(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property (1) Organization11111111111111111111111I1111111111111i1111liiiii International Bureau (10) International Publication Number (43) International Publication Date W O 2019/161280 Al 22 August 2019 (22.08.2019) W IP0I PCT (51) InternationalPatent Classification: ve, Foster City, California 94404 (US). NGO, Vinh Xu C07D 401/14 (2006.01) C07D 401/12 (2006.01) an; 17179 Oak Street, Fountain Valley, California 92708 C07D 231/54(2006.01) CO7C45/61(2006.01) (US). O'KEEFE, Brian Michael; c/o Gilead Sciences, C07D 231/56 (2006.01) C07D 495/10 (2006.01) Inc., 333 Lakeside Drive, Foster City, California 94404 C07D 339/06 (2006.01) C07D 213/61 (2006.01) (US). RAINEY, Trevor James; c/o Gilead Sciences, Inc., 94404 (US). (21) International Application Number: 333 Lakeside Drive, Foster City, California PCT/US2019/018323 ROBERTS, Benjamin James; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). (22) International Filing Date: SHI, Bing; c/o Gilead Sciences, Inc., 333 Lakeside Dri 15 February 2019 (15.02.2019) ve, Foster City, California 94404 (US). STEINHUEBEL, Dietrich P.; c/o Gilead Sciences, Inc., 333 Lakeside Dri (25)FilingvLanguage: English e, Foster City, California 94404 (US). TSE, Winston C.; (26) Publication Language: English 801 Windblown Lane, Redwood City, California 94065 (US). WAGNER, Anna Michelle; c/o Gilead Sciences, (30) Priority Data: Inc., 333 Lakeside Drive, Foster City, California 94404 62/710,575 16February2018(16.02.2018) US (US). WANG, Xianghong; c/o Gilead Sciences, Inc., 333 (71) Applicant: GILEAD SCIENCES, INC. [US/US]; 333 Lakeside Drive, Foster City, California 94404 (US). WOL Lakeside Drive, Foster City, California 94404 (US). CKENHAUER, Scoff Alan; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). (72) Inventors: ALLAN, Kevin McCormack; c/o Gilead WONG, Chloe Yuyi; c/o Gilead Sciences, Inc., 333 Lake Sciences, Inc., 333 Lakeside Drive, Foster City, Califor- side Drive, Foster City, California 94404 (US). ZHANG, nia 94404 (US). BATTEN, Amanda Lynn; c/o Gilead Jennifer R.; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Sciences, Inc., 333 Lakeside Drive, Foster City, California FosterCity,California94404(US). 94404 (US). BRIZGYS, Gediminas; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (74) Agent: CHOI, Lydia B. et al.; Gilead Sciences, Inc., 333 (US). DHAR, Sachin; c/o Gilead Sciences, Inc., 333 Lake- Lakeside Drive, Foster City, California 94404 (US). side Drive, Foster City, California 94404 (US). DOXSEE, (81)DesignatedStates(unlessotherwiseindicated,forevery IanJames;doGileadSciences,Inc.,333LakesideDve' kind ofnational protection available): AE, AG, AL, AM, Foster City, California 94404 (US). GOLDBERG, Alex; c/ AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, California 94404 (US). HEUMANN, Lars V.; c/o Gilead DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, Sciences, Inc., 333 Lakeside Drive, Foster City, Califor- HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, nia 94404 (US). HUANG, Zilin; c/o Gilead Sciences, Inc., KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 333 Lakeside Drive, Foster City, California 94404 (US). MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, KADUNCE, Nathaniel Thomas; c/o Gilead Sciences, Inc., OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 333 Lakeside Drive, Foster City, California 94404 (US). SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, KAZERANI, Shahrokh; c/o Gilead Sciences, Inc., 333 TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Lakeside Drive, Foster City, California 94404 (US). LEW, Willard; c/o Gilead Sciences, Inc., 333 Lakeside Dri = (54) Title: METHODS AND INTERMEDIATES FOR PREPARING A THERAPEUTIC COMPOUND USEFUL IN THE TREAT MENT OF RETROVIRIDAE VIRAL INFECTION (57) Abstract: The present disclosure relates to methods and intermediates useful for preparing a compound of formula (I): (I) or a co-crystal, solvate, salt or combination there F F of. FA NH F, N N Me CF3 Me 'o W O 2019/161280 A11IIII I1 1111DI|I|||||||||||||||||||||||||H|||||||||||||||||||||||||||| (84) Designated States (unless otherwise indicated, for every kind of regionalprotection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: - as to applicant'sentitlement to apply for and be granteda patent (Rule 4.17(ii)) - as to the applicant'sentitlement to claim the priority of the earlier application (Rule 4.17(iii)) Published: - with internationalsearch report (Art. 21(3)) WO 2019/161280 PCT/US2019/018323 METHODS AND INTERMEDIATES FOR PREPARING A THERAPEUTIC COMPOUND USEFUL IN THE TREATMENT OF RETROVIRIDAE VIRAL INFECTION CROSS REFERENCE TO RELATED APPLICATIONS [0001] This Application claims the benefit of U.S. Provisional Application 62/710,575, filed on February 16, 2018, the entire content of which is hereby incorporated by reference in its entirety. FIELD [00021 The present disclosure relates to methods and intermediates for the synthesis of novel compounds for use in the treatment of a Reroviridae viral infection, including an infection caused by the HIV virus. BACKGROUND [00031 The present disclosure relates generally to the field of organic synthetic methodology for the preparation of antiviral compounds and their synthetic intermediates. [00041 Positive-single stranded RNA viruses comprising the Retroviridae family include those of the subfamily Orthoretrovirinae and genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus,Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human and animal diseases. Among the Lentivirus, IV-1 Iinfection in humans leads to depletion of T helper cells and immune dysfunction, producing immunodeficiency and vulnerability to opportunistic infections. Treating HIV-1 infections with highly active antiretroviral therapies (HAART) has proven to be effective at reducing viral load and significantly delaying disease progression (Hammer, S.M., et al.; JAMA 2008, 300: 555-570). However, these treatments could lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, B., InternationalJournal offnfetious diseasess 2009, 13:552-559; Smith, R. J., et al., Science 2010, 327:697-701). Therefore, there is a pressing need to discover and synthesize new antiretroviral agents that are active against emerging drug-resistant HIV variants. [0005] U S. Patent Application No. 15/680,041 discloses novel compounds useful for treating a Retroviridace viral infection, including an infection caused by the HIV virus. One specific compound identified therein is a compound of formula I: 1 WO 2019/161280 PCT/US2019/018323 F F F F N CI -- Y H N N Me F3 N F- Me- '0 [00061 There is currently a need for improved synthetic methods and intermediates that can be used to prepare the compound of formula I and co-crystals, solvates, salts, and combinations thereof There is also a need for improved methods for preparing intermediate compounds that can be used to prepare the compound of formula I and its co-crystals, solvates, salts, and combinations thereof. The improved methods and intermediates may reduce the cost, time, and/or the amount of waste associated with the existing methods for preparing the compound of formula I and co-crystals, solvates, salts, and combinations thereof SUMMARY [0007] In some embodiments, the present disclosure provides a process for making a compound of formula I: F F F F H N Ci -N H N N Me F3 /I F3 Me, 8O or a co-crystal, solvate, salt or combination thereof The compound of formula I may also be named or identified as: N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl) 1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5 difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. [0008] In some embodiments, disclosed herein is a process for preparing a compound of formula I: 2 WO 2019/161280 PCT/US2019/018323 F F F F A H N CI -NH F3 N N Me FF3 or a co-crystal, solvate, salt, or combination thereof, comprising: (a) combining a compound of formula VIII: F F H 2N Br NN Br VIII or a co-crystal, solvate, salt, or combination thereof, with a compound of formulaIX: Mei< IX or a co-crystal, solvate, or combination thereof, under alkynylation conditions to provide the compound of formula VI: F F H 2N Br NN Me' 8'0 VI or a co-crystal, solvate, salt, or combination thereof, (b) combining the compound of formula VI or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII: 3 WO 2019/161280 PCT/US2019/018323 F F OH F3 VII or a co-crystal, solvate, salt, or combination thereof, under amide coupling conditions to provide a compound of formula IV: F F F F H N _N N N NBr F3 Me%*O IV or aco-crystal, solvate, salt, or combination thereof; (c) combining the compound of formulaIV or aco-crystal, solvate, salt, or combination thereofwith acompound of formula V: cl RN NH2 ~F3 V or aco-crystal, solvate, salt, or combination thereofwherein Ris B(OH)2b, [B(OCH-(Me)CH 2 C(Me20), B((],2-di-O)C6 H4),B(OCH2LC(Me) 2 CH12 0), BF 4 K, B(O2CCH2N(Me)CH 2CO),or B(OC(Me) 2C(Me) 2 ), under palladium-catalyzed cross-coupling conditions to provide acompound of formula III: 4 WO 2019/161280 PCT/US2019/018323 F F F F H N Ci F 3 N NH2 F3 MeflO III or a co-crystal, solvate, salt, or combination thereof; and (d) combining the compound of formula II or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent under mesylating conditions to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.