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WO 2017/035230 Al 2 March 2017 (02.03.2017) P O P C T

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WO 2017/035230 Al 2 March 2017 (02.03.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/035230 Al 2 March 2017 (02.03.2017) P O P C T (51) International Patent Classification: (74) Agents: MARQUART, Timothy, A. et al; Gilead Sci C07D 487/04 (2006.01) A61P 31/12 (2006.01) ences, Inc., 333 Lakeside Drive, Foster City, CA 94404 A61K 31/519 (2006.01) (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2016/048396 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 24 August 2016 (24.08.2016) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/210,281 26 August 2015 (26.08.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: GILEAD SCIENCES, INC. [US/US]; 333 Lakeside Drive, Foster City, CA 94404 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: BONDY, Steven, S.; 4525 Une PI, Haiku, HI GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 96708 (US). MCFADDEN, Ryan; C/o Gilead Sciences, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Inc., 333 Lakeside Drive, Foster City, CA 94404 (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, [Continued on nextpage] (54) Title: DEUTERATED TOLL-LIKE RECEPTOR MODULATORS (57) Abstract: The present invention provides deuterated analogs of toll like receptor modulator compounds having the structures of formula (X) or (Y), processes for making those analogs, and their therapeutic methods of use. ' R H w o 2017/035230 Illlll II Hill lllll Hill llll I II III lllll Hill lllll Hill Hill ilimn i i llll SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, — as to the applicant's entitlement to claim the priority of GW, KM, ML, MR, NE, SN, TD, TG). the earlier application (Rule 4.1 ?'(in)) Declarations under Rule 4.17: Published: — as to applicant's entitlement to apply for and be granted — with international search report (Art. 21(3)) a patent (Rule 4.1 7(H)) DEUTERATED TOLL-LIKE RECEPTOR MODULATORS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 62/210281, filed August 26, 2015, which is incorporated herein in its entirety for all purposes. FIELD [0002] The present disclosure relates generally to deuterated analogs of toll like receptor modulator compounds, processes for making those analogs, and their therapeutic methods of use. BACKGROUND [0003] The innate immune system provides the body with a first line defense against invading pathogens. In an innate immune response, an invading pathogen is recognized by a germline-encoded receptor, the activation of which initiates a signaling cascade that leads to the induction of cytokine expression. Innate immune system receptors have broad specificity, recognizing molecular structures that are highly conserved among different pathogens. One family of these receptors is known as Toll-like receptors (TLRs), due to their homology with receptors that were first identified and named in Drosophila, and are present in cells such as macrophages, dendritic cells, and epithelial cells. [0004] There are at least ten different TLRs in mammals. Ligands and corresponding signaling cascades have been identified for some of these receptors. For example, TLR2 is activated by the lipoprotein of bacteria (e.g., E. coli.), TLR3 is activated by double-stranded RNA, TLR4 is activated by lipopolysaccharide (i.e., LPS or endotoxin) of Gram-negative bacteria (e.g., Salmonella and E. coli 0157:H7), TLR5 is activated by flagellin of motile bacteria (e.g., Listeria), TLR7 recognizes and responds to imiquimod and TLR9 is activated by unmethylated CpG sequences of pathogen DNA. The stimulation of each of these receptors leads to activation of the transcription factor NF-κΒ , and other signaling molecules that are involved in regulating the expression of cytokine genes, including those encoding tumor necrosis factor-alpha (TNF-a), interleukin-1 (IL-1), and certain chemokines. Agonists of TLR-7 are immunostimulants and induce the production of endogenous interferon-a in vivo. [0005] There are a number of diseases, disorders, and conditions linked to TLRs such that therapies using a TLR agonist are believed promising, including but not limited to melanoma, non-small cell lung carcinoma, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, hepatic fibrosis, and viral infections such as HBV, Flaviviridae viruses, HCV, HPV, RSV, SARS, HIV, or influenza [0006] The compound 4-amino-2-butoxy-8-(4-(pyrrolidin-l-ylmethyl)benzyl)-7,8- dihydropteridin-6(5H)-one (Compound (I)) and the compound 4-amino-2-butoxy-8-(3- (pyrrolidin-l-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound (II)), are each known to be a modulator of TLR-7, as described, for example, in U.S. Patent 8,367,670. Those compounds have the following structures: Compound (I) Compound (II) Those compounds have been studied for the treatment of various viral infections, including HCV, HBV, and HIV. However, deuterated analogs of the compound are not currently known. [0007] Deuteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles has been demonstrated previously with some classes of drugs. Increased levels of deuterium incorporation may affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of the compounds described therein. Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. For example, deuterated 4-amino-2-butoxy-8-(3-(pyrrolidin-l-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)- one and deuterated 4-amino-2-butoxy-8-(4-(pyrrolidin-l-yl)benzyl)-7,8-dihydropteridin- 6(5H)-one may have altered pharmacokinetic, pharmacologic and/or toxicologic profiles when compared to 4-amino-2-butoxy-8-(3-(pyrrolidin-l-ylmethyl)benzyl)-7,8- dihydropteridin-6(5H)-one and 4-amino-2-butoxy-8-(4-(pyrrolidin-l -yl)benzyl)-7,8- dihydropteridin-6(5H)-one having naturally occurring levels of deuterium. [0008] Provided herein are compounds of the formula r wherein: R^o R29 are each independently selected from hydrogen and deuterium, wherein at least one of R1 to R29 is deuterium; or a pharmaceutically acceptable salt, isomer, or mixture thereof. [0009] Also provided are pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, isomer, or mixture thereof, and a pharmaceutically acceptable excipient. [0010] Also provided is a method of treating or preventing a disease or condition responsive to the modulation of TLR-7, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, isomer, or mixture thereof. [0011]Also provided is a method of treating or preventing a disease or condition responsive to the modulation of TLR-7, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, isomer, or mixture thereof, and at least one additional therapeutic agent. [0012] Kits comprising the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the foregoing are also provided. Articles of manufacture comprising a unit dose of the compounds, or pharmaceutically acceptable salts thereof, of the foregoing are also provided. Methods of preparing compounds of the present disclosure are also provided. DETAILED DESCRIPTION [0013] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. [0014] The present application provides pharmaceutically acceptable salts, hydrates, solvates, isomers, tautomers, stereoisomers, enantiomers, racemates, atropisomers, polymorphs, prodrugs, or a mixture thereof, of the compounds described herein. [0015] "Pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" refer to salts of pharmaceutical compounds that retain the biological effectiveness and properties of the underlying compound, and which are not biologically or otherwise undesirable. There are acid addition salts and base addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Acids and bases useful for reaction with an underlying compound to form pharmaceutically acceptable salts (acid addition or base addition salts respectively) are known to one of skill in the art. Similarly, methods of preparing pharmaceutically acceptable salts from an underlying compound (upon disclosure) are known to one of skill in the art and are disclosed in for example, Berge, at al.
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