of each peak will be the sum of the 2Θ angle of the reference peak and the relative 2Θ angle of that peak. For example, if the reference peak has a 2Θ angle of 18.6°, the relative peaks will have 2Θ angles of 19.2°, 21.3°, and 26.9°; if the reference peak has a 2Θ angle of 18.7°, the relative peaks will have 2Θ angles of 19.3°, 21.4°, and 27.0°; if the reference peak has a 26 angle of 18.8°, the relative peaks will have 2Θ angles of 19.4°, 21.5°, and 27.1 °; etc. In some embodiments, I-263a Form 1 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 18.9 ± 0.3°, and having peaks at 2Θ angles of -3.8°, 0.6°, 2.7°, 4.6°, 7.4°, and 8.3° relative to the reference peak. In some embodiments, I-263a Form 1 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 18.9 ± 0.3°, and having peaks at 2Θ angles of -9.2°, -3.8°, -2.6°, - 1.9°, 0.6°, 2.7°, 4.6°, 7.4°, and 8.3° and 9.9° relative to the reference peak. Any of the peaks that one skilled in the art considers as informing the polymorphic form of the material can serve as the reference peak and the relative peaks can then be calculated. For example, if the reference peak has a 2Θ angle of 21 .6°, then the relative peaks will have 2Θ angles of -2.7°, -2.1°, and 5.6° relative to the reference peak.

[0208] In some embodiments, the chemical entity according to the disclosure is or comprises substantially crystalline I-263a Form 1. In some embodiments, the chemical entity according to the disclosure comprises at least 70% by weight crystalline I-263a Form 1. In some embodiments, the chemical entity according to the disclosure comprises at least 80% by weight crystalline I-263a Form 1. In some embodiments, the chemical entity according to the disclosure comprises at least 90% by weight crystalline I-263a Form 1. In some embodiments, the chemical entity according to the disclosure comprises at least 95% by weight crystalline I-263a Form 1.

[0209] FIG. 4 shows a differential scanning calorimetry (DSC) profile of I-263a Form 1. The DSC thermogram plots the heat flow as a function of temperature from a sample, the temperature rate change being about 10 °C / min. In some embodiments, I-263a Form 1 is characterized by a DSC profile substantially as shown in FIG. 4. FIG. 4 shows an endotherm event with onset of about 179.4 °C and peak at about 184.0 °C. FIG. 4 also shows an exotherm event with onset of about 279.0 °C and peak at about 282.4 °C. In some embodiments, I-263a Form 1 is characterized by a DSC profile having an endotherm event with onset of about 179.4 °C. In some embodiments, I-263a Form 1 is characterized by a DSC profile having an endotherm event with peak at about 184.0 °C. In someembodiments, I-263a Form 1 is characterized by a DSC profile having an exotherm event with onset of about 279.0 °C. In some embodiments, I-263a Form 1 is characterized by a DSC profile having an exotherm event with peak at about 282.4 °C.

[0210] FIG. 5 shows a thermal gravimetric analysis (TGA) profile of I-263a Form 1. The TGA thermogram plots the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C / min. FIG. 5 shows approximately 0.9 % weight loss to 170.4°C. In some embodiments, I-263a Form 1 is characterized by a TGA profile substantially as shown in FIG. 5. In some embodiments, I-263a Form 1 is characterized by a TGA profile having about 0.9 % weight loss to 170.4°C.

[0211] FIG. 6 shows a raman pattern of I-263a Form 1 including data in the region of 500 cm"1to 3000 cm"1. In some embodiments, I-263a Form 1 is characterized by a raman pattern substantially as shown in FIG. 6. FIG. 7 shows a raman pattern of I-263a Form 1 including data in the region of 200 cm"1to 1600 cm". In some embodiments, I-263a Form 1 is characterized by a raman pattern substantially as shown in FIG. 7.

[0212] In some embodiments, I-263a Form 1 is characterized by a raman pattern with a peak at 1441 cm"1. In some embodiments, I-263a Form 1 is characterized by a raman pattern with a peak at 1604 cm"1. In some embodiments, I-263a Form 1 is characterized by a raman pattern with a peak at 1583 cm"1. In some embodiments, I-263a Form 1 is characterized by a raman pattern with a peak at 1381 cm"1. In some embodiments, I-263a Form 1 is characterized by a raman pattern with a peaks at 1441 , 1604, 1583, and 1381 cm"' . In some embodiments, I-263a Form 1 is characterized by a raman pattern with a peaks at 1441 , 1604, and 1583 cm"1. In some embodiments, I-263a Form 1 is characterized by a raman pattern with a peaks at 1441 and 1604 cm" 1.

[0213] In some embodiments, I-263a Form 1 is characterized by at least one of the following features (I-i)-(I-v):(I-i) an XRPD pattern having peaks at 2Θ angles of 21.6°, 19.5°, 18.9°, and 27.2°;(I-ii) a DSC profile substantially as shown in FIG. 4;(I-iii) a TGA profile substantially as shown in FIG. 5;(I-iv) a raman pattern substantially as shown in FIG. 6;(I-v) a raman pattern substantially as shown in FIG. 7.

[0214] In some embodiments, I-263a Form 1 is characterized by at least two of the features (I-i)- (I-v). In some embodiments, I-263a Form 1 is characterized by at least three of the features (I-i)-(I-v). In some embodiments, I-263a Form 1 is characterized by at least four of the features (I-i)-(I-v). In some embodiments, I-263a Form 1 is characterized by all five of the features (I-i)-(I-v).

[0215] In some embodiments, the chemical entity I-263a is a hydrate. In some embodiments, the chemical entity I-263a is a sesquihydrate. In some embodiments, the chemical entity I-263a is a hydrate comprising between 2 and 3 equivalents of H20.

[0216] I-263a Form 2. Provided herein is an assortment of characterizing information, which is sufficient, but not all of which is necessary, to describe crystalline Form 2 sesquihydrate compound I- 263a ("I-263a Form 2"). I-263a Form 2 may be prepared by crystallization of I-263a from a solvent system containing water (e.g., distilled water) and an organic solvent such as methanol, ethanol, isopropyl alcohol, acetonitrile, formamide, or 1 ,4-dioxane.

[0217] Figure 14 shows an X-ray powder diffraction (XRPD) pattern of I-263a Form 2 of obtained using CuKa radiation. Peaks identified in Figure 14 include those listed in the table below.

[0218] In some embodiments, I-263a Form 2 is characterized by an XRPD pattern having a peak at 2Θ angle 19.0°. In some embodiments, I-263a Form 2 is characterized by an XRPD pattern having peaks at 2Θ angles of 19.0° and 13.0°. In some embodiments, I-263a Form 2 is characterized by an XRPD pattern having peaks at 2Θ angles of 19.0°, 13.0°, 22.0° and 3. Γ. In some embodiments, I- 263a Form 2 is characterized by an XRPD pattern having peaks at 2Θ angles of 19.0°, 13.0°, 22.0°, 3. Γ, 27.1 °, 10.9° and 22.4°. In some embodiments, I-263a Form 2 is characterized by an XRPD pattern having peaks at 2Θ angles of 19.0°, 13.0°, 22.0°, 3. P, 27.1 °, 10.9°, 22.4°, 26.2°, 1 1.9°, 25. Γ and 21.1 °. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.1 °. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.2°. In some embodiments, the2Θ angles given above have an error tolerance of ±0.3°. In some embodiments, I-263a Form 2 is characterized by an XRPD pattern substantially as shown in Figure 14.

[0219] In some embodiments, I-263a Form 2 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 3.1 ± 0.3°, and having peaks at 2Θ angles of 9.9°, 15.9° and 18.9° relative to the reference peak. The term "reference peak" refers to a peak in the XRPD diffractogram that one skilled in the art considers as informing the polymorphic form of the material, i.e. , differentiated from instrument noise. By "relative" it is meant that the observed 2Θ angle of each peak will be the sum of the 2Θ angle of the reference peak and the relative 2Θ angle of that peak. For example, if the reference peak has a 2Θ angle of 2.8°, the relative peaks will have 2Θ angles of 12.7°, 18.7° and 21.7°; if the reference peak has a 2Θ angle of 2.9°, the relative peaks will have 2Θ angles of 12.8°, 18.8° and 21.8°; if the reference peak has a 2Θ angle of 3.0°, the relative peaks will have 2Θ angles of 12.9°, 18.9° and 21.9°; etc. In some embodiments, I-263a Form 2 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 3.1 ± 0.3°, and having peaks at 2Θ angles of 7.8°, 9.9°, 15.9°, 18.9°, 19.3° and 24.0° relative to the reference peak. In some embodiments, I-263a Form 2 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 3.1 ± 0.3°, and having peaks at 2Θ angles of 7.8°, 8.8°, 9.9°, 15.9°, 18.0°, 18.9°, 19.3°, 22.0°, 23. and 24.0° relative to the reference peak. Any of the peaks that one skilled in the art considers as informing the polymorphic form of the material can serve as the reference peak and the relative peaks can then be calculated. For example, if the reference peak has a 2Θ angle of 19.0°, then the relative peaks will have 2Θ angles of - 15.9°, -6.0° and 3.0° relative to the reference peak.

[0220] Karl Fischer measurements of I-263a Form 2 show a water content of about 4.8%. A thermal gravimetric analysis (TGA) profile of I-263a Form 2 can show that the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C / min, is approximately 5 % weight loss to 50.7°C. The TGA profile can also show that the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C / min, is approximately 10.1 % weight loss to 252.8°C. A differential scanning calorimetry (DSC) profile of I-263a Form 2 can show the following regarding the heat flow as a function of temperature from a sample of I-263a Form 2, the temperature rate change being about 10 °C / min. In some embodiments, I-263a Form 2 is characterized by an endotherm event with a peak at about 47.7 °C. In some embodiments, I-263a Form 2 is characterized by an endotherm event with a peak at about 60.7 °C. In some embodiments, I-263a Form 2 is characterized by an endotherm event with a peak at about 73.8 °C. In some embodiments, I-263a Form 2 is characterized by an exotherm event with a peak at about 132.9 °C. In some embodiments, I-263a Form 2 is characterized by an exotherm event with a peak at about 149.3 °C.

[0221] In some embodiments, I-263a Form 2 is characterized by at least one of the following features (I-i)-(I-iv):(I-i) an XRPD pattern having peaks at 2Θ angles of 3.1 °, 13.0°, 19.0°, and 22.0° as shown in FIG. 14;(I-ii) a DSC profile characterized by at least two of an endotherm event with a peak at about 47.7 °C, an endotherm event with a peak at about 60.7 °C, an endotherm event with a peak at about 73.8 °C, an exotherm event with a peak at about 132.9 °C, and an exotherm event with a peak at about 149.3 °C; (I-iii) a TGA profile characterized by at least one of approximately 5 % weight loss to 50.7°C and approximately 10.1 % weight loss to 252.8°C(I-iv) a water content of about 4.8% according to Karl Fischer measurements.

[0222] In some embodiments, I-263a Form 2 is characterized by at least two of the features (I-i)- (I-iv). In some embodiments, I-263a Form 2 is characterized by at least three of the features (I-i)-(I- iv). In some embodiments, I-263a Form 2 is characterized by all four of the features (I-i)-(I-iv).

[0223] I-263a Form 3. Provided herein is an assortment of characterizing information, which is sufficient, but not all of which is necessary, to describe crystalline Form 3 hydrate compound I-263a ("I-263a Form 3")- I-263a Form 3 may be prepared by crystallization of I-263a from aqueous 50 mM citrate buffer at about pH 4.5.

[0224] Figure 15 shows an X-ray powder diffraction (XRPD) pattern of I-263a Form 3 of obtained using CuAOi radiation. Peaks identified in Figure 15 include those listed in the table below.25.4 25.6%27.2 13.2%

[0225] In some embodiments, I-263a Form 3 is characterized by an XRPD pattern having a peak at 2Θ angle 15.6°. In some embodiments, I-263a Form 3 is characterized by an XRPD pattern having peaks at 2Θ angles of 15.6° and 16.2°. In some embodiments, I-263a Form 3 is characterized by an XRPD pattern having peaks at 2Θ angles of 15.6°, 16.2°, 18.0° and 20.0°. In some embodiments, I- 263a Form 3 is characterized by an XRPD pattern having peaks at 2Θ angles of 15.6°, 16.2°, 18.0°, 19.2°, 20.0°, 22.3°, and 23.1 °. In some embodiments, I-263a Form 3 is characterized by an XRPD pattern having peaks at 2Θ angles of 15.6°, 16.2°, 18.0°, 19.2°, 20.0°, 22.3°, 23.1 °, 20.3°, 20.7°, 21.8°, and 25.4°. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.1 °. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.2°. In some embodiments, the 2Θ angles given above have an error tolerance of ±0.3°. In some embodiments, I-263a Form 3 is characterized by an XRPD pattern substantially as shown in Figure 14.

[0226] In some embodiments, I-263a Form 3 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 1 .6 ± 0.3°, and having peaks at 2Θ angles of 0.6°, 2.4° and 4.4° relative to the reference peak. The term "reference peak" refers to a peak in the XRPD diffractogram that one skilled in the art considers as informing the polymorphic form of the material, i.e., differentiated from instrument noise. By "relative" it is meant that the observed 2Θ angle of each peak will be the sum of the 2Θ angle of the reference peak and the relative 2Θ angle of that peak. For example, if the reference peak has a 2Θ angle of 15.3°, the relative peaks will have 2Θ angles of 15.9°, 17.7° and 19.7°; if the reference peak has a 2Θ angle of 15.4°, the relative peaks will have 2Θ angles of 16.0°, 17.8° and 19.8°; if the reference peak has a 2Θ angle of 15.5°, the relative peaks will have 2Θ angles of 16.1 °, 17.9° and 19.9°; etc. In some embodiments, I-263a Form 3 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 15.6 ± 0.3°, and having peaks at 2Θ angles of 0.6°, 2.4°, 3.6°, 4.4°, 6.7°, and 7.5° relative to the reference peak. In some embodiments, I-263a Form 3 is characterized by an XRPD pattern having a reference peak with a 2Θ angle of 15.6 ± 0.3°, and having peaks at 2Θ angles of 0.6°, 2.4°, 3.6°, 4.4°, 4.7°, 5.1°, 6.2°, 6.7°, 7.5°, and 9.8° relative to the reference peak. Any of the peaks that one skilled in the art considers as informing the polymorphic form of the material can serve as the reference peak and the relative peaks can then be calculated. For example, if the reference peak has a 2Θ angle of 18.0°, then the relative peaks will have 2Θ angles of - 2.4°, - 1.8° and 2.0° relative to the reference peak.

[0227] FIG. 16 shows a therm...