(12) United States Patent (10) Patent No.: US 9,670,205 B2 Aktoudianakis Et Al

USOO9670205B2

(12) United States Patent (10) Patent No.: US 9,670,205 B2 Aktoudianakis et al. (45) Date of Patent: Jun. 6, 2017

(54) TOLL LIKE RECEPTOR MODULATOR FOREIGN PATENT DOCUMENTS COMPOUNDS EP 042593 A1 12, 1981 EP O322133 A1 6, 1989 (71) Applicant: Gilead Sciences, Inc., Foster City, CA EP 404355 A1 12, 1990 (US) JP 2000038350 A 2, 2000 JP 2000053.653. A 2, 2000 JP 2000053654 A 2, 2000 (72) Inventors: Evangelos Aktoudianakis, Redwood WO WO-9307124 A1 4f1993 City, CA (US); Gregory Chin, San WO WO-9427439 A1 12, 1994 Francisco, CA (US); Richard L. WO WO-0121619 A1 3, 2001 Mackman, Millbrae, CA (US); Samuel WO WO-03001887 A2 1, 2003 WO WO-2006050843 A1 5, 2006 E. Metobo, Newark, CA (US); Michael WO WO-2006069805 A2 T 2006 R. Mish, Foster City, CA (US); WO WO-2006135993 A1 12/2006 Hyung-jung Pyun, Fremont, CA (US); WO WO-2007093901 A1 8, 2007 Jeff Zablocki, Los Altos, CA (US) WO WO-2008OO97O6 A1 1, 2008 WO WO-2008O3O455 A2 3, 2008 WO WO-2008077649 A1 T 2008 (73) Assignee: GILEAD SCIENCES, INC., Foster WO WO-2008077651 A1 T 2008 City, CA (US) WO WO-2008154221 A2 12/2008 WO WO-2009003669 A2 1, 2009 (*) Notice: Subject to any disclaimer, the term of this WO WO-201OOO2998 A1 1, 2010 patent is extended or adjusted under 35 WO WO-2010O42489 A2 4/2010 WO WO-2O10046639 A1 4/2010 U.S.C. 154(b) by 0 days. WO WO-2010092340 A1 8, 2010 WO WO-2011057148 A1 5, 2011 (21) Appl. No.: 15/059,070 WO WO-2O11072275 A2 6, 2011 WO WO-20110976O7 A1 8, 2011 (22) Filed: Mar. 2, 2016 WO WO-2011 135259 A1 11/2011 WO WO-2012O58601 A1 5, 2012 (65) Prior Publication Data WO WO-2012.136834 A1 10, 2012 WO WO-2012.156498 A1 11 2012 US 2016/0289229 A1 Oct. 6, 2016 WO WO-2013060881 A1 5, 2013 WO WO-2013090840 A1 6, 2013 (Continued) Related U.S. Application Data (60) Provisional application No. 62/250,403, filed on Nov. OTHER PUBLICATIONS 3, 2015, provisional application No. 62/128.397, filed Bigorgne et al (2010) “TLRs inHepatic Cellular Crosstalk” Gas on Mar. 4, 2015. troenterology Research and Practice, Article ID 618260 pp. 1-7. Cervantes, J. et al.(2012) “TLR8: the forgotten relatuve (51) Int. Cl. revindicated” Cellular & Molecular Immunology 9:434-438. CO7D 47L/04 (2006.01) Colonna, M. et al (2004) “Plasmacytoid dendritic cells in immu (52) U.S. Cl. nity' Nature Immunology 5(12)0:1219-1226. CPC ...... C07D 471/04 (2013.01) O'Neill, L. et al (2013) “The history of Toll-like receptors— (58) Field of Classification Search redefining innate immunity”. Nature Reviews/immunology 13:453 CPC ...... CO7D 471/04 460. See application file for complete search history. Partial International Search Report for PCT/US2016/020499 mailed May 3, 2016. Chapman, N. et al (1947) “Synthethic Antimalarials. Part XVI. (56) References Cited 4-Dialkylaminoalkylaminoquinazolines. Variation of Substituents U.S. PATENT DOCUMENTS in the 6-and 7-Positions” Journal of the Chemical Society 890-899. Examination Report No. 1 for Australian Patent No. 2016216673 4,608,383 A 8, 1986 Wiedemann et al. dated Sep. 5, 2016. 5,064,833. A 11/1991 Ife et al. International Search Report for PCT/US2016/020499 dated Jul. 13, 8,143,394 B2 3/2012 Watkins et al. 2019. 8,232,278 B2 7/2012 De Jonghe et al. 8,367,670 B2 2/2013 Desai et al. (Continued) 8,536,187 B2 9/2013 Canales et al. 8,637,531 B2 1/2014 Bondy et al. Primary Examiner — Timothy Thomas 8,729,089 B2 5/2014 Bondy et al. (74) Attorney, Agent, or Firm — Timothy A. Marquart 8,901,133 B2 12/2014 Ren et al. 8,916,575 B2 * 12/2014 McGowan ...... CO7D 239,95 (57) ABSTRACT 514,266.1 8,969,363 B2 3/2015 Castro et al. The present disclosure relates generally to toll like receptor 2008.0004285 A1 1/2008 De Jonghe et al. modulator compounds, such as diamino pyrido3.2 Dipy 2008. O182870 A1 7/2008 Bondy et al. rimidine compounds and pharmaceutical compositions 2009,003.6430 A1 2/2009 De Jonghe et al. 2012/O122838 A1 5, 2012 Ren et al. which, among other things, modulate toll-like receptors (e.g. 2012fO238587 A1 9, 2012 Lee et al. TLR-8), and methods of making and using them. 2013, OO29982 A1 1/2013 Castro et al. 2013,0109693 A1 5, 2013 Routier et al. 16 Claims, No Drawings US 9,670.205 B2 Page 2

(56) References Cited

FOREIGN PATENT DOCUMENTS

WO WO-20131-17615 A1 8, 2013 WO WO-2013174947 A1 11 2013 WO WO-2014023813 A1 2, 2014 WO WO-2O14056.953 A1 4/2014 WO WO-2014O76221 A1 5, 2014 WO WO-2014 120995 A2 8, 2014 WO WO-2014 128189 A1 8, 2014 WO WO-2015O14815 A1 2, 2015 WO WO-2015 191752 A1 12/2015

OTHER PUBLICATIONS Kaczanoska, S. et al. (2013) “TLR agonists: our best frenemy in cancer immunotherapy” Journal of Leukocyte Biology 93(6):847 863. Search Report for Korean Patent Application 10-2016-7023289 dated Aug. 25, 2016 with English translation. Xagorari (2008) "Toll-Like Receptors and Viruses: Induction of Innate Antiviral Immune Responses” The Open Microbiology Jour nal 2:49-59. Yin, P. et al. (2012) "Synthesis of 2,4-Diaminoquinazolines and Tricyclis Quinazolines by Cascade Reductive Cyclization of Methyl N-Cyano-2-notrobenzimidates.” The Journal of Organic Chemistry T7:2649-2658. Examination Report dated Nov. 14, 2016 for AU Patent Application No. 2016216673. Examination Report dated Nov. 29, 2016 or EP Patent Application No. 1671 1723.3. Notice of Preliminary Rejection dated Oct. 14, 2016 for Korean Patent Application No. 10-2016-7023289. Office Action dated Dec. 27, 2016 for U.S. Appl. No. 15/264,401. * cited by examiner US 9,670,205 B2 1. 2 TOLL LIKE RECEPTOR MODULATOR COMPOUNDS R (J) YNH CROSS REFERENCE TO RELATED R X APPLICATIONS n NN This application claims priority to U.S. Provisional Appli R2 21 as als NH2 cation No. 62/128,397, filed Mar. 4, 2015, and 62/250,403, filed Nov. 3, 2015, both of which are incorporated herein in 10 R3 their entireties for all purposes.

FIELD 15 or a pharmaceutically acceptable salt thereof, wherein: This application relates generally to toll like receptor X is N or CR; modulator compounds, including diamino pyrido3.2 Dipy R" is selected from the group consisting of hydrogen, rimidine compounds, and pharmaceutical compositions halogen, Calkyl, CN, NR'R'', S(O).R", and which, among other things, modulate toll-like receptors (e.g. OR", wherein Calkyl is optionally substituted with 1 TLR-8), and methods of making and using them. to 5 R' groups; R is selected from the group consisting of hydrogen, BACKGROUND halogen, Calkyl, CN, NR'R'', S(O).R" and OR", wherein Calkyl is optionally substituted with 1 The toll-like receptor (TLR) family plays a fundamental 25 to 5 R' groups; role in pathogen recognition and activation of innate immu R is selected from the group consisting of hydrogen, nity. Toll-like receptor 8 (TLR-8) is predominantly halogen, Calkyl, CN, NR'R''. —S(O), R', and expressed by myeloid immune cells and activation of this OR", wherein Calkyl is optionally substituted with 1 receptor stimulates a broad immunological response. Ago 30 to 5 R' groups; nists of TLR-8 activate myeloid dendritic cells, monocytes, monocyte-derived dendridic cells and Kupffer cells leading R" is C. alkyl which is optionally substituted with 1 to to the production of proinflammatory cytokines and 5 substituents independently selected from halogen, chemokines, such as interleukin-18 (IL-18), interleukin-12 OR, NR'R'', CN, C(O)R, C(O)OR", (IL-12), tumor necrosis factor-alpha (TNF-C.), and inter 35 C(O)NR'R'', OC(O)NR'R'', NRC(O)R’, feron-gamma (IFN-Y). Such agonists also promote the NRC(O)NR', NRC(O)OR', SR', S(O), increased expression of co-stimulatory molecules Such as R", -S(O)NR'R'', -NR'S(O).R, Chaloalkyl, CD8 cells, major histocompatibility complex molecules C-cycloalkyl, 3 to 6 membered heterocyclyl wherein (MAIT, NK cells), and chemokine receptors. the 3 to 6 membered heterocyclyl has 1 to 3 heteroa 40 toms selected from oxygen, nitrogen, and Sulfur, Co Collectively, activation of these innate and adaptive aryl, and 5 to 10 membered heteroaryl wherein the 5 to immune responses induces an immune response and pro 10 membered heteroaryl has 1 to 3 heteroatoms vides a therapeutic benefit in various conditions involving Selected from oxygen, nitrogen, and Sulfur, autoimmunity, inflammation, allergy, asthma, graft rejec tion, graft versus host disease (GvHD), infection, cancer, wherein each Cecycloalkyl, 3 to 6 membered heterocy and immunodeficiency. For example, with respect to hepa 45 clyl, Co aryl, and 5 to 10 membered heteroaryl is titis B, activation of TLR8 on professional antigen present optionally substituted with 1 to 5 R' groups: ing cells (pAPCs) and other intrahepatic immune cells is R" is selected from hydrogen, halogen, Calkyl, CN, associated with induction of IL-12 and proinflammatory - NR'R'', -S(O) R', and OR", wherein Calkyl is cytokines, which is expected to augment HBV-specific T cell 50 optionally substituted with 1 to 5 R' groups responses, activate intrahepatic NK cells and drive recon each R" is independently selected from the group con stitution of antiviral immunity. See e.g. Wille-Reece, U. et sisting of halogen, Chaloalkyl, CN, NR'R'', al. J Exp Med 203, 1249-1258 (2006); Peng, G. et al., S(O) R', and OR; Science 309, 1380-1384 (2005); Jo, J. et al., PLoS Pathogens each R' is independently selected from the group con 10, e1004210 (2014) and Watashi, K. et al., J Biol Chem 55 sisting of halogen, Calkyl, Chaloalkyl, CN. 288, 31715-31727 (2013). - NR'R', S(O) R', and OR"; and Given the potential to treat a wide array of diseases, there each R" and Rare independently selected from the group remains a need for novel modulators of toll like receptors, consisting of hydrogen and Calkyl; wherein each for example TLR-8. Potent and selective modulators of Calkyl is optionally substituted with 1 to 5 substitu TLR-8 that have reduced potential for off target liabilities 60 ents independently selected from halogen, hydroxyl, are particularly desirable. amino. 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms SUMMARY Selected from oxygen, nitrogen, and Sulfur, and Cha 65 loalkyl: The present disclosure provides a compound of Formula provided that when X is N, R is C1, R is H and R is H (J): then R is not CHCHOMe or CHCHSOMe. US 9,670,205 B2 3 The present disclosure provides a compound of Formula

(I): Formula (IV)

(I) 5 YNH R N n NN 10 R2 an als NH2 R3 wherein: 15 R" is selected from the group consisting of hydrogen, or a pharmaceutically acceptable salt thereof, wherein: halogen, C alkyl, CN, and OR, wherein C alkyl is R" is selected from the group consisting of hydrogen, optionally substituted with 1 to 5 R' groups; halogen, Calkyl, CN, NR'R'', S(O).R", and R is selected from the group consisting of hydrogen, OR", wherein Calkyl is optionally substituted with 1 halogen, C. alkyl, CN, and OR, wherein Ce alkyl to 5 R' groups: optionally substituted with 1 to 5 R' groups; R is selected from the group consisting of hydrogen, R is selected from the group consisting of hydrogen, halogen, Ce alkyl, CN, and OR, wherein Ce alkyl is halogen, Calkyl, CN, NR'R'', S(O).R" and optionally substituted with 1 to 5 R' groups: OR", wherein Calkyl is optionally substituted with 1 R'' is selected from the group consisting of C-2 alkyl, to 5 R' groups; 25 C. cycloalkyl, and Chaloalkyl; R is selected from the group consisting of hydrogen, R'' is selected from C alkyl, halogen, —OR", halogen, Calkyl, CN, — NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', -S(O) R', and OR", wherein Calkyl is NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) optionally substituted with 1 to 5 R' groups; NR, NRC(O)OR. - SR", S(O) R', S(O), 30 NR'R''. - NRS(O).R., C haloalkyl, C. R" is C. alkyl which is optionally substituted with 1 to cycloalkyl, 3 to 6 membered heterocyclyl wherein the 5 substituents independently selected from halogen, 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms OR, NR'R'', CN, C(O)R’, C(O)OR, selected from oxygen, nitrogen, and Sulfur, Co aryl, C(O)NR'R'', OC(O)NR'R'', NRC(O)R’, and 5 to 10 membered heteroaryl wherein the 5 to 10 NRC(O)NR', NRC(O)OR', SR', S(O), 35 membered heteroaryl has 1 to 3 heteroatoms selected R", -S(O)NR'R'', -NR'S(O).R, Chaloalkyl, from oxygen, nitrogen, and Sulfur, wherein the C C-cycloalkyl, 3 to 6 membered heterocyclyl wherein alkyl group is optionally substituted with 1 or 2 sub the 3 to 6 membered heterocyclyl has 1 to 3 heteroa stituents independently selected from halogen, —OR', toms selected from oxygen, nitrogen, and Sulfur, Co NR'R'', CN, C(O)R, C(O)OR, C(O) 40 NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) aryl, and 5 to 10 membered heteroaryl wherein the 5 to NR, NRC(O)OR. - SR", S(O) R', S(O), 10 membered heteroaryl has 1 to 3 heteroatoms NR'R'', NRS(O).R. C. haloalkyl, C-cy Selected from oxygen, nitrogen, and Sulfur, cloalkyl, 3 to 6 membered heterocyclyl wherein the 3 wherein each Cecycloalkyl, 3 to 6 membered heterocy to 6 membered heterocyclyl has 1 to 3 heteroatoms clyl, Co aryl, and 5 to 10 membered heteroaryl is 45 Selected from oxygen, nitrogen, and Sulfur, Co aryl, optionally substituted with 1 to 5 R' groups; and 5 to 10 membered heteroaryl wherein the 5 to 10 each R” is independently selected from the group con membered heteroaryl has 1 to 3 heteroatoms selected sisting of halogen, Chaloalkyl, CN, NR'R'', from oxygen, nitrogen, and Sulfur, S(O) R', and OR; R" is selected from C alkyl, halogen, —OR", 50 NR'R'', CN, C(O)R, C(O)OR, C(O) each R is independently selected from the group con NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) sisting of halogen, Calkyl, Chaloalkyl, CN, NR, NRC(O)OR', SR, S(O) R', S(O), - NR'R', S(O) R', and OR"; and NR'R'', NRS(O).R, C, haloalkyl, C. each R" and Rare independently selected from the group cycloalkyl, 3 to 6 membered heterocyclyl wherein the consisting of hydrogen and Calkyl; wherein each 55 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms Calkyl is optionally substituted with 1 to 5 substitu selected from oxygen, nitrogen, and Sulfur, Co aryl, ents independently selected from halogen, hydroxyl, and 5 to 10 membered heteroaryl wherein the 5 to 10 amino. 5 to 10 membered heteroaryl wherein the 5 to membered heteroaryl has 1 to 3 heteroatoms selected 10 membered heteroaryl has 1 to 3 heteroatoms from oxygen, nitrogen, and Sulfur, wherein the C Selected from oxygen, nitrogen, and Sulfur, and Cha 60 alkyl is optionally substituted with 1 to 2 substituents loalkyl: independently selected from halogen, —OR, NR'R'', CN, C(O)R, C(O)OR, C(O) provided that when R' is C1, R is H and R is H then R' NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) is not CHCHOMe or CHCHSOMe. NR, NRC(O)OR. - SR", S(O) R', S(O), 65 NR'R'', NRS(O).R, C, haloalkyl, C. The present disclosure provides a compound of Formula cycloalkyl, 3 to 6 membered heterocyclyl wherein the (IV): 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms US 9,670,205 B2 5 6 Selected from oxygen, nitrogen, and Sulfur, Co aryl, In certain embodiments, a compound of the present dis and 5 to 10 membered heteroaryl wherein the 5 to 10 closure, or a pharmaceutically acceptable salt thereof, for membered heteroaryl has 1 to 3 heteroatoms selected use in treating or preventing a disease or condition respon from oxygen, nitrogen, and Sulfur, sive to the modulation of TLR-8, is provided. In certain each R' is independently selected from the group con embodiments, the disease or condition is a viral infection. sisting of halogen, CN, NR'R'', and OR"; and In certain embodiments, a compound of the present dis each R" and R is independently selected from the group closure, or a pharmaceutically acceptable salt thereof, for consisting of hydrogen and C alkyl, wherein each use in treating or preventing hepatitis B, is provided C. alkyl is optionally substituted with 1 to 3 substitu In certain embodiments, the use of a compound of the ents independently selected from halogen, —OH, and 10 present disclosure, or a pharmaceutically acceptable salt NH. thereof, for the manufacture of a medicament for treating or In certain embodiments, the present disclosure provides a preventing a disease or condition responsive to the modu pharmaceutical composition comprising a compound of the lation of TLR-8, is provided. present disclosure, or a pharmaceutically acceptable salt In certain embodiments, the use of a compound of the thereof, and a pharmaceutically acceptable excipient. In 15 present disclosure, or a pharmaceutically acceptable salt certain embodiments, the pharmaceutical composition com thereof, for the manufacture of a medicament for treating or prises one or more additional therapeutic agents. preventing hepatitis B, is provided. In certain embodiments, a method of modulating TLR-8 Kits comprising the compounds, or pharmaceutically is provided, comprising administering a compound of the acceptable salts thereof, or pharmaceutical compositions of present disclosure, or a pharmaceutically acceptable salt the foregoing are also provided. Articles of manufacture thereof, to an individual (e.g. a human). comprising a unit dose of the compounds, or pharmaceuti In certain embodiments, a method of treating or prevent cally acceptable salts thereof, of the foregoing are also ing a disease or condition responsive to the modulation of provided. Methods of preparing compounds of the present TLR-8 is provided, comprising administering to an indi disclosure are also provided. vidual (e.g. a human) in need thereof a therapeutically 25 effective amount of a compound of the present disclosure, or DETAILED DESCRIPTION a pharmaceutically acceptable salt thereof. In certain embodiments, the method of treating or preventing a disease The description below is made with the understanding or condition responsive to the modulation of TLR-8, com that the present disclosure is to be considered as an exem prises administering one or more additional therapeutic 30 plification of the claimed Subject matter, and is not intended agents. to limit the appended claims to the specific embodiments In certain embodiments, a method of treating or prevent illustrated. The headings used throughout this disclosure are ing a viral infection is provided, comprising administering to provided for convenience and are not to be construed to limit an individual (e.g. a human) in need thereofatherapeutically the claims in any way. Embodiments illustrated under any effective amount a compound of the present disclosure, or a 35 heading may be combined with embodiments illustrated pharmaceutically acceptable salt thereof. under any other heading. In certain embodiments, a method of treating or prevent I. Definitions ing a hepatitis B viral infection is provided, comprising Unless defined otherwise, all technical and scientific administering to an individual (e.g. a human) in need thereof terms used herein have the same meaning as commonly a therapeutically effective amount of a compound of the 40 understood by one of ordinary skill in the art. A dash at the present disclosure, or a pharmaceutically acceptable salt front or end of a chemical group is a matter of convenience thereof. In certain embodiments, the method of treating or to indicate the point of attachment to a parent moiety; preventing a hepatitis B viral infection comprises adminis chemical groups may be depicted with or without one or tering one or more additional therapeutic agents. In certain more dashes without losing their ordinary meaning. A prefix embodiments, the individual is a human infected with hepa 45 Such as “C.” or (C-C) indicates that the following group titis B. has from u to V carbonatoms, where u and V are integers. For In certain embodiments, a method of treating or prevent example, "Calkyl indicates that the alkyl group has from ing a HIV infection is provided, comprising administering to 1 to 6 carbon atoms. an individual (e.g. a human) in thereof a therapeutically “Alkyl is a linear or branched saturated monovalent effective amount a compound of the present disclosure, or a 50 hydrocarbon. For example, an alkyl group can have 1 to 10 pharmaceutically acceptable salt thereof. In certain embodi carbon atoms (i.e., (C-o)alkyl) or 1 to 8 carbon atoms (i.e., ments, the method of treating or preventing a HIV infection (Cs)alkyl) or 1 to 6 carbon atoms (i.e., (C. alkyl) or 1 to comprises administering one or more additional therapeutic 4 carbon atoms (i.e., (C)alkyl). Examples of alkyl groups agents. In certain embodiments, the individual is a human include, but are not limited to, methyl (Me. —CH), ethyl infected with HIV (e.g. HIV-1). 55 (Et, —CHCH), 1-propyl (n-Pr, n-propyl. —CH2CHCH), In certain embodiments, a method of treating a hyperpro 2-propyl (i-Pr. i-propyl, -CH(CH)), 1-butyl (n-Bu, n-bu liferative disease (e.g. cancer) is provided, comprising tyl, —CH2CHCH-CH-), 2-methyl-1-propyl (i-Bu, i-butyl, administering to an individual (e.g. a human) in thereof a —CH-CH(CH)), 2-butyl (s-Bu, s-butyl, —CH(CH) therapeutically effective amount a compound of the present CHCH), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH)), disclosure, or a pharmaceutically acceptable salt thereof. In 60 1-pentyl (n-pentyl, —CH2CH2CH2CHCH), 2-pentyl certain embodiments, the method of treating a hyperprolif (—CH(CH)CHCHCH), 3-pentyl ( CH(CHCH)), erative disease (e.g. cancer) comprises administering one or 2-methyl-2-butyl ( C(CH) CHCH), 3-methyl-2-butyl more additional therapeutic agents. In certain embodiments, (-CH(CH)CH(CH)), 3-methyl-1-butyl ( CHCHCH the individual is a human. (CH)), 2-methyl-1-butyl ( CHCH(CH)CHCH), In certain embodiments, a compound of the present dis 65 1-hexyl ( CHCH2CH2CH2CHCH), 2-hexyl ( CH closure, or a pharmaceutically acceptable salt thereof, for (CH)CHCHCHCH), 3-hexyl (-CH(CHCH.) use in medical therapy is provided. (CHCHCH)), 2-methyl-2-pentyl (—C(CH) US 9,670,205 B2 7 8 CHCHCH), 3-methyl-2-pentyl ( CH(CH)CH(CH) the multiple condensed ring system can be connected to each CHCH), 4-methyl-2-pentyl ( CH(CH)CHCH(CH)), other via fused, spiro and bridged bonds when allowed by 3-methyl-3-pentyl ( C(CH)(CHCH)), 2-methyl-3-pen Valency requirements. It is also to be understood that when tyl ( CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl ( C reference is made to a certain atom-range membered aryl (CH)-CH(CH)), 3.3-dimethyl-2-butyl ( CH(CH)C (e.g., 6-10 membered aryl), the atom range is for the total (CH), and octyl (-(CH2)CH). ring atoms of the aryl. For example, a 6-membered aryl “Alkenyl is a linear or branched monovalent hydrocar would include phenyl and a 10-membered aryl would bon radical with at least one carbon-carbon double bond. For include naphthyl and 1, 2, 3, 4-tetrahydronaphthyl. Non example, an alkenyl group can have 2 to 8 carbon atoms limiting examples of aryl groups include, but are not limited (i.e., C.s alkenyl), or 2 to 6 carbon atoms (i.e., Calkenyl) 10 to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, or 2 to 4 carbon atoms (i.e., C alkenyl). Examples of anthracenyl, and the like. Suitable alkenyl groups include, but are not limited to, The term "heteroaryl as used herein refers to a single ethylene or vinyl ( CH=CH-), allyl ( CH-CH=CH-), aromatic ring that has at least one atom other than carbon in 5-hexenyl ( CHCHCHCH-CH=CH-), and 3-hexenyl the ring, wherein the atom is selected from the group ( CHCH-CH=CHCHCH). 15 consisting of oxygen, nitrogen and Sulfur, "heteroaryl also “Alkynyl is a linear or branched monovalent hydrocar includes multiple condensed ring systems that have at least bon radical with at least one carbon-carbon triple bond. For one such aromatic ring, which multiple condensed ring example, an alkynyl group can have 2 to 8 carbon atoms systems are further described below. Thus, "heteroaryl' (i.e., C.s alkyne.) or 2 to 6 carbon atoms (i.e., C2-alkynyl) includes single aromatic rings of from about 1 to 6 carbon or 2 to 4 carbon atoms (i.e., C alkynyl). Examples of atoms and about 1-4 heteroatoms selected from the group alkynyl groups include, but are not limited to, acetylenyl consisting of oxygen, nitrogen and Sulfur. The Sulfur and ( C=CH), propargyl ( CH-C=CH), and —CH2— nitrogen atoms may also be present in an oxidized form C=C CH. provided the ring is aromatic. Exemplary heteroaryl ring The term “halo' or “halogen' as used herein refers to systems include but are not limited to pyridyl, pyrimidinyl, fluoro (—F), chloro ( Cl), bromo ( Br) and iodo (—I). 25 oxazolyl or furyl. “Heteroaryl also includes multiple con The term “haloalkyl as used herein refers to an alkyl as densed ring systems (e.g., ring systems comprising 2, 3 or 4 defined herein, wherein one or more hydrogen atoms of the rings) wherein a heteroaryl group, as defined above, is alkyl are independently replaced by a halo Substituent, condensed with one or more rings selected from heteroaryls which may be the same or different. For example, C-sha (to form for example 1.8-naphthyridinyl), heterocycles, (to loalkyl is a Cisalkyl wherein one or more of the hydrogen 30 form for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), atoms of the Cisalkyl have been replaced by a halo Sub carbocycles (to form for example 5,6,7,8-tetrahydroqui stituent. Examples of haloalkyl groups include but are not nolyl) and aryls (to form for example indazolyl) to form the limited to fluoromethyl, fluorochloromethyl, difluoromethyl, multiple condensed ring system. Thus, a heteroaryl (a single difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl aromatic ring or multiple condensed ring system) has about and pentafluoroethyl. 35 1-20 carbon atoms and about 1-6 heteroatoms within the The term "heteroalkyl as used herein refers to an alkyl as heteroaryl ring. Such multiple condensed ring systems may defined herein, wherein one or more of the carbon atoms of be optionally Substituted with one or more (e.g., 1, 2, 3 or 4) the alkyl are replaced by an O, S, or NR7, wherein each R' oxo groups on the carbocycle or heterocycle portions of the is independently H or Calkyl. For example, Chet condensed ring. The rings of the multiple condensed ring eroalkyl intends a heteroalkyl of one to eight carbons 40 system can be connected to each other via fused, spiro and wherein one or more carbon atoms is replaced by a heteroa bridged bonds when allowed by valency requirements. It is tom (e.g., O, S, NR7, OH, SH or N(R).), which may the to be understood that the individual rings of the multiple same or different. Examples of heteroalkyls include but are condensed ring system may be connected in any order not limited to methoxymethyl, ethoxymethyl, methoxy, relative to one another. It is to be understood that the point 2-hydroxyethyl and N,N'-dimethylpropylamine. A heteroa 45 of attachment for a heteroaryl or heteroaryl multiple con tom of a heteroalkyl may optionally be oxidized or alky densed ring system can be at any Suitable atom of the lated. A heteroatom may be placed at any interior position of heteroaryl or heteroaryl multiple condensed ring system the heteroalkyl group or at a position at which the group is including a carbon atom and a heteroatom (e.g., a nitrogen). attached to the remainder of the molecule. Examples It also to be understood that when a reference is made to a include, but are not limited to. —CHOCH, 50 certain atom-range membered heteroaryl (e.g., a 5 to 10 —CHCH-NHCH, - CHCHN(CH) CH, membered heteroaryl), the atom range is for the total ring —CH-SCHCH, -S(O)CH, CHCHS(O)CH, atoms of the heteroaryl and includes carbon atoms and CHCHOCH, CHCHNOCH, CHCHN(CH)CH, heteroatoms. For example, a 5-membered heteroaryl would —CHNHOCH and —CHOS(CH), include a thiazolyl and a 10-membered heteroaryl would The term “aryl as used herein refers to a single all carbon 55 include a quinolinyl. Exemplary heteroaryls include but are aromatic ring or a multiple condensed all carbon ring system not limited to pyridyl, pyrrolyl pyrazinyl, pyrimidinyl, wherein at least one of the rings is aromatic. For example, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, in certain embodiments, an aryl group has 6 to 20 carbon oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiaz atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl olyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, includes a phenyl radical. Aryl also includes multiple con 60 indazolyl, quinoxalyl, quinazolyl. 5,6,7,8-tetrahydroisoqui densed ring systems (e.g., ring systems comprising 2, 3 or 4 nolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyr rings) having about 9 to 20 carbon atoms in which at least rolo2,3-bipyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4.5, one ring is aromatic and wherein the other rings may be 6,7-tetrahydro-1H-indazole and 3b.4.4a,5-tetrahydro-1H aromatic or not aromatic (i.e., carbocycle). Such multiple cyclopropa3.4cyclopenta 1.2-cpyrazole. condensed ring systems are optionally Substituted with one 65 The term “cycloalkyl refers to a single saturated or or more (e.g., 1, 2 or 3) oxo groups on any carbocycle partially unsaturated all carbon ring having 3 to 20 annular portion of the multiple condensed ring system. The rings of carbon atoms (i.e., Co cycloalkyl), for example from 3 to US 9,670,205 B2 10 12 annular atoms, for example from 3 to 10 annular atoms. pounds listed in Tables 1 and 3. A compound of the present The term “cycloalkyl also includes multiple condensed, disclosure also includes the compounds of Examples 1-118 saturated and partially unsaturated all carbon ring systems As used herein, “delaying development of a disease or (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). condition means to defer, hinder, slow, retard, stabilize Accordingly, cycloalkyl includes multicyclic carbocyles and/or postpone development of the disease or condition. Such as a bicyclic carbocycles (e.g., bicyclic carbocycles This delay can be of varying lengths of time, depending on having about 6 to 12 annular carbon atoms such as bicyclo the history of the disease and/or individual being treated. As 3.1.0 hexane and bicyclo2.1.1 hexane), and polycyclic is evident to one skilled in the art, a sufficient or significant carbocycles (e.g. tricyclic and tetracyclic carbocycles with delay can, in effect, encompass prevention, in that the up to about 20 annular carbon atoms). The rings of a 10 individual does not develop the disease or condition. For multiple condensed ring system can be connected to each example, a method that “delays” development of AIDS is a other via fused, spiro and bridged bonds when allowed by method that reduces the probability of disease development Valency requirements. Non-limiting examples of monocy in a given time frame and/or reduces extent of the disease in clic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, a given time frame, when compared to not using the method. 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 15 Such comparisons may be based on clinical studies, using a cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cy statistically significant number of Subjects. For example, the clohex-3-enyl. development of AIDS can be detected using known meth The term "heterocyclyl or "heterocycle” as used herein ods, such as confirming an individual’s HIV status and refers to a single Saturated or partially unsaturated non assessing the individual's T-cell count or other indication of aromatic ring or a non-aromatic multiple ring system that AIDS development, such as extreme fatigue, weight loss, has at least one heteroatom in the ring (i.e., at least one persistent diarrhea, high fever, Swollen lymph nodes in the annular heteroatom selected from oxygen, nitrogen, and neck, armpits or groin, or presence of an opportunistic Sulfur). Unless otherwise specified, a heterocyclyl group has condition that is known to be associated with AIDS (e.g., a from 5 to about 20 annular atoms, for example from 3 to 12 condition that is generally not present in individuals with annular atoms, for example from 5 to 10 annular atoms. 25 functioning immune systems but does occur in AIDS Thus, the term includes single Saturated or partially unsatu patients). Development may also refer to disease progres rated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from sion that may be initially undetectable and includes occur about 1 to 6 annular carbon atoms and from about 1 to 3 rence, recurrence and onset. annular heteroatoms selected from the group consisting of As used herein, “prevention' or “preventing refers to a oxygen, nitrogen and Sulfur in the ring. The rings of the 30 regimen that protects against the onset of the disease or multiple condensed ring system can be connected to each disorder Such that the clinical symptoms of the disease do other via fused, spiro and bridged bonds when allowed by not develop. Thus, “prevention” relates to administration of Valency requirements. Heterocycles include, but are not a therapy (e.g., administration of a therapeutic Substance) to limited to, aZetidine, aziridine, imidazolidine, morpholine, a subject before signs of the disease are detectable in the oxirane (epoxide), oxetane, piperazine, piperidine, pyrazo 35 Subject (e.g., administration of a therapeutic Substance to a lidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydro Subject in the absence of detectable infectious agent (e.g., furan, tetrahydrothiophene, dihydropyridine, tetrahydro virus) in the subject). The subject may be an individual at pyridine, quinuclidine, N-bromopyrrolidine, risk of developing the disease or disorder. Such as an N-chloropiperidine, and the like. individual who has one or more risk factors known to be The term “oxo' as used herein refers to —O. 40 associated with development or onset of the disease or As used herein, “treatment’ or “treating is an approach disorder. Thus, in certain embodiments, the term “prevent for obtaining beneficial or desired results. For purposes of ing HBV infection” refers to administering to a subject who the present disclosure, beneficial or desired results include, does not have a detectable HBV infection an anti-HBV but are not limited to, alleviation of a symptom and/or therapeutic substance. It is understood that the subject for diminishment of the extent of a symptom and/or preventing 45 anti-HBV preventative therapy may be an individual at risk a worsening of a symptom associated with a disease or of contracting the HBV virus. Thus, in certain embodiments, condition. In one embodiment, “treatment” or “treating the term “preventing HIV infection” refers to administering includes one or more of the following: a) inhibiting the to a subject who does not have a detectable HIV infection an disease or condition (e.g., decreasing one or more symptoms anti-HIV therapeutic substance. It is understood that the resulting from the disease or condition, and/or diminishing 50 subject for anti-HIV preventative therapy may be an indi the extent of the disease or condition); b) slowing or vidual at risk of contracting the HIV virus. arresting the development of one or more symptoms asso As used herein, an “at risk” individual is an individual ciated with the disease or condition (e.g., stabilizing the who is at risk of developing a condition to be treated. An disease or condition, delaying the worsening or progression individual “at risk” may or may not have detectable disease of the disease or condition); and c) relieving the disease or 55 or condition, and may or may not have displayed detectable condition, e.g., causing the regression of clinical symptoms, disease prior to the treatment of methods described herein. ameliorating the disease state, delaying the progression of “At risk” denotes that an individual has one or more so the disease, increasing the quality of life, and/or prolonging called risk factors, which are measurable parameters that survival. correlate with development of a disease or condition and are A “compound of the present disclosure' includes com 60 known in the art. An individual having one or more of these pounds disclosed herein, for example a compound of the risk factors has a higher probability of developing the present disclosure includes compounds of Formula (J), (I), disease or condition than an individual without these risk (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), and the com factor(s). For example, individuals at risk for AIDS are those pounds listed in Table 1. A compound of the present disclo having HIV. Sure also includes compounds of Formula (J), (I), (Ia), (Ib). 65 As used herein, the term “therapeutically effective (II), (IIa), (IIb), (III), (IIIa), (IIIb), (VI), (IVa), (IVb). (IVc), amount’ or “effective amount” refers to an amount that is (IVd), the compounds of Examples 1-113, and the com effective to elicit the desired biological or medical response, US 9,670,205 B2 11 12 including the amount of a compound that, when adminis sifier which has been approved by the United States Food tered to a subject for treating a disease, is sufficient to effect and Drug Administration as being acceptable for use in such treatment for the disease. The effective amount will humans or domestic animals vary depending on the compound, the disease, and its As used herein, modulation of a receptor includes ago severity and the age, weight, etc., of the Subject to be treated. nism, partial agonism, antagonism, partial antagonism, or The effective amount can include a range of amounts. AS is inverse agonism of a receptor. understood in the art, an effective amount may be in one or The nomenclature used herein to name the Subject com more doses, i.e., a single dose or multiple doses may be pounds is illustrated in the Examples and elsewhere herein. required to achieve the desired treatment endpoint. An As used herein, "co-administration' includes administra effective amount may be considered in the context of admin 10 tion of unit dosages of the compounds disclosed herein istering one or more therapeutic agents, and a single agent before or after administration of unit dosages of one or more may be considered to be given in an effective amount if, in additional therapeutic agents, for example, administration of conjunction with one or more other agents, a desirable or the compound disclosed herein within seconds, minutes, or beneficial result may be or is achieved. Suitable doses of any 15 hours of the administration of one or more additional co-administered compounds may optionally be lowered due therapeutic agents. For example, in some embodiments, a to the combined action (e.g., additive or synergistic effects) unit dose of a compound of the present disclosure is admin of the compounds. istered first, followed within seconds or minutes by admin As used herein, an "agonist' is a Substance that stimulates istration of a unit dose of one or more additional therapeutic its binding partner, typically a receptor. Stimulation is agents. Alternatively, in other embodiments, a unit dose of defined in the context of the particular assay, or may be one or more additional therapeutic agents is administered apparent in the literature from a discussion herein that makes first, followed by administration of a unit dose of a com a comparison to a factor or Substance that is accepted as an pound of the present disclosure within seconds or minutes. “agonist' or an “antagonist of the particular binding partner In some embodiments, a unit dose of a compound of the under Substantially similar circumstances as appreciated by 25 present disclosure is administered first, followed, after a those of skill in the art. Stimulation may be defined with period of hours (e.g., 1-12 hours), by administration of a unit respect to an increase in a particular effect or function that dose of one or more additional therapeutic agents. In other is induced by interaction of the agonist or partial agonist embodiments, a unit dose of one or more additional thera with a binding partner and can include allosteric effects. peutic agents is administered first, followed, after a period of 30 hours (e.g., 1-12 hours), by administration of a unit dose of As used herein, an “antagonist' is a Substance that inhibits a compound of the present disclosure. its binding partner, typically a receptor. Inhibition is defined Provided are also pharmaceutically acceptable salts, in the context of the particular assay, or may be apparent in hydrates, Solvates, tautomeric forms, polymorphs, and pro the literature from a discussion herein that makes a com drugs of the compounds described herein. “Pharmaceuti parison to a factor or Substance that is accepted as an 35 cally acceptable' or “physiologically acceptable' refer to “agonist' or an “antagonist of the particular binding partner compounds, salts, compositions, dosage forms and other under Substantially similar circumstances as appreciated by materials which are useful in preparing a pharmaceutical those of skill in the art. Inhibition may be defined with composition that is suitable for veterinary or human phar respect to a decrease in a particular effect or function that is maceutical use. induced by interaction of the antagonist with a binding 40 The compounds of described herein may be prepared partner, and can include allosteric effects. and/or formulated as pharmaceutically acceptable salts. As used herein, a “partial agonist' or a "partial antago Pharmaceutically acceptable salts are non-toxic salts of a nist' is a substance that provides a level of stimulation or free base form of a compound that possesses the desired inhibition, respectively, to its binding partner that is not fully pharmacological activity of the free base. These salts may be or completely agonistic or antagonistic, respectively. It will 45 derived from inorganic or organic acids or bases. For be recognized that stimulation, and hence, inhibition is example, a compound that contains a basic nitrogen may be defined intrinsically for any substance or category of Sub prepared as a pharmaceutically acceptable salt by contacting stances to be defined as agonists, antagonists, or partial the compound with an inorganic or organic acid. Non agonists. limiting examples of pharmaceutically acceptable salts As used herein, “intrinsic activity” or “efficacy” relates to 50 include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, Some measure of biological effectiveness of the binding phosphates, monohydrogen-phosphates, dihydrogenphos partner complex. With regard to receptor pharmacology, the phates, metaphosphates, pyrophosphates, chlorides, bro context in which intrinsic activity or efficacy should be mides, iodides, acetates, propionates, decanoates, capry defined will depend on the context of the binding partner lates, acrylates, formates, isobutyrates, caproates, (e.g., receptor/ligand) complex and the consideration of an 55 heptanoates, propiolates, oxalates, malonates. Succinates, activity relevant to a particular biological outcome. For Suberates, sebacates, fumarates, maleates, butyne-1,4-dio example, in some circumstances, intrinsic activity may vary ates, hexyne-1,6-dioates, benzoates, chlorobenzoates, meth depending on the particular second messenger system ylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxy involved. Where such contextually specific evaluations are benzoates, phthalates, Sulfonates, methylsulfonates, relevant, and how they might be relevant in the context of 60 propylsulfonates, besylates, Xylenesulfonates, naphthalene the present disclosure, will be apparent to one of ordinary 1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phe skill in the art. nylpropionates, phenylbutyrates, citrates, lactates, Y-hy “Pharmaceutically acceptable excipient' includes without droxybutyrates, glycolates, tartrates, and mandelates. Lists limitation any adjuvant, carrier, excipient, glidant, Sweeten of other suitable pharmaceutically acceptable salts are found ing agent, diluent, preservative, dye? colorant, flavor 65 in Remington: The Science and Practice of Pharmacy, 21 enhancer, Surfactant, Wetting agent, dispersing agent, Sus Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., pending agent, stabilizer, isotonic agent, Solvent, or emul 2006. US 9,670,205 B2 13 14 Examples of “pharmaceutically acceptable salts' of the A “tautomer refers to a proton shift from one atom of a compounds disclosed herein also include salts derived from molecule to another atom of the same molecule. The present an appropriate base. Such as an alkali metal (for example, disclosure includes tautomers of any said compounds. Sodium, potassium), an alkaline earth metal (for example, A “solvate” is formed by the interaction of a solvent and magnesium), ammonium and NX (wherein X is C-C, a compound. Solvates of salts of the compounds described alkyl). Also included are base addition salts, such as sodium herein are also provided. Hydrates of the compounds or potassium salts. described herein are also provided. Provided are also compounds described herein or phar A "prodrug includes any compound that becomes a maceutically acceptable salts, isomers, or a mixture thereof, compound described herein when administered to a Subject, in which from 1 to n hydrogen atoms attached to a carbon 10 e.g., upon metabolic processing of the prodrug. atom may be replaced by a deuterium atom or D. in which n is the number of hydrogen atoms in the molecule. As The terms “combination antiretroviral therapy” (“cART) known in the art, the deuterium atom is a non-radioactive refers to combinations or “cocktails” of antiretroviral medi isotope of the hydrogen atom. Such compounds may cations used to treat human viral infections, including HIV increase resistance to metabolism, and thus may be useful 15 infections. As used herein, the terms “combination antiret for increasing the half-life of the compounds described roviral therapy' and “cART include combinations and regi herein or pharmaceutically acceptable salts, isomer, or a mens often referred to as Highly Active Antiretroviral mixture thereof when administered to a mammal. See, e.g., Therapy (HAART). HAART and cART combinations and Foster, “Deuterium Isotope Effects in Studies of Drug regimens commonly include multiple, often two or more, Metabolism', Trends Pharmacol. Sci., 5(12):524-527 drugs such as nucleoside reverse transcriptase inhibitors (1984). Such compounds are synthesized by means well (NRTIs), non-nucleoside reverse transcriptase inhibitors known in the art, for example by employing starting mate (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 rials in which one or more hydrogen atoms have been agonists, and/or integrase inhibitors. replaced by deuterium. The terms “latent HIV reservoir”, “HIV latent reservoir, Examples of isotopes that can be incorporated into the 25 “HIV reservoir, “latent reservoir', and “latent HIV infec disclosed compounds also include isotopes of hydrogen, tion” refer to a condition in which resting CD4+T lympho carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, cytes or other cells are infected with HIV but are not actively and iodine, such as H, H, C, C, C, N, N, O, producing HIV. The presently inactive HIV infected cells are 7O, O, P, P, S, F, C1, I, and I, respectively. referred to as “latently infected cells'. Antiretroviral therapy Substitution with positron emitting isotopes, such as 'C, 30 (ART) can reduce the level of HIV in the blood to an 'F, 'O and 'N, can be useful in Positron Emission undetectable level, while latent reservoirs of HIV continue Topography (PET) studies for examining substrate receptor to survive. When a latently infected cell is reactivated, the occupancy. Isotopically-labeled compounds of Formula (I), cell begins to produce HIV (HIV replication). can generally be prepared by conventional techniques II. Compounds known to those skilled in the art or by processes analogous 35 The present disclosure provides a compound of Formula to those described in the Examples as set out below using an (J): appropriate isotopically-labeled reagent in place of the non labeled reagent previously employed. (J) The compounds of the embodiments disclosed herein, or R their pharmaceutically acceptable salts may contain one or 40 YNH more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms R! X that may be defined, in terms of absolute Stereochemistry, as N1 SN (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all Such possible isomers, as 45 R2 21N als NH2 well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers R3 may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chro or a pharmaceutically acceptable salt thereof, wherein: matography and fractional crystallization. Conventional 50 X is N or CR'; techniques for the preparation/isolation of individual R" is selected from the group consisting of hydrogen, enantiomers include chiral synthesis from a suitable opti halogen, Calkyl, CN, NR'R''. —S(O), R', and cally pure precursor or resolution of the racemate (or the OR", wherein Calkyl is optionally substituted with 1 racemate of a salt or derivative) using, for example, chiral to 5 R' groups; high pressure liquid chromatography (HPLC). When the 55 R is selected from the group consisting of hydrogen, compounds described herein contain olefinic double bonds halogen, Calkyl, CN, NR'R'', S(O)R and or other centres of geometric asymmetry, and unless speci OR", wherein Calkyl is optionally substituted with 1 fied otherwise, it is intended that the compounds include to 5 R' groups: both E and Z geometric isomers. Likewise, all tautomeric R is selected from the group consisting of hydrogen, forms are also intended to be included. 60 halogen, Calkyl, CN, NR'R'', S(O).R", and A “stereoisomer refers to a compound made up of the OR", wherein Calkyl is optionally substituted with 1 same atoms bonded by the same bonds but having different to 5 R' groups: three-dimensional structures, which are not interchangeable. R" is C. alkyl which is optionally substituted with 1 to The present disclosure contemplates various stereoisomers 5 substituents independently selected from halogen, and mixtures thereof and includes “enantiomers', which 65 OR, NR'R'', CN, C(O)R, C(O)OR", refers to two stereoisomers whose molecules are non-Super C(O)NR'R'', OC(O)NR'R'', NRC(O)R’, imposable mirror images of one another. NRC(O)NR, NRC(O)CR', SR, S(O), US 9,670,205 B2 15 16 R", -S(O)NR'R'', -NR'S(O).R, Chaloalkyl, toms selected from oxygen, nitrogen, and Sulfur, Co C-cycloalkyl, 3 to 6 membered heterocyclyl wherein aryl, and 5 to 10 membered heteroaryl wherein the 5 to the 3 to 6 membered heterocyclyl has 1 to 3 heteroa 10 membered heteroaryl has 1 to 3 heteroatoms toms selected from oxygen, nitrogen, and Sulfur, Co Selected from oxygen, nitrogen, and Sulfur, aryl, and 5 to 10 membered heteroaryl wherein the 5 to wherein each Cecycloalkyl, 3 to 6 membered heterocy 10 membered heteroaryl has 1 to 3 heteroatoms clyl, Co aryl, and 5 to 10 membered heteroaryl is Selected from oxygen, nitrogen, and Sulfur, optionally substituted with 1 to 5 R' groups; wherein each Cecycloalkyl, 3 to 6 membered heterocy each R' is independently selected from the group con clyl, Co aryl, and 5 to 10 membered heteroaryl is sisting of halogen, Chaloalkyl, CN, NR'R'', optionally substituted with 1 to 5 R' groups; 10 S(O) R', and OR; R' is selected from hydrogen, halogen, Calkyl, CN, each R is independently selected from the group con - NR'R'', -S(O) R', and OR", wherein Calkyl is sisting of halogen, Calkyl, Chaloalkyl, CN, optionally substituted with 1 to 5 R' groups - NR'R', S(O) R', and OR"; and each R" and Rare each R' is independently selected from the group con independently selected from the group consisting of H sisting of halogen, Chaloalkyl, CN, NR'R'', 15 and Calkyl, wherein each Calkyl is optionally S(O) R', and OR; substituted with 1 to 5 substituents independently each R’ is independently selected from the group con Selected from halogen, hydroxyl, amino. 5 to 10 mem sisting of halogen, Calkyl, Chaloalkyl, CN, bered heteroaryl wherein the 5 to 10 membered het - NR'R', S(O) R', and OR"; and eroaryl has 1 to 3 heteroatoms selected from oxygen, each R" and Rare independently selected from the group nitrogen, and sulfur, and Chaloalkyl: consisting of hydrogen and Calkyl, wherein each provided that when R' is C1, R is H and R is H then R' Calkyl is optionally substituted with 1 to 5 substitu is not CHCHOMe or CHCHSOMe. ents independently selected from halogen, hydroxyl, In certain embodiments of a compound of Formula (J) or amino. 5 to 10 membered heteroaryl wherein the 5 to 25 (I), R is Cls alkyl which is optionally substituted with 1 to 10 membered heteroaryl has 1 to 3 heteroatoms 5 Substituents independently selected from the group con selected from oxygen, nitrogen, and Sulfur, and Cha sisting of halogen, —OR", NR'R'', CN, -C(O)R", loalkyl: C(O)OR, C(O)NR'R'', OC(O)NR'R'', NRC(O) provided that when X is N, R is C1, R is Hand R is H R, NRC(O)NR, NRC(O)OR', SR, S(O), R, then R is not CHCHOMe or CHCHSOMe. 30 —S(O)NR'R'', NRS(O).R, Chaloalkyl, C-cy In certain embodiments of Formula (J), X is CR''. In cloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 certain embodiments of Formula (J), X is N. membered heterocyclyl has 1 to 3 heteroatoms selected from The present disclosure provides a compound of Formula oxygen, nitrogen, and sulfur, Co aryl, and 5 to 10 mem (I): bered heteroaryl wherein the 5 to 10 membered heteroaryl 35 has 1 to 3 heteroatoms selected from oxygen, nitrogen, and Sulfur, and wherein each Cecycloalkyl, 3 to 6 membered (I) heterocyclyl, Co aryl, and 5 to 10 membered heteroaryl is YNH optionally substituted with 1 to 5 R' groups. In certain embodiments of a compound of Formula (J) or R! N 40 (I), R is C alkyl optionally substituted with 1 to 5 n NN Substituents independently selected from the group consist ing of halogen, —OR, C(O)OR", C(O)NR'R', SR, R2 21N als NH2 Chaloalkyl, Cecycloalkyl, 3 to 6 membered heterocy clyl, and Co aryl; wherein each Cecycloalkyl, 3 to 6 R3 45 membered heterocyclyl, and Co aryl is optionally Substi tuted with 1 to 5 R' groups. In certain embodiments of a or a pharmaceutically acceptable salt thereof, wherein: compound of Formula (J) or (I), R is Cls alkyl optionally R" is selected from the group consisting of hydrogen, substituted with 1 to 5 substituents independently selected halogen, Calkyl, CN, NR'R''. —S(O), R', and from the group consisting of halogen, —OR", C(O)OR, OR", wherein Calkyl is optionally substituted with 1 50 NRC(O)R', SR", Chaloalkyl, Cecycloalkyl, 3 to 6 to 5 R' groups: membered heterocyclyl, and Co aryl; wherein each R is selected from the group consisting of hydrogen, Cecycloalkyl, 3 to 6 membered heterocyclyl, and Co aryl halogen, Calkyl, CN, NR'R'', S(O).R" and is optionally substituted with 1 to 5 R' groups. OR", wherein Calkyl is optionally substituted with 1 In certain embodiments of a compound of Formula (J) or to 5 R' groups: 55 (I), R is C, alkyl optionally substituted with 1 to 3 R is selected from the group consisting of hydrogen, Substituents independently selected from the group consist halogen, Calkyl, CN, NR'R'', S(O).R", and ing of halogen, -OR", —C(O)OR", —C(O)NR'R''. - SR", OR", wherein Calkyl is optionally substituted with 1 —Chaloalkyl, Cecycloalkyl, 3 to 6 membered hetero to 5 R' groups; cyclyl and Co-o aryl; wherein each Cs-cycloalkyl and Co-o R" is C. alkyl which is optionally substituted with 1 to 60 aryl is optionally substituted with 1 to 3 R' groups. In 5 substituents independently selected from halogen, certain embodiments of a compound of Formula (J) or (I), OR, NR'R'', CN, C(O)R, C(O)OR", R" is Cls alkyl optionally substituted with 1 to 3 substituents C(O)NR'R'', OC(O)NR'R'', NRC(O)R’, independently selected from the group consisting of halo NRC(O)NR, NRC(O)CR', SR, S(O), gen, —OR", —C(O)OR", NRC(O)R’, - SR", —C, R", -S(O)NR'R'', -NR'S(O).R, Chaloalkyl, 65 haloalkyl, Cecycloalkyl, 3 to 6 membered heterocyclyl and C-cycloalkyl, 3 to 6 membered heterocyclyl wherein Coo aryl; wherein each Cs-cycloalkyl and Co aryl is the 3 to 6 membered heterocyclyl has 1 to 3 heteroa optionally substituted with 1 to 3 R' groups. US 9,670,205 B2 17 18 In certain embodiments of a compound of Formula (J) or -continued (I), R is C alkyl optionally substituted with 1 or 2 substituents independently selected halogen, —OR', —C(O)CR, —C(O)NR'R''. - SR", Chaloalkyl, C-cy cloalkyl, 3 to 6 membered heterocyclyl and Co aryl; wherein each Cecycloalkyl and Caryl is optionally substituted with 1 to 3 R' groups and wherein RandR are each independently hydrogen or Calkyl, wherein the Ca wn alkyl is optionally substituted with NH, OH, or pyridyl. In certain embodiments of a compound of Formula (J) or (I), R" is Cls alkyl which is optionally substituted with 1 or 2 Substituents independently selected from the group consist ing of halogen, --OR", C(O)CR", NRC(O)R’, - SR", Chaloalkyl, C-cycloalkyl, 3 to 6 membered heterocyclyl and Co-o aryl; wherein each C3-cycloalkyl and Co aryl is optionally substituted with 1 to 3 R' groups and wherein R and R are each independently hydrogen or C, alkyl, wherein each C alkyl is optionally substituted with —NH, OH, or pyridyl. In certain embodiments of a compound of Formula (J) or (I), R is C, alkyl optionally substituted with 1 or 2 Substituents independently selected from the group consist ing of OH, CF –C(O)OH, -C(O)OCH, C(O)NH2, SCH, C(O)NHCH, C(O)NHCHCH-NH, C(O) NHCHCH-OH, -C(O)NHCH-pyridyl, phenyl, tetrahy drofuranyl, and cyclopropyl. In certain embodiments of a compound of Formula (J) or (I), R is Cls alkyl which is 25 optionally substituted with 1 or 2 substituents independently selected from OH, CF – C(O)OH, -C(O)OCH SCH, NHC(O)CH, -NHC(O)CHCH-NH, -NHC(O) CHCH-OH, -NHC(O)CH-pyridyl, phenyl, tetrahydro furanyl, and cyclopropyl. In certain embodiments of a compound of Formula (J) or (I), R is C. alkyl optionally substituted with 1 or 2 Substituents independently selected from the group consist ing of OH, CF –C(O)OH, -C(O)OCH, C(O)NH2, SCH, C(O)NHCH, C(O)NHCHCH-NH, C(O) NHCHCH-OH, and C(O)NHCH-pyridyl. In certain embodiments of a compound of Formula (J) or (I), R is C. /NOH alkyl which is optionally substituted with 1 or 2 substituents independently selected from OH, CF, —C(O)OH, C(O) OCH, SCH, -NHC(O)CH, -NHC(O)CHCH-NH, r r —NHC(O)CHCH-OH, -NHC(O)CH-pyridyl, phenyl, tetrahydrofuranyl, and cyclopropyl. In certain embodiments of a compound of Formula (J) or (I), R is C, alkyl which is optionally substituted with OH. In certain embodiments of a compound of Formula (J) or (I), 45 R" is Cls alkyl which is optionally substituted with OH. In certain embodiments of a compound of Formula (J) or (I), R" is Cls alkyl which is substituted with NHC(O)CHs. In certain embodiments of a compound of Formula (J) or (I), R is C. alkyl which is optionally substituted with OH. 50 In certain embodiments of a compound of Formula (J) or (I), R" is C, alkyl which is substituted with NHC(O)CH. In certain embodiments of a compound of Formula (J) or NH N (I), R has at least one chiral center. In certain embodiments, the at least one chiral center is in the S configuration. In 55 certain embodiments, the at least one chiral center is in the R configuration. In certain embodiments of a compound of Formula (J) or In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of: (I), R is selected from the group consisting of: 60

Q Q- V. 65 QQ- V. US 9,670,205 B2 19 20 -continued -continued

US 9,670,205 B2 21 22 -continued -continued

2N. 2N. 5 HN / HN 2N NH2 v

F O

50 O In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of:

55 FC NH SN NH2

NH2 wn- OH OH v. 65 US 9,670,205 B2 23 24 -continued -continued

H H N 1 N1MV 5 OH and OH O O O CF F F

OH OH 10 In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of:

F OH F OH N NH/OH F al H

OH Y 25 NH -> a v. F

NH N-1No.O O 35

r R 40

45 e voHN vicHN M F 50

OH OH 55 In certain embodiments of a compound of Formula (J) or Q (I), R is selected from the group consisting of:

O O H N 65 F O O US 9,670,205 B2 25 26 -continued -continued

and 5 NH OH O O F O " In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of: NH/NH. 15 O

\ and S. 2O NH N

H N 1 30 O F

In certain embodiments of a compound of Formula (J) or 3s (I), R is selected from the group consisting of:

NH2 '' NH2 w

40 O O

N NH/OH

O O s): US 9,670,205 B2 27 28 -continued -continued

5 O N NH2 Q

10 Ns 's- OH OH Q

2O OH Q-w C.

O s OH OH 25 w

50 In certain embodiments of a compound of Formula (J) or Z \ (I), R is selected from the group consisting of: NH sN NH2

FC OH

OH '' OH CF3 65 US 9,670,205 B2 29 30

-continued -continued

s' OH s OH s OH x w w

15 F s

25 ". OH and * w OH

In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of: US 9,670,205 B2 31 32 -continued -continued

H O ".w C1OH aCOH 5

HO 10 OH OH N

NH N1 No

". ns1 '' OH /MV \, 55 HO In certain embodiments of a compound of Formula (J) or ".w OH ".w OH (I), R is selected from the group consisting of:

H N N NH/OH 65 O O US 9,670,205 B2 33 34 -continued -continued

s). NH C)SN O

H 15 ". NH /NOH vC O

w 1 w 1 O O 25 s F F

In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of: 30

40 In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of:

N NH-/OH 50

O OH OH

60 H H Na 1. and N S so 1 NH / NH2 O O 65 In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of: US 9,670,205 B2 35 36 -continued

OH OH OH H s Ns S.1. 1 O|No and O 10 In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of:

CF OH OH s

H H Na S 1. N so and O O

40 In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of:

45 w

60 H

WS N1N O|Yo and O

65 In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of: US 9,670,205 B2 37 38

cCF 5

In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of:

OH OH 65 CF In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of: US 9,670,205 B2 39 40 -continued -continued

O NH2 OH N 5 'n-so CF

O O

N S 2O

OH OH v- OH

30 OH O- OH N N N/OH XX

35 O Do ". OH OH 40 HO O OH OH

O 55 NH OH In certain embodiments of a compound of Formula (J) or (I), R is selected from the group consisting of 60

FC OH NH/NH, and 65 O US 9,670,205 B2 41 -continued Formula II R R9

5 R7 HN R6 a 9 R N R5 n n N 10 In certain embodiments of a compound of Formula (J) or R2 an als NH2 (I), R is R3

15 or a pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of hydrogen, w halogen, and methyl; R is selected from the group consisting of hydrogen, halogen, and methyl; or RandR together forman oxo group; In certain embodiments of a compound of Formula (J) or R’ is selected from the group consisting of hydrogen, (I), R is halogen, OR" and NR'R'': 25 R is selected from the group consisting of hydrogen and methyl; H R is is selected from the group consisting of C. alkyl, w 1 Cs-cycloalkyl, and —S Calkyl: 30 R" and R are independently selected from the group O consisting of hydrogen and Calkyl; wherein each Calkyl is optionally substituted with 1 to 3 substitu In certain embodiments of a compound of Formula (J) or ents independently selected from the group consisting (I), R is of halogen, hydroxyl, and pyridyl; and R', R, and R' 35 are as otherwise defined herein. For example, in Formula (II), (IIa), and (IIb), R' is selected from the group consisting of hydrogen, halogen, Calkyl, CN, NR'R'', S(O) R', and OR, wherein w 40 Calkyl is optionally substituted with 1 to 5 R”groups; R is selected from the group consisting of hydrogen, halogen, Calkyl, CN, NR'R'', -S(O)R and OR", wherein Calkyl is optionally substituted with 1 to 5 R' groups; In certain embodiments of a compound of Formula (J) or and R is selected from the group consisting of hydrogen, (I), R is 45 halogen, Calkyl, CN, NR'R'', S(O).R", and OR", wherein Calkyl is optionally substituted with 1 to 5 R' groups: In certain embodiments, the compound of Formula (II) is a compound of Formula (IIa) 1 50 O Formula IIa

In certain embodiments of a compound of Formula (J) or (I), R is

65 In certain embodiments, the compound of Formula (J) or In certain embodiments, the compound of Formula (II) is (I) is a compound of Formula (II) a compound of Formula (IIb) US 9,670,205 B2 43 44 In certain embodiments of a compound of Formula (IIa), Formula IIb

10 is selected from

In certain embodiments of the compound of Formula (II), 15 (IIa), or (IIb), R is hydrogen; R is hydrogen; or RandR together form an oxo group; R is OR or NR'R'': R is hydrogen; R is C alkyl, cyclopropyl or - SCH: R* and R” are independently selected from the group consisting of hydrogen and Calkyl, wherein each Calkyl is option ally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl, pyrid-2-yl, and CF, and R", R, and R are as otherwise defined herein. In certain embodiments, R and R are hydrogen. In certain embodi ments, R is OH or NH2. In certain embodiments, R' and R' are hydrogen. 25 In certain embodiments of a compound of Formula (IIa),

35 is selected from

US 9,670,205 B2 45 46 In certain embodiments of a compound of formula (IIb), -continued

R R9 5 R7 R6 R5 a 10 is selected from In certain embodiments of a compound of formula (IIb).

OH OH CF

is selected from On NH2 25

O O

Ns 30 OH OH

65 US 9,670,205 B2 47 48 -continued Formula (IIIa)

NH n1N NH2

In certain embodiments the compound of Formula (III) is 15 a compound of Formula (IIIb)

IIIb.

OH and OH. R7 HN R6 R N R5 n n N In certain embodiments of the compound of Formula (II), 25 (IIa), or (IIb), R is hydrogen, R is hydrogen, or Rand R' als together form an oxo group, R7 is OR or NR'R'', R is R2 21\ NH2 hydrogen, R is Calkyl, cyclopropyl or - SCH3, and R' R3 and Rare independently selected from the group consisting of hydrogen and Calkyl; wherein each Calkyl is option 30 ally substituted with 1 to 3 substituents independently In certain embodiments of the compound of Formula (III), selected from halogen, hydroxyl, pyrid-2-yl, and CF. In (IIIa), or (IIIb), Rand Rare both hydrogen and R is OR", certain embodiments of the compound of Formula (II), (IIa), wherein R is hydrogen or Calkyl. In certain embodiments or (IIb), R is OH or NH. of the compound of Formula (III), (IIIa), or (IIIb), RandR 35 are both hydrogen and R is OH. In certain embodiments of In certain embodiments of a compound of Formula (J), the compound of Formula (III), (IIIa), or (IIIb), R. R. R. Formula (I), or Formula (II), the compound is a compound and Rare each hydrogen, and R is OH. of Formula (III) In certain embodiments of the compound of Formula (III), (IIIa), or (IIIb), R and R together form an oxo group and 40 R’ is selected from the group consisting of OR" and NR'R''. Formula (III) wherein R and R are independently selected from the group consisting of hydrogen and Calkyl. In certain R7 embodiments of the compound of Formula (III), (IIIa), or HN R6 45 (IIIb), R and R together form an oxo group and R is R N R5 selected from the group consisting of OR" and NR'R'', n n N wherein R and R are independently selected from the group consisting of hydrogen and methyl. R2 21- als NH2 In certain embodiments of a compound of Formula (J), or 50 Formula (I), the compound is a compound of Formula (IV): R3

Formula (IV) wherein

R is hydrogen; 55 R is hydrogen; or RandR together form an oxo group; R’ is selected from the group consisting of OR" and NR'R'; R" and R are independently selected from the group consisting of hydrogen and Calkyl; wherein each 60 Calkyl is optionally substituted with 1 to 3 substitu ents independently selected from the group consisting of halogen and hydroxyl and R', R, and R are as otherwise defined herein. 65 The R', R, and R groups of Formula (IV) are as defined In certain embodiments the compound of Formula (III) is above for Formula (J) or (I). The R', R'' and R' groups are a compound of Formula (IIIa) as defined above for R' in Formula (J) or Formula (I). US 9,670,205 B2 49 50 In certain embodiments, the compound of Formula (IV), halogen groups. In certain embodiments, R is selected from or a pharmaceutically acceptable salt thereof, is a compound hydrogen, methyl, ethyl, fluoro, chloro, bromo, CF, CN, of Formula (IVa): OH, OMe, and OEt. In certain embodiments, R is selected from hydrogen, methyl, fluoro, and chloro. In certain embodiments, R is selected from hydrogen and fluoro. In Formula (IVa) certain embodiments, R is selected from hydrogen, halo gen, NH, C alkyl, CN, and OR', wherein C alkyl is optionally substituted with 1 to 5 R' groups. In certain embodiments, R is selected from hydrogen, methyl, ethyl, 10 NH, fluoro, chloro, bromo, CF, CN, OH, OMe, and OEt. R of Formula (IV), (IVa) and (IVb) can be any suitable group selected from hydrogen, halogen, Calkyl, CN, - NR'R'', -S(O) R', and OR", wherein Calkyl is optionally substituted with 1 to 5 R' groups. In certain 15 embodiments, R is selected from hydrogen, halogen, C. alkyl, CN, and OR", wherein C alkyl is optionally sub stituted with 1 to 5 R' groups. In certain embodiments, R In certain embodiments, the compound of Formula (IV), can be selected from hydrogen, halogen, and C alkyl. In or a pharmaceutically acceptable salt thereof, is a compound certain embodiments, R can be selected from hydrogen, of Formula (IVb): methyl, fluoro, and chloro. In certain embodiments, R can be selected from hydrogen and methyl. In certain embodi ments, R is selected from hydrogen, halogen, NH, C, Formula (IVb) alkyl, CN, and OR", wherein Calkyl is optionally substi tuted with 1 to 5 R' groups. In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is the compound wherein R' is selected from the group consisting of hydrogen, halogen, C-alkyl, CN, -NR'R''. 30 —S(O) R', and OR, wherein Calkyl is optionally sub stituted with 1 to 5R'groups, R is selected from the group consisting of hydrogen, halogen, C-alkyl, CN, NR'R''. —S(O) R' and OR", wherein Calkyl is optionally sub stituted with 1 to 5 R' groups, and R is selected from the 35 group consisting of hydrogen, halogen, Calkyl, CN. The groups R', R. R. R', R'' and R' of Formula (IVa) - NR'R'', -S(O) R', and OR", wherein Calkyl is and (IVb) are as defined for Formula (J), (I) or (IV) above, optionally substituted with 1 to 5 R' groups. or as defined below, or any combination thereof. In certain embodiments, the compound of Formula (IV), R' of Formula (IV), (IVa) and (IVb) can be any suitable (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, group selected from hydrogen, halogen, Calkyl, CN. 40 is the compound wherein R' is selected from the group —NR'R'', -S(O) R', and OR", wherein Calkyl is consisting of hydrogen, halogen, and C alkyl, wherein optionally substituted with 1 to 5 R' groups. In certain C. alkyl is optionally substituted with 1 to 5 halogen embodiments, R' is selected from hydrogen, halogen, C. groups, R is selected from the group consisting of hydro alkyl, CN, and OR", wherein C alkyl is optionally sub gen, halogen, C. alkyl, CN and OR, wherein C- alkyl is stituted with 1 to 5 R' groups. In certain embodiments, R' 45 optionally substituted with 1 to 5 halogen groups, and R is can be hydrogen, halogen, and C alkyl, wherein C- alkyl selected from the group consisting of hydrogen, halogen, is optionally Substituted with 1 to 5 halogen groups. In and C alkyl. certain embodiments, R' can be hydrogen, fluoro, chloro, In certain embodiments, the compound of Formula (IV), bromo, methyl or ethyl, wherein each methyl or ethyl group (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is optionally Substituted with 1 to 5 halogen groups. In 50 is the compound wherein R' is selected from the group certain embodiments, R' can be hydrogen, fluoro, chloro, consisting of hydrogen, methyl, fluoro, chloro, and CF, R bromo, methyl or ethyl, wherein each methyl or ethyl group is selected from the group consisting of hydrogen, methyl, is optionally substituted with 1 to 5 fluoro groups. In certain ethyl, fluoro, chloro, bromo, CF, CN, OH, OMe, and OEt, embodiments, R' can be hydrogen, methyl, fluoro, chloro, and R is selected from the group consisting of hydrogen, and CFs. In certain embodiments, R' can be hydrogen. In 55 methyl, fluoro, and chloro. certain embodiments, R' is selected from hydrogen, halo In certain embodiments, the compound of Formula (IV), gen, NH, C alkyl, CN, and OR', wherein C alkyl is (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 5 R' groups. is the compound wherein R' is selected from the group R° of Formula (IV), (IVa) and (IVb) can be any suitable consisting of hydrogen, methyl, fluoro, chloro, and CF, R group selected from hydrogen, halogen, Calkyl, CN, 60 is selected from the group consisting of hydrogen, methyl, -NR'R'', S(O)R and OR, wherein Calkyl is ethyl, NH, fluoro, chloro, bromo, CF, CN, OH, OMe, and optionally substituted with 1 to 5 R' groups. In certain OEt, and R is selected from the group consisting of hydro embodiments, R is selected from hydrogen, halogen, gen, methyl, fluoro, and chloro. Calkyl, CN, and OR, wherein C alkyl optionally In certain embodiments, the compound of Formula (IV), substituted with 1 to 5 R' groups. In certain embodiments, 65 (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, R is selected from hydrogen, halogen, Cls alkyl, CN and is the compound wherein R' is hydrogen, R is selected from OR", wherein C- alkyl is optionally substituted with 1 to 5 the group consisting of hydrogen, methyl, ethyl, fluoro, US 9,670,205 B2 51 52 chloro, and bromo, and R is selected from the group wherein R' can be selected from C, alkyl, -C(O)NR'R'', consisting of hydrogen and methyl. and 5 membered heteroaryl having 1 to 3 nitrogen heteroa In certain embodiments, the compound of Formula (IV), toms, wherein C- alkyl is optionally substituted with 1 to (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, 5 substituents independently selected from halogen, —OH, is the compound wherein R' is hydrogen. R is selected from NRR, NRC(O)R, NRS(O),R, and C. the group consisting of hydrogen and fluoro, and R is haloalkyl, and each R" and R is independently selected selected from the group consisting of hydrogen and methyl. from the group consisting of hydrogen and C alkyl, In certain embodiments, R' of Formula (IV), (IVa) and wherein each C alkyl is optionally substituted with 1 to 3 (IVb) can be any Suitable group selected from hydrogen, substituents independently selected from hydroxyl and C. alkyl, C. cycloalkyl, and C- haloalkyl. In certain 10 amino. In certain embodiments, the compound of Formula embodiments, the compound of Formula (IV), (IVa) or (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt (IVb), or a pharmaceutically acceptable salt thereof, is the thereof, wherein R'' is C alkyl, optionally substituted compound wherein R' is selected from the group consisting with 1 to 3 substituents independently selected from halo of hydrogen, C alkyl and C. haloalkyl. In certain gen, OH, -NH. NHC(O)—Calkyl, - NHS(O) embodiments, the compound of Formula (IV), (IVa) or 15 C. alkyl, and C- haloalkyl. In certain embodiments, the (IVb), or a pharmaceutically acceptable salt thereof, is the compound of Formula (IV), (IVa) or (IVb), or a pharma compound wherein R' is selected from the group consisting ceutically acceptable salt thereof, wherein R' is methyl or of C alkyl and Chaloalkyl. In certain embodiments, the ethyl, each optionally substituted with 1 or 2 substituents compound of Formula (IV), (IVa) or (IVb), or a pharma independently selected from halogen, —OH, -NH2, ceutically acceptable salt thereof, is the compound wherein —NHC(O)—C-alkyl, and C. haloalkyl. In certain R' can be selected from hydrogen, methyl, ethyl or CF. In embodiments, the compound of Formula (IV), (IVa) or certain embodiments, the compound of Formula (IV), (IVa) (IVb), or a pharmaceutically acceptable salt thereof, wherein or (IVb), or a pharmaceutically acceptable salt thereof, is the R' is methyl or ethyl, wherein the methyl or ethyl is compound wherein R' can be selected from methyl, ethyl or substituted with 1 or 2 substituents independently selected CF. In certain embodiments, the compound of Formula 25 from —OH and —NHC(O)CH. In certain embodiments, (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt the compound of Formula (IV), (IVa) or (IVb), or a phar thereof, is the compound wherein R' can be selected from maceutically acceptable salt thereof, wherein R' can be hydrogen, methyl, or CF. In certain embodiments, the selected from CHOH, CHCH-OH, CH(Me)OH, compound of Formula (IV), (IVa) or (IVb), or a pharma ceutically acceptable salt thereof, is the compound wherein 30 R' can be selected from methyl, or CF. In certain embodi ments, the compound of Formula (IV), (IVa) or (IVb), or a CHCH-OH, C(O)NH CHCH-NH C(O)NH-(pyridin pharmaceutically acceptable salt thereof, is the compound 2-ylmethyl), imidazolyl, and triazolyl. In certain embodi wherein R' can be selected from hydrogen or methyl. In ments, the compound of Formula (IV), (IVa) or (IVb), or a certain embodiments, the compound of Formula (IV), (IVa) 35 pharmaceutically acceptable salt thereof, wherein R' can be or (IVb), or a pharmaceutically acceptable salt thereof, selected from CHOH, CH(Me)OH, CH(CHF)OH, and wherein R'' is selected from the group consisting of methyl CH-NHC(O)Ne. In certain embodiments, the compound of and CF. In certain embodiments, the compound of Formula Formula (IV), (IVa) or (IVb), or a pharmaceutically accept (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt able salt thereof, wherein R' can be selected from CH-OH, thereof, is the compound wherein R'' is methyl. In certain 40 CH(Me)OH, and CH-NHC(O)Ne. In certain embodiments, embodiments, the compound of Formula (IV), (IVa) or the compound of Formula (IV), (IVa) or (IVb), or a phar (IVb), or a pharmaceutically acceptable salt thereof, is the maceutically acceptable salt thereof, wherein R' is compound wherein R' is hydrogen. - CH-OH or -CH2NC(O)CH. R° of Formula (IV), (IVa) and (IVb) can be any suitable In certain embodiments, the compound of Formula (IV), group selected from C-alkyl, halogen, OR", NR'R''. 45 (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, CN, C(O)R, C(O)OR, C(O)NR'R'', OC(O) wherein R is C, alkyl substituted with - NRC(O)R’, NR'R'', NRC(O)R’, NRC(O)NR', NRC(O)OR, wherein each R" and R is independently selected from the - SR", S(O) R', S(O)NR'R'', NRS(O).R. C. group consisting of hydrogen and C alkyl, wherein each haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl C. alkyl is optionally substituted with 1 to 3 substituents wherein the 3 to 6 membered heterocyclyl has 1 to 3 50 independently selected from hydroxyl and amino. heteroatoms selected from oxygen, nitrogen, and Sulfur, R" of Formula (IV), (IVa) and (IVb) can be any suitable Caryl, and 5 to 10 membered heteroaryl wherein the 5 group selected from C, alkyl, halogen, —OR", NR'R''. to 10 membered heteroaryl has 1 to 3 heteroatoms selected CN, C(O)R, C(O)OR, C(O)NR'R'', OC(O) from oxygen, nitrogen, and sulfur, wherein the C- alkyl NR'R'', NRC(O)R’, NRC(O)NR', NRC(O)OR, group is optionally substituted with 1 to 5 substituents 55 - SR", S(O) R', S(O)NR'R'', NRS(O).R. C. independently selected from halogen, —OR", NR'R''. haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl CN, C(O)R, C(O)OR, C(O)NR'R'', OC(O) wherein the 3 to 6 membered heterocyclyl has 1 to 3 NR'R'', NRC(O)R’, NRC(O)NR', NRC(O)OR, heteroatoms selected from oxygen, nitrogen, and Sulfur, - SR", S(O) R', S(O)NR'R'', NRS(O).R. C. Caryl, and 5 to 10 membered heteroaryl wherein the 5 haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl 60 to 10 membered heteroaryl has 1 to 3 heteroatoms selected wherein the 3 to 6 membered heterocyclyl has 1 to 3 from oxygen, nitrogen, and Sulfur, wherein the C- alkyl is heteroatoms selected from oxygen, nitrogen, and Sulfur, optionally substituted with 1 to 5 substituents independently Caryl, and 5 to 10 membered heteroaryl wherein the 5 selected from halogen, —OR, NR'R'', CN, C(O)R’, to 10 membered heteroaryl has 1 to 3 heteroatoms selected C(O)OR, C(O)NR'R'', OC(O)NR'R'', NRC(O) from oxygen, nitrogen, and Sulfur. 65 R, NRC(O)NR, NRC(O)OR', SR, S(O), R, In certain embodiments, the compound of Formula (IV), —S(O)NR'R'', NRS(O).R. C. haloalkyl, C. (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to US 9,670,205 B2 53 54 6 membered heterocyclyl has 1 to 3 heteroatoms selected independently be selected from hydrogen, methyl, ethyl, from oxygen, nitrogen, and sulfur, Co aryl, and 5 to 10 CHCH-OH, and CHCH-NH. In certain embodiments, R' membered heteroaryl wherein the 5 to 10 membered het and R' can each independently be selected from hydrogen, eroaryl has 1 to 3 heteroatoms selected from oxygen, nitro methyl and ethyl. In certain embodiments, R and R' can gen, and Sulfur. each independently be selected from hydrogen and methyl. In certain embodiments, the compound of Formula (IV), In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is the compound wherein R' is C. alkyl optionally sub is the compound wherein: stituted with 1 to 2 substituents independently selected from R" is selected from the group consisting of hydrogen, halogen and —OH. In certain embodiments, the compound 10 of Formula (IV), (IVa) or (IVb), or a pharmaceutically halogen, Calkyl, CN, NR'R'', S(O).R", and acceptable salt thereof, is the compound wherein R' is C. OR", wherein Calkyl is optionally substituted with 1 alkyl optionally substituted with 1 to 2 halogen substituents. to 5 R' groups: In certain embodiments, the compound of Formula (IV), R is selected from the group consisting of hydrogen, (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, 15 halogen, Calkyl, CN, NR'R'', S(O)R and is the compound wherein R' is C alkyl. Representative OR", wherein Calkyl is optionally substituted with 1 C. alkyl groups for R' include, but are not limited to, to 5 R' groups: n-propyl, iso-propyl. n-butyl, sec-butyl, iso-butyl, tert-butyl, R is selected from the group consisting of hydrogen, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl and halogen, Calkyl, CN, NR'R'', S(O).R", and 3-pentyl. In certain embodiments, the compound of Formula OR", wherein Calkyl is optionally substituted with 1 (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt to 5 R' groups; thereof, is the compound wherein R' is propyl, butyl or R'' is selected from the group consisting of hydrogen, pentyl. In certain embodiments, the compound of Formula C. alkyl, C. cycloalkyl, and Chaloalkyl, (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt R" is selected from Cs alkyl, halogen, OR", thereof, is the compound wherein R' is n-propyl. n-butyl or 25 NR'R'', CN, C(O)R, C(O)OR, C(O) n-pentyl. In certain embodiments, the compound of Formula NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt NR, NRC(O)OR. - SR", S(O) R', S(O), thereof, is the compound wherein R' is propyl or butyl. NR'R''. - NRS(O).R., C haloalkyl, C. R' of Formula (IV), (IVa) and (IVb) can be any suitable cycloalkyl, 3 to 6 membered heterocyclyl wherein the group selected from halogen, Chaloalkyl, CN, NR'R''. 30 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms S(O) R', and OR". In certain embodiments, each R' can Selected from oxygen, nitrogen, and Sulfur, Co aryl, independently be selected from halogen, CN, NR'R'', and and 5 to 10 membered heteroaryl wherein the 5 to 10 OR". In certain embodiments, each R' can independently membered heteroaryl has 1 to 3 heteroatoms selected be selected from halogen, CN, NR'R'', and OR". In from oxygen, nitrogen, and Sulfur, wherein the C certain embodiments, each R' can independently be halo 35 alkyl group is optionally substituted with 1 to 5 sub gen. In certain embodiments, each R' can independently be stituents independently selected from halogen, —OR', selected from fluoro, chloro, bromo, CN, —NH, OH, OMe, NR'R'', CN, C(O)R, C(O)OR, C(O) and OEt. In certain embodiments, each R' can indepen NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) dently be selected from fluoro and chloro. NR, NRC(O)OR. - SR", S(O) R', S(O), R" and R of Formula (IV), (IVa) and (IVb) can each 40 NR'R''. - NRS(O).R., C haloalkyl, C. independently be any Suitable group selected from the group cycloalkyl, 3 to 6 membered heterocyclyl wherein the consisting of hydrogen and Calkyl; wherein each 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms Calkyl is optionally substituted with 1 to 5 substituents Selected from oxygen, nitrogen, and Sulfur, Co aryl, independently selected from halogen, hydroxyl, amino. 5 to and 5 to 10 membered heteroaryl wherein the 5 to 10 10 membered heteroaryl wherein the 5 to 10 membered 45 membered heteroaryl has 1 to 3 heteroatoms selected heteroaryl has 1 to 3 heteroatoms selected from oxygen, from oxygen, nitrogen, and Sulfur, nitrogen, and sulfur, and Chaloalkyl. In certain embodi R" is selected from C alkyl, halogen, —OR", ments, R" and R' can each independently be selected from NR'R'', CN, C(O)R, C(O)OR, C(O) hydrogen and C alkyl, wherein each C alkyl is option NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) ally substituted with 1 to 3 substituents independently 50 NR, NRC(O)OR. - SR", S(O) R', S(O), selected from halogen, hydroxyl, amino, and Chaloalkyl. NR'R'', NRS(O).R, C, haloalkyl, C. In certain embodiments, R and R' can each independently cycloalkyl, 3 to 6 membered heterocyclyl wherein the be selected from hydrogen and C alkyl, wherein each C 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms alkyl is optionally substituted with 1 to 3 substituents selected from oxygen, nitrogen, and Sulfur, Co aryl, independently selected from hydroxyl and amino. In certain 55 and 5 to 10 membered heteroaryl wherein the 5 to 10 embodiments, Rand R' can each independently be selected membered heteroaryl has 1 to 3 heteroatoms selected from hydrogen and C alkyl, wherein each C alkyl is from oxygen, nitrogen, and Sulfur, wherein the C optionally substituted with 1 substituent selected from alkyl is optionally substituted with 1 to 5 substituents hydroxyl and amino. In certain embodiments, Rand R' can independently selected from halogen, —OR, each independently be selected from hydrogen and C 60 NR'R'', CN, C(O)R, C(O)OR, C(O) alkyl. In certain embodiments, Rand R' can each indepen NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) dently be selected from hydrogen, methyl, ethyl, propyl. NR, NRC(O)OR. - SR", S(O) R', S(O), butyl, CF, CHCF, CHCHCF CH-OH, CHCH-OH, NR'R''. - NRS(O).R. C. haloalkyl, C. CH-NH and CHCH-NH2. In certain embodiments, R* and cycloalkyl, 3 to 6 membered heterocyclyl wherein the R” can each independently be selected from hydrogen, 65 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms methyl, ethyl, CF, CHOH, CHCH-OH, CH-NH and Selected from oxygen, nitrogen, and Sulfur, Co aryl, CHCH-NH2. In certain embodiments, R and R' can each and 5 to 10 membered heteroaryl wherein the 5 to 10 US 9,670,205 B2 55 56 membered heteroaryl has 1 to 3 heteroatoms selected 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms from oxygen, nitrogen, and Sulfur, selected from oxygen, nitrogen, and Sulfur, Co aryl, each R” is independently selected from the group con and 5 to 10 membered heteroaryl wherein the 5 to 10 sisting of halogen, CN, NR'R'', and OR"; and membered heteroaryl has 1 to 3 heteroatoms selected each R" and R is independently selected from the group from oxygen, nitrogen, and Sulfur, consisting of hydrogen and C alkyl, wherein each each R" is independently selected from the group con C. alkyl is optionally substituted with 1 to 3 substitu sisting of halogen, CN, NR'R'', and OR"; and ents independently selected from halogen, hydroxyl, each R" and R is independently selected from the group amino, and Chaloalkyl. consisting of hydrogen and C alkyl, wherein each In certain embodiments, the compound of Formula (IV), 10 C. alkyl is optionally substituted with 1 to 3 substitu (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, ents independently selected from halogen, hydroxyl, is the compound wherein: amino, and Chaloalkyl. R" is selected from the group consisting of hydrogen, In certain embodiments, the compound of Formula (IV), halogen, Calkyl, CN, NR'R''. —S(O), R', and (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, OR", wherein Calkyl is optionally substituted with 1 15 is the compound wherein: to 5 R' groups; R" is selected from the group consisting of hydrogen, R is selected from the group consisting of hydrogen, halogen, Ce alkyl, CN, and OR, wherein Ce alkyl is halogen, Calkyl, CN, NR'R'', S(O).R" and optionally substituted with 1 to 5 R' groups; OR", wherein Calkyl is optionally substituted with 1 R is selected from the group consisting of hydrogen, to 5 R' groups: halogen, C. alkyl, CN, and OR, wherein Ce alkyl R is selected from the group consisting of hydrogen, optionally substituted with 1 to 5 R' groups: halogen, Calkyl, CN, NR'R'', S(O).R", and R is selected from the group consisting of hydrogen, OR", wherein Calkyl is optionally substituted with 1 halogen, C alkyl, CN, and OR, wherein C alkyl is to 5 R' groups: optionally substituted with 1 to 5 R' groups; R' is selected from the group consisting of C-2 alkyl, 25 R'' is selected from the group consisting of hydrogen, C. cycloalkyl, and Chaloalkyl; C-2 alkyl, C. cycloalkyl, and C1s haloalkyl, R" is selected from Cs alkyl, halogen, —OR", R" is selected from Cs alkyl, halogen, OR", NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR, NRC(O)OR', SR, S(O) R', S(O), 30 NR, NRC(O)OR', SR, S(O), R', S(O), NR'R'', NR"S(O).R, C, haloalkyl, C. NR'R'', NRS(O).R, C, haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl wherein the cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms Selected from oxygen, nitrogen, and Sulfur, Co aryl, Selected from oxygen, nitrogen, and Sulfur, Co aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 35 and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and Sulfur, wherein the C from oxygen, nitrogen, and Sulfur, wherein the C alkyl group is optionally substituted with 1 to 5 sub alkyl group is optionally substituted with 1 to 5 sub stituents independently selected from halogen, —OR', stituents independently selected from halogen, —OR', NR'R'', CN, C(O)R, C(O)OR, C(O) 40 NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR, NRC(O)OR', SR, S(O) R', S(O), NR, NRC(O)OR', SR, S(O), R', S(O), NR'R'', NR"S(O).R, C, haloalkyl, C. NR'R'', NRS(O).R, C, haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl wherein the cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms 45 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms Selected from oxygen, nitrogen, and Sulfur, Co aryl, Selected from oxygen, nitrogen, and Sulfur, Co aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and Sulfur, from oxygen, nitrogen, and Sulfur, R" is selected from C, alkyl, halogen, —OR", 50 R" is selected from C, alkyl, halogen, OR", NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR, NRC(O)OR. - SR", S(O) R', S(O), NR, NRC(O)OR. - SR", S(O) R', S(O), NR'R''. - NRS(O).R. C. haloalkyl, C. NR'R''. - NRS(O).R. C. haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl wherein the 55 cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms Selected from oxygen, nitrogen, and Sulfur, Co aryl, Selected from oxygen, nitrogen, and Sulfur, Co aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and Sulfur, wherein the C 60 from oxygen, nitrogen, and Sulfur, wherein the C alkyl is optionally substituted with 1 to 5 substituents alkyl is optionally substituted with 1 to 5 substituents independently selected from halogen, —OR', independently selected from halogen, —OR', NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR, NRC(O)OR. - SR", S(O) R', S(O), 65 NR, NRC(O)OR. - SR", S(O) R', S(O), NR'R''. - NRS(O).R. C. haloalkyl, C. NR'R''. - NRS(O).R. C. haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl wherein the cycloalkyl, 3 to 6 membered heterocyclyl wherein the US 9,670,205 B2 57 58 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, Co aryl, selected from oxygen, nitrogen, and Sulfur, Co aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and Sulfur, from oxygen, nitrogen, and Sulfur, each R” is independently selected from the group con sisting of halogen, CN, NR'R'', and OR"; and each R' is independently selected from the group con each R" and R is independently selected from the group sisting of halogen, CN, NR'R'', and OR"; and consisting of hydrogen and C alkyl, wherein each each R" and R is independently selected from the group C. alkyl is optionally substituted with 1 to 3 substitu 10 consisting of hydrogen and C alkyl, wherein each ents independently selected from halogen, hydroxyl, C. alkyl is optionally substituted with 1 to 3 substitu amino, and Chaloalkyl. ents independently selected from halogen, hydroxyl, In certain embodiments, the compound of Formula (IV), amino, and Chaloalkyl. (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, In certain embodiments, the compound of Formula (IV), is the compound wherein: 15 (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, R" is selected from the group consisting of hydrogen, wherein R' is methyl or CF, R'' is —CHOH, -CH(Me) halogen, Ce alkyl, CN, and OR, wherein Ce alkyl is OH or - CH-NHC(O)CH, and R' is selected from the optionally substituted with 1 to 5 R' groups; group consisting of propyl, butyl and pentyl. R is selected from the group consisting of hydrogen, In certain embodiments, the compound of Formula (IV), halogen, C. alkyl, CN, and OR, wherein Ce alkyl (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 5 R' groups; wherein R' is methyl or CF, R'' is —CHOH, -CH(Me) R is selected from the group consisting of hydrogen, OH, CH-NHCH(CH)(CF) or - CH-NHC(O)CH, and halogen, Calkyl, CN, and OR, wherein C alkyl is R" is selected from the group consisting of propyl, butyl optionally substituted with 1 to 5 R' groups; and pentyl. R' is selected from the group consisting of C-2 alkyl, 25 C. cycloalkyl, and Chaloalkyl; In certain embodiments, the compound of Formula (IV), R" is selected from Cs alkyl, halogen, —OR", (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, NR'R'', CN, C(O)R, C(O)OR, C(O) wherein R' is methyl, R'' is —CH-OH or -CH-NHC(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) CH, and R' is selected from the group consisting of propyl NR, NRC(O)OR', SR, S(O) R', S(O), 30 and butyl. NR'R'', NR"S(O).R, C, haloalkyl, C. In certain embodiments, the compound of Formula (IV), cycloalkyl, 3 to 6 membered heterocyclyl wherein the or a pharmaceutically acceptable salt thereof, wherein the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms moiety Selected from oxygen, nitrogen, and Sulfur, Co aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 35 membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and Sulfur, wherein the C alkyl group is optionally substituted with 1 to 5 sub stituents independently selected from halogen, —OR', NR'R'', CN, C(O)R, C(O)OR, C(O) 40 NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR, NRC(O)OR', SR, S(O) R', S(O), is NR'R'', NR"S(O).R, C, haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms 45 Selected from oxygen, nitrogen, and Sulfur, Co aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and Sulfur, OH OH R" is selected from C, alkyl, halogen, —OR", 50 NR'R'', CN, C(O)R, C(O)OR, C(O) - NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR, NRC(O)OR. - SR", S(O) R', S(O), NR'R''. - NRS(O).R. C. haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl wherein the 55 CF 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms OH Selected from oxygen, nitrogen, and Sulfur, Co aryl, OH and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and Sulfur, wherein the C 60 alkyl is optionally substituted with 1 to 5 substituents independently selected from halogen, —OR', NR'R'', CN, C(O)R, C(O)OR, C(O) NR'R'', OC(O)NR'R'', NRC(O)R’, NRC(O) NR, NRC(O)OR. - SR", S(O) R', S(O), 65 s OH NR'R''. - NRS(O).R. C. haloalkyl, C. cycloalkyl, 3 to 6 membered heterocyclyl wherein the US 9,670,205 B2 59 60 -continued R13 R11 5 X. ns.1 1 so O is O O 10 In certain embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein the moiety 15 x OH s OH s OH w w

1S H CF 3 w N x' OH 25 w

O s s

30 OH OH OH OH ".w OH ".w OH

s s 35

OH OH H H 40

c Qk Ns so1. ". <- O O O s

45 In certain embodiments, the compound of Formula (IV) OH OH or (IVa), or a pharmaceutically acceptable salt thereof, wherein the moiety

S^"SS R12 H H N1 N so 55 O O is

H H vC1 N N CF 60 O O CH3 s

In certain embodiments, the compound of Formula (IV) 65 xx2. x OH, XX OH , or (IVa), or a pharmaceutically acceptable Salt thereof, wherein the moiety US 9,670,205 B2 61 62 -continued

5 ve vew O 10

H ''' OH, xx 15 ".w N Y O

In certain embodiments, the compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt thereof, 2O wherein the moiety

R13 RI w' OH, w Ns 1 s or 25 so X. O

can also be drawn as the moiety 30 H R13 R11 ".w N 1 R12. O 35 In certain embodiments, the compound of Formula (IV) or (IVa), or a pharmaceutically acceptable Salt thereof, In certain embodiments, the compound of Formula (IV) wherein the moiety or (IVb), or a pharmaceutically acceptable salt thereof, wherein the moiety 40 R13X. R11 45 is is

50 ". 1 CF 3 ". N1 CF 3 CH3 O ÖH, 55 In certain embodiments, the compound of Formula (IV) or (IVa), or a pharmaceutically acceptable Salt thereof, wherein the moiety 60 R13X. R11 65 is US 9,670,205 B2 63 64 In certain embodiments, the compound of Formula (IV) from propyl and butyl. In certain embodiments, the com or (IVb), or a pharmaceutically acceptable salt thereof, pound of Formula (IV), (IVa), or (IVc), or a pharmaceuti wherein the moiety cally acceptable salt thereof, is a compound wherein R is hydrogen, chloro, or fluoro, R' is —CH-OH or CH-NHC (O)CH, and R' is selected from butyl or pentyl. In certain embodiments, the compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IVd)

Formula (IVd)

In certain embodiments, the compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IVc) The R', R. R. R', R, R and R groups of Formula (IVd) can be as defined above for Formula (J), (I), (IV), or 25

(IVa), or any combination thereof. R' can be any suitable Formula (IVc) group selected from hydrogen, C alkyl and Chaloalkyl. In certain embodiments, the compound of Formula (IV), (IVa) or (IVd), or a pharmaceutically acceptable salt thereof, is a compound wherein R' can be selected from hydrogen, 30 C. alkyl and Chaloalkyl. In certain embodiments, the compound of Formula (IV), (IVa) or (IVd), or a pharma ceutically acceptable salt thereof, is a compound wherein R' can be selected from hydrogen, methyl, ethyl and CF. In certain embodiments, the compound of Formula (IV), 35 (IVa) or (IVd), or a pharmaceutically acceptable salt thereof, The R. R'' and R' groups of Formula (IVc) are as is a compound wherein R' can be hydrogen. defined above for Formula (J), (I), (IV) or (IVa), or any In certain embodiments, the compound of Formula (IVd), combination thereof. For example, R can be selected from or a pharmaceutically acceptable salt thereof, is the com hydrogen, halogen, C. alkyl, CN and OR, wherein C pound wherein R' is selected from the group consisting of alkyl is optionally substituted with 1 to 5 halogen groups, 40 hydrogen, halogen, C alkyl, CN, and OR", wherein C R' can be selected from C, alkyl, -C(O)NR'R'', and 5 alkyl is optionally substituted with 1 to 5 R' groups, R is membered heteroaryl having 1 to 3 nitrogen heteroatoms, selected from the group consisting of hydrogen, halogen, wherein C alkyl is optionally substituted with 1 to 5 C. alkyl, CN, and OR", wherein C alkyl optionally Substituents independently selected from halogen, —OH, substituted with 1 to 5 R' groups, R is selected from the NRR, NRC(O)R, NRS(O),R, and C. 45 group consisting of hydrogen, halogen, Ce alkyl, CN, and haloalkyl, and R' can be C. alkyl optionally substituted OR", wherein C alkyl is optionally substituted with 1 to 5 with 1 to 2 substituents independently selected from halogen R" groups, R'' is C alkyl or CF, R' is selected from the and —OH. In certain embodiments, the compound of For group consisting of hydrogen, Calkyl and Chaloalkyl, mula (IV), (IVa), or (IVc), or a pharmaceutically acceptable R" is C alkyl optionally substituted with 1 to 2 halogen salt thereof, is a compound wherein R can be selected from 50 substituents, each R" is independently selected from the hydrogen, methyl, ethyl, fluoro, chloro, bromo, CF, CN, group consisting of halogen, C-haloalkyl, CN, -NR'R''. OH, OMe, and OEt, and R' can be selected CH-OH, S(O).R", and OR", and each R" and R is independently CHCH-OH, CH(Me)OH, CH(CHF)OH, CH(CHF)OH, selected from the group consisting of hydrogen and C CH(CF)OH, CF, CH-NH, CH-NHC(O)Me, CH(CHF) alkyl, wherein each C alkyl is optionally substituted with NHC(O)Me, CHNHS(O)Me, C(O)NH, C(O)NHMe, 55 1 to 3 substituents independently selected from halogen, C(O)NH CHCH-OH, C(O)NH CHCH-NH, C(O) hydroxyl, amino, and Chaloalkyl. NH-(pyridin-2-ylmethyl), imidazolyl, and triazolyl, and R' In certain embodiments, the compound of Formula (IVd), can be propyl, butyl or pentyl. In certain embodiments, the or a pharmaceutically acceptable salt thereof, is the com compound of Formula (IV). (IVa), or (IVc), or a pharma pound wherein R' is selected from the group consisting of ceutically acceptable salt thereof, is a compound wherein R 60 hydrogen, halogen, and Cls alkyl, R is selected from the can be selected from hydrogen, methyl, fluoro, and chloro, group consisting of hydrogen, halogen, and C alkyl, R is and R' can be selected CH-OH, CH(Me)OH, CH(CHF) selected from the group consisting of hydrogen, halogen, OH, and CH-NHC(O)Ne, and R' can be propyl, butyl or and C alkyl, R' is C alkyl or CF, R' is selected from pentyl. In certain embodiments, the compound of Formula the group consisting of hydrogen, C-2alkyl and C (IV), (IVa), or (IVc), or a pharmaceutically acceptable salt 65 haloalkyl, R' is C. alkyl optionally substituted with 1 to thereof, is a compound wherein R is hydrogen or fluoro, R' 2 halogen substituents, and each R" and R is independently is —CH-OH or -CH-NHC(O)CH, and R' is selected selected from the group consisting of hydrogen and C US 9,670,205 B2 65 66 alkyl, wherein each C alkyl is optionally substituted with In certain embodiments, the compound of Formula (IVd), 1 to 3 substituents independently selected from halogen, or a pharmaceutically acceptable Salt thereof, has the struc hydroxyl, amino, and Chaloalkyl. ture: In certain embodiments, the compound of Formula (IVd), or a pharmaceutically acceptable Salt thereof, has the struc- 5 ture:

15 wherein R' is C. alkyl. R', R and R can be as defined above for Formula (J), (I), (IV), (IVa) or (IVd). In certain embodiments, the compound of Formula (IVd), or a pharmaceutically acceptable Salt thereof, has the struc wherein R is selected from the group consisting of hydro- 20 ture: gen, methyl, fluoro, and chloro, R is selected from the group consisting of hydrogen and methyl, R' is selected from the group consisting of hydrogen, C alkyl and Chaloalkyl, R13 R" is C. alkyl, and R is methyl or ethyl, each optionally H substituted with hydroxyl or amino. 25 HNW N In certain embodiments, the compound of Formula (IVd), N O or a pharmaceutically acceptable Salt thereof, has the struc ture: rsrs R2 4\ als NH2 30 wherein R is selected from the group consisting of hydro gen and F, and R' is C. alkyl. In certain embodiments, R and R' can be as defined above for Formula (J), (I), (IV), or (IVa), or any combination thereof. In certain embodiments, the compound of Formula (IVd), 35 or a pharmaceutically acceptable Salt thereof, has the struc ture:

wherein R is selected from the group consisting of hydro- 40 gen, methyl, fluoro, and chloro, R'' is selected from the group consisting of hydrogen, C alkyl and Chaloalkyl, R" is C. alkyl, and R is methyl or ethyl, each optionally substituted with hydroxyl or amino. In certain embodiments, R° and R' can be as defined above for Formula (J), (I), (IV), 45 or (IVa), or any combination thereof. In certain embodiments, the compound of Formula (IVd), or a pharmaceutically acceptable Salt thereof, has the struc wherein R is selected from the group consisting of hydro ture: gen, Cl, and F, and R' is C-alkyl. In certain embodiments, 50 RandR' can be as defined above for Formula (J), (I), (IV), R' s or (IVa), or any combination thereof. s H In certain embodiments, the compound of Formula (IVd), N Rb or a pharmaceutically acceptable Salt thereof, has the struc HN ture: 55 N R12a O rsrs 21 as als NH2 60 wherein R is selected from the group consisting of hydro gen and methyl, R'" is selected from the group consisting of hydrogen, C-2 alkyl and Cls haloalkyl, R' is C. alkyl, 65 and R is methyl or ethyl, each optionally substituted with hydroxyl or amino. US 9,670,205 B2 67 68 wherein R is selected from the group consisting of hydro- -continued gen and methyl, and R' is Calkyl. In certain embodiments, the compound of Formula (J), (I), or (IV), is selected from:

or a pharmaceutically acceptable salt thereof. 50 In certain embodiments, the compound of Formula (J), (I), or (IV), is selected from:

US 9,670,205 B2 69 70 -continued selected from the group consisting of hydrogen, halogen, and C- alkyl, R' is selected from the group consisting of hydrogen, C-2 alkyl and Cls haloalkyl, R' is C. alkyl optionally substituted with 1 to 2 halogen Substituents, and

each R" and R is independently selected from the group consisting of hydrogen and C alkyl, wherein each C alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl, amino, and Chaloalkyl. 10 In certain embodiments, the compound of Formula (J), (I), or (IV), or a pharmaceutically acceptable salt thereof, is a compound of the following formula:

or a pharmaceutically acceptable salt thereof. 15 In certain embodiments, the compound of Formula (J), (I), or (IV), or a pharmaceutically acceptable salt thereof, is a compound of the following formula:

R13 H HNYX- Rb R N R12a O N NN 25 wherein R' is C. alkyl. R', R and R can be as defined R2 21- als NH2 above for Formula (J), (I), (IV), (IVa) or (IVd). In certain embodiments of a compound of Formula (J), R3 (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R' is hydrogen, 30 halogen, or C-alkyl optionally substituted with 1 to 5 R' wherein R' is selected from the group consisting of hydro groups. In certain embodiments of a compound of Formula gen, halogen, C. alkyl, CN, and OR, wherein Ce alkyl is (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), optionally substituted with 1 to 5 R' groups, R is selected or (IVd), R' is hydrogen, halogen, or C-alkyl optionally from the group consisting of hydrogen, halogen, C alkyl, 35 substituted with 1 to 5 R' groups. CN, and OR", wherein C alkyl optionally substituted with In certain embodiments of a compound of Formula (J), 1 to 5 R' groups, R is selected from the group consisting (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R' is hydrogen, of hydrogen, halogen, C. alkyl, CN, and OR, wherein halogen, or C-alkyl optionally substituted with 1 to 5 C, alkyl is optionally substituted with 1 to 5 R' groups, halogens. In certain embodiments of a compound of For R'" is selected from the group consisting of hydrogen, C 40 mula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb). (IV), (IVa), alkyl and Cls haloalkyl, R' is C. alkyl optionally substi (IVb) or (IVd), R' is hydrogen, halogen, or C-alkyl option tuted with 1 to 2 halogen substituents, each R is indepen ally substituted with 1 to 5 halogens. dently selected from the group consisting of halogen, In certain embodiments of a compound of Formula (J), Chaloalkyl, CN, NR'R', S(O) R', and OR, and each (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R' is hydrogen, Cl, R" and R is independently selected from the group consist 45 CH, or CF. In certain embodiments of a compound of ing of hydrogen and C alkyl, wherein each C- alkyl is Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), optionally substituted with 1 to 3 substituents independently (IVa), (IVb) or (IVd), R is hydrogen, C1, CH, or CF. selected from halogen, hydroxyl, amino, and Chaloalkyl. In certain embodiments of a compound of Formula (J), In certain embodiments, the compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R is hydrogen, (I), or (IV), or a pharmaceutically acceptable salt thereof, is 50 halogen, CN, or Calkyl optionally substituted with 1 to 5 a compound of the following formula: R" groups. In certain embodiments of a compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb). (IVc), or (IVd), R is hydrogen, halogen, CN, R13 H or Calkyl optionally substituted with 1 to 5 R' groups. In certain embodiments of a compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R is hydrogen, HNYX- r Rb halogen, CN or Calkyl optionally substituted with 1 to 5 R N R12a O halogens. In certain embodiments of a compound of For n NN mula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb). (IV), (IVa), 60 (IVb). (IVc), or (IVd), R is hydrogen, halogen, CN or R2 an als NH2 Calkyl optionally substituted with 1 to 5 halogens. In certain embodiments of a compound of Formula (J), R3 (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R is hydrogen, CH, —CHCH. F. Br, Cl, or CN. In certain embodiments wherein R' is selected from the group consisting of hydro 65 of a compound of Formula (J), (I), (II), (IIa), (IIb), (III), gen, halogen, and Cls alkyl, R is selected from the group (IIIa), (IIIb), (IV), (IVa), (IVb). (IVc), or (IVd), R is consisting of hydrogen, halogen, and Cls alkyl, R is hydrogen, CH, —CHCH. F. Br, Cl, or CN.

US 9,670,205 B2 73 74 In certain embodiments, the compound of Formula (J) or -continued (I) is selected from: N

US 9,670,205 B2 75 76 -continued -continued

US 9,670,205 B2 77 78

-continued

or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (J) or (I) is selected from: US 9,670,205 B2 79 80 -continued -continued

US 9,670,205 B2 81 82 -continued -continued

OH w w OH HN 5 HN and N N-1s n NN n alsN F 21 Nals NH2 10 F 2 N NH2

s or a pharmaceutically acceptable salt thereof. OH In certain embodiments, the compound of Formula (J) is HN is selected from: N n SN

F 2 Nals NH2 2O w OH HN or a pharmaceutically acceptable salt thereof. F NN In certain embodiments, the compound of Formula (J) or es (I) is selected from: 25 F N 2 NH2

, and 30 HNW w OH NN 35 2 N NH2

OH HN

45 NN

Nals NH2

50 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (J) or (I) is selected from:

65 US 9,670,205 B2 83 84

-continued -continued US 9,670,205 B2 85 86 -continued -continued

US 9,670,205 B2 87 88 -continued -continued

US 9,670,205 B2 89 90 -continued -continued

US 9,670,205 B2 91 92

-continued -continued F F US 9,670,205 B2 93 94 -continued -continued

NN1 SN O

F 4\ als NH2 10 NH2:

or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (J),

15 (I), (IV), or (IVa) is selected from: US 9,670,205 B2 95 96 -continued In certain embodiments, the compound of Formula (J), (I), (IV), or (IVa) is selected from:

N O n n N 15 C 4N als NH2

30 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (J), 35 (I), (IV), or (IVa) is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (J),

(I), (IV), or (IVa) is selected from: 40

50 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (J), (I), (IV), or (IVa) is selected from:

65 or a pharmaceutically acceptable salt thereof. US 9,670,205 B2 97 98 -continued -continued

or a pharmaceutically acceptable salt thereof. As used herein, “a compound of Formula (I)” includes compounds for Formula (II) (IIa), (IIb), (III), (IIIa), (IIIb). (IV), (IVa), (IVb). (IVc), or (IVd). 55 III. Compositions In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g. a compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb). (IVc), or 60 (IVd)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agent, as more fully set forth below. 65 Pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be prepared with one or more pharmaceutically US 9,670,205 B2 99 100 acceptable excipients which may be selected in accord with The amount of active ingredient that may be combined ordinary practice. Tablets may contain excipients including with the inactive ingredients to produce a dosage form may glidants, fillers, binders and the like. Aqueous compositions vary depending upon the intended treatment Subject and the may be prepared in sterile form, and when intended for particular mode of administration. For example, in some delivery by other than oral administration generally may be embodiments, a dosage form for oral administration to isotonic. All compositions may optionally contain excipients humans may contain approximately 1 to 1000 mg of active such as those set forth in the Rowe et al, Handbook of material formulated with an appropriate and convenient Pharmaceutical Excipients, 6" edition, American Pharma amount of a pharmaceutically acceptable excipient. In cer cists Association, 2009. Excipients can include ascorbic acid tain embodiments, the pharmaceutically acceptable excipi and other antioxidants, chelating agents such as EDTA, 10 ent varies from about 5 to about 95% of the total composi carbohydrates Such as dextrin, hydroxyalkylcellulose, tions (weight:weight). hydroxyalkylmethylcellulose, stearic acid and the like. In In certain embodiments, a composition comprising a certain embodiments, the composition is provided as a Solid compound of the present disclosure (e.g. a compound of dosage form, including a solid oral dosage form. Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), The compositions include those suitable for various 15 (IVa), (IVb). (IVc), or (IVd)), or a pharmaceutically accept administration routes, including oral administration. The able salt thereof in one variation does not contain an agent compositions may be presented in unit dosage form and may that affects the rate at which the active ingredient is metabo be prepared by any of the methods well known in the art of lized. Thus, it is understood that compositions comprising a pharmacy. Such methods include the step of bringing into compound of the present disclosure in one aspect do not association the active ingredient (e.g., a compound of the comprise an agent that would affect (e.g., slow, hinder or present disclosure or a pharmaceutical salt thereof) with one retard) the metabolism of a compound of the present dis or more pharmaceutically acceptable excipients. The com closure or any other active ingredient administered sepa positions may be prepared by uniformly and intimately rately, sequentially or simultaneously with a compound of bringing into association the active ingredient with liquid the present disclosure. It is also understood that any of the excipients or finely divided solid excipients or both, and 25 methods, kits, articles of manufacture and the like detailed then, if necessary, shaping the product. Techniques and herein in one aspect do not comprise an agent that would formulations generally are found in Remington: The Science affect (e.g., slow, hinder or retard) the metabolism of a and Practice of Pharmacy, 21 Edition, Lippincott Williams compound of the present disclosure or any other active and Wilkins, Philadelphia, Pa., 2006. ingredient administered separately, sequentially or simulta Compositions described herein that are suitable for oral 30 neously with a compound of the present disclosure. administration may be presented as discrete units (a unit IV. Methods dosage form) including but not limited to capsules, cachets The present disclosure provides for methods of treating or tablets each containing a predetermined amount of the diseases or conditions that are responsive to the modulation active ingredient. In one embodiment, the pharmaceutical of toll-like receptors (e.g. TLR-8 receptors). While not composition is a tablet. 35 wishing to be bound by any one theory, the presently Pharmaceutical compositions disclosed herein comprise disclosed compounds are believed to modulate TLR-8 one or more compounds disclosed herein, or a pharmaceu receptors as agonists. As is understood by those of skill in tically acceptable salt thereof, together with a pharmaceu the art, modulators of TLR-8 may, to some degree, modulate tically acceptable excipient and optionally other therapeutic other toll-like receptors (e.g. TLR-7). As such, in certain agents. Pharmaceutical compositions containing the active 40 embodiments, the compounds disclosed herein may also ingredient may be in any form suitable for the intended modulate TLR-7 to a measurable degree. In certain embodi method of administration. When used for oral use for ments, those compounds that modulate TLR-8 to a higher example, tablets, troches, lozenges, aqueous or oil suspen degree than TLR-7 are considered selective modulators of sions, dispersible powders or granules, emulsions, hard or TLR-8. Exemplary methods of measuring the each com Soft capsules, syrups or elixirs may be prepared. Composi 45 pounds respective modulation of TLR-7 and TLR-8 are tions intended for oral use may be prepared according to any described in the Examples provided herein. In certain method known to the art for the manufacture of pharma embodiments, the compounds disclosed herein are selective ceutical compositions and Such compositions may contain modulators of TLR-8. one or more excipients including Sweetening agents, flavor In certain embodiments, a method of modulating TLR-8 ing agents, coloring agents and preserving agents, in order to 50 is provided, comprising administering a compound of the provide a palatable preparation. Tablets containing the active present disclosure, or a pharmaceutically acceptable salt ingredient in admixture with non-toxic pharmaceutically thereof, to an individual (e.g. a human). acceptable excipients which are suitable for manufacture of In certain embodiments, a method of modulating TLR-8 tablets are acceptable. These excipients may be, for in vitro is provided. example, inert diluents, such as calcium or sodium carbon 55 In certain embodiments, the present disclosure provides a ate, lactose, lactose monohydrate, croScarmellose Sodium, compound of the present disclosure, or a pharmaceutically povidone, calcium or Sodium phosphate; granulating and acceptable salt thereof, for use as a research tool, e.g., for use disintegrating agents, such as maize starch, or alginic acid: in identifying modulators of TLR-8 binding agents, such as cellulose, microcrystalline cellulose, In certain embodiments, the present disclosure provides starch, gelatin or acacia; and lubricating agents, such as 60 methods for the treatment or prevention of diseases or magnesium Stearate, Stearic acid or talc. Tablets may be conditions in an individual (e.g. a human) in need thereof, uncoated or may be coated by known techniques including comprising administering a compound of the present dis microencapsulation to delay disintegration and adsorption in closure or a pharmaceutically acceptable salt thereof. In the gastrointestinal tract and thereby provide a Sustained certain embodiments, the methods comprise administering action over a longer period. For example, a time delay 65 one or more additional therapeutic agents. Treatment with a material Such as glyceryl monostearate or glyceryl distearate compound of the present disclosure typically results in the alone or with a wax may be employed. stimulation of an immune response to the particular disease US 9,670,205 B2 101 102 or condition being treated. Diseases or conditions contem In certain embodiments, a compound of the present dis plated by the present disclosure include those affected by the closure, or a pharmaceutically acceptable salt thereof, for modulation of toll-like receptors (e.g. TLR-8). In certain use in medical therapy is provided. In certain embodiments, embodiments, a method of treating or preventing a disease a compound of the present disclosure or a pharmaceutically or condition responsive to the modulation of TLR-8 is 5 acceptable salt thereof, for use in treating or preventing a provided, comprising administering to a human a therapeu disease or condition responsive to the modulation of TLR-8, tically effective amount of a compound of the present is provided. In certain embodiments, the disease or condition disclosure, or a pharmaceutically acceptable salt thereof. is a viral infection as set forth herein. Exemplary diseases, disorders and conditions include but In certain embodiments, the use of a compound of the are not limited to conditions involving autoimmunity, 10 present disclosure, or a pharmaceutically acceptable salt inflammation, allergy, asthma, graft rejection, graft versus thereof, for the manufacture of a medicament for treating or host disease (GvHD), infectious diseases, cancer, and immu preventing a disease or condition responsive to the modu nodeficiency. lation of TLR-8, is provided. In certain embodiments, infectious diseases include dis In certain embodiments, the present disclosure also pro eases such as hepatitis A, hepatitis B (HBV), hepatitis C 15 vides methods for treating a hepatitis B viral infection, (HCV), hepatitis D (HDV), HIV, human papillomavirus comprising administering to an individual (e.g. a human) (HPV), respiratory syncytial virus (RSV), severe acute infected with hepatitis B virus a therapeutically effective respiratory syndrome (SARS), influenza, parainfluenza, amount a compound of the present disclosure or a pharma cytomegalovirus, dengue, herpes simplex virus-1, herpes ceutically acceptable salt thereof. Typically, the individual is simplex virus-2, leishmania infection, and respiratory Syn- 20 Suffering from a chronic hepatitis B infection, although it is cytial virus. In certain embodiments, infectious diseases within the scope of the present disclosure to treat people who include diseases such as hepatitis A, hepatitis B (HBV), are acutely infected with HBV. hepatitis D (HDV), HIV, human papillomavirus (HPV), The present disclosure also provides methods for treating respiratory syncytial virus (RSV), severe acute respiratory a hepatitis C viral infection, comprising administering to an syndrome (SARS), influenza, parainfluenza, cytomegalovi- 25 individual (e.g. a human) infected with hepatitis C virus a rus, dengue, herpes simplex virus-1, herpes simplex virus-2. therapeutically effective amount a compound of the present leishmania infection, and respiratory syncytial virus. disclosure or a pharmaceutically acceptable salt thereof. In certain embodiments, a method of treating or prevent Typically, the individual is suffering from a chronic hepatitis ing a viral infection is provided, comprising administering to C infection, although it is within the scope of the present an individual (e.g. a human) a therapeutically effective 30 disclosure to treat people who are acutely infected with amount a compound of the present disclosure, or a pharma HCV. ceutically acceptable salt thereof. In one embodiment, the Treatment of HBV or HCV in accordance with the present method can be used to induce an immune response against disclosure typically results in the stimulation of an immune multiple epitopes of a viral infection in a human. Induction response against HBV or HCV in an individual (e.g. a of an immune response against viral infection can be 35 human) being infected with HBV or HCV, respectively, and assessed using any technique that is known by those of skill a consequent reduction in the viral load of HBV or HCV in in the art for determining whether an immune response has the infected individual. Examples of immune responses occurred. Suitable methods of detecting an immune include production of antibodies (e.g., IgG antibodies) and/ response for the present disclosure include, among others, or production of cytokines, such as interferons, that modu detecting a decrease in viral load or antigen in a subject's 40 late the activity of the immune system. The immune system serum, detection of IFN-gamma-secreting peptide specific T response can be a newly induced response, or can be cells, and detection of elevated levels of one or more liver boosting of an existing immune response. In particular, the enzymes, such as alanine transferase (ALT) and aspartate immune system response can be seroconversion against one transferase (AST). In one embodiment, the detection of or more HBV or HCV antigens. IFN-gamma-secreting peptide specific T cells is accom- 45 As described more fully herein, compounds of the present plished using an ELISPOT assay. Another embodiment disclosure can be administered with one or more additional includes reducing the viral load associated with HBV infec therapeutic agent(s) to an individual (e.g. a human) infected tion, including a reduction as measured by PCR testing. with HBV or HCV. The additional therapeutic agent(s) can In certain embodiments, the present invention provides a be administered to the infected individual (e.g. a human) at method for enhancing the efficacy of a vaccine by co- 50 the same time as a compound of the present disclosure or administering with the vaccine, a therapeutically effective before or after administration of a compound of the present amount of a compound of the present disclosure, or a disclosure. For example, in certain embodiments, when used pharmaceutically acceptable salt thereof, to an individual to treat or prevent HCV, a compound of the present disclo (e.g. a human). In certain embodiments, the compound of Sure may be administered with one or more additional the present disclosure or a pharmaceutically acceptable salt 55 therapeutic agent(s) selected from the group consisting of thereof, may be co-administered with a vaccine to boost the interferons, ribavirin or its analogs, HCV NS3 protease immune response by allowing the production of a higher inhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 amount of antibodies or by allowing a longer lasting pro protease inhibitors, alpha-glucosidase 1 inhibitors, hepato tection. In certain embodiments, the compounds of the protectants, nucleoside or nucleotide inhibitors of HCV present disclosure, or a pharmaceutically acceptable salt 60 NS5B polymerase, non-nucleoside inhibitors of HCV NS5B thereof, may be used as vaccine adjuvants to increase the polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclo efficacy and response to the immunization with a particular philin inhibitors, HCV IRES inhibitors, pharmacokinetic antigen. In certain embodiments, co-administering the com enhancers, and other drugs for treating HCV, or mixtures pounds of the present disclosure, or a pharmaceutically thereof. Specific examples are more fully described below. acceptable salt thereof, with a vaccine, may influence the 65 Further, in certain embodiments, when used to treat or way a vaccine’s antigen is presented to the immune system prevent HBV, a compound of the present disclosure may be and enhance the vaccine’s efficacy. administered with one or more additional therapeutic US 9,670,205 B2 103 104 agent(s) selected from the group consisting of HBV DNA In certain embodiments, an immune response can be polymerase inhibitors, toll-like receptor 7 modulators, toll induced against one or more antigens of HBV or HCV. For like receptor 8 modulators, Toll-like receptor 7 and 8 modu example, an immune response can be induced against the lators, Toll-like receptor 3 modulators, interferon alpha HBV surface antigen (HBSAg), or against the small form of ligands, HBS Ag inhibitors, compounds targeting HbcAg, the HBV Surface antigen (Small S antigen), or against the cyclophilin inhibitors, HBV therapeutic vaccines, HBV pro medium form of the HBV surface antigen (medium S phylactic vaccines, HBV viral entry inhibitors, NTCP inhibi antigen), or against a combination thereof. Again by way of tors, antisense oligonucleotide targeting viral mRNA, short example, an immune response can be induced against the interfering RNAs (siRNA), hepatitis B virus E antigen HBV surface antigen (HBSAg) and also against other HBV inhibitors, HBX inhibitors, cccDNA inhibitors, HBV anti 10 bodies including HBV antibodies targeting the surface anti derived antigens, such as the core polymerase or X-protein. gens of the hepatitis B virus, thymosin agonists, cytokines, Induction of an immune response against HCV or HBV nucleoprotein inhibitors (HBV core or capsid protein inhibi can be assessed using any technique that is known by those tors), stimulators of retinoic acid-inducible gene 1, Stimu of skill in the art for determining whether an immune lators of NOD2, recombinant thymosin alpha-1 and hepatitis 15 response has occurred. Suitable methods of detecting an B virus replication inhibitors, and combinations thereof. immune response for the present disclosure include, among Specific examples are more fully described below. others, detecting a decrease in viral load in a individuals In certain embodiments, the present disclosure provides a serum, such as by measuring the amount of HBV DNA or method for ameliorating a symptom associated with an HBV HCV DNA in a subject’s blood using a PCR assay, and/or by infection or HCV infection, wherein the method comprises measuring the amount of anti-HBV antibodies, or anti-HCV administering to an individual (e.g. a human) infected with antibodies, in the Subject’s blood using a method Such as an hepatitis B virus or hepatitis C virus a therapeutically ELISA. effective amount of a compound of the present disclosure, or In certain embodiments, a compound of a compound of a pharmaceutically acceptable salt thereof, wherein the the present disclosure (e.g. a compound of Formula (I)), or therapeutically effective amount is sufficient to ameliorate a 25 a pharmaceutically acceptable salt thereof, for use in treating symptom associated with the HBV infection or HCV infec or preventing a HBV infection is provided. In certain tion. Such symptoms include the presence of HBV virus embodiments, a compound of the present disclosure (e.g. a particles (or HCV virus particles) in the blood, liver inflam compound of Formula (I)), or a pharmaceutically acceptable mation, jaundice, muscle aches, weakness and tiredness. salt thereof, for use in treating or preventing a HCV infection In certain embodiments, the present disclosure provides a 30 method for reducing the rate of progression of a hepatitis B is provided. In certain embodiments, a compound of the viral infection or a hepatitis C virus infection, in an indi present disclosure (e.g. a compound of Formula (I)), or a vidual (e.g. a human), wherein the method comprises admin pharmaceutically acceptable salt thereof, for the manufac istering to an individual (e.g. a human) infected with hepa ture of a medicament for treating or preventing a HBV titis B virus or hepatitis C virus a therapeutically effective 35 infection is provided. In certain embodiments, a compound amount of a compound of the present disclosure, or a of the present disclosure (e.g. a compound of Formula (I)), pharmaceutically acceptable salt thereof, wherein the thera or a pharmaceutically acceptable salt thereof, for the manu peutically effective amount is sufficient to reduce the rate of facture of a medicament for treating or preventing a HCV progression of the hepatitis B viral infection or hepatitis C infection is provided. viral infection. The rate of progression of the infection can 40 In certain embodiments, the present disclosure also pro be followed by measuring the amount of HBV virus particles vides methods for treating a Retroviridae viral infection or HCV virus particles in the blood. (e.g., an HIV viral infection) in an individual (e.g., a human), In certain embodiments, the present disclosure provides a comprising administering a compound of the present dis method for reducing the viral load associated with HBV closure, or a pharmaceutically acceptable Salt thereof, to the infection or HCV infection, wherein the method comprises 45 individual. administering to an individual (e.g. a human) infected with In certain embodiments, the present disclosure also pro HBV or HCV a therapeutically effective amount of a com vides methods for treating a HIV infection (e.g. a HIV-1 pound of the present disclosure, or a pharmaceutically infection), comprising administering to an individual (e.g. a acceptable salt thereof, wherein the therapeutically effective human) infected with HIV virus a therapeutically effective amount is sufficient to reduce the HBV viral load or the HCV 50 amount of a compound of the present disclosure, or a viral load in the individual. pharmaceutically acceptable salt thereof. In certain embodi In certain embodiments, the present disclosure provides a ments, the individual in need thereof is a human who has method of inducing or boosting an immune response against been infected with HIV. In certain embodiments, the indi hepatitis B virus or hepatitis C virus in an individual (e.g. a vidual in need thereof is a human who has been infected with human), wherein the method comprises administering a 55 HIV but who has not developed AIDS. In certain embodi therapeutically effective amount of a compound of the ments, the individual in need thereof is an individual at risk present disclosure, or a pharmaceutically acceptable salt for developing AIDS. In certain embodiments, the individual thereof, to the individual, wherein a new immune response in need thereof is a human who has been infected with HIV against hepatitis B virus or hepatitis C virus is induced in the and who has developed AIDS. individual, or a preexisting immune response against hepa 60 In certain embodiments, a method for treating or prevent titis B virus or hepatitis C virus is boosted in the individual. ing an HIV viral infection in an individual (e.g., a human), Seroconversion with respect to HBV or HCV can be induced comprising administering a compound of the present dis in the individual. Examples of immune responses include closure, or a pharmaceutically acceptable Salt thereof, to the production of antibodies, such as IgG antibody molecules, individual is provided. and/or production of cytokine molecules that modulate the 65 In certain embodiments, a method for inhibiting the activity of one or more components of the human immune replication of the HIV virus, treating AIDS or delaying the system. onset of AIDS in an individual (e.g., a human), comprising US 9,670,205 B2 105 106 administering a compound of the present disclosure, or a ture of a medicament for an HIV virus infection in an pharmaceutically acceptable salt thereof, to the individual is individual (e.g., a human) is provided. In certain embodi provided. ments, a compound of the present disclosure (e.g. a com In certain embodiments, a method for preventing an HIV pound of Formula (I)), or a pharmaceutically acceptable salt infection in an individual (e.g., a human), comprising thereof, for use in the prophylactic or therapeutic treatment administering a compound of the present disclosure, or a of an HIV virus infection is provided. pharmaceutically acceptable salt thereof, to the individual is In certain embodiments, in the methods of use, the provided. In certain embodiments, the individual is at risk of administration is to an individual (e.g., a human) in need of contracting the HIV virus, Such as an individual who has one the treatment. In certain embodiments, in the methods of or more risk factors known to be associated with of con 10 use, the administration is to an individual (e.g., a human) tracting the HIV virus. who is at risk of developing AIDS. In certain embodiments, a method for treating an HIV Provided herein is a compound of the present disclosure infection in an individual (e.g., a human), comprising (e.g. a compound of Formula (I)), or a pharmaceutically administering a compound of the present disclosure, or a acceptable salt thereof, for use in therapy. In one embodi pharmaceutically acceptable salt thereof, to the individual is 15 ment, the compound of the present disclosure, or a pharma provided. ceutically acceptable salt thereof, is for use in a method of In certain embodiments, a method for treating an HIV treating an HIV viral infection or the replication of the HIV infection in an individual (e.g., a human), comprising virus or AIDS or delaying the onset of AIDS in an individual administering to the individual in need thereof a therapeu (e.g., a human). tically effective amount of a compound of the present Also provided herein is a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in disclosure (e.g. a compound of Formula (I)), or a pharma combination with a therapeutically effective amount of one ceutically acceptable salt thereof, for use in a method of or more additional therapeutic agents selected from the treating or preventing HIV in an individual in need thereof. group consisting of HIV protease inhibiting compounds, In certain embodiments, the individual in need thereof is a HIV non-nucleoside inhibitors of reverse transcriptase, HIV 25 human who has been infected with HIV. In certain embodi nucleoside inhibitors of reverse transcriptase, HIV nucleo ments, the individual in need thereof is a human who has tide inhibitors of reverse transcriptase, HIV integrase inhibi been infected with HIV but who has not developed AIDS. In tors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, certain embodiments, the individual in need thereof is an CCR5 inhibitors, capsid polymerization inhibitors, and other individual at risk for developing AIDS. In certain embodi drugs for treating HIV, and combinations thereof is pro 30 ments, the individual in need thereof is a human who has vided. been infected with HIV and who has developed AIDS. In certain embodiments, a compound of the present inven Also provided herein is a compound of the present tion is administered to a patient where active HIV gene disclosure (e.g. a compound of Formula (I)), or a pharma expression has been Suppressed by administration of anti ceutically acceptable salt thereof, for use in the therapeutic retroviral therapy (including combination antiretroviral 35 treatment or delaying the onset of AIDS. therapy” or “cART). Also provided herein is a compound of the present In certain embodiments, a method of reducing the latent disclosure (e.g. a compound of Formula (I)), or a pharma HIV reservoir in a human infected with HIV is provided, the ceutically acceptable salt thereof, for use in the prophylactic method comprising administering to the human a pharma or therapeutic treatment of an HIV infection. ceutically effective amount of a compound of the present 40 In certain embodiments, the HIV infection is an HIV-1 disclosure. In certain embodiments, the method further infection. comprises administering one or more anti-HIV agents. In Additionally, the compounds of this disclosure are useful certain embodiments, the method further comprises admin in the treatment of cancer or tumors (including dysplasias, istering antiretroviral therapy (including combination anti Such as uterine dysplasia). These includes hematological retroviral therapy’ or “cART). In certain embodiments, 45 malignancies, oral carcinomas (for example of the lip, active HIV gene expression in the human has been Sup tongue or pharynx), digestive organs (for example esopha pressed by administration of antiretroviral therapy (includ gus, stomach, Small intestine, colon, large intestine, or ing combination antiretroviral therapy’ or “cART). rectum), peritoneum, liver and biliary passages, pancreas, In certain embodiments, a compound of the present dis respiratory system Such as larynx or lung (Small cell and closure, or a pharmaceutically acceptable salt thereof for use 50 non-Small cell), bone, connective tissue, skin (e.g., mela in medical therapy of an HIV viral infection (e.g. HIV-1 or noma), breast, reproductive organs (fallopian tube, uterus, the replication of the HIV virus (e.g. HIV-1) or AIDS or cervix, testicles, ovary, or prostate), urinary tract (e.g., delaying the onset of AIDS in an individual (e.g., a human)) bladder or kidney), brain and endocrine glands such as the is provided. thyroid. In Summary, the compounds of this disclosure are In certain embodiments, a compound of the present dis 55 employed to treat any neoplasm, including not only hema closure, or a pharmaceutically acceptable salt thereof for use tologic malignancies but also solid tumors of all kinds. In in the manufacture of a medicament for treating an HIV viral certain embodiments, the compounds are useful for treating infection or the replication of the HIV virus or AIDS or a form of cancer selected from ovarian cancer, breast cancer, delaying the onset of AIDS in an individual (e.g., a human). head and neck cancer, renal cancer, bladder cancer, hepato One embodiment provides a compound of the present dis 60 cellular cancer, and colorectal cancer. closure, or a pharmaceutically acceptable salt thereof, for Hematological malignancies are broadly defined as pro use in the prophylactic or therapeutic treatment of an HIV liferative disorders of blood cells and/or their progenitors, in infection or AIDS or for use in the therapeutic treatment or which these cells proliferate in an uncontrolled manner. delaying the onset of AIDS is provided. Anatomically, the hematologic malignancies are divided In certain embodiments, the use of a compound of the 65 into two primary groups: lymphomas—malignant masses of present disclosure (e.g. a compound of Formula (I)), or a lymphoid cells, primarily but not exclusively in lymph pharmaceutically acceptable salt thereof, for the manufac nodes, and leukemias—neoplasm derived typically from US 9,670,205 B2 107 108 lymphoid or myeloid cells and primarily affecting the bone pharmaceutically acceptable salt thereof for the manufacture marrow and peripheral blood. The lymphomas can be sub of a medicament for treating a hyperproliferative disease divided into Hodgkin’s Disease and Non-Hodgkin’s lym (e.g. cancer) is provided. phoma (NHL). The later group comprises several distinct V. Administration entities, which can be distinguished clinically (e.g. aggres One or more of the compounds of the present disclosure sive lymphoma, indolent lymphoma), histologically (e.g. (also referred to herein as the active ingredients), can be follicular lymphoma, mantle cell lymphoma) or based on the administered by any route appropriate to the condition to be origin of the malignant cell (e.g. B lymphocyte, T lympho treated. Suitable routes include oral, rectal, nasal, topical cyte). Leukemias and related malignancies include acute (including buccal and Sublingual), transdermal, vaginal and myelogenous leukemia (AML), chronic myelogenous leu 10 parenteral (including Subcutaneous, intramuscular, intrave kemia (CML), acute lymphoblastic leukemia (ALL) and nous, intradermal, intrathecal and epidural), and the like. It chronic lymphocytic leukemia (CLL). Other hematological will be appreciated that the preferred route may vary with for malignancies include the plasma cell dyscrasias including example the condition of the recipient. An advantage of multiple myeloma, and the myelodysplastic syndromes. certain compounds disclosed herein is that they are orally In certain embodiments, the compounds of the present 15 bioavailable and can be dosed orally. disclosure are useful in the treatment of B-cell lymphoma, A compound of the present disclosure. Such as a com lymphoplasmacytoid lymphoma, fallopian tube cancer, head pound of Formula (I), may be administered to an individual and neck cancer, ovarian cancer, and peritoneal cancer. in accordance with an effective dosing regimen for a desired In certain embodiments, the compounds of the present period of time or duration, Such as at least about one month, disclosure are useful in the treatment of hepatocellular at least about 2 months, at least about 3 months, at least carcinoma, gastric cancer, and/or colorectal cancer. In cer about 6 months, or at least about 12 months or longer. In one tain embodiments, the compounds of the present disclosure variation, the compound is administered on a daily or are useful in the treatment of prostate cancer, breast cancer, intermittent schedule for the duration of the individual’s life. and/or ovarian cancer. In certain embodiments, the com The dosage or dosing frequency of a compound of the pounds of the present disclosure are useful in the treatment 25 present disclosure may be adjusted over the course of the of recurrent or metastatic squamous cell carcinoma. treatment, based on the judgment of the administering In certain embodiments, a method of treating a hyperpro physician. liferative disease, comprising administering to an individual The compound may be administered to an individual (e.g. a human) in need thereof a therapeutically effective (e.g., a human) in an effective amount. In certain embodi amount of a compound of the present disclosure, or a 30 ments, the compound is administered once daily. pharmaceutically acceptable salt thereof, is provided. In In certain embodiments, methods for treating or prevent certain embodiments, the hyperproliferative disease is can ing a disease or condition in a human are provided, com cer. In certain embodiments, the cancer is a Solid tumor. In prising administering to the human a therapeutically effec certain embodiments, the cancer is selected from ovarian tive amount of a compound of the present disclosure, or a cancer, breast cancer, head and neck cancer, renal cancer, 35 pharmaceutically acceptable salt thereof, in combination bladder cancer, hepatocellular cancer, and colorectal cancer. with a therapeutically effective amount of one or more (e.g., In certain embodiments, the cancer is a lymphoma. In one, two, three, four, one or two, one to three, or one to four) certain embodiments, the cancer is Hodgkin’s lymphoma. In additional therapeutic agents. As modulators of TLR-8 may certain embodiments, the cancer is non-Hodgkin’s lym be used in the treatment of various diseases or conditions, phoma. In certain embodiments, the cancer is B-cell lym 40 the particular identity of the additional therapeutic agents phoma. In certain embodiments, the cancer is selected from will depend on the particular disease or condition being B-cell lymphoma; fallopian tube cancer, head and neck treated. cancer, ovarian cancer and peritoneal cancer. In certain The compound of Formula (J), (I), (II), (IIa), (IIb), (III), embodiments, the method further comprises administering (IIIa), (IIIb), (IV), (IVa), (IVb). (IVc), or (IVd) can be one or more additional therapeutic agents as more fully 45 administered by any useful route and means, such as by oral described herein. or parenteral (e.g., intravenous) administration. Therapeuti In certain embodiments, the cancer is prostate cancer, cally effective amounts of the compound of Formula (J), (I), breast cancer, ovarian cancer, hepatocellular carcinoma, (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb). (IVc), gastric cancer, colorectal cancer and/or recurrent or meta or (IVd) are from about 0.00001 mg/kg body weight per day static Squamous cell carcinoma. In certain embodiments, the 50 to about 10 mg/kg body weight per day, Such as from about cancer is prostate cancer, breast cancer, and/or ovarian 0.0001 mg/kg body weight per day to about 10 mg/kg body cancer. In certain embodiments, the cancer is hepatocellular weight per day, or such as from about 0.001 mg/kg body carcinoma, gastric cancer, and/or colorectal cancer. In cer weight per day to about 1 mg/kg body weight per day, or tain embodiments, the cancer is recurrent or metastatic Such as from about 0.01 mg/kg body weight per day to about squamous cell carcinoma. 55 1 mg/kg body weight per day, or Such as from about 0.05 In some embodiments, in the methods of use, the admin mg/kg body weight per day to about 0.5 mg/kg body weight istration is to an individual (e.g., a human) in need of the per day, or Such as from about 0.3 ug to about 30 mg per day, treatment. or such as from about 30 ug to about 300 ug per day. Additional examples of diseases, disorders, or conditions A compound of the present disclosure (e.g., any com include psoriasis, systemic lupus erythematosusand allergic 60 pound of Formula (I)) may be combined with one or more rhinitis additional therapeutic agents in any dosage amount of the In one embodiment, the compound of the present disclo compound of the present disclosure (e.g., from 1 mg to 1000 Sure, or a pharmaceutically acceptable salt thereof, is for use mg of compound). Therapeutically effective amounts of the in a method of treating a hyperproliferative disease (e.g. compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), cancer) in an individual (e.g., a human). 65 (IIIb), (IV), (IVa), (IVb). (IVc), or (IVd), are from about Also provided herein is the use of a compound of the 0.01 mg per dose to about 1000 mg per dose, such as from present disclosure (e.g. a compound of Formula (I)) or a about 0.01 mg per dose to about 100 mg per dose, or such US 9,670,205 B2 109 110 as from about 0.1 mg per dose to about 100 mg per dose, or Sure, or a pharmaceutically acceptable salt thereof, is com Such as from about 1 mg per dose to about 100 mg per dose, bined with three additional therapeutic agents. In further or Such as from about 1 mg per dose to about 10 mg per dose. embodiments, a compound of the present disclosure, or a Other therapeutically effective amounts of the compound of pharmaceutically acceptable salt thereof, is combined with Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), four additional therapeutic agents. The one, two, three, four (IVa), (IVb). (IVc), or (IVd) are about 1 mg per dose, or or more additional therapeutic agents can be different thera about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, peutic agents selected from the same class of therapeutic 55, 60, 65, 70, 75, 80, 85,90, 95, or about 100 mg per dose. agents, and/or they can be selected from different classes of Other therapeutically effective amounts of the compound of therapeutic agents. Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), 10 In certain embodiments, when a compound of the present (IVa), (IVb). (IVc), or (IVd) are about 100 mg per dose, or disclosure is combined with one or more additional thera about 125, 150, 175, 200, 225, 250,275,300, 350, 400, 450, peutic agents as described herein, the components of the or about 500 mg per dose. A single dose can be administered composition are administered as a simultaneous or sequen hourly, daily, or weekly. For example, a single dose can be tial regimen. When administered sequentially, the combina administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once 15 tion may be administered in two or more administrations. every 24 hours. A single dose can also be administered once In certain embodiments, a compound of the present dis every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose closure is combined with one or more additional therapeutic can also be administered once every 1 week, 2, 3, or once agents in a unitary dosage form for simultaneous adminis every 4 weeks. In certain embodiments, a single dose can be tration to a patient, for example as a solid dosage form for administered once every week. A single dose can also be oral administration. administered once every month. In certain embodiments, a compound of the present dis The frequency of dosage of the compound of Formula (J), closure is administered with one or more additional thera (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), peutic agents. Co-administration of a compound of the (IVc), or (IVd) will be determined by the needs of the present disclosure with one or more additional therapeutic individual patient and can be, for example, once per day or 25 agents generally refers to simultaneous or sequential admin twice, or more times, per day. Administration of the com istration of a compound of the present disclosure and one or pound continues for as long as necessary to treat the HBV more additional therapeutic agents, such that therapeutically or HCV infection. For example, Compound I can be admin effective amounts of the compound disclosed herein and one istered to a human being infected with HBV or HCV for a or more additional therapeutic agents are both present in the period of from 20 days to 180 days or, for example, for a 30 body of the patient. period of from 20 days to 90 days or, for example, for a Co-administration includes administration of unit dosages period of from 30 days to 60 days. of the compounds disclosed herein before or after adminis Administration can be intermittent, with a period of tration of unit dosages of one or more additional therapeutic several or more days during which a patient receives a daily agents, for example, administration of the compound dis dose of the compound of Formula (J), (I), (II), (IIa), (IIb). 35 closed herein within seconds, minutes, or hours of the (III), (IIIa), (IIIb), (IV), (IVa), (IVb). (IVc), or (IVd), fol administration of one or more additional therapeutic agents. lowed by a period of several or more days during which a For example, in Some embodiments, a unit dose of a patient does not receive a daily dose of the compound. For compound of the present disclosure is administered first, example, a patient can receive a dose of the compound every followed within seconds or minutes by administration of a other day, or three times per week. Again by way of 40 unit dose of one or more additional therapeutic agents. example, a patient can receive a dose of the compound each Alternatively, in other embodiments, a unit dose of one or day for a period of from 1 to 14 days, followed by a period more additional therapeutic agents is administered first, of 7 to 21 days during which the patient does not receive a followed by administration of a unit dose of a compound of dose of the compound, followed by a Subsequent period the present disclosure within seconds or minutes. In some (e.g., from 1 to 14 days) during which the patient again 45 embodiments, a unit dose of a compound of the present receives a daily dose of the compound. Alternating periods disclosure is administered first, followed, after a period of of administration of the compound, followed by non-admin hours (e.g., 1-12 hours), by administration of a unit dose of istration of the compound, can be repeated as clinically one or more additional therapeutic agents. In other embodi required to treat the patient. ments, a unit dose of one or more additional therapeutic In one embodiment, pharmaceutical compositions com 50 agents is administered first, followed, after a period of hours prising a compound of the present disclosure, or a pharma (e.g., 1-12 hours), by administration of a unit dose of a ceutically acceptable salt thereof, in combination with one compound of the present disclosure. or more (e.g., one, two, three, four, one or two, one to three, VI. Combination Therapy for HBV or one to four) additional therapeutic agents, and a pharma In certain embodiments, a method for treating or prevent ceutically acceptable excipient are provided. 55 ing an HBV infection in a human having or at risk of having In one embodiment, kits comprising a compound of the the infection is provided, comprising administering to the present disclosure, or a pharmaceutically acceptable salt human a therapeutically effective amount of a compound of thereof, in combination with one or more (e.g., one, two, the present disclosure, or a pharmaceutically acceptable salt three, four, one or two, one to three, or one to four) thereof, in combination with a therapeutically effective additional therapeutic agents are provided. 60 amount of one or more (e.g., one, two, three, four, one or In certain embodiments, a compound of the present dis two, one to three or one to four) additional therapeutic closure, or a pharmaceutically acceptable salt thereof, is agents. In one embodiment, a method for treating an HBV combined with one, two, three, four or more additional infection in a human having or at risk of having the infection therapeutic agents. In certain embodiments, a compound of is provided, comprising administering to the human a thera the present disclosure, or a pharmaceutically acceptable salt 65 peutically effective amount of a compound of the present thereof, is combined with two additional therapeutic agents. disclosure, or a pharmaceutically acceptable salt thereof, in In other embodiments, a compound of the present disclo combination with a therapeutically effective amount of one US 9,670,205 B2 111 112 or more (e.g., one, two, three, four, one or two, one to three WO2014/076221 (Janssen), WO2014/128189 (Janssen), or one to four) additional therapeutic agents. U.S. Publication No. 2014/0350031 (Janssen), WO2014/ In certain embodiments, the present disclosure provides a 023813 (Janssen), U.S. Publication No. 2008/0234251 (Ar method for treating an HBV infection, comprising admin ray Biopharma), U.S. Publication No. 2008/0306050 (Array istering to a patient in need thereof a therapeutically effec Biopharma), U.S. Publication No. 2010/0029585 (VentirX tive amount of a compound of the present disclosure, or a Pharma), U.S. Publication No. 2011/0092485 (VentirX pharmaceutically acceptable salt thereof, in combination Pharma), US2011/0118235 (Ventirx Pharma), U.S. Publica with a therapeutically effective amount of one or more tion No. 2012/0082658 (Ventirx Pharma), U.S. Publication additional therapeutic agents which are Suitable for treating No. 2012/02196.15 (VentirX Pharma), U.S. Publication No. an HBV infection. In certain embodiments, one or more 10 2014/0066432 (VentirX Pharma), U.S. Publication No. 2014/ additional therapeutic agents includes, for example, one, 0088085 (Ventirx Pharma), U.S. Publication No. 2014/ two, three, four, one or two, one to three or one to four 0275167 (Novira Therapeutics), U.S. Publication No. 2013/ additional therapeutic agents. 0251673 (Novira Therapeutics), U.S. Pat. No. 8,513,184 In the above embodiments, the additional therapeutic (Gilead Sciences), U.S. Publication No. 2014/0030221 agent may be an anti-HBV agent. For example, in some 15 (Gilead Sciences), U.S. Publication No. 2013/0344030 embodiments, the additional therapeutic agent is selected (Gilead Sciences), U.S. Publication No. 2013/0344029 from the group consisting of HBV combination drugs, HBV (Gilead Sciences), U.S. Publication No. 2014/0343032 DNA polymerase inhibitors, immunomodulators, toll-like (Roche), WO2014037480 (Roche), U.S. Publication No. receptor modulators (modulators of TLR-1, TLR-2, TLR-3, 2013/0267517 (Roche), WO2014131847 (Janssen), TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, WO2014033176 (Janssen), WO2014033170 (Janssen), TLR-11, TLR-12 and TLR-13), interferon alpha receptor WO2014033.167 (Janssen), U.S. Publication No. 2014/ ligands, hyaluronidase inhibitors, recombinant IL-7, hepa 0330015 (Ono Pharmaceutical), U.S. Publication No. 2013/ titis B Surface antigen (HBSAg) inhibitors, compounds tar 0079327 (Ono Pharmaceutical), U.S. Publication No. 2013/ geting hepatitis B core antigen (HbcAg), cyclophilin inhibi 0217880 (Ono pharmaceutical), and other drugs for treating tors, HBV therapeutic vaccines, HBV prophylactic vaccines, 25 HBV, and combinations thereof. In some embodiments, the HBV viral entry inhibitors, NTCP (Na+-taurocholate additional therapeutic agent is further selected from hepatitis cotransporting polypeptide) inhibitors, antisense oligonucle B surface antigen (HBSAg) secretion or assembly inhibitors, otide targeting viral mRNA, short interfering RNAs TCR-like antibodies, IDO inhibitors, cccDNA epigenetic (siRNA), miRNA gene therapy agents, endonuclease modu modifiers, IAPs inhibitors, SMAC mimetics, and com lators, inhibitors of ribonucleotide reductase, hepatitis B 30 pounds such as those disclosed in US20100015178 (Incyte), virus E antigen inhibitors, recombinant Scavenger receptor A In certain embodiments, the additional therapeutic is (SRA) proteins, Src kinase inhibitors, HBX inhibitors, selected from the group consisting of HBV combination cccDNA inhibitors, short synthetic hairpin RNAs (sshR drugs, HBV DNA polymerase inhibitors, toll-like receptor 7 NAs), HBV antibodies including HBV antibodies targeting modulators, toll-like receptor 8 modulators, Toll-like recep the surface antigens of the hepatitis B virus and bispecific 35 tor 7 and 8 modulators, Toll-like receptor 3 modulators, antibodies and “antibody-like therapeutic proteins (such as interferon alpha receptor ligands, HBS Ag inhibitors, com DARTSR, Duobodies.(R), Bites(R), XmAbs(R), TandAbs(R, Fab pounds targeting HbcAg, cyclophilin inhibitors, HBV thera derivatives), CCR2 chemokine antagonists, thymosin ago peutic vaccines, HBV prophylactic vaccines, HBV viral nists, cytokines, nucleoprotein inhibitors (HBV core or entry inhibitors, NTCP inhibitors, antisense oligonucleotide capsid protein inhibitors), stimulators of retinoic acid-induc 40 targeting viral mRNA, short interfering RNAs (siRNA), ible gene 1, stimulators of NOD2, stimulators of NOD1, hepatitis B virus E antigen inhibitors, HBX inhibitors, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, cccDNA inhibitors, HBV antibodies including HBV anti lymphotoxin beta receptor activators, Natural Killer Cell bodies targeting the Surface antigens of the hepatitis B virus, Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 thymosin agonists, cytokines, nucleoprotein inhibitors inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-asso 45 (HBV core or capsid protein inhibitors), stimulators of ciated protein 4 inhibitors, CD137 inhibitors, Killer cell retinoic acid-inducible gene 1, stimulators of NOD2, stimu lectin-like receptor subfamily G member 1 inhibitors, TIM-3 lators of NOD1, recombinant thymosin alpha-1, BTK inhibi inhibitors, B- and T-lymphocyte attenuator inhibitors, tors, and hepatitis B virus replication inhibitors, and com CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG binations thereof. In certain embodiments, the additional Interferon Lambda, recombinant thymosin alpha-1, BTK 50 therapeutic is selected from hepatitis B surface antigen inhibitors, modulators of TIGIT, modulators of CD47, (HBSAg) secretion or assembly inhibitors and IDO inhibi modulators of SIRPalpha, modulators of ICOS, modulators tOrS. of CD27, modulators of CD70, modulators of OX40, modu In certain embodiments a compound of the present dis lators of NKG2D, modulators of Tim-4, modulators of closure (e.g. a compound of Formula (I)) is formulated as a B7-H4, modulators of B7-H3, modulators of NKG2A, 55 tablet, which may optionally contain one or more other modulators of GITR, modulators of CD160, modulators of compounds useful for treating HBV. In certain embodi HEVEM, modulators of CD161, modulators of AX1, modu ments, the tablet can contain another active ingredient for lators of Mer, modulators of Tyro, gene modifiers or editors treating HBV, such as HBV DNA polymerase inhibitors, such as CRISPR (including CRISPR Cas9), zinc finger immunomodulators, toll-like receptor modulators (modula nucleases or synthetic nucleases (TALENs), Hepatitis B 60 tors of TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, virus replication inhibitors, compounds such as those dis TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR closed in U.S. Publication No. 2010/0143301 (Gilead Sci 13), modulators of tir7, modulators of tir8, modulators of ences), U.S. Publication No. 2011/0098248 (Gilead Sci tlr7 and tlr8, interferon alpha receptor ligands, hyaluronidase ences), U.S. Publication No. 2009/0047249 (Gilead inhibitors, hepatitis B surface antigen (HBSAg) inhibitors, Sciences), U.S. Pat. No. 8,722,054 (Gilead Sciences), U.S. 65 compounds targeting hepatitis B core antigen (HbcAg), Publication No. 2014/004.5849 (Janssen), U.S. Publication cyclophilin inhibitors, HBV viral entry inhibitors, NTCP No. 2014/0073642 (Janssen), WO2014/056953 (Janssen), (Na+-taurocholate cotransporting polypeptide) inhibitors, US 9,670,205 B2 113 114 endonuclease modulators, inhibitors of ribonucleotide (5) Toll-like receptor 8 modulators selected from the group reductase, hepatitis B virus E antigen inhibitors, Src kinase consisting of motolimod, residuimod, 3M-051, 3M-052, inhibitors, HBX inhibitors, cccDNA inhibitors, CCR2 MCT-465, IMO-4200, VTX-763, VTX-1463: chemokine antagonists, thymosin agonists, nucleoprotein (6) Toll-like receptor 3 modulators selected from the group inhibitors (HBV core or capsid protein inhibitors), stimula- 5 consisting of rintatolimod, poly-ICLC. MCT-465. MCT tors of retinoic acid-inducible gene 1, stimulators of NOD2. 475, Riboxxon, Riboxxim and ND-1.1; stimulators of NOD1, Arginase-1 inhibitors, STING ago- (7) Interferon alpha receptor ligands selected from the group nists, PI3K inhibitors, lymphotoxin beta receptor activators, consisting of interferon alpha-2b (Intron A(R), pegylated Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte- interferon alpha-2a (Pegasys(R), interferon alpha 1b (Hap activation gene 3 inhibitors, CD160 inhibitors, cytotoxic 10 genR), Veldona, Infradure, Roferon-A, YPEG-interferon T-lymphocyte-associated protein 4 inhibitors, CD137 inhibi- alfa-2a (YPEG-rhlFNalpha-2a), P-1101, Algeron, Alfa - rona, Ingaron (interferon gamma), rSIFN-co (recombi tors, Killer cell lectin-like receptor subfamily G member 1 nant Super compound interferon), Ypeginterferon alfa-2b inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenua- (YPEG-rhlFNalpha-2b), MOR-22, peginterferon alfa-2b tor inhibitorS, CD305 inhibitors, PD-1 inhibitors, PD-L1 15 (PEG-Intron(R), Bioferon, Novaferon, Inmutag (Inferon), inhibitors, BTK inhibitors, modulators of TIGIT, modulators Multiferon(R), interferon alfa-n1 (Humoferon(R), interferon of CD47, modulators of SIRP alpha, modulators of ICOS, beta-1a (Avonex(R), Shaferon, interferon alfa-2b modulators of CD27, modulators of CD70, modulators of (AXXO), Alfaferone, interferon alfa-2b (BioGeneric OX40, modulators of NKG2D, modulators of Tim-4, modu- Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, lators of B7-H4, modulators of B7-H3, modulators of 20 BLAUFERON-B, BLAUFERON-A, Intermax Alpha, NKG2A, modulators of GITR, modulators of CD160, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B, modulators of HEVEM, modulators of CD161, modulators interferon alfa-2b (IFN, Laboratorios Bioprofarma), of Ax1, modulators of Mer, modulators of Tyro, and Hepa- alfainterferona 2b, Kalferon, Pegnano, Feronsure, Pegi titis B virus replication inhibitors, and combinations thereof. Hep, interferon alfa 2b (Zydus-Cadila), Optipeg A. Realfa In certain embodiments, the tablet can contain another active 25 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa ingredient for treating HBV, such as hepatitis B surface 2b (Virchow), peginterferon alfa-2b (Amega), Reaferon antigen (HBSAg) secretion or assembly inhibitors, cccDNA EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b epigenetic modifiers, IAPs inhibitors, SMAC mimetics, and (Changchun Institute of Biological Products), Anterferon, IDO inhibitors. Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, In certain embodiments, such tablets are suitable for once 30 SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b and daily dosing. Interapo (Interapa): In certain embodiments, the additional therapeutic agent (8) Hyaluronidase inhibitors selected from the group con is selected from one or more of: sisting of astodrimer, (1) Combination drugs selected from the group consisting of (9) Modulators of IL-10; tenofovir disoproxil fumarate+emtricitabine (TRU- 35 (10) HBs.Ag inhibitors selected from the group consisting of VADAR); adefovir--clevudine and GBV-015, as well as HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, combination drugs selected from ABX-203+lamivudine-- REP 9AC, REP-9C and REP 9AC", as well as HBs.Ag PEG-IFNalpha, ABX-203+adefovir+PEG-IFNalpha, and inhibitors selected from REP-9, REP-2139, REP-2139 INO-9112+RG7944 (INO-1800): Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP (2) HBV DNA polymerase inhibitors selected from the 40 2053, REP-2031 and REP-006 and REP-9AC" group consisting of besifovir, entecavir (Baraclude R), (11) Toll like receptor 9 modulators selected from CYT003, adefovir (HepseraR), tenofovir disoproxil fumarate as well as Toll like receptor 9 modulators selected from (Viread(R), tenofovir alafenamide, tenofovir, tenofovir CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, disoproxil, tenofovir alafenamide fumarate, tenofovir IMO-9200, agatolimod, DIMS-9054, DV-1179, AZD alafenamide hemifumarate, tenofovir dipivoxil, tenofovir 45 1419, MGN-1703, and CYT-003-QbG10; dipivoxil fumarate, tenofovir octadecyloxyethyl ester, tel- (12) Cyclophilin inhibitors selected from the group consist bivudine (TyzekaR), pradefovir, Clevudine, emitricitabine ing of OCB-030, SCY-635 and NVP-018; (EmtrivaR), ribavirin, lamivudine (Epivir-HBV(R), phos- (13) HBV Prophylactic vaccines selected from the group phazide, famciclovir, SNC-019754, FMCA, fusolin, consisting of Hexaxim, Heplisav, Mosquirix, DTwP-HEBV AGX-1009 and metacavir, as well as HBV DNA poly- 50 vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; merase inhibitors selected from AR-II-04-26 and LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heber HS-10234: penta L., DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetra (3) Immunomodulators selected from the group consisting bhay, hepatitis B prophylactic vaccine (Advax Super D), of rintatolimod, imidol hydrochloride, ingaron, dermaVir, Hepatrol-07, GSK-223192A, Engerix B(R), recombinant plaquenil (hydroxychloroquine), proleukin, hydroxyurea, 55 hepatitis B vaccine (intramuscular, Kangtai Biological mycophenolate mofetil (MPA) and its ester derivative Products), recombinant hepatitis B vaccine (Hansenual mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, polymorpha yeast, intramuscular, Hualan Biological polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR- Engineering), Bimmugen, Euforavac, Eutravac, anrix 22, BMS-936559 and IR-103, as well as immunomodu- DTaP-IPV-Hep B, Infanrix-DTaP-IPV-Hep B-Hib, Pent lators selected from INO-91 12, polymer polyethyl- 60 abio Vaksin DTP-HB-Hib, Comvac 4. Twinrix, Euvax-B, eneimine (PEI), Gepon, VGV-1, MOR-22, BMS-93.6559, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV RO-701 1785, RO-6871765 and IR-103; vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, (4) Toll-like receptor 7 modulators selected from the group Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, consisting of GS-9620, GSK-224.5035, imiquimod, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, residuimod, DSR-6434, DSP-3025, IMO-4200, MCT- 65 Hebsulin, Recombivax HB, Revac B. mcf. Revac B+, 465, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, Fendrix, DTwP-HepB-Hib, DNA-001, Shanó, rhHBSAG TMX-202 RG-7863 and RG-7795; vaccine, and DTaP-rHB-Hib vaccine; US 9,670,205 B2 115 116 (14) HBV Therapeutic vaccines selected from the group gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, consisting of HBSAG-HBIG complex, Bio-Hep-B, NAS RG-7666, GSK-2636771, DS-7423, panulisib, GSK VAC, abi-HB (intravenous), ABX-203, Tetrabhay, 2269557, GSK-2126458, CUDC-907, PQR-309, INCB GX-110E, GS-4774, peptide vaccine (epsilonPA-44), 040093, pilaralisib, BAY-1082439, puquitinib mesylate, Hepatrol-07, NASVAC (NASTERAP), IMP-321, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN BEVAC, Revac B. mcf. Revac B+, MGN-1333, KW-2, 1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR CVI-HBV-002, AltraHepB, VGX-6200, FP-02, TG-1050, 260301 and CLR-1401; NU-500, HBVax, im/TriGrid/antigen vaccine, Mega (32) cccDNA inhibitors selected from the group consisting CD40L-adjuvanted vaccine, HepE-V, NO-1800, recombi of BSBI-25; nant VLP-based therapeutic vaccine (HBV infection, VLP 10 Biotech), AdTG-17909, AdTG-17910 AdTG-18202, (33) PD-L1 inhibitors selected from the group consisting of ChronVac-B, and Lim HBV, as well as HBV Therapeutic MEDI-0680, RG-7446, durvalumab, KY-1003, KD-033, vaccines selected from FP-02.2 and RG7944 (INO-1800): MSB-0010718C, TSR-042, ALN-PDL, STI-A1014 and (15) HBV viral entry inhibitor selected from the group BMS-936559; consisting of Myrcludex B; 15 (34) PD-1 inhibitors selected from the group consisting of (16) Antisense oligonucleotide targeting viral mRNA nivolumab, pembrolizumab, pidilizumab, BGB-108 and selected from the group consisting of ISIS-HBVRx; mDX-400; (17) short interfering RNAs (siRNA) selected from the (35) BTK inhibitors selected from the group consisting of group consisting of TKM-HBV (TKM-HepE), ALN ACP-196, dasatinib, ibrutinib, PRN-1008, SNS-062, HBV, SR-008, ddRNAi and ARC-520; ONO-4059, BGB-3 111, MSC-2364447, X-022, spebru (18) Endonuclease modulators selected from the group tinib, TP-4207, HM-71224, KBP-7536, AC-0025; consisting of PGN-514; (19). Inhibitors of ribonucleotide (36) Other drugs for treating HBV selected from the group reductase selected from the group consisting of Trimidox; consisting of gentiopicrin (gentiopicroside), nitazoxanide, (20) Hepatitis B virus E antigen inhibitors selected from the birinapant, NOV-205 (Molixan: BAM-205), Oligotide, group consisting of Wogonin; 25 Mivotilate, Feron, levamisole, Ka Shu Ning, Alloferon, (21) HBV antibodies targeting the surface antigens of the WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, hepatitis B virus selected from the group consisting of KW-3, BP-Inter-014, oleanolic acid, HepE-nRNA, cTP-5 GC-1 102, XTL-17, XTL-19, XTL-001, KN-003 and fully (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hep human monoclonal antibody therapy (hepatitis B virus bama, IBPB-006IA, Hepuyinfen, Daskloster 0014-01, infection, Humabs BioMed), as well as HBV antibodies 30 Jiangantai (Ganxikang), picroside, GA5 NM-HBV, Dask targeting the Surface antigens of the hepatitis B virus loster-0039, hepulantai, IMB-2613, TCM-800B and selected from IV Hepabulin SN: ZH-2N, as well as other drugs for treating HBV selected (22) HBV antibodies including monoclonal antibodies and from reduced glutathione, and RO-6864018; and polyclonal antibodies selected from the group consisting (37) The compounds disclosed in US20100143301 (Gilead of Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B 35 Sciences), US20110098248 (Gilead Sciences), Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP. US20090047249 (Gilead Sciences), U.S. Pat. No. 8,722, HepaGam B. igantibe, Niuliva, CT-P24, hepatitis B 054 (Gilead Sciences), US20140045849 (Janssen), immunoglobulin (intravenous, pH4, HBV infection, US20140073642 (Janssen), WO2014/056953 (Janssen), Shanghai RAAS Blood Products) and Fovepta (BT-088); WO2014/076221 (Janssen), WO2014/128189 (Janssen), (23) CCR2 chemokine antagonists selected from the group 40 US20140350031 (Janssen), WO2014/023813 (Janssen), consisting of propagermanium; US20080234251 (Array Biopharma), US20080306050 (24) Thymosin agonists selected from the group consisting (Array Biopharma), US20100029585 (VentirX Pharma), of Thymalfasin; US20110092485 (Ventirx Pharma), US20110118235 (25) Cytokines selected from the group consisting of recom (VentirX Pharma), US20120082658 (Ventirx Pharma), binant IL-7, CYT-107, interleukin-2 (IL-2, Immunex): 45 US201202196.15 (Ventirx Pharma), US20140066432 recombinant human interleukin-2 (Shenzhen Neptunus) (VentirX Pharma), US20140088085 (VentirXPharma), and celmoleukin, as well as cytokines selected from US20140275167 (Novira therapeutics), US20130251673 IL-15, IL-21, IL-24, (Novira therapeutics), U.S. Pat. No. 8,513,184 (Gilead (26) Nucleoprotein inhibitors (HBV core or capsid protein Sciences), US20140030221 (Gilead Sciences), inhibitors) selected from the group consisting of NVR 50 US20130344030 (Gilead Sciences), US20130344029 1221, NVR-3778, BAY 41-4109, morphothiadine mesi (Gilead Sciences), US2O140343O32 (Roche), late and DVR-23; WO2014037480 (Roche), US20130267517 (Roche), (27) Stimulators of retinoic acid-inducible gene 1 selected WO2014131847 (Janssen), WO2014033176 (Janssen), from the group consisting of SB-9200, SB-40, SB-44, WO2014033170 (Janssen), WO2014033167 (Janssen), ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198 55 US20140330015 (Ono pharmaceutical), US20130079327 and ORI-7170; (Ono pharmaceutical), and US20130217880 (Ono phar (28) Stimulators of NOD2 selected from the group consist maceutical), and the compounds disclosed in ing of SB-9200; US2010.0015178 (Incyte). (29) Recombinant thymosin alpha-1 selected from the group Also included in the list above are: consisting of NL-004 and PEGylated thymosin alpha 1: 60 (38) IDO inhibitors selected from the group consisting of (30) Hepatitis B virus replication inhibitors selected from epacadostat (INCB24360), F-001287, resminostat (4SC the group consisting of isothiafludine, IQP-HBV. 201), SN-35837, NLG-919, GDC-0919, and indoximod: RM-5038 and Xingantie: (39) Arginase inhibitors selected from CB-1158, C-201, and (31) PI3K inhibitors selected from the group consisting of resminostat; and idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, 65 (40) Cytotoxic T-lymphocyte-associated protein 4 (ipi4) neratinib, rigosertib, rigosertib sodium, EN-3342, TGR inhibitors selected from ipilumimab, belatacept, PSI-001, 1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, PRS-010, tremelimumab, and JHL-1155. US 9,670,205 B2 117 118 In certain embodiments, a compound of the present dis assembly inhibitors, TCR-like antibodies, cccDNA epigen closure, or a pharmaceutically acceptable salt thereof, is etic modifiers, IAPs inhibitors, SMAC mimetics, and IDO combined with one, two, three, four or more additional inhibitors. therapeutic agents. In certain embodiments, a compound of In another specific embodiment, a compound of the the present disclosure, or a pharmaceutically acceptable salt 5 present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. thereof, is combined with an HBV DNA polymerase inhibi In other embodiments, a compound of the present disclo tor and at least one additional therapeutic agent selected Sure, or a pharmaceutically acceptable salt thereof, is com from the group consisting of: HBV viral entry inhibitors, bined with three additional therapeutic agents. In further NTCP inhibitors, HBX inhibitors, cccDNA inhibitors, HBV embodiments, a compound of the present disclosure, or a 10 antibodies targeting the Surface antigens of the hepatitis B pharmaceutically acceptable salt thereof, is combined with virus, short interfering RNAs (siRNA), miRNA gene four additional therapeutic agents. The one, two, three, four therapy agents, short synthetic hairpin RNAs (sshRNAs), or more additional therapeutic agents can be different thera and nucleoprotein inhibitors (HBV core or capsid protein peutic agents selected from the same class of therapeutic inhibitors). agents, and/or they can be selected from different classes of 15 In another specific embodiment, a compound of the therapeutic agents. present disclosure, or a pharmaceutically acceptable salt In a specific embodiment, a compound of the present thereof, is combined with an HBV DNA polymerase inhibi disclosure, or a pharmaceutically acceptable Salt thereof, is tor, one or two additional therapeutic agents selected from combined with an HBV DNA polymerase inhibitor. In the group consisting of immunomodulators, toll-like recep another specific embodiment, a compound of the present tor modulators (modulators of TLR-1, TLR-2, TLR-3, TLR disclosure, or a pharmaceutically acceptable Salt thereof, is 4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, combined with an HBV DNA polymerase inhibitor and at TLR-12 and TLR-13), HBs.Ag inhibitors, HBV therapeutic least one additional therapeutic agent selected from the vaccines, HBV antibodies including HBV antibodies target group consisting of immunomodulators, toll-like receptor ing the Surface antigens of the hepatitis B virus and bispe modulators (modulators of TLR-1, TLR-2, TLR-3, TLR-4, 25 cific antibodies and “antibody-like therapeutic proteins TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, (such as DARTSR, Duobodies(R), Bites.(R), Xmabs(R), Tand TLR-12 and TLR-13), interferon alpha receptor ligands, Abs(R, Fab derivatives), cyclophilin inhibitors, stimulators hyaluronidase inhibitors, recombinant IL-7, HBS Ag inhibi of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 tors, compounds targeting HbcAg, cyclophilin inhibitors, inhibitors, Arginase-1 inhibitors, PI3K inhibitors and stimu HBV therapeutic vaccines, HBV prophylactic vaccines 30 lators of NOD2, and one or two additional therapeutic agents HBV viral entry inhibitors, NTCP inhibitors, antisense oli selected from the group consisting of: HBV viral entry gonucleotide targeting viral mRNA, short interfering RNAs inhibitors, NTCP inhibitors, HBX inhibitors, cccDNA inhibi (siRNA), miRNA gene therapy agents, endonuclease modu tors, HBV antibodies targeting the surface antigens of the lators, inhibitors of ribonucleotide reductase, Hepatitis B hepatitis B virus, short interfering RNAs (siRNA), miRNA virus E antigen inhibitors, recombinant Scavenger receptor A 35 gene therapy agents, short synthetic hairpin RNAS (SShR (SRA) proteins, Src kinase inhibitors, HBX inhibitors, NAs), and nucleoprotein inhibitors (HBV core or capsid cccDNA inhibitors, short synthetic hairpin RNAs (sshR protein inhibitors). In certain embodiments one or two NAs), HBV antibodies including HBV antibodies targeting additional therapeutic agents is further selected from hepa the surface antigens of the hepatitis B virus and bispecific titis B Surface antigen (HBSAg) secretion or assembly antibodies and “antibody-like therapeutic proteins (such as 40 inhibitors, TCR-like antibodies, and IDO inhibitors. DARTSR, Duobodies.(R), Bites(R), XmAbs(R), TandAbs(R, Fab In a particular embodiment, a compound of the present derivatives), CCR2 chemokine antagonists, thymosin ago disclosure, or a pharmaceutically acceptable Salt thereof, is nists, cytokines, nucleoprotein inhibitors (HBV core or combined with one, two, three, four or more additional capsid protein inhibitors), stimulators of retinoic acid-induc therapeutic agents selected from adefovir (HepseraR), teno ible gene 1, stimulators of NOD2, stimulators of NOD1, 45 fovir disoproxil fumarate+emtricitabine (TRUVADAR), Arginase-1 inhibitors, STING agonists, PI3K inhibitors, tenofovir disoproxil fumarate (Viread(R), entecavir (Bara lymphotoxin beta receptor activators, Natural Killer Cell clude?R), lamivudine (Epivir-HBV(R), tenofovir alafena Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 mide, tenofovir, tenofovir disoproxil, tenofoviralafenamide inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-asso fumarate, tenofovir alafenamide hemifumarate, telbivudine ciated protein 4 inhibitors, CD137 inhibitors, Killer cell 50 (Tyzeka(R), Clevudine(R), emtricitabine (EmtrivaR), lectin-like receptor subfamily G member 1 inhibitors, TIM-3 peginterferon alfa-2b (PEG-Intron(R), Multiferon(R), inter inhibitors, B- and T-lymphocyte attenuator inhibitors, feron alpha 1b (HapgenR), interferon alpha-2b (Intron A(R), CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG pegylated interferon alpha-2a (PegasyS(R), interferon alfa Interferon Lambda, recombinant thymosin alpha-1, BTK n1(Humoferon(R), ribavirin, interferon beta-la (AvoneXOR), inhibitors, modulators of TIGIT, modulators of CD47, 55 Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, modulators of SIRPalpha, modulators of ICOS, modulators Oligotide, Zutectra, Shaferon, interferon alfa-2b (AXXO), of CD27, modulators of CD70, modulators of OX40, modu Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron, lators of NKG2D, modulators of Tim-4, modulators of interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, B7-H4, modulators of B7-H3, modulators of NKG2A, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, modulators of GITR, modulators of CD160, modulators of 60 Realdiron, Lansition, Pegaferon, PDferon-B, interferon alfa HEVEM, modulators of CD161, modulators of AX1, modu 2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, lators of Mer, modulators of Tyro, gene modifiers or editors Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b such as CRISPR (including CRISPR Cas9), zinc finger (Zydus-Cadila), Optipeg A. Realfa 2B, Reliferon, interferon nucleases or synthetic nucleases (TALENs), and Hepatitis B alfa-2b (Amega), interferon alfa-2b (Virchow), peginter virus replication inhibitors. In certain embodiments the at 65 feron alfa-2b (Amega), Reaferon-EC, Proquiferon, Unif least one additional therapeutic agent is further selected eron, Urifron, interferon alfa-2b (Changchun Institute of from hepatitis B Surface antigen (HBSAg) secretion or Biological Products), Anterferon, Shanferon, MOR-22, US 9,670,205 B2 119 120 interleukin-2 (IL-2, Immunex), recombinant human inter inhibitors, antisense oligonucleotide targeting viral mRNA, leukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, short interfering RNAs (siRNA), miRNA gene therapy Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, agents, endonuclease modulators, inhibitors of ribonucle Alloferon and celmoleukin otide reductase, Hepatitis B virus E antigen inhibitors, In a particular embodiment, a compound of the present recombinant scavenger receptor A (SRA) proteins, Src disclosure, or a pharmaceutically acceptable Salt thereof, is kinase inhibitors, HBX inhibitors, cccDNA inhibitors, short combined with entecavir (BaracludeR), adefovir (Heps synthetic hairpin RNAs (sshRNAs), HBV antibodies includ era.R.), tenofovir disoproxil fumarate (Viread(R), tenofovir ing HBV antibodies targeting the Surface antigens of the alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafe hepatitis B virus and bispecific antibodies and “antibody namide fumarate, tenofoviralafenamide hemifumarate, tel 10 like therapeutic proteins (such as DARTs(R), Duobodies(R), bivudine (Tyzeka(R) or lamivudine (Epivir-HBVR) Bites(R, Xmabs(R, TandAbs(R, Fab derivatives), CCR2 In a particular embodiment, a compound of the present chemokine antagonists, thymosin agonists, cytokines, disclosure, or a pharmaceutically acceptable Salt thereof, is nucleoprotein inhibitors (HBV core or capsid protein inhibi combined with entecavir (BaracludeR), adefovir (Heps tors), stimulators of retinoic acid-inducible gene 1, Stimu era.R.), tenofovir disoproxil fumarate (Viread(R), tenofovir 15 lators of NOD2, stimulators of NOD1, recombinant thy alafenamide hemifumarate, telbivudine (TyZeka(R) or lami mosin alpha-1, Arginase-1 inhibitors, STING agonists, PI3K vudine (Epivir-HBV(R). inhibitors, lymphotoxin beta receptor activators, Natural In a particular embodiment, a compound of the present Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation disclosure, or a pharmaceutically acceptable salt thereof is gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lympho combined with a PD-1 inhibitor. In a particular embodiment, cyte-associated protein 4 inhibitors, CD137 inhibitors, a compound of the present disclosure, or a pharmaceutically Killer cell lectin-like receptor subfamily G member 1 inhibi acceptable salt thereof is combined with a PD-L1 inhibitor. tors, TIM-3 inhibitors, B- and T-lymphocyte attenuator In a particular embodiment, a compound of the present inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibi disclosure, or a pharmaceutically acceptable salt thereof is tors, PEG-Interferon Lambd, BTK inhibitors, modulators of combined with an IDO inhibitor. In a particular embodi 25 TIGIT, modulators of CD47, modulators of SIRPalpha, ment, a compound of the present disclosure, or a pharma modulators of ICOS, modulators of CD27, modulators of ceutically acceptable salt thereof is combined with an IDO CD70, modulators of OX40, modulators of NKG2D, modu inhibitor and a PD-1 inhibitor. In a particular embodiment, lators of Tim-4, modulators of B7-H4, modulators of B7-H3, a compound of the present disclosure, or a pharmaceutically modulators of NKG2A, modulators of GITR, modulators of acceptable salt thereof, is combined with an IDO inhibitor 30 CD160, modulators of HEVEM, modulators of CD161, and a PD-L1 inhibitor. In a particular embodiment, a com modulators of Axl, modulators of Mer, modulators of Tyro, pound of the present disclosure, or a pharmaceutically gene modifiers or editors such as CRISPR (including acceptable salt thereof, is combined with a TLR7 modulator, CRISPR Cas9), zinc finger nucleases or synthetic nucleases Such as GS-9620. (TALENs), a and Hepatitis B virus replication inhibitors. In In a particular embodiment, a compound of the present 35 certain embodiments, the at least one additional therapeutic disclosure, or a pharmaceutically acceptable Salt thereof, is agent is further selected from hepatitis B surface antigen combined with a TLR7 modulator and an IDO inhibitor. In (HBSAg) secretion or assembly inhibitors, TCR-like anti a particular embodiment, a compound of the present disclo bodies, IDO inhibitors, cccDNA epigenetic modifiers, IAPs Sure, or a pharmaceutically acceptable salt thereof, is com inhibitors, and SMAC mimetics. bined with a TLR7 modulator such as GS-9620 and an IDO 40 In a particular embodiment, a compound of the present inhibitor Such as epacadostat. disclosure, or a pharmaceutically acceptable Salt thereof, is In a particular embodiment, a compound of the present combined with a first additional therapeutic agent selected disclosure, or a pharmaceutically acceptable Salt thereof, is from the group consisting of entecavir (Baraclude R), combined with (4-amino-2-butoxy-8-({3-(pyrrolidin-1-yl) adefovir (HepseraR), tenofovir disoproxil fumarate methylphenyl)methyl)-7,8-dihydropteridin-6(5H)-one) or 45 (Viread(R), tenofoviralafenamide, tenofovir, tenofovir diso a pharmaceutically acceptable salt thereof. proxil, tenofovir alafenamide fumarate, tenofovir alafena As used herein, GS-9620 (4-amino-2-butoxy-8-({3-(pyr mide hemifumarate, telbivudine (Tyzeka(R) or lamivudine rolidin-1-yl)methylphenyl)methyl)-7,8-dihydropteridin-6 (Epivir-HBV(R) and at least a one additional therapeutic (5H)-one), includes pharmaceutically acceptable salts agent selected from the group consisting of peginterferon thereof. J. Med. Chem., 2013, 56 (18), pp 7324-7333. 50 alfa-2b (PEG-Intron(R), Multiferon(R), interferon alpha 1b In a particular embodiment, a compound of the present (HapgenR), interferon alpha-2b (Intron A(R), pegylated disclosure, or a pharmaceutically acceptable Salt thereof, is interferon alpha-2a (Pegasys(R), interferon alfa-n1 (Humof combined with a first additional therapeutic agent selected eron(R), ribavirin, interferon beta-la (AvoneXR), Bioferon, from the group consisting of entecavir (Baraclude R), Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, adefovir (HepseraR), tenofovir disoproxil fumarate 55 Zutectra, Shaferon, interferon alfa-2b (AXXO), Alfaferone, (Viread(R), tenofoviralafenamide, tenofovir, tenofovir diso interferon alfa-2b (BioGeneric Pharma), Feron, interferon proxil, tenofovir alafenamide fumarate, tenofovir alafena alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON mide hemifumarate, telbivudine (Tyzeka(R) or lamivudine B. BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, (Epivir-HBV(R) and at least one additional therapeutic agent Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laborato selected from the group consisting of immunomodulators, 60 rios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, toll-like receptor modulators (modulators of TLR-1, TLR-2, Feronsure, Pegi Hep, interferon alfa 2b (Zydus-Cadila), TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, Optipeg A. Realfa 2B, Reliferon, interferon alfa-2b TLR-10, TLR-11, TLR-12 and TLR-13), interferon alpha (Amega), interferon alfa-2b (Virchow), peginterferon alfa receptor ligands, hyaluronidase inhibitors, recombinant 2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, IL-7, HBSAg inhibitors, compounds targeting HbcAg, 65 interferon alfa-2b (Changchun Institute of Biological Prod cyclophilin inhibitors, HBV Therapeutic vaccines, HBV ucts), Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2, prophylactic vaccines, HBV viral entry inhibitors, NTCP Immunex), recombinant human interleukin-2 (Shenzhen US 9,670,205 B2 121 122 Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, mide hemifumarate, or tenofoviralafenamide. A compound INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleu of the present disclosure (e.g., a compound of Formula (I)) kin. may be combined with the agents provided herein in any In a particular embodiment, a compound of the present dosage amount of the compound (e.g., from 50 mg to 500 disclosure, or a pharmaceutically acceptable Salt thereof, is mg of compound) the same as if each combination of combined with a first additional therapeutic agent selected dosages were specifically and individually listed. A com from the group consisting of entecavir (Baraclude R), pound of the present disclosure (e.g., a compound of For adefovir (HepseraR), tenofovir disoproxil fumarate mula (I)) may be combined with the agents provided herein (Viread(R), tenofoviralafenamide, tenofovir, tenofovir diso in any dosage amount of the compound (e.g. from about 1 proxil, tenofovir alafenamide fumarate, tenofovir alafena 10 mg to about 150 mg of compound) the same as if each mide hemifumarate, telbivudine (Tyzeka(R) or lamivudine combination of dosages were specifically and individually (Epivir-HBV(R) and at least one additional therapeutic agent listed. selected from the group consisting of HBV viral entry In certain embodiments, a compound of the present dis inhibitors, NTCP inhibitors, HBX inhibitors, cccDNA inhibi closure, or a pharmaceutically acceptable salt thereof, is tors, HBV antibodies targeting the surface antigens of the 15 combined with 100-400 mg tenofovir disoproxil fumarate, hepatitis B virus, short interfering RNAs (siRNA), miRNA tenofovir disoproxil hemifumarate, or tenofovir disoproxil. gene therapy agents, short synthetic hairpin RNAS (SShR In certain embodiments, a compound of the present disclo NAs), and nucleoprotein inhibitors (HBV core or capsid Sure, or a pharmaceutically acceptable salt thereof, is com protein inhibitors). bined with 100-150; 100-200, 100-250; 100-300; 100-350; In a particular embodiment, a compound of the present 150-200; 150-250: 150-300; 150-350: 150-400; 200-250; disclosure, or a pharmaceutically acceptable Salt thereof, is 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or combined with a first additional therapeutic agent selected 300-400 mg tenofovir disoproxil fumarate, tenofovir diso from the group consisting of entecavir (Baraclude R), proxil hemifumarate, or tenofovir disoproxil. In certain adefovir (HepseraR), tenofovir disoproxil fumarate embodiments, a compound of the present disclosure, or a (Viread(R), tenofoviralafenamide, tenofovir, tenofovir diso 25 pharmaceutically acceptable salt thereof, is combined with proxil, tenofovir alafenamide fumarate, tenofovir alafena 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil mide hemifumarate, telbivudine (Tyzeka(R) or lamivudine hemifumarate, or tenofovir disoproxil. In certain embodi (Epivir-HBV(R), one or two additional therapeutic agents ments, a compound of the present disclosure, or a pharma selected from the group consisting of immunomodulators, ceutically acceptable salt thereof, is combined with 250 mg toll-like receptor modulators (modulators of TLR-1, TLR-2, 30 tenofovir disoproxil fumarate, tenofovir disoproxil hemifu TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, marate, or tenofovir disoproxil. In certain embodiments, a TLR-10, TLR-11, TLR-12 and TLR-13), HBs.Ag inhibitors, compound of the present disclosure, or a pharmaceutically HBV therapeutic vaccines, HBV antibodies including HBV acceptable salt thereof, is combined with 150 mg tenofovir antibodies targeting the Surface antigens of the hepatitis B disoproxil fumarate, tenofovir disoproxil hemifumarate, or virus and bispecific antibodies and “antibody-like thera 35 tenofovir disoproxil. A compound of the present disclosure peutic proteins (such as DARTs(R), Duobodies(R), Bites.(R), (e.g., a compound of Formula (I)) may be combined with the Xm Abs(R), TandAbs(R, Fab derivatives), cyclophilin inhibi agents provided herein in any dosage amount of the com tors, stimulators of retinoic acid-inducible gene 1, PD-1 pound (e.g., from 50 mg to 500 mg of compound) the same inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3K as if each combination of dosages were specifically and inhibitors and stimulators of NOD2, and one or two addi 40 individually listed. A compound of the present disclosure tional therapeutic agents selected from the group consisting (e.g., a compound of Formula (I)) may be combined with the of HBV viral entry inhibitors, NTCP inhibitors, HBX inhibi agents provided herein in any dosage amount of the com tors, cccDNA inhibitors, HBV antibodies targeting the sur pound (e.g., from about 1 mg to about 150 mg of compound) face antigens of the hepatitis B virus, short interfering RNAs the same as if each combination of dosages were specifically (siRNA), miRNA gene therapy agents, short synthetic hair 45 and individually listed. pin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV Also provided herein is a compound of the present core or capsid protein inhibitors). In certain embodiments, disclosure (e.g., a compound of Formula (I)), or a pharma the one or two additional therapeutic agents is further ceutically acceptable Salt thereof, and one or more additional selected from hepatitis B surface antigen (HBSAg) secretion active ingredients for treating HBV, for use in a method of or assembly inhibitors, TCR-like antibodies, and IDO 50 treating or preventing HBV. inhibitors. Also provided herein is a compound of the present In certain embodiments, a compound of the present dis disclosure (e.g., a compound of Formula (I)), or a pharma closure, or a pharmaceutically acceptable salt thereof, is ceutically acceptable salt thereof, for use in a method of combined with 5-30 mg tenofovir alafenamide fumarate, treating or preventing HBV, wherein the compound, or a tenofovir alafenamide hemifumarate, or tenofovir alafena 55 pharmaceutically acceptable salt thereof is administered mide. In certain embodiments, a compound of the present simultaneously, separately or sequentially with one or more disclosure, or a pharmaceutically acceptable Salt thereof, is additional therapeutic agents fort for treating HBV. combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; VII. Combination Therapy for HCV or 10-30 mg tenofovir alafenamide fumarate, tenofovir In certain embodiments, a method for treating or prevent alafenamide hemifumarate, or tenofovir alafenamide. In 60 ing an HCV infection in a human having or at risk of having certain embodiments, a compound of the present disclosure, the infection is provided, comprising administering to the or a pharmaceutically acceptable salt thereof, is combined human a therapeutically effective amount of a compound of with 10 mg tenofoviralafenamide fumarate, tenofoviralafe the present disclosure, or a pharmaceutically acceptable salt namide hemifumarate, or tenofovir alafenamide. In certain thereof, in combination with a therapeutically effective embodiments, a compound of the present disclosure, or a 65 amount of one or more (e.g., one, two, three, one or two, or pharmaceutically acceptable salt thereof, is combined with one to three) additional therapeutic agents. In one embodi 25 mg tenofovir alafenamide fumarate, tenofovir alafena ment, a method for treating an HCV infection in a human US 9,670,205 B2 123 124 having or at risk of having the infection is provided, com (2) Ribavirin and its analogs selected from the group con prising administering to the human a therapeutically effec sisting of ribavirin (Rebetol, Copegus), and taribavirin tive amount of a compound of the present disclosure, or a (Viramidine); pharmaceutically acceptable salt thereof, in combination (3) NS5A inhibitors selected from the group consisting of with a therapeutically effective amount of one or more (e.g., 5 Compound A.1 (described below), Compound A.2 (de one, two, three, one or two, or one to three) additional scribed below), Compound A.3 (described below), ABT therapeutic agents. 267, Compound A4 (described below), JNJ-479.10382, In certain embodiments, the present disclosure provides a daclatasvir (BMS-790052), ABT-267, Samatasvir, method for treating an HCV infection, comprising admin 10 MK-8742, MK-8404, EDP-239, IDX-719, PPI-668, istering to a patient in need thereof a therapeutically effec GSK-2336805, ACH-3102, A-831, A-689, AZD-2836 tive amount of a compound of the present disclosure, or a (A-831), AZD-7295 (A-689), and BMS-790052: pharmaceutically acceptable salt thereof, in combination (4) NS5B polymerase inhibitors selected from the group with a therapeutically effective amount of one or more consisting of Sofosbuvir (GS-7977), Compound A.5 (de additional therapeutic agents which are Suitable for treating 15 an HCV infection. scribed below), Compound A.6 (described below), ABT In the above embodiments, the additional therapeutic 333, Compound A.7 (described below), ABT-072, Com agent may be an anti-HCV agent. For example, in some pound A.8 (described below), tegobuvir (GS-9190), embodiments, the additional therapeutic agent is selected GS-9669, TMC647055, ABT-333, ABT-072, setrobuvir from the group consisting of interferons, ribavirin or its (ANA-598), IDX-21437, filibuvir (PF-868554), VX-222, analogs, HCV NS3 protease inhibitors, HCV NS4 protease IDX-375, IDX-184, IDX-102, BI-207127, valopicitabine inhibitors, HCV NS3/NS4 protease inhibitors, alpha-glu (NM-283), PSI-6130 (R1656), PSI-7851, BCX-4678, cosidase 1 inhibitors, hepatoprotectants, nucleoside or nesbuvir (HCV-796), BILB 1941, MK-0608, NM-107, nucleotide inhibitors of HCV NS5B polymerase, non R7128, VCH-759, GSK625433, XTL-2125, VCH-916, nucleoside inhibitors of HCV NS5B polymerase, HCV 25 JTK-652, MK-3281, VBY-708, A848837, GL59728, NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, A-63890, A-48773, A-48547, BC-2329, BMS-791325, HCV IRES inhibitors, and pharmacokinetic enhancers, com BILB-1941, AL-335, AL-516 and ACH-3422; pounds such as those disclosed in US2010/0310512, (5) Protease (NS3, NS3-NS4) inhibitors selected from the US2013/0102525, and WO2013/185093, or combinations group consisting of Compound A.9, Compound A.10, thereof. 30 Compound A.11, ABT-450, Compound A.12 (described In certain embodiments a compound of the present dis below), simeprevir (TMC-435), boceprevir (SCH closure (e.g., a compound of Formula (I)) is formulated as 503034), narlaprevir (SCH-900518), vaniprevir (MK a tablet, which may optionally contain one or more other 7009), MK-5172, danoprevir (ITMN-191), sovaprevir compounds useful for treating HCV. In certain embodi 35 (ACH-1625), neceprevir (ACH-2684), Telaprevir (VX ments, the tablet can contain another active ingredient for 950), VX-813, VX-500, faldaprevir (BI-201335), asuna treating HCV. Such as interferons, ribavirin or its analogs, previr (BMS-650032), BMS-605339, VBY-376, PHX HCVNS3 protease inhibitors, HCV NS4 protease inhibitors, 1766, YH5531, BILN-2065, and BILN-2061; HCV NS3/NS4 protease inhibitors, alpha-glucosidase 1 (6) Alpha-glucosidase 1 inhibitors selected from the group inhibitors, hepatoprotectants, nucleoside or nucleotide 40 consisting of celgosivir (MX-3253), Miglitol, and inhibitors of HCV NS5B polymerase, non-nucleoside UT-231B: inhibitors of HCV NS5B polymerase, HCV NS5A inhibi (7) Hepatoprotectants selected from the group consisting of tors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, and pharmacokinetic enhancers, or combinations emericasan (IDN-6556), ME-3738, GS-9450 (LB thereof. 45 84451), silibilin, and MitoO; In certain embodiments, such tablets are suitable for once (8) TLR-7 agonists selected from the group consisting of daily dosing. imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD In certain embodiments, the additional therapeutic agent 8848 (DSP-3025), and SM-360320; is selected from one or more of: (9) Cyclophillin inhibitors selected from the group consist (1) Interferons selected from the group consisting of pegy 50 ing of DEBIO-025, SCY-635, and NIM811; lated riFN-alpha2b (PEG-Intron), pegylated rFN-alpha (10) HCV IRES inhibitors selected from the group consist 2a (Pegasys), rFN-alpha 2b (Intron A), rIFN-alpha 2a ing of MCI-067: (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaf (11) Pharmacokinetic enhancers selected from the group erone, Alfanative, Multiferon, subalin), interferon alfa 55 consisting of BAS-100, SPI-452, PF-4194477, TMC con-1 (Infergen), interferon alpha-n1 (Wellferon), inter 41629, GS-9350, GS-9585, and roxythromycin; and feron alpha-n3 (Alferon), interferon-beta (Avonex, (12) Other anti-HCV agents selected from the group con DL-8234), interferon-omega (omega DUROS, Biomed sisting of thymosin alpha 1 (Zadaxin), nitazoxanide 510), albinterferon alpha-2b (Albuferon), IFN alpha XL, (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), BLX-883 (Locteron), DA-3021, glycosylated interferon 60 KPE02003002, actilon (CPG-10101), GS-9525, KRN alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon 7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, lambda (PEGylated IL-29), or belerofon, IFN alpha-2b ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, 18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, pegylated IFN-beta, oral interferon alpha, feron, reaferon, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), intermax alpha, r-IFN-beta, and infergen--actimmuneriba 65 Oglufanide, VX-497 (merimepodib) NIM811, benzimi virin and ribavirin analogs, e.g., rebetol, copegus, dazole derivatives, benzo-1,2,4-thiadiazine derivatives, VX-497, and viramidine (taribavirin); and phenylalanine derivatives; US 9,670,205 B2 125 126 Compound A.1 is an inhibitor of the HCV NS5A protein and is represented by the following chemical structure:

(see, e.g., U.S. Application Publication No. 20100310512 A1). Compound A.2 is an NS5A inhibitor and is represented by the following chemical structure: O

35 Compound A.3 is an NS5A inhibitor and is represented by the following chemical structure:

50 Compound A.4 is an NS5A inhibitor and is represented by the following chemical structure:

| r or SS US 9,670,205 B2 127 128 (see U.S. Application Publication No. 2013/0102525 and references therein.) Compound A.5 is an NS5B Thumb II polymerase inhibi tor and is represented by the following chemical structure:

H O N \/ '. N 1 y H

F Compound A.6 is a nucleotide inhibitor prodrug designed to inhibit replication of viral RNA by the HCV NS5B polymerase, and is represented by the following chemical Structure: N1 Compound A.10 is an HCV protease inhibitor and is represented by the following chemical structure: N n N 25 s 2 ), s O O {llN N NH2. C O HN, I P l No w e2F

Compound A.7 is an HCV polymerase inhibitor and is represented by the following structure: H O N NHSOCH 35

o1 40

* Compound A.11 is an HCV protease inhibitor and is (see U.S. Application Publication No. 2013/0102525 and represented by the following chemical structure: references therein). Compound A.8 is an HCV polymerase inhibitor and is represented by the following structure: NHSOCH 50 C S )— O N 2 NH n N

(see U.S. Application Publication No. 2013/0102525 and references therein). 65 Compound A.9 is an HCV protease inhibitor and is represented by the following chemical structure: US 9,670,205 B2 129 130 Compound A.12 is an HCV protease inhibitor and is -continued represented by the following chemical structure:

In another embodiment, the additional therapeutic agent used in combination with the pharmaceutical compositions (see U.S. Application Publication No. 2013/0102525 and as described herein is a cyclophillin inhibitor, including for references therein). example, a cyclophilin inhibitor disclosed in WO2013/ In one embodiment, the additional therapeutic agent used 25 185093. Non-limiting examples in addition to those listed in combination with the pharmaceutical compositions as above include the following: described herein is a HCV NS3 protease inhibitor. Non limiting examples include the following:

30 N

2 N

O NH 35 OH,

NH O O O O Q O O N 40 \/ NH N1

45 F

C NX--( 55

O III OH,

O 60 H N SY X.v' OH, and

65 US 9,670,205 B2 131 132

-continued -continued

NH 10 O O O N O

N H 15 and stereoisomers and mixtures of stereoisomers thereof. In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable Salt thereof, is combined with a HCV NS5B polymerase inhibitor. In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS5B polymerase inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of 25 the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS5B polymerase inhibi tor, a HCV NS3 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt 30 thereof, is combined with a HCV NS5B polymerase inhibi tor, a HCV NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS5B polymerase inhibi 35 tor, a HCV NS3/NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS3 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a 40 compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined 45 with a HCV NS3/NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS3 protease inhibitor, a pharmacokinetic enhancer and a HCV NS5A inhibitor. In 50 another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable Salt thereof, is combined with a HCV NS4 protease inhibitor, a pharma cokinetic enhancer and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, 55 or a pharmaceutically acceptable salt thereof, is combined with a HCV NS3/NS4 protease inhibitor, a pharmacokinetic enhancer and a HCV NS5A inhibitor. In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable Salt thereof, is 60 combined with one, two, three, four or more additional therapeutic agents selected from simeprevir, MK-8742, MK-8408, MK-5172, ABT-450, ABT-267, ABT-333, sofos buvir, sofosbuvir-i-ledipasvir, Sofosbuvir+GS-5816, sofosbu vir+GS-9857+ledipasvir, ABT-450+ ABT-267+ritonavir, 65 ABT-450+ABT-267+ribavirin-i-ritonavir, ABT-450+ABT 267+ribavirin-i-ABT-333+ritonavir, ABT-530+ABT-493, MK-8742+MK-5172, MK-8408+MK-3682+MK-5172, US 9,670,205 B2 133 134 MK-8742+MK-3682+MK-5172, daclatasvir, interferon, present disclosure, or a pharmaceutically acceptable salt pegylated interferon, ribavirin, samatasvir, MK-3682, ACH thereof, is co-administered with GS-9857. In certain 3422, AL-335, IDX-21437, IDX-21459, tegobuvir, setrobu embodiments, a compound of the present disclosure, or a Vir, Valopicitabine, boceprevir, narlaprevir, Vaniprevir, dano pharmaceutically acceptable salt thereof, is co-administered previr, Sovaprevir, neceprevir, telaprevir, faldaprevir, with IDX-21459. In certain embodiments, a compound of asunaprevir, ledipasvir, GS-5816, GS-9857, ACH-3102, the present disclosure, or a pharmaceutically acceptable salt ACH-3422+ACH-3102, ACH-3422+sovaprevir-i-ACH thereof, is co-administered with boceprevir. In certain 3102, asunaprevir, asunaprevir-daclatasvir, AL-516, and embodiments, a compound of the present disclosure, or a Vedroprevir. pharmaceutically acceptable salt thereof, is co-administered In certain embodiments, a compound of the present dis 10 with ledipasvir. In certain embodiments, a compound of the closure, or a pharmaceutically acceptable salt thereof, is present disclosure, or a pharmaceutically acceptable salt co-administered with Simeprevir. In certain embodiments, a thereof, is co-administered with AL-516. compound of the present disclosure, or a pharmaceutically In various methods, Compound A.1 is administered in an acceptable salt thereof, is co-administered with MK-8742 or amount ranging from about 10 mg/day to about 200 mg/day. MK-8408. In certain embodiments, a compound of the 15 For example, the amount of Compound A.1 can be about 30 present disclosure, or a pharmaceutically acceptable salt mg/day, about 45 mg/day, about 60 mg/day, about 90 thereof, is co-administered with MK-5172. In certain mg/day, about 120 mg/day, about 135 mg/day, about 150 embodiments, a compound of the present disclosure, or a mg/day, about 180 mg/day. In some methods, Compound pharmaceutically acceptable salt thereof, is co-administered A.1 is administered at about 90 mg/day. In various methods, with ABT-450, ABT-267, or ABT-333. In certain embodi Compound A.2 is administered in an amount ranging from ments, a compound of the present disclosure, or a pharma about 50 mg/day to about 800 mg/day. For example, the ceutically acceptable salt thereof, is co-administered with amount of Compound A.2 can be about 100 mg/day, about Viekirat (a combination of ABT-450, ABT-267, and ritona 200 mg/day, or about 400 mg/day. In some methods, the vir). In certain embodiments, a compound of the present amount of Compound A.3 is about 10 mg/day to about 200 disclosure, or a pharmaceutically acceptable Salt thereof, is 25 mg/day. For example, the amount of Compound A.3 can be co-administered with daclatasvir. In certain embodiments, a about 25 mg/day, about 50 mg/day, about 75 mg/day, or compound of the present disclosure, or a pharmaceutically about 100 mg/day. acceptable salt thereof, is co-administered with sofosbuvir. In various methods, Sofosbuvir is administered in an In certain embodiments, a compound of the present disclo amount ranging from about 10 mg/day to about 1000 Sure, or a pharmaceutically acceptable salt thereof, is co 30 mg/day. For example, the amount of Sofosbuvir can be about administered with Harvoni (sofosbuvir-i-ledipasvir). In cer 100 mg/day, about 200 mg/day, about 300 mg/day, about tain embodiments, a compound of the present disclosure, or 400 mg/day, about 500 mg/day, about 600 mg/day, about a pharmaceutically acceptable Salt thereof, is co-adminis 700 mg/day, about 800 mg/day. In some methods, sofosbuvir tered with Sofosbuvir and GS-5816. In certain embodiments, is administered at about 400 mg/day. a compound of the present disclosure, or a pharmaceutically 35 Also provided herein is a compound of the present acceptable salt thereof, is co-administered with SofosbuVir-- disclosure (e.g., a compound of Formula (I)), or a pharma GS-9857+ledipasvir. In certain embodiments, a compound ceutically acceptable Salt thereof, and one or more additional of the present disclosure, or a pharmaceutically acceptable therapeutic agents for treating HCV, for use in a method of salt thereof, is co-administered with ABT-450+ABT-267+ treating or preventing HCV. ribavirin-i-ritonavir. In certain embodiments, a compound of 40 Also provided herein is a compound of the present the present disclosure, or a pharmaceutically acceptable salt disclosure (e.g., a compound of Formula (I)), or a pharma thereof, is co-administered with ABT-450+ABT-267+riba ceutically acceptable salt thereof, for use in a method of virin-i-ABT-333+ritonavir. In certain embodiments, a com treating or preventing HCV, wherein the compound or a pound of the present disclosure, or a pharmaceutically pharmaceutically acceptable salt thereof is administered acceptable salt thereof, is co-administered with ABT-530+ 45 simultaneously, separately or sequentially with one or more ABT-493. In certain embodiments, a compound of the additional therapeutic agents for treating HCV. present disclosure, or a pharmaceutically acceptable salt VIII. Combination Therapy for HIV thereof, is co-administered with MK-8408+MK-3682+MK In certain embodiments, a method for treating or prevent 5172. In certain embodiments, a compound of the present ing an HIV infection in a human having or at risk of having disclosure, or a pharmaceutically acceptable Salt thereof, is 50 the infection is provided, comprising administering to the co-administered with MK-8742+MK-5172. In certain human a therapeutically effective amount of a compound of embodiments, a compound of the present disclosure, or a the present disclosure, or a pharmaceutically acceptable salt pharmaceutically acceptable salt thereof, is co-administered thereof, in combination with a therapeutically effective with MK-3682. In certain embodiments, a compound of the amount of one or more (e.g., one, two, three, one or two, or present disclosure, or a pharmaceutically acceptable salt 55 one to three) additional therapeutic agents. In one embodi thereof, is co-administered with ACH-3422. In certain ment, a method for treating an HIV infection in a human embodiments, a compound of the present disclosure, or a having or at risk of having the infection is provided, com pharmaceutically acceptable salt thereof, is co-administered prising administering to the human a therapeutically effec with AL-335. In certain embodiments, a compound of the tive amount of a compound of the present disclosure, or a present disclosure, or a pharmaceutically acceptable salt 60 pharmaceutically acceptable salt thereof, in combination thereof, is co-administered with ACH-3422+ACH-3102. In with a therapeutically effective amount of one or more (e.g., certain embodiments, a compound of the present disclosure, one, two, three, one or two, or one to three) additional or a pharmaceutically acceptable salt thereof, is co-admin therapeutic agents. istered with ACH-3422+sovaprevir-i-ACH-3102. In certain In certain embodiments, the present disclosure provides a embodiments, a compound of the present disclosure, or a 65 method for treating an HIV infection, comprising adminis pharmaceutically acceptable salt thereof, is co-administered tering to a patient in need thereof a therapeutically effective with GS-5816. In certain embodiments, a compound of the amount of a compound of the present disclosure, or a US 9,670,205 B2 135 136 pharmaceutically acceptable salt, thereof, in combination tors, HIV non-nucleoside or non-nucleotide inhibitors of with a therapeutically effective amount of one or more reverse transcriptase, HIV nucleoside or nucleotide inhibi additional therapeutic agents which are Suitable for treating tors of reverse transcriptase, HIV integrase inhibitors, HIV an HIV infection. In certain embodiments, one or more non-catalytic site (or allosteric) integrase inhibitors, phar additional therapeutic agents includes, for example, one, 5 macokinetic enhancers, and combinations thereof. two, three, four, one or two, one to three or one to four In certain embodiments a compound of the present dis additional therapeutic agents. closure is formulated as a tablet, which may optionally In the above embodiments, the additional therapeutic contain one or more other compounds useful for treating agent may be an anti-HIV agent. For example, in some HIV. In certain embodiments, the tablet can contain another embodiments, the additional therapeutic agent is selected 10 active ingredient for treating HIV, such as HIV protease from the group consisting of HIV protease inhibitors, HIV inhibitors, HIV non-nucleoside or non-nucleotide inhibitors non-nucleoside or non-nucleotide inhibitors of reverse tran of reverse transcriptase, HIV nucleoside or nucleotide scriptase, HIV nucleoside or nucleotide inhibitors of reverse inhibitors of reverse transcriptase, HIV integrase inhibitors, transcriptase, HIV integrase inhibitors, HIV non-catalytic HIV non-catalytic site (or allosteric) integrase inhibitors, site (or allosteric) integrase inhibitors, HIV entry inhibitors 15 pharmacokinetic enhancers, and combinations thereof. (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibi In certain embodiments, such tablets are suitable for once tors) and CD4 attachment inhibitors), CXCR4 inhibitors, daily dosing. gp120 inhibitors, G6PD and NADH-oxidase inhibitors, HIV In certain embodiments, the additional therapeutic agent vaccines, HIV maturation inhibitors, latency reversing is selected from one or more of: agents (e.g., histone deacetylase inhibitors, proteasome (1) Combination drugs selected from the group consisting of inhibitors, protein kinase C (PKC) activators, and BRD4 ATRIPLAR (efavirenz+tenofovir disoproxil fumarate+ inhibitors), compounds that target the HIV capsid (“capsid emtricitabine), COMPLERAR (EVIPLERAR, rilpiv inhibitors'; e.g., capsid polymerization inhibitors or capsid irine--tenofovir disoproxil fumarate+emtricitabine), disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibi STRIBILDR (elvitegravir-cobicistat-i-tenofovir diso tors, HIV p24 capsid protein inhibitors), pharmacokinetic 25 proxil fumarate--emitricitabine), dolutegravir--abacavir enhancers, immune-based therapies (e.g., Pd-1 modulators, sulfate--lamivudine, TRIUMEQR (dolutegravir--aba Pd-L1 modulators, toll like receptors modulators, IL-15 cavir-lamivudine), lamivudine--nevirapine--zidovudine, agonists.), HIV antibodies, bispecific antibodies and “anti dolutegravir-rilpivirine, atazanavir Sulfate--cobicistat, body-like therapeutic proteins (e.g., DARTs(R), Duobod darunavir--cobicistat, efavirenz+lamivudine--tenofovir ies(R), Bites(R), XmAbs(R, TandAbs(R, Fab derivatives) 30 disoproxil fumarate, tenofovir alafenamide hemifumar including those targeting HIV gp120 or gp41, combination ate--emitricitabine+cobicistat+elvitegravir, Vacc-4X+ro drugs for HIV, HIV p17 matrix protein inhibitors, IL-13 midepsin, darunavir-i-tenofovir alafenamide hemifumar antagonists, Peptidyl-prolyl cis-trans isomerase A modula ate+emtricitabine--cobicistat, APH-0812, raltegravir-- tors, Protein disulfide isomerase inhibitors, Complement lamivudine, KALETRAR (ALUVIAR, lopinavir-- C5a receptor antagonists, DNA methyltransferase inhibitor, 35 ritonavir), atazanavir sulfate--ritonavir, COMBIVIRR HIV vif gene modulators, HIV-1 viral infectivity factor (zidovudine--lamivudine, AZT-3TC), EPZICOMR) inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, (LivexaR), abacavir sulfate--lamivudine, ABC+3TC), Hck tyrosine kinase modulators, mixed lineage kinase-3 TRIZIVIRR (abacavir sulfate+zidovudine--lamivudine, (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein ABC+AZT-3TC), TRUVADAR (tenofovir disoproxil inhibitors, Integrin antagonists, Nucleoprotein inhibitors, 40 fumarate+emtricitabine, TDF+FTC), tenofoviri-lamivu Splicing factor modulators, COMM domain containing pro dine and lamivudine--tenofovir disoproxil fumarate, as tein 1 modulators, HIV Ribonuclease H inhibitors, Retro well as combinations drugs selected from dolutegravir cyclin modulators, CDK-9 inhibitors, Dendritic ICAM-3 rilpivirine hydrochloride, atazanavir--cobicistat, tenofovir grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibi alafenamide hemifumarate--emtricitabine, tenofovir tors, HIV POL protein inhibitors, Complement Factor H 45 alafenamide+emtricitabine, tenofovir alafenamide hemi modulators, Ubiquitin ligase inhibitors, Deoxycytidine fumarate+emtricitabine-rilpivirine, tenofovir alafena kinase inhibitors, Cyclin dependent kinase inhibitors Pro mide+emtricitabine-rilpivirine, doravirine--lamivudine-- protein convertase PC9 stimulators, ATP dependent RNA tenofovir disoproxil fumarate, doravirine--lamivudine-- helicase DDX3X inhibitors, reverse transcriptase priming tenofovir disoproxil; complex inhibitors, PI3K inhibitors, compounds such as 50 (2) HIV protease inhibitors selected from the group consist those disclosed in WO 2013/006738 (Gilead Sciences), US ing of amprenavir, atazanavir, fosamprenavir, foSampre 2013/0165489 (University of Pennsylvania), WO 2013/ navir calcium, indinavir, indinavir Sulfate, lopinavir, rito 091096A1 (Boehringer Ingelheim), WO 2009/062285 navir, nelfinavir, nelfinavir mesylate, saquinavir, (Boehringer Ingelheim), US20140221380 (Japan Tobacco), saquinavir mesylate, tipranavir, brecanavir, darunavir, US20140221378 (Japan Tobacco), WO 2010/130034 55 DG-17, TMB-657 (PPL-100) and TMC-310911; (Boehringer Ingelheim), WO 2013/159064 (Gilead Sci (3) HIV non-nucleoside or non-nucleotide inhibitors of ences), WO 2012/145728 (Gilead Sciences), WO2012/ reverse transcriptase selected from the group consisting of 003497 (Gilead Sciences), WO2014/100323 (Gilead Sci delavirdine, delavirdine mesylate, nevirapine, etravirine, ences), WO2012/145728 (Gilead Sciences), WO2013/ dapivirine, doravirine, rilpivirine, efavirenz, KM-023, 159064 (Gilead Sciences) and WO 2012/003498 (Gilead 60 VM-1500, lentinan and AIC-292; Sciences) and WO 2013/006792 (Pharma Resources), and (4) HIV nucleoside or nucleotide inhibitors of reverse tran other drugs for treating HIV, and combinations thereof. In scriptase selected from the group consisting of VIDEXOR) Some embodiments, the additional therapeutic agent is fur and VIDEXR EC (didanosine, ddl), zidovudine, emitric ther selected from Vif dimerization antagonists and HIV itabine, didanosine, stavudine, Zalcitabine, lamivudine, gene therapy. 65 censavudine, abacavir, abacavir Sulfate, amdoxovir, elvu In certain embodiments, the additional therapeutic is citabine, alovudine, phosphazid, foZivudine tidoxil, apric selected from the group consisting of HIV protease inhibi itabine, amdoxovir, KP-1461, fosalvudine tidoxil, teno US 9,670,205 B2 137 138 fovir, tenofovir disoproxil, tenofovir disoproxil fumarate, ADVAX, MYM-V201, MVA-CMDR, ETV-01 and DNA tenofovir disoproxil hemifumarate, tenofovir alafena Ad5 gag?pol/nef/nev (HVTN505), as well as HIV vac mide, tenofovir alafenamide hemifumarate, tenofovir cines selected from monomeric gp120 HIV-1 subtype C alafenamide fumarate, adefovir, adefovir dipivoxil, and vaccine (Novartis), HIV-TriMix-mRNA, MVATG-17401, festinavir, ETV-01, CDX-1401, and rcAd26.MOS 1. HIV-Env; (5) HIV integrase inhibitors selected from the group con (16) HIV antibodies, bispecific antibodies and “antibody sisting of curcumin, derivatives of curcumin, chicoric like therapeutic proteins (such as DARTs(R), Duobod acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic ies(R), Bites(R, Xmabs(R), TandAbs(R, Fab derivatives) acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricar including BMS-93.6559, TMB-360 and those targeting boxylic acid, derivatives of aurintricarboxylic acid, caf 10 HIV gp120 or gp41 selected from the group consisting of feic acid phenethyl ester, derivatives of caffeic acid phen bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+ ethyl ester, tyrphostin, derivatives of tyrphostin, C2G12+C4E10, 3-BNC-117, PGT145, PGT121, quercetin, derivatives of quercetin, raltegravir, elvitegra MDXO10 (ipilimumab), VRCO1, A32, 7B2, 10E8 and vir, dolutegravir and cabotegravir, as well as HIV inte VRC07, as well as HIV antibodies such as VRC-07-523; grase inhibitors selected from JTK-351; 15 (17) latency reversing agents selected from the group con (6) HIV non-catalytic site, or allosteric, integrase inhibitors sisting of Histone deacetylase inhibitors such as (NCINI) selected from the group consisting of CX-051.68, Romidepsin, Vorinostat, panobinostat; Proteasome inhibi CX-05045 and CX-14442: tors such as Velcade; protein kinase C (PKC) activators (7) HIV gp41 inhibitors selected from the group consisting such as Indolactam, Prostratin, Ingenol B and DAG of enfuvirtide, sifuvirtide and albuvirtide; lactones, Ionomycin, GSK-343, PMA, SAHA, BRD4 (8) HIV entry inhibitors selected from the group consisting inhibitors, IL-15, JQ1, disulfram, and amphotericin B; of cenicriviroc; (18) HIV nucleocapsid p7 (NCp7) inhibitors selected from (9) HIV gp120 inhibitors selected from the group consisting the group consisting of aZodicarbonamide; of Radha-108 (Receptol) and BMS-663068; (19) HIV maturation inhibitors selected from the group (10) CCR5 inhibitors selected from the group consisting of 25 consisting of BMS-955176 and GSK-2838232: aplaviroc, Vicriviroc, maraviroc, cenicriviroc. PRO-140, (20) PI3K inhibitors selected from the group consisting of Adaptavir (RAP-101), TBR-220 (TAK-220), nifeviroc idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, (TD-0232), TD-0680, and vMIP (Haimipu); neratinib, rigosertib, rigosertib sodium, EN-3342, TGR (11) CD4 attachment inhibitors selected from the group 1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, consisting of ibalizumab; 30 gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, (12) CXCR4 inhibitors selected from the group consisting of RG-7666, GSK-2636771, DS-7423, panulisib, GSK plerixafor, ALT-1188, vMIP and Haimipu: 2269557, GSK-2126458, CUDC-907, PQR-309, INCB (13) Pharmacokinetic enhancers selected from the group 040093, pilaralisib, BAY-1082439, puquitinib mesylate, consisting of cobicistat and ritonavir, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN (14) Immune-based therapies selected from the group con 35 1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR sisting of dermaVir, interleukin-7. plaquenil (hydroxy 260301 and CLR-1401; chloroquine), proleukin (aldesleukin, IL-2), interferon (21) the compounds disclosed in WO 2004/096286 (Gilead alfa, interferon alfa-2b, interferon alfa-n3, pegylated Sciences), WO 2006/110157 (Gilead Sciences), WO interferon alfa, interferon gamma, hydroxyurea, myco 2006/015261 (Gilead Sciences), WO 2013/006738 phenolate mofetil (MPA) and its ester derivative myco 40 (Gilead Sciences), US 2013/0165489 (University of phenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, Pennsylvania), US20140221380 (Japan Tobacco), polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR US20140221378 (Japan Tobacco), WO 2013/006792 22, BMS-93.6559, toll-like receptors modulators (TLR-1, (Pharma Resources), WO 2009/062285 (Boehringer TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, Ingelheim), WO 2010/130034 (Boehringer Ingelheim), TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13), rinta 45 WO 2013/091096A1 (Boehringer Ingelheim), WO 2013/ tolimod and IR-103; 159064 (Gilead Sciences), WO 2012/145728 (Gilead Sci (15) HIV vaccines selected from the group consisting of ences), WO2012/003497 (Gilead Sciences), WO2014/ peptide vaccines, recombinant Subunit protein vaccines, 100323 (Gilead Sciences), WO2012/145728 (Gilead live vector vaccines, DNA vaccines, virus-like particle Sciences), WO2013/159064 (Gilead Sciences) and WO vaccines (pseudovirion vaccine), CD4-derived peptide 50 2012/003498 (Gilead Sciences); and vaccines, vaccine combinations, rgp120 (AIDSVAX), (22) other drugs for treating HIV selected from the group ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) consisting of BanLec, MK-8507, AG-1105, TR-452, (RV 144), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, MK-8591, REP 9, CYT-107, allisporivir, NOV-205, IND DCVax-001 (CDX-2401), PEP-6409, Vacc-4x, Vacc-C5, 02, metenkefalin, PGN-007, Acemannan, Gamimune, VAC-3S, multiclade DNA recombinant adenovirus-5 55 Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR-576, 101, Tat Oyi vaccine, AVX-201, HIV-LAMP-vax, Ad35, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adju gene therapy, Block Aide, ABX-464, SCY-635, naltrexone vanted vaccines, Tatimmune, GTU-multiHIV (FIT-06), and PA-1050040 (PA-040); and other drugs for treating AGS-004, gp140 deltaV2.TV1+MF-59, rVSVIN HIV-1 60 HIV selected from AAV-eCD4-Ig gene therapy, TEV gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35 901 10, TEV-90112, TEV-901 11, TEV-901 13, deferiprone, GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV and HS-10234. PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, Vichrepol, In certain embodiments, the additional therapeutic agent rAAV1-PG9DP, GOVX-B11, GOVX-B21, ThV-01, is a compound disclosed in US 2014-0221356 (Gilead TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade 65 Sciences, Inc.) for example (2R.5S,13aR)-N-(2,4-difluo C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, robenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octa TL-01, SAV-001, AE-H, MYM-V 101, CombiHIV vac, hydro-2,5-methanopyrido1'.2:45pyrazino.2.1-b1.3ox US 9,670,205 B2 139 140 azepine-10-carboxamide, (2S,5R,13aS)-N-(2,4- Epzicom R. (LivexaR), abacavir sulfate+lamivudine, ABC+ difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a 3TC), Trizivir R (abacavir sulfate--zidovudine--lamivudine, octahydro-2,5-methanopyrido1'.2:4.5 pyrazino.2.1-b1.3 ABC+AZT-3TC), adefovir, adefovir dipivoxil, StribildR) oxazepine-10-carboxamide, (1S,4R,12aR)-N-(2,4- (elvitegravir--cobicistat+tenofovir disoproxil fumarate-- difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a emtricitabine), rilpivirine, rilpivirine hydrochloride, Com octahydro-1,4-methanodipyrido 1,2-a: 1,2'-dpyrazine-9- plera.R. (Eviplera R, rilpivirine--tenofovir disoproxil fumar carboxamide, (1R,4S.12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6- ate+emtricitabine), Cobicistat, AtriplaR (efavirenz+ trifluorobenzyl)-1,2,3,4,6,8,12. 12a-octahydro-1,4- tenofovir disoproxil fumarate--emitricitabine), atazanavir, methanodipyrido 1,2-a:1'2'-dpyrazine-9-carboxamide, atazanavir Sulfate, dolutegravir, elvitegravir, Aluvia(R) (Kale (2R,5 S.13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluoroben 10 tra R, lopinavir-i-ritonavir), ritonavir, emitricitabine, atazana Zyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido1'.2: vir sulfate-ritonavir, darunavir, lamivudine, Prolastin, fos 4.5 pyrazino.2.1-b1.3oxazepine-10-carboxamide, and amprenavir, foSamprenavir calcium, efavirenz, Combivir R (1R,4 S, 12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-di (zidovudine--lamivudine, AZT-3TC), etravirine, nelfinavir, oXo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyridol, nelfinavir mesylate, interferon, didanosine, stavudine, indi 2-a: 1,2'-dpyrazine-9-carboxamide, US2O15-OO18298 15 navir, indinavir Sulfate, tenofoviri-lamivudine, Zidovudine, (Gilead Sciences, Inc.) and US2015-0018359 (Gilead Sci nevirapine, saquinavir, saquinavir meSylate, aldesleukin, ences, Inc.), Zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine In certain embodiments, a compound of the present dis mesylate, Radha-108 (Receptol), Hlviral, lamivudine--teno closure, or a pharmaceutically acceptable salt thereof, is fovir disoproxil fumarate, efavirenz+lamivudine--tenofovir combined with one, two, three, four or more additional disoproxil fumarate, phosphazid, lamivudine--nevirapine-- therapeutic agents. In certain embodiments, a compound of Zidovudine, abacavir, abacavir Sulfate, tenofovir, tenofovir the present disclosure, or a pharmaceutically acceptable salt disoproxil, tenofovir disoproxil fumarate, tenofoviralafena thereof, is combined with two additional therapeutic agents. mide and tenofovir alafenamide hemifumarate. In certain In other embodiments, a compound of the present disclo embodiments, the one, two, three, four or more additional Sure, or a pharmaceutically acceptable salt thereof, is com 25 therapeutic agents are further selected from raltegravir bined with three additional therapeutic agents. In further lamivudine, atazanavir Sulfate-cobicistat, atazanavir-cobi embodiments, a compound of the present disclosure, or a cistat, darunavir-cobicistat, darunavir--cobicistat, atazanavir pharmaceutically acceptable salt thereof, is combined with Sulfate-cobicistat, atazanavir-cobicistat. four additional therapeutic agents. The one, two, three, four In a particular embodiment, a compound of the present or more additional therapeutic agents can be different thera 30 disclosure, or a pharmaceutically acceptable Salt thereof, is peutic agents selected from the same class of therapeutic combined with one, two, three, four or more additional agents, and/or they can be selected from different classes of therapeutic agents selected from Triumeq R (dolutegravir-- therapeutic agents. abacavir-lamivudine), dolutegravir--abacavir Sulfate-lami In a specific embodiment, a compound of the present Vudine, raltegravir, Truvada(R) (tenofovir disoproxil fumar disclosure, or a pharmaceutically acceptable Salt thereof, is 35 ate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, combined with an HIV nucleoside or nucleotide inhibitor of Epzicom R. (LivexaR), abacavir sulfate+lamivudine, ABC+ reverse transcriptase and an HIV non-nucleoside inhibitor of 3TC), Trizivir R (abacavir sulfate--zidovudine--lamivudine, reverse transcriptase. In another specific embodiment, a ABC+AZT-3TC), adefovir, adefovir dipivoxil, StribildR) compound of the present disclosure, or a pharmaceutically (elvitegravir--cobicistat+tenofovir disoproxil fumarate-- acceptable salt thereof, is combined with an HIV nucleoside 40 emtricitabine), rilpivirine, rilpivirine hydrochloride, Com or nucleotide inhibitor of reverse transcriptase, and an HIV plera.R. (Eviplera R, rilpivirine--tenofovir disoproxil fumar protease inhibiting compound. In a further embodiment, a ate+emtricitabine), cobicistat, AtriplaR (efavirenz+ compound of the present disclosure, or a pharmaceutically tenofovir disoproxil fumarate--emitricitabine), atazanavir, acceptable salt thereof, is combined with an HIV nucleoside atazanavir Sulfate, dolutegravir, elvitegravir, Aluvia(R) (Kale or nucleotide inhibitor of reverse transcriptase, an HIV 45 tra R, lopinavir-i-ritonavir), ritonavir, emitricitabine, atazana non-nucleoside inhibitor of reverse transcriptase, and an vir sulfate-ritonavir, darunavir, lamivudine, Prolastin, fos HIV protease inhibiting compound. In an additional embodi amprenavir, foSamprenavir calcium, efavirenz, Combivir R ment, a compound of the present disclosure, or a pharma (zidovudine--lamivudine, AZT-3TC), etravirine, nelfinavir, ceutically acceptable salt thereof, is combined with an HIV nelfinavir mesylate, interferon, didanosine, stavudine, indi nucleoside or nucleotide inhibitor of reverse transcriptase, 50 navir, indinavir Sulfate, tenofoviri-lamivudine, Zidovudine, an HIV non-nucleoside inhibitor of reverse transcriptase, nevirapine, saquinavir, saquinavir meSylate, aldesleukin, and a pharmacokinetic enhancer. In certain embodiments, a Zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine compound of the present disclosure, or a pharmaceutically mesylate, Radha-108 (Receptol), Hlviral, lamivudine--teno acceptable salt thereof, is combined with one or more fovir disoproxil fumarate, efavirenz+lamivudine--tenofovir additional therapeutic agents selected from HIV nucleoside 55 disoproxil fumarate, phosphazid, lamivudine--nevirapine-- inhibitor of reverse transcriptase, an integrase inhibitor, and Zidovudine, (2R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hy a pharmacokinetic enhancer. In another embodiment, a droxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-metha compound of the present disclosure, or a pharmaceutically nopyrido1'.2:4.5 pyrazino.2.1-b1,3oxazepine-10 acceptable salt thereof, is combined with two HIV nucleo carboxamide, (2S.5R.13aS)-N-(2,4-difluorobenzyl)-8- side or nucleotide inhibitors of reverse transcriptase. 60 hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5- In a particular embodiment, a compound of the present methanopyrido1'.2:45pyrazino.2.1-b1,3oxazepine-10 disclosure, or a pharmaceutically acceptable Salt thereof, is carboxamide, (1S,4R,12aR)-N-(2,4-difluorobenzyl)-7- combined with one, two, three, four or more additional hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4- therapeutic agents selected from Triumeq R (dolutegravir methanodipyrido 1,2-a:1'2'-dpyrazine-9-carboxamide, abacavir-lamivudine), dolutegravir--abacavir Sulfate-lami 65 (1R,4S.12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluoroben Vudine, raltegravir, Truvada(R) (tenofovir disoproxil fumar Zyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyridol, ate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, 2-a: 1,2'-dpyrazine-9-carboxamide, (2R.5 S.13aR)-8-hy US 9,670,205 B2 141 142 droxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13. mg tenofovir disoproxil fumarate, tenofovir disoproxil 13a-octahydro-2,5-methanopyrido1'.2:45pyrazino.2.1-b hemifumarate, or tenofovir disoproxil and 200 mg emitric 1.3oxazepine-10-carboxamide, and (1R,4S.12aR)-N-(2,4- itabine. In certain embodiments, a compound of the present difluorobenzyl)-7-hydroxy-6, 8-dioxo-1,2,3,4,6,8,12,12a disclosure, or a pharmaceutically acceptable Salt thereof, is octahydro-1,4-methanodipyrido 1,2-a: 1,2'-dpyrazine-9- 5 combined with 300 mg tenofovir disoproxil fumarate, teno carboxamide abacavir, abacavir sulfate, tenofovir, tenofovir fovir disoproxil hemifumarate, or tenofovir disoproxil and disoproxil, tenofovir disoproxil fumarate, tenofoviralafena 200 mg emitricitabine. A compound of the present disclosure mide and tenofovir alafenamide hemifumarate. (e.g., a compound of formula (I)) may be combined with the In a particular embodiment, a compound of the present agents provided herein in any dosage amount of the com disclosure, or a pharmaceutically acceptable Salt thereof, is 10 pound (e.g., from 50 mg to 500 mg of compound) the same combined with abacavir sulfate, tenofovir, tenofovir diso as if each combination of dosages were specifically and proxil, tenofovir disoproxil fumarate, tenofovir disoproxil individually listed. A compound of the present disclosure hemifumarate, tenofovir alafenamide or tenofovir alafena (e.g., a compound of Formula (I)) may be combined with the mide hemifumarate. agents provided herein in any dosage amount of the com In a particular embodiment, a compound of the present 15 pound (e.g. from about 1 mg to about 150 mg of compound) disclosure, or a pharmaceutically acceptable Salt thereof, is the same as if each combination of dosages were specifically combined with tenofovir, tenofovir disoproxil, tenofovir and individually listed. disoproxil fumarate, tenofovir alafenamide, or tenofovir In certain embodiments a compound of the present dis alafenamide hemifumarate. closure, or a pharmaceutically acceptable salt thereof, is In a particular embodiment, a compound of the present combined with (2R,5S.13aR)-N-(2,4-difluorobenzyl)-8-hy disclosure, or a pharmaceutically acceptable Salt thereof, is droxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-metha combined with a first additional therapeutic agent selected nopyrido1'.2:4.5 pyrazino.2, 1-b1,3oxazepine-10-car from the group consisting of abacavir Sulfate, tenofovir, boxamide, (2S.5R.13aS)-N-(2,4-difluorobenzyl)-8- tenofovir disoproxil, tenofovir disoproxil fumarate, tenofo hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5- Vir alafenamide, and tenofovir alafenamide hemifumarate 25 methanopyrido1'.2:45pyrazino.2.1-b1,3oxazepine-10 and a second additional therapeutic agent selected from the carboxamide, (1S,4R,12aR)-N-(2,4-difluorobenzyl)-7- group consisting of emitricitabine and lamivudine. hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4- In a particular embodiment, a compound of the present methanodipyrido 1,2-a:1'2'-dpyrazine-9-carboxamide, disclosure, or a pharmaceutically acceptable Salt thereof, is (1R,4S.12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluoroben combined with a first additional therapeutic agent selected 30 Zyl)-1,2,3,4,6,8,12, 12a-octahydro-1,4-methanodipyrido1, from the group consisting of tenofovir, tenofovir disoproxil, 2-a: 1,2'-dpyrazine-9-carboxamide, (2R,5S,13aR)-8-hy tenofovir disoproxil fumarate, tenofovir alafenamide, and droxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13, tenofoviralafenamide hemifumarate and a second additional 13a-octahydro-2,5-methanopyrido1'.2:4.5 pyrazino.2.1-b therapeutic agent, wherein the second additional therapeutic 1.3oxazepine-10-carboxamide, or (1R,4S.12aR)-N-(2,4- agent is emitricitabine. 35 difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a In certain embodiments, a compound of the present dis octahydro-1,4-methanodipyrido 1,2-a:1'2'-dpyrazine-9- closure, or a pharmaceutically acceptable salt thereof, is carboxamide. combined with 5-30 mg tenofovir alafenamide fumarate, Also provided herein is a compound the present disclo tenofovir alafenamide hemifumarate, or tenofovir alafena Sure (e.g., a compound of Formula (I)), or a pharmaceuti mide and 200 mg emitricitabine. In certain embodiments, a 40 cally acceptable salt thereof, and one or more additional compound of the present disclosure, or a pharmaceutically therapeutic agents for treating HIV, for use in a method of acceptable salt thereof, is combined with 5-10; 5-15; 5-20; treating or preventing HIV. 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofoviralafena Also provided herein is a compound of the present mide fumarate, tenofovir alafenamide hemifumarate, or disclosure (e.g., a compound of Formula (I)), or a pharma tenofoviralafenamide and 200 mg emitricitabine. In certain 45 ceutically acceptable salt thereof, for use in a method of embodiments, a compound of the present disclosure, or a treating or preventing HIV, wherein the compound or a pharmaceutically acceptable salt thereof, is combined with pharmaceutically acceptable salt thereof is administered 10 mg tenofovir alafenamide fumarate, tenofovir alafena simultaneously, separately or sequentially with one or more mide hemifumarate, or tenofovir alafenamide and 200 mg additional therapeutic agents for treating HIV. emitricitabine. In certain embodiments, a compound of the 50 In certain embodiments, a method for treating hyperpro present disclosure, or a pharmaceutically acceptable salt liferative disorders such as cancer in a human is provided, thereof, is combined with 25 mg tenofovir alafenamide comprising administering to the human a therapeutically fumarate, tenofoviralafenamide hemifumarate, or tenofovir effective amount of a compound of the present disclosure, or alafenamide and 200 mg emitricitabine. A compound of the a pharmaceutically acceptable salt thereof, in combination present disclosure (e.g., a compound of formula (I)) may be 55 with a therapeutically effective amount of one or more (e.g., combined with the agents provided herein in any dosage one, two, three, one or two, or one to three) additional amount of the compound (e.g., from 1 mg to 500 mg of therapeutic agents. In one embodiment, a method for treat compound) the same as if each combination of dosages were ing hyperproliferative disorders such as cancer in a human specifically and individually listed. is provided, comprising administering to the human a thera In certain embodiments, a compound of the present dis 60 peutically effective amount of a compound of the present closure, or a pharmaceutically acceptable salt thereof, is disclosure, or a pharmaceutically acceptable salt thereof, in combined with 200-400 mg tenofovir disoproxil fumarate, combination with a therapeutically effective amount of one tenofovir disoproxil hemifumarate, or tenofovir disoproxil or more (e.g., one, two, three, one or two, or one to three) and 200 mg emitricitabine. In certain embodiments, a com additional therapeutic agents. pound of the present disclosure, or a pharmaceutically 65 IX. Combination Therapy for Cancer acceptable salt thereof, is combined with 200-250; 200-300; In certain embodiments, the present disclosure provides a 200-350; 250-350; 250-400; 350–400; 300-400; or 250-400 method for treating hyperproliferative disorders such as US 9,670,205 B2 143 144 cancer, comprising administering to a patient in need thereof IDH1 inhibitors, BRD4 inhibitors, TPL2 inhibitors: A2B a therapeutically effective amount of a compound of the inhibitors: TBK1 inhibitors; IKK inhibitors: BCR inhibitors, present disclosure, or a pharmaceutically acceptable salt, agents inhibiting the RAS/RAF/ERK pathway, protein thereof, in combination with a therapeutically effective kinase C (PKC) modulators, modulators of growth factor amount of one or more additional therapeutic agents which receptors such as epidermal growth factor receptor (EGFr). are suitable for treating hyperproliferative disorders such as platelet derived growth factor receptor (PDGFr), erbB2, CaCC. erbB4, ret, vascular endothelial growth factor receptor In the above embodiments, the additional therapeutic (VEGFr), tyrosine kinase with immunoglobulin-like and agent may be an anti-cancer agent. For example, in some epidermal growth factor homology domains (TIE-2), insulin embodiments, the additional therapeutic agent is selected 10 growth factor-I (IGFI) receptor, macrophage colony stimu from the group consisting of chemotherapeutic agents, lating factor (cfms), BTK, ckit, cmet, fibroblast growth immunotherapeutic agents, radiotherapeutic agents, anti factor (FGF) receptors, Trk receptors (TrkA, TrkB, and neoplastic agents, anti-hormonal agents, anti-angiogenic TrkC), ephrin (eph) receptors, and the RET protooncogene, agents, anti-fibrotic agents, therapeutic antibodies, tyrosine modulators of tyrosine kinases including cSrc, Lck, Fyn, kinase inhibitors, JAK inhibitors, Hedgehog inhibitors, 15 Yes, cAbl, FAK (Focal adhesion kinase) and Bcr-Abl, modu HDAC inhibitors, Discoidin domain receptor (DDR) inhibi lators of PKB family kinases, modulators of TGF beta tors, MMP9 inhibitors, LOXL inhibitors, ASK1 inhibitors, receptor kinases, inhibitors of Ras oncogene including PI3K inhibitors, BTK inhibitors, SYK inhibitors, mTOR inhibitors of famesyltransferase, geranyl-geranyl trans inhibitors, AKT inhibitors, Mitogen or Extracellular Regu ferase, and CAAX proteases, anti-sense oligonucleotides, lated Kinase (MEK) inhibitors, blockers of Raf kinases ribozymes, Bcl-2 family protein inhibitors, proteasome (rafk), CDK inhibitors, JNK inhibitors, MAPK inhibitors, inhibitors, Heat shock protein HSP90 inhibitors, combina Raf inhibitors, ROCK inhibitors, Tie2 inhibitors, Myo tion drugs and immunotherapy, and other drugs for treating inositol signaling inhibitors, phospholipase C blockers, anti hyperproliferative disorders such as cancer, and combina CD19 antibodies, anti-CD20 antibodies, anti-MN-14 anti tions thereof. bodies, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 25 In certain embodiments, such tablets are suitable for once antibodies, cancer vaccines based upon the genetic makeup daily dosing. In certain embodiments, the additional thera of an individual patient’s tumor. IDH1 inhibitors, BRD4 peutic agent is selected from one or more of inhibitors, TPL2 inhibitors: A2B inhibitors: TBK1 inhibi (1) Chemotherapeutic agents selected from the group con tors; IKK inhibitors; BCR inhibitors, agents inhibiting the sisting of anti-metabolites/anti-cancer agents, such as RAS/RAF/ERK pathway, protein kinase C (PKC) modula 30 pyrimidine analogs (floXuridine, capecitabine, and cytara tors, modulators of growth factor receptors such as epider bine); purine analogs, folate antagonists and related mal growth factor receptor (EGFr), platelet derived growth inhibitors, antiproliferative/antimitotic agents including factor receptor (PDGFr), erbB2, erbB4, ret, vascular natural products such as Vinca alkaloid (vinblastine, Vin endothelial growth factor receptor (VEGFr), tyrosine kinase cristine) and microtubule Such as taxane (paclitaxel, doc with immunoglobulin-like and epidermal growth factor 35 etaxel), vinblastin, nocodazole, epothilones and navel homology domains (TIE-2), insulin growth factor-I (IGFI) bine, epidipodophyllotoxins (etoposide, teniposide); receptor, macrophage colony stimulating factor (cfms), DNA damaging agents (actinomycin, amsacrine, buSul BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, fan, carboplatin, chlorambucil, cisplatin, cyclophosph Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) recep amide, Cytoxan, dactinomycin, daunorubicin, doxorubi tors, and the RET protooncogene, modulators of tyrosine 40 cin, epirubicin, iphosphamide, melphalan, kinases including cSrc, Lck, Fyn, Yes, cAbl, FAK (Focal merchlorehtamine, mitomycin, mitoxantrone, nitroSou adhesion kinase) and Bcr-Abl, modulators of PKB family rea, procarbazine, taxol, taxotere, teniposide, etoposide, kinases, modulators of TGFbeta receptor kinases, inhibitors triethylenethiophosphoramide); antibiotics Such as dac of Ras oncogene including inhibitors of famesyltransferase, tinomycin (actinomycin D), daunorubicin, doxorubicin geranyl-geranyl transferase, and CAAX proteases, anti 45 (adriamycin), idarubicin, anthracyclines, mitoxantrone, sense oligonucleotides, ribozymes, Bcl-2 family protein bleomycins, plicamycin (mithramycin) and mitomycin; inhibitors, proteasome inhibitors, Heat shock protein HSP90 enzymes (L-asparaginase which systemically metabolizes inhibitors, combination drugs and immunotherapy, and other L-asparagine and deprives cells which do not have the drugs for treating hyperproliferative disorders such as can capacity to synthesize their own asparagine); antiplatelet cer, and combinations thereof. 50 agents; antiproliferative/antimitotic alkylating agents In certain embodiments a compound of the present dis Such as nitrogen mustards cyclophosphamide and ana closure is formulated as a tablet, which may optionally logs, melphalan, chlorambucil), and (hexamethyl contain one or more other compounds useful for treating melamine and thiotepa), alkyl nitrosoureas (BCNU) and cancer. In certain embodiments, the tablet can contain analogs, streptozocin, traZenes-dacarbazinine (DTIC); another active ingredient for treating cancer, Such as che 55 antiproliferative/antimitotic antimetabolites such as folic motherapeutic agents, immunotherapeutic agents, radio acid analogs (methotrexate); platinum coordination com therapeutic agents, anti-neoplastic agents, anti-fibrotic plexes (cisplatin, OXiloplatinim, carboplatin), procarba agents, anti-hormonal agents, anti-angiogenic agents, Tyro Zine, hydroxyurea, mitotane, aminoglutethimide; hor sine kinase inhibitors, JAK inhibitors, Hedgehog inhibitors, mones, hormone analogs (estrogen, tamoxifen, goserelin, HDAC inhibitors, Discoidin domain receptor (DDR) inhibi 60 bicalutamide, nilutamide) and aromatase inhibitors (letro tors, MMP9 inhibitors, LOXL inhibitors, ASK1 inhibitors, Zole, anastrozole); anticoagulants (heparin, synthetic PI3K inhibitors, BTK inhibitors, SYK inhibitors, mTOR heparin salts and other inhibitors of thrombin); fibrin inhibitors, AKT inhibitors, Mitogen or Extracellular Regu olytic agents (such as tissue plasminogen activator, Strep lated Kinase (MEK) inhibitors, blockers of Raf kinases tokinase and urokinase), aspirin, dipyridamole, ticlopi (rafk), CDK inhibitors, JNK inhibitors, MAPK inhibitors, 65 dine, clopidogrel; antimigratory agents; antisecretory Raf inhibitors, ROCK inhibitors, Tie2 inhibitors, Myo agents (breveldin); immunosuppressives tacrolimus, inositol signaling inhibitors, phospholipase C blockers, Sirolimus azathioprine, mycophenolate; compounds US 9,670,205 B2 145 146 (TNP-470, genistein) and growth factor inhibitors (vas elformthine; elliptinium acetate; an epothilone; etoglucid: cular endothelial growth factor inhibitors, fibroblast gallium nitrate; hydroxyurea; lentinan; leucovorin; growth factor inhibitors); angiotensin receptor blocker, lonidamine; maytansinoids such as maytansine and nitric oxide donors; anti-sense oligonucleotides; cell cycle ansamitocins; mitoguaZone; mitoxantrone; mopidamol; inhibitors and differentiation inducers (tretinoin): inhibi nitracrine; pentostatin: phenamet; pirarubicin; losoxan tors, topoisomerase inhibitors (doxorubicin (adriamycin), trone; fluoropyrimidine; folinic acid; podophyllinic acid; daunorubicin, dactinomycin, eniposide, epirubicin, idaru 2-ethylhydrazide; procarbazine; PSK(r); razoxane: bicin, irinotecan and mitoxantrone, topotecan, irinotecan), rhizoxin; sizofiran; Spirogermanium; tenuaZonic acid; tri corticosteroids (cortisone, dexamethasone, hydrocorti aziquone; 2.2.2"-tricUorotriemylamine; trichothecenes Sone, methylpednisolone, prednisone, and prednisolone); 10 (especially T-2 toxin, Verracurin A, roridin A and growth factor signal transduction kinase inhibitors; dys anguidine); urethane; Vindesine; dacarbazine; mannomus function inducers, toxins such as Cholera toxin, ricin, tine, mitobronitol; mitolactol; pipobroman, gacytosine; Pseudomonas exotoxin, Bordetella pertussis adenylate arabinoside (“Ara-C); cyclophosphamide; thiopeta; tax cyclase toxin, or diphtheria toxin, and caspase activators, oids, paclitaxel (Taxol) and docetaxel (Taxotere); chromatin, alkylating agents such as thiotepa and cyclo 15 chlorambucil; gemcitabine (Gemzar), 6-thioguanine; phosphamide (Cytoxan, Endoxan, Endoxana, CycloStin), mercaptopurine; methotrexate; platinum analogs such as alkyl Sulfonates Such as buSulfan, improSulfan and pipo cisplatin and carboplatin; platinum; ifosfamide; mitroX Sulfan; aziridines such as benzodopa, carboquone, antrone; Vancristine; vinorelbine (Navelbine); novan meturedopa, and uredopa; emylerumines and memylam trone; teniposide; edatrexate; daunomycin; aminopterin; elamines including alfretamine, triemylenemelamine, tri Xeoloda; ibandronate; CPT-11: topoisomerase inhibitor ethylenephosphoramide, triethylenethiophosphoramide RFS 2000; difluoromethylomithine (DMFO); retinoids and trimemylolomelamine; acetogenins (especially bul such as retinoic acid; capecitabine and FOLFIRI (fluo latacin and bullatacinone); a camptothecin (including rouracil, leucovorin, and irinotecan); synthetic analogue topotecan); bryostatin: cally statin: (2) Anti-hormonal agents selected from the group consisting CC-1065 (including its adozelesin, carzelesin and bizele 25 of anti-estrogens and selective estrogen receptor modu sin synthetic analogues); cryptophycins (articularly cryp lators (SERMs), including, for example, tamoxifen (in tophycin 1 and cryptophycin 8); dolastatin; duocarmycin cluding Nolvadex), raloxifene, droloxifene, 4-hydroxyta (including the synthetic analogues, KW-2189 and CBI moxifen, trioxifene, keoxifene, LY 1 17018, onapristone, TMI); eleutherobin, pancratistatin; a sarcodictyin; spong and toremifene; inhibitors of the enzyme aromatase, istatin: nitrogen mustards such as chlorambucil, chlomap 30 which regulates estrogen production in the adrenal glands, hazine, cholophosphamide, estramustine, ifosfamide, Such as, for example, 4(5)-imidazoles, aminoglutethim mechlorethamine, mechlorethamine oxide hydrochloride, ide, megestrol acetate, exemestane, formestane, fadro melphalan, novembichin, phenesterine, prednimustine, Zole, Vorozole, letrozole and anastroZole, and anti-andro trofosfamide, uracil mustard; nitrosoureas Such as car gens such as flutamide, nilutamide, bicalutamide, mustine, chlorozotocin, foremustine, lomustine, 35 leuprolide, and goserelin; nimustine, ranimustine; antibiotics Such as the enediyne (3) Anti-angiogenic agents selected from the group consist antibiotics (e.g., calicheamicin, especially calicheamicin ing of retinoid acid and derivatives thereof, gammall and calicheamicin phill, see, e.g., Agnew, Chem. 2-methoxyestradiol, ANGIOSTATIN, ENDOSTATIN, Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including Suramin, squalamine, tissue inhibitors of metalloprotein dynemicin A; bisphosphonates, such as clodronate; an 40 ase-1, tissue inhibitors of metalloproteinase-2, plasmino esperamicin; as well as neocarzinostatin chromophore gen activator inhibitor-1, plasminogen activator inbibitor and related chromoprotein enediyne antibiotic chromo 2, cartilage-derived inhibitors, paclitaxel (nab-paclitaxel), mophores), aclacinomysins, actinomycin, authramycin, platelet factor 4, protamine Sulphate (clupeine), Sulphated aZaserine, bleomycins, cactinomycin, carabicin, carmino chitin derivatives (prepared from queen crab shells), Sul mycin, carzinophilin, chromomycins, dactinomycin, 45 phated polysaccharide peptidoglycan complex (sp-pg), daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, staurosporine, modulators of matrix metabolism, includ doxorubicin (including morpholino-doxorubicin, cyano ing for example, proline analogs ((1-aZetidine-2-carbox morpholino-doxorubicin, 2-pyrrolino-doxorubicin, ylic acid (LACA), cishydroxyproline, d.I-3,4-dehydro PEGylated liposomal doxorubicin and deoxydoxorubi proline, thiaproline, ..alpha.-dipyridyl, beta cin), epirubicin, esorubicin, idarubicin, marcellomycin, 50 aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2 mitomycins such as mitomycin C, mycophenolic acid, (3h)-oxazolone; methotrexate, mitoxantrone, heparin, nogalamycin, olivomycins, peplomycin, potfiromycin, interferons, 2 macroglobulin-serum, chimp-3, chymosta puromycin, quelamycin, rodorubicin, streptonigrin, Strep tin, beta-cyclodextrin tetradecasulfate, eponemycin; fum toZocin, tubercidin, ubenimex, Zinostatin, Zorubicin; anti agillin, gold Sodium thiomalate, d-penicillamine (CDPT), metabolites such as methotrexate and 5-fluorouracil 55 beta-1-anticollagenase-serum, alpba-2-antiplasmin, (5-FU); folic acid analogues such as demopterin, metho bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4- trexate, pteropterin, trimetrexate; purine analogs such as chloroanthronilic acid disodium or “CCA, thalidomide; fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; angiostatic steroid, cargboxynaminolmidazole; metallo pyrimidine analogues such as ancitabine, azacitidine, proteinase inhibitors such as BB94, antibodies, preferably 6-azauridine, carmofur, dideoxyuridine, doxifluridine, 60 monoclonal antibodies against these angiogenic growth enocitabine, floXuridine; androgens such as calusterone, factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, dromostanolone propionate, epitiostanol, mepitioStane, VEGF-C, HGF/SF. Ang-1/Ang-2 and the compounds testolactone; anti-adrenals such as aminoglutethimide, disclosed in Ferrara N. and Alitalo, K. “Clinical applica mitotane, triloStane; folic acid replinisher such as frolinic tion of angiogenic growth factors and their inhibitors' acid; aceglatone; aldophosphamide glycoside; aminole 65 (1999) Nature Medicine 5:1359–1364; Vulinic acid; eniluracil; amsacrine; hestrabucil; bisant (4) Anti-fibrotic agents selected from the group consisting rene; ediatraxate; defofamine; demecolcine; diaziquone; of beta-aminoproprionitrile (BAPN), primary amines US 9,670,205 B2 147 148 reacting with the carbonyl group of the active site of the (8) Histone deacetylase (HDAC) inhibitors selected from the lysyl oxidases, and more particularly those which pro group consisting of pracinostat, romidepsin, Vorinostat duce, after binding with the carbonyl, a product stabilized and panobinostat; by resonance, such as the following primary amines: (9) Tyrosine kinase inhibitors selected from the group con emylenemamine, hydrazine, phenylhydrazine, and their sisting of: lestaurtinib, gefitinib, erlotinib and Sunitinib; derivatives, semicarbazide, and urea derivatives, amino (10) Discoidin domain receptor (DDR) inhibitors selected nitriles, such as beta-aminopropionitrile (BAPN), or 2-ni from the group consisting of the inhibitors disclosed in troethylamine, unsaturated or saturated haloamines, such US2009/0142345, US2011/0287011, WO2013/027802, as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoro WO2013/034933, and U.S. Provisional Application No. ethylamine, 3-bromopropylamine, p-halobenzylamines, 10 61/705,044: Selenohomocysteine lactone, copper chelating agents, (11) MMP9 inhibitors selected from the group consisting of: indirect inhibitors such as compounds blocking the alde marimastat (BB-2516), cipemastat (Ro 32-3555), and the hyde derivatives originating from the oxidative deamina inhibitors described in WO2012/027721: tion of the lysyl and hydroxylysyl residues by the lysyl 15 (12) LOXL inhibitors selected from the group consisting of: oxidases, such as the thiolamines, in particular D-penicil the antibodies described in WO2009/017833, the antibod lamine, or its analogues such as 2-amino-5-mercapto-5- ies described in WO2009/017833, WO2009/035791 and methylhexanoic acid, D-2-amino-3-methyl-3-((2-acet WO/2011/097513; amidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3- (13) ASK1 inhibitors selected from the group consisting of: ((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1- the compounds described in WO2011/008709 and dimethyl-2-amino-2-carboxyethyl)dithio)butane WO/2013/112741; Sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol Sul (14) PI3K inhibitors selected from the group consisting of: phanate, sodium-4-mercaptobutanesulphinate trihydrate, the compounds described in U.S. Pat. No. 7,932,260, U.S. the compounds disclosed in U.S. Pat. Nos. 4.965,288, Provisional Application Nos. 61/543,176: 61/581,528: 4,997,854, 4,943,593, 5,021,456; 5,5059,714; 5,120,764; 25 61/745,429: 61/745,437; and 61/835,333, PI3K II, TGR 5,182,297: 5,252,608 and U.S. Patent Application No. 1202, AMG-319, GSK2269557, X-339, X-414, RP5090, 2004/0248871; KAR4141, XL499, OXY111A, duvelisib, IPI-443, (5) Therapeutic antibodies selected from the group consist GSK2636771, BAY 10824391, TGX221, RG-7666, ing of abagovomab, adecatumumab, afutuzumab, alem CUDC-907, PQR-309, DS-7423, panulisib, AZD-8186, tuZumab, altumomab, amatuximab, anatumomab, arcitu 30 CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, UCB-5857, taselisib, INCB-040093, momab, bavituximab, bectumomab, bevacizumab, pilaralisib, BAY-1082439, puduitinib mesylate, XL-765, bivatuZumab, blinatumomab, brentuximab, cantuzumab, gedatolisib, VS-5584, copanlisib, CAI orotate, alpelisib, catumaXomab, cetuximab, citatuZumab, cixutumumab, buparlisib, BAY 80-6946, BYL719, PX-866, RG7604, clivatuZumab, conatumumab, daratumumab, drozitumab, 35 MLN1117, WX-037, AEZS-129, PA799, ZSTK474, duligotumab, dusigitumab, detumomab, dacetuZumab, RP-6530, AS252424, LY294.002, TG100115, LY294.002, dalotuZumab, ecromeximab, elotuZumab, ensituximab, BEZ235, XL 147 (SAR245408), SAR-245409, GDC ertumaxomab, etaracizumab, farietuZumab, ficlatuZumab, 0941, BKM120, CH5132799, XL756, MLN-1117, figitumumab, flanVotumab, futuximab, ganitumab, gem SF-1126, RV-1729, sonolisib, GDC-0980, CLR-1401, tuZumab, girentuximab, glembatumumab, ibritumomab, 40 perifosine and wortmannin; igovomab, imgatuZumab, indatuximab, inotuZumab, inte (15) BTK inhibitors selected from the group consisting of: tumumab, ipilimumab, iratumumab, labetuZumab, lexa ibrutinib, HM71224, ONO-4059 and CC-292: tumumab, lintuZumab, lorVotuZumab, lucatumumab, (16) SYK inhibitors selected from the group consisting of: mapatumumab, matuZumab, milatuZumab, minretu tamatinib (R406), fostamatinib (R788), PRT062607, momab, mitumomab, moxetumomab, namatumab, nap 45 BAY-61-3606, NVP-QAB 205 AA, R112, R343, and the tumomab, necitumumab, nimotuZumab, nofetumomabn, compounds described in U.S. Pat. No. 8,450.321; ocaratuZumab. ofatumumab, olaratumab, onartuzumab, (17) mTOR inhibitors selected from the group consisting of: oportuZumab, oregovomab, panitumumab, parsatuZumab, temsirolimus, everolimus, ridaforolimus, deforolimus, patritumab, pemtumomab, pertuzumab, pintumomab, pri OSI-027, AZD2014, CC-223, RAD001, LY294.002, tumumab, racotumomab, radretumab, rillotumumab, 50 BEZ235, rapamycin, Ku-0063794, and PP242: rituximab, robatumumab, Satumomab, SibrotuZumab, sil (18) AKT inhibitors selected from the group consisting of: tuximab, simtuzumab, Solitomab, tacatuZumab, taplitu perifosine, MK-2206, GDC-0068 and GSK795; momab, tenatumomab, teprotumumab, tigatuZumab, tosi (19) MEK inhibitors selected from the group consisting of: tumomab, trastuzumab, tucotuZumab, ublituximab, trametinib, selumetinib, cobimetinib, MEK162, VeltuZumab, VorsetuZumab, Votumumab, Zalutumumab, 55 PD-325901, PD-035901, AZD6244, and CI-1040: alemtuzumab, VeltuZumab, apolizumab, bevacizumab, (20) CDK inhibitors selected from the group consisting of: epratuZumab, to situmomab, galiximab, ibritumomab, AT-7519, alvocidib, palbociclib and SNS-032: lumiliximab, milatuZumab, obinutuZumab. ofatumumab, (21) JNK inhibitors selected from the group consisting of: CC49 and 3F8, wherein the antibody may be further CC-401; labeled or combined with a radioisotope particle. Such as 60 (22) MAPK inhibitors selected from the group consisting of: indium In 111, yttrium Y 90, iodine I-131; VX-702, SB203580 and SB202190: (6); JAK inhibitors selected from the group consisting of: (23) Raf inhibitors selected from the group consisting of: ruxolitinib, fedratinib, tofacitinib, baricitinib, lestaurtinib, PLX4720; pacritinib, momelotinib, XL019, AZD1480, (24) ROCK inhibitors selected from the group consisting of: INCB039110, LY2784544, BMS911543, and NS018; 65 Rho-15; (7) Hedgehog inhibitors selected from the group consisting (25) Tie2 inhibitors selected from the group consisting of: of Saridegib; AMG-Tie2-1: US 9,670,205 B2 149 150 (26) Myo-inositol signaling inhibitors such as phospholipase hydrochloride, motexafin gadolinium, mycophenolate C blockers and Myoinositol analogues described in mofetil, nelarabine, oblimersen Obatoclax, oblimersen, oct Powis, G., and Kozikowski A. (1994) New Molecular reotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, Targets for Cancer Chemotherapy ed., Paul Workman and PD0332991, PEGylated liposomal doxorubicin hydrochlo David Kerr, CRC press 1994, London; 5 ride, pegfilgrastim, Pentstatin (Nipent), perifosine, Predni (27) Bcl-2 family protein inhibitors selected from the group solone, Prednisone, selicilib, recombinant interferon alfa, consisting of ABT-263, ABT-199 and ABT-737; recombinant interleukin-12, recombinant interleukin-11, (28) IKK inhibitors selected from the group consisting of: recombinant filt3 ligand, recombinant human thrombopoi BMS-345541; etin, rituximab, Sargramostim, sildenafil citrate, simvastatin, (29) Proteasome inhibitors selected from the group consist 10 Sirolimus, Styryl Sulphones, tacrolimus, tanespimycin, tem ing of bortezomib; Sirolimus, thalidomide, therapeutic allogeneic lymphocytes, (30) Protein kinase C (PKC) inhibitors selected from the thiotepa, tipifamib, Vincristine, Vincristine sulfate, vinorel group consisting of bryostatin 1 and enZastaurin; bine ditartrate, Vorinostat (SAHA), vorinostat, FR (fludara (31) Heat shock protein HSP90 inhibitors selected from the bine, rituximab), CHOP (cyclophosphamide, doxorubicin, group consisting of Geldanamycin; 15 Vincristine, prednisone), CVP (cyclophosphamide, Vincris (32) Combination drugs selected from the group consisting tine and prednisone), FCM (fludarabine, cyclophosphamide, of FR (fludarabine, rituximab), FCR (fludarabine, cyclo mitoxantrone), FCR (fludarabine, cyclophosphamide, ritux phosphamide, rituximab), R-CHOP (rituximab plus imab), hyperCVAD (hyperfractionated cyclophosphamide, CHOP), R-CVP (rituximab plus CVP), R-FCM (ritux Vincristine, doxorubicin, dexamethasone, methotrexate, cyt imab plus FCM), R-ICE (rituximab-ICE), CHOP (cyclo arabine), ICE (iphosphamide, carboplatin and etoposide), phosphamide, doxorubicin, Vincristine, prednisone), CVP MCP (mitoxantrone, chlorambucil, and prednisolone), (cyclophosphamide, Vincristine and prednisone), FCM R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus (fludarabine, cyclophosphamide, mitoxantrone), hyperC CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab VAD (hyperfractionated cyclophosphamide, Vincristine, ICE), and R MCP (RMCP). doxorubicin, dexamethasone, methotrexate, cytarabine), 25 Any of the methods of treatment provided may be used to ICE (iphosphamide, carboplatin and etoposide), MCP treat cancer at various stages. By way of example, the cancer (mitoxantrone, chlorambucil, and prednisolone), and R stage includes but is not limited to early, advanced, locally MCP (RMCP); and advanced, remission, refractory, reoccurred after remission (33) other drugs for treating cancer selected from the group and progressive. consisting of aldesleukin, alvocidib, CHIR-12.12, ha20, 30 In addition, the Subject may be a human who is under tiuxetan, PRO131921, SGN-40, WT-1 analog peptide going one or more standard therapies, such as chemotherapy, vaccine, WT1 126-134 peptide vaccine, autologous radiotherapy, immunotherapy, surgery, or combination human tumor-derived HSPPC-96, GTOP-99 (MyVax(R), thereof. Accordingly, one or more anti-cancer agents may be antineoplaston AS2-1, antineoplaston A10, anti-thymo administered before, during, or after administration of che cyte globulin, beta alethine, arsenic trioxide, amifostine, 35 motherapy, radiotherapy, immunotherapy, Surgery or com aminocamptothecin, lenalidomide, caspofungin, clofara bination thereof. bine, ixabepilone, cladribine, chlorambucil, Curcumin, The therapeutic treatments can be supplemented or com Vinorelbine, tipifamib, tanespimycin, sildenafil citrate, bined with any of the abovementioned therapies with stem denileukin diftitox, simvastatin, epoetin alfa, fenretinide, cell transplantation or treatment. One example of modified filgrastim, mesna, mitoxantrone, lenalidomide, fludara 40 approach is radioimmunotherapy, wherein a monoclonal bine, mycophenolate mofetil, nelarabine, octreotide, oxa antibody is combined with a radioisotope particle, such as liplatin, pegfilgrastim, recombinant interleukin-12, indium In 111, yttrium Y 90, iodine 1-131. Examples of recombinant interleukin-11, recombinant flt3 ligand, combination therapies include, but are not limited to, Iodine recombinant human thrombopoietin, Sargramostim, lym 131 to situmomab (Bexxar R), Yttrium-90 ibritumomab tiux phokine-activated killer cells, omega-3 fatty acids, 45 etan (Zevalin(R), Bexxar R with CHOP. recombinant interferon alfa, therapeutic allogeneic lym Other therapeutic procedures include peripheral blood phocytes and cyclosporine analogs. stem cell transplantation, autologous hematopoietic stem In a particular embodiment, a compound of the present cell transplantation, autologous bone marrow transplanta disclosure, or a pharmaceutically acceptable Salt thereof, is tion, antibody therapy, biological therapy, enzyme inhibitor combined with one, two, three, four or more additional 50 therapy, total body irradiation, infusion of stem cells, bone therapeutic agents selected from ibrutinib, aldesleukin, alvo marrow ablation with stem cell support, in vitro-treated cidib, antineoplaston AS2-1, antineoplaston A10, anti-thy peripheral blood stem cell transplantation, umbilical cord mocyte globulin, amifostine trihydrate, aminocamptothecin, blood transplantation, immunoenzyme technique, pharma arsenic trioxide, beta alethine, ABT-263, ABT-199, ABT cological study, low-LET cobalt-60 gamma ray therapy, 737, BMS-345541, bortezomib, bryostatin 1, busulfan, car 55 bleomycin, conventional Surgery, radiation therapy, and boplatin, campath-1H, CC-5103, carmustine, caspofungin nonmyeloablative allogeneic hematopoietic stem cell trans acetate, clofarabine, cisplatin, Cladribine (LeuStarin), plantation. Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclo Also provided herein is a compound of the present phosphamide (Cyloxan, Endoxan, Endoxana, CycloStin), disclosure (e.g., a compound of Formula (I)), or a pharma denileukin diftitox, dexamethasone, DT PACE, docetaxel, 60 ceutically acceptable Salt thereof, and one or more additional dolastatin 10, Doxorubicin (Adriamycin R, Adriblastine), therapeutic agents for treating cancer, for use in a method of doxorubicin hydrochloride, enZastaurin, epoetin alfa, etopo treating cancer. side, everolimus (RAD001), fenretinide, filgrastim, mel Also provided herein is a compound of the present phalan, mesna, flavopiridol, fludarabine (Fludara), Geldan disclosure (e.g., a compound of Formula (I)), or a pharma amycin (17 AAG), ifosfamide, irinotecan hydrochloride, 65 ceutically acceptable salt thereof, for use in a method of ixabepilone, lenalidomide (Revlimid(R), lymphokine-acti treating cancer, wherein the compound or a pharmaceuti vated killer cells, melphalan, methotrexate, mitoxantrone cally acceptable Salt thereof is administered simultaneously, US 9,670,205 B2 151 152 separately or sequentially with one or more additional W. Greene and P. G. M. Wuts, “Protective Groups in Organic therapeutic agents for treating cancer. Synthesis,” 4 ed., Wiley, New York 2006. The protecting X. Kits groups may be removed at a convenient Subsequent stage The present disclosure provides a kit comprising a com using methods known from the art. pound of the present disclosure or a pharmaceutically acceptable salt thereof. The kit may further comprise XII. Examples instructions for use, e.g., for use in modulating a toll-like Exemplary chemical entities useful in methods of the receptor (e.g. TLR-8). Such as for use in treating a disease, embodiments will now be described by reference to illus disorder, or condition. In certain embodiments the use is for trative synthetic schemes for their general preparation herein treating a HIV, HBV, or HCV infection. In certain embodi 10 and the specific examples that follow. Artisans will recog ments the use is for treating a HBV infection. The instruc nize that, to obtain the various compounds herein, starting tions for use are generally written instructions, although materials may be suitably selected so that the ultimately electronic storage media (e.g., magnetic diskette or optical desired substituents will be carried through the reaction disk) containing instructions are also acceptable. scheme with or without protection as appropriate to yield the The present disclosure also provides a pharmaceutical kit 15 desired product. Alternatively, it may be necessary or desir comprising one or more containers comprising a compound able to employ, in the place of the ultimately desired of the present disclosure or a pharmaceutically acceptable Substituent, a Suitable group that may be carried through the salt thereof. Optionally associated with such container(s) reaction scheme and replaced as appropriate with the desired can be a notice in the form prescribed by a governmental substituent. Furthermore, one of skill in the art will recog agency regulating the manufacture, use or sale of pharma nize that the transformations shown in the schemes below ceuticals, which notice reflects approval by the agency for may be performed in any order that is compatible with the the manufacture, use or sale for human administration. Each functionality of the particular pendant groups. Each of the component (if there is more than one component) can be reactions depicted in the general Schemes is preferably run packaged in separate containers or some components can be at a temperature from about 0°C. to the reflux temperature combined in one container where cross-reactivity and shelf 25 of the organic solvent used. Unless otherwise specified, the life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or Sub-unit doses. Kits variables are as defined above in reference to Formulas (I) may also include multiple unit doses of the compounds and or (J). instructions for use and be packaged in quantities Sufficient Representative syntheses of compounds of the present for storage and use in pharmacies (e.g., hospital pharmacies 30 disclosure are described in schemes below, and the particular and compounding pharmacies). examples that follow. XI. Compound Preparation Scheme 1 shows a representative synthesis of the com Also provided are articles of manufacture comprising a pounds of the embodiments. The methodology is compatible unit dosage of a compound of the present disclosure or a with a wide variety of functionalities. pharmaceutically acceptable salt thereof, in Suitable pack 35 aging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed. The embodiments are also directed to processes and intermediates useful for preparing the Subject compounds or pharmaceutically acceptable salts thereof. Many general references providing commonly known chemical synthetic schemes and conditions useful for Syn thesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7" edition, Wiley-Interscience, 2013.) Compounds as described herein can be purified by any of the means known in the art, including chromatographic means. Such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash col umn chromatography and ion exchange chromatography. Any Suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modem Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer various -e- Chromatography, E. Stahl (ed.), Springer-Verlag, New York, conditions 1969. During any of the processes for preparation of the Subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules con cerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. US 9,670,205 B2 153 154 -continued -continued

OAlkyl

o1 various Her conditions

In Scheme 1, compounds of formula A1 (where R', R, and R are as defined herein or are suitably protected 25 derivatives of R', R, and R) are converted to the corre sponding 4-amino.2-chloro heterocycle by reaction with a nuclephilic amine in the presence of a Suitable base (such as DIPEA) at room temperature. The compound of formula A2 30 is then treated with 2,4-dimethoxybenzylamine at elevated temperature resulting in a 2,4-diaminopyrimidine of formula A3. In cases where R', R, and R is a diversifiable chemical group such as C1 or Br, further replacement of R', R, and R by a variety of methods including cyanation, nucleophilic 35 aromatic displacement, and metal catalyzed cross coupling reactions such as Suzuki couplings is carried out to provide products of formula A4. Treatment with a suitable acid (such as trifluoroacetic acid) leads to certain compounds of For mula (I) or (J). Where suitable, other leaving groups may be 40 used in place of the Cl group(s) of A1. (I) Scheme 2 describes a general route which is used to prepare certain compounds of Formula (I) or (J). 2,4-dichloro pyrido-pyrimidines of formula A1 (where 45 R", R., and Rare as defined herein or are suitably protected derivatives of R', R, and R) are converted to the corre sponding 4-amino.2-chloro heterocycle by reaction with an amino acid ester (such as L-norvaline methyl ester) in the 50 presence of a suitable base (such as DIPEA) at room temperature to provide a compound of formula B1, where G is an the sidechain of the amino acid. The compound of formula B1 is then treated with 2,4-dimethoxybenzylamine in a microwave reactor at a suitable temperature (such as 55 about 135° C.), resulting in a 2,4-diaminopyrimidine of formula B2. Hydrolysis of the ester group via treatment with a suitable base (such as aqueous KOH/THF) provides prod uct of formula B3 where Z is hydroxyl. Further reaction of the resulting carboxylic acid leads to modification of Z via 60 HATU-promoted amide formation with various amines. Protecting group removal with a suitable acid (such as trifluoroacetic acid) at room temperature then leads to cer tain compounds of Formula (J) or (I). 65 Scheme 3 shows a representative synthesis of the com B1 pounds of the embodiments. The methodology is compatible with a wide variety of functionalities. US 9,670,205 B2 155 156 -continued Halogen

Halogen

10 A1 As described above C1 is contacted with a suitable agent, 1. Optional OH modification Such as triphosgene and dioxane, to result in a compound of 2. R-NH D1. The compound D1 may be further halogenated under 15 suitable conditions, such as treatment with POCl and PCls, to provide a compound of formula A1. In certain instances, the above processes further involve

the step of forming a salt of a compound of the present disclosure. Embodiments are directed to the other processes described herein; and to the product prepared by any of the processes described herein. Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references 25 that are cited and discussed throughout the present specifi cation. See, e.g., Loudon, Organic Chemistry, 5' edition, (I) New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7" edition, Wiley-Interscience, 2013. An amide of formula C1 (where R', R, and R are as 30 The Examples provided herein describe the synthesis of defined herein or are suitably protected derivatives of R', compounds disclosed herein as well as intermediates used to R°, and R, and Z' is NH or O-alkyl) is converted to a prepare the compounds. It is to be understood that individual compound of formula C2, under Suitable reaction condi steps described herein may be combined. It is also to be tions. For example, the compound of formula C1 is con understood that separate batches of a compound may be 35 combined and then carried forth in the next synthetic step. tacted with chloroformamidine hydrochloride under suitable In the following description of the Examples, specific conditions to provide C2. The hydroxyl group may be embodiments are described. These embodiments are further modified, for example by introducing any suitable described in sufficient detail to enable those skilled in the art leaving group. Such as a tosyl group, prior to contacting with to practice certain embodiments of the present disclosure. R NH. Alternatively, R NH may be directly coupled Other embodiments may be utilized and logical and other to C2 in the presence of a Suitable coupling agent, for 40 changes may be made without departing from the scope of example, BOP reagent, under suitable conditions. the disclosure. The following description is, therefore, not Additionally, a compound of Formula A1 (where R', R, intended to limit the scope of the present disclosure. and R are as defined herein or are suitably protected The methods of the present invention generally provide a derivatives of R', R, and R) may be prepared as described specific enantiomer or diastereomer as the desired product, in the scheme below. It is understood that A1 may be further 45 although the stereochemistry of the enantiomer or diaste modified to prepare compounds of Formula (I) as more fully reomer was not determined in all cases. When the stereo described herein. chemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereo 50 center even though the compound can be substantially enantiomerically or disatereomerically pure.

EXAMPLE 1.

n-BuNH2. (i-Pr)2NEt: o1 Halogenation He HN

65 (i-Pr)2NEt US 9,670,205 B2 157 158 -continued Synthesis of N'-(2,4-dimethoxybenzyl)-N'-(pentan-2-yl) pyrido3.2-dpyrimidine-2,4-diamine (2A): 2A was synthe sized following the procedure described above for prepara tion of 1A, replacing butan-1-amine with 2-aminopentane. MS (m/z) 382.17 M+H". Synthesis of N'-(pentan-2-yl)pyrido3.2-dipyrimidine-2, TFA 4-diamine (2B); 2B was prepared following the procedure described for 1B to yield the title compound (2B) as its TFA salt. "H NMR (400 MHz, Methanol-d) & 8.61 (dd, J=44, 10 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.74 (dd, J=8.5, 4.4 Hz, 1H), 4.60-4.46 (m, 1H), 1.74 (dtd, J=13.5, 8.3, 6.7 HZ, 1H), 1.68-1.55 (m, 1H), 1.44 (d. J–74 Hz, 2H), 1.32 (d. J=6.6 Hz, 3H), 0.95 (t, J–74 Hz, 3H). MS (m/z) 232.11 1A 15 M+H". F NMR (377 MHz, Methanol-d4) 8 -77.5. EXAMPLE 3

1B Synthesis of N-butyl-N'-(2,4-dimethoxybenzyl)pyrido 3,2-dipyrimidine-2,4-diamine (1A): To a solution of 2,4- dichloropyrido3.2-dpyrimidine (CASi39551-54-7, Sup 30 plied by Astatech, Inc.) (50 mg, 0.25 mmol) in THF (2 mL) was added butan-1-amine (0.03 mL, 0.28 mmol) and N,N- diisopropylethylamine (0.13 ml, 0.75 mmol). After stirring Synthesis of (S)-2-((2-((2,4-dimethoxybenzyl)amino) at room temperature for 30 minutes, 2,4-dimethoxyben pyrido3.2-dpyrimidin-4-yl)amino)-4-methylpentan-1-ol Zylamine (0.19 ml, 1.25 mmol) and N,N-diisopropylethyl 35 (3A): 3A was synthesized following the above procedure for amine (0.13 ml, 0.75 mmol) were added and the mixture was 1A, replacing butan-1-amine with (S)-(+)-leucinol. MS heated to 100° C. After 16 hours, the reaction was cooled to (m/z) 412.19 M+H". room temperature, diluted with ethyl acetate, washed with Synthesis of (S)-2-((2-aminopyrido 3,2-dpyrimidin-4- water and brine, dried over NaSO, and concentrated in yl)amino)-4-methylpentan-1-ol (3B): 3B was synthesized vacuo. The product (1A) was obtained after flash chroma using the procedure described above for the preparation of tography. MS (m/z): 368. 14 M+H". 40 Synthesis of N-butylpyrido|3,2-dipyrimidine-2,4-di 1B to yield the title compound (3B) as its TFA salt. H NMR amine (1B): 1A was dissolved in trifluoroacetic acid (3 mL). (400 MHz, Methanol-da) & 8.62 (dd, J–4.4, 1.3 Hz, 1H), After 30 minutes, the reaction was diluted with water and 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.74 (dd, J=8.5, 4.4 Hz, 1H), methanol. After 60 minutes, the mixture was concentrated in 4.74-4.58 (m. 1H), 3.71 (h, J=6.2 Hz, 2H), 1.76-1.58 (m, vacuo. The residue was then co-evaporated with methanol 45 2H), 1.52 (td, J=10.6, 3.5 Hz, 1H), 0.98 (t, J=6.4 Hz, 6H). three times and filtered in methanol to afford the title product MS (m/z) 262.15 M+H". F NMR (377 MHz, Methanol 1B as a trifluoroacetic acid salt. H NMR (400 MHz, d4) 8 -77.6 Methanol-d) & 8.59 (dd, J=4.4, 1.4 Hz, 1H), 7.82 (dd, J=8.5, 1.4 Hz, 1H), 7.72 (dd, J=8.5, 4.4 Hz, 1H), 3.66 (t, J–7.3 Hz, EXAMPLE 4 2H), 1.78-1.62 (m, 2H), 1.43 (dq, J=14.7, 7.4 Hz, 2H), 0.98 50 (t, J–74 Hz, 3H). MS (m/z): 218.10M+H". F NMR (377 MHz, Methanol-da) 8 -77.6. EXAMPLE 2

65 Synthesis of (S)-3-cyclopropyl-2-((2-((2,4-dimethoxy benzyl)amino)pyrido3.2-dpyrimidin-4-yl)amino)propan 1-ol (4A): 4A was prepared using the procedure described

US 9,670,205 B2 165 166 then extracted with EtOAc (3 times). The organic layer was -continued separated, dried over NaSO filtered and concentrated under reduced pressure. The product (18B) was obtained after flash chromatography. MS (m/z): 216.8 M+H" Synthesis of 2-amino-7-bromopyrido 3,2-dipyrimidin-4- 5 DMB-amine ol (18C): To a flask containing 3-amino-5-bromopicolina -e- mide (18B) (205 mg, 0.1 mmol. 1 equiv.) was added A chloroformamadine hydrochloride (140 mg, 1.3 equiv.). The mixture was heated to 165° C. overnight. It was allowed to cool to room temperature, then filtered and washed with water and ethyl ether. The residue was allowed to air dry to 10 furnish 2-amino-7-bromopyrido3,2-dipyrimidin-4-ol (1C) 19C which was used without further purification. MS (m/z): 239.9 M+H" Synthesis of N-(7-bromo-4-hydroxypyrido 3,2-dipyrimi OH din-2-yl)acetamide (18D): To a flask containing 2-amino-7- HN TFA bromopyrido 3.2-dpyrimidin-4-ol (1C) (155 mg, 0.64 N mmol. 1 equiv.) was added acetic anhydride (3 mL). The N NN mixture was heated to 115° C. for 4 hrs. It was concentrated under reduced pressure. It was filtered and washed with diethyl ether and hexane and allowed to air dry to obtain C 4N als NHDMB N-(7-bromo-4-hydroxypyrido3.2-dpyrimidin-2-yl)acet amide (18D). MS (m/z): 282.9 M+H". 19D Synthesis of N-(7-bromo-4-chloropyrido 3,2-dipyrimi din-2-yl)acetamide (18E): Into a solution of N-(7-bromo-4- hydroxypyrido3.2-dpyrimidin-2-yl)acetamide (18D) (200 25 mg, 0.71 mmol. 1 equiv.) was added acetonitrile (2 ml) and POC1 (1 ml) followed by DIPEA (0.12 mL, 0.71 mmol. 1 equiv.). The mixture was refluxed for 6 hours. The mixture was concentrated under reduced pressure. To it was added water (20 mL) then extracted with EtOAc (3 times). The organic layer was separated, dried over NaSO, filtered and 30 concentrated under reduced pressure to afford the title 19E product N-(7-bromo-4-chloropyrido3.2-dpyrimidin-2-yl) acetamide (18E). MS (m/z): 298.9 (+H". Synthesis of (S)-2-((2-amino-7-bromopyrido3.2-dpy Synthesis of 2,4,7-trichloropyrido 3,2-dpyrimidine rimidin-4-yl)amino)pentan-1-ol (18F): To a solution of 35 (19B): Into a microwave vial was added pyrido 3,2-d N-(7-bromo-4-chloropyrido3.2-dpyrimidin-2-yl)acet pyrimidine-2,4-diol (19A) (200 mg, 1.2 mmol. 1 equiv.) is amide (18E) (215 mg 0.71 mmol. 1 equiv.) was added DMF added POCl (2.5 mL) and PC1s (1.53 g, 7.4 mmol. 6 equiv.). (1.5 ml) followed by DIPEA (0.38 mL, 2.1 mmol, 3 equiv.) The mixture was heated to 160° C. for 3 hr in microwave and (S)-(+)-2-Amino-1-pentanol (55 mg, 3.6 mmol. 5 reactor. The reaction mixture was concentrated under equiv.). The reaction was allowed to stir overnight. It was 40 reduced pressure and partitioned between EtOAc and H.O. concentrated under reduced pressure and purified by reverse The organics were separated, dried, and removed in vacuo. phase HPLC to furnish the title compound (18F) as its TFA The residue purified by column chromatography on silica to salt. "H NMR (400 MHz, Methanol-da) & 8.41 (d. J–2.0 Hz, provide the title compound. MS (m/z): 236.6M+H". 1H), 7.83 (d. J=2.0 Hz, 1H), 4.34 (dd, J–8.5, 5.4 Hz, 1H), Synthesis of (S)-2-((2,7-dichloropyrido 3,2-dipyrimidin 3.65-3.53 (m, 3H), 1.67-1.49 (m, 3H), 1.41-1.24 (m, 3H), 45 4-yl)amino)pentan-1-ol (19C): To a solution of 2,4,7-trichlo 0.86 (t, J=7.4 Hz, 5H). 'F NMR (377 MHz, CD,OD) & ropyrido3.2-dpyrimidine (19B) (160 mg. 0.68 mmol. 1 -77.52. MS (m/z): 368.2 M+H. equiv.) was added dioxane (4 ml) followed by DIPEA (0.18 mL, 1.2 mmol. 1.5 equiv.) and (S)-(+)-2-Amino-1-pentanol EXAMPLE 19 (85 mg. 0.82 mmol. 1.1 equiv.). The reaction was allowed to 50 stir for an hr. It was concentrated under reduced pressure and used as is to provide the title compound. MS (m/z): 301.1 M+H". OH Synthesis of (S)-2-((7-chloro-2-((2,4-dimethoxybenzyl) amino)pyrido3.2-dpyrimidin-4-yl)amino)pentan-1-ol N n NN POC 3 55 (19D): To a solution of (R)-2-((2,7-dichloropyrido 3,2-d pyrimidin-4-yl)amino)pentan-1-ol (19C) (206 mg, 0.68 22. 160°PCls C. mmol. 1 equiv.) was added dioxane (4 ml) followed by 4\ OH DIPEA (0.24 mL, 1.4 mmol. 2 equiv.) and 2,4-demethoxy benzylamine (0.30 mL, 2.0 mmol. 3 equiv.). The reaction 60 was allowed heated at 120° C. overnight. The reaction mixture was partitioned between EtOAc and HO. The L-norvallinol organics were separated, dried, and removed in vacuo. The -e- DIPEAf residue purified by column chromatography on silica to dioxane provide the title compound. MS (m/z): 432.2 M+H". 65 Synthesis of (S)-2-((2-amino-7-chloropyrido 3.2-dpy rimidin-4-yl)amino)pentan-1-ol (19E): Into a solution of (S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido3. US 9,670,205 B2 167 168 2-dpyrimidin-4-yl)amino)pentan-1-ol (19D) (35 mg, 0.08 Synthesis of (S)-2-((2-((2,4-dimethoxybenzyl)amino)-7- mmol. 1 equiv.) was added DCM (2 mL) and TFA (0.5 mL). methylpyrido3.2-dpyrimidin-4-yl)amino)pentan-1-ol After 3 hours the reaction mixture was concentrated under (19F): Into a vial containing (S)-2-((7-chloro-2-((2,4-dime reduced pressure and purified by reverse phase HPLC to thoxybenzyl)amino)pyrido3,2-dipyrimidin-4-yl)amino) furnish the title compound (19E) as its TFA salt. H NMR pentan-1-ol (19D) (25 mg 0.06 mmol. 1 equiv.) was added (400 MHz, Methanol-da) & 8.48 (d. J–2.0 Hz, 1H), 7.78 (d. methylboronic acid (8 mg, 0.14 mmol. 2.5 equiv.), potas J=2.1 Hz, 1H), 4.48 (dd, J=8.6, 5.3 Hz, 1H), 3.93-3.74 (m, sium phosphate tribasic (37 mg, 0.17 mmol. 3 equiv.). 2H), 3.71 (d. J=5.2 Hz, 3H), 1.77-1.57 (m, 2H), 1.50-1.36 palladium(0)-tetrakis(triphenylphosphine) (7 mg, 0.006 (m. 1H), 1.28 (s. 2H), 0.97 (t, J=74 Hz, 4H). 'F NMR (377 mmol, 0.1 equiv.) along with dioxane (2 mL) and water (2 MHz, Methanol-da) 8 -77.59 (d. J=80.2 Hz). MS (m/z): 10 mL). The mixture is heated to 150° C. for 1 hr in a 282.1 M+H". microwave reactor. The reaction mixture was partitioned between EtOAc and HO. The organics were separated, General Scheme for Examples 20-22 dried, and removed in vacuo to furnish the title compound which was used directly. MS (m/z): 474.3 +H". Synthesis of (S)-2-((2-amino-7-methylpyrido 3.2-dpy 15 rimidin-4-yl)amino)pentan-1-ol (20): Into the a flask con taining 19F was added THF (2 mL), water (2 mL) followed by 2,3-dichloro-5,6-dicyanobenzoquinone (26 mg, 20.11 OH mmol. 2 equiv.) After stirring overnight, the reaction mixture HN Pod cat. was partitioned between EtOAc and H.O.The organics were -e- N boronic acid separated, dried, and removed in vacuo. Purification was n n N or Zincate carried out using flash column chromatography to furnish the title compound (20). H NMR (400 MHz, Methanol-d4) C 4N als NHDMB & 8.35 (d. J=1.1 Hz, 1H), 7.49 (s, 1H), 4.54-4.34 (m, 1H), 3.70 (d. J=5.0 Hz, 2H), 1.84-1.61 (m, 2H), 1.56-1.35 (m, 19D 25 2H), 0.97 (t, J–7.3 Hz, 3H). MS (m/z); 262.1 M+H". EXAMPLE 21 OH TFA He 30 21

NHDMB OH 19F R = CH3 35 19H R = CHCH 19J R = CN

40 OH HN Synthesis of (S)-2-((2-amino-7-ethylpyrido 3,2-dipyrimi N din-4-yl)amino)pentan-1-ol (21) was prepared according to n n N the procedure used for 20, instead using ethylboronic acid in 45 place of methylboronic acid. "H NMR (400 MHz, Methanol R 4N als NH2 d4) & 8.65-8.30 (m. 1H), 7.62 (s, 1H), 4.61-4.38 (m, 1H), 20 R = CH3 3.80–3.64 (m, 2H), 2.84 (q, J=7.6 Hz, 2H), 1.71 (tdd, J=8.3, 21 R = CHCH 6.5, 2.2 Hz, 2H), 1.43 (dddd, J=12.4, 7.4, 5.1, 2.5 Hz, 2H), 22 R = CN 1.39-1.23 (m, 4H), 0.97 (t, J=7.3 Hz, 3H). MS (m/z): 276.2 50 M+H". EXAMPLE 22 EXAMPLE 20

55 22 2O

OH HN 60

N n n N

4N als NH2 65 US 9,670,205 B2 169 170 Synthesis of (S)-2-amino-4-(1-hydroxypentan-2-yl) (85 uL, 3.0 mmol. 3 equiv.). The reaction was allowed amino)pyrido3.2-dpyrimidine-7-carbonitrile (22) was pre heated at 120° C. overnight. The reaction mixture parti pared according to the two step procedure used for 20, tioned between EtOAc and H2O. The organics were sepa instead using Zn(CN), in place of methylboronic acid. "H rated, dried, and removed in vacuo. The residue purified by NMR (400 MHz, DMSO-d6) & 7.93 (d. J=1.7 Hz, 1H), 7.24 5 column chromatography on silica to provide the title com (d. J=1.7 Hz, 1H), 2.95-2.68 (m,3H), 0.76 (d. J=7.3 Hz, 2H), pound. MS (m/z): 446.9 M+H". 0.47 (d. J=7.6 Hz, 1H), 0.02 (t, J–7.4 Hz, 4H). MS (m/z): Synthesis (R)-2-((2-amino-7-chloropyrido 3,2-dipyrimi 273.3 M+H". din-4-yl)amino)hexan-1-ol (23C): To a solution of (R)-2- ((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido 3.2-d EXAMPLE 23 10 pyrimidin-4-yl)amino)hexan-1-ol (20B) (50 mg, 0.11 mmol. 1 equiv.) was added DCM (2 mL) and TFA (0.5 mL). After 3 hours the reaction mixture was concentrated under reduced C pressure and purified by reverse phase HPLC to furnish the 15 title compound (23C) as its TFA salt. H NMR (400 MHz, N Methanol-d4) & 8.60 (d. J=2.1 Hz, 1H), 7.90 (d. J=2.1 Hz, n n N D-Norleucinol Her 1H), 4.58-4.44 (m. 1H), 3.79-3.63 (m, 3H), 1.86-1.61 (m, DIPEA dioxane 2H), 1.52-124 (m, 5H), 1.01-0.79 (m, 4H). F NMR (377 2 C N C MHz, Methanol-da) 8 -77.61. MS (m/z): 296.2 M+H".

EXAMPLE 24

DMB-amine O H 25 A 2 N o1 NBS ACN C 1s NH2 30 23A 24A O C

w OH Br N 1.

HN 21 o1 HN NH TFA -e- 35 160° C.

23B 40 BOP, amine -e- DBU, DMF HNY w OH 45 N n n N

C 4n. als NH2 50 23C

Synthesis of (R)-2-((2.7-dichloropyrido 3,2-dipyrimidin 4-yl)amino)hexan-1-ol (23A): To a solution of 2,4,7-trichlo ropyrido3.2-dpyrimidine (19B) (45 mg, 0.19 mmol. 1 55 equiv.) was added dioxane (4 ml) followed by DIPEA (41 LL, 0.23 mmol. 1.2 equiv.) and (R)-(-)-2-Amino-1-hexanol 97% (24.7 mg, 0.21 mmol. 1.1 equiv.). The reaction was Synthesis of methyl 3-amino-6-bromo-5-fluoropicolinate allowed to stir for an hr. It was concentrated under reduced (24B): To a solution of methyl 3-amino-5-fluoropicolinate pressure and used as is to provide the title compound. MS 60 (24A) (270 mg 0.22 mmol. 1 equiv.) was added acetonitrile (m/z): 316.2M+H". (5 mL) and N-bromosuccinimide (310 mg, 0.24 mmol. 1.1 Synthesis of (R)-2-((7-chloro-2-(2,4-dimethoxybenzyl) equiv.). The reaction was allowed to stir at room temperature amino)pyrido3.2-dpyrimidin-4-yl)amino)hexan-1-ol overnight. The reaction mixture partitioned between EtOAc (23B): To a solution of (R)-2-((2.7-dichloropyrido 3.2-d and H2O. The organics were separated, dried, and removed pyrimidin-4-yl)amino)hexan-1-ol (23A) (60 mg, 0.19 mmol. 65 in vacuo. The residue purified by column chromatography 1 equiv.) was added dioxane (4 ml) followed by DIPEA (68 on silica to provide the title compound. MS (m/z): 250.2 LL, 0.38 mmol. 2 equiv.) and 2,4-demethoxybenzylamine M+H". US 9,670,205 B2 171 172 Synthesis of 2-amino-6-chloro-7-fluoropyrido3.2-dpy -continued rimidin-4-ol (24C): To a flask containing methyl 3-amino 6-bromo-5-fluoropicolinate (24B) (200 mg. 0.80 mmol. 1 equiv.) was added chloroformamadine hydrochloride (185 mg, 1.61 mmol. 2 equiv.). The mixture was heated to 165° C. overnight. It was allowed to cool down to room tempera ture it was filtered and washed with water and ethyl ether. The residue was allowed to air dry to provide the title compound (24C). Approximately, 25% of the product is the corresponding side product 2-amino-6-bromo-7-fluoro pyrido3.2-dpyrimidin-4-ol. The material was used without 10 further purification. MS (m/z): 260.0 M+H". Synthesis of Synthesis of 2-amino-6-chloro-7-fluoro pyrido3.2-dpyrimidin-4-ol (24D): To a flask 2-amino-6- chloro-7-fluoropyrido 3.2-dpyrimidin-4-ol (24C) (50 mg. 0.23 mmol. 1 equiv.) is added (Benzotriazol-1-yloxy)tris 15 25D (dimethylamino)phosphonium hexafluorophosphate 97% (BOP Reagent) (123 mg 0.28 mmol. 1.2 equiv.). (S)-(+)-2- Amino-1-pentanol, 97% (48 mg 0.47 mmol. 2 equiv.) and DBU (105 uL, 0.70 mmol, 3 equiv.) and DMF (3 mL). The mixture was allowed to stir at room temperature overnight and purified by reverse phase HPLC to furnish the title compound (24D) as its TFA salt. H NMR (400 MHz, Methanol-d4) & 7.86-7.63 (m, 1H), 4.64-4.47 (m, 1H), 3.72 (d. J=5.5 Hz, 2H), 1.82-1.61 (m, 3H), 1.56-1.35 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). ''F NMR (377 MHz, Methanol-d4) 25 8 -77.54, -110.63 (d. J=8.2 Hz). MS (m/z): 300.2 M+H". EXAMPLE 25

30 25E

Synthesis of N-butyl-8-methylpyrido|3,2-dipyrimidine n-butylamine 2,4-diamine (25E). Beginning from intermediate 25A, treat He 35 DIPEATHF ment with 1.05 equiv butan-1-amine in THF/DIPEA at RT gave 25B, which was concentrated to a residue and carried forward directly. Heating with excess 2,4-dimethoxyben Zylamine in THF/DIPEA led to compound 25C, with char 25A 40 acteristic MS (m/z): 416.2 M+H". Following the procedure reported by Hasnik et. al in Synthesis, 2009, 1309-1317, instead of the expected 6-methylation via potassium methyl trifluoroborate, protonolysis of the intermediate heteroaryl 1) DMB-amine Pd complex led mainly to isolation of 25D, and finally to -e- 45 N-butyl-8-methylpyrido|3,2-dipyrimidine-2,4-diamine C N DIPEATHF 25E upon treatment of 25D in excess TFA and final purifi rsrs A cation via HPLC to provide the title compound (25E) as its a\ als C TFA salt. "H NMR (400 MHz, Methanol-da) & 8.48 (d. J=1.1 HZ, 1H), 7.61 (d. J=1.1 Hz, 1H), 3.67 (d. J=7.2 Hz, 2H), 2.52 50 (s, 3H), 1.75-1.68 (m, 2H), 1.4.6-1.35 (m, 2H), 0.98 (t, J–7.3 Hz, 3H). 'F NMR (377 MHz, Methanol-d4) 8 -77.6. MS (m/z): 232.1 M+H".

EXAMPLE 26 55

PoCl2 --- PArligand 1. CsCO3 NH O toluene? 60 L-norvallinol Water Ho KCHBF DIPEATHF

o1 65 25C 25A US 9,670,205 B2 174 -continued EXAMPLE 27

OH C DMB-amine

-e- DIPEATHF n N L-norvallinol He

A DIPEATHF 2 10 N C

26B OH HN DMB-amine 15 OH N DIPEA HN N NN A

C N n n N PoCl2 4N als C PArligand 27a 21 2 1. Cs2CO3 N NH O toluene? Water

KCHBF

25 o1 TFA 26C --

OH 30 HN

N 1. TFA n n N O -e- o1 27b. a\ els2 N rt 35 H

40 26D

OH HN 45 N n n N Synthesis of (S)-2-((2-chloropyrido 3,2-dpyrimidin-4- yl)amino)pentan-1-ol (27C): To a solution of 2,4-dichloro an als NH2 pyrido3.2-dpyrimidine (160 mg. 0.68 mmol. 1 equiv.) was added THF (4 ml) followed by DIPEA (0.18 mL, 1.2 mmol, 1.5 equiv.) and (S)-(+)-2-amino-1-pentanol (85 mg. 0.82 26E mmol. 1.1 equiv.). The reaction was allowed to stir for 1 h. The reaction was concentrated under reduced pressure and 55 used as is to provide 27A. MS (m/z): 267.1M+H". Synthesis of (S)-2-((2-((2,4-dimethoxybenzyl)amino) pyrido3.2-dpyrimidin-4-yl)amino)pentan-1-ol (27B): To a Synthesis of (S)-2-((2-amino-8-methylpyrido3.2-dpy solution of (S)-2-((2-chloropyrido3.2-dpyrimidin-4-yl) rimidin-4-yl)amino)pentan-1-ol (26E): Beginning from amino)pentan-1-ol (27A) (206 mg, 0.68 mmol. 1 equiv.) was intermediate 25A and following the synthetic sequence 60 added is added THF (4 ml) followed by DIPEA (0.24 mL, reported above for the synthesis of 25E, but instead using 1.4 mmol. 2 equiv.) and 2,4-dimethoxybenzylamine (0.30 L-norvalinol in place ofbutan-1-amine, 26E was obtained as mL, 2.0 mmol. 3 equiv.). The reaction was heated at 135° C. its TFA salt. H NMR (400 MHz, Methanol-da) & 8.50 (d. via microwave reactor for 30 minutes. The reaction mixture J–4.6 Hz, 1H), 7.63 (dq, J=4.5, 0.8 Hz, 1H), 4.60-449 (m, was partitioned between EtOAc and H2O. The organics were 1H), 3.78-3.70 (m, 2H), 2.53 (s, 3H), 1.81-1.64 (m, 2H), 65 separated, dried, and removed in vacuo. The residue was 1.52-1.34 (m, 2H), 0.97 (t, J–7.3 Hz, 3H). IF NMR (377 purified by column chromatography on silica to provide MHz, Methanol-da) 8 -77.7. MS (m/z): 262.2 M+H" 27B. MS (m/z): 398.2 M+H". US 9,670,205 B2 175 176 Synthesis of (S)-2-((2-amino-3,2-dipyrimidin-4-yl) 1H), 8.18-7.50 (m, 2H), 3.62 (q, J=6.7 Hz, 1H), 2.39-2.27 amino)pentan-1-ol (27C): Into a solution of (S)-2-((2-((2,4- (m. 1H), 1.93-1.84 (m, 1H). F NMR (377 MHz, Methanol dimethoxybenzyl)amino)pyrido3.2-dpyrimidin-4-yl) d4) 8 -65.5, 75.6. MS (m/z): 272.1 M+H" amino)pentan-1-ol (27B) (35 mg, 0.08 mmol. 1 equiv.) was added DCM (2 mL) and TFA (0.5 mL). After 3 hours the EXAMPLE 30 reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to furnish the title compound (27C) as its TFA salt. H NMR (400 MHz, Methanol-d4) & 8.65 (dd, J–4.3, 1.5 Hz, 1H), 7.85-7.73 (m, 2H), 4.55 (s, 1H), 3.76-3.70 (m, 2H), 1.77-1.66 (m, 2H), 10 1.44 (td, J–7.3, 4.2 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). F NMR (377 MHz, Methanol-d4) 8 -77.6. MS (m/z): 248.2 M+H" OCH 15 1Mad. KOH EXAMPLE 28 O Hs 1. THF O

28 H o1 5A

OH Following the general procedure described above for the 30 synthesis of 1B, 2,4-dichloropyrido3.2-dpyrimidine was 1) HATUDIPEA 1. - -- instead reacted with 1.1 equiv (S)-1,1,1-trifluoropentan-2- O 2,4-dimethoxy amine in place of 1-butan-amine and then carried through benzylamine or the steps as reported above in Example 1 to provide (S)- MeNH in THF 35 N'-(1,1,1-trifluoropentan-2-yl)pyrido3,2-dipyrimidine-2, 2) TFArt 4-diamine (28). "H NMR (400 MHz, DMSO-d6) & 9.87 (s, o1 1H), 8.67 (dd, J=44, 1.5 Hz, 1H), 7.95-7.81 (m, 2H), 5.13 3OA (t, J=8.9 HZ, 1H), 2.21-2.10 (m, 1H), 1.74 (dd, J=12.1, 7.1 HZ, 1H), 1.44-1.36 (m, 1H), 1.27 (dq, J=13.7, 7.1 Hz, 1H), 0.89 (t, J=7.3 Hz, 3H). ''F NMR (377 MHz, Methanol-d4) 40 8 -73.9, -74.1. MS (m/z): 286.1 M+H".

EXAMPLE 29

29 CF

Synthesis of (S)-2-((2-aminopyrido 3,2-dpyrimidin-4- yl)amino)pentanamide (30B). Beginning from 50 mg of the intermediate compound 5A previously described above, 55 treatment with 1 equiv. aq. KOH in THF/MEOH (4 mL) for 1 h gave, upon removal of solvent, intermediate 30A, MS (m/z): 399.1 M+H". 30A was treated with 1.5 equiv HATU and 3 equiv DIPEA in 2 mL DMF, with quenching by excess Following the general procedure described above for the 60 2,4-dimethoxybenzylamine (DMB) to provide the interme synthesis of 1B, 2,4-dichloropyrido3.2-dpyrimidine was diate amide. After global DMB removal via TFA treatment, instead reacted with 1.1 equiv 4,4,4-trifluorobutylamine in HPLC purification of the product residue provided title place of 1-butan-amine and then carried through the steps as compound 30B as its TFA salt. H NMR (400 MHz, Metha reported above for Example 1 to provide N'-(4,4,4-trifluo nol-d) & 8.67 (ddd, J=9.2, 4.3, 1.5 Hz, 1H), 7.89-7.73 (m, robutyl)pyrido3.2-dpyrimidine-2,4-diamine (29) after 65 2H), 4.00-3.59 (m. 1H), 2.81 (s. 2H), 2.22-1.79 (m, 2H), HPLC purification as its TFA salt. "H NMR (400 MHz, 1.48 (tt, J=9.8, 7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). 'F NMR DMSO-d6) 89.74 (t, J=6.0 Hz, 1H), 8.63 (dd, J–4.4, 1.4 Hz, (377 MHz, Methanol-d4) 8 -77.6. MS (m/z): 261.1 M+H". US 9,670,205 B2 177 178 EXAMPLE 31 -continued

1Mad. KOH THF 10 Synthesis of N-butyl-6-(trifluoromethyl)pyrido3.2-d pyrimidine-2,4-diamine (32). Beginning from 10 mg com pound 1B, the synthesis of which is reported in Example 1, and proceeding with chemistry described by Yining et al. in 15 PNAS, 2011, 108, 14411, 1B was heated at 55° C. in DMSO in the presence of 10 equivalents of zinc trifluorimethane sulfinate and 10 equiv t-butylhydroperoxide 70% aq. solu tion. After 24 h, the reaction mixture was injected directly onto HPLC for final purification to provide the title com pound (32) as the corresponding TFA salt. H NMR (400 MHz, Methanol-d) & 8.15 (d. J=8.7 Hz, 1H), 8.01 (dd. 1) HATUDIPEA Her J=8.8, 0.8 Hz, 1H), 3.82-3.56 (m, 2H), 1.83-1.61 (m, 2H), 2,4-dimethoxy 1.58-131 (m, 2H), 0.99 (t, J–74 Hz, 3H). 'F NMR (377 benzylamine or MHz, Methanol-da) 8 -69.0, -77.6. MS (m/z): 286.1 MeNH2 in THF 25 M+H". 2) TFArt EXAMPLE 33

Synthesis of (S)-2-((2-aminopyrido 3,2-dipyrimidin-4- yl)amino)-N-methylpentanamide (31). 50 mg of 30A was treated with 1.5 equiv HATU and 3 equiv DIPEA in 2 mL 45 DMF, with quenching by 1.0 M methylamine in THF to provide the intermediate methylamide. After standard DMB removal via TFA treatment, HPLC purification of the prod uct residue provided title compound 31 as its TFA salt. "H NMR (400 MHz, Methanol-d) & 8.68 (dd, J–4.3, 1.5 Hz, 1H), 7.89-7.76 (m, 2H), 4.85 (m, 1H), 2.76 (s, 3H), 2.08 1.85 (m, 2H), 1.45 (dddd, J=16.5, 13.8, 11.5, 7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). ''F NMR (377 MHz, Methanol-d4) 8 -77.9. MS (m/z): 275.1 M+H" 55 Synthesis of (S)-2-((2-amino-6-methylpyrido 3.2-dpy rimidin-4-yl)amino)pentan-1-ol (33). 50 mg compound 6B, EXAMPLE 32 (0.11 mmol. 1 equiv) in 10 mL (1:1 EtOH/EtOAc) was reacted with 28 mg 5% Pd/Cat 70° C. under 1 atm H. After overnight, the reaction was filtered to remove catalyst and 60 the product chromatographed on silica gel, eluting at 25% t-butyl hydroperoxide MeOH/75% EtOAc to provide the title compound (33) as its Hip TFA salt. H NMR (400 MHz, Methanol-d4) & 7.74 (d. J=8.6 Zinc trifluoromethanesulfinate HZ, 1H), 7.65 (d. J=8.6 Hz, 1H), 4.54 (ddd, J=12.4, 7.3, 5.2 DMSO HZ, 1H), 3.75 (d. J=5.2 Hz, 2H), 2.65 (s.3H), 1.73 (q, J–7.5 rt to 55° C. 65 Hz, 2H), 1.44 (ddt, J=14.6, 7.4, 4.2 Hz, 2H), 0.98 (t, J–7.3 Hz, 3H). 'F NMR (377 MHz, Methanol-d4) 8 -77.7. MS (m/z) 262.14 M+H".

US 9,670,205 B2 183 184 Synthesis of (S)-2-((2-amino-7-fluoropyrido 3.2-dpy rimidin-4-yl)amino)pentan-1-ol (43C):

OH HN 5 NaOMe He dimethylsulfone, N MeOH N NH HCI 140 C. n n N n o1 -- ul He 1 hour C NH2 C 4N als NHDMB 10 2 NH2 19D 43A

TFA 15

Methyl 3-amino-5-fluoropicolinate (43A) (830 mg, 4.88 mmol), chloroformamidine hydrochloride (1121.64 mg. 9.76 mmol), dimethyl sulfone (4592.09 mg, 48.78 mmol) OH and a stir bar were charged into a sealed pressure tube and HN 25 heated to 160° C. for 1 hour. At this time reaction was allowed to cool, 50 mL of water was added and the solution N stirred with heating for 30 minutes. Precipitates were filtered n SN off and the mother liquor was purified by reverse phase HPLC using ACN/HO with 0.1% TFA as the eluent on a No 4N als NH2 Hydro-RP column with a 2 to 5% ACN gradient. Solvents were removed under reduced pressure and the residue was azeotroped 2x with methanol, 2x with DCM before sonica (S)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methoxy tion in ether. Precipitates were filtered and air dried to afford pyrido3.2-dpyrimidin-4-yl)amino)pentan-1-ol (42A): Into 210 mg (23.9%) of 2-amino-7-fluoropyrido3,2-dpyrimi a vial containing (S)-2-((7-chloro-2-((2,4-dimethoxybenzyl) 35 din-4-ol (43B) as a white solid. "H NMR (400 MHz, amino)pyrido3.2-dpyrimidin-4-yl)amino)pentan-1-ol DMSO-d6) & 8.43 (d. J=2.5 Hz, 1H), 7.48 (dd, J=10.1, 2.5 (19D) (50 mg, 0.11 mmol. 1 equiv.) was added NaOMe (65 Hz, 1H), 7.23 (s. 2H), 'F NMR (376 MHz, DMSO-d6) & LL, 1.1 mmol. 10 equiv.) and methanol (2 mL). The mixture -75.15, -119.96. MS (m/z) 181.0 M+H". was heated to 150° C. for 30 min. in a microwave reactor. Compound 43C was synthesized via a BOP-C1 promoted The reaction mixture was partitioned between EtOAc and 40 coupling of 43B with (S)-norvalinol, which provided the H2O. The organic layer was separated, dried, and removed title compound (43C) as its TFA salt after final HPLC in vacuo. The residue was purified by column chromatog purification. H NMR (400 MHz, Methanol-d4) & 8.56 (d. raphy on silica to provide the title compound. MS (m/z): J=2.4 Hz, 1H), 7.61 (dd, J=8.8, 2.5 Hz, 1H), 4.56 (dq, 428.2 M+H". Compound 42B was synthesized via TFA treatment of as J=12.7, 6.4., 6.0 Hz, 1H), 3.80–3.69 (m, 2H), 1.78 (ddd, 42A to yield the title compound (42B) as the TFA salt after J=18.8, 11.4, 3.7 Hz, 2H), 1.53-1.33 (m, 2H), 0.97 (t, J=7.4 final HPLC purification. "H NMR (400 MHz, Methanol-d4) Hz, 3H). 'F NMR (377 MHz, Methanol-d4) 8 -77.64, & 8.32 (d. J–2.5 Hz, 1H), 7.21 (d. J–2.5 Hz, 1H), 4.57-4.45 -118.17 (d. J=8.8 Hz). MS (m/z) 266.2 M+H". (m. 1H), 4.00 (s.3H), 3.77-3.67 (m, 2H), 1.80-1.63 (m, 2H), EXAMPLE 44 1.50-139 (m, 2H), 0.97 (t, J–74 Hz, 3H). 'F NMR (377 so MHz, Methanol-da) 8 -77.52. MS (m/z) 278.2 M+H".

EXAMPLE 43 44

43C

OH HN 60

N n NN (R)-2-((2-amino-7-fluoropyrido 3,2-dipyrimidin-4-yl) F 4N als NH2 65 amino)hexan-1-ol (44). Compound 44 was synthesized fol lowing the procedure described above for preparation of 43C, instead reacting intermediate 43B with (R)-norleucinol US 9,670,205 B2 185 and proceeding with the above reported sequence to yield -continued the title compound (44) as the TFA salt after final HPLC OH purification. "H NMR (400 MHz, Methanol-d4) & 8.57 (d. NH dimethylsulfone, F J=2.4 Hz, 1H), 7.60 (dd, J=8.8, 2.4 Hz, 1H), 4.53 (dq, J=8.7, HCI 140° C. N N 5.6 Hz, 1H), 3.72 (d. J=5.4 Hz, 2H), 1.72 (m, 2H), 1.52-1.28 1 hour C NH2 (m, 4H), 1.04–0.82 (m,3H). F NMR (377 MHz, Methanol 2 d4) 8 -77.60, -118.13 (d. J=8.6 Hz). MS (m/z) 280.2 F N NH2 M+H". 46B 10 EXAMPLE 45 2-amino-6,7-difluoroquinazolin-4-ol (46B) was synthe sized following the procedure described above for prepara tion of 43B, instead reacting intermediate 46A in place of 43A and proceeding with the above reported sequence to 45 15 yield the title compound (46C) as the TFA salt after final HPLC purification. "H NMR (400 MHz, DMSO-d6)'H NMR (400 MHz, DMSO-d) & 7.83 (t, J=9.7 Hz, 1H), 7.31-7.22 (m, 1H), 7.19 (s, 1H). 'F NMR (376 MHz, DMSO-d) 8 -74.93, -128.78, -144.35. MS (m/z) 1980 M+H". Compound (46C) was synthesized via a BOP-C1 pro moted coupling of 46B with (R)-norleucinol, which pro vided the title compound (46C) as its TFA salt after final 25 HPLC purification. "H NMR (400 MHz, Methanol-d4) & (S)-2-((2-amino-7-fluoropyrido 3,2-dpyrimidin-4-yl) 8.29 (dd, J=11.0, 7.9 Hz, 1H), 7.35 (dd, J=10.6, 6.8 Hz, 1H), amino)hexan-1-ol (45). Compound 45 was synthesized fol 4.67-4.53 (m. 1H), 3.80-3.59 (m, 2H), 1.77-1.63 (m, 2H), lowing the procedure described above for preparation of 149-1.30 (m, 4H), 0.91 (td, J–7.0, 6.3, 2.2 Hz, 3H). F 43C, instead reacting intermediate 43B with (S)-norleucinol NMR (376 MHz, Methanol-d4) 8 -77.71, -127.97 (ddd, and proceeding with the above reported sequence to yield 30 J–21.5, 10.6, 7.9 Hz), -142.27 (ddd, J-21.4, 11.0, 6.9 Hz). the title compound (45) as the TFA salt after final HPLC MS (m/z). 297.2 M+H". purification. H NMR (400 MHz, Methanol-d4) & 8.57 (d. J=2.4 Hz, 1H), 7.60 (dd, J=8.8, 2.4 Hz, 1H), 4.53 (dq, J=8.7, 5.6 Hz, 1H), 3.72 (d. J=5.4 Hz, 2H), 1.72 (m, 2H), 1.52-1.28 35 (m, 4H), 1.04–0.82 (m,3H). F NMR (376 MHz, Methanol EXAMPLE 47 d4) 8 -77.60, -118.13 (d. J=8.6 Hz). MS (m/z) 280.2 M+H". OH 40 EXAMPLE 46 n N BOP, amine als DBU, DMF 46C N NH2 45 47A

w OH HNY OH F NN 50

F Nals NH2

55 Synthesis of (R)-2-((2-amino-6,7-difluoroquinazolin-4- yl)amino)hexan-1-ol (46C): (R)-2-((2-aminoquinazolin-4-yl)amino)hexan-1-ol (47B) 60 was synthesized via a BOP-Cl promoted coupling of 47A with (R)-norleucinol, which provided the title compound (47B) as its TFA salt after final HPLC purification. H NMR (400 MHz, Methanol-d4) & 8.22 (ddd, J=8.3, 1.3, 0.6 Hz, 1H), 7.78 (ddd, J=8.4, 7.3, 1.3 Hz, 1H), 7.50-7.33 (m, 2H), 65 4.7.1-4.56 (m. 1H), 3.80–3.61 (m, 2H), 1.81-1.64 (m, 2H), 46A 1.47-1.31 (m, 4H), 0.92 (h, J=3.2 Hz, 3H). 'F NMR (376 MHz, Methanol-da) 8 -77.69. MS (m/z) 261.1 M+H". US 9,670,205 B2 187 188 EXAMPLE 48 butan-1-amine (CAS#959833-70-6, Fluorochem Ltd. UK), (0.03 mL, 0.56 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.15 mmol). The mixture was stirred at rt for 30 minutes, 2,4-dimethoxybenzylamine (0.19 ml, 1.25 mmol) 48 and N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) were added, and the mixture was heated to 1000° C. After 16 h, the reaction was cooled to rt, diluted with EtOAc, washed OH with water and brine, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was Subjected 10 to silica gel chromatography eluting with 0-100% EtOAc in hexanes to provide, after removal of Volatiles in vacuo, compound 49A. LCMS (m/z): 469.18 M+H". Nals NH2 Synthesis of (S)-N'-(1-aminopropan-2-yl)pyrido3.2-d 15 pyrimidine-2,4-diamine (49). 49A (50 mg, was dissolved in Synthesis (S)-2-((2-aminoquinazolin-4-yl)amino)hexan TFA (3 mL). After 30 minutes, the reaction was diluted with 1-ol (48) was prepared in a similar fashion to 47B, instead water and methanol. After 60 minutes, the mixture was using (S)-norleucinol in place of (R)-norleucinol. "H NMR concentrated in vacuo. The residue was then dissolved in (400 MHz, Methanol-d4) & 8.22 (ddd, J=8.3, 1.3, 0.6 Hz, methanol and filtered to provide, after removal of volatiles 1H), 7.78 (ddd, J=8.4, 7.3, 1.3 Hz, 1H), 7.50-7.33 (m, 2H), in vacuo, compound 49 as its TFA salt. H NMR (400 MHz, 4.7.1-4.56 (m. 1H), 3.80–3.61 (m, 2H), 1.81-1.64 (m, 2H), Methanol-d4) & 8.67 (ddd, J=9.0, 4.2, 1.6 Hz, 1H), 7.85-7.68 1.47-1.31 (m, 4H), 0.92 (h, J=3.2 Hz, 3H). 'F NMR (376 (m. 2H), 4.82 (m, 1H), 3.34 (d. 2H), 1.39 (d. 3H). F NMR MHz, Methanol-da) 8 -77.69. MS (m/z) 261.1 M+H". (377 MHz, Methanol-d4) 8 -77.8. LCMS (m/z): 219.03 M+H"; to 0.29 min. (LC/MS HPLC method B). EXAMPLE 49 25 EXAMPLE SO

HN --Nils (i-Pr).NEt:1. oHC O O HN O 4N HCI

o1 l s N dioxane (i-Pr).NEt O N\ H O 51c 40

TFA He O 45 s' N HNY oHCI o1 O 49A 50a 50

DIPEATHF -- then DMB-NH2 N Synthesis of(S)-tert-butyl (2-((2-(2,4-dimethoxybenzyl) HNW A amino)pyrido3.2-dpyrimidin-4-yl)amino)propyl)carbam oHCI ate (49A). A solution of 2,4-dichloropyrido3,2-dipyrimi 65 O dine (100 mg, 0.5 mmol) in THF (2 mL), was treated with 50a (S)-tert-butyl (2-aminopropyl)carbamate hydrochloride US 9,670,205 B2 189 -continued EXAMPLE 51

TFA BocO --

10 OH HNY (R)-norleucinol

50b 15 O PPh3, DIAD He phthalimide OH THF O NW H 51b.

O hydrazine 25 -e- > ul w N EtOH, A O N\ H O 51c 30

Synthesis of (R)-2-(2-aminohexyl)isoindoline-1,3-dione O AcCl 35 DCM, TEA hydrochloride (50a). To phthalimide 51c (180 mg, 0.53 s NH2 mmol) was added 4N HCl in dioxane (20 mL). The reaction O NW was stirred at rt for 6 hand then the volatiles were removed H in vacuo to provide crude 50a which was carried forward 51d directly into the next step without further purification. LCMS (m/z): 246.93 M+H". 40 Synthesis of (R)-methyl 2-((2-(2,4-dimethoxybenzyl) O 4N HCI amino)pyrido3.2-dpyrimidin-4-yl)amino)hexanoate (50b). -e- A solution of 2,4-dichloropyrido3.2-dpyrimidine (100 mg. > O l Nw dioxane 0.5 mmol) in THF (2 mL) was treated with 50a, (150 mg. 45 H 0.53 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.15 O mmol). The mixture was stirred at rt for 30 minutes, and 51e 2,4-dimethoxybenzylamine (0.38 mL, 2.5 mmol) and N.N- diisopropylethylamine (0.13 mL, 0.75 mmol) were added and the mixture was heated to 125° C. After 24 h, the 50 reaction was cooled to rt, diluted with EtOAc (50 mL), washed with water (25 mL), brine (25 mL), dried over H NaSO, filtered and concentrated in vacuo. The resulting y' N residue was subjected to silica gel chromatography eluting 55 inHCI with 0-100% EtOAc in hexanes to give, after removal of O volatiles in vacuo, compound 50b. 51f

Synthesis of (R)-N'-(1-aminohexan-2-yl)pyrido3.2-d pyrimidine-2,4-diamine (50). 50b (15 mg, 0.04 mmol) was dissolved in TFA (3 mL). After 60 minutes the mixture was (i-Pr).NEt; then concentrated to a residue in vacuo followed by co-evapora H 1. tion with MeOH, to provide the title compound 50 as its HNw'N-NA2 C O oHCI HN bis-TFA salt. "H NMR (400 MHz, MeOH-d) & 8.68 (m, 51f 1H), 7.81-7.83 (m, 2H), 4.89 (m, 1H), 3.91 (m, 2H), 3.61 O1 (m. 1H) 1.92-1.79 (m, 2H), 1.55-1.48 (m, 4H), 0.98 (t, J–7.4 65 Hz, 3H), F NMR (377 MHz, MeOH-d4) 8 -77.9. LCMS (i-Pr).NEt (m/z): 261.14 M+H"; t0.30 min. US 9,670,205 B2 191 192 -continued mmol). After the mixture was stirred for 30 minutes, 2,4- dimethoxybenzylamine (0.38 mL, 2.5 mmol) and N.N- diisopropylethylamine (0.13 mL, 0.75 mmol) were added, and the mixture was heated to 115° C. After heating for 16 5 h, the reaction was cooled to rt, diluted with EtOAc (100 mL), washed with water (100 mL), brine (100 mL), dried TFA over NaSO, filtered and concentrated in vacuo. The result ing residue was subjected to silica gel flash chromatography eluting with 0-100% EtOAc in hexanes to provide 51a. '' LCMS (m/z): 453.33 (M+H". Synthesis of (R)-N-(2-((2-aminopyrido 3,2-dipyrimidin 4-yl)amino)hexyl)acetamide (51). 51a (60 mg, 0.133 mmol) was dissolved in TFA (3 mL). After 60 minutes, the mixture 15 was concentrated in vacuo. The residue was taken up in 51a. MeOH, filtered and concentrated in vacuo, to give the title compound 51 as its TFA salt. H NMR (400 MHz, MeOH d) 8.65 (dd, J–4.3, 1.5 Hz, 1H), 7.86-7.73 (m, 2H), 4.68 4.55 (m, 4H), 3.59 (dd, J=13.9, 4.3 Hz, 4H), 3.34-3.23 (m, 20 3H), 1.88 (s, 3H), 1.78-1.67 (m, 2H), 1.39 (ddd, J=7.7, 5.1, 2.4 Hz, 4H), 0.91 (ddt, J=8.3, 4.7, 3.0 Hz, 3H). 'F NMR (377 MHz, MeOH-d4) 8 -77.7. LCMS (m/z): 303.15 M+H"; to 0.68 min. (LC/MS HPLC method B). 25 EXAMPLE 52

(R)-norleucinol (0.5g, 4.3 mmol) was treated with BocO 30 (1.2 equiv, 5.2 mmol) and excess N,N-diisopropylethylam ine in DCM (20 mL). The reaction mixture was stirred for O MSC 3 hand then filtered through a silica gel plug. Removal of DCM, TEA the volatiles provided 51b as a crude residue that was used 35 O--- NH2 without further purification. LCMS (m/z): 218.23 M+H". H Compound 51b (0.7g, 3.22 mmol) was reacted with PPh. 51d (1.1 g, 3.9 mmol), phthalimide (573 mg, 3.9 mmol), and DIAD (810 mg, 4.0 mmol) in THF (30 mL). The mixture was stirred for 3 h, and then partitioned between EtOAc (200 40 mL) and water (200 mL). The organic layer was separated, washed with brine (100 mL), dried over NaSO, filtered O 4N HCI and concentrated in vacuo. The residue was subjected to > ls dioxane O NWX n1S silica gel chromatography eluting with 0-100% EtOAc in H so hexanes to provide 51c. LCMS (m/z): 347.24 M+H". 45 O Imide 51c (300 mg. 0.87 mmol) was treated with excess hydrazine hydrate (0.2 mL, 6.25 mmol) in EtOH (30 mL) 52b and refluxed for 16 h. The mixture was concentrated in vacuo to provide intermediate 51d as a crude residue that was carried forward directly. Intermediate 51d (0.87 mmol) 50 was dissolved in DCM (10 mL) and treated with AcCl (0.1 mL, 1.2 mmol), followed by TEA (0.26 mL, 1.8 mmol). The mixture was stirred for 3 h, and then the reaction was diluted HN' Ns S. with DCM (50 mL). The mixture was then washed with HCI |no water (50 mL), brine (50 mL), dried over NaSO, filtered 55 O and then concentrated under reduced pressure to provide 52c

51e. LCMS (m/z): 259.21 M+H". Intermediate 51e (0.3 g) was treated with 4N HCl in dioxanes (20 mL) and stirred for 4 hat rt. The volatiles were (i-Pr).NEt; then removed in vacuo to provide the hydrochloride 51f which --e-1. was used without further purification. LCMS (m/z): 159.45 M+H". Synthesis of (R)-N-(2-((2-(2,4-dimethoxybenzyl)amino) pyrido3.2-dpyrimidin-4-yl)amino)hexyl)acetamide (51a). A solution of 2,4-dichloropyrido3.2-dpyrimidine (100 mg. 65 0.5 mmol) in THF (2 mL was treated with 51f. (200 mg, 0.53 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.15 US 9,670,205 B2 193 194 -continued (m,3H). 'F NMR (377 MHz, MeOH-d4) & -77.7. LCMS (m/z): 339.21 M+H"; to 0.83 min. (LC/MS HPLC method B). EXAMPLE 53 Ns 1. O TFA 2 -- o1 (i-Pr).NEt; then NH o1 SOMe HN 15 53A 52A

30 N-Boc-protected intermediate 51d (188 mg, 0.87 mmol) was dissolved in DCM (10 mL) and treated with methane sulfonyl chloride (0.78 uL, 114 mg, 1 mmol) and TEA (0.26 mL, 1.8 mmol). After 3 h, EtOAc (100 mL) was added and the resulting mixture washed with water (100 mL), brine 35 (100 mL), dried over NaSO, filtered and concentrated in vacuo to provide 52b. LCMS (m/z): 295.24 M+H". Following the synthesis of 51 ffrom 51e, intermediate 52b (0.87 mmol) was converted to the crude hydrochloride salt 52c which was then carried forward without purification. 40 Synthesis of (R)-N-(2-((2-(2,4-dimethoxybenzyl)amino) pyrido3.2-dpyrimidin-4-yl)amino)hexyl)methanesulfona mide (52A). A solution of 2,4-dichloropyrido 3,2-dipyrimi dine (50 mg, 0.25 mmol) in THF (2 mL) was treated with 45 crude 52c, (85 mg, 0.43 mmol) and N,N-diisopropylethyl amine (0.25 mL, 1.15 mmol). The mixture was stirred at rt Compound 61C (0.22 g, 0.69 mmol) was mesylated for 30 minutes, 2,4-dimethoxybenzylamine (0.19 mL, 1.25 following the procedure for the formation of 61D but instead mmol) and N,N-diisopropylethylamine (0.13 mL, 0.75 replacing acetyl chloride with methanesulfonyl chloride mmol) were added, and the mixture was heated to 115° C. 50 (0.06 mL, 0.8 mmol) to give a quantitative yield of the After 16 h, the reaction was cooled to rt, diluted with EtOAc corresponding mesylated intermediate. The resulting Sulfo (100 mL), washed with de-ionised water (100 mL), brine namide was then subjected to Pd/C hydrogenation followed (100 mL), dried over NaSO, filtered and concentrated in by N-BOC removal, as described in the preparation of 61E vacuo. The residue was Subjected to silica gel chromatog from 61D to give the crude product 53A as its hydrochloride 55 salt. LCMS (m/z): 209.1 M+H". raphy eluting with 0-100% EtOAc in hexanes to provide Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino) 52A. LCMS (m/z): 489.25 M+H". pyrido3.2-dpyrimidin-4-yl)amino)-2-methylhexyl)meth Synthesis of (R)-N-(2-((2-aminopyrido 3,2-dipyrimidin anesulfonamide (53B). A solution of 2,4-dichloropyrido3. 4-yl)amino)hexyl)methanesulfonamide (52). 52A (30 mg. 2-dpyrimidine (100 mg 0.5 mmol) in THF (4 mL) was 0.06 mmol) was dissolved in TFA (3 mL). After 60 minutes, 60 treated with crude 53A (0.69 mmol), and N,N-diisopropyl the mixture was concentrated in vacuo. The residue was then ethylamine (0.5 mL, 2.3 mmol). After heating at 75° C. for diluted with MeOH, filtered, and concentrated in vacuo to 4 h, 2,4-dimethoxybenzylamine (0.4 mL, 2.5 mmol) and afford the title product 52 as its TFA salt. "H NMR (400 additional N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) MHz, MeOH-d) & 8.65 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd. were added and the mixture was heated to 115° C. After 16 J=8.5, 1.4 Hz, 1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.58 (t, 65 h, the reaction was cooled to rt, diluted with EtOAc (100 J=6.1 Hz, 1H), 3.52-3.26 (m, 2H), 2.93 (s, 3H), 1.75 (dd. mL), washed with de-ionised water (100 mL), brine (100 J=9.6, 4.0 Hz, 2H), 1.39 (td, J=8.5, 7.6, 3.5 Hz, 4H), 0.91 mL), dried over NaSO, filtered and concentrated under