Substituted 6-azabenzimidazole compounds as HPK1 inhibitors

Abstract

The present disclosure relates generally to certain 6-azabenzimidazole compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by hematopoietic progenitor kinase 1 (HPK1) inhibitors, such as HBV, HIV, cancer, and / or a hyper-proliferative disease.

Description

(19) *EP004671244A1* (11) EP 4 671 244 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 31.12.2025 Bulletin 2026 / 01 (21) Application number: 25201731.4 (22) Date of filing: 30.10.2019 (51) International Patent Classification (IPC): C07D 471 / 04 (2006.01) C07D 519 / 00 (2006.01) A61P 35 / 00 (2006.01) A61P 31 / 18 (2006.01) A61P 31 / 20 (2006.01) A61K 31 / 437 (2006.01) (52) Cooperative Patent Classification (CPC): C07D 471 / 04; A61P 31 / 18; A61P 31 / 20; A61P 35 / 00; C07D 519 / 00 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 31.10.2018 US 201862753339 P 28.06.2019 US 201962868550 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 24150846.4 / 4 371 987 19813990.9 / 3 873 903 (71) Applicant: Gilead Sciences, Inc. Foster City, CA 94404 (US) (72) Inventors: • BALAN, Gayatri Foster City, 94404 (US) • BARTLETT, Mark, J. Foster City, 94404 (US) • CHANDRASEKHAR, Jayaraman Foster City, 94404 (US) • CODELLI, Julian A. Foster City, 94404 (US) • CONWAY, John H. Foster City, 94404 (US) • COSMAN, Jennifer L. Foster City, 94404 (US) • KALLA, Rao V. Foster City, 94404 (US) • KASUN, Zachary A. Foster City, 94404 (US) • KIM, Musong Foster City, 94404 (US) • LEE, Seung H. Foster City, 94404 (US) • LO, Jennifer R. Foster City, 94404 (US) • LOYER-DREW, Jennifer A. Foster City, 94404 (US) • MITCHELL, Scott A. Kenmore, 98028 (US) • PERRY, Thao D. Foster City, 94404 (US) • PHILLIPS, Gary B. Issaquah, 98029 (US) • SALVO, Patrick J. Foster City, 94404 (US) • SWAMINATHAN, Sundaramoorthi Foster City, 94404 (US) • VAN VELDHUIZEN, Joshua J. Foster City, 94404 (US) • YEUNG, Suet, C. Foster City, 94404 (US) • ZABLOCKI, Jeff Los Altos, 94022 (US) (74) Representative: Müller, Christian Stefan Gerd ZSP Patentanwälte PartG mbB Hansastraße 32 80686 München (DE) Remarks: •This application was filed on 11‑09‑2025 as a divisional application to the application mentioned under INID code 62. •Claims filed after the date of filing of the application / after the date of receipt of the divisional application (Rule 68(4) EPC) (54) SUBSTITUTED 6‑AZABENZIMIDAZOLE COMPOUNDS AS HPK1 INHIBITORS (57) The present disclosure relates generally to cer- tain 6-azabenzimidazole compounds, pharmaceutical compositions comprising said compounds, andmethods of making and using said compounds and pharmaceu- tical compositions. The compounds and compositions disclosed herein may be used for the treatment or pre- ventionofdiseases, disorders, or infectionsmodifiableby hematopoietic progenitor kinase 1 (HPK1) inhibitors, such as HBV, HIV, cancer, and / or a hyper-proliferative disease. EP 4 67 1 24 4 A 1 Processed by Luminess, 75001 PARIS (FR) Description CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62 / 753,339, filed October 31, 2018 and U.S. Provisional Application No. 62 / 868,550, filed June 28, 2019, each of which is incorporated herein in its entirety for all purposes. FIELD

[0002] This disclosure relates generally to certain 6-azabenzimidazole compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. BACKGROUND

[0003] Immuno-oncology is a burgeoning 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, allowing for a boost in the immune response against cancer cells. Current therapies utilizing these antibodies are highlighted by both significant and durable response tomany different cancers but also by low overall response rates (<25%). Understanding and 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 an inroad to expand upon 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 Tcells, B cells, and dendritic cells (Hu et al., Gens Dev, 1996; Alzabin et al., J Immunol 2009). In Tcells, HPK1 serves as a negative regulator of Tcell receptor (TCR) signaling (Liou et al., Immunity 2000; Sauer et al., JBC 2001) by phosphorylating SLP76 on serine 376, which induces the association of SLP76with 14‑3‑3 proteins, and leads to the disassociation of the signaling complex (Di Bartolo et al., JEM 2007).Further supporting the roleofHPK1asanegative regulator ofTCRsignaling,murineHPK1deficientTcellsorHPK1 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 provide a novel way to enhance anti-tumor immunity and also provide a way to increase the response to checkpoint receptor blockade. SUMMARY

[0005] In one aspect, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: one of R1 and R2 is H, ‑CN, ‑OH, halogen, or C1‑6 alkyl, and the other of R1 and R2 is H, halogen, or C1‑6 alkyl, wherein eachC1‑6 alkyl is optionally substitutedwith1‑3groups independently selected from ‑OHandhalogen, or 2 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 R1 and R2 together with the carbon to which they are attached form a C3‑7 monocyclic cycloalkyl or a 4‑6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, andS,wherein the C3‑7 monocyclic cycloalkyl and the 4‑6 membered monocyclic heterocyclyl are each optionally substituted with oneR11 and are each optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, or R1 and R2 together form =O; R11 is i) 4‑6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, ii) ‑S(O)2C1‑6 alkyl, iii) ‑S(O)2C3‑7 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or v) ‑C(O)R21; R21 is i) H, ii) C3‑7 monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, iii) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iv) 5‑6 membered monocyclic heteroaryl having 1‑4 heteroatoms independently selected from N, O, and S, wherein the 5‑6 membered monocyclic heteroaryl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, v) ‑NH2, vi) ‑NH(C1‑6 alkyl), wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, vii) ‑N(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, viii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, or ix) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, d) C1‑3 alkoxy, e) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from -CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, f) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, and g) ‑OC(O)C1‑6 alkyl optionally substituted with one ‑OH; R3 and R13 are each H, or R3 and R13 together form =O; L1 is a cyclobutylene optionally substitutedwith 1‑6 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; X is ‑NR15R16, wherein R15 and R16 are independently i) H, ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, 3 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, d) C1‑3 alkoxy, e) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, and f) 5‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 5‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; or X is a 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18; each R18 is independently i) ‑CN, ii) a halogen, iii) ‑OH, iv) C1‑6 alkoxy optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, v) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, vi) ‑COOH, or vii)‑C(O)N(R22)2, wherein each R22 is independently H or C1‑6 alkyl; X1 is N or CR17; R4, R5, R6, R10 and R17 are each independently H, halogen, C1‑3 alkyl, or C1‑3 alkoxy; R7 is i) H, ii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or iii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; Z is ‑O‑, ‑C(R8)2‑, or ‑NR8‑; each R8 is independently H or C1‑3 alkyl; R9a, R9b, R9c, R9d, and R9e are independently i) H, ii) halogen, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, iv) ‑NH2, v) ‑NH(C1‑6alkyl),wherein theC1‑6alkyl isoptionally substitutedwith1‑3groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, vi) ‑N(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different, and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, vii) ‑P(O)(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different, and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, viii) ‑S(O)2C1‑6 alkyl, 4 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 ix) ‑S(O)2N(R23)2, wherein each R23 is independently H or C1‑6 alkyl, x) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑OH, b) halogen, c) C1‑3 alkoxy, d) C3‑7 monocyclic cycloalkyl, e) 5‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 5‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from oxo and C1‑3 alkyl, and f) ‑NR20C(O)OC1‑3 alkyl, wherein R20 is H or C1‑3 alkyl, xi) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, xii) 5‑6memberedmonocyclic heteroaryl having 1‑4 heteroatoms independently selected fromN, O, and S, wherein the 5‑6 membered monocyclic heteroaryl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, xiii) 4‑6 membered monocyclic heterocyclyl having 1‑3 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, xiv) ‑COOH, xv) ‑C(O)N(R19)2, or xvi) ‑C1‑3 alkylC(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2 or ‑C1‑3 alkylC(O)N(R19)2; and each R19 is independently i) H, ii) ‑S(O)2C1‑6 alkyl, iii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, iv) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑6 alkyl, and C1‑6 alkoxy, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) 4‑6memberedmonocyclic heterocyclyl having 1‑3 heteroatoms independently selected fromN,O, andS, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy.

[0006] In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0007] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0008] In one aspect, the present disclosure provides methods of inhibiting HPK1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0009] In one aspect, the present disclosure provides methods of treating a disease or disorder associated with increased HPK1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0010] In oneaspect, thepresent disclosureprovidesmethodsof increasingT-cell activation inasubject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a 5 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0011] In oneaspect, thepresent disclosureprovidesmethodsof treatingcancer in asubject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0012] In one aspect, the present disclosure providesmethods of inhibiting the growth or proliferation of cancer cells in a subject inneed thereof, comprisingadministering to thesubject a therapeuticallyeffectiveamountof acompoundprovided herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. DETAILED DESCRIPTION I. Definitions

[0013] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subjectmatter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0015] As used in the present disclosure, the following words, phrases and symbols 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.

[0016] A dash ("‑") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, ‑CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groupsmay be depictedwith orwithout one ormore dasheswithout losing their ordinarymeaning. Awavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. A solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom. For example,Ra in the below structure can be attached to any of the five carbon ring atomsorR3 can replace the hydrogen attached to the nitrogen ring atom:

[0017] The prefix "Cu-v" indicates that the following group has from u to v carbon atoms. For example, "C1‑6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term "x-y membered" rings, wherein x and y are numerical ranges, suchas "3 to12-memberedheterocyclyl", refers toa ringcontainingx-yatoms (e.g.,3‑12), ofwhichup to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0018] Also, certain commonly usedalternative chemical namesmayormaynot beused. For example, a divalent group suchasadivalent "alkyl" group, a divalent "aryl" group, etc.,mayalsobe referred to asan "alkylene" groupor an "alkylenyl" group, or alkylyl group, an "arylene" group or an "arylenyl" group, or arylyl group, respectively.

[0019] "A compound disclosed herein" or "a compound of the present disclosure" or "a compound provided herein" or "a compounddescribed herein" refers to the compoundsof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb,Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc. Also included are the specific compounds of Examples 1 to 297.

[0020] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Also, the term "about X" includes description of "X".

[0021] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e.,C1‑20 alkyl), 1 to 8 carbon atoms (i.e.,C1‑8 alkyl), 1 to 6 carbon atoms (i.e.,C1‑6 alkyl), or 1 to 4 carbon atoms (i.e.,C1‑4 alkyl). Examples of alkyl groups includemethyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having 6 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 that numberof carbonsmaybeencompassed; thus, for example, "butyl" includesn-butyl (i.e., ‑(CH2)3CH3), sec-butyl (i.e., - CH(CH3)CH2CH3), isobutyl (i.e., ‑CH2CH(CH3)2) and tert-butyl (i.e., ‑C(CH3)3); and "propyl" includes n-propyl (i.e., ‑(CH2)2CH3) and isopropyl (i.e., ‑CH(CH3)2).

[0022] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2‑20 alkenyl), 2 to 8 carbon atoms (i.e., C2‑8 alkenyl), 2 to 6 carbon atoms (i.e., C2‑6 alkenyl), or 2 to 4 carbon atoms (i.e., C2‑4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2- butadienyl and 1,3-butadienyl).

[0023] "Alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2‑20 alkynyl), 2 to 8 carbon atoms (i.e., C2‑8 alkynyl), 2 to 6 carbon atoms (i.e., C2‑6 alkynyl), or 2 to 4 carbon atoms (i.e., C2‑4 alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0024] "Alkoxy" refers to the group "alkyl-O‑". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. "Haloalkoxy" refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0025] "Acyl" refers to a group ‑C(=O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0026] "Amido" refers to both a "C-amido" group which refers to the group ‑C(=O)NRyRz and an "N-amido" group which refers to the group ‑NRyC(=O)Rz, wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0027] "Amino" refers to the group ‑NRyRz wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0028] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6‑20 aryl), 6 to 12 carbon ring atoms (i.e., C6‑12 aryl), or 6 to 10 carbon ring atoms (i.e., C6‑10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in anywaywith heteroaryl definedbelow. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.

[0029] "Cyano" or "carbonitrile" refers to the group ‑CN.

[0030] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from3 to 20 ring carbon atoms (i.e., C3‑20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3‑12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3‑10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3‑8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3‑6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] "Bridged" refers toa ring fusionwhereinnon-adjacentatomsona ringare joinedbyadivalent substituent, suchas alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0032] The term "fused" refers to a ring which is bound to an adjacent ring.

[0033] "Spiro" refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl‑4-methylpiperidine,wherein the cyclopentane and piperidine, respectively, are the spiro substituents.

[0034] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0035] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected fromnitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C1‑20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C3‑12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3‑8 heteroaryl); and1 to5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ringheteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompassor overlapwith aryl as defined above.

[0036] "Heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a non-aromatic cyclic alkyl group, with one ormore ring heteroatoms independently selected fromnitrogen, oxygen and sulfur. As used herein, "heterocyclyl" or "heterocyclic ring" or "heterocycle" refer to rings that are saturated or partially saturated unless otherwise indicated, e.g., in some embodiments "heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to rings that are partially saturated where 7 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 specified. The term "heterocyclyl" or "heterocyclic ring" or "heterocycle" includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond). A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms (i.e., C2‑20 heterocyclyl), 2 to 12 carbon ring atoms (i.e., C2‑12 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C2‑10 heterocyclyl), 2 to 8 carbon ring atoms (i.e., C2‑8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C3‑12 heterocyclyl), 3 to 8 carbon ring atoms (i.e., C3‑8 heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C3‑6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected fromnitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged- heterocyclyl" refers to a four- to ten-membered cyclic moiety connectedat twonon-adjacent atomsof theheterocyclylwith oneormore (e.g.,1or2) four‑ to ten-memberedcyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, "bridged-heterocyclyl" includes bicyclic and tricyclic ring systems. Also as used herein, the term "spiro-heterocyclyl" refers to a ring system inwhich a three‑ to ten-memberedheterocyclyl hasoneormoreadditional ring, wherein the one or more additional ring is three‑ to ten-membered cycloalkyl or three‑ to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three‑ to ten-membered heterocyclyl. Examples of the spiro‑ heterocyclyl include bicyclic and tricyclic ring systems, such as 2-oxa‑7-azaspiro[3.5]nonanyl, 2- oxa‑6-azaspiro[3.4]octanyl, and 6-oxa‑1-azaspiro[3.3]heptanyl. As used herein, the terms "heterocycle", "heterocyclyl", and "heterocyclic ring" are used interchangeably. In some embodiments, a heterocyclyl is substituted with an oxo group.

[0037] "Hydroxy" or "hydroxyl" refers to the group ‑OH.

[0038] "Oxo" refers to the group (=O) or (O).

[0039] "Sulfonyl" refers to the group ‑S(O)2Rc, where Rc is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0040] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group representsan ‑NHgroupunlessotherwise indicated.Similarly, unlessotherwiseexpressed, hydrogenatom(s) are implied and deemed present where necessary in view of the knowledge of one of skill in the art to complete valency or provide stability.

[0041] The terms "optional" or "optionally"mean that the subsequently described event or circumstancemayormaynot occur, and that the description includes instanceswhere said event or circumstance occurs and instances in which it does not. Also, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0042] The term "substituted"means that any one ormore hydrogen atoms on the designated atomor group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.When used tomodify a chemical group, the term "substituted"may describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

[0043] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "sub- stituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl; "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to an heteroaryl group having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano and "substituted sulfonyl" refers to a group ‑S(O)2R, in which R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each ofwhich is substituted. In other embodiments, the substituentsmaybe further substitutedwith halo, alkyl, 8 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0044] In someembodiments, asubstitutedcycloalkyl, a substitutedheterocyclyl, a substitutedaryl, and / or asubstituted heteroaryl includes a cycloalkyl, a heterocyclyl, an aryl, and / or a heteroaryl that has a substituent on the ring atom towhich the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl is attached to the rest of the compound. For example, in the below moiety, the cyclopropyl is substituted with a methyl group:

[0045] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)‑ or (S)‑ or, as (D)‑ or (L)‑ for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (‑), (R)‑ and (S)‑, or (D)‑ and (L)‑ isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, "scalemic mixture" is a mixture of stereoisomers at a ratio other than 1: 1.

[0046] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers andmixtures thereof and includes "enantiomers", which refers to two stereoisomers whosemolecules are non-superimposable mirror images of one another.

[0047] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers at a ratio other than 1: 1 is a "scalemic" mixture.

[0048] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other.

[0049] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compounds provided herein.

[0050] Someof the compounds provided herein exist as tautomeric isomers. Tautomeric isomers are in equilibriumwith oneanother.For example, amidecontainingcompoundsmayexist inequilibriumwith imidic acid tautomers.Regardlessof which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0051] A"solvate" is formedby the interactionof a solvent andacompound.Solvatesof salts of the compoundsprovided herein are also provided. Hydrates of the compounds provided herein are also provided.

[0052] Any formula or structure provided herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 2H, 3H, 13C and 14C are incorporated, are also provided herein. Such isotopically labelled compoundsmaybeuseful inmetabolic studies, reaction kinetic studies, detection or imaging techniques, suchas positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0053] Thepresent disclosure also includes compoundsof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc inwhich from1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and 9 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 are thus useful for increasing the half-life of any compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524‑527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0054] Deuterium labelled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivohalf-life, reduceddosage requirementsand / oran improvement in therapeutic index. An 18F labeled compoundmay be useful for PETor SPECTstudies. Isotopically labeled compounds of this disclosure andprodrugs thereof cangenerally bepreparedby carryingout theproceduresdisclosed in the schemesor in theexamplesandpreparationsdescribedbelowbysubstitutinga readily available isotopically labeled reagent for anon- isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc.

[0055] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure, any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0056] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0057] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharma- ceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substitutedalkyl amines, di(substitutedalkyl) amines, tri(substitutedalkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(sub- stitutedalkenyl) amines,mono, di or tri cycloalkyl amines,mono, di or tri arylamines ormixedamines, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso- propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethyl- piperidine, and the like.

[0058] Pharmaceuticallyacceptableacidadditionsaltsmaybeprepared from inorganicandorganicacids.Saltsderived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0059] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersionmedia, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0060] "Treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one ormore symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0061] "Prevention" or "preventing" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compoundsmay, in someembodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0062] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0063] The term "therapeutically effective amount" or "effective amount" of a compound described herein or pharma- 10 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 ceutically acceptable salts, isomer, or amixture thereofmeans an amount sufficient to effect treatmentwhen administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amountmay be an amount sufficient to decrease a symptomof a disease or condition responsive to inhibition of hematopoietic progenitor kinase 1 (HPK1) activity. The therapeutically effective amount may vary dependingon the subject, and thediseaseor conditionbeing treated, theweight andageof the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0064] The term "inhibition" indicates a decrease in the baseline activity of a biological activity or process. "Inhibition of activity of HPK1" or variants thereof refers to a decrease inHPK1activity as a direct or indirect response to the presence of a compound of the present disclosure relative to the HPK1 activity in the absence of the compound of the present disclosure. "Inhibition of HPK1" refers to a decrease in HPK1 activity as a direct or indirect response to the presence of a compound provided herein relative to the HPK1 activity in the absence of the compound provided herein. In some embodiments, the inhibition ofHPK1activitymaybe compared in the samesubject prior to treatment, or other subjects not receiving the treatment. II. Compounds

[0065] In one aspect, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: one of R1 and R2 is H, ‑CN, ‑OH, halogen, or C1‑6 alkyl, and the other of R1 and R2 is H, halogen, or C1‑6 alkyl, wherein eachC1‑6 alkyl is optionally substitutedwith1‑3groups independently selected from ‑OHandhalogen, or R1 and R2 together with the carbon to which they are attached form a C3‑7 monocyclic cycloalkyl or a 4‑6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, andS,wherein the C3‑7 monocyclic cycloalkyl and the 4‑6 membered monocyclic heterocyclyl are each optionally substituted with oneR11 and are each optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, or R1 and R2 together form =O; R11 is i) 4‑6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, ii) ‑S(O)2C1‑6 alkyl, iii) ‑S(O)2C3‑7 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or v) ‑C(O)R21; R21 is 11 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 i) H, ii) C3‑7 monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, iii) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iv) 5‑6 membered monocyclic heteroaryl having 1‑4 heteroatoms independently selected from N, O, and S, wherein the 5‑6 membered monocyclic heteroaryl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, v) ‑NH2, vi) ‑NH(C1‑6 alkyl), wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, vii) ‑N(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, viii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, or ix) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, d) C1‑3 alkoxy, e) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, f) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, and g) ‑OC(O)C1‑6 alkyl optionally substituted with one ‑OH; R3 and R13 are each H, or R3 and R13 together form =O; L1 is a cyclobutylene optionally substitutedwith 1‑6 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; X is ‑NR15R16, wherein R15 and R16 are independently i) H, ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, d) C1‑3 alkoxy, e) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, and f) 5‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 5‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from -OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; or X is a 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑10 membered monocyclic, fused bicyclic, 12 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18; each R18 is independently i) ‑CN, ii) a halogen, iii) ‑OH, iv) C1‑6 alkoxy optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, v) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, vi) ‑COOH, or vii)‑C(O)N(R22)2, wherein each R22 is independently H or C1‑6 alkyl; X1 is N or CR17; R4, R5, R6, R10 and R17 are each independently H, halogen, C1‑3 alkyl, or C1‑3 alkoxy; R7 is i) H, ii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or iii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; Z is ‑O‑, ‑C(R8)2‑, or ‑NR8‑; each R8 is independently H or C1‑3 alkyl; R9a, R9b, R9c, R9a, and R9e are independently i) H, ii) halogen, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, iv) ‑NH2, v) ‑NH(C1‑6alkyl),wherein theC1‑6alkyl isoptionally substitutedwith1‑3groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, vi) ‑N(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different, and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, vii) ‑P(O)(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different, and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, viii) ‑S(O)2C1‑6 alkyl, ix) ‑S(O)2N(R23)2, wherein each R23 is independently H or C1‑6 alkyl, x) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑OH, b) halogen, c) C1‑3 alkoxy, d) C3‑7 monocyclic cycloalkyl, e) 5‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 5‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from oxo and C1‑3 alkyl, and f) ‑NR20C(O)OC1‑3 alkyl, wherein R20 is H or C1‑3 alkyl, xi) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, xii) 5‑6memberedmonocyclic heteroaryl having 1‑4 heteroatoms independently selected fromN, O, and S, wherein the 5‑6 membered monocyclic heteroaryl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, xiii) 4‑6 membered monocyclic heterocyclyl having 1‑3 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- 13 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 dently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, xiv) ‑COOH, xv) ‑C(O)N(R19)2, or xvi) ‑C1‑3 alkylC(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2 or ‑C1‑3 alkylC(O)N(R19)2; and each R19 is independently i) H, ii) ‑S(O)2C1‑6 alkyl, iii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, iv) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑6 alkyl, and C1‑6 alkoxy, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) 4‑6memberedmonocyclic heterocyclyl having 1‑3 heteroatoms independently selected fromN,O, andS, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy.

[0066] In some embodiments, the compound of Formula I is of Formula II, or a pharmaceutically acceptable salt thereof, wherein each R12 is independently ‑OH, halogen, C1‑3 alkyl, or C1‑3 alkoxy; and n is 0, 1, 2, 3, or 4; and the remaining variables are as defined as in Formula I.

[0067] In some embodiments, the compound of Formula I or II is of Formula IIa, 14 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in Formula I.

[0068] In some embodiments, the compound of Formula I, II or IIa is of Formula IIb: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in Formula I.

[0069] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, L1 is a cyclobutyleneoptionally substitutedwith1, 2, 3, 4, 5, or 6groups independently selected from ‑OH,halogen,C1‑3alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, L1 is a cyclobutylene. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, L1 is a cyclobutylene substituted with one C1‑3 alkyl group. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, L1 is a cyclobutylene substituted with one methyl group.

[0070] In some embodiments of the compound of Formula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R12 is OH. In some embodiments of the compound of Formula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R12 is halogen. In some embodiments of the compound of Formula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R12 isC1‑3 alkyl. In someembodiments of the compoundof Formula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R12 is C1‑3 alkoxy. In some embodiments of the compound of Formula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R12 is methyl.

[0071] In some embodiments of the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, n is 0, 1, 2, 3,or 4. In someembodimentsof thecompoundofFormula II or IIa, orapharmaceutically acceptablesalt thereof, n is0, 1, 2, or3. In someembodimentsof thecompoundofFormula II or IIa, orapharmaceutically acceptablesalt thereof, n is0, 1, or 2. In someembodimentsof thecompoundofFormula II or IIa, or a pharmaceutically acceptable salt thereof, n is 0or 1. In some embodiments of the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, n is 0. In some embodiments of the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, n is 1. In some embodiments of the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, n is 2. In some embodiments of the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, n is 3. In some embodiments of the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, n is 4.

[0072] In someembodimentsof thecompoundofFormula II, IIa, or IIb, or apharmaceutically acceptable salt thereof, n is 1 and R12 is C1‑3 alkyl. In some embodiments of the compound of Formula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, n is 1 andR12 ismethyl. In someembodiments of the compound of Formula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, n is 1 and R12 is C1‑3 alkyl. In some embodiments of the compound of Formula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, n is 1 and R12 is methyl.

[0073] In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R4 isH. In someembodiments of the compoundof Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R4 ishalogen. In someembodimentsof thecompoundofFormula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R4 is fluoro. In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof,R4 isC1‑3 alkyl. In someembodimentsof thecompoundofFormula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R4 is C1‑3 alkoxy.

[0074] In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R5 isH. In someembodiments of the compoundof Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R5 ishalogen. In someembodimentsof thecompoundofFormula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R5 is C1‑3 alkyl. In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R5 is C1‑3 alkoxy.

[0075] In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R6 isH. In someembodiments of the compoundof Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R6 15 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 is halogen. In someembodimentsof thecompoundofFormula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R6 is C1‑3 alkyl. In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R6 is C1‑3 alkoxy.

[0076] In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R10 is H. In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R10 is halogen. In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R10 is C1‑3 alkyl. In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R10 is C1‑3 alkoxy.

[0077] In some embodiments of the compound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptable salt thereof, R4, R5, R6, and R10 are H.

[0078] In some embodiments, the compound of Formula I, II, or IIa is of Formula III, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in Formula I.

[0079] In some embodiments, the compound of Formula I, II, IIa, IIb, and III is of Formula IIIa: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in Formula I.

[0080] In some embodiments, the compound of Formula I, II, or IIa is of Formula III, 16 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein: one of R1 and R2 is ‑OH, halogen or C1‑3 alkyl, and the other of R1 and R2 is halogen or C1‑3 alkyl, or R1 and R2 together with the carbon to which they are attached form a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; R11 is i) 4‑6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from -CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, ii) ‑S(O)2C1‑3 alkyl, iii) ‑S(O)2C3‑5 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or v) ‑C(O)R21; R21 is i)C3‑7monocyclic or bridgedbicyclic cycloalkyl optionally substitutedwith1‑3groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, ii) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, or iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, and d) C1‑3 alkoxy, R3 and R13 are each H, or R3 and R13 together form =O; n is 0 or 1; R12 is C1‑3 alkyl; X is ‑NR15R16, wherein R15 and R16 are independently i) H, 17 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑7 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from g) ‑OH, h) halogen, and i) C1‑3 alkoxy; or X is a 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18; each R18 is independently i) a halogen, ii) ‑OH, or iii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; X1 is N or CH; R7 is i)C1‑6alkyl optionally substitutedwith1‑3groups independently selected from ‑OH,halogen,C1‑3alkoxy,and C3‑7 monocyclic cycloalkyl, or ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; Z is ‑O‑ or NH; R9a, R9b, R9c, R9a, and R9e are independently i) H, ii) halogen, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, v) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from -OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, or vi) ‑C(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2; each R19 is independently i) H, ii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or iii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0081] In some embodiments, the compound of Formula I, II, IIa, IIb or III is of Formula IIIa: 18 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein: one of R1 and R2 is ‑OH, halogen or C1‑3 alkyl, and the other of R1 and R2 is halogen or C1‑3 alkyl, or R1 and R2 together with the carbon to which they are attached form a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; R11 is i) 4‑6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from -CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, ii) ‑S(O)2C1‑3 alkyl, iii) ‑S(O)2C3‑5 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or v) ‑C(O)R21; R21 is i)C3‑7monocyclic or bridgedbicyclic cycloalkyl optionally substitutedwith1‑3groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, ii) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, or iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, and d) C1‑3 alkoxy, R3 and R13 are each H, or R3 and R13 together form =O; R12 is C1‑3 alkyl; X is ‑NR15R16, wherein R15 and R16 are independently i) H, 19 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑7 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from -OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from a) ‑OH, b) halogen, and c) C1‑3 alkoxy; or X is a 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18; each R18 is independently i) a halogen, ii) ‑OH, or iii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; X1 is N or CH; R7 is i)C1‑6alkyl optionally substitutedwith1‑3groups independently selected from ‑OH,halogen,C1‑3alkoxy,and C3‑7 monocyclic cycloalkyl, or ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; Z is ‑O‑ or NH; R9a, R9b, R9c, R9a, and R9e are independently i) H, ii) halogen, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, v) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, or vi) ‑C(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2; each R19 is independently i) H, ii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or iii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0082] In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R3 and R13 together form =O. In some embodiments of the compound of Formula I, II, IIa, IIb, or IIIa, or a pharmaceutically acceptable salt thereof, R3 and R13 are each H.

[0083] In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, X1 is CR17. 20 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55

[0084] In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R17 is H. In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R17 is halogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R17 is C1‑3 alkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R17 is C1‑3 alkoxy.

[0085] In some embodiments of the compound of Formula I, II, IIa, IIb, III or IIIa, or a pharmaceutically acceptable salt thereof, X1 is CH. In some embodiments of the compound of Formula I, II, IIa, IIb, III or IIIa, or a pharmaceutically acceptable salt thereof, X1 is N.

[0086] In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, Z is ‑NR8‑. In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, Z is ‑C(R8)2‑.

[0087] In some embodiments of the compound of Formula I, II, IIa, IIb, III or IIIa, or a pharmaceutically acceptable salt thereof, R8 isH. In someembodiments of the compoundof Formula I, II, IIa, IIb, III or IIIa, or a pharmaceutically acceptable salt thereof, R8 is C1‑3 alkyl.

[0088] In some embodiments of the compound of Formula I, II, IIa, IIb, III or IIIa, or a pharmaceutically acceptable salt thereof, Z is ‑NH‑. In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, Z is ‑CH2‑. In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, Z is ‑O‑.

[0089] In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R4, R5, R6, R10, and R17 are H. In some embodiments of the compound of Formula I, II, IIa, IIb, III or IIIa, or a pharmaceutically acceptable salt thereof, R4, R5, R6, and R10 are H; X1 is CH; and Z is NH. In some embodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R4, R5, R6, andR10 are H; X1 is N; and Z is NH.

[0090] In some embodiments, the compound of Formula I, II, IIa, or III, is of Formula IV, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in Formula I.

[0091] In some embodiments, the compound of Formula I, II, IIa, or III, is of Formula IV, or a pharmaceutically acceptable salt thereof, 21 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 wherein: one of R1 and R2 is ‑OH, halogen or C1‑3 alkyl, and the other of R1 and R2 is halogen or C1‑3 alkyl, or R1 and R2 together with the carbon to which they are attached form a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; R11 is i) 4‑6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, ii) ‑S(O)2C1‑3 alkyl, iii) ‑S(O)2C3‑4 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or v) ‑C(O)R21; R21 is i)C3‑7monocyclic or bridgedbicyclic cycloalkyl optionally substitutedwith1‑3groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, ii) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from -CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, or iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, and d) C1‑3 alkoxy, X is ‑NR15R16, wherein R15 and R16 are independently i) H, ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑7 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from a) ‑OH, b) halogen, and c) C1‑3 alkoxy; or X is a 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18; each R18 is independently i) a halogen, ii) ‑OH, or 22 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 iii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from -OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; R7 is i)C1‑6alkyl optionally substitutedwith1‑3groups independently selected from ‑OH,halogen,C1‑3alkoxy,and C3‑7 monocyclic cycloalkyl, or ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; R9a, R9b, R9c, R9d, and R9e are independently i) H, ii) halogen, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, v) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, or vi) ‑C(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d , and R9e is ‑C(O)N(R19)2; each R19 is independently i) H, ii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or iii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0092] In some embodiments, the compound of Formula I, II, IIa, or III, is of Formula IVa: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in Formula I.

[0093] In some embodiments, the compound of Formula I, II, IIa, or III, is of Formula IVa: 23 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein: one of R1 and R2 is ‑OH, halogen or C1‑3 alkyl, and the other of R1 and R2 is halogen or C1‑3 alkyl, or R1 and R2 together with the carbon to which they are attached form a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; R11 is i) 4‑6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, ii) ‑S(O)2C1‑3 alkyl, iii) ‑S(O)2C3‑4 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or v) ‑C(O)R21; R21 is i)C3‑7monocyclic or bridgedbicyclic cycloalkyl optionally substitutedwith1‑3groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, ii) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, or iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, and d) C1‑3 alkoxy, X is ‑NR15R16, wherein R15 and R16 are independently i) H, ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑7 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, 24 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from a) ‑OH, b) halogen, and c) C1‑3 alkoxy; or X is a 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18; each R18 is independently i) a halogen, ii) ‑OH, or iii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; R7 is i)C1‑6alkyl optionally substitutedwith1‑3groups independently selected from ‑OH,halogen,C1‑3alkoxy,and C3‑7 monocyclic cycloalkyl, or ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; R9a, R9b, R9c, R9a, and R9e are independently i) H, ii) halogen, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, v) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, or vi) ‑C(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d and R9e is ‑C(O)N(R19)2; each R19 is independently i) H, ii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or iii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from -CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0094] In some embodiments, the compound of Formula I, II, IIa, IIb, III, or IIIa, is of Formula IVb or IVc: 25 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in Formula I.

[0095] In some embodiments, the compound of Formula I, II, IIa, IIb, III, or IIIa, is of Formula IVb or IVc: or a pharmaceutically acceptable salt thereof, wherein: one of R1 and R2 is ‑OH, halogen or C1‑3 alkyl, and the other of R1 and R2 is halogen or C1‑3 alkyl, or R1 and R2 together with the carbon to which they are attached form a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from -OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; R11 is i) 4‑6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, ii) ‑S(O)2C1‑3 alkyl, iii) ‑S(O)2C3‑4 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or v) ‑C(O)R21; R21 is i)C3‑7monocyclic or bridgedbicyclic cycloalkyl optionally substitutedwith1‑3groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy, ii) 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, 26 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, or iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, and d) C1‑3 alkoxy, R12 is C1‑3 alkyl; X is ‑NR15R16, wherein R15 and R16 are independently i) H, ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from -OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑7 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups indepen- dently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy, or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from a) ‑OH, b) halogen, and c) C1‑3 alkoxy; or X is a 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18; each R18 is independently i) a halogen, ii) ‑OH, or iii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; R7 is i)C1‑6alkyl optionally substitutedwith1‑3groups independently selected from ‑OH,halogen,C1‑3alkoxy,and C3‑7 monocyclic cycloalkyl, or ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; R9a, R9b, R9c, R9a, and R9e are independently i) H, ii) halogen, iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl, iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, v) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, or vi) ‑C(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2; each R19 is independently i) H, 27 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 ii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl, or iii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0096] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 andR2 is H, ‑CN, ‑OH, halogen, or C1‑6 alkyl, and the other of R1 andR2 is H, halogen, or C1‑6 alkyl, wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH and halogen, or R1 and R2 together with the carbon to which they are attached form a C3‑7 monocyclic cycloalkyl or a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the C3‑7 monocyclic cycloalkyl and the 4‑6 membered monocyclic heterocyclyl are each optionally substituted with one R11 and are each optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, or R1 and R2 together form =O.

[0097] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 and R2 is ‑OH, halogen, or C1‑3 alkyl, and the other of R1 and R2 is halogen or C1‑3 alkyl, or R1 andR2 togetherwith the carbon towhich they are attached forma4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy.

[0098] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together form =O.

[0099] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one ofR1 andR2 isH, ‑CN, -OH, halogen, orC1‑6 alkyl, and theother ofR1 andR2 isH, halogen, or C1‑6 alkyl, wherein theC1‑6 alkyl is optionally substitutedwith 1‑3groups independently selected from ‑OHandhalogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 andR2 isH and the other of R1 andR2 isH, halogen, or C1‑6 alkyl, wherein theC1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH and halogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 andR2 is ‑CNand the other of R1 and R2 is H, halogen, or C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OHand halogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 and R2 is ‑OH and the other of R1 and R2 is H, halogen, orC1‑6 alkyl, wherein theC1‑6 alkyl is optionally substitutedwith 1‑3groups independently selected from ‑OHand halogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, oneofR1 andR2 is halogenand theother ofR1 andR2 isH, halogen, orC1‑6 alkyl, wherein theC1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OHand halogen. In some embodiments of the compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,or IVc,or apharmaceutically acceptablesalt thereof, oneofR1andR2 isC1‑6 alkyl and the other of R1 andR2 isH, halogen, or C1‑6 alkyl, wherein eachC1‑6 alkyl is optionally substitutedwith 1‑3 groups independently selected from ‑OHand halogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 andR2 isC1‑3 alkyl and the other of R1 and R2 is H, halogen, or C1‑6 alkyl, wherein the C1‑3 alkyl and the C1‑6 alkyl are each optionally substituted with 1‑3 groups independently selected from ‑OHand halogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one ofR1 andR2 isC1‑3 alkyl and theother ofR1 andR2 isH, halogen, or C1‑6 alkyl, wherein the C1‑3 alkyl is substituted with 1‑3OH groups. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 and R2 is methyl, ethyl, or propyl and the other of R1 and R2 is H, halogen, or C1‑6 alkyl, wherein the methyl, ethyl, or propyl are each substituted with one OH group.

[0100] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, oneofR1andR2 is ‑OH,halogen,orC1‑3alkyl, and theotherofR1andR2 ishalogenorC1‑3alkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 and R2 is ‑OH and the other of R1 and R2 is halogen or C1‑3 alkyl. In some embodiments of the 28 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,or IVc,or apharmaceutically acceptablesalt thereof, oneofR1andR2 is halogen and the other of R1 and R2 is halogen or C1‑3 alkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 andR2 is C1‑3 alkyl and the other of R1 and R2 is halogen or C1‑3 alkyl.

[0101] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, oneofR1andR2 is ‑OH,fluoro,methyl, or ethyl and theotherofR1andR2 is fluoro,methyl, or ethyl. In someembodimentsof the compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or apharmaceutically acceptable salt thereof, one of R1 and R2 is ‑OH and the other of R1 and R2 is fluoro, methyl, or ethyl. In some embodiments of the compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,or IVc,or apharmaceutically acceptablesalt thereof, oneofR1andR2 is fluoroand theother ofR1andR2 is fluoro,methyl, or ethyl. In someembodimentsof the compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one ofR1 andR2 ismethyl and the other ofR1 and R2 is fluoro,methyl, or ethyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 and R2 is ethyl and the other of R1 and R2 is fluoro, methyl, or ethyl.

[0102] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 andR2 are both fluoro,methyl, or ethyl. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 are both fluoro. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 are both methyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 are both ethyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one of R1 andR2 is ‑OHand the other of R1 and R2 is methyl.

[0103] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 andR2 togetherwith the carbon towhich they are attached formaC3‑7monocyclic cycloalkyl or a 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, andS,wherein the C3‑7 monocyclic cycloalkyl and the 4‑6 membered monocyclic heterocyclyl are each optionally substituted with one R11 and are each optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together with the carbon to which they are attached form a C3‑7 monocyclic cycloalkyl optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo,C1‑3 alkyl, andC1‑3 alkoxy. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together with the carbon to which they are attached form a C3‑7 monocyclic cycloalkyl substituted with one R11. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together with the carbon to which they are attached form a C3 cycloalkyl substituted with one R11. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 andR2 togetherwith the carbon towhich they are attached form a C3 cycloalkyl.

[0104] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together with the carbon to which they are attached form a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6membered monocyclic heterocyclyl is optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together with the carbon to which they are attached forma 4‑6memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN,O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is substituted with one R11.

[0105] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together with the carbon to which they are attached form an azetidinyl optionally substitutedwith oneR11 andoptionally substitutedwith 1 or 2 groups independently selected from ‑OH, halogen, oxo,C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 andR2 togetherwith the carbon towhich they are attached formanazetidinyl substituted with one R11.

[0106] In some embodiments, the compound of Formula I, II, IIa, III, or IV is of Formula V: 29 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0107] In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa, or IVb is of Formula Va: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0108] In some embodiments, the compound of Formula I, II, IIa, III, or IVa is of Formula Vb: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0109] In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa, or IVc is of Formula Vc: 30 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0110] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together with the carbon to which they are attached form a piperidinyl optionally substituted with one R11 and optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 andR2 together with the carbon towhich they are attached form a piperidinyl substituted with one R11.

[0111] In some embodiments, the compound of Formula I, II, IIa, III, or IV is of Formula VI: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0112] In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa, or IVb is of Formula VIa: 31 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0113] In some embodiments, the compound of Formula I, II, IIa, III, or IVa is of Formula VIb: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0114] In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa, or IVc is of Formula VIc: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0115] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically 32 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 acceptable salt thereof, R1 andR2 together with the carbon towhich they are attached form a tetrahydropyranyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R1 and R2 together with the carbon to which they are attached form a tetrahydropyranyl.

[0116] In some embodiments, the compound of Formula I, II, IIa, III, or IV is of Formula VII: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0117] In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa, or IVb is of Formula VIIa: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0118] In some embodiments, the compound of Formula I, II, IIa, III, or IVa is of Formula VIIb: 33 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0119] In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa, or IVc is of Formula VIIc: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0120] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is i) 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH, halogen, oxo,C1‑3 alkyl, andC1‑3 alkoxy; ii) ‑S(O)2C1‑6 alkyl; iii) ‑S(O)2C3‑7monocyclic cycloalkyl; iv)C1‑6 alkyl optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; or v) ‑C(O)R21.

[0121] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is i) 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH, halogen, oxo,C1‑3 alkyl, andC1‑3 alkoxy; ii) ‑S(O)2C1‑3 alkyl; iii) ‑S(O)2C3‑5monocyclic cycloalkyl; iv)C1‑6 alkyl optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; or v) ‑C(O)R21.

[0122] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is i) 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH, halogen, oxo,C1‑3 alkyl, andC1‑3 alkoxy; ii) ‑S(O)2C1‑3 alkyl; iii) ‑S(O)2C3‑4monocyclic cycloalkyl; iv)C1‑6 alkyl optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; or v) ‑C(O)R21.

[0123] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is a 4 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is oxetanyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, andC1‑3 alkoxy. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is oxetanyl.

[0124] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is ‑S(O)2C1‑6 alkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb, orVIc, or apharmaceutically acceptable salt thereof, R11 is ‑S(O)2C1‑3alkyl. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is ‑S(O)2CH3.

[0125] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, orVIc, or a pharmaceutically acceptable salt thereof,R11 is ‑S(O)2C3‑7monocyclic cycloalkyl. In someembodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically 34 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 acceptable salt thereof, R11 is ‑S(O)2C3‑5 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is ‑S(O)2C3‑4 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is ‑S(O)2(cyclopropyl). In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VI, or a pharmaceutically acceptable salt thereof, R11 is ‑S(O)2CH3 or ‑S(O)z(cyclopropyl).

[0126] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is C1‑6 alkyl optionally substitutedwith 1‑3 groups independently selected from - CN, ‑OH, halogen, C1‑3 alkoxy, andC3‑7monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIc, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb, orVIc, or apharmaceutically acceptable salt thereof, R11 is C1‑6 alkyl optionally substitutedwith 1‑3 groups independently selected from ‑CN, ‑OH, halogen, andC1‑3 alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof,R11 is anethyl optionally substitutedwith 1‑3halogens. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R11 is ‑CH2CHF2.

[0127] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R11 is ‑C(O)R21.

[0128] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is i) H; ii) C3‑7monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy; iii) 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, andC1‑3 alkoxy; iv) 5‑6memberedmonocyclic heteroaryl having 1‑4 heteroatoms independently selected from N, O, and S, wherein the 5‑6 membered monocyclic heteroaryl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; v) ‑NH2; vi) ‑NH(C1‑6 alkyl), wherein the C1‑6 alkyl is optionally substitutedwith 1‑3 groups independently selected from ‑CN, ‑OH, halogen, andC1‑3 alkoxy; vii) ‑N(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy; viii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl; or ix) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, d) C1‑3 alkoxy, e) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, f) 4‑6memberedmonocyclic heterocyclyl having1or2heteroatoms independently selected fromN,O,andS,wherein the4‑6memberedmonocyclic heterocyclyl is optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy, and g) ‑OC(O)C1‑6 alkyl optionally substituted with one ‑OH.

[0129] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is i) C3‑7 monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy; ii) 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo,C1‑3 alkyl, andC1‑3 alkoxy; iii) C1‑6 alkoxyoptionally substitutedwith1‑3groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl; or iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0130] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is C3‑7 monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is cyclopropyl, cyclobutyl, cyclopentyl, or C5 bridged bicyclic cycloalkyl, 35 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 eachofwhich is optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH,halogen,C1‑3 alkyl, andC1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH and halogen. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is cyclopropyl, cyclobutyl, cyclopentyl, or C5 bridged bicyclic cycloalkyl, each of which is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, methyl, and ‑OCH3. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is cyclopropyl optionally substituted with one group selected from ‑CN, ‑OH, fluoro, methyl, ‑CH2OH, and ‑OCH3. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is cyclobutyl optionally substitutedwith one group selected from fluoro,methyl, and ‑OCH3. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is cyclopentyl optionally substitutedwith one ‑OH. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is a C5 bridged bicyclic cycloalkyl optionally substituted with one group selected from ‑OH and fluoro. As used herein, a C5 bridged bicyclic cycloalkyl includes but is not limited to: which is the same as

[0131] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is H. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is ‑NH2. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is ‑NH(C1‑6 alkyl), wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb, orVIc, or apharmaceutically acceptable salt thereof, R21 is ‑N(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0132] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is a 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof,R21 is oxetanyl optionally substitutedwithonegroupselected frommethyl, ethyl, and isopropyl. In someembodiments of the compoundof Formula I, II, IIa, IIb III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is oxetanyl optionally substituted with one methyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is tetrahydrofuranyl optionally substituted with one methyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is tetrahydropyranyl optionally substituted with one methyl.

[0133] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is a 5‑6 membered monocyclic heteroaryl having 1‑4 heteroatoms independently selected from N, O, and S, wherein the 5‑6 membered monocyclic heteroaryl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy. In some 36 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is a 5-membered heteroaryl having 1‑4 heteroatoms independently selected from N, O, and S, wherein the 5-membered heteroaryl is optionally substituted with 1‑3 groups independently selected from ‑OH,halogen,methyl, and ‑OCH3. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, or triazolyl, each of which is optionally substituted with 1‑3 groups independently selected from - OH,halogen,C1‑3 alkyl, andC1‑3 alkoxy. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb,Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is oxazolyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is thiazolyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is isoxazolyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is oxadiazolyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is triazolyl optionally substituted with one methyl.

[0134] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is a C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from - OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is a C1‑3 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, andC3‑7monocyclic cycloalkyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is a C1‑3 alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is ‑OCH3.

[0135] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is C1‑6 alkyl optionally substitutedwith 1‑3 groups independently selected from: - CN; ‑OH; halogen; C1‑3 alkoxy; C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; 4‑6 membered monocyclic heterocyclyl having1or 2heteroatoms independently selected fromN,O, andS,wherein the4‑6memberedmonocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; and - OC(O)C1‑6 alkyl optionally substituted with one ‑OH. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑CN; ‑OH; halogen; C1‑3 alkoxy; and 4‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑6membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3alkyl, andC1‑3alkoxy. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb, Vc,VI,VIa,VIb, orVIc, or apharmaceutically acceptablesalt thereof,R21 isC1‑6 alkyl optionally substitutedwith1‑3groups independently selected from -CN, ‑OH, halogen, oxetanyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb, orVIc, or apharmaceutically acceptable salt thereof, R21 is C1‑6 alkyl optionally substitutedwith 1‑3 groups independently selected from ‑CN, ‑OH, halogen, andC1‑3 alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, each of which is optionally substitutedwith 1‑3 groups independently selected from ‑CN, ‑OH, halogen, oxetanyl, andC1‑3 alkoxy. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,orVIc,or a pharmaceutically acceptable salt thereof, R21 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, each of which is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0136] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, orVIc, or apharmaceutically acceptablesalt thereof,R21 ismethyloptionally substitutedwithonegroupselected from ‑CN, ‑OH,andoxetanyl. In someembodimentsof the compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 ismethyl optionally substitutedwith one group selected from ‑CNand ‑OH. In someembodimentsof the compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is ethyl optionally substituted with one group selected from ‑OH, fluoro, and ‑OCH3. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is n-propyl optionally substituted with one ‑OH. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is isopropyl optionally substituted with one group selected from ‑CN, ‑OHand ‑OCH3. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va,Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is isobutyl optionally substituted with one ‑OH. In 37 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is tert-butyl optionally substituted with one group selected from ‑OH, fluoro, and ‑OCH3.

[0137] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, orVIc, or apharmaceutically acceptablesalt thereof,R21 ismethyloptionally substitutedwithonegroupselected from ‑CN, ‑OH, and oxetanyl; ethyl optionally substituted with one group selected from ‑OH, fluoro, and ‑OCH3; n-propyl optionally substituted with one ‑OH; isopropyl optionally substituted with one group selected from ‑CN, ‑OH and ‑OCH3; isobutyl optionally substitutedwith one ‑OH; tert-butyl optionally substitutedwith one group selected from ‑OH, fluoro, and ‑OCH3; ‑OCH3; cyclopropyl optionally substituted with one group selected from ‑CN, ‑OH, fluoro, methyl, - CH2OH, and ‑OCH3; cyclobutyl optionally substituted with one group selected from fluoro, methyl, and ‑OCH3; cyclopentyl optionally sub- stituted with one ‑OH; C5 bridged bicyclic cycloalkyl optionally substituted with one group selected from ‑OH and fluoro; oxetanyl optionally substituted with one group selected from methyl, ethyl, and isopropyl; tetrahydrofuranyl optionally substituted with one methyl; tetrahydropyranyl optionally substituted with one methyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyl optionally substituted with one methyl.

[0138] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, orVIc, or a pharmaceutically acceptable salt thereof,R21 ismethyl optionally substitutedwith onegroup selected from ‑CN and ‑OH; ethyl optionally substitutedwith one group selected from ‑OH, fluoro, and ‑OCH3; n-propyl optionally substituted with one ‑OH; isopropyl optionally substituted with one group selected from ‑CN, ‑OH and ‑OCH3; isobutyl optionally substituted with one ‑OH; tert-butyl optionally substituted with one group selected from ‑OH, fluoro, and ‑OCH3; ‑OCH3; cyclopropyl optionally substitutedwith one group selected from ‑CN, ‑OH, fluoro,methyl, ‑CH2OH, and -OCH3; cyclobutyl optionally substitutedwith one group selected from fluoro,methyl, and -OCH3; cyclopentyl optionally substitutedwith one ‑OH; C5 bridged bicyclic cycloalkyl optionally substituted with one group selected from ‑OH and fluoro; or oxetanyl optionally substituted with one group selected from methyl, ethyl, and isopropyl.

[0139] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is methyl; methyl substituted with one oxetanyl; ‑CH2OH;‑CH2 (CN); ethyl; - CH(CH3)OH; ‑CH(CH3)CH2OH; ‑CH(CH3)OCH3; ‑CH(OH)CH2CH3; isopropyl; ‑C(CH3)2OH; - C(CH3)2OCH3; ‑C(CH3)2CN; tert-butyl; ‑C(CH3)2CH2OH; ‑C(CH3)2CH2OCH3; ‑C(CH3)2CH2F; ‑CH(OH)CH(CH3)2; ‑OCH3; cyclopropyl; cyclopropyl substituted with one methyl; cyclopropyl substituted with one fluoro; cyclopropyl substituted with one -OCH3; cyclopropyl substituted with one ‑OH; cyclopropyl substituted with one ‑CN; cyclopropyl substituted with one ‑CH2OH; cyclobutyl; cyclobutyl substituted with one ‑OCH3; cyclobutyl substituted with one methyl; cyclobutyl substituted with one fluoro; cyclopentyl substituted with one ‑OH; C5 bridged bicyclic cycloalkyl; C5 bridged bicyclic cycloalkyl substituted with one fluoro; C5 bridged bicyclic cycloalkyl substituted with one ‑OH; oxetanyl; oxetanyl substitutedwithonemethyl; oxetanyl substitutedwithoneethyl; oxetanyl substitutedwithone isopropyl; tetrahydrofuranyl; tetrahydrofuranyl substitutedwith onemethyl; tetrahydropyranyl; tetrahydropyranyl substitutedwith onemethyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyl substituted with one methyl.

[0140] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is methyl; ‑CH2OH; ‑CH2(CN); ethyl; ‑CH(CH3)OH; ‑CH(CH3) CH2OH; - CH(CH3)OCH3; ‑CH(OH)CH2CH3; isopropyl; ‑C(CH3)2OH; ‑C(CH3)2OCH3; ‑C(CH3)2CN; tert-butyl; ‑C(CH3)2CH2OH; ‑C(CH3)2CH2OCH3; ‑C(CH3)2CH2F; ‑CH(OH)CH(CH3)2; ‑OCH3; cyclopropyl; cyclopropyl substituted with onemethyl; cyclopropyl substituted with one fluoro; cyclopropyl substituted with one ‑OCH3; cyclopropyl substituted with one ‑OH; cyclopropyl substituted with one ‑CN; cyclopropyl substituted with one ‑CH2OH; cyclobutyl; cyclobutyl substituted with one methyl; cyclobutyl substituted with one fluoro; cyclopentyl substituted with one ‑OH; C5 bridged bicyclic cycloalkyl; C5 bridged bicyclic cycloalkyl substitutedwith one fluoro; C5 bridged bicyclic cycloalkyl substitutedwith one ‑OH; oxetanyl; oxetanyl substituted with one methyl; oxetanyl substituted with one ethyl; or oxetanyl substituted with one isopropyl.

[0141] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 ismethyl; methyl substituted with one oxetanyl; ethyl; ‑CH(CH3) OH; - CH(CH3)OCH3; ‑CH(OH)CH2CH3; isopropyl; ‑C(CH3)2OH; ‑C(CH3)2OCH3; ‑C(CH3)2CN; tert-butyl; ‑C(CH3)2CH2OH; ‑C(CH3)2CH2OCH3; ‑C(CH3)2CH2F; ‑CH(OH)CH(CH3)2; ‑OCH3; cyclopropyl; cyclopropyl substituted withonemethyl; cyclopropyl substitutedwithonefluoro; cyclopropyl substitutedwithone ‑OH;cyclopropyl substitutedwith one ‑OCH3; cyclopropyl substituted with one ‑CN; cyclobutyl; cyclobutyl substituted with one methyl; cyclobutyl sub- stituted with one ‑OCH3; cyclobutyl substituted with one fluoro; cyclopentyl substituted with one ‑OH; C5 bridged bicyclic cycloalkyl; C5 bridged bicyclic cycloalkyl substituted with one fluoro; C5 bridged bicyclic cycloalkyl substituted with one ‑OH; oxetanyl; oxetanyl substituted with one methyl; oxetanyl substituted with one ethyl; oxetanyl substituted with one isopropyl; tetrahydrofuranyl; tetrahydrofuranyl substituted with one methyl; tetrahydropyranyl; tetrahydropyranyl sub- stituted with one methyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyl substituted with one methyl.

[0142] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIb, VIb, orVIc, or a pharmaceutically acceptable salt thereof,R21 ismethyl; ethyl; ‑CH(CH3)OH; isopropyl; ‑C(CH3)2OH; tert-butyl; 38 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 ‑OCH3; cyclopropyl; cyclopropyl substituted with onemethyl; cyclopropyl substituted with one ‑OH; cyclobutyl; cyclobutyl substituted with one methyl; C5 bridged bicyclic cycloalkyl; C5 bridged bicyclic cycloalkyl substituted with one fluoro; C5 bridged bicyclic cycloalkyl substituted with one ‑OH; oxetanyl; or oxetanyl substituted with one methyl.

[0143] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIb, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R21 is methyl.

[0144] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R11 is: 39 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55

[0145] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof,R9a,R9b,R9c,R9d, andR9eare independently i)H; ii) halogen; iii) C1‑6 alkoxyoptionally substitutedwith 1‑3groups independently selected from ‑OH,halogen,C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl; iv) ‑NH2; v) ‑NH(C1‑6 alkyl), wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, andC1‑3 alkoxy; vi) ‑N(C1‑6 alkyl)2, wherein eachC1‑6 alkyl can be the sameor different, andwherein eachC1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, andC1‑3 alkoxy; vii) ‑P(O)(C1‑6 alkyl)2, wherein eachC1‑6 alkyl can be the sameor different, andwherein eachC1‑6 alkyl is optionally substitutedwith 1‑3groups independently selected from ‑OH,halogen, andC1‑3 alkoxy; viii) ‑S(O)2C1‑6 alkyl; ix) ‑S(O)2N(R23)2, wherein each R23 is independently H or C1‑6 alkyl; x) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑OH, b) halogen, c) C1‑3 alkoxy, d) C3‑7 monocyclic cycloalkyl, e) 5‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 5‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from oxo and C1‑3 alkyl, and f) ‑NR20C(O)OC1‑3 alkyl, wherein R20 is H or C1‑3 alkyl; xi) C3‑7monocyclic cycloalkyl optionally substitutedwith 1‑3 groups independently selected from -OH, halogen,C1‑3 alkyl, andC1‑3 alkoxy; xii) 5‑6memberedmonocyclic heteroaryl having 1‑4 heteroatoms independently selected fromN,O, and S,wherein the 5‑6memberedmonocyclic heteroaryl is optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; xiii) 4‑6 membered monocyclic heterocyclyl having 1‑3 heteroatoms indepen- dently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from -OH, halogen, oxo, C1‑3 alkyl, andC1‑3 alkoxy; xiv) ‑COOH; xv) ‑C(O)N(R19)2; or xvi) ‑C1‑3 alkylC(O)N(R19)2; wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0146] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof,R9a,R9b,R9c,R9d, andR9eare independently i)H; ii) a halogen; iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, andC3‑7monocyclic cycloalkyl; iv) ‑NH2; v) ‑NH(C1‑3 alkyl), wherein theC1‑3 alkyl is optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, andC1‑3 alkoxy; vi) ‑N(C1‑3 alkyl)2, wherein eachC1‑3 alkyl can be the sameor different, andwherein eachC1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy; vii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; or viii) ‑C(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O) N(R19)2.

[0147] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof,R9a,R9b,R9c,R9d, andR9eare independently i)H; ii) a halogen; iii) C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl; iv) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; v) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; or vi) ‑C(O)N(R19)2; wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0148] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof,R9a,R9b,R9c,R9d, andR9eare independently i)H; ii) halogen; iii) ‑NH2; iv) ‑NH(C1‑3 alkyl); v) ‑N(C1‑3 alkyl)2, wherein each C1‑3 alkyl is the same or different; vi) C1‑3 alkyl optionally substituted with 1‑3 groups independently selected from -OH and halogen; vii) - OCH3 optionally substituted with 1‑3 halogen groups; viii) cyclopropyl; or ix) ‑C(O)N(R19)2; wherein one ormore of R9a, R9b, R9c, R9d, andR9e is ‑C(O) N(R19)2.

[0149] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof,R9a,R9b,R9c,R9d, andR9eare independently i)H; ii) halogen; iii) C1‑3 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH and halogen; iv) - OCH3 optionally substituted with 1‑3 halogen groups; v) cyclopropyl; or vi) ‑C(O)N(R19)2; wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0150] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore R9a, R9b, R9c, R9d, and R9e is H and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0151] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, 40 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 VIc,VII,VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof, oneormoreR9a,R9b,R9c,R9d, andR9e ishalogen andoneormoreofR9a,R9b,R9c,R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more R9a, R9b, R9c, R9d, and R9e is fluoro or chloro and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O) N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more R9 is fluoro and one or more of R9a, R9b, R9c, R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore R9 is chloro and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0152] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, andR9e is C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C3‑7 monocyclic cycloalkyl and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑OCH3 optionally substituted with 1‑3 fluoro groups andoneormoreofR9a,R9b,R9c,R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑OCH3 or ‑OCF3 and one or more of R9a, R9b, R9c, R9d, and R9e is - C(O)N(R19)2. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, andR9e is ‑OCH3andoneormoreofR9a,R9b,R9c, R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is - OCF3 and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O) N(R19)2.

[0153] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, oneormore ofR9a,R9b,R9c, R9d, andR9e is ‑NH2 and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0154] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑NH(C1‑6 alkyl), wherein theC1‑6 alkyl is optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, andC1‑3 alkoxy andone ormore ofR9a, R9b,R9c, R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑NH(C1‑3 alkyl), wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy and one or more of R9a, R9b, R9c, R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, and R9e is ‑NH(C1‑3 alkyl) and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0155] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑N(C1‑6 alkyl)2, wherein each C1‑6 alkyl can be the same or different, and wherein each C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, andC1‑3 alkoxy andoneormore ofR9a,R9b,R9c, R9d, andR9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑N(C1‑3 alkyl)2, wherein each C1‑3 alkyl can be the same or different, and wherein each C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy and one or more of R9a, R9b, R9c, R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, and R9e is ‑N(C1‑3 alkyl)2, wherein eachC1‑3 alkyl is the same or different, and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI,VIa,VIb,VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof, oneormoreofR9a,R9b,R9c,R9d, and R9e is ‑N(CH3)2 and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0156] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof, oneormoreofR9a,R9b,R9c,R9d, andR9e is ‑P(O) (C1‑6 alkyl)2,wherein eachC1‑6 alkyl canbe the sameor different, andwherein eachC1‑6 alkyl is optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, oneormoreofR9a,R9b,R9c,R9a, andR9e is - P(O)(C1‑3 alkyl)2,whereineachC1‑3 alkyl canbe thesameordifferent, andwherein eachC1‑3 alkyl is optionally substituted 41 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 with 1‑3 groups independently selected from ‑OH, halogen, andC1‑3 alkoxy andoneormore ofR9a,R9b,R9c, R9d, andR9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑P(O)(C1‑3 alkyl)2 and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑P(O)(CH‑3)2 and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0157] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑S(O)2C1‑6 alkyl andoneormoreofR9a,R9b,R9c,R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IV, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, andR9e is ‑S(O)2N(R23)2, wherein eachR23 is independently H or C1‑6 alkyl and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is 5‑6 membered monocyclic heteroaryl having 1‑4 heteroatoms independently selected from N, O, and S, wherein the 5‑6 membered monocyclic heteroaryl is optionally substitutedwith 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, andC1‑3 alkoxy and one ormore of R9a, R9b, R9c, R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI, VIa,VIb,VIc,VII, VIIa,VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, oneormoreofR9a, R9b, R9c, R9d, and R9e is 4‑6memberedmonocyclic heterocyclyl having 1‑3 heteroatoms independently selected fromN, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy and one or more of R9a, R9b, R9c, R9a, and R9e is ‑C(O) N(R19)2. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is ‑COOH and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0158] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, andR9e is C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is cyclopropyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, andR9e is cyclopropyl and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0159] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, andR9e is C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from a) ‑OH, b) halogen, c) C1‑3 alkoxy, d) C3‑7 monocyclic cycloalkyl, e) 5‑6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 5‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from oxo and C1‑3 alkyl, and f) ‑NR20C(O)OC1‑3 alkyl, wherein R20 is H or C1‑3 alkyl; and wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0160] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, andR9e is C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is C1‑3 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH and halogen and one or more of R9a, R9b, R9c, R9a, and R9e is - C(O)N(R19)2. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is methyl optionally 42 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 substituted with 1‑3 groups independently selected from ‑OHand fluoro and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R9a, R9b, R9c, R9d, andR9e is ethyl optionally substituted with one -OH and one or more of R9a, R9b, R9c, R9d, and R9e is-C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or more of R9a, R9b, R9c, R9d, and R9e is methyl, ethyl, ‑CF3, ‑CHF2, ‑CH2OH, or-CH(CH3)OH and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof one ormore of R9a, R9b , R9c , R9d, andR9e is or ‑CH2OHand one ormore ofR9a, R9b , R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0161] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore ofR9a,R9b,R9c, R9d, andR9e is ‑C1‑3 alkylC(O)N(R19)2 and one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0162] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof, oneormoreofR9a,R9b,R9c,R9d, andR9e is ‑C(O) N(R19)2.

[0163] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof,R9a,R9b,R9c,R9d, andR9eare independently i)H; ii) fluoro; iii) chloro; iv) methyl optionally substituted with 1‑3 groups independently selected from ‑OH and fluoro; v) ethyl optionally substituted with one ‑OH; vi) ‑OCH3 optionally substituted with 1‑3 fluoro groups; vii) cyclopropyl; or viii) ‑C(O) N(R19)2; and wherein one or more of R9a, R9b, R9c, R9a, and R9e is ‑C(O)N(R19)2.

[0164] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9a, R9b, R9c, R9d, andR9e are independently H, fluoro, chloro,methyl, ethyl, ‑OCH3, ‑CF3, ‑CHF2, ‑CH2OH, ‑CH(CH3)OH, ‑OCF3, cyclopropyl, ‑N(CH3)2, or-C(O)N(R19)2; and wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof,R9a,R9b,R9c,R9a, andR9eare independentlyH, fluoro, chloro,methyl, ethyl, ‑OCH3, ‑CF3, ‑CHF2, ‑CH2OH, ‑CH(CH3)OH, ‑OCF3, cyclopropyl, or ‑C(O)N(R19)2; and wherein one or more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0165] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9a, R9b, R9c, R9d, andR9e are independently H, fluoro, chloro, methyl, ethyl, ‑CH2OH, ‑OCH3, ‑CF3, ‑OCF3, cyclopropyl, ‑N(CH3)2, or ‑C(O)N(R19)2; and wherein one or moreofR9a,R9b,R9c,R9d, andR9e is ‑C(O)N(R19)2. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9a, R9b, R9c, R9d, and R9e are independently H, fluoro, chloro, methyl, ethyl, ‑CF3, ‑OCF3, cyclopropyl, or ‑C(O)N(R19)2; and whereinoneormoreofR9a,R9b,R9c,R9d, andR9e is ‑C(O)N(R19)2. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9a,R9b,R9c,R9d, andR9e are independentlyH, fluoro, chloro,methyl, ethyl, or ‑C(O)N(R19)2; andwherein oneor more of R9a, R9b, R9c, R9d, and R9e is ‑C(O)N(R19)2.

[0166] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII,VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof, oneofR9a,R9b,R9c, andR9eare independentlyH, fluoro, chloro,methyl, or ethyl. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9a is H or fluoro. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9b is H or methyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9b is H, fluoro, or methyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9c is H, fluoro, chloro,methyl, ethyl, ‑CF3, ‑OCF3, or cyclopropyl. In someembodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9c is H, fluoro, and chloro. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9c is methyl. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9e is H. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9d is ‑C(O)N(R19)2.

[0167] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof, eachR19 is independently i)H; ii) ‑S(O)2C1‑6 alkyl; 43 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 iii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; iv) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑6 alkyl, and C1‑6 alkoxy, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from - CN, ‑OH, halogen, and C1‑3 alkoxy; or v) 4‑6 membered monocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy.

[0168] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R19 is independently i) H; ii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl; or iii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen,C1‑3 alkyl, andC1‑3 alkoxy,wherein theC1‑3 alkyl is optionally substitutedwith 1‑3groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0169] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or bothR19 is H. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IV, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, oneR19 isH. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, both R19 are H.

[0170] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or bothR19 isC1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both R19 is C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH,halogen,andC1‑3alkoxy. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both R19 is C1‑4 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy.

[0171] In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, or Vc, or a pharmaceutically acceptable salt thereof, one or both R19 is C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from - CN, ‑OH, halogen, C1‑6 alkyl, and C1‑6 alkoxy, wherein the C1‑3 alkyl is optionally substitutedwith 1‑3 groups independently selected from ‑CN, ‑OH, halogen, andC1‑3 alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both R19 is C3‑7 monocyclic cycloalkyl optionally substituted with 1‑6 groups independently selected from ‑CN, ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substitutedwith 1‑3 groups independently selected from ‑CN, ‑OH, halogen, andC1‑3 alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both R19 is C3‑5 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, wherein the C1‑3 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy.

[0172] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both R19 is ‑S(O)2C1‑6 alkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both R19 is 4‑6 membered monocyclic heterocyclyl having 1‑3 heteroatoms independently selected from N, O, and S, wherein the 4‑6 membered monocyclic heterocyclyl is optionally substituted with 1‑6 groups independently selected from -CN, ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy.

[0173] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, eachR19 is independently i) H; ii) methyl; iii) ethyl optionally substituted with 1 or 2 groups independently selected from ‑OH, fluoro, and ‑OCH3; iv) n-propyl optionally substitutedwith 1 or 2 groups independently selected from fluoro and ‑OCH3; v) isopropyl optionally substitutedwith 1 or 2 fluoro groups; vi) n-butyl; vii) isobutyl optionally substituted with 1 or 2 fluoro groups; viii) sec-butyl; ix) tert-butyl; x) cyclopropyl optionally substituted with one methyl group, wherein the methyl is optionally substituted with 1‑3 groups independently selected from fluoro and ‑OCH3; or xi) cyclobutyl.

[0174] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, eachR19 is independently i) H; ii)methyl; iii) ethyl; iv) ‑CH2CH2OH; v) ‑CH2CH2OCH3; vi) ‑CH2CHF2; vii) ‑CH2C(CH3)F2; vii) ‑CH(CH3)CH2F; ix) ‑CH(CH2F)2; x) n-propyl; xi) isopropyl; xii) ‑CH(CH3)CHF2; xiii) ‑CH2CH2CHF2; xiv) isobutyl; xv) sec-butyl; xvi) tert-butyl; xvii) ‑CH2CH2CH2OCH3; xviii) cyclopropyl; xix) cyclopropyl substituted with one group selected from ‑CH2F, ‑CHF2 and ‑CH2OCH3; or xx) cyclobutyl.

[0175] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, 44 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, eachR19 is independently i) H; ii)methyl; iii) ethyl; iv) ‑CH2CH2OH; v) ‑CH2CH2OCH3; vi) ‑CH2CHF2; vii) ‑CH2C(CH3)F2; viii) n-propyl; ix) isopropyl; x) - CH(CH3)CH2F; xi) ‑CH(CH3)CHF2; xii) ‑CH(CH2F)2; xiii) ‑CH2CH2CHF2; xiv) isobutyl; xv) sec-butyl; xvi) tert-butyl; xvii) cyclopropyl; xviii) cyclopropyl substituted with one group selected from ‑CH2F, ‑CHF2 and ‑CH2OCH3; or xix) cyclobutyl.

[0176] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof, eachR19 is independentlyH,methyl, isopropyl, or cyclopropyl, wherein the cyclopropyl is optionally substitutedwith one group selected from ‑CH2F, ‑CHF2 and -CH2OCH3.

[0177] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, oneR19 is H and the other R19 is H,methyl, ethyl, or isopropyl.

[0178] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R9a, R9b, R9c, and R9e are independently H, fluoro, chloro, methyl, or ethyl and R9d is ‑C(O)N(R19)2; wherein each R9d is independently H or cyclopropyl, wherein the cyclopropyl is optionally substituted with a methyl, and awherein the methyl is optionally substituted with 1‑3 groups independently selected fromfluoro and ‑OCH3. In someembodiments, R9a,R9b,R9c, andR9e are independentlyH, fluoro, chloro, methyl, or ethyl and R9d is ‑C(O)N(R19)2; wherein each R19 is independently H or cyclopropyl, wherein the cyclopropyl is optionally substituted with a methyl, and wherein the methyl is optionally substituted with 1‑3 groups fluoro groups. In someembodiments,R9a,R9b,R9c, andR9e are independentlyH, fluoro, chloro,methyl, or ethyl andR9d is ‑C(O) NH(R19); wherein R19 is cyclopropyl optionally substituted with a methyl, and wherein the methyl is optionally substituted with 1‑3groups fluoro groups. In someembodiments,R9a,R9b,R9c, andR9e are independentlyH, fluoro, or chloro andR9d is ‑C(O)NH(R19); wherein R19 is cyclopropyl optionally substituted with a methyl, and wherein the methyl is optionally substitutedwith 1‑3groups fluorogroups. In someembodiments,R9a,R9b, andR9c are independently fluoroor chloro,R9e is H, and R9d is - C(O)NH(R19); wherein R19 is cyclopropyl optionally substituted with a methyl, wherein the methyl is optionally substituted with 1‑3 groups fluoro groups. In some embodiments, R9d is

[0179] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is i) H; ii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7monocyclic cycloalkyl; or iii) C3‑7monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from - OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy.

[0180] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is H.

[0181] In someembodiments of the compound of Formula I, II, IIb, IIa, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is methyl, ethyl, isopropyl, or sec-butyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is ethyl, isopropyl, or sec-butyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is isopropyl.

[0182] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, andC1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is cyclopropyl optionally substituted with one methyl group. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is cyclopropyl.

[0183] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R7 is methyl, ethyl, isopropyl, sec-butyl, or cyclopropyl, wherein the cyclopropyl is optionally substituted with one methyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof,R7 isethyl, isopropyl, sec-butyl, or cyclopropyl. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable 45 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 salt thereof, R7 is isopropyl or cyclopropyl.

[0184] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is NR15R16, wherein R15 and R16 are independently i) H; ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑7 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy; or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, d) C1‑3 alkoxy, e) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, and f)5‑6memberedmonocyclic heterocyclyl having1or2heteroatoms independently selected fromN,O,andS,wherein the5‑6memberedmonocyclic heterocyclyl is optionally substitutedwith1‑3groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy.

[0185] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is NR15 R16 , wherein R15 and R16 are independently i) H; ii) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy; iii) 4‑7memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4‑7 membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy; iv) ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy; or v) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy.

[0186] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is NR15R16, wherein R15 and R16 are independently i) H; or ii) C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from -OH, halogen, and C1‑3 alkoxy.

[0187] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is H. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one of R15 and R16 is H.

[0188] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, andC1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is a cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc,VII, VIIa,VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, oneor both ofR15 andR16 is a cyclobutyl optionally substituted with 1 or 2 groups independently selected from ‑OH and fluoro. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both ofR15 andR16 is a cyclohexyl optionally substitutedwith 1 or 2 fluoro groups. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is a cyclobutyl; cyclobutyl substituted with one ‑OH; cyclobutyl substituted with 2 fluoro groups; or cyclohexyl substituted with 2 fluoro groups.

[0189] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is 4‑7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected fromN, O, and S, wherein the 4‑7membered monocyclic heterocyclyl is optionally substituted with 1‑3 groups independently selected from - OH, halogen, oxo, C1‑3 alkyl, andC1‑3 alkoxy. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is 5‑7 memberedmonocyclic heterocyclyl optionally substitutedwith1‑3groups independently selected from ‑OH,halogen,C1‑3 46 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 alkyl, andC1‑3 alkoxy. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is tetrahydropyranyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is tetrahydropyranyl optionally substitutedwithonegroupselected fromfluoroandmethyl. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII,VIIa,VIIb, orVIIc,or apharmaceutically acceptablesalt thereof, one or both of R15 and R16 is tetrahydropyranyl; tetrahydropyranyl substituted with one fluoro group; or tetrahydropyranyl substituted with one methyl group.

[0190] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is a cyclobutyl, cyclopentyl, cyclohexyl, or tetrahydropyranyl, each of which is optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy.

[0191] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is ‑C(O)C1‑6 alkyl, wherein the C1‑6 alkyl is optionally substituted with 1‑3 groups independently selected from ‑CN, ‑OH, halogen, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is ‑C(O)tert-butyl.

[0192] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 andR16 is C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from a) ‑CN, b) ‑OH, c) halogen, d) C1‑3 alkoxy, e) C3‑7 monocyclic cycloalkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkyl, and C1‑3 alkoxy, and f)5‑6memberedmonocyclic heterocyclyl having1or2heteroatoms independently selected fromN,O,andS,wherein the5‑6memberedmonocyclic heterocyclyl is optionally substitutedwith1‑3groups independently selected from ‑OH, halogen, oxo, C1‑3 alkyl, and C1‑3 alkoxy.

[0193] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 andR16 is C1‑6 alkyl optionally substituted with 1‑6 groups independently selected from ‑OH, halogen, and C1‑3 alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, and ‑OCH3. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is i) methyl; ii) isopropyl; iii) isobutyl optionally substituted with one group selected from ‑OH, fluoro, and ‑OCH3; iv) sec-butyl; or v)C5alkyl optionally substitutedwith ‑OCH3. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one or both of R15 and R16 is i) methyl; ii) isopropyl; iii) isobutyl; iv) ‑CH2C(CH3)2F; v) ‑CH2C(CH3)2OCH3; vi) - CH2C(CH3)2OH; vii) sec-butyl; or viii) ‑CH2C(CH3)2CH2OCH3.

[0194] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R15 and R16 are independently i) H; ii) methyl; iii) isopropyl; iv) isobutyl optionally substitutedwith one group selected from ‑OH, fluoro, and ‑OCH3; v) sec-butyl; vi) C5 alkyl optionally substituted with ‑OCH3; vii) ‑C(O)(tert-butyl); viii) cyclobutyl optionally substituted with 1 or 2 groups indepen- dently selected from ‑OHand fluoro; ix) cyclohexyl optionally substituted with 1 or 2 fluoro groups; or x) tetrahydropyranyl optionally substituted with one group selected from fluoro and methyl.

[0195] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R15 and R16 are independently i) H; ii) methyl; iii) isopropyl; iv) isobutyl; v) ‑CH2C(CH3)2F; vi) ‑CH2C(CH3)2OCH3; vii) ‑CH2C(CH3)2OH; viii) sec-butyl; ix) - CH2C(CH3)2CH2OCH3; x) ‑C(O)(tert-butyl); xi) cyclobutyl; xii) cyclobutyl substituted with one ‑OH; xiii) cyclobutyl substituted with 2 fluoro groups; xiv) cyclohexyl substituted with 2 fluoro groups; xv) tetrahydropyranyl; xvi) tetrahydro- pyranyl substituted with one fluoro group; or xvii) tetrahydropyranyl substituted with one methyl group. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R15 and R16 are independently i) H; ii) isopropyl; iii) 47 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 ‑CH2C(CH3)2F; iv) ‑CH2C(CH3)2OH; v) ‑CH2C(CH3)2OCH3; vi) ‑C(O)(tert-butyl); vii) cyclobutyl substituted with 2 fluoro groups; viii) cyclohexyl substituted with 2 fluoro groups; or ix) tetrahydropyranyl substituted with one methyl group.

[0196] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R15 and R16 are independently H, methyl, or isobutyl, wherein the isobutyl is optionally substituted with one group selected from ‑OH, fluoro, and ‑OCH3. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one of R15 and R16 is H or methyl and the other of R15 and R16 is isobutyl optionally substituted with one group selected from ‑OH, fluoro, and ‑OCH3. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R15 and R16 are independently H, methyl, isobutyl, ‑CH2C(CH3)2OCH3, CH2C(CH3)2OH, or CH2C(CH3)2F.

[0197] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one of R15 and R16 is H and the other of R15 and R16 is i) isopropyl; iii) - CH2C(CH3)2F; iv) ‑CH2C(CH3)2OH; v) ‑CH2C(CH3)2OCH3; vi) ‑C(O)(tert-butyl); vii) cyclobutyl substituted with 2 fluoro groups; viii) cyclohexyl substituted with 2 fluoro groups; or ix) tetrahydropyranyl substituted with one methyl group.

[0198] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is a 4‑10memberedmonocyclic, fusedbicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected fromN,O, andS, wherein the 4‑10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18.

[0199] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is a 4‑8memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1‑3 heteroatoms independently selected fromN,O, andS, wherein the 4‑8 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1‑5 R18.

[0200] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is which is optionally substituted with 1‑5 R18. As used herein, is a 4‑10memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl with at least one nitrogen ring atom,wherein the nitrogen ring atom is the point of attachment for the 4‑10memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl.

[0201] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is 48 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 each of which is optionally substituted with 1‑5 R18.

[0202] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is each of which is optionally substituted with 1‑5 R18.

[0203] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is each of which is optionally substituted with 1‑5 R18.

[0204] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl, each of which is optionally substituted with 1‑5 R18.

[0205] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is azetidinyl optionally substitutedwith 1‑4R18. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is azetidinyl optionally substitutedwith 1‑3R18. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is azetidinyl optionally substituted with 1‑2 R18. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, 49 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is pyrrolidinyl optionally substituted with 1‑5 R18. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, X is piperidinyl optionally substitutedwith 1‑5R18. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is morpholinyl optionally substituted with 1‑5 R18.

[0206] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is each of which is optionally substituted with 1‑5 R18.

[0207] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is each of which is optionally substituted with 1‑4 R18.

[0208] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is eachofwhich is optionally substitutedwith 1‑3R18. Inembodiments of the compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is which is optionally substituted with 1‑3R18. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is each of which is optionally substituted with 1‑3 R18.

[0209] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is 50 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 which is optionally substituted with 1‑4 R18.

[0210] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is which is optionally substituted with 1‑3 R18.

[0211] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is which is optionally substituted with 1‑4 R18.

[0212] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is which is optionally substituted with 1‑3 R18.

[0213] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is unsubstituted. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is substitutedwith 1‑5R18. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof,X is substitutedwith1‑4R18. In someembodimentsof thecompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII,VIIa,VIIb, orVIIc, orapharmaceutically acceptablesalt thereof,X is substitutedwith 1‑3R18. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is substituted with 1‑2 R18.

[0214] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is substituted with one R18. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is substitutedwith twoR18. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is substituted with three R18. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is substituted with four R18. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII,VIIa,VIIb, orVIIc, or apharmaceutically acceptable salt thereof,X is substituted with five R18.

[0215] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, two R18 are attached to the same carbon.

[0216] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, eachR18 is independently i) ‑CN; ii) a halogen; iii) ‑OH; iv)C1‑6alkoxyoptionally substitutedwith1‑3groups independently selected from ‑OH,halogen,C1‑3alkoxy, andC3‑7 monocyclic cycloalkyl; v) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 51 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 alkoxy, andC3‑7monocyclic cycloalkyl; vi) - COOH;or vii) ‑C(O)N(R22)2,wherein eachR22 is independentlyHorC1‑6 alkyl.

[0217] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, eachR18 is independently i) a halogen; ii) ‑OH; or iii) C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl.

[0218] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R18 is independently ‑OH, fluoro, or C1‑3 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH and halogen.

[0219] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R18 is independently ‑OH, fluoro, or methyl optionally substituted with 1‑3 groups independently selected from ‑OH and fluoro.

[0220] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or five R18 is ‑CN. In some embodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or fiveR18 is a halogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or fiveR18 is fluoro. In someembodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or fiveR18 is ‑OH. In someembodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or five R18 is ‑COOH. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or fiveR18 is ‑C(O)N(R22)2,wherein eachR22 is independentlyHorC1‑6 alkyl. In someembodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or five R18 is C1‑6 alkoxy optionally substituted with 1‑3 groups independently selected from ‑OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl.

[0221] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or five R18 is C1‑6 alkyl optionally substituted with 1‑3 groups independently selected from -OH, halogen, C1‑3 alkoxy, and C3‑7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or five R18 is C1‑3 alkyl optionally substituted with 1‑3 groups independently selected from ‑OH and halogen. In some embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or fiveR18 is amethyl optionally substitutedwith 1‑3groups independently selected from ‑OHandfluoro. In someembodimentsof the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or five R18 is a methyl.

[0222] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa,VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one, two, three, four, or fiveR18 is fluoroormethyl.

[0223] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is 52 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55

[0224] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

[0225] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is 53 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55

[0226] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

[0227] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is selected from the group consisting of:

[0228] In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is 54 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55

[0229] In some embodiments of the compound of Formula I, II, IIa, or III, the compound is selected from the group consisting of: 55 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 56 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 57 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 58 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 59 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 60 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 61 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof. 62 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55

[0230] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is selected from the group consisting of: 63 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 64 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 65 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 66 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 67 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 68 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 69 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 70 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is selected from the group consisting of: 71 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 72 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments of the compounds of Formula I, II, IIa, IIb, III, or IIIa, the compound is: 73 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 74 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 75 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 76 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 77 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 78 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments of the compounds of Formula I, II, IIa, IIb, III, or IIIa, the compound is: 79 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 80 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 81 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 82 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 83 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments of the compounds of Formula I, II, IIa, IIb, III, or IIIa, the compound is: 84 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments of the compounds of Formula I, II, IIa, IIb, III, or IIIa, the compound is: or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments of the compounds of Formula I, II, IIa, IIb, III, or IIIa, the compound is: or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments of the compounds of Formula I, II, IIa, IIb, III, or IIIa, the compound is: 85 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments of the compound of Formula I, II, IIa, III, IV, or VI, the compound is: or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments of the compound of Formula I, II, IIa, III, IV, or VI, the compound is: or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: 86 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments of the compound of Formula I, II, IIa, III, IV, or VI, the compound is: or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments of the compound of Formula I, II, IIa, III, IV, or VI, the compound is: 87 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: 88 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments of the compound of Formula I, II, IIa, III, IV, or VI, the compound is: or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: 89 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments of the compound of Formula I, II, IIa, III, or IV, the compound is: 90 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments of the compound of Formula I, II, IIa, III, IV, or V, the compound is: or a pharmaceutically acceptable salt thereof. III. Compositions and Kits

[0254] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of the compounds provided herein or pharmaceutically acceptable salts, isomer, or amixture thereof and one ormore pharmaceutically acceptable vehicles selected fromcarriers, adjuvants andexcipients. Thecompoundsprovidedhereinmaybe the sole active ingredient or one of the active ingredients of the pharmaceutical compositions. Suitable pharmaceutically acceptable vehiclesmay include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0255] In oneaspect, providedhereinarepharmaceutical compositionscomprisingacompoundprovidedherein (e.g.,a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0256] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the one or more additional therapeutic agents include agents that are therapeutic for a hepatitis B virus (HBV) infection, human immunodeficiency virus (HIV) infection, cancer, or a hyper-proliferative disease. In some embodiments, the one or more additional therapeutic agents include PD1 inhibitors and / or PDL1 inhibitors. In some embodiments, the one or more additional therapeutic agents that are therapeutic for HBV infection include PDL1 91 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 inhibitorsand / orPDL1 inhibitors. In someembodiments, theoneormoreadditional therapeuticagents that are therapeutic for cancer or hyper-proliferative disease include PD1 inhibitors and / or PDL1 inhibitors.

[0258] In someembodiments, the oneormoreadditional therapeutic agents includeagents that are therapeutic forHBV infection. In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafe- namide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa‑2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha‑2b (Intron A®), pegylated interferon alpha‑2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin, interferon beta‑1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa‑2b (Axxo), Alfaferone, interferon alfa‑2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, IntermaxAlpha,Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferona2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa‑2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa‑2b, Anterferon, Shanferon,MOR‑22, interleukin‑2 (IL‑2), recombinant human interleukin‑2 (ShenzhenNeptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0259] In some embodiments, the one ormore additional therapeutic agents include agents that are therapeutic for HIV infection. In someembodiments, the oneormoreadditional therapeutic agents is selected from thegroup consisting of: 4’- ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamidehemifumarate, emtricitabine, and lamivudine,orapharmaceuticallyacceptable salt of anyof the foregoing,or any combinations thereof.

[0260] In some embodiments, the one or more additional therapeutic agents include PD1 inhibitors and / or PDL1 inhibitors. In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: nivolumab, lambrolizumab, pembrolizumab, pidilizumab,PDR001,TSR‑001, atezolizumab, durvalumab, or avelumab, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0261] In some embodiments, the one or more additional therapeutic agents include agents that are therapeutic for cancer or hyper-proliferative disease. In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: rituxan, doxorubicin, gemcitabine, pidilizumab, TSR‑042, BMS‑986016, ruxolitinib, N‑(cya- nomethyl)‑4‑[2‑(4-morpholinoanilino)pyrimidin‑4-yl]benzamide, XL147, BKM120, GDC‑0941, BAY80‑6946, PX‑866, CH5132799, XL756, BEZ235, and GDC‑0980, wortmannin, LY294002, PI3K II, TGR‑1202, AMG‑319, GSK2269557, X‑339, X‑414, RP5090, KAR4141, XL499, OXY111A, IPI‑145, IPI‑443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117, WX‑037, AEZS‑129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI‑549, INCB050465, (S)‑2‑(1‑((9H-purin‑6-yl)amino)propyl)‑5-fluoro‑3-phenylquinazolin‑4(3H)‑one, (S)‑2‑(1‑((9H-pur- in‑6-yl)amino)ethyl)‑6-fluoro‑3-phenylquinazolin‑4(3H)‑one, (S)‑2‑(1‑((9H-purin‑6-yl)amino)ethyl)‑3‑(2,6-difluorophe- nyl)quinazolin‑4(3H)‑one, (S)‑4-amino‑6‑((1‑(5-chloro‑4-oxo‑3-phenyl‑3,4-dihydroquinazolin‑2-yl)ethyl)amino)pyrimi- dine‑5-carbonitrile, and ipilimumab, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0262] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0263] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical compositionsmay be administered by variousmethods including, for example, rectal, buccal, intranasal and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intra-arterial injection, intra- venously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0264] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions,with sesameoil, cornoil, cottonseedoil, or peanut oil, aswell aselixirs,mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0265] Oral administration may be another route for administration of the compounds provided herein. Administration maybevia, for example, capsule or enteric coated tablets. Inmaking thepharmaceutical compositions that includeat least one compound provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, the active ingredient (suchasa compoundprovidedherein) is usually diluted byanexcipient and / or enclosedwithin sucha carrier that canbe in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspen- sions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged 92 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 powders.

[0266] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrroli- done, cellulose, sterile water, syrup, andmethyl cellulose or any combinations thereof. The pharmaceutical compositions can additionally include lubricating agents such as talc, magnesium stearate, andmineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents; or any combinations thereof.

[0267] The pharmaceutical compositions that include at least one compound described herein or pharmaceutically acceptable salts, isomer, or amixture thereof can be formulated soas to provide quick, sustainedor delayed release of the active ingredient (such as a compound provided herein) after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in themethodsof thepresent disclosureemploys transdermal delivery devices ("patches").Such transdermal patches maybeused toprovidecontinuousordiscontinuous infusionof thecompoundsprovidedherein in controlledamounts.The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0268] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharma- ceutical excipient to formasolid preformulation composition containing ahomogeneousmixture of a compounddescribed herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0269] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0270] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharma- ceuticallyacceptable, aqueousororganic solvents, ormixtures thereof, andpowders.The liquidor solid compositionsmay contain suitable pharmaceutically acceptable excipients as described supra. In someembodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solventsmaybenebulizedbyuseof inert gases.Nebulized solutionsmaybe inhaleddirectly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositionsmay be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0271] In one aspect, provided herein are kits that comprise a compound provided herein, (e.g.,a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In someembodiments, the kit comprises a compoundprovided herein (e.g.,a compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

[0272] In some embodiments, the kits further comprise one ormore (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0273] In one aspect, provided herein are articles of manufacture that comprise a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof in a suitable container. In some embodiments, the container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag. IV. Methods

[0274] Themethods provided herein may be applied to cell populations in vivo or ex vivo. "In vivo"means within a living individual, as within an animal or human. In this context, the methods provided herein may be used therapeutically in an individual. "Ex vivo"means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. 93 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 Exemplary tissue samples include tumors and biopsies thereof. In this context, the present disclosure may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present disclosure may be used ex vivo to determine the optimal schedule and / or dosing of administration of a HPK1 inhibitor for a given indication, cell type, individual, andotherparameters. Informationgleaned fromsuchusemaybeused forexperimental purposesor in the clinic to set protocols for in vivo treatment.Otherex vivouses forwhich the present disclosuremaybe suited are described beloworwill becomeapparent to thoseskilled in theart. Theselectedcompoundsmaybe further characterized toexamine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0275] In one aspect, the present disclosure provides methods of inhibiting HPK1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0276] In one aspect, the present disclosure provides methods of treating a disease or disorder associated with increased HPK1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0277] In oneaspect, thepresent disclosureprovidesmethodsof increasingT-cell activation inasubject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0278] In oneaspect, thepresent disclosureprovidesmethodsof treatingcancer inasubject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0279] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, transitional cell carcinoma, urothelial cancer. In some embodiments, the cancer is a solid tumor.

[0280] In one aspect, the present disclosure providesmethods of inhibiting the growth or proliferation of cancer cells in a subject inneed thereof, comprisingadministering to thesubject a therapeuticallyeffectiveamountof acompoundprovided herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0281] In some embodiments, the abovemethods further comprise administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: Inducible T-cell costimulator (ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA‑4)‑blocking antibodies, PD1 and / or PD-L1 inhibitors, Cluster of Differentiation 47 (CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28 agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8) agonists, Tcell immunoglobulin and mucin domain‑3 (TIM‑3) inhibitors, lymphocyteactivationgene3 (LAG‑3) inhibitors,CEACAM1 inhibitors, Tcell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, V-domain immunoglobulin (Ig)‑containing suppressor of T-cell activation (VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors, STING agonists, C-X-C chemokine receptor type 4 (CXCR‑4) inhibitors,B7-H3 inhibitors,CD73 inhibitors, inhibitoryRNA, IL2 / 15 / 17 fusionproteins,MKNK1 / 2 inhibitors, JAK inhibitors, and PI3K inhibitors, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0283] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR‑001, atezolizumab, durvalu- mab, avelumab, pidilizumab, TSR‑042, BMS‑986016, ruxolitinib, N‑(cyanomethyl)‑4‑[2‑(4-morpholinoanilino)pyrimi- din‑4-yl]benzamide, XL147, BKM120, GDC‑0941, BAY80‑6946, PX‑866, CH5132799, XL756, BEZ235, and GDC‑0980, wortmannin, LY294002, PI3K II, TGR‑1202, AMG‑319, GSK2269557, X‑339, X‑414, RP5090, KAR4141, XL499, OXY111A, IPI‑145, IPI‑443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117, WX‑037, AEZS‑129,PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI‑549, INCB050465, (S)‑2‑(1‑((9H-purin‑6-yl) amino)propyl)‑5-fluoro‑3-phenylquinazolin‑4(3H)‑one, (S)‑2‑(1‑((9H-purin‑6-yl)amino)ethyl)‑6-fluoro‑3-phenylquinazo- lin‑4(3H)‑one, (S)‑2‑(1‑((9H-purin‑6-yl)amino)ethyl)‑3‑(2,6-difluorophenyl)quinazolin‑4(3H)‑one, (S)‑4-amino‑6‑((1‑(5- chloro‑4-oxo‑3-phenyl‑3,4-dihydroquinazolin‑2-yl)ethyl)amino)pyrimidine‑5-carbonitrile, and ipilimumab, or a pharma- ceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0284] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. 94 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55

[0285] In one aspect, the present disclosure provides methods of treating or preventing a hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compoundprovidedherein (e.g.,acompoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0286] In some embodiments, the method of treating or preventing a HBV infection further comprises administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA)and ddRNAi endonucleasemodulators, ribonucleo- tide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein mod- ulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine‑2, 3-dioxygenase (IDO) pathway inhibitors, PD‑1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha‑1 agonists, Bruton’s tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0288] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafe- namide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa‑2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha‑2b (Intron A®), pegylated interferon alpha‑2a (Pegasys®), interferon alfa-n1(Humoferon®), ribavirin, interferon beta‑1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa‑2b (Axxo), Alfaferone, interferon alfa‑2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, IntermaxAlpha,Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferona2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa‑2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa‑2b, Anterferon, Shanferon,MOR‑22, interleukin‑2 (IL‑2), recombinant human interleukin‑2 (ShenzhenNeptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0289] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafe- namide fumarate, tenofovir alafenamide hemifumarate, telbivudine and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0290] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0291] In one aspect, the present disclosure provides methods of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compoundprovidedherein (e.g.,acompoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0292] In some embodiments, the method of treating or preventing a HIV infection further comprises administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIVantibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17matrix protein inhibitors, IL‑13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV‑1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV‑1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase‑3 (MLK‑3) inhibitors, HIV‑1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK‑9 inhibitors, dendritic ICAM‑3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, 95 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0294] In someembodiments, theoneormoreadditional therapeutic agents is selected from thegroupconsisting ofHIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcrip- tase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, andother drugs for treatingHIV, or apharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

[0295] In some embodiments, the one ormore additional therapeutic agents is selected from the group consisting of 4’- ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0296] In some embodiments, the one ormore additional therapeutic agents is selected from the group consisting of 4’- ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0297] In some embodiments, the one ormore additional therapeutic agents is selected from the group consisting of 4’- ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0298] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each thereof.

[0299] In some embodiments, the one or more additional therapeutic agents is emtricitabine or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, themethod of treating or preventing a HIV infection further comprises administering one or more additional therapeutic agents selected from the group consisting of 4’-ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof, and further comprises administering another therapeutic agent selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each thereof.

[0301] In some embodiments, themethod of treating or preventing a HIV infection further comprises administering one or more additional therapeutic agents selected from the group consisting of 4’-ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof, and further comprises administering another therapeutic agent selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each thereof.

[0302] In some embodiments, themethod of treating or preventing a HIV infection further comprises administering one or more additional therapeutic agents selected from the group consisting of 4’-ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil fumarate, and tenofovir disoproxil hemifumarate, or a pharmaceu- tically acceptable salt of any of the foregoing, or any combinations thereof, and further comprises administering another therapeutic agent selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt thereof.

[0303] In someembodiments, themethods described herein comprise administering a therapeutically effective amount of a compoundprovidedherein (e.g., a compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein.

[0304] In oneaspect, providedherein is a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0305] In oneaspect, providedherein is a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting hematopoietic progenitor kinase 1 (HPK1) activity in a subject in need thereof.

[0306] In oneaspect, providedherein is a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder associated with increased hematopoietic progenitor kinase 1 (HPK1) activity in a subject in need thereof.

[0307] In oneaspect, providedherein is a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, for use in a method of increasing T-cell activation in a subject in need thereof.

[0308] In oneaspect, providedherein is a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject in need thereof.

[0309] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, 96 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, transitional cell carcinoma, and urothelial cancer. In some embodiments, the cancer is a solid tumor.

[0310] In oneaspect, providedherein is a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof.

[0311] In some embodiments, the use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of: Inducible T-cell costimulator (ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA‑4)‑blocking anti- bodies, PD1and / or PD-L1 inhibitors, Cluster of Differentiation 47 (CD47) inhibitors, OX40 agonists, GITRagonists, CD27 agonists, CD28agonists,CD40agonists, CD137agonists, Toll-like receptor 8 (TLR8) agonists, Tcell immunoglobulin and mucin domain‑3 (TIM‑3) inhibitors, lymphocyte activation gene 3 (LAG‑3) inhibitors, CEACAM1 inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, V-domain immunoglobulin (Ig)‑containing suppressor of T-cell activation (VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors, STING agonists, C-X-C chemokine receptor type 4 (CXCR‑4) inhibitors, B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2 / 15 / 17 fusion proteins, MKNK1 / 2 inhibitors, JAK inhibitors, and PI3K inhibitors, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0313] In some embodiments, the use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of: rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR‑001, atezoli- zumab, durvalumab, avelumab, pidilizumab, TSR‑042, BMS‑986016, ruxolitinib, N‑(cyanomethyl)‑4‑[2‑(4-morpholinoa- nilino)pyrimidin‑4-yl]benzamide, XL147, BKM120, GDC‑0941, BAY80‑6946, PX‑866, CH5132799, XL756, BEZ235, and GDC‑0980, wortmannin, LY294002, TGR‑1202, AMG‑319, GSK2269557, X‑339, X‑414, RP5090, KAR4141, XL499, OXY111A, IPI‑145, IPI‑443,GSK2636771,BAY10824391, buparlisib, BYL719,RG7604,MLN1117,WX‑037, AEZS‑129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI‑549, INCB050465, (S)‑2‑(1‑((9H-purin‑6-yl)amino) propyl)‑5-fluoro‑3-phenylquinazolin‑4(3H)‑one, (S)‑2‑(1‑((9H-purin‑6-yl)amino)ethyl)‑6-fluoro‑3-phenylquinazo- lin‑4(3H)‑one, (S)‑2‑(1‑((9H-purin‑6-yl)amino)ethyl)‑3‑(2,6-difluorophenyl)quinazolin‑4(3H)‑one, (S)‑4-amino‑6‑((1‑(5- chloro‑4-oxo‑3-phenyl‑3,4-dihydroquinazolin‑2-yl)ethyl)amino)pyrimidine‑5-carbonitrile, and ipilimumab, or a pharma- ceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0314] In some embodiments, the use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of idelalisib, tirabrutinib, momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0315] In oneaspect, providedherein is a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing a hepatitis B virus (HBV) infection in a subject in need thereof.

[0316] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable thereof.

[0317] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA)and ddRNAi endonuclease modulators, ribonucelotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBVantibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine‑2, 3-dioxygenase (IDO) pathway inhibitors, PD‑1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha‑1 agonists, Bruton’s tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, andotherHBVdrugs, or apharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

[0318] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine 97 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 (Emtriva®), peginterferon alfa‑2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha‑2b (Intron A®), pegylated interferon alpha‑2a (Pegasys®), interferon alfa-n1(Humoferon®), ribavirin, interferon beta‑1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa‑2b (Axxo), Alfaferone, interferon alfa‑2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, IntermaxAlpha,Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferona2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa‑2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa‑2b, Anterferon, Shanferon,MOR‑22, interleukin‑2 (IL‑2), recombinant human interleukin‑2 (ShenzhenNeptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0319] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0320] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0321] In oneaspect, providedherein is a compounddisclosedherein, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof.

[0322] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0323] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non- nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors,HIVnon-catalytic site (or allosteric) integrase inhibitors,HIVentry inhibitors,HIVmaturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL‑13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV‑1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV‑1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase‑3 (MLK‑3) inhibitors, HIV‑1 splicing inhibitors, Rev protein inhibitors, integrin antago- nists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonu- cleaseH inhibitors, retrocyclinmodulators,CDK‑9 inhibitors, dendritic ICAM‑3grabbing nonintegrin 1 inhibitors, HIVGAG protein inhibitors, HIV POL protein inhibitors, Complement Factor Hmodulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0324] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non- nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0325] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of 4’-ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0326] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of 4’-ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof. 98 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55

[0327] In someembodiments, theuse in amethodof treatingor preventingahepatitisBvirus (HBV) infection inasubject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of 4’-ethynyl‑2-fluoro‑2’-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0328] In someembodiments, the uses described herein comprise administering a therapeutically effective amount of a compoundprovidedherein (e.g., a compoundofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable salt thereof. V. Administration

[0329] The compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.

[0330] A compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about onemonth, at least about 2months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.

[0331] The specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kgmay be appropriate. In some embodiments, about 0.1 and 100mg / kgmay be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

[0332] The daily dosage may also be described as a total amount of a compound described herein administered per doseor per day.Daily dosageof a compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 15 to 150 mg / day.

[0333] The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0334] The compounds of the present disclosure may be administered to an individual (e.g., a human) in a therapeu- tically effective amount. In some embodiments, the compound is administered once daily.

[0335] The compounds provided herein can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compoundmay include from about 0.00001mg / kg bodyweight per day to about 10mg / kg bodyweight per day, suchas fromabout 0.0001mg / kg bodyweight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg bodyweight per day, or such as from about 0.01mg / kg bodyweight per day to about 1mg / kg bodyweight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of the compounds provided herein include from about 0.3 mg to about 30 mg per day, or fromabout30mg toabout300mgperday, or fromabout0.3µg toabout 30mgperday, or fromabout30µg toabout 300µg per day.

[0336] A compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of compound). Therapeutically effective amountsmay include fromabout 0.1mgper dose to about 1000mgper dose, suchas fromabout 50mgper dose to about 500mgper dose, or such as fromabout 100mgper dose to about 400mgper dose, or such as fromabout 150mg perdose toabout 350mgperdose, or suchas fromabout 200mgperdose toabout 300mgperdose, or suchas fromabout 0.01mgper dose to about 1000mgper dose, or suchas fromabout 0.01mgper dose toabout 100mgper dose, or suchas from about 0.1 mg per dose to about 100mg per dose, or such as from about 1 mg per dose to about 100mg per dose, or suchas fromabout 1mgperdose toabout10mgperdose,or suchas fromabout1mgperdose toabout 1000mgperdose. 99 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 Other therapeutically effective amounts of the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb,VIc,VII,VIIa,VIIb, orVIIcareabout1mgperdose,orabout2, 3, 4, 5, 6, 7, 8, 9, 10, 15,20,25, 30,35,40, 45,50,55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of the compound of the present disclosureareabout100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0337] In some embodiments, the methods described herein comprise administering to the subject an initial daily dose of about 1 to 500 mg of a compound p herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, once per week, once every two weeks, once every three weeks, or once a month.

[0338] When administered orally, the total daily dosage for a human subject may be between about 1mg and 1,000mg, betweenabout 10‑500mg / day, betweenabout 50‑300mg / day, betweenabout 75‑200mg / day, or between about 100‑150 mg / day. In someembodiments, the total daily dosage for a humansubjectmaybeabout 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000mg / day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 200, 300, 400, 500, 600, 700, or 800mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg / day administered in a single dose.

[0339] In some embodiments, the total daily dosage for a human subject may be about 100 mg / day administered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 150mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 200mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 250mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 300mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 350mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 400mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 450mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 500mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 550mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 600mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 650mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 700mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 750mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 800mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 850mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 900mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a humansubjectmaybe about 950mg / dayadministered in a single dose. In someembodiments, the total daily dosage for a human subjectmay be about 1000mg / day administered in a single dose.

[0340] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered onceevery1day, 2, 3, 4, 5, 6, or onceevery7days.Asingledosecanalsobeadministeredonceevery1week, 2, 3, or once every 4 weeks. In certain embodiments, a single dose can be administered once every week. A single dose can also be administered once every month. In some embodiments, a compound disclosed herein is administered once daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in a method disclosed herein.

[0341] The frequency of dosage of the compound of the present disclosure will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the HBV infection, HIV infection, cancer, hyper-proliferative disease, or any other indicationdescribedherein. For example, a compoundcanbeadministered toahumanbeing infectedwithHBV for a period of from 20 days to 180 days or, for example, for a period of from 20 days to 90 days or, for example, for a period of from 30 days to 60 days.

[0342] Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound. For example, a patient can receive a dose of the compound every other day, or three timesperweek.Again bywayof example, a patient can receive adoseof the compoundeachday for a periodof from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound. Alternating periods of administration of the compound, followed by non-administration of the compound, can be repeated as clinically required to treat the patient.

[0343] The compounds of the present disclosure or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitablemode described above. Also, administration or treatment with the 100 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 compoundsmay be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternatedwith resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous. VI. Combination Therapy

[0344] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0345] In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administra- tions.

[0346] In some embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

[0347] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

[0348] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents. The compounds disclosed herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in someembodiments, a unit dose of a compound disclosedherein is administered first, followedwithin seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1‑12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1‑12 hours), by administration of a unit dose of a compound disclosed herein.

[0349] In someembodiments a compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va,Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, is formulated as a tablet, which may optionally contain one or more other compounds useful for treating the disease being treated. In certain embodiments, the tablet can contain another active ingredient for treating a HBV infection, HIV infection, cancer, or a hyper-proliferative disease. In some embodiments, such tablets are suitable for once daily dosing

[0350] Also provided herein are methods of treatment in which a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V,Va,Vb,Vc,VI,VIa,VIb,VIc,VII, VIIa,VIIb, orVIIc, or a tautomerorpharmaceutically acceptable salt thereof, is given to a patient in combinationwith one ormore additional therapeutic agents or therapy. In someembodiments, the total daily dosage of a compound of Formula I, II, IIa, III, IV, or V, or a tautomer, or a pharmaceutically acceptable salt thereof,may be about 300 mg / day administered in a single dose for a human subject. HBV Combination Therapy

[0351] In certain embodiments, a method for treating or preventing an HBV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating an HBV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0352] In certain embodiments, the present disclosure provides a method for treating an HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein or a 101 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one ormore (e.g., one, two, three, four, oneor two, one to three, or one to four) additional therapeutic agentswhichare suitable for treatinganHBV infection.

[0353] The compounds described herein may be used or combined with one or more of a chemotherapeutic agent, an immunomodulator, an immunotherapeutic agent, a therapeutic antibody, a therapeutic vaccine, a bispecific antibody and "antibody-like" therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), an antibody-drug conjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases , TALENs), cell therapies such as CAR-T (chimeric antigen receptor T-cell), and TCR-T (an engineered T cell receptor) agent or any combination thereof.

[0354] In certain embodiments, a compoundofFormula (J) is formulatedasa tablet,whichmayoptionally contain oneor moreother compoundsuseful for treatingHBV. In certainembodiments, the tablet cancontainanother active ingredient for treating HBV, such as 3-dioxygenase (IDO) inhibitors, Apolipoprotein A1 modulator, arginase inhibitors, B- and T- lymphocyte attenuator inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist and modulator, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid X receptor agonist, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors, Hepatitis B large envelope protein modulator, Hepatitis B large envelope protein stimulator, Hepatitis B structural protein modulator, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, Hepatitis virus structural protein inhibitor, HIV‑1 reverse transcriptase inhibitor, Hyaluronidase inhibitor, IAPs inhibitors, IL‑2 agonist, IL‑7 agonist, immunomodulators, indoleamine‑2 inhibitors, inhibitors of ribonucleotide reductase, Inter- leukin‑2 ligand, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte-activation gene 3 inhibitors, lymphotoxin beta receptor activators, modulators of Axl, modulators of B7-H3, modulators of B7-H4, modulators of CD160, modulators of CD161, modulators of CD27, modulators of CD47, modulators of CD70, modulators of GITR, modulatorsofHEVEM,modulatorsof ICOS,modulatorsofMer,modulatorsofNKG2A,modulatorsofNKG2D,modulators of OX40, modulators of SIRPalpha, modulators of TIGIT, modulators of Tim‑4, modulators of Tyro, Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulator, Nucleo- protein inhibitor, nucleoprotein modulators, PD‑1 inhibitors, PD-L1 inhibitors, Peptidylprolyl isomerase inhibitor, phos- phatidylinositol‑3 kinase (PI3K) inhibitors, Retinoic acid-inducible gene 1 stimulator, Reverse transcriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymerase inhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinase inhibitor, stimulator of interferongene (STING)agonists, stimulatorsofNOD1,Tcell surfaceglycoproteinCD28 inhibitor, T- cell surface glycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand, Tim‑3 inhibitors, TLR‑3 agonist, TLR‑7 agonist, TLR‑9 agonist, TLR9 gene stimulator, toll-like receptor (TLR) modulators, Viral ribonucleotide reductase inhibitor, and combinations thereof. HBV Combination Drugs

[0355] Examples of combination drugs for the treatment of HBV include TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX‑203, lamivudine, and PEG-IFN-alpha; ABX‑203 adefovir, and PEG-IFNalpha; and INO‑1800 (INO‑9112 and RG7944). Other HBV Drugs

[0356] Examples of other drugs for the treatment of HBV include alpha-hydroxytropolones, amdoxovir, beta-hydro- xycytosine nucleosides, AL‑034, CCC‑0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), JNJ‑56136379, nitazoxanide, birinapant, NJK14047, NOV‑205 (molixan, BAM‑205), oligotide, mivotilate, feron, GST- HG‑131, levamisole, Ka Shu Ning, alloferon, WS‑007, Y‑101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW‑3, BP-Inter‑014, oleanolic acid, HepB-nRNA, cTP‑5 (rTP‑5), HSK-II‑2, HEISCO‑106‑1, HEISCO‑106, Hepbarna, IBPB‑006IA, Hepuyin- fen, DasKloster 0014‑01, ISA‑204, Jiangantai (Ganxikang), MIV‑210, OB-AI‑004, PF‑06, picroside, DasKloster‑0039, hepulantai, IMB‑2613, TCM‑800B, reduced glutathione, RO‑6864018, RG‑7834, UB‑551, and ZH‑2N, and the com- pounds disclosed in US20150210682, (Roche), US 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche). 102 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 HBV Vaccines

[0357] HBV vaccines include both prophylactic and therapeutic vaccines. Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP‑0101; LBVW‑0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V‑419, CVI-HBV‑001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol‑07, GSK‑223192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramus- cular, HualanBiological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI‑20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA‑001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hib vaccine.

[0358] Examples of HBV therapeutic vaccines include HBsAG-HBIG complex, ARB‑1598, Bio-Hep-B, NASVAC, abi- HB (intravenous), ABX‑203, Tetrabhay, GX‑110E, GS‑4774, peptide vaccine (epsilonPA‑44), Hepatrol‑07, NASVAC (NASTERAP), IMP‑321, BEVAC, Revac B mcf, Revac B+, MGN‑1333, KW‑2, CVI-HBV‑002, AltraHepB, VGX‑6200, FP‑02, FP‑02.2, TG‑1050, NU‑500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO‑1800), recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG‑17909, AdTG‑17910 AdTG‑18202, ChronVac-B, TG‑1050, and Lm HBV. HBV DNA Polymerase Inhibitors

[0359] Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil , tenofovir dipivoxil fumarate, tenofovir octadecylox- yethyl ester, CMX‑157, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocilovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir, SNC‑019754, FMCA, AGX‑1009, AR-II‑04‑26, HIP‑1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS‑10234. Immunomodulators

[0360] Examples of immunomodulators include rintatolimod, imidol hydrochloride, ingaron, derma Vir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ‑440, WF‑10,AB‑452, ribavirin, IL‑12, INO‑9112, polymer polyethyleneimine (PEI), Gepon, VGV‑1, MOR‑22, CRV‑431, JNJ‑0535, TG‑1050, ABI-H2158, BMS‑936559,GS‑9688, RO‑7011785, RG‑7854, AB‑506, RO‑6871765, AIC‑649, and IR‑103. Toll-like Receptor (TLR) Modulators

[0361] TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3 modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH‑33, MCT‑465, MCT‑475, and ND‑1.1.

[0362] Examples of TLR7 modulators include GS‑9620 (vesatolimod), GSK‑2245035, imiquimod, resiquimod, DSR‑6434, DSP‑3025, IMO‑4200, MCT‑465, MEDI‑9197, 3M‑051, SB‑9922, 3M‑052, Limtop, D, telratolimod, SP‑0509, TMX‑30X, TMX‑202, RG‑7863, RG‑7795, LHC‑165, RG‑7854, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences).

[0363] Examples of TLR8 modulators include motolimod, resiquimod, 3M‑051, 3M‑052, MCT‑465, IMO‑4200, VTX‑763, VTX‑1463, GS‑9688 and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Jans- sen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Jans- sen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US Patent No. 9670205, US20160289229, US Patent Application No. 15 / 692161, and US Patent Application No. 15 / 692093.

[0364] Examples of TLR9modulators includeBB‑001,BB‑006,CYT‑003, IMO‑2055, IMO‑2125, IMO‑3100, IMO‑8400, IR‑103, IMO‑9200, agatolimod, DIMS‑9054, DV‑1079, DV‑1179, AZD‑1419, leftolimod (MGN‑1703), litenimod, and 103 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 CYT‑003-QbG10.

[0365] Examples of TLR7, TLR8 and TLR9 modulators include the compounds disclosed in WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen), WO2018045150(Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc), WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695 (DynavaxTechnologies),WO2016055553 (Roche),WO2015168279 (Novartis),WO2016107536 (MedshineDiscovery), WO2018086593 (Livo (Shanghai) Pharmaceutical), WO2017106607 (Merck), WO2017061532 (Sumitomo Dainippon Pharma), WO2016023511 (Chia Tai Tianqing Pharmaceutical), WO2017076346 (Chia Tai Tianqing Pharmaceutical), WO2017046112 (Roche), WO2018078149 (Roche), WO2017040233 (3M Co), WO2016141092 (Gilead Sciences), WO2018049089 (BristolMyers Squibb), WO2015057655 (Eisai Co Ltd), WO2017001307 (Roche), WO2018005586 (BristolMyers Squibb), WO201704023(3M Co), WO2017163264 (Council of Scientific and Industrial Research (India)), WO2018046460 (GlaxoSmithKline Biologicals),WO2018047081 (Novartis),WO2016142250 (Roche),WO2015168269 (Novartis),WO201804163 (Roche),WO2018038877 (3MCo),WO2015057659 (EisaiCoLtd),WO2017202704 (Roche), WO2018026620 (BristolMyers Squibb), WO2016029077 (Janus Biotherapeutics), WO201803143 (Merck), WO2016096778 (Roche), WO2017190669 (Shanghai De Novo Pharmatech), US09884866 (University of Minnesota), WO2017219931 (Sichuan KelunBiotech Biopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054 (Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas), WO2015023958 (University of Kansas). Interferon Alpha Receptor Ligands

[0366] Examples of interferon alpha receptor ligands include interferon alpha‑2b (INTRON A®), pegylated interferon alpha‑2a (PEGASYS®), PEGylated interferon alpha‑1b, interferon alpha 1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPEG-interferon alfa‑2a (YPEG-rhIFNalpha‑2a), P‑1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), Ypeginterferon alfa‑2b (YPEG-rhIFNalpha‑2b), MOR‑22, peginterferon alfa‑2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alfa-n1 (HUMOFERON®), interferon beta‑1a (AVONEX®), Shaferon, interferon alfa‑2b (Axxo), Alfaferone, interferon alfa‑2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa‑2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon, interferon alfa‑2b (Amega), interferon alfa‑2b (Virchow), ropeginterferon alfa‑2b, rHSA-IFN alpha‑2a (recombinant human serum albumin intereferon alpha 2a fusion protein), rHSA-IFN alpha 2b, recombinant human interferon alpha‑(1b, 2a, 2b), peginterferon alfa‑2b (Amega), peginterferon alfa‑2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa‑2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha‑2b, SFR‑9216, and Interapo (Interapa). Hyaluronidase Inhibitors

[0367] Examples of hyaluronidase inhibitors include astodrimer. Hepatitis B Surface Antigen (HBsAg) Inhibitors

[0368] Examples of HBsAg inhibitors include HBF‑0259, PBHBV‑001, PBHBV‑2‑15, PBHBV‑2‑1, REP‑9AC, REP‑9C, REP‑9, REP‑2139, REP‑2139-Ca, REP‑2165, REP‑2055, REP‑2163, REP‑2165, REP‑2053, REP‑2031 and REP‑006, and REP‑9AC’.

[0369] Examples of HBsAg secretion inhibitors include BM601. Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors

[0370] Examples of Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN‑2041, AGEN‑1884, ipilumimab, belatacept, PSI‑001, PRS‑010, Probody mAbs, tremelimumab, and JHL‑1155. Cyclophilin Inhibitors

[0371] Examples of cyclophilin inhibitors include CPI‑431‑32, EDP‑494, OCB‑030, SCY‑635, NVP‑015, NVP‑018, NVP‑019, STG‑175, and the compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences). 104 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 HBV Viral Entry Inhibitors

[0372] Examples of HBV viral entry inhibitors include Myrcludex B. Antisense Oligonucleotide Targeting Viral mRNA

[0373] Examplesof antisenseoligonucleotide targeting viralmRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6- LRx, GSK‑3389404, RG‑6004. Short Interfering RNAs (siRNA) and ddRNAi

[0374] Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR‑008, HepB-nRNA, andARC‑520, ARC‑521, ARB‑1740, ARB‑1467.

[0375] Examples of DNA-directed RNA interference (ddRNAi) include BB-HB‑331. Endonuclease Modulators

[0376] Examples of endonuclease modulators include PGN‑514. Ribonucelotide Reductase Inhibitors

[0377] Examples of inhibitors of ribonucleotide reductase include Trimidox. HBV E Antigen Inhibitors

[0378] Examples of HBV E antigen inhibitors include wogonin. Covalently Closed Circular DNA (cccDNA) Inhibitors

[0379] Examples of cccDNA inhibitors include BSBI‑25, and CHR‑101. Farnesoid X receptor agonist

[0380] Examples of farnesoid x receptor agonist such as EYP‑001, GS‑9674, EDP‑305, MET‑409, Tropifexor, AKN‑083, RDX‑023, BWD‑100, LMB‑763, INV‑3, NTX‑023‑1, EP‑024297 and GS‑8670. HBV Antibodies

[0381] Examples of HBV antibodies targeting the surface antigens of the hepatitis B virus include GC‑1102, XTL‑17, XTL‑19, KN‑003, IV Hepabulin SN, and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed).

[0382] Examples of HBV antibodies, including monoclonal antibodies and polyclonal antibodies, include Zutectra, ShangShengGanDi, UmanBig (Hepatitis BHyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGamB, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT‑088).

[0383] Fully human monoclonal antibodies include HBC‑34. CCR2 Chemokine Antagonists

[0384] Examples of CCR2 chemokine antagonists include propagermanium. Thymosin Agonists

[0385] Examples of thymosin agonists include Thymalfasin, recombinant thymosin alpha 1 (GeneScience). Cytokines

[0386] Examples of cytokines include recombinant IL‑7, CYT‑107, interleukin‑2 (IL‑2, Immunex), recombinant human 105 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 interleukin‑2 (Shenzhen Neptunus), IL‑15, IL‑21, IL‑24, and celmoleukin. Nucleoprotein modulators

[0387] Nucleoprotein modulators may be either HBV core or capsid protein inhibitors. Examples of nucleoprotein modulators include GS‑4882, AB‑423, AT‑130, GLS4, NVR‑1221, NVR‑3778, AL‑3778, BAY 41‑4109, morphothiadine mesilate, ARB‑168786, ARB‑880, JNJ‑379, RG‑7907, HEC‑72702, AB‑506, ABI-H0731, JNJ‑440, ABI-H2158 and DVR‑23.

[0388] Examples of capsid inhibitors include the compounds disclosed in US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Jans- sen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), WO2017198744 (Roche), US 20170334882 (Novira), US 20170334898 (Roche), WO2017202798 (Roche), WO2017214395 (Enanta), WO2018001944 (Roche), WO2018001952 (Roche), WO2018005881 (Novira), WO2018005883 (Novira), WO2018011100 (Roche), WO2018011160 (Roche), WO2018011162(Roche), WO2018011163 (Roche), WO2018036941 (Roche), WO2018043747 (Kyoto Univ), US20180065929 (Janssen), WO2016168619 (Indiana University), WO2016195982 (The Penn State Foundation), WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira).

[0389] Examplesof transcript inhibitors include thecompoundsdisclosed inWO2017013046 (Roche),WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta). WO2017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma). Retinoic Acid-inducible Gene 1 Stimulators

[0390] Examples of stimulators of retinoic acid-inducible gene 1 includeSB‑9200, SB‑40, SB‑44,ORI‑7246, ORI‑9350, ORI‑7537, ORI‑9020, ORI‑9198, and ORI‑7170, RGT‑100. NOD2 Stimulators

[0391] Examples of stimulators of NOD2 include SB‑9200. Phosphatidylinositol 3-kinase (PI3K) Inhibitors

[0392] Examples of PI3K inhibitors include idelalisib, ACP‑319, AZD‑8186, AZD‑8835, buparlisib, CDZ‑173, CLR‑457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN‑3342, TGR‑1202, alpelisib, duvelisib, IPI‑549, UCB‑5857, taselisib, XL‑765, gedatolisib,ME‑401,VS‑5584, copanlisib,CAI orotate, perifosine,RG‑7666,GSK‑2636771,DS‑7423, panulisib, GSK‑2269557, GSK‑2126458, CUDC‑907, PQR‑309, INCB‑40093, pilaralisib, BAY‑1082439, puquitinib mesylate, SAR‑245409, AMG‑319, RP‑6530, ZSTK‑474, MLN‑1117, SF‑1126, RV‑1729, sonolisib, LY‑3023414, SAR‑260301,TAK‑117, HMPL‑689, tenalisib, voxtalisib, and CLR‑1401. Indoleamine‑2, 3-dioxygenase (IDO) Pathway Inhibitors

[0393] Examples of IDO inhibitors include epacadostat (INCB24360), resminostat (4SC‑201), indoximod, F‑001287, SN‑35837, NLG‑919, GDC‑0919, GBV‑1028, GBV‑1012, NKTR‑218, and the compounds disclosed in US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.). PD‑1 Inhibitors

[0394] Examples of PD‑1 inhibitors include cemiplimab, nivolumab, pembrolizumab, pidilizumab, BGB‑108, STI- A1014, SHR‑1210, PDR‑001, PF‑06801591, IBI‑308, GB‑226, STI‑1110, JNJ‑63723283, CA‑170, durvalumab, atezo- lizumab and mDX‑400, JS‑001, Camrelizumab, Sintilimab, Sintilimab, tislelizumab, BCD‑100, BGB-A333, 106 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 JNJ‑63723283, GLS‑010 (WBP‑3055), CX‑072, AGEN‑2034, GNS‑1480 (Epidermal growth factor receptor antagonist; Programmed cell death ligand 1 inhibitor), CS‑1001, M‑7824 (PD-L1 / TGF-β bifunctional fusion protein), Genolimzumab, BMS‑936559. PD-L1 Inhibitors

[0395] Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP‑224, MEDI‑0680, RG‑7446, GX-P2, durvalumab, KY‑1003, KD‑033,MSB‑0010718C, TSR‑042, ALN-PDL, STI-A1014,GS‑4224,CX‑072, andBMS‑936559.

[0396] Examples of PD‑1 inhibitors include the compounds disclosed in WO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624, WO2014151634 (BristolMyers Squibb Co), WO201317322 (Bris- tolMyers Squibb Co), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp), WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO2018119221 (Incyte Corp), WO2018118848 (BristolMyers Squibb Co), WO20161266460 (BristolMyers Squibb Co), WO2017087678 (BristolMyers Squibb Co), WO2016149351 (BristolMyers Squibb Co), WO2015033299 (Aurigene Discovery Technologies Ltd), WO2015179615 (Eisai Co Ltd; Eisai Research Institute), WO2017066227 (BristolMyers Squibb Co), WO2016142886 (Aurigene Discovery Technologies Ltd), WO2016142852 (Aurigene Discovery Technologies Ltd), WO2016142835 (Aurigene Discovery Technologies Ltd; Individual), WO2016142833 (Aurigene Discovery Technologies Ltd), WO2018085750 (BristolMyers Squibb Co), WO2015033303 (Aurigene Discovery Technologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co; Individual; Texas A&M University System), WO2015160641 (BristolMyers Squibb Co), WO2017079669 (Incyte Corp), WO2015033301 (Aurigene Discovery Technologies Ltd), WO2015034820 (BristolMyers Squibb Co), WO2018073754 (Aurigene Discovery Technologies Ltd), WO2016077518 (BristolMyers Squibb Co), WO2016057624 (BristolMyers Squibb Co), WO2018044783 (Incyte Corp), WO2016100608 (BristolMyers Squibb Co), WO2016100285 (BristolMyers Squibb Co), WO2016039749 (BristolMyers Squibb Co), WO2015019284 (Cambridge Enterprise Ltd), WO2016142894 (Aurigene Discovery Technologies Ltd), WO2015134605 (BristolMyers Squibb Co), WO2018051255 (Aurigene Dis- covery Technologies Ltd), WO2018051254 (Aurigene Discovery Technologies Ltd), WO2017222976 (Incyte Corp), WO2017070089 (Incyte Corp), WO2018044963 (BristolMyers Squibb Co), WO2013144704 (Aurigene Discovery Tech- nologies Ltd), WO2018013789 (Incyte Corp), WO2017176608 (BristolMyers Squibb Co),WO2018009505 (BristolMyers Squibb Co), WO2011161699 (Aurigene Discovery Technologies Ltd), WO2015119944 (Incyte Corp; Merck Sharp & Dohme Corp), WO2017192961 (Incyte Corp), WO2017106634 (Incyte Corp), WO2013132317 (Aurigene Discovery Technologies Ltd), WO2012168944 (Aurigene Discovery Technologies Ltd), WOO015036927 (Aurigene Discovery Technologies Ltd),WO2015044900 (Aurigene Discovery Technologies Ltd), WO2018026971 (Arising International).

[0397] Other examplesofPD‑1and / orPDL‑1 inhibitors include the compoundsdisclosed inU.S.ProvisionalSerialNos. 62 / 630187, 62 / 640534, 62 / 736116, and 62 / 747029. Recombinant Thymosin Alpha‑1

[0398] Examples of recombinant thymosin alpha‑1 include NL‑004 and PEGylated thymosin alpha‑1. Bruton’s Tyrosine Kinase (BTK) Inhibitors

[0399] Examples of BTK inhibitors include ABBV‑105, acalabrutinib (ACP‑196), ARQ‑531, BMS‑986142, dasatinib, ibrutinib, GDC‑0853, PRN‑1008, SNS‑062, ONO‑4059, BGB‑3111, ML‑319, MSC‑2364447, RDX‑022, X‑022, AC‑058, RG‑7845, spebrutinib, TAS‑5315, TP‑0158, TP‑4207, HM‑71224, KBP‑7536, M‑2951, TAK‑020, AC‑0025, and the compounds disclosed in US20140330015 (Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), and US20130217880 (Ono Pharmaceutical). KDM Inhibitors

[0400] Examples of KDM5 inhibitors include the compounds disclosed in WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel).

[0401] Examples of KDM1 inhibitors include the compounds disclosed in US9186337B2 (Oryzon Genomics), GSK‑2879552, and RG‑6016. 107 EP 4 671 244 A1 5 10 15 20 25 30 35 40 45 50 55 STING agonists

[0402] Examples of STINGagonists includeSB‑11285, AdVCA0848, STINGVAX, and the compounds disclosed inWO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (AduroBiotech),US20170158724 (GlaxoSmithkiline),WO2017075477 (AduroBiotech),US20170044206 (Merck),WO 2014179760 (University of California), WO2018098203 (Janssn), WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda), WO2018067423 (Merck), WO2018060323 (Boehringer). Non-nucleoside reverse transcriptase inhibitors (NNRTI)

[0403] Examples of NNRTI include the compounds disclosed in WO2018118826 (Merck), WO2018080903(Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), WO2008005555 (Gilead). HBV Replication Inhibitors

[0404] Examples of hepatitis B virus replication inhibitors include isothiafludine, IQP-HBV, RM‑5038, and Xingantie. Arginase inhibitors

[0405] Examples of Arginase inhibitors include CB‑1158, C‑201, and resminostat. Gene Therapy and Cell Therapy

[0406] Gene therapy and cell therapy includes the geneticmodification to silence agene; genetic approaches to directly kill the infectedcells; the infusionof immunecells designed to replacemostof thepatient’sown immunesystem toenhance the immune response to infected cells, or activate the patient’s own immune system to kill infected cells, or find and kill the infected cells; and genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection. Gene Editors

[0407] Examples of genome editing systems include a CRISPR / Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and ameganuclease system; e.g., cccDNA elimination via targeted cleavage, and altering one or more of the hepatitis B virus (HBV)...

Claims

1. A pharmaceutical composition comprising: a compound of Formula I, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient or carrier, and one or more additional therapeutic agents, or pharmaceutically acceptable salts thereof; wherein, in Formula I: one of R1 and R2 is H, -CN, -OH, halogen, or C1-6 alkyl, and the other of R1 and R2 is H, halogen, or C1-6 alkyl, wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen, or R1 and R2 together with the carbon to which they are attached form a C3-7 monocyclic cycloalkyl or a 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the C3-7 monocyclic cycloalkyl and the 4-6 membered monocyclic heterocyclyl are each optionally substituted with one R11 and are each optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy, or R1 and R2 together form =O; R11 is i) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy, ii) -S(O)2C1-6 alkyl, iii) -S(O)2C3-7 monocyclic cycloalkyl, iv) C1-6 alkyl optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl, or v) -C(O)R21; R21 is i) H, ii) C3-7 monocyclic or bridged bicyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1-3 alkyl, and C1-3 alkoxy, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, and C1-3 alkoxy, iii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy, iv) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1-3 alkyl, and C1-3 alkoxy, v) -NH2, vi) -NH(C1-6 alkyl), wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, and C1-3 alkoxy, vii) -N(C1-6 alkyl)2, wherein each C1-6 alkyl can be the same or different and wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, and C1-3 alkoxy, viii) C1-6 alkoxy optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl, and C3-7 monocyclic cycloalkyl, or ix) C1-6 alkyl optionally substituted with 1-3 groups independently selected from a) -CN, b) -OH, c) halogen, d) C1-3 alkoxy, e) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1-3 alkyl, and C1-3 alkoxy, f) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy, and g) -OC(O)C1-6 alkyl optionally substituted with one -OH; R3 and R13 are each H, or R3 and R13 together form =O; L1 is a cyclobutylene optionally substituted with 1-6 groups independently selected from -OH, halogen, C1-3 alkyl, and C1-3 alkoxy; X is -NR15R16, wherein R15 and R16 are independently i) H, ii) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl, and C1-3 alkoxy, iii) 4-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy, iv) -C(O)C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, and C1-3 alkoxy, or v) C1-6 alkyl optionally substituted with 1-6 groups independently selected from a) -CN, b) -OH, c) halogen, d) C1-3 alkoxy, e) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl, and C1-3 alkoxy, and f) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy; or X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is optionally substituted with 1-5 R18; each R18 is independently i) -CN, ii) a halogen, iii) -OH, iv) C1-6 alkoxy optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl, v) C1-6 alkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl, vi) -COOH, or vii)-C(O)N(R22)2, wherein each R22 is independently H or C1-6 alkyl; X1 is N or CR17; R4, R5, R6, R10 and R17 are each independently H, halogen, C1-3 alkyl, or C1-3 alkoxy; R7 is i) H, ii) C1-6 alkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl, or iii) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl, and C1-3 alkoxy; Z is -O-, -C(R8)2-, or -NR8-; each R8 is independently H or C1-3 alkyl; R9a, R9b, R9c, R9d , and R9e are independently i) H, ii) halogen, iii) C1-6 alkoxy optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl, and C3-7 monocyclic cycloalkyl, iv) -NH2, v) -NH(C1-6 alkyl), wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, and C1-3 alkoxy, vi) -N(C1-6 alkyl)2, wherein each C1-6 alkyl can be the same or different, and wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, and C1-3 alkoxy, vii) -P(O)(C1-6 alkyl)2, wherein each C1-6 alkyl can be the same or different, and wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, and C1-3 alkoxy, viii) -S(O)2C1-6 alkyl, ix) -S(O)2N(R23)2, wherein each R13 is independently H or C1-6 alkyl, x) C1-6 alkyl optionally substituted with 1-3 groups independently selected from a) -OH, b) halogen, c) C1-3 alkoxy, d) C3-7 monocyclic cycloalkyl, e) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from oxo and C1-3 alkyl, and f) -NR20C(O)OC1-3 alkyl, wherein R20 is H or C1-3 alkyl, xi) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl, and C1-3 alkoxy, xii) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein the 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl, and C1-3 alkoxy, xiii) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy, xiv) -COOH, xv) -C(O)N(R19)2, or xvi) -C1-3 alkylC(O)N(R19)2, wherein one or more of R9a, R9b, R9c, R9d, and R9e is -C(O)N(R19)2 or -C1-3 alkylC(O)N(R19)2; and each R19 is independently i) H, ii) -S(O)2C1-6 alkyl, iii) C1-6 alkyl optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C1-3 alkoxy, and C3-7 monocyclic cycloalkyl, iv) C3-7 monocyclic cycloalkyl optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C1-3 alkyl, and C1-3 alkoxy, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, and C1-3 alkoxy, or v) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl, and C1-3 alkoxy.

2. The pharmaceutical composition of claim 1, whrerein the compound of Formula I is a compound according to any one of Examples 1 to 297.

3. The pharmaceutical composition of claim 1 or 2, wherein the one or more additional therapeutic agents include agents that are therapeutic for a hepatitis B virus (HBV) infection, human immunodeficiency virus (HIV) infection, cancer, or a hyper-proliferative disease.

4. The pharmaceutical composition of any one of the preceding claims, wherein the one or more additional therapeutic agents is selected from the group consisting of: adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

5. The pharmaceutical composition of any one of claims 1 to 3, wherein the one or more additional therapeutic agents is selected from the group consisting of: 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine, and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

6. The pharmaceutical composition of any one of claims 1 to 3, wherein the one or more additional therapeutic agents is selected from the group consisting of: nivolumab, lambrolizumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, or avelumab, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

7. The pharmaceutical composition of any one of claims 1 to 3, wherein the one or more additional therapeutic agents is selected from the group consisting of: rituxan, doxorubicin, gemcitabine, pidilizumab, TSR-042, BMS-986016, ruxolitinib, N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide, XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, wortmannin, LY294002, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117, WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one, (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and ipilimumab, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

8. The pharmaceutical composition of any one of claims 1 to 3, wherein the one or more additional therapeutic agents is selected from the group consisting of idelalisib, tirabrutinib, momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

9. The pharmaceutical composition of any one of claims 1 to 8, for use in therapy.

10. The pharmaceutical composition of any one of claims 1 to 3 and 6 to 8 for use in (A) a method of increasing T-cell activation in a subject in need thereof; (B) a method of treating cancer in a subject in need thereof, wherein the cancer is preferably selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, transitional cell carcinoma, and urothelial cancer; or (C) a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof.

11. The pharmaceutical composition of any one of claims 1 to 4 for use in a method of treating or preventing a hepatitis B virus (HBV) infection in a subject in need thereof.

12. The pharmaceutical composition of any one of claims 1 to 3 and 5, , for use in a method of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof.

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