CAPSID HIBITORS FOR THE TREATMENT OF HIV

Description

FIELD

[0001] This disclosure relates generally to novel compounds, pharmaceutical compositions comprising said compounds, and said novel compounds and pharmaceutical compositions for use in methods of making and using said compounds and pharmaceutical compositions. In some embodiments, the novel compounds provided herein may be used in the treatment of a Retroviridae viral infection including an infection caused by the HIV virus.BACKGROUND

[0002] Positive-single stranded RNA viruses comprising the Retroviridae family include those of the subfamily Orthoretrovirinae and genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human and animal diseases. Among the Lentivirus, HIV-1 infection in humans leads to depletion of T helper cells and immune dysfunction, producing immunodeficiency and vulnerability to opportunistic infections. Treating HIV-1 infections with highly active antiretroviral therapies (HAART) has proven to be effective at reducing viral load and significantly delaying disease progression (Hammer, S.M., et al.; JAMA 2008, 300: 555-570). However, these treatments could lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, R. J., et al., Science 2010, 327:697-701). Therefore, there is a pressing need to discover new antiretroviral agents that are active against emerging drug-resistant HIV variants. There is a need for compounds that are potent and stable and exhibit improved pharmacokinetic and / or pharmacodynamic profiles for the treatment of a Retroviridae viral infection including an infection caused by the HIV virus. WO 2019 / 035904 relates to pharmaceutically acceptable salts, cocrystals, and crystalline forms thereof, of a compound which is N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, which is useful in the treatment of a Retroviridae viral infection including an infection caused by the HIV virus. WO 2018 / 035359 relates to compounds which are useful in the treatment of a Retroviridae viral infection including an infection caused by the HIV virus. WO 2019 / 035973 relates to choline salts, and crystalline forms thereof, of a compound which is N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, which is useful in the treatment and prevention of a Retroviridae viral infection including an infection caused by the HIV virus. WO 20201018459 relates to compounds, or a pharmaceutically acceptable salt thereof, which are useful in the treatment of an HIV infection in heavily treatment-experienced patients with multidrug resistant HIV infection.SUMMARY

[0003] In one aspect, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2< and R 3< are each independently H or C 1-3 alkyl; each R 5< is halogen which may be the same or different; R 1< is H, -CN, halogen, C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, -C(O)NR 6< R 6< , -NR 6< R 6< , -NR 7< C(O)R 8< , or -C(O)R 8< , wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-4 membered monocyclic heterocyclyl, 5-7 membered monocyclic heterocyclyl, or 5-9 membered fused or bridged bicyclic heterocyclyl, wherein the C 3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-7 membered monocyclic heterocyclyl, and 5-9 membered fused or bridged bicyclic heterocyclyl are each optionally substituted with 1-5 R 16< groups wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S, and wherein the 5-7 membered monocyclic heterocyclyl and 5-9 membered fused or bridged bicyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 16< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, -C(O)NR 6< R 6< , -NR 6< R 6< , -NR 6< C(O)R 8< , or -C(O)R 8< , wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; R 4< is a phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, or 9-12 membered fused tricyclic heteroaryl, wherein the phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl are each optionally substituted with 1-3 R 4a< groups, and wherein the 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 4a< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-8 alkoxy, -NR 6< R 6< , -NR 7< S(o) 2 R 9< , -NR 7< S(O) 2 NR 6< R 6< , -NR 7< C(O)R 8< , -NR 7< C(O)R 10< NR 6< R 6< , -NR 7< C(O)NR 6< R 6< , or -C(O)NR 6< R 6< , wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, or two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl; each R 6< is independently H, C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, or 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, and wherein the C 3-7 monocyclic cycloalkyl and 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy; or both R 6< , together with the nitrogen to which they are attached, form a 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S; each R 7< is independently H or C 1-8 alkyl which may be the same or different, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; each R 8< is independently -OH, C 1-8 alkyl, C 1-8 alkoxy, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 4-6 membered monocyclic heteroaryl, wherein the C 1-8 alkyl and C 1-8 alkoxy are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 4-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 4-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 9< is independently C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 10< is C 1-4 alkylene, which may be the same or different; Ring A, together with the two carbons to which it is attached, forms a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each substituted with one Z group and each have 1-3 ring heteroatoms independently selected from N, O, and S; is: Z is i) oxo, ii) -OH, iii) -CN, iv) C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one group selected from -OH and C 1-4 alkoxy, and wherein the C 1-5 alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) C 6-8 alkyl, wherein the C 6-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, vi) -Z 1< -Z 2< -Z 3< -Z 4< , wherein Z 1< is C 2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein Z 2< and Z 3< are each independently C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, or 7-10 membered spirocyclic heterocyclylene, wherein the C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z 4< is a C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S, vii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, viii) -S(C 1-8 alkyl), wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, ix) -NR 11< R 12< , wherein one of R 11< and R 12< is H or C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein each C 1-8 alkyl is substituted with 1-3 R 17< groups, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S, x) C 6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , and -NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, xi) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xii) 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiii) 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiv) 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, or xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups; each R 17< is independently -OH, halogen, -CN, C 1-4 alkoxy, -NR 6< R 6< , C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl, wherein the C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 13< is independently oxo, -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -NR 6< R 6< , -C(O)R 10< NR 6< R 6< , -C(O)NR 6< R 6< , -C(O)R 8< , C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 R 14< groups, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 14< is independently halogen, C 1-4 alkyl, -C(O)R 8< , 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, CN, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 ; wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 15< is independently C 1-3 alkyl, which may be the same or different; and n is 0, 1, 2, or 3.

[0004] 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.

[0005] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (i.e., 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 (i.e., one, two, three, or four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0006] In one aspect, the present disclosure provides a compound provided herein (i.e., a compounds of Formula I, Ia, II, or IIa), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein for use in 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 the compound provided herein (i.e., a compound of Formula I, Ia, II, or IIa), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition provided herein.DETAILED DESCRIPTION I. Definitions

[0007] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, 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.

[0008] 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.

[0009] 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.

[0010] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH 2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy 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, R a< in the below structure can be attached to any of the five carbon ring atoms or R a< can replace the hydrogen attached to the nitrogen ring atom:

[0011] The prefix "C u-v " indicates that the following group has from u to v carbon atoms. For example, "C 1-6 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, such as "3 to12-membered heterocyclyl", refers to a ring containing x-y atoms (i.e., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0012] Also, certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be referred to as an "alkylene" group or an "alkylenyl" group, or alkylyl group, an "arylene" group or an "arylenyl" group, or arylyl group, respectively.

[0013] "A compound disclosed herein" or "a compound of the present disclosure" or "a compound provided herein" or "a compound described herein" refers to the compounds of Formula I, II, IIa, III, IV, and / or V. Also included are the specific compounds of Examples 1 to 195.

[0014] 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".

[0015] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), 1 to 4 carbon atoms (i.e., C 1-4 alkyl), 1 to 3 carbon atoms (i.e., C 1-3 alkyl), or 1 to 2 carbon atoms (i.e., C 1-2 alkyl). Examples of alkyl groups include methyl, 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 that number of carbons may be encompassed; thus, for example, "butyl" includes n-butyl (i.e. -(CH 2 ) 3 CH 3 ), sec-butyl (i.e. -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e. -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e. -C(CH 3 ) 3 ); and "propyl" includes n-propyl (i.e. -(CH 2 ) 2 CH 3 ) and isopropyl (i.e. -CH(CH 3 ) 2 ).

[0016] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0017] "Alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0018] "Alkylene" refers to a divalent and unbranched saturated hydrocarbon chain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C 1-20 alkylene), 1 to 12 carbon atoms (i.e., C 1-12 alkylene), 1 to 8 carbon atoms (i.e., C 1-8 alkylene), 1 to 6 carbon atoms (i.e., C 1-6 alkylene), 1 to 4 carbon atoms (i.e., C 1-4 alkylene), 1 to 3 carbon atoms (i.e., C 1-3 alkylene), or 1 to 2 carbon atoms (i.e., C 1-2 alkylene). Examples of alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. In some embodiments, an alkylene is optionally substituted with an alkyl group. Examples of substituted alkylene groups include -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 CH(CH 2 CH 3 )-, -CH 2 C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 -, -CH(CH 3 )CH(CH 3 )-, -CH 2 C(CH 2 CH 3 )(CH 3 )-, and -CH 2 C(CH 2 CH 3 ) 2 .

[0019] "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.

[0020] "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.

[0021] "Amido" refers to both a "C-amido" group which refers to the group -C(=O)NR y< R z< and an "N-amido" group which refers to the group -NR y< C(=O)R z< , wherein R y< and R z< are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0022] "Amino" refers to the group -NR y< R z< wherein R y< and R z< are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0023] "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., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.

[0024] "Cyano" or "carbonitrile" refers to the group -CN.

[0025] "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 from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0026] "Bridged" refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0027] The term "fused" refers to a ring which is bound to an adjacent ring.

[0028] "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.

[0029] "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 (-CHF 2 ) and trifluoromethyl (-CF 3 ).

[0030] "Heteroalkylene" refers to a divalent and unbranched saturated hydrocarbon chain having one, two, or three heteroatoms selected from NH, O, or S. As used herein, a heteroalkylene has 1 to 20 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-20 heteroalkylene); 1 to 8 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-8 heteroalkylene); 1 to 6 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S S (i.e., C 1-6 heteroalkylene); 1 to 4 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-4 heteroalkylene); 1 to 3 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-3 heteroalkylene); or 1 to 2 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-3 heteroalkylene). For example, -CH 2 O- is a C 1 heteroalkylene and -CH 2 SCH 2 - is a C 2 heteroalkylene. Examples of heteroalkylene groups include -CH 2 CH 2 OCH 2 -, - CH 2 SCH 2 OCH 2 -, -CH 2 O-, and -CH 2 NHCH 2 -. In some embodiments, a heteroalkylene is optionally substituted with an alkyl group. Examples of substituted heteroalkylene groups include -CH(CH 3 )N(CH 3 )CH 2 -, -CH 2 OCH(CH 3 )-, -CH 2 CH(CH 2 CH 3 )S-, -CH 2 NHC(CH 3 ) 2 -, - C(CH 3 ) 2 SCH 2 -, -CH(CH 3 )N(CH 3 )CH(CH 3 )O-, -CH 2 SC(CH 2 CH 3 )(CH 3 )-, and - CH 2 C(CH 2 CH 3 ) 2 NH-.

[0031] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C 1-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl); and 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 from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0032] "Heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a non-aromatic cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, 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 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., C 2-20 heterocyclyl), 2 to 12 carbon ring atoms (i.e., C 2-12 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C 2-10 heterocyclyl), 2 to 8 carbon ring atoms (i.e., C 2-8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C 3-12 heterocyclyl), 3 to 8 carbon ring atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C 3-6 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 from nitrogen, 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 connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four- to ten-membered cyclic 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 in which a three- to ten-membered heterocyclyl has one or more additional 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.

[0033] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0034] "Oxo" refers to the group (=O) or (O).

[0035] "Sulfonyl" refers to the group -S(O) 2 R c< , where R c< is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0036] As used herein, "2-oxa-6-azaspiro[3.3]heptane" has the structure:

[0037] As used herein, "2,5-diazabicyclo[2.2.1]heptane" has the structure:

[0038] As used herein, "2,6-diazaspiro[3.3]heptane" has the structure:

[0039] As used herein, "1,6-diazaspiro[3.3]heptane" has the structure:

[0040] As used herein, "2,7-diazaspiro[3.5]nonane" has the structure:

[0041] As used herein, "1-oxa-3,8-diazaspiro[4.5]decane" has the structure:

[0042] As used herein, "5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine" has the structure:

[0043] As used herein, "2,3-dihydrobenzo[b][1,4]dioxine" has the structure:

[0044] As used herein, "1H-benzo[d]imidazole" has the structure:

[0045] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an -NH group unless otherwise indicated. Similarly, unless otherwise expressed, hydrogen atom(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.

[0046] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where 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.

[0047] The term "substituted" means that any one or more hydrogen atoms on the designated atom or 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 substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify 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.

[0048] In some embodiments, a substituted cycloalkyl, a substituted heterocyclyl, a substituted aryl, and / or a substituted heteroaryl includes a cycloalkyl, a heterocyclyl, an aryl, and / or a heteroaryl that has a substituent on the ring atom to which 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:

[0049] 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.

[0050] 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 and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0051] "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.

[0052] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0053] 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.

[0054] Some of the compounds provided herein exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of 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.

[0055] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds provided herein are also provided. Hydrates of the compounds provided herein are also provided.

[0056] 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 2< H (deuterium, D), 3< H (tritium), 11< C, 13< C, 14< C, 15< N, 18< F , 31< P, 32< P, 35< S, 36< Cl and 125< I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 2< H, 3< H, 13< C and 14< C are incorporated, are also provided herein. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0057] The present disclosure also includes compounds of Formula I, II, or IIa, in which from 1 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 are thus useful for increasing the half-life of any compound of Formula I, II, or IIa, 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.

[0058] 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 greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An 18< F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I, II, or IIa.

[0059] 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.

[0060] 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.

[0061] 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. Pharmaceutically 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, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, 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-ethylpiperidine, and the like.

[0062] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived 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.

[0063] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, 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.

[0064] "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 (i.e., decreasing one or more 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 (i.e., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (i.e., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (i.e., 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).

[0065] "Prevention" or "preventing" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0066] "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.

[0067] The term "therapeutically effective amount" or "effective amount" of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to activation of protein kinase C (PKC). The therapeutically effective amount may vary depending on the subject, and the disease or condition being treated, the weight and age of 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.II. Compounds

[0068] In one aspect, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2< and R 3< are each independently H or C 1-3 alkyl; each R 5< is halogen which may be the same or different; R 1< is H, -CN, halogen, C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, -C(O)NR 6< R 6< , -NR 6< R 6< , -NR 7< C(O)R 8< , or -C(O)R 8< , wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-4 membered monocyclic heterocyclyl, 5-7 membered monocyclic heterocyclyl, or 5-9 membered fused or bridged bicyclic heterocyclyl, wherein the C 3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-7 membered monocyclic heterocyclyl, and 5-9 membered fused or bridged bicyclic heterocyclyl are each optionally substituted with 1-5 R 16< groups, wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S, and wherein the 5-7 membered monocyclic heterocyclyl and 5-9 membered fused or bridged bicyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 16< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, -C(O)NR 6< R 6< , -NR 6< R 6< , -NR 6< C(O)R 8< , or -C(O)R 8< , wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; R 4< is a phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, or 9-12 membered fused tricyclic heteroaryl, wherein the phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl are each optionally substituted with 1-3 R 4a< groups, and wherein the 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 4a< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-8 alkoxy, -NR 6< R 6< , -NR 7< S(o) 2 R 9< , -NR 7< S(O) 2 NR 6< R 6< , -NR 7< C(O)R 8< , -NR 7< C(O)R 10< NR 6< R 6< , -NR 7< C(O)NR 6< R 6< , or -C(O)NR 6< R 6< , wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, or two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl; each R 6< is independently H, C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, or 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, and wherein the C 3-7 monocyclic cycloalkyl and 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy; or both R 6< , together with the nitrogen to which they are attached, form a 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S; each R 7< is independently H or C 1-8 alkyl which may be the same or different, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from - OH, halogen, -CN, and C 1-4 alkoxy; each R 8< is independently -OH, C 1-8 alkyl, C 1-8 alkoxy, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 4-6 membered monocyclic heteroaryl, wherein the C 1-8 alkyl and C 1-8 alkoxy are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 4-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 4-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 9< is independently C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 10< is C 1-4 alkylene, which may be the same or different; Ring A, together with the two carbons to which it is attached, forms a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each substituted with one Z group and each have 1-3 ring heteroatoms independently selected from N, O, and S; is: Z is i) oxo, ii) -OH, iii) -CN, iv) C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one group selected from -OH and C 1-4 alkoxy, and wherein the C 1-5 alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) C 6-8 alkyl, wherein the C 6-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, vi) -Z 1< -Z 2< -Z 3< -Z 4< , wherein Z 1< is C 2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN and C 1-4 alkoxy, wherein Z 2< and Z 3< are each independently C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, or 7-10 membered spirocyclic heterocyclylene, wherein the C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z 4< is a C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S, vii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, viii) -S(C 1-8 alkyl), wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, ix) -NR 11< R 12< , wherein one of R 11< and R 12< is H or C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein each C 1-8 alkyl is substituted with 1-3 R 17< groups, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S, x) C 6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , and -NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, xi) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xii) 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiii) 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiv) 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, or xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups; each R 17< is independently -OH, halogen, -CN, C 1-4 alkoxy, -NR 6< R 6< , C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl, wherein the C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 13< is independently oxo, -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -NR 6< R 6< , -C(O)R 10< NR 6< R 6< , -C(O)NR 6< R 6< , -C(O)R 8< , C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 R 14< groups, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 14< is independently halogen, C 1-4 alkyl, -C(O)R 8< , 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, CN, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 ; wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 15< is independently C 1-3 alkyl, which may be the same or different; and n is 0, 1, 2, or 3.

[0069] In some embodiments, the compound of Formula I is of Formula Ia: or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 2< and R 3< are each independently H or C 1-3 alkyl; each R 5< is halogen which may be the same or different; R 1< is H, -CN, halogen, C 1-8 alkyl, or C 3-7 monocyclic cycloalkyl, wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl or 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl and 5-9 membered fused or bridged bicyclic cycloalkyl are each optionally substituted with 1-5 R 16a< groups; each R 16a< is independently -OH, halogen, -CN, C 1-8 alkyl, C 1-4 alkoxy, and C 3-7 monocyclic cycloalkyl, wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; R 4< is a phenyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 9-12 membered fused or bridged tricyclic heterocyclyl, wherein the phenyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 9-12 membered fused or bridged tricyclic heterocyclyl are each optionally substituted with 1-3 R 4a< groups, and wherein the 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 9-12 membered fused or bridged tricyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 4a< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-8 alkoxy, -NR 6< R 6< , -NR 7< S(O) 2 R 9< , or -C(O)NR 6< R 6< , wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, or two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl; each R 6< is independently H, C 1-8 alkyl, or C 3-7 monocyclic cycloalkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, and wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy; each R 7< is independently H or C 1-8 alkyl which may be the same or different, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; each R 8< is independently -OH, C 1-8 alkyl, or C 1-8 alkoxy; each R 9< is independently C 1-8 alkyl or C 3-7 monocyclic cycloalkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, and wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy; each R 10< is C 1-4 alkylene, which may be the same or different; Ring A, together with the two carbons to which it is attached, forms a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each substituted with one Z group and each have 1-3 ring heteroatoms independently selected from N, O, and S; is: Z is i) oxo, ii) -OH, iii) -CN, iv) C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one group selected from -OH and C 1-4 alkoxy, and wherein the C 1-5 alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) C 6-8 alkyl, wherein the C 6-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, vi) -Z 1< -Z 2< -Z 3< -Z 4< , wherein Z 1< is C 2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein Z 2< is a C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, and 5-6 membered monocyclic heteroarylene, are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, wherein Z 3< is a 5-6 membered monocyclic heterocyclylene or 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z 4< is a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, vii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, viii) -S(C 1-4 alkyl), wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, ix) -NR 11< R 12< , wherein one of R 11< and R 12< is H or C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein each C 1-8 alkyl is substituted with 1-3 R 17a< groups; wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, x) C 6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , and -NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, xi) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xii) 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiii) 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiv) 8-10 membered fused bicyclic heteroaryl optionally substituted with 1-3 R 13< groups, or xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups; each R 17a< is independently -OH, halogen, -CN, C 1-4 alkoxy, -NR 6< R 6< , C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 13< is independently oxo, -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -NR 6< R 6< , -C(O)R 10< NR 6< R 6< , -C(O)NR 6< R 6< , -C(O)R 8< , C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, or 8-10 membered fused bicyclic heteroaryl, wherein the C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, and 8-10 membered fused bicyclic heteroaryl are each optionally substituted with 1-3 R 14< groups, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, and 8-10 membered fused bicyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R 14< is independently halogen, C 1-4 alkyl, -C(O)R 8< , or 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, CN, and C 1-4 alkoxy, and wherein the 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S is optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 ; each R 15< is independently C 1-3 alkyl, which may be the same or different; and n is 0, 1, 2, or 3.

[0071] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, n is 0, 1, 2, or 3. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, n is 0. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, n is 1. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, n is 2. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, n is 3.

[0072] In some embodiments, the compound of Formula I is of Formula II: or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the compound of Formula I, Ia, or II is of Formula IIa: or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 2< and R 3< are each independently H or C 1-3 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 2< and R 3< is H and the other of R 2< and R 3< is C 1-3 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 2< and R 3< is H and the other of R 2< and R 3< is methyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 2< and R 3< is H and the other of R 2< and R 3< is ethyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 2< and R 3< is H and the other of R 2< and R 3< is propyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 2< and R 3< is H and the other of R 2< and R 3< is isopropyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, both R 2< and R 3< are H. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 2< and R 3< are each independently methyl, ethyl, propyl, or isopropyl.

[0075] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 5< is halogen which may be the same or different. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 5< is independently chloro, fluoro, bromo, or iodo. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 5< is independently chloro, fluoro, or bromo. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 5< is fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, two R 5< are fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 5< is fluoro.

[0076] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-4 membered monocyclic heterocyclyl, 5-7 membered monocyclic heterocyclyl, or 5-9 membered fused or bridged bicyclic heterocyclyl, wherein the C 3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-7 membered monocyclic heterocyclyl, and 5-9 membered fused or bridged bicyclic heterocyclyl are each optionally substituted with 1-5 R 16< groups wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S, and wherein the 5-7 membered monocyclic heterocyclyl and 5-9 membered fused or bridged bicyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0077] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl or 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl and the 5-9 membered fused or bridged bicyclic cycloalkyl are each optionally substituted with 1-5 R 16a< groups.

[0078] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a cyclohexyl or 6-7 membered fused or bridged bicyclic cycloalkyl, wherein the cyclohexyl and 6-7 membered fused or bridged bicyclic cycloalkyl are each optionally substituted with 1-5 halogens.

[0079] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-5 R 16a< groups.

[0080] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-5 R 16a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-5 groups independently selected from -OH, halogen, -CN, and C 1-8 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3 - 7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-5 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-5 fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a cyclopentyl, wherein the cyclopentyl is substituted with 1-5 fluoro.

[0081] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a C 3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a cyclopentyl or cyclohexyl.

[0082] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a cyclohexyl, wherein the cyclohexyl is optionally substituted with 1-5 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a cyclohexyl, wherein the cyclohexyl is substituted with 1-5 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a cyclohexyl, wherein the cyclohexyl is substituted with 1-4 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a cyclohexyl, wherein the cyclohexyl is substituted with 1-5 fluoro.

[0083] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the 5-9 membered fused or bridged bicyclic cycloalkyl is optionally substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the 5-9 membered fused or bridged bicyclic cycloalkyl is optionally substituted with 1-5 R 16a< groups.

[0084] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the 5-9 membered fused or bridged bicyclic cycloalkyl is substituted with 1-5 groups independently selected from -OH, halogen, -CN, and C 1-8 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the 5-9 membered fused or bridged bicyclic cycloalkyl is substituted with 1-5 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the 5-9 membered fused or bridged bicyclic cycloalkyl is substituted with 1-4 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the 5-9 membered fused or bridged bicyclic cycloalkyl is substituted with 1-5 fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 6-8 membered fused or bridged bicyclic cycloalkyl, wherein the 6-8 membered fused or bridged bicyclic cycloalkyl is substituted with 1-5 fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 6-membered fused or bridged bicyclic cycloalkyl, wherein the 6-membered fused or bridged bicyclic cycloalkyl is substituted with 1-5 fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 7-membered fused or bridged bicyclic cycloalkyl, wherein the 7-membered fused or bridged bicyclic cycloalkyl is substituted with 1-5 fluoro.

[0085] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 6-7 membered fused or bridged bicyclic cycloalkyl, wherein the 6-7 membered fused or bridged bicyclic cycloalkyl is optionally substituted with 1-5 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 6-7 membered fused or bridged bicyclic cycloalkyl, wherein the 6-7 membered fused or bridged bicyclic cycloalkyl is substituted with 1-5 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 6-7 membered fused or bridged bicyclic cycloalkyl, wherein the 6-7 membered fused or bridged bicyclic cycloalkyl is substituted with 1-4 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 6-7 membered fused or bridged bicyclic cycloalkyl, wherein the 6-7 membered fused or bridged bicyclic cycloalkyl is substituted with 1-3 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 6-7 membered fused or bridged bicyclic cycloalkyl, wherein the 6-7 membered fused or bridged bicyclic cycloalkyl is substituted with 1-3 fluoro.

[0086] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 3-4 membered monocyclic heterocyclyl, wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 3-4 membered monocyclic heterocyclyl, wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-5 R 16a< groups.

[0087] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 3-4 membered monocyclic heterocyclyl, wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S and is substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 3-4 membered monocyclic heterocyclyl, wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S and is substituted with 1-5 R 16a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 3-4 membered monocyclic heterocyclyl having 1-2 ring heteroatoms independently selected from N, O, and S.

[0088] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-7 membered monocyclic heterocyclyl, wherein the 5-7 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-7 membered monocyclic heterocyclyl, wherein the 5-7 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-5 R 16a< groups.

[0089] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-7 membered monocyclic heterocyclyl, wherein the 5-7 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-7 membered monocyclic heterocyclyl, wherein the 5-7 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-5 R 16a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-7 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0090] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic heterocyclyl, wherein the 5-9 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic heterocyclyl, wherein the 5-9 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-5 R 16a< groups.

[0091] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic heterocyclyl, wherein the 5-9 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-5 R 16< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic heterocyclyl, wherein the 5-9 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-5 R 16a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B, together with the two carbons to which it is attached, forms a 5-9 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0092] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B is cyclohexyl, tetrahydropyranyl, each of which is optionally substituted with 1-5 groups independently selected from oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, -C(O)NR 6< R 6< , -NR 6< R 6< , - NR 6< C(O)R 8< , and -C(O)R 8< .

[0093] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B is cyclohexyl, tetrahydropyranyl, each of which is optionally substituted with 1-4 groups independently selected from oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, -C(O)NR 6< R 6< , -NR 6< R 6< , - NR 6< C(O)R 8< , and -C(O)R 8< .

[0094] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B is a cyclohexyl, each of which is optionally substituted with 1-5 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B is a cyclohexyl, each of which is optionally substituted with 1-5 fluoro.

[0095] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 16< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, -C(O)NR 6< R 6< , -NR 6< R 6< , -NR 6< C(O)R 8< , or -C(O)R 8< , wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy.

[0096] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 16a< is independently -OH, halogen, -CN, C 1-8 alkyl, C 1-4 alkoxy, and C 3-7 monocyclic cycloalkyl, wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy.

[0097] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, is:

[0098] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, is:

[0099] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is H, -CN, halogen, C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, -C(O)NR 6< R 6< , -NR 6< R 6< , -NR 7< C(O)R 8< , or -C(O)R 8< , wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is H, -CN, halogen, C 1-8 alkyl, or C 3-7 monocyclic cycloalkyl, wherein the C 1-8 alkyl and C 3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy.

[0100] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is H. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is -CN.

[0101] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is halogen. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is chloro, fluoro, bromo, or iodo. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is chloro, fluoro, or bromo.

[0102] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 halogens.

[0103] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-8 alkyl, wherein the C 1-8 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with 1-3 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-3 alkyl, wherein the C 1-3 alkyl is substituted with 1-3 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-3 alkyl, wherein the C 1-3 alkyl is substituted with 1-3 fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is methyl substituted with 1-3 fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is ethyl substituted with 1-3 fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is -CHF 2 or -CF 3 .

[0104] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-8 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-6 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 1-4 alkyl.

[0105] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from - OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is C 3-7 monocyclic cycloalkyl.

[0106] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is -C(O)NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is - NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is -NR 7< C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 1< is - C(O)R 8< .

[0107] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, or 9-12 membered fused tricyclic heteroaryl, wherein the phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl are each optionally substituted with 1-3 R 4a< groups, and wherein the 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0108] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a phenyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 9-12 membered fused or bridged tricyclic heterocyclyl, wherein the phenyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 9-12 membered fused or bridged tricyclic heterocyclyl are each optionally substituted with 1-3 R 4a< groups, and wherein the 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 9-12 membered fused or bridged tricyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0109] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a phenyl or 9-10 membered fused or bridged bicyclic heterocyclyl, wherein the phenyl and 9-10 membered fused or bridged bicyclic heterocyclyl are each optionally substituted with 1-3 R 4a< groups and wherein the 9-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S.

[0110] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a phenyl, wherein the phenyl is optionally substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a phenyl, wherein the phenyl is substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a phenyl.

[0111] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 5-6 membered monocyclic heterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 5-6 membered monocyclic heterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 5-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0112] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0113] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0114] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-10 membered fused or bridged bicyclic heterocyclyl, wherein the 9-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-10 membered fused or bridged bicyclic heterocyclyl, wherein the 9-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0115] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0116] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-12 membered fused or bridged tricyclic heterocyclyl, wherein the 9-12 membered fused or bridged tricyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-12 membered fused or bridged tricyclic heterocyclyl, wherein the 9-12 membered fused or bridged tricyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-12 membered fused or bridged tricyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0117] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-12 membered fused tricyclic heteroaryl, wherein the 9-12 membered fused tricyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-12 membered fused tricyclic heteroaryl, wherein the 9-12 membered fused tricyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 4a< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is a 9-12 membered fused tricyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0118] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is each of which is optionally substituted with 1-3 R 4a< groups.

[0119] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is each of which is substituted with 1-3 R 4a< groups.

[0120] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is each of which is optionally substituted with 1-3 R 4a< groups.

[0121] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is each of which is substituted with 1-3 R 4a< groups.

[0122] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is which is optionally substituted with 1-3 R 4a< groups.

[0123] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< is which is substituted with 1-3 R 4a< groups.

[0124] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 4a< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-8 alkoxy, -NR 6< R 6< , -NR 7< S(O) 2 R 9< , -NR 7< S(O) 2 NR 6< R 6< , -NR 7< C(O)R 8< , -NR 7< C(O)R 10< NR 6< R 6< , -NR 7< C(O)NR 6< R 6< , or -C(O)NR 6< R 6< , wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy; or two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 4a< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-8 alkoxy, -NR 6< R 6< , -NR 7< S(O) 2 R 9< , or -C(O)NR 6< R 6< , wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from - OH, halogen, -CN, and C 1-4 alkoxy; or two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl.

[0125] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 4a< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-8 alkoxy, -NR 6< R 6< , -NR 7< S(O) 2 R 9< , -NR 7< S(O) 2 NR 6< R 6< , -NR 7< C(O)R 8< , -NR 7< C(O)R 10< NR 6< R 6< , -NR 7< C(O)NR 6< R 6< , or -C(O)NR 6< R 6< , wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 4a< is independently oxo, -OH, halogen, -CN, C 1-8 alkyl, C 1-8 alkoxy, -NR 6< R 6< , -NR 7< S(O) 2 R 9< , or - C(O)NR 6< R 6< , wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy.

[0126] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 4a< is independently oxo, halogen, -CN, C 1-8 alkyl, -NR 6< R 6< , -NR 7< S(O) 2 R 9< , or -C(O)NR 6< R 6< .

[0127] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is oxo. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is oxo. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -OH.

[0128] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is halogen. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is fluoro or chloro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is chloro.

[0129] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -CN. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is - CN.

[0130] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is C 1-8 alkyl, wherein the C 1-8 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is C 1-8 alkyl.

[0131] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is C 1-4 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is methyl, ethyl, propyl, or isopropyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is methyl.

[0132] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is C 1-8 alkoxy.

[0133] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -NH 2 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is -NH 2 .

[0134] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -NR 7< S(O) 2 R 9< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -NHS(O) 2 R 9< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is -NHS(O) 2 R 9< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is -NHS(O) 2 (C 1-4 alkyl). In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is -NHS(O) 2 CH 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is -NHS(O) 2 CH 2 CH 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is -NHS(O) 2 (C 3-5 cycloalkyl). In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is -NHS(O) 2 (cyclopropyl).

[0135] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -NR 7< S(O) 2 NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -NR 7< C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is - NR 7< C(O)R 10< NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -NR 7< C(O)NR 6< R 6< .

[0136] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -C(O)NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 4a< is -C(O)NH 2 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 4a< is -C(O)NH 2 .

[0137] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a C 3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a C 3-5 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, two R 4a< of the 1-3 R 4a< groups are attached to the same carbon and the two R 4a< , together with the carbon to which they are attached, form a cyclopropyl.

[0138] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< optionally substituted with 1-3 R 4a< groups is:

[0139] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< optionally substituted with 1-3 R 4a< groups is:

[0140] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4< optionally substituted with 1-3 R 4a< groups is: or

[0141] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 6< is independently H, C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, or 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, and wherein the C 3-7 monocyclic cycloalkyl and 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy; or both R6, together with the nitrogen to which they are attached, form a 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0142] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 6< is independently H, C 1-8 alkyl, or C 3-7 monocyclic cycloalkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, and wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy.

[0143] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 6< is independently H or C 1-4 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 6< is independently H or methyl.

[0144] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is H.

[0145] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is C 1-8 alkyl, wherein the C 1-8 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is C 1-8 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is C 1-4 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is methyl.

[0146] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is C 3-7 monocyclic cycloalkyl.

[0147] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 6< is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0148] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, both R 6< , together with the nitrogen to which they are attached, form a 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0149] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 7< is independently H or C 1-8 alkyl which may be the same or different, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 7< is independently H or C 1-4 alkyl which may be the same or different, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 7< is independently H or C 1-3 alkyl which may be the same or different.

[0150] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 7< is H. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 7< is C 1-8 alkyl which may be the same or different, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 7< is C 1-8 alkyl which may be the same or different, wherein the C 1-8 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 7< is C 1-8 alkyl which may be the same or different. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 7< is C 1-4 alkyl which may be the same or different, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 7< is C 1-4 alkyl which may be the same or different, wherein the C 1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 7< is C 1-4 alkyl which may be the same or different. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 7< is C 1-3 alkyl which may be the same or different.

[0151] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 8< is independently -OH, C 1-8 alkyl, C 1-8 alkoxy, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 4-6 membered monocyclic heteroaryl, wherein the C 1-8 alkyl and C 1-8 alkoxy are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 4-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 4-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0152] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 8< is independently -OH, C 1-8 alkyl, or C 1-8 alkoxy.

[0153] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is -OH.

[0154] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-8 alkyl, wherein the C 1-8 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-8 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-4 alkyl.

[0155] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-8 alkoxy, wherein the C 1-8 alkoxy is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-8 alkoxy, wherein the C 1-8 alkoxy is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-8 alkoxy.

[0156] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-5 alkoxy, wherein the C 1-5 alkoxy is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-5 alkoxy, wherein the C 1-5 alkoxy is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 1-5 alkoxy.

[0157] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is C 3-7 monocyclic cycloalkyl.

[0158] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0159] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is 4-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is 4-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 8< is 4-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0160] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 9< is independently C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0161] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 9< is independently C 1-8 alkyl or C 3-7 monocyclic cycloalkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, and wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy.

[0162] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 9< is independently C 1-3 alkyl or C 3-5 monocyclic cycloalkyl.

[0163] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 1-8 alkyl, wherein the C 1-8 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 1-8 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 1-4 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 1-3 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is methyl, ethyl, propyl, or isopropyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 9< is methyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 9< is ethyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 9< is propyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 9< is isopropyl.

[0164] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 3-5 monocyclic cycloalkyl, wherein the C 3-5 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 3-5 monocyclic cycloalkyl, wherein the C 3-5 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is C 3-5 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R 9< is cyclopropyl.

[0165] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0166] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 9< is 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0167] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 10< is C 1-4 alkylene, which may be the same or different. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 10< is independently methylene, ethylene, propylene, isopropylene, butylene, or isobutylene. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R 10< is -CH(CH 3 ) 2 -.

[0168] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, is: In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring A, together with the two carbons to which it is attached, forms a 5-6 membered monocyclic heteroaryl, wherein 5-6 membered monocyclic heteroaryl is substituted with one Z group and has 1-3 ring heteroatoms independently selected from N, O, and S. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring A, together with the two carbons to which it is attached, forms a 5-6 membered monocyclic heteroaryl, wherein 5-6 membered monocyclic heteroaryl is substituted with one Z group and has 1-3 ring heteroatoms independently selected from N, O, and S, wherein one or two ring heteroatoms is a nitrogen.

[0169] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, is:

[0170] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, is:

[0171] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is i) oxo, ii) -OH, iii) -CN, iv) C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one group selected from -OH and C 1-4 alkoxy, and wherein the C 1-5 alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) C 6-8 alkyl, wherein the C 6-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, vi) -Z 1< -Z 2< -Z 3< -Z 4< , wherein Z 1< is C 2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein Z 2< and Z 3< are each independently C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, or 7-10 membered spirocyclic heterocyclylene, wherein the C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z 4< is a C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S, vii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, viii) -S(C 1-8 alkyl), wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, ix) -NR 11< R 12< , wherein one of R 11< and R 12< is H or C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein each C 1-8 alkyl is substituted with 1-3 R 17< groups, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S, x) C 6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , and -NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, xi) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xii) 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiii) 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiv) 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, or xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups.

[0172] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is i) oxo, ii) -OH, iii) -CN, iv) C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one group selected from -OH and C 1-4 alkoxy, and wherein the C 1-5 alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) C 6-8 alkyl, wherein the C 6-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, vi) -Z 1< -Z 2< -Z 3< -Z 4< , wherein Z 1< is C 2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein Z 2< is a C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, wherein Z 3< is a 5-6 membered monocyclic heterocyclylene or 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z 4< is a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, vii) C 3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, viii) -S(C 1-4 alkyl), wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, ix) -NR 11< R 12< , wherein one of R 11< and R 12< is H or C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein each C 1-8 alkyl is substituted with 1-3 R 17a< groups, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, x) C 6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , and -NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, xi) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xii) 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiii) 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups, xiv) 8-10 membered fused bicyclic heteroaryl optionally substituted with 1-3 R 13< groups, or xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R 13< groups.

[0173] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is oxo.

[0174] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -OH or -CN. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -OH. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -CN.

[0175] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one group selected from -OH and C 1-4 alkoxy, and wherein the C 1-5 alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one group selected from -OH and C 1-4 alkoxy, and wherein the C 1-5 alkyl is further substituted with 1-2 groups independently selected from -OH, halogen, and -CN. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one group independently selected from -OH and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 1-5 alkyl, wherein the C 1-5 alkyl is substituted with one -OH. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -C(CH 3 ) 2 H.

[0176] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 6-8 alkyl, wherein the C 6-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 6-8 alkyl, wherein the C 6-8 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 6-8 alkyl.

[0177] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -Z 1< -Z 2< -Z 3< -Z 4< , wherein Z 1< is C 2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein Z 2< and Z 3< are each independently C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, or 7-10 membered spirocyclic heterocyclylene, wherein the C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z 4< is a C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0178] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -Z 1< -Z 2< -Z 3< -Z 4< , wherein Z 1< is C 2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy, wherein Z 2< is a C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, wherein Z 3< is a 5-6 membered monocyclic heterocyclylene or 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z 4< is a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0179] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 1< is C 2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 1< is C 2-6 alkynylene substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 1< is C 2-6 alkynylene. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 1< is C 2-4 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 1< is C 2-4 alkynylene substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 1< is C 2-4 alkynylene. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 1< is C 2 alkynylene.

[0180] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, or 7-10 membered spirocyclic heterocyclylene, wherein the C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0181] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0182] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 3-7 monocyclic cycloalkylene, wherein the C 3-7 monocyclic cycloalkylene is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 3-7 monocyclic cycloalkylene, wherein the C 3-7 monocyclic cycloalkylene is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 3-7 monocyclic cycloalkylene.

[0183] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 6-10 monocyclic or fused bicyclic arylene, wherein the C 6-10 monocyclic or fused bicyclic arylene is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 6-10 monocyclic or fused bicyclic arylene, wherein the C 6-10 monocyclic or fused bicyclic arylene is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 6-10 monocyclic or fused bicyclic arylene. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is phenylene.

[0184] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 4-6 membered monocyclic heterocyclylene, wherein the 4-6 membered monocyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 4-6 membered monocyclic heterocyclylene, wherein the 4-6 membered monocyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 4-6 membered monocyclic heterocyclylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0185] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heteroarylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heteroarylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 5-6 membered monocyclic heteroarylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0186] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 8-10 membered fused or bridged bicyclic heterocyclylene, wherein the 8-10 membered fused or bridged bicyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 8-10 membered fused or bridged bicyclic heterocyclylene, wherein the 8-10 membered fused or bridged bicyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 8-10 membered fused or bridged bicyclic heterocyclylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0187] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 8-10 membered fused bicyclic heteroarylene, wherein the 8-10 membered fused bicyclic heteroarylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 8-10 membered fused bicyclic heteroarylene, wherein the 8-10 membered fused bicyclic heteroarylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 8-10 membered fused bicyclic heteroarylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0188] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 7-10 membered spirocyclic heterocyclylene, wherein the 7-10 membered spirocyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 7-10 membered spirocyclic heterocyclylene, wherein the 7-10 membered spirocyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is 7-10 membered spirocyclic heterocyclylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0189] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 1< is C 2 alkynylene and Z 2< is phenylene.

[0190] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, or 7-10 membered spirocyclic heterocyclylene, wherein the C 3-7 monocyclic cycloalkylene, C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0191] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 5-6 membered monocyclic heterocyclylene or 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0192] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is C 3-7 monocyclic cycloalkylene, wherein the C 3-7 monocyclic cycloalkylene is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is C 3-7 monocyclic cycloalkylene, wherein the C 3-7 monocyclic cycloalkylene is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is C 3-7 monocyclic cycloalkylene.

[0193] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is C 6-10 monocyclic or fused bicyclic arylene, wherein the C 6-10 monocyclic or fused bicyclic arylene is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is C 6-10 monocyclic or fused bicyclic arylene, wherein the C 6-10 monocyclic or fused bicyclic arylene is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is C 6-10 monocyclic or fused bicyclic arylene.

[0194] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 4-6 membered monocyclic heterocyclylene, wherein the 4-6 membered monocyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 4-6 membered monocyclic heterocyclylene, wherein the 4-6 membered monocyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 4-6 membered monocyclic heterocyclylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0195] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heteroarylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heteroarylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 5-6 membered monocyclic heteroarylene having 1-3 ring heteroatoms independently selected from N, O, and S. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is imidazolylene.

[0196] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 8-10 membered fused or bridged bicyclic heterocyclylene, wherein the 8-10 membered fused or bridged bicyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 8-10 membered fused or bridged bicyclic heterocyclylene, wherein the 8-10 membered fused or bridged bicyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 8-10 membered fused or bridged bicyclic heterocyclylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0197] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 8-10 membered fused bicyclic heteroarylene, wherein the 8-10 membered fused bicyclic heteroarylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 8-10 membered fused bicyclic heteroarylene, wherein the 8-10 membered fused bicyclic heteroarylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 8-10 membered fused bicyclic heteroarylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0198] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 7-10 membered spirocyclic heterocyclylene, wherein the 7-10 membered spirocyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 7-10 membered spirocyclic heterocyclylene, wherein the 7-10 membered spirocyclic heterocyclylene has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 3< is 7-10 membered spirocyclic heterocyclylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0199] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 3-7 monocyclic cycloalkyl, C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0200] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0201] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is C 3-7 monocyclic cycloalkyl.

[0202] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is C 6-10 monocyclic or fused bicyclic aryl, wherein the C 6-10 monocyclic or fused bicyclic aryl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is C 6-10 monocyclic or fused bicyclic aryl, wherein the C 6-10 monocyclic or fused bicyclic aryl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is C 6-10 monocyclic or fused bicyclic aryl.

[0203] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0204] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is a 5-6 membered monocyclic heterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with one group selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is a 5-6 membered monocyclic heterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with one group selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is a 5-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0205] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is pyrrolidinyl substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is pyrrolidinyl substituted with one -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is pyrrolidinyl.

[0206] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0207] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0208] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0209] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from - OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 4< is 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0210] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z 2< is C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the C 6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 4-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and Z 3< is a 5-6 membered monocyclic heterocyclylene or 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, and -C(O)R 8< , and wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0211] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 3-7 monocyclic cycloalkyl or -S(C 1-4 alkyl), wherein the C 3-7 monocyclic cycloalkyl and the C 1-4 alkyl are each optionally substituted with 1-2 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 3-7 monocyclic cycloalkyl or -S(C 1-4 alkyl), wherein the C 3-7 monocyclic cycloalkyl and the C 1-4 alkyl are each substituted with 1-2 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 3-7 monocyclic cycloalkyl or -S(C 1-4 alkyl).

[0212] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is cyclopropyl.

[0213] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(C 18 alkyl), wherein the C 1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(C 18 alkyl), wherein the C 1-8 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(C 18 alkyl).

[0214] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(C 1-4 alkyl), wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(C 1-4 alkyl), wherein the C 1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C 14 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(C 1-4 alkyl). In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(methyl), -S(ethyl), -S(propyl), or -S(isopropyl). In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(CH 3 ).

[0215] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H or C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein each C 1-8 alkyl is substituted with 1-3 R 17< groups, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0216] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H or C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein each C 1-8 alkyl is substituted with 1-3 R 17a< groups, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0217] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein each C 1-8 alkyl is substituted with 1-3 R 17< groups, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0218] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-8 alkyl, wherein the C 1-8 alkyl is substituted with 1-3 R 17< groups.

[0219] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 R 17< groups.

[0220] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-8 alkyl, wherein the C 1-8 alkyl is substituted with 1-3 R 17a< groups.

[0221] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 R 17a< groups.

[0222] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, and -CN.

[0223] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 groups independently selected from C 1-4 alkoxy and -NR 6< R 6< , and wherein the C 1-4 alkoxy is optionally substituted with one C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with one group selected from -OH, methoxy, -OCH 2 CH 2 OCH 3 , or -N(C 1-3 alkyl) 2 , wherein each C 1-3 alkyl may be the same or different.

[0224] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with 1-3 R 17a< groups.

[0225] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with one group selected from cyclopropyl, morpholinyl, and imidazolyl, wherein the cyclopropyl, morpholinyl, and imidazolyl are each optionally substituted with one group selected from -OH, halogen, and C 1-4 alkoxy.

[0226] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein -NR 11< R 12< is

[0227] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0228] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is cyclopropyl, oxetanyl, tetrahydrofuranyl, or pyrrolidinyl, each of which is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy.

[0229] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0230] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is cyclopropyl, oxetanyl, tetrahydrofuranyl, or pyrrolidinyl, each of which is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy.

[0231] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo and C 1-4 alkyl, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0232] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each substituted with 1-3 groups independently selected from oxo and C 1-4 alkyl, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0233] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is cyclopropyl, oxetanyl, tetrahydrofuranyl, or pyrrolidinyl.

[0234] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl.

[0235] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is cyclopropyl, wherein the cyclopropyl is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is cyclopropyl, wherein the cyclopropyl is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is cyclopropyl.

[0236] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0237] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is oxetanyl, tetrahydrofuranyl, or pyrrolidinyl, wherein the oxetanyl, tetrahydrofuranyl, and pyrrolidinyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is oxetanyl, tetrahydrofuranyl, or pyrrolidinyl, wherein the oxetanyl, tetrahydrofuranyl, and pyrrolidinyl are each substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is oxetanyl, tetrahydrofuranyl, or pyrrolidinyl.

[0238] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0239] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is pyrazolyl, wherein the pyrazolyl is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is pyrazolyl, wherein the pyrazolyl is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is pyrazolyl.

[0240] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0241] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0242] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is H and the other of R 11< and R 12< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is H and the other of R 11< and R 12< is 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0243] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein -NR 11< R 12< is

[0244] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein each C 1-8 alkyl is substituted with 1-3 R 17< groups, wherein the C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0245] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, wherein each C 1-8 alkyl is substituted with 1-3 R 17< groups.

[0246] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-6 alkyl and the other of R 11< and R 12< is C 1-6 alkyl, wherein each C 1-6 alkyl is substituted with 1-3 R 17< groups.

[0247] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is C 1-8 alkyl, wherein each C 1-8 alkyl is substituted with 1-3 R 17a< groups.

[0248] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-6 alkyl and the other of R 11< and R 12< is C 1-6 alkyl, wherein each C 1-6 alkyl is substituted with 1-3 R 17a< groups.

[0249] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 17< is independently -OH, halogen, -CN, C 1-4 alkoxy, -NR 6< R 6< , C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl, wherein the C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0250] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 17a< is independently -OH, halogen, -CN, C 1-4 alkoxy, -NR 6< R 6< , C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the C 1-4 alkoxy, C 3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0251] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl, wherein the C 3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is C 3-7 monocyclic cycloalkyl.

[0252] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0253] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0254] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0255] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0256] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR 11< R 12< , wherein one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C 1-4 alkyl, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R 11< and R 12< is C 1-8 alkyl and the other of R 11< and R 12< is 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0257] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(0)NR 6< R 6< , -C(O)R 8< , and -NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0258] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 6-10 monocyclic or fused bicyclic aryl substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(0)NR 6< R 6< , -C(O)R 8< , and -NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0259] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C 6-10 monocyclic or fused bicyclic aryl.

[0260] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is phenyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(0)NR 6< R 6< , -C(O)R 8< , and - NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0261] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is phenyl substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , -NR 6< R 6< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(0)NR 6< R 6< , -C(O)R 8< , and -NR 6< R 6< , and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0262] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is phenyl, wherein the phenyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with one -C(O)R 8< and each have 1-3 ring heteroatoms independently selected from N, O, and S. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is phenyl, wherein the phenyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -C(O)NR 6< R 6< , -C(O)R 8< , 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with one -C(O)R 8< and each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0263] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is phenyl, wherein the phenyl is optionally substituted 1-3 groups independently selected from halogen, -C(O)NR 6< R 6< , morpholinyl, or piperazinyl, wherein the morpholinyl and piperazinyl are each optionally substituted with one -C(O)R 8< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is phenyl, wherein the phenyl is substituted 1-3 groups independently selected from halogen, -C(0)NR 6< R 6< , morpholinyl, or piperazinyl, wherein the morpholinyl and piperazinyl are each optionally substituted with one -C(O)R 8< .

[0264] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is

[0265] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is phenyl.

[0266] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 R 13< groups and each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0267] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 R 13< groups and each have 1-3 ring heteroatoms independently selected from N, O, and S, wherein at least one ring heteroatom is a nitrogen.

[0268] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-2 R 13< groups and each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0269] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-2 R 13< groups and each have 1-3 ring heteroatoms independently selected from N, O, and S, wherein at least one ring heteroatom is a nitrogen.

[0270] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspirl[3.3]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is optionally substituted with 1-3 R 13< groups.

[0271] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspirl[3.3]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is optionally substituted with 1-2 R 13< groups.

[0272] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspirl[3.3]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is substituted with 1-3 R 13< groups.

[0273] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspirl[3.3]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is substituted with 1-2 R 13< groups.

[0274] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspirl[3.3]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl.

[0275] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0276] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl, wherein the azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl are each optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl, wherein the azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl are each substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl.

[0277] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0278] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 2,5-diazabicyclo[2.2.1]heptanyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl, wherein the 2,5-diazabicyclo[2.2.1]heptanyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, and 2,3-dihydrobenzo[b][1,4]dioxinyl are each optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 2,5-diazabicyclo[2.2.1]heptanyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl, wherein the 2,5-diazabicyclo[2.2.1]heptanyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, and 2,3-dihydrobenzo[b][1,4]dioxinyl are each substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 2,5-diazabicyclo[2.2.1]heptanyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl.

[0279] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0280] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, pyrazolyl, imidazolyl, or pyrimidinyl, wherein the pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, pyrazolyl, imidazolyl, and pyrimidinyl are each optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, pyrazolyl, imidazolyl, or pyrimidinyl, wherein the pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, pyrazolyl, imidazolyl, and pyrimidinyl are each substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, pyrazolyl, imidazolyl, or pyrimidinyl.

[0281] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0282] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is isoindolinyl or 1H-benzo[d]imidazolyl, wherein the isoindolinyl and 1H-benzo[d]imidazolyl are each optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is isoindolinyl or 1H-benzo[d]imidazolyl, wherein the isoindolinyl and 1H-benzo[d]imidazolyl are each substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is isoindolinyl or 1H-benzo[d]imidazolyl.

[0283] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0284] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, or 1-oxa-3,8-diazaspiro[4.5]decanyl, wherein the 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, and 1-oxa-3,8-diazaspiro[4.5]decanyl are each optionally substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, or 1-oxa-3,8-diazaspiro[4.5]decanyl, wherein the 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, and 1-oxa-3,8-diazaspiro[4.5]decanyl are each substituted with 1-3 R 13< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, or 1-oxa-3,8-diazaspiro[4.5]decanyl.

[0285] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is wherein Ring Z a< is a 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have one ring heteroatom that is nitrogen and each optionally have 1-2 additional ring heteroatoms independently selected from N, O, and S, and Ring Z a< is optionally substituted with 1-3 R 13< groups.

[0286] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is wherein Ring Z a< is a 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have one ring heteroatom that is nitrogen and each optionally have 1-2 aring heteroatoms independently selected from N, O, and S, and Ring Z a< is optionally substituted with 1-2 R 13< groups.

[0287] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring Z a< is each of which is optionally substituted with 1-3 R 13< groups.

[0288] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring Z a< is each of which is optionally substituted with 1-2 R 13< groups.

[0289] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 13< is independently oxo, -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -NR 6< R 6< , -C(O)R 10< NR 6< R 6< , -C(O)NR 6< R 6< , -C(O)R 8< , C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 R 14< groups, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0290] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 13< is independently oxo, -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -NR 6< R 6< , -C(O)R 10< NR 6< R 6< , -C(O)NR 6< R 6< , -C(O)R 8< , C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, or 8-10 membered fused bicyclic heteroaryl, wherein the C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, and 8-10 membered fused bicyclic heteroaryl are each optionally substituted with 1-3 R 14< groups, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, and 8-10 membered fused bicyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0291] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 13< is independently oxo, -OH, halogen, -CN, C 1-4 alkyl, C 1-4 alkoxy, -NR 6< R 6< , -C(O)R 10< NR 6< R 6< , -'C(O)NR 6< R 6< , -C(O)R 8< , C 6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, or 8-10 membered fused bicyclic heteroaryl, wherein the C 6-10 monocyclic or fused bicyclic aryl is optionally substituted with 1-3 R 14< groups and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, and 8-10 membered fused bicyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0292] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 13< is independently oxo, -OH, halogen, methyl, ethyl, isopropyl, -NR 6< R 6< , -C(O)R 10< NR 6< R 6< , -C(O)NR 6< R 6< , -C(O)R 8< , phenyl, oxetanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridinyl, pyrimidinyl, or 1H-benzo[d]imidazolyl, wherein the phenyl is optionally substituted with one R 14< group.

[0293] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is oxo. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is -OR. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is halogen. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is -CN. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is C 1-4 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is -NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is -C(O)R 10< NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is -C(O)NR 6< R 6< . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is -C(O)R 9< .

[0294] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is C 6-10 monocyclic or fused bicyclic aryl, wherein the C 6-10 monocyclic or fused bicyclic aryl is optionally substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is C 6-10 monocyclic or fused bicyclic aryl, wherein the C 6-10 monocyclic or fused bicyclic aryl is substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is C 6-10 monocyclic or fused bicyclic aryl.

[0295] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0296] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0297] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0298] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0299] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 R 14< groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 13< is 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0300] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 14< is independently halogen, C 1-4 alkyl, -C(O)R 8< , 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, CN, and C 1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 ; wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S.

[0301] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 14< is independently halogen, C 1-4 alkyl, -C(O)R 8< , or 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, CN, and C 1-4 alkoxy, and wherein 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S is optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 .

[0302] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 14< is independently halogen, C 1-4 alkyl, or 5-6 membered monocyclic heteroaryl, wherein the C 1-4 alkyl is optionally substituted with 1-3 halogens, and wherein the 5-6 membered heteroaryl is optionally substituted with -CH 2 OCH 2 CH 2 Si(CH 3 ) 3 and has 1-3 ring heteroatoms independently selected from N, O, and S.

[0303] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 14< is independently halogen, C 1-4 alkyl, or imidazolyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 halogens, and wherein the imidazolyl is optionally substituted with -CH 2 OCH 2 CH 2 Si(CH 3 ) 3 .

[0304] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is halogen. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is -C(O)R 8< .

[0305] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, CN, and C 1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, CN, and C 1-4 alkoxy.

[0306] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1-3 halogens. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is C 1-4 alkyl, wherein the C 1-4 alkyl is substituted with 1-3 halogens.

[0307] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is C 1-4 alkyl.

[0308] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 4-6 membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0309] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0310] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is imidazolyl, wherein the imidazolyl is optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is imidazolyl, wherein the imidazolyl is substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is imidazolyl, wherein the imidazolyl is optionally substituted with -CH 2 OCH 2 CH 2 Si(CH 3 ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is imidazolyl.

[0311] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 8-10 membered fused or bridged bicyclic heterocyclyl, wherein the 8-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0312] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0313] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is optionally substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with -OR 10< Si(R 15< ) 3 . In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 14< is 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0314] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R 15< is independently C 1-3 alkyl, which may be the same or different. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 15< is methyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 15< is ethyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 15< is propyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R 15< is isopropyl.

[0315] In some embodiments of the compound of Formula I, Ia, II, or IIa, the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0316] In one aspect, provided herein are compounds having the structures: or a pharmaceutically acceptable salt thereof.III. Compositions and Kits

[0317] 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 a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. The compounds provided herein may be the sole active ingredient or one of the active ingredients of the pharmaceutical compositions. Suitable pharmaceutically acceptable vehicles may 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.).

[0318] In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein (i.e., a compound of Formula I, Ia, II, or IIa), 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.

[0319] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (i.e., 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 (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the one or more additional therapeutic agents include agents that are therapeutic for HIV infection. In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: islatravir, bictegravir or a pharmaceutically acceptable salt thereof, 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.

[0321] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical compositions may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0322] 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 sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. In some embodiments, the compounds and pharmaceutical compositions disclosed herein are administered by subcutaneous injection.

[0323] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of inj ectables.

[0324] In some embodiments, the sterile injectable preparation disclosed herein may also be a sterile injectable solution or suspension prepared from a reconstituted lyophilized powder in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0325] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. In certain embodiments the suspension is a microsuspension. In certain embodiments the suspension is a nanosuspension.

[0326] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will include one or more excipients. Excipients should be compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. Examples of suitable excipients are well known to the person skilled in the art of parenteral formulation and may be found e.g., in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[0327] Examples of solubilizing excipients in a parenteral formulation (e.g., an SC or IM formulation) include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338, 188, or 207). In some embodiments, disclosed herein is a parenteral administration (e.g., an SC or IM formulation) that comprises a compound of Formula I, Ia, II, or IIb, or a pharmaceutical salt thereof, and a poloxamer, in particular poloxamer 338. In some embodiments, the amount of poloxamer (e.g., poloxamer 388) in a parenteral administration disclosed herein is less than about 5%, such as less than about 3%, about 2%, about 1%, or about 0.5%.

[0328] Examples of solubilizing excipients in a parenteral formulation (e.g., an SC or IM formulation) include, but are not limited to, polysorbates (such as polysorbate 20 or 80) , poloxamers (such as poloxamer 338, 188, or 207). In some embodiments, disclosed herein is a parenteral administration (e.g., an SC or IM formulation) that comprises a compound of Formula I, Ia, II, or IIb, or a pharmaceutical salt thereof, and a poloxamer.

[0329] In some embodiments, the compounds and pharmaceutical compositions disclosed herein are administered with implants.

[0330] Oral administration may be another route for administration of the compounds provided herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, the active ingredient (such as a compound provided herein) is usually diluted by an excipient and / or enclosed within such a carrier that can be 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, suspensions, 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 powders.

[0331] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combinations thereof. The pharmaceutical compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents; or any combinations thereof.

[0332] The pharmaceutical compositions that include at least one compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof can be formulated so as to provide quick, sustained or 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 the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts. 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.

[0333] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described 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.

[0334] 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.

[0335] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.IV. Compounds and compositions for use in methods of treatment

[0336] The methods 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. 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 HIV capsid inhibitor as disclosed herein for a given cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the present disclosure may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine 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.

[0337] In one aspect, the present disclosure provides a compound provided herein (i.e., a compound of Formula I, Ia, II, or IIa), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein for use in 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 compound provided herein (i.e., a compound of Formula I, Ia, II, or IIa), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0338] In some embodiments, the methods provided herein further comprise administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0339] 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, 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 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, 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.

[0340] In some embodiments, the one or more additional therapeutic agents is 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...

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H or C1-3 alkyl; each R5 is halogen which may be the same or different; R1 is H, -CN, halogen, C1-8 alkyl, C3-7 monocyclic cycloalkyl, -C(O)NR6R6, -NR6R6, -NR7C(O)R8, or -C(O)R8, wherein the C1-8 alkyl and C3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy; Ring B, together with the two carbons to which it is attached, forms a C3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-4 membered monocyclic heterocyclyl, 5-7 membered monocyclic heterocyclyl, or 5-9 membered fused or bridged bicyclic heterocyclyl, wherein the C3-7 monocyclic cycloalkyl, 5-9 membered fused or bridged bicyclic cycloalkyl, 3-7 membered monocyclic heterocyclyl, and 5-9 membered fused or bridged bicyclic heterocyclyl are each optionally substituted with 1-5 R16 groups, wherein the 3-4 membered monocyclic heterocyclyl has 1-2 ring heteroatoms independently selected from N, O, and S, and wherein the 5-7 membered monocyclic heterocyclyl and 5-9 membered fused or bridged bicyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R16 is independently oxo, -OH, halogen, -CN, C1-8 alkyl, C1-4 alkoxy, C3-7 monocyclic cycloalkyl, -C(O)NR6R6, -NR6R6, -NR6C(O)R8, or -C(O)R8, wherein the C1-8 alkyl and C3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy; R4 is a phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, or 9-12 membered fused tricyclic heteroaryl, wherein the phenyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl are each optionally substituted with 1-3 R4a groups, and wherein the 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, 9-12 membered fused or bridged tricyclic heterocyclyl, and 9-12 membered fused tricyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R4a is independently oxo, -OH, halogen, -CN, C1-8 alkyl, C1-8 alkoxy, -NR6R6, -NR7S(O)2R9, -NR7S(O)2NR6R6, -NR7C(O)R8, -NR7C(O)R10NR6R6, -NR7C(O)NR6R6, or -C(O)NR6R6, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, or two R4a of the 1-3 R4a groups are attached to the same carbon and the two R4a, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl; each R6 is independently H, C1-8 alkyl, C3-7 monocyclic cycloalkyl, or 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and wherein the C3-7 monocyclic cycloalkyl and 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy; or both R6, together with the nitrogen to which they are attached, form a 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S; each R7 is independently H or C1-8 alkyl which may be the same or different, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy; each R8 is independently -OH, C1-8 alkyl, C1-8 alkoxy, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 4-6 membered monocyclic heteroaryl, wherein the C1-8 alkyl and C1-8 alkoxy are each optionally substituted with 1-3 groups independently selected from -OH, halogen, - CN, and C1-4 alkoxy, wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 4-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 4-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R9 is independently C1-8 alkyl, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R10 is C1-4 alkylene, which may be the same or different; Ring A, together with the two carbons to which it is attached, forms a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each substituted with one Z group and each have 1-3 ring heteroatoms independently selected from N, O, and S; wherein is: Z is i) oxo, ii) -OH, iii) -CN, iv) C1-5 alkyl, wherein the C1-5 alkyl is substituted with one group selected from -OH and C1-4 alkoxy, and wherein the C1-5 alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) C6-8 alkyl, wherein the C6-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) -Z1-Z2-Z3-Z4, wherein Z1 is C2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, wherein Z2 and Z3 are each independently C3-7 monocyclic cycloalkylene, C6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, or 7-10 membered spirocyclic heterocyclylene, wherein the C3-7 monocyclic cycloalkylene, C6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8, and wherein the 4-6 membered monocyclic heterocyclylene, 5-6 membered monocyclic heteroarylene, 8-10 membered fused or bridged bicyclic heterocyclylene, 8-10 membered fused bicyclic heteroarylene, and 7-10 membered spirocyclic heterocyclylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z4 is a C3-7 monocyclic cycloalkyl, C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C3-7 monocyclic cycloalkyl, C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S, vii) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, viii) -S(C1-8 alkyl), wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, ix) -NR11R12, wherein one of R11 and R12 is H or C1-8 alkyl and the other of R11 and R12 is C1-8 alkyl, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein each C1-8 alkyl is substituted with 1-3 R17 groups, wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S, x) C6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, -C(O)NR6R6, -C(O)R8, -NR6R6, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, - C(O)NR6R6, -C(O)R8, and -NR6R6, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, xi) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups, xii) 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups, xiii) 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups, xiv) 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups, or xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups; each R17 is independently -OH, halogen, -CN, C1-4 alkoxy, -NR6R6, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl, wherein the C1-4 alkoxy, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 groups independently selected from oxo, - OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R13 is independently oxo, -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, -NR6R6, -C(O)R10NR6R6, -C(O)NR6R6, -C(O)R8, C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with 1-3 R14 groups, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R14 is independently halogen, C1-4 alkyl, -C(O)R8, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the C1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, CN, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl are each optionally substituted with C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with -OR10Si(R15)3; wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R15 is independently C1-3 alkyl, which may be the same or different; and n is 0, 1, 2, or 3.

2. The compound of claim 1, wherein the compound is of Formula Ia: or a pharmaceutically acceptable salt thereof.

3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H or C1-3 alkyl; each R5 is halogen which may be the same or different; R1 is H, -CN, halogen, C1-8 alkyl, or C3-7 monocyclic cycloalkyl, wherein the C1-8 alkyl and C3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy; Ring B, together with the two carbons to which it is attached, forms a C3-7 monocyclic cycloalkyl or 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl and 5-9 membered fused or bridged bicyclic cycloalkyl are each optionally substituted with 1-5 R16a groups; each R16a is independently -OH, halogen, -CN, C1-8 alkyl, C1-4 alkoxy, and C3-7 monocyclic cycloalkyl, wherein the C1-8 alkyl and C3-7 monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy; R4 is a phenyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 9-12 membered fused or bridged tricyclic heterocyclyl, wherein the phenyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 9-12 membered fused or bridged tricyclic heterocyclyl are each optionally substituted with 1-3 R4a groups, and wherein the 8-10 membered fused or bridged bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 9-12 membered fused or bridged tricyclic heterocyclyl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R4a is independently oxo, -OH, halogen, -CN, C1-8 alkyl, C1-8 alkoxy, -NR6R6, -NR7S(O)2R9, or -C(O)NR6R6, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, or two R4a of the 1-3 R4a groups are attached to the same carbon and the two R4a, together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl; each R6 is independently H, C1-8 alkyl, or C3-7 monocyclic cycloalkyl, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and wherein the C3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy; each R7 is independently H or C1-8 alkyl which may be the same or different, wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy; each R8 is independently -OH, C1-8 alkyl, or C1-8 alkoxy; each R9 is independently C1-8 alkyl or C3-7 monocyclic cycloalkyl wherein the C1-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and wherein the C3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy; each R10 is C1-4 alkylene, which may be the same or different; Ring A, together with the two carbons to which it is attached, forms a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each substituted with one Z group and each have 1-3 ring heteroatoms independently selected from N, O, and S; is: Z is i) oxo, ii) -OH, iii) -CN, iv) C1-5 alkyl, wherein the C1-5 alkyl is substituted with one group selected from -OH and C1-4 alkoxy, and wherein the C1-5 alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) C6-8 alkyl, wherein the C6-8 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) -Z1-Z2-Z3-Z4, wherein Z1 is C2-6 alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, wherein Z2 is a C6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the C6-10 monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, and 5-6 membered monocyclic heteroarylene, are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8, and wherein the 4-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, wherein Z3 is a 5-6 membered monocyclic heterocyclylene or 5-6 membered monocyclic heteroarylene, wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8, and wherein the 5-6 membered monocyclic heterocyclylene and 5-6 membered monocyclic heteroarylene each have 1-3 ring heteroatoms independently selected from N, O, and S, and wherein Z4 is a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8, and wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, vii) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, viii) -S(C1-4 alkyl), wherein the C1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, ix) -NR11R12, wherein one of R11 and R12 is H or C1-8 alkyl and the other of R11 and R12 is C1-8 alkyl, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein each C1-8 alkyl is substituted with 1-3 R17a groups; wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, x) C6-10 monocyclic or fused bicyclic aryl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, -C(O)NR6R6, -C(O)R8, -NR6R6, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, -C(O)NR6R6, -C(O)R8, and -NR6R6, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, xi) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups, xii) 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups, xiii) 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups, or xiv) 8-10 membered fused bicyclic heteroaryl optionally substituted with 1-3 R13 groups, or xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R13 groups; each R17a is independently -OH, halogen, -CN, C1-4 alkoxy, -NR6R6, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the C1-4 alkoxy, C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R13 is independently oxo, -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, -NR6R6, -C(O)R10NR6R6, -C(O)NR6R6, -C(O)R8, C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, or 8-10 membered fused bicyclic heteroaryl, wherein the C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, and 8-10 membered fused bicyclic heteroaryl are each optionally substituted with 1-3 R14 groups, and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, and 8-10 membered fused bicyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; each R14 is independently halogen, C1-4 alkyl, -C(O)R8, or 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the C1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, CN, and C1-4 alkoxy, and wherein the 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S is optionally substituted with C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with -OR10Si(R15)3; each R15 is independently C1-3 alkyl, which may be the same or different; and n is 0, 1, 2, or 3.

4. The compound of any one of claims 1-3, wherein n is 2.

5. The compound of any one of claims 1, 3, and 4, wherein the compound is of Formula II: or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-5, wherein the compound is of Formula IIa: or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R5 is fluoro, and / or wherein R2 and R3 are H.

8. The compound of any one of claims 1-2 and 4-7, or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclohexyl, tetrahydropyranyl, each of which is optionally substituted with 1-4 groups independently selected from oxo, -OH, halogen, -CN, C1-8 alkyl, C1-4 alkoxy, C3-7 monocyclic cycloalkyl, -C(O)NR6R6, -NR6R6, -NR6C(O)R8, and -C(O)R8.

9. The compound of any one of claims 1-2 and 4-8, or a pharmaceutically acceptable salt thereof, wherein is: or wherein is:

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-4 alkyl optionally substituted with 1-3 halogens or wherein R1 is -CHF2 or -CF3.

11. The compound of any one of claims 1-7 and 10, or a pharmaceutically acceptable salt thereof, wherein Ring B, together with the two carbons to which it is attached, forms a cyclohexyl or 6-7 membered fused or bridged bicyclic cycloalkyl, wherein the cyclohexyl and 6-7 membered fused or bridged bicyclic cycloalkyl are each optionally substituted with 1-5 halogens.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein (a) R4 is each of which is optionally substituted with 1-3 R4a groups; or (b) R4 is a phenyl or 9-10 membered fused or bridged bicyclic heterocyclyl, wherein the phenyl and 9-10 membered fused or bridged bicyclic heterocyclyl are each optionally substituted with 1-3 R4a groups and wherein the 9-10 membered fused or bridged bicyclic heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S; or (c) R4 is each of which is optionally substituted with 1-3 R4a groups; or (d) R4 is which is optionally substituted with 1-3 R4a groups.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein (a) each R4a is independently oxo, halogen, -CN, C1-8 alkyl, -NR6R6, -NR7S(O)2R9, or - C(O)NR6R6, or wherein two R4a of the 1-3 R4a groups are attached to the same carbon and the two R4a, together with the carbon to which they are attached, form a cyclopropyl, a cyclobutyl, or cyclopentyl; and / or (b) each R7 is independently H or C1-3 alkyl; and / or (c) each R9 is independently C1-3 alkyl or C3-5 monocyclic cycloalkyl.

14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R4 optionally substituted with 1-3 R4a groups is: or wherein R4 optionally substituted with 1-3 R4a groups is: or 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein is:

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein Z1 is C2 alkynylene and Z2 is phenylene; and / or wherein Z3 is a 5-6 membered monocyclic heteroarylene having 1-3 ring heteroatoms independently selected from N, O, and S; and / or wherein Z4 is a 5-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with one group independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8.

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein (a) Z is oxo; or (b) Z is -OH or -CN; or (c) Z is C3-7 monocyclic cycloalkyl or -S(C1-4 alkyl), wherein the C3-7 monocyclic cycloalkyl and the C1-4 alkyl are each optionally substituted with 1-2 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy; or (d) Z is -NR11R12; optionally wherein (i) one of R11 and R12 is H and the other of R11 and R12 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, and -CN; or (ii) one of R11 and R12 is H and the other of R11 and R12 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from C1-4 alkoxy and -NR6R6, and wherein the C1-4 alkoxy is optionally substituted with one C1-4 alkoxy, optionally wherein the C1-6 alkyl is substituted with one group selected from -OH, methoxy, -OCH2CH2OCH3, or -N(C1-3 alkyl)2, wherein each C1-3 alkyl may be the same or different; or (iii) one of R11 and R12 is H and the other of R11 and R12 is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with one group independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S, optionally wherein the C1-6 alkyl of R11 and R12 is substituted with one group selected from cyclopropyl, morpholinyl, and imidazolyl, wherein the cyclopropyl, morpholinyl, and imidazolyl are each optionally substituted with one group selected from -OH, halogen, and C1-4 alkoxy; or (iv) NR11R12 is or (v) one of R11 and R12 is H and the other of R11 and R12 is C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, are each optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, CN, C1-4 alkyl, and C1-4 alkoxy, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; or (vi) one of R11 and R12 is H and the other of R11 and R12 is C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from oxo and C1-4 alkyl, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; or (vii) one of R11 and R12 is H and the other of R11 and R12 is cyclopropyl, oxetanyl, tetrahydrofuranyl, or pyrrolidinyl, each of which is optionally substituted with 1-3 groups independently selected from oxo, -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy; or (viii) -NR11R12 is or (e) Z is phenyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, -C(O)NR6R6, -C(O)R8, 4-6 membered monocyclic heterocyclyl, and 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with one -C(O)R8 and each have 1-3 ring heteroatoms independently selected from N, O, and S, or (f) Z is phenyl optionally substituted with 1-3 groups independently selected from halogen, - C(O)NR6R6, morpholinyl, or piperazinyl, wherein the morpholinyl and piperazinyl are each optionally substituted with one -C(O)R8; or (g) Z is 18. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein (a) Z is 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl: (i) are each optionally substituted with 1-3 R13 groups and each have 1-3 ring heteroatoms independently selected from N, O, and S; or (ii) are each optionally substituted with 1-2 R13 groups and each have 1-3 ring heteroatoms independently selected from N, O, and S, or (iii) each have 1-3 ring heteroatoms independently selected from N, O, and S, wherein at least one ring heteroatom is a nitrogen; or (b) Z is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is optionally substituted with 1-3 R13 groups; or (c) Z is wherein Ring Za is a 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl, 8-10 membered fused or bridged bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl each have one ring heteroatom that is nitrogen and each optionally have 1-2 additional ring heteroatoms independently selected from N, O, and S, and Ring Za is optionally substituted with 1-3 R13 groups, optionally wherein Ring Za is optionally substituted with 1-2 R13 groups or optionally wherein Ring Za is each of which is optionally substituted with 1-3 R13 groups; and / or wherein each R13 is independently oxo, -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, - NR6R6, -C(O)R10NR6R6, -C(O)NR6R6, -C(O)R8, C6-10 monocyclic or fused bicyclic aryl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, or 8-10 membered fused bicyclic heteroaryl, wherein the C6-10 monocyclic or fused bicyclic aryl is optionally substituted with 1-3 R14 groups and wherein the 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused or bridged bicyclic heterocyclyl, and 8-10 membered fused bicyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; or wherein each R13 is independently oxo, -OH, halogen, methyl, ethyl, isopropyl, -NR6R6, -C(O)R10NR6R6, -C(O)NR6R6, -C(O)R8, phenyl, oxetanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridinyl, pyrimidinyl, or 1H-benzo[d]imidazolyl, wherein the phenyl is optionally substituted with one R14 group.

19. The compound of any one of claims 1-15 and 18, or a pharmaceutically acceptable salt thereof, wherein (a) each R14 is independently halogen, C1-4 alkyl, or 5-6 membered monocyclic heteroaryl, wherein the C1-4 alkyl is optionally substituted with 1-3 halogens, and wherein the 5-6 membered heteroaryl is optionally substituted with -CH2OCH2CH2Si(CH3)3 and has 1-3 ring heteroatoms independently selected from N, O, and S, optionally wherein R14 is imidazolyl optionally substituted with -CH2OCH2CH2Si(CH3)3; or (b) each R6 is independently H or C1-4 alkyl, or each R6 is independently H or methyl; or (c) R10 is -CH(CH3)2-; or (d) R8 is C1-5 alkoxy.

20. The compound of any one of claims 1, 3-5, and 7, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

21. A compound that is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier, optionally further comprising one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

23. A compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for use in a method 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 the compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, optionally wherein the method further comprises administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof; optionally wherein (a) 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, 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 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, 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; or (b) the one or more additional therapeutic agents is 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; or (c) the one or more additional therapeutic agents is selected from the group consisting of islatravir, 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; or (d) the one or more 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.