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(2006.01) C07d 413/14 ( 2 (51) International Patent Classification: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, A61P 35/00 (2006.01) A61K 31/538 (2006.01) SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, C07D 413/14 (2006.01) A61K 31/5383 (2006.01) TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. C07D 498/04 (2006.01) (84) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of regional protection available) . ARIPO (BW, GH, PCT/US2020/033955 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (22) International Filing Date: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 2 1 May 2020 (21.05.2020) EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (25) Filing Language: English MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, (26) Publication Language: English KM, ML, MR, NE, SN, TD, TG). (30) Priority Data: 62/85 1,875 23 May 2019 (23.05.2019) US Declarations under Rule 4.17: — as to applicant's entitlement to apply for and be granted a (71) Applicant: GILEAD SCIENCES, INC. [US/US]; 333 patent (Rule 4.17(H)) Lakeside Drive, Foster City, California 94404 (US). — as to the applicant's entitlement to claim the priority of the (72) Inventors: AKTOUDIANAKIS, Evangelos; c/o Gilead earlier application (Rule 4.17(iii)) Sciences, Inc., 333 Lakeside Drive, Foster City, Califor¬ Published: nia 94404 (US). CHANDRASEKHAR, Jayaraman; c/ — with international search report (Art. 21(3)) o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). CODELLI, Julian A.; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, Califor¬ nia 94404 (US). CONWAY, John H.; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). ELBEL, Kristyna M.; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). KALLA, Rao V.; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). METOBO, Sa¬ muel E.; c/o Gilead Sciences Inc., 333 Lakeside Drive, Fos¬ ter City, California 94404 (US). MITCHELL, Scott A.; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, Cal¬ ifornia 94404 (US). PERRY, Thao; c/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). SIMONOVICH, Scott P.; c/o Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404 (US). ZIEBENHAUS, Christopher A.; c/o Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404 (US). (74) Agent: BAJPAI, Reena et al.; Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (54) Title: SUBSTITUTED EXO-METHYLENE-OXINDOLES WHICH ARE HPK1/MAP4K1 INHIBITORS (57) Abstract: The present disclosure relates generally to certain ene-oxindole compounds, pharmaceutical compositions comprising thereof. Also disclosed are methods of making and using said compounds and pharmaceutical compositions. The compounds and com¬ positions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by hematopoietic progenitor kinase 1 (HPKl) inhibitors, such as HBV, HIV, cancer, and/or a hyper-proliferative disease. SUBSTITUTED ENEOXINDOLES AND USES THEREOF CROSS REFERENCE [0001] This application claims priority to U.S. Provisional Application No. 62/851,875, filed May 23, 2019, which is incorporated herein in its entirety for all purposes. FIELD [0002] This disclosure relates generally to certain eneoxindole compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. BACKGROUND [0003] Immuno-oncology is an active area of cancer research, highlighted by inhibitor antibodies against the immune checkpoint receptors CTLA4, PD-1 and PD-L1. Targeted disruption of these checkpoint pathways releases the immune cell from key regulatory pathways, promoting an increase in immune responses against cancer cells. Current therapies utilizing these checkpoint inhibitors are highlighted by significant and durable responses to many different cancers. Unfortunately, these responses are often coupled to low overall response rates across patient populations (<25%). Improving these response rates is a formidable goal, and the combination of checkpoint blockade with other immune activating agents or cell based therapies could provide a useful tool for expanding patient responses. [0004] Hematopoietic progenitor kinase 1 (HPK1), a STE20 ser/thr kinase from the germinal center family of kinases, regulates the function of diverse immune populations including T cells, B cells, and dendritic cells (Hu et al., Gens Dev, 1996; Alzabin et al., J Immunol 2009). In T cells, HPK1 negatively regulates T cell receptor (TCR) signaling (Liou et al., Immunity 2000; Sauer et al., JBC 2001) by phosphorylating SLP76 on serine 376. Association of SLP76 with 14-3-3 protein subsequently leads to the disassociation of the signaling complex (Di Bartolo et al., JEM 2007). Further supporting the role of HPK1 as a negative regulator of TCR signaling, murine HPK1 deficient T cells or HPK1 kinase inactive mutant T cells have enhanced ERK 1/2 activation and effector cytokine secretion upon TCR activation compared to their wild-type counterparts (Shui et al., Nat Immunol 2007; Hernandez et al., Cell Reports 2018). Accordingly, a small molecule inhibitor of HPK1 could offer a method for increasing the response to checkpoint receptor blockade therapy. SUMMARY [0005] Disclosed herein are compounds of Formula I: or pharmaceutically acceptab A is N or CR1 ; 1 2 3 1 3 each R , R , and R is independently H, halogen,-CN, -N(R )2 , C1 -C3 alkyl, C1 - 1 3 C3 haloalkyl, C2 -C3 alkynyl, C1 -C3 alkoxy, or -SO2R , wherein the C2 -C3 alkynyl is unsubstituted or substituted with 1 , 2 , o r 3 R9 groups; one of B and E is and the other is J; J is H, -CN, C1 -C3 y , or C3 -C6 cycloalkyl; wherein the C1 -C3 alkyl or C3 -C6 cycloalkyl is unsubstituted or substituted with 1, 2, or 3 R1 0 groups; W is NR or S; X is N or CR5 ; Y is N or CR6 ; Z is N or CR7 ; X1 is NH; R4 is H; 5 6 7 8 each R , R , and R is independently H, halogen, -CN, -CON(R )2 , - 1 3 1 3 1 3 1 3 NR C(O)R , -SO2N(R )2 , C1 -C3 alkyl, C1 -C3 alkoxy, -N(R )2 , C3 -C6 cycloalkyl, C6 - C1 0 aryl, 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 4-6 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the C1 -C3 alkyl, C1 -C3 alkoxy, C3 -C6 cycloalkyl, C6 -C1 0 aryl, 5-10 membered heteroaryl, or 4-6 membered heterocyclyl is unsubstituted or substituted with 1, 2, or 3 R1 1 groups; or wherein R5 and R6 or R6 and R7 together with atoms to which they are attached form a phenyl or a 5-6 membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3 R1 1 groups; 8 each R is independently H or C1 -C3 alkyl, wherein the C1 -C3 alkyl is unsubstituted or substituted with 1, 2, or 3 R1 2 groups; or wherein two R8 groups together with the nitrogen they are attached to form a 4-6 membered heterocyclic ring having 1 or 2 heteroatoms selected from the group consisting of N, O, or S, wherein the 4-6 membered heterocyclic ring is unsubstituted or substituted with 1, 2, or 3 R1 2 groups; 9 1 3 each R is independently -OR , C1 -C3 alkyl, or C3 -C6 cycloalkyl; each R1 0 and R1 1 is independently selected from the group consisting of -OR1 3 , 8 8 1 3 1 3 1 3 halogen, CN, -N(R )2 , -CON(R )2 , -N(R )COR , -S(O)2 R , C1 -C3 alkyl, C3 -C6 cycloalkyl, 4-6 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C6 -C1 0 aryl, and 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; 1 2 1 3 1 3 each R is independently -OR , C1 -C3 alkyl, or -N(R )2 ; wherein the C1 -C3 alkyl is unsubstituted or substituted with 1, 2, or 3 groups independently selected from - 1 3 1 3 OR and -N(R )2 ; 1 3 each R is independently H or C1 -C3 alkyl, wherein the C1 -C3 alkyl is unsubstituted or substituted with 1, 2, or 3 R2 2 groups; each R2 2 is independently selected from the group consisting of halogen, -OH, C1 -C3 alkyl, C1 -C3 alkoxy, -NH2 , -NH(C1 -C3 alkyl), -N(C1 -C3 alkyl)2 wherein each C1 -C3 alkyl is same or different, C3 -C6 cycloalkyl, 4-6 membered heterocyclyl with 1, 2, or 3 heteroatoms selected from N, O, and S, C6 -C1 0 aryl, and 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; and is a group of formula: wherein L1 is N or CR1 9 ; n is 0, 1 or 2; m is 0, 1, or 2; p is 0,1, 2, 3, 4, 5, or 6; 1 9 1 3 1 3 R is H, -OR , halogen, CN, -N(R )2 , or C1 -C3 alkyl; 2 0 1 3 1 3 each R is independently -OR , halogen, CN, -N(R )2 , or C1 -C3 alkyl; and 2 1 1 3 1 3 each R is independently -OR , oxo, halogen, CN, -N(R )2 , or C1 -C3 alkyl; or two R2 1 groups on same or adjoining atoms are joined together to form a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring having 1 or 2 heteroatoms selected from N, O, and S.
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