Capsid inhibitors for the treatment of HIV

Abstract

The present disclosure relates generally to compounds of Formula I represented below: [Image disponible dans le document PDF, Image available in the PDF document] The present disclosre also relates to pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of a Retroviridae viral infection, including an infection caused by the HIV virus.

Description

CAPSID INHIBITORS FOR THE TREATMENT OF HIV CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 044,086, filed June 25, 2020. FIELD

[0002] This disclosure relates generally to novel compounds, pharmaceutical compositions comprising said compounds, and 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

[0003] 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. SUMMARY

[0004] In one aspect, provided herein is a compound of Formula I, [Image disponible dans le document PDF, Image available in the PDF document] Formula I or a pharmaceutically acceptable salt thereof, wherein <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> are each independently H or <semantics>ℂ1−3<annotation encoding="application / x-tex">\mathbb{C}_{1-3}< / annotation>< / semantics> 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, <semantics>−NR7C(O)R8<annotation encoding="application / x-tex">-NR^{7}C(O)R^{8}< / annotation>< / semantics>, or <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^{8}< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 CA 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, <semantics>−NR7S(O)2R9<annotation encoding="application / x-tex">-NR^{7}S(O)_{2}R^{9}< / annotation>< / semantics>, <semantics>−NR7S(O)2NR6R6<annotation encoding="application / x-tex">-NR^{7}S(O)_{2}NR^{6}R^{6}< / annotation>< / semantics>, <semantics>−NR7C(O)R8<annotation encoding="application / x-tex">-NR^{7}C(O)R^{8}< / annotation>< / semantics>, <semantics>−NR7C(O)R10NR6R6<annotation encoding="application / x-tex">-NR^{7}C(O)R^{10}NR^{6}R^{6}< / annotation>< / semantics>, <semantics>−NR7C(O)NR6R6<annotation encoding="application / x-tex">-NR^{7}C(O)NR^{6}R^{6}< / annotation>< / semantics>, or <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^{6}R^{6}< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>R′<annotation encoding="application / x-tex">R'< / annotation>< / semantics> is independently H or <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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; Z is i) oxo, ii) -OH, iii) -CN, iv) <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group selected from -OH and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^{1}-Z^{2}-Z^{3}-Z^{4}< / annotation>< / semantics> wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, wherein <semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}^2< / annotation>< / semantics> and <semantics>ℤ3<annotation encoding="application / x-tex">\mathbb{Z}^3< / annotation>< / semantics> are each independently <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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 CA independently selected from N, O, and S, and wherein <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is a <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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(<semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl), wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17<annotation encoding="application / x-tex">R^{17}< / annotation>< / semantics> groups, wherein the C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic CA 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, <semantics>𝒙<annotation encoding="application / x-tex">\mathbf{x}< / annotation>< / semantics>) <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, -C(O)NR6R6, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, and <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, 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 <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> groups, xiv) 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> groups, or xv) 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl is optionally substituted with <semantics>−OR10Si(R15)3<annotation encoding="application / x-tex">-OR^{10}Si(R^{15})_3< / annotation>< / semantics>; 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.

[0005] 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.

[0006] 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.

[0007] In one aspect, the present disclosure provides methods of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a 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. DETAILED DESCRIPTION I. Definitions

[0008] 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.

[0009] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0010] 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.

[0011] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical 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, Ra in the below structure can be attached to any of the five carbon ring atoms or Ra can replace the hydrogen attached to the nitrogen ring atom: [Image disponible dans le document PDF, Image available in the PDF document]

[0012] The prefix "Cu-v" indicates that the following group has from u to v carbon atoms. For example, "C1-6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term "x-y membered" rings, wherein x and y are numerical ranges, such as "3 to 12- 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.

[0013] 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.

[0014] "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.

[0015] 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 <semantics>±10%<annotation encoding="application / x-tex">\pm 10\%< / annotation>< / semantics>. In other embodiments, the term "about" includes the indicated amount <semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics> 5%. In certain other embodiments, the term "about" includes the indicated amount <semantics>±1%<annotation encoding="application / x-tex">\pm 1\%< / annotation>< / semantics>. Also, the term "about X" includes description of "X".

[0016] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., <semantics>C1−20<annotation encoding="application / x-tex">C_{1-20}< / annotation>< / semantics> alkyl), 1 to 12 carbon atoms (i.e., <semantics>C1−12<annotation encoding="application / x-tex">C_{1-12}< / annotation>< / semantics> alkyl), 1 to 8 carbon atoms (i.e., <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl), 1 to 6 carbon atoms (i.e., <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl), 1 to 4 carbon atoms (i.e., <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl), 1 to 3 carbon atoms (i.e., <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl), or 1 to 2 carbon atoms (i.e., <semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics> 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. -(CH2)3CH3), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3); and "propyl" includes n-propyl (i.e. <semantics>−(CH2)2CH3<annotation encoding="application / x-tex">-(CH_2)_2CH_3< / annotation>< / semantics>) and isopropyl (i.e. <semantics>−CH(CH3)2<annotation encoding="application / x-tex">-CH(CH_3)_2< / annotation>< / semantics>).

[0017] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., <semantics>C2−20<annotation encoding="application / x-tex">C_{2-20}< / annotation>< / semantics> alkenyl), 2 to 8 carbon atoms (i.e., <semantics>C2−8<annotation encoding="application / x-tex">C_{2-8}< / annotation>< / semantics> alkenyl), 2 to 6 carbon atoms (i.e., <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkenyl), or 2 to 4 carbon atoms (i.e., <semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics> alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0018] "Alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., <semantics>C2−8<annotation encoding="application / x-tex">C_{2-8}< / annotation>< / semantics> alkynyl), 2 to 6 carbon atoms (i.e., <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynyl), or 2 to 4 carbon atoms (i.e., <semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics> alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0019] "Alkylene" refers to a divalent and unbranched saturated hydrocarbon chain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C1-20 alkylene), 1 to 12 carbon atoms (i.e., <semantics>C1−12<annotation encoding="application / x-tex">C_{1-12}< / annotation>< / semantics> alkylene), 1 to 8 carbon atoms (i.e., <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkylene), 1 to 6 carbon atoms (i.e., <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylene), 1 to 4 carbon atoms (i.e., <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkylene), 1 to 3 carbon atoms (i.e., <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkylene), or 1 to 2 carbon atoms (i.e., C1-2 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(CH3)CH2-, -CH2CH(CH3)-, -CH2CH(CH2CH3)-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH2C(CH2CH3)(CH3)-, and -CH2C(CH2CH3)2.

[0020] "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.

[0021] "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. <semantics>𝑪i<annotation encoding="application / x-tex">\mathbf{C}_{i}< / annotation>< / semantics>

[0022] "Amido" refers to both a "C-amido" group which refers to the group -C(=O)NRyRz and an "N-amido" group which refers to the group -NRyC(=O)Rz, wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0023] "Amino" refers to the group -NRyRz wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0024] "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., <semantics>C6−20<annotation encoding="application / x-tex">C_{6-20}< / annotation>< / semantics> aryl), 6 to 12 carbon ring atoms (i.e., <semantics>C6−12<annotation encoding="application / x-tex">C_{6-12}< / annotation>< / semantics> aryl), or 6 to 10 carbon ring atoms (i.e., <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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.

[0025] "Cyano" or "carbonitrile" refers to the group -CN.

[0026] "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., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., <semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics> cycloalkyl), 3 to 10 ring carbon atoms (i.e., <semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics> cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0027] "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.

[0028] The term "fused" refers to a ring which is bound to an adjacent ring.

[0029] "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.

[0030] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0031] "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., <semantics>C1−20<annotation encoding="application / x-tex">C_{1-20}< / annotation>< / semantics> heteroalkylene); 1 to 8 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-8 heteroalkylene); 1 to 6 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S S (i.e., C1-6 heteroalkylene); 1 to 4 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-4 heteroalkylene); 1 to 3 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> heteroalkylene); or 1 to 2 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-3 heteroalkylene). For example, -CH2O- is a C1 heteroalkylene and -CH2SCH2- is a C2 heteroalkylene. Examples of heteroalkylene groups include -CH2CH2OCH2-, - CH2SCH2OCH2-, -CH2O-, and -CH2NHCH2-. In some embodiments, a heteroalkylene is optionally substituted with an alkyl group. Examples of substituted heteroalkylene groups include -CH(CH3)N(CH3)CH2-, -CH2OCH(CH3)-, -CH2CH(CH2CH3)S-, -CH2NHC(CH3)2-, - <semantics>C(CH3)2SCH2<annotation encoding="application / x-tex">C(CH_3)_2SCH_2< / annotation>< / semantics>-, <semantics>−CH(CH3)N(CH3)CH(CH3)O<annotation encoding="application / x-tex">-CH(CH_3)N(CH_3)CH(CH_3)O< / annotation>< / semantics>-, <semantics>−CH2SC(CH2CH3)(CH3)<annotation encoding="application / x-tex">-CH_2SC(CH_2CH_3)(CH_3)< / annotation>< / semantics>-, and - <semantics>CH2C(CH2CH3)2NH<annotation encoding="application / x-tex">CH_2C(CH_2CH_3)_2NH< / annotation>< / semantics>-.

[0032] "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., C1-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., <semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics> heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 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. CA

[0033] "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., <semantics>C2−20<annotation encoding="application / x-tex">C_{2-20}< / annotation>< / semantics> heterocyclyl), 2 to 12 carbon ring atoms (i.e., <semantics>C2−12<annotation encoding="application / x-tex">C_{2-12}< / annotation>< / semantics> heterocyclyl), 2 to 10 carbon ring atoms (i.e., <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics> heterocyclyl), 2 to 8 carbon ring atoms (i.e., <semantics>C2−8<annotation encoding="application / x-tex">C_{2-8}< / annotation>< / semantics> heterocyclyl), 3 to 12 carbon ring atoms (i.e., <semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics> heterocyclyl), 3 to 8 carbon ring atoms (i.e., <semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics> heterocyclyl), or 3 to 6 carbon ring atoms (i.e., <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> 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.

[0034] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0035] "Oxo" refers to the group (=O) or (O).

[0036] "Sulfonyl" refers to the group <semantics>−S(O)2Rc<annotation encoding="application / x-tex">-S(O)_2R^c< / annotation>< / semantics>, where <semantics>Rc<annotation encoding="application / x-tex">R^c< / annotation>< / semantics> is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, CA ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0037] As used herein, "2-oxa-6-azaspiro[3.3]heptane" has the structure: [Image disponible dans le document PDF, Image available in the PDF document]

[0038] As used herein, "2,5-diazabicyclo[2.2.1]heptane" has the structure: [Image disponible dans le document PDF, Image available in the PDF document]

[0039] As used herein, "2,6-diazaspiro[3.3]heptane" has the structure: [Image disponible dans le document PDF, Image available in the PDF document]

[0040] As used herein, "1,6-diazaspiro[3.3]heptane" has the structure: [Image disponible dans le document PDF, Image available in the PDF document]

[0041] As used herein, "2,7-diazaspiro[3.5]nonane" has the structure: [Image disponible dans le document PDF, Image available in the PDF document]

[0042] As used herein, "1-oxa-3,8-diazaspiro[4.5]decane" has the structure: [Image disponible dans le document PDF, Image available in the PDF document]

[0043] As used herein, "5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine" has the structure: [Image disponible dans le document PDF, Image available in the PDF document]

[0044] As used herein, "2,3-dihydrobenzo[b][1,4]dioxine" has the structure: [Image disponible dans le document PDF, Image available in the PDF document]

[0045] As used herein, "1H-benzo[d]imidazole" has the structure: [Image disponible dans le document PDF, Image available in the PDF document] .

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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: [Image disponible dans le document PDF, Image available in the PDF document]

[0050] 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 <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>- or <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>- or, as <semantics>(D)<annotation encoding="application / x-tex">(D)< / annotation>< / semantics>- or <semantics>(L)<annotation encoding="application / x-tex">(L)< / annotation>< / semantics>- 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 (-), <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>- and <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>-, or <semantics>(D)<annotation encoding="application / x-tex">(D)< / annotation>< / semantics>- and <semantics>(L)<annotation encoding="application / x-tex">(L)< / annotation>< / semantics>- 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 (IIPLC). 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.

[0051] 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.

[0052] "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.

[0053] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] Any formula or structure provided herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 2H, 3H, 13C and 14C are incorporated, are also provided herein. Such isotopically labelled 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.

[0058] 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 CA 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.

[0059] 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 18F 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] "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). C

[0066] "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.

[0067] "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.

[0068] 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. П. Compounds

[0069] In one aspect, provided herein is a compound of Formula I, [Image disponible dans le document PDF, Image available in the PDF document] Formula I or a pharmaceutically acceptable salt thereof, wherein <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> are each independently H or <semantics>ℂ1−3<annotation encoding="application / x-tex">\mathbb{C}_{1-3}< / annotation>< / semantics> alkyl; each R3 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, CA -NR<semantics>7<annotation encoding="application / x-tex">^{7}< / annotation>< / semantics>C(O)R<semantics>8<annotation encoding="application / x-tex">^{8}< / annotation>< / semantics>, or -C(O)R<semantics>8<annotation encoding="application / x-tex">^{8}< / annotation>< / semantics>, 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 <semantics>R16<annotation encoding="application / x-tex">R^{16}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 CA membered fused tricyclic heteroaryl each have 1-3 ring heteroatoms independently selected from N, O, and S; eac [Image disponible dans le document PDF, Image available in the PDF document] 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 <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 R' is independently H or C1-8 alkyl which may be the same or different, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from - OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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; Z is i) OXO, ii) -OH, iii) -CN, iv) <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> 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, <semantics>𝒗)<annotation encoding="application / x-tex">\mathbf{v})< / annotation>< / semantics> <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^{1}-Z^{2}-Z^{3}-Z^{4}< / annotation>< / semantics> wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, CA and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, wherein <semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}^2< / annotation>< / semantics> and <semantics>ℤ3<annotation encoding="application / x-tex">\mathbb{Z}^3< / annotation>< / semantics> are each independently <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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 <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is a <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 CA independently selected from -OH, halogen, -CN, C1-4 alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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) <semantics>−S(C1−8 alkyl)<annotation encoding="application / x-tex">-S(C_{1-8} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17<annotation encoding="application / x-tex">R^{17}< / annotation>< / semantics> groups, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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, <semantics>𝒙<annotation encoding="application / x-tex">\mathbf{x}< / annotation>< / semantics>) <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic aryl optionally substituted with 1-3 CA 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, -C(O)NR6R6, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, and <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, 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 <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> 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 <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> groups, xiv) 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, 8- 10 membered fused or bridged bicyclic heterocyclyl, 8-10 CA 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 <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl is optionally substituted with <semantics>−OR10Si(R15)3<annotation encoding="application / x-tex">-OR^{10}Si(R^{15})_3< / annotation>< / semantics>; 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 <semantics>R15<annotation encoding="application / x-tex">R^{15}< / annotation>< / semantics> is independently <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, which may be the same or different; and n is 0, 1, 2, or 3.

[0070] In some embodiments, the compound of Formula I is of Formula Ia: [Image disponible dans le document PDF, Image available in the PDF document] Formula Ia or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> are each independently H or <semantics>ℂ1−3<annotation encoding="application / x-tex">\mathbb{C}_{1-3}< / annotation>< / semantics> 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 <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 CA monocyclic cycloalkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is independently oxo, -OH, halogen, -CN, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy, -NR6R6, <semantics>−NR7S(O)2R9<annotation encoding="application / x-tex">-NR^7S(O)_2R^9< / annotation>< / semantics>, or <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl; each R6 is independently H, C1-8 alkyl, or C3-7 monocyclic cycloalkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy; each <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> is independently H or <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy; each <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is independently -OH, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, or <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy; each <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is independently <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl or <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and CA wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy; each <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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; Zis i) oxo, ii) -OH, iii) -CN, iv) <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group selected from -OH and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, V) <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^{1}-Z^{2}-Z^{3}-Z^{4}< / annotation>< / semantics> wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, wherein <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is a <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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, CA wherein <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>, 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 <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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 <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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, V11) C3-7 monocyclic cycloalkyl optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy, viii) <semantics>−S(C1−4 alkyl)<annotation encoding="application / x-tex">-S(C_{1-4} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17a<annotation encoding="application / x-tex">R^{17a}< / annotation>< / semantics> 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) <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, -C(O)NR6R6, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, and <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, 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 <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> groups, X11) 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 <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> groups, 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 <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> is independently oxo, -OH, halogen, -CN, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 <semantics>1−3R14<annotation encoding="application / x-tex">1-3 R^{14}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> 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.

[0072] 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.

[0073] In some embodiments, the compound of Formula I is of Formula II: [Image disponible dans le document PDF, Image available in the PDF document] Formula II or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the compound of Formula I, Ia, or II is of Formula IIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula IIa or a pharmaceutically acceptable salt thereof. CA

[0075] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are each independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> is H and the other of <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> is <semantics>ℂ1−3<annotation encoding="application / x-tex">\mathbb{C}_{1-3}< / annotation>< / semantics> alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> is H and the other of <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> is methyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R2 and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is H and the other of <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is ethyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R2 and R3 is H and the other of R2 and R3 is propyl. In some embodiments of the compound of Formula I, Ia, II, or Ha, or a pharmaceutically acceptable salt thereof, one of <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> is H and the other of <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and R3 is isopropyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, both <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> are H. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R2 and R3 are each independently methyl, ethyl, propyl, or isopropyl.

[0076] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R5 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 R5 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 R5 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 R5 is fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, two R5 are fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R5 is fluoro. |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 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 CA 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.

[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 C3-7 monocyclic cycloalkyl or 5-9 membered fused or bridged bicyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl and the 5-9 membered fused or bridged bicyclic cycloalkyl are each optionally substituted with 1-5 <semantics>R16a<annotation encoding="application / x-tex">R^{16a}< / annotation>< / semantics> groups.

[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 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.

[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 C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is optionally substituted with 1-5 R16 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 C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is optionally substituted with 1-5 R16a groups.

[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 C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-5 R16 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 C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-5 R16a 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 C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-5 groups independently selected from -OH, halogen, -CN, and <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 C3- 7 monocyclic cycloalkyl, wherein the C3-7 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 C3-7 monocyclic cycloalkyl, wherein the C3-7 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.

[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 C3-7 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.

[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 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.

[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 optionally substituted with 1-5 R16 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 R16a groups.

[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 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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.

[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 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 CA 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.

[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 optionally substituted with 1-5 R16 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 <semantics>R16a<annotation encoding="application / x-tex">R^{16a}< / annotation>< / semantics> groups.

[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 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 R16 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 R16a 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.

[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 optionally substituted with 1-5 R16 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 R16a groups.

[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 5-7 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 R16 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 R16a 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.

[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 optionally substituted with 1-5 R16 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 R16a groups. CA

[0092] 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 R16 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 R16a 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.

[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, [Image disponible dans le document PDF, Image available in the PDF document] each of which is optionally substituted with 1-5 groups independently selected from oxo, -OH, halogen, -CN, C1-8 alkyl, C1-4 alkoxy, C3-7 monocyclic cycloalkyl, -C(O)NR6R6, -NR6R6, - <semantics>NR6C(O)R8<annotation encoding="application / x-tex">NR^6C(O)R^8< / annotation>< / semantics>, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>.

[0094] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B is cyclohexyl, tetrahydropyranyl, [Image disponible dans le document PDF, Image available in the PDF document] 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, - <semantics>NR6C(O)R8<annotation encoding="application / x-tex">NR^6C(O)R^8< / annotation>< / semantics>, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>.

[0095] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Ring B is a cyclohexyl, [Image disponible dans le document PDF, Image available in the PDF document] 43 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, [Image disponible dans le document PDF, Image available in the PDF document] • each of which is optionally substituted with 1-5 fluoro.

[0096] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy.

[0097] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy.

[0098] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] is: CA [Image disponible dans le document PDF, Image available in the PDF document] <semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>

[0099] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] is: [Image disponible dans le document PDF, Image available in the PDF document]

[0100] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is H, -CN, halogen, C1-8 alkyl, or <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy.

[0101] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is H. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is -CN.

[0102] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is halogen. In some embodiments of the compound CA of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 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, R1 is chloro, fluoro, or bromo.

[0103] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 halogens.

[0104] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, wherein the C1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> 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, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> 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, R1 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, R1 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, R1 is -CHF2 or -CF3. CA

[0105] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is C1-6 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl.

[0106] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from - OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl.

[0107] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is -C(O)NR6R6. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is - NR6R6. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is -NR7C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is - <semantics>C(O)R8<annotation encoding="application / x-tex">C(O)R^8< / annotation>< / semantics>.

[0108] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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 CA heterocyclyl, and 9-12 membered fused tricyclic heteroaryl 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, 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.

[0110] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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.

[0111] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics> is a phenyl, wherein the phenyl is optionally substituted with 1-3 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is a phenyl, wherein the phenyl is substituted with 1-3 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics> is a phenyl.

[0112] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or Ha, or a pharmaceutically acceptable salt thereof, <semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics> is a 5-6 membered monocyclic heterocyclyl 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, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is a 5-6 membered monocyclic heteroaryl 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, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is a 8-10 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, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is a 9-10 membered fused or bridged bicyclic heterocyclyl 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, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is a 8-10 membered fused bicyclic heteroaryl 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, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is a 9-12 membered fused or bridged tricyclic heterocyclyl 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, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 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 R4a groups. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is a 9-12 membered fused tricyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S. CA

[0119] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is [Image disponible dans le document PDF, Image available in the PDF document] , each of which is optionally substituted with 1-3 R4a groups.

[0120] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is [Image disponible dans le document PDF, Image available in the PDF document] , each of which is substituted with 1-3 R4a groups.

[0121] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is [Image disponible dans le document PDF, Image available in the PDF document] each of which is optionally substituted with 1-3 R4a groups.

[0122] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is CA [Image disponible dans le document PDF, Image available in the PDF document] each of which is substituted with 1-3 R4a groups.

[0123] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is [Image disponible dans le document PDF, Image available in the PDF document] which is optionally substituted with 1-3 R4a groups.

[0124] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 is [Image disponible dans le document PDF, Image available in the PDF document] which is substituted with 1-3 R4a groups.

[0125] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R4a is independently oxo, -OH, halogen, -CN, C1-8 alkyl, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy, <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, <semantics>−NR7S(O)2R9<annotation encoding="application / x-tex">-NR^7S(O)_2R^9< / annotation>< / semantics>, <semantics>−NR7S(O)2NR6R6<annotation encoding="application / x-tex">-NR^7S(O)_2NR^6R^6< / annotation>< / semantics>, <semantics>−NR7C(O)R8<annotation encoding="application / x-tex">-NR^7C(O)R^8< / annotation>< / semantics>, <semantics>−NR7C(O)R10NR6R6<annotation encoding="application / x-tex">-NR^7C(O)R^{10}NR^6R^6< / annotation>< / semantics>, <semantics>−NR7C(O)NR6R6<annotation encoding="application / x-tex">-NR^{7}C(O)NR^{6}R^{6}< / annotation>< / semantics>, or <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^{6}R^{6}< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy; or two <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> 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. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R4a is independently oxo, -OH, halogen, -CN, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy, -NR6R6, -NR7S(O)2R9, or <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>. wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from - OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy; or two <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> of the 1-3 <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> 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.

[0126] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R4a is independently oxo, -OH, halogen, -CN, C1-8 alkyl, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy, <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, <semantics>−NR7S(O)2R9<annotation encoding="application / x-tex">-NR^7S(O)_2R^9< / annotation>< / semantics>, <semantics>−NR7S(O)2NR6R6<annotation encoding="application / x-tex">-NR^7S(O)_2NR^6R^6< / annotation>< / semantics>, <semantics>−NR7C(O)R8<annotation encoding="application / x-tex">-NR^7C(O)R^8< / annotation>< / semantics>, <semantics>−NR7C(O)R10NR6R6<annotation encoding="application / x-tex">-NR^7C(O)R^{10}NR^6R^6< / annotation>< / semantics>, -NR7C(O)NR6R6, or -C(O)NR6R6, wherein the C1-8 alkyl is optionally substituted with 1-3 CA groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R4a is independently oxo, -OH, halogen, -CN, C1-8 alkyl, C1-8 alkoxy, -NR6R6, -NR7S(O)2R9, or - <semantics>C(O)NR6R6<annotation encoding="application / x-tex">C(O)NR^6R^6< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy.

[0127] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R4a is independently oxo, halogen, -CN, C1-8 alkyl, <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, <semantics>−NR7S(O)2R9<annotation encoding="application / x-tex">-NR^7S(O)_2R^9< / annotation>< / semantics>, or <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>.

[0128] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is oxo. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R4a is oxo. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is -OH.

[0129] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is halogen. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is fluoro or chloro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R4a is fluoro. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R4a is chloro.

[0130] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is -CN. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R4a is - CN.

[0131] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl. CA

[0132] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is C1-4 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a 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 <semantics>ℝ4a<annotation encoding="application / x-tex">\mathbb{R}^{4a}< / annotation>< / semantics> is methyl.

[0133] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is C1-8 alkoxy.

[0134] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is -NR6R6. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is -NH2. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R4a is -NH2.

[0135] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is <semantics>−NR7S(O)2R9<annotation encoding="application / x-tex">-NR^7S(O)_2R^9< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is -NHS(O)2<semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is -NHS(O)2<semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is -NHS(O)2(C1-4 alkyl). In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R4a is -NHS(O)2CH3. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R4a is -NHS(O)2CH2CH3. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is <semantics>−NHS(O)2(C3−5<annotation encoding="application / x-tex">-NHS(O)_2(C_{3-5}< / annotation>< / semantics> cycloalkyl). In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is -NHS(O)2(cyclopropyl).

[0136] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a CA pharmaceutically acceptable salt thereof, one or more R4a is -NR7S(O)2NR6R6. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> is <semantics>−NR7C(O)R8<annotation encoding="application / x-tex">-NR^7C(O)R^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is - NR7C(O)R10NR6R6. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is -NR7C(O)NR6R6.

[0137] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is -C(O)NR6R6. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R4a is -C(O)NH2. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R4a is -C(O)NH2.

[0138] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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 C3-5 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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, cyclobutyl, or cyclopentyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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.

[0139] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 optionally substituted with 1-3 R4a groups is: [Image disponible dans le document PDF, Image available in the PDF document] , CA [Image disponible dans le document PDF, Image available in the PDF document] . • [Image disponible dans le document PDF, Image available in the PDF document] ^ •

[0140] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, R4 optionally substituted with 1-3 R4a groups is: [Image disponible dans le document PDF, Image available in the PDF document] ٠

[0141] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics> optionally substituted with 1-3 <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> groups is: [Image disponible dans le document PDF, Image available in the PDF document] • CA [Image disponible dans le document PDF, Image available in the PDF document]

[0142] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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.

[0143] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R6 is independently H, C1-8 alkyl, or C3-7 monocyclic cycloalkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy.

[0144] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R6 is independently H or C1-4 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R6 is independently H or methyl.

[0145] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R6 is H.

[0146] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ6<annotation encoding="application / x-tex">\mathbb{R}^6< / annotation>< / semantics> is <semantics>ℂ1−4<annotation encoding="application / x-tex">\mathbb{C}_{1-4}< / annotation>< / semantics> alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R6 is methyl.

[0147] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R6 is C3-7 monocyclic cycloalkyl, 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. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ6<annotation encoding="application / x-tex">\mathbb{R}^6< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ6<annotation encoding="application / x-tex">\mathbb{R}^6< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl.

[0148] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R6 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, C1-4 alkyl, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R6 is 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, both <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, 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.

[0150] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each <semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics> is independently H or <semantics>ℂ1−8<annotation encoding="application / x-tex">\mathbb{C}_{1-8}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R' is independently H or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R7 is independently H or C1-3 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, one or more R7 is H. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics> is <semantics>ℂ1−8<annotation encoding="application / x-tex">\mathbb{C}_{1-8}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>ℂ1−8<annotation encoding="application / x-tex">\mathbb{C}_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics> is <semantics>ℂ1−8<annotation encoding="application / x-tex">\mathbb{C}_{1-8}< / annotation>< / semantics> 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 <semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics> is <semantics>ℂ1−4<annotation encoding="application / x-tex">\mathbb{C}_{1-4}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics> is <semantics>ℂ1−4<annotation encoding="application / x-tex">\mathbb{C}_{1-4}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> is <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl which may be the same or different.

[0152] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is independently -OH, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy, CA C3-7 monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 4-6 membered monocyclic heteroaryl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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.

[0153] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R8 is independently -OH, C1-8 alkyl, or C1-8 alkoxy.

[0154] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R8 is -OH.

[0155] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics> is <semantics>ℂ1−4<annotation encoding="application / x-tex">\mathbb{C}_{1-4}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, wherein the C1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl.

[0156] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy CA is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy.

[0157] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkoxy, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkoxy is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkoxy, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkoxy is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics> is <semantics>ℂ1−5<annotation encoding="application / x-tex">\mathbb{C}_{1-5}< / annotation>< / semantics> alkoxy.

[0158] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R8 is C3-7 monocyclic cycloalkyl, 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. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl.

[0159] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R8 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R8 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a CA pharmaceutically acceptable salt thereof, one or more R8 is 4-6 membered monocyclic heterocyclyl 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, one or more R8 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R8 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R8 is 4-6 membered monocyclic heteroaryl having 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 <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is independently <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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.

[0162] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each R9 is independently C1-8 alkyl or C3-7 monocyclic cycloalkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy. (

[0163] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is independently <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl or <semantics>C3−5<annotation encoding="application / x-tex">C_{3-5}< / annotation>< / semantics> monocyclic cycloalkyl.

[0164] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics> is <semantics>ℂ1−4<annotation encoding="application / x-tex">\mathbb{C}_{1-4}< / annotation>< / semantics> alkyl, wherein the C1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 is C1-4 alkyl, wherein the C1-4 alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 is C1-3 alkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 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 R9 is methyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R9 is ethyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R9 is propyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R9 is isopropyl.

[0165] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 is C3-7 monocyclic cycloalkyl, 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. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 is C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-3 groups C / independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 is C3-5 monocyclic cycloalkyl, wherein the <semantics>C3−5<annotation encoding="application / x-tex">C_{3-5}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1- 3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is <semantics>C3−5<annotation encoding="application / x-tex">C_{3-5}< / annotation>< / semantics> monocyclic cycloalkyl, wherein the <semantics>C3−5<annotation encoding="application / x-tex">C_{3-5}< / annotation>< / semantics> monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is <semantics>C3−5<annotation encoding="application / x-tex">C_{3-5}< / annotation>< / semantics> monocyclic cycloalkyl. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one R9 is cyclopropyl.

[0166] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 is 4-6 membered monocyclic heterocyclyl 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, one or more R9 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 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, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one or more R9 is 5-6 membered monocyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0168] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, each <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 R10 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, R10 is -CH(CH3)2-.

[0169] 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 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.

[0170] 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 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 one or two ring heteroatoms is a nitrogen.

[0171] 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 heterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl 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 heterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl 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.

[0172] 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.

[0173] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] is: [Image disponible dans le document PDF, Image available in the PDF document]

[0174] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] is: [Image disponible dans le document PDF, Image available in the PDF document]

[0175] 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) <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group selected from -OH and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^{1}-Z^{2}-Z^{3}-Z^{4}< / annotation>< / semantics> wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, wherein <semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}^2< / annotation>< / semantics> and <semantics>ℤ3<annotation encoding="application / x-tex">\mathbb{Z}^3< / annotation>< / semantics> are each independently <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>, 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 CA 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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) <semantics>−S(C1−8 alkyl)<annotation encoding="application / x-tex">-S(C_{1-8} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17<annotation encoding="application / x-tex">R^{17}< / annotation>< / semantics> 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 CA independently selected from oxo, -OH, halogen, -CN, C1-4 alkyl, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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) <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, and <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, 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 <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> 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 <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> groups.

[0176] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C / i) oxo, ii) -OH, iii) -CN, iv) <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group selected from -OH and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^{1}-Z^{2}-Z^{3}-Z^{4}< / annotation>< / semantics>. wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, wherein <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is a <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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 <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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) <semantics>−S(C1−4 alkyl)<annotation encoding="application / x-tex">-S(C_{1-4} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17a<annotation encoding="application / x-tex">R^{17a}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, and <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, and wherein the 4-6 membered monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl each have 1-3 ring heteroatoms CA 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 <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> 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 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.

[0177] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is oxo.

[0178] 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.

[0179] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group selected from -OH and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> 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 <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group selected from -OH and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> 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 C1-5 alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group independently selected from -OH and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> 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, <semantics>Z<annotation encoding="application / x-tex">Z< / annotation>< / semantics> is <semantics>−C(CH3)2OH<annotation encoding="application / x-tex">-C(CH_3)_2OH< / annotation>< / semantics>.

[0180] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C6-8 alkyl.

[0181] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^1-Z^2-Z^3-Z^4< / annotation>< / semantics>, wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, wherein <semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}^2< / annotation>< / semantics> and <semantics>ℤ3<annotation encoding="application / x-tex">\mathbb{Z}^3< / annotation>< / semantics> are each independently <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene, <semantics>ℂ6−10<annotation encoding="application / x-tex">\mathbb{C}_{6-10}< / annotation>< / semantics> 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 <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is a <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 CA 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.

[0182] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^1-Z^2-Z^3-Z^4< / annotation>< / semantics>, wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, wherein <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is a <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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 <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>, 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 <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is a 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclyl and 5-6 membered CA monocyclic heteroaryl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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.

[0183] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z1 is C2-6 alkynylene substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics> alkynylene substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics> alkynylene. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics> alkynylene.

[0184] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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.

[0185] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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.

[0186] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z2 is C3-7 monocyclic cycloalkylene, wherein the C3-7 monocyclic cycloalkylene is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene.

[0187] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene is substituted with 1-3 groups independently selected from -OH, halogen, -CN, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}^2< / annotation>< / semantics> is <semantics>ℂ6−10<annotation encoding="application / x-tex">\mathbb{C}_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is phenylene.

[0188] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is 4-6 membered monocyclic heterocyclylene, CA 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is 4-6 membered monocyclic 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, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z2 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}^2< / annotation>< / semantics> is 5-6 membered monocyclic heteroarylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0190] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z2 is 8-10 membered fused or bridged bicyclic heterocyclylene having 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, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}^2< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is 8-10 membered fused bicyclic heteroarylene having 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, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is 7-10 membered spirocyclic heterocyclylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0193] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics> alkynylene and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is phenylene.

[0194] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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.

[0195] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, 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.

[0196] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>ℤ3<annotation encoding="application / x-tex">\mathbb{Z}^3< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>ℤ3<annotation encoding="application / x-tex">\mathbb{Z}^3< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkylene.

[0197] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene is substituted with 1-3 groups independently selected from -OH, halogen, -CN, CA <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene.

[0198] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is 4-6 membered monocyclic 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, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^{8}< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z3 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, <semantics>ℤ3<annotation encoding="application / x-tex">\mathbb{Z}^3< / annotation>< / semantics> is imidazolylene.

[0200] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z3 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In CA some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z3 is 8-10 membered fused or bridged bicyclic heterocyclylene having 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, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z3 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is 8-10 membered fused bicyclic heteroarylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0202] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z3 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is 7-10 membered spirocyclic heterocyclylene having 1-3 ring heteroatoms independently selected from N, O, and S.

[0203] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a CA pharmaceutically acceptable salt thereof, Z4 is 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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.

[0204] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>, 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.

[0205] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 is C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl.

[0206] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 is C6-10 monocyclic or fused bicyclic aryl, wherein the C6-10 monocyclic or fused bicyclic aryl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic aryl, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic aryl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic aryl.

[0207] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 is 4-6 membered monocyclic 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, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 is a 5-6 membered monocyclic heterocyclyl 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, Z4 is pyrrolidinyl substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is pyrrolidinyl substituted with one -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>. In some embodiments of the compound CA of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is pyrrolidinyl.

[0210] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is 5-6 membered monocyclic heteroaryl having 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, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 is 8-10 membered fused or bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0212] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl has С 1-3 ring heteroatoms independently selected from N, O, and S and is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is 8-10 membered fused bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0213] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z4 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, C1-4 alkyl, C1-4 alkoxy, and -C(O)R8. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is 7-10 membered spirocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S.

[0214] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, and 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>, and CA 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.

[0215] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl or <semantics>−S(C1−4<annotation encoding="application / x-tex">-S(C_{1-4}< / annotation>< / semantics> alkyl), wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl and the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl are each optionally substituted with 1- 2 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl or <semantics>−S(C1−4 alkyl)<annotation encoding="application / x-tex">-S(C_{1-4} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl and the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl are each substituted with 1-2 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C3-7 monocyclic cycloalkyl or -S(C1- 4 alkyl).

[0216] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C3-7 monocyclic cycloalkyl, wherein the C3-7 monocyclic cycloalkyl is substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is C3-7 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.

[0217] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, <semantics>Z<annotation encoding="application / x-tex">Z< / annotation>< / semantics> is <semantics>−S(C1−8<annotation encoding="application / x-tex">-S(C_{1-8}< / annotation>< / semantics> alkyl), wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>−S(C1−8 alkyl)<annotation encoding="application / x-tex">-S(C_{1-8} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C1−8 alkyl<annotation encoding="application / x-tex">C_{1-8} \text{ alkyl}< / annotation>< / semantics> is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(C1-8 alkyl). C /

[0218] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>−S(C1−4 alkyl)<annotation encoding="application / x-tex">-S(C_{1-4} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C1−4 alkyl<annotation encoding="application / x-tex">C_{1-4} \text{ alkyl}< / annotation>< / semantics> is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is <semantics>−S(C1−4 alkyl)<annotation encoding="application / x-tex">-S(C_{1-4} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C1−4 alkyl<annotation encoding="application / x-tex">C_{1-4} \text{ alkyl}< / annotation>< / semantics> is substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -S(C1-4 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, <semantics>Z<annotation encoding="application / x-tex">Z< / annotation>< / semantics> is <semantics>−S(CH3)<annotation encoding="application / x-tex">-S(CH_3)< / annotation>< / semantics>.

[0219] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H or C1-8 alkyl and the other of <semantics>ℝ11<annotation encoding="application / x-tex">\mathbb{R}^{11}< / annotation>< / semantics> and <semantics>ℝ12<annotation encoding="application / x-tex">\mathbb{R}^{12}< / annotation>< / semantics> is <semantics>ℂ1−8<annotation encoding="application / x-tex">\mathbb{C}_{1-8}< / annotation>< / semantics> alkyl, <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17<annotation encoding="application / x-tex">R^{17}< / annotation>< / semantics> 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.

[0220] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H or C1-8 alkyl and the other of <semantics>ℝ11<annotation encoding="application / x-tex">\mathbb{R}^{11}< / annotation>< / semantics> and <semantics>ℝ12<annotation encoding="application / x-tex">\mathbb{R}^{12}< / annotation>< / semantics> is <semantics>ℂ1−8<annotation encoding="application / x-tex">\mathbb{C}_{1-8}< / annotation>< / semantics> alkyl, <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein each <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17a<annotation encoding="application / x-tex">R^{17a}< / annotation>< / semantics> groups, CA 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.

[0221] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17<annotation encoding="application / x-tex">R^{17}< / annotation>< / semantics> groups, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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.

[0222] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17<annotation encoding="application / x-tex">R^{17}< / annotation>< / semantics> groups.

[0223] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17<annotation encoding="application / x-tex">R^{17}< / annotation>< / semantics> groups.

[0224] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17a<annotation encoding="application / x-tex">R^{17a}< / annotation>< / semantics> groups.

[0225] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17a<annotation encoding="application / x-tex">R^{17a}< / annotation>< / semantics> groups.

[0226] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, and -CN.

[0227] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy and -NR6R6, and wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy is optionally substituted with one C1-4 alkoxy. In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, one of R11 and R12 is II and the other of R11 and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> 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.

[0228] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17a<annotation encoding="application / x-tex">R^{17a}< / annotation>< / semantics> groups.

[0229] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> 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 C1-4 alkoxy.

[0230] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein -NR11R12 is [Image disponible dans le document PDF, Image available in the PDF document]

[0231] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is -NR11R12, wherein one of R11 and R12 is H and the other of <semantics>ℝ11<annotation encoding="application / x-tex">\mathbb{R}^{11}< / annotation>< / semantics> and <semantics>ℝ12<annotation encoding="application / x-tex">\mathbb{R}^{12}< / annotation>< / semantics> is <semantics>ℂ3−7<annotation encoding="application / x-tex">\mathbb{C}_{3-7}< / annotation>< / semantics> 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.

[0232] In some embodiments of the compound of Formula I, Ia, II, or IIa, or a pharmaceuticall...

Claims

<pat:ClaimStatement>WHAT IS CLAIMED IS:< / pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A compound of Formula I, [Image disponible dans le document PDF, Image available in the PDF document] Formula I or a pharmaceutically acceptable salt thereof, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are each independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> 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, <semantics>−NR7C(O)R8<annotation encoding="application / x-tex">-NR^7C(O)R^8< / annotation>< / semantics>, or <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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, <semantics>−NR7S(O)2R9<annotation encoding="application / x-tex">-NR^7S(O)_2R^9< / annotation>< / semantics>, <semantics>−NR7S(O)2NR6R6<annotation encoding="application / x-tex">-NR^7S(O)_2NR^6R^6< / annotation>< / semantics>, <semantics>−NR7C(O)R8<annotation encoding="application / x-tex">-NR^7C(O)R^8< / annotation>< / semantics>, <semantics>−NR7C(O)R10NR6R6<annotation encoding="application / x-tex">-NR^7C(O)R^{10}NR^6R^6< / annotation>< / semantics>, -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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> is independently H or <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl and <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy are each optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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; Z is i) oxo, ii) -OH, iii) -CN, iv) <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group selected from -OH and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, v) <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^{1}-Z^{2}-Z^{3}-Z^{4}< / annotation>< / semantics> wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, wherein <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> and <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> are each independently <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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 <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> is a <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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, V111) -S(<semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl), wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17<annotation encoding="application / x-tex">R^{17}< / annotation>< / semantics> 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, <semantics>𝒙<annotation encoding="application / x-tex">\mathbf{x}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, -C(O)NR6R6, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, and <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, 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, X1) 4-6 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S and optionally substituted with <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl is optionally substituted with <semantics>−OR10Si(R15)3<annotation encoding="application / x-tex">-OR^{10}Si(R^{15})_3< / annotation>< / semantics>; 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 <semantics>R15<annotation encoding="application / x-tex">R^{15}< / annotation>< / semantics> is independently <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, which may be the same or different; and n is 0, 1, 2, or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>2. The compound of claim 1, wherein the compound is of Formula Ia: [Image disponible dans le document PDF, Image available in the PDF document] Formula Ia 370 or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are each independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl; each R5 is halogen which may be the same or different; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is H, -CN, halogen, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, or <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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, <semantics>−NR7S(O)2R9<annotation encoding="application / x-tex">-NR^7S(O)_2R^9< / annotation>< / semantics>, or <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 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 <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy; each <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> is independently H or <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl which may be the same or different, wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy; each <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is independently -OH, <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, or <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkoxy; each <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is independently <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl or <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl wherein the <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, and wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, C1-4 alkyl, and C1-4 alkoxy; each <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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; Z is i) oxo, ii) -OH, iii) -CN, iv) <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is substituted with one group selected from -OH and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and wherein the <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkyl is optionally further substituted with 1-2 groups independently selected from -OH, halogen, and -CN, <semantics>𝒗<annotation encoding="application / x-tex">\mathbf{v}< / annotation>< / semantics> <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl, wherein the <semantics>C6−8<annotation encoding="application / x-tex">C_{6-8}< / annotation>< / semantics> alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and C1-4 alkoxy, vi) <semantics>−Z1−Z2−Z3−Z4<annotation encoding="application / x-tex">-Z^{1}-Z^{2}-Z^{3}-Z^{4}< / annotation>< / semantics>, wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynylene optionally substituted with 1-3 groups independently selected from -OH, halogen, -CN, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, wherein <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is a <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic arylene, 4-6 membered monocyclic heterocyclylene, or 5-6 membered monocyclic heteroarylene, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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 <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, and -C(O)<semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>, 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 <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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) <semantics>−S(C1−4 alkyl)<annotation encoding="application / x-tex">-S(C_{1-4} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl, <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl, 4-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl, wherein each <semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> alkyl is substituted with 1-3 <semantics>R17a<annotation encoding="application / x-tex">R^{17a}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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, <semantics>𝒙<annotation encoding="application / x-tex">\mathbf{x}< / annotation>< / semantics> <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy, -C(O)NR6R6, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, and <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, 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 <semantics>1−3R13<annotation encoding="application / x-tex">1-3 R^{13}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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 <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl is optionally substituted with <semantics>−OR10Si(R15)3<annotation encoding="application / x-tex">-OR^{10}Si(R^{15})_3< / annotation>< / semantics>; each <semantics>R15<annotation encoding="application / x-tex">R^{15}< / annotation>< / semantics> is independently <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl, which may be the same or different; and n is 0, 1, 2, or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. The compound of any one of claims 1-3, wherein n is 2. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. The compound of any one of claims 1, 3, and 4, wherein the compound is of Formula II: [Image disponible dans le document PDF, Image available in the PDF document] Formula II or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>6. The compound of any one of claims 1-5, wherein the compound is of Formula IIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula IIa or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R5 is fluoro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are H. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>9. The compound of any one of claims 1-2 and 4-8, or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclohexyl, tetrahydropyranyl, [Image disponible dans le document PDF, Image available in the PDF document] 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, <semantics>−NR6C(O)R8<annotation encoding="application / x-tex">-NR^6C(O)R^8< / annotation>< / semantics>, and <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. The compound of any one of claims 1-2 and 4-9, or a pharmaceutically acceptable salt thereof, wherein [Image disponible dans le document PDF, Image available in the PDF document] is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl optionally substituted with 1-3 halogens. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. The compound of any one of claims 1-9 and 11, or a pharmaceutically acceptable salt thereof, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is -CHF2 or -CF3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13< / pat:ClaimNumber> <pat:ClaimText>13. The compound of any one of claims 1-8 and 11-12, 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14< / pat:ClaimNumber> <pat:ClaimText>14. The compound of any one of claims 1-9 and 11-13, or a pharmaceutically acceptable salt thereof, wherein [Image disponible dans le document PDF, Image available in the PDF document] is: [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15< / pat:ClaimNumber> <pat:ClaimText>15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4 is [Image disponible dans le document PDF, Image available in the PDF document] , each of which is optionally substituted with 1-3 R4a groups. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00016"> <pat:ClaimNumber>16< / pat:ClaimNumber> <pat:ClaimText>16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00017"> <pat:ClaimNumber>17< / pat:ClaimNumber> <pat:ClaimText>17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4 is [Image disponible dans le document PDF, Image available in the PDF document] each of which is optionally substituted with 1-3 R4a groups. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00018"> <pat:ClaimNumber>18< / pat:ClaimNumber> <pat:ClaimText>18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R4 is [Image disponible dans le document PDF, Image available in the PDF document] which is optionally substituted with 1-3 R4a groups. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00019"> <pat:ClaimNumber>19< / pat:ClaimNumber> <pat:ClaimText>19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein each R4a is independently oxo, halogen, -CN, C1-8 alkyl, -NR6R6, -NR7S(O)2R9, or <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00020"> <pat:ClaimNumber>20< / pat:ClaimNumber> <pat:ClaimText>20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein each <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> is independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00021"> <pat:ClaimNumber>21< / pat:ClaimNumber> <pat:ClaimText>21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein each <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is independently <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl or <semantics>C3−5<annotation encoding="application / x-tex">C_{3-5}< / annotation>< / semantics> monocyclic cycloalkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00022"> <pat:ClaimNumber>22< / pat:ClaimNumber> <pat:ClaimText>22. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00023"> <pat:ClaimNumber>23< / pat:ClaimNumber> <pat:ClaimText>23. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R4 optionally substituted with 1-3 R4a groups is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , . 1 • < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00024"> <pat:ClaimNumber>24< / pat:ClaimNumber> <pat:ClaimText>24. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R4 optionally substituted with 1-3 R4a groups is: [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00025"> <pat:ClaimNumber>25< / pat:ClaimNumber> <pat:ClaimText>25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein 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 one or two ring heteroatoms is a nitrogen. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00026"> <pat:ClaimNumber>26< / pat:ClaimNumber> <pat:ClaimText>26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein [Image disponible dans le document PDF, Image available in the PDF document] is: [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00027"> <pat:ClaimNumber>27< / pat:ClaimNumber> <pat:ClaimText>27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein [Image disponible dans le document PDF, Image available in the PDF document] is: i i [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00028"> <pat:ClaimNumber>28< / pat:ClaimNumber> <pat:ClaimText>28. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Z is oxo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00029"> <pat:ClaimNumber>29< / pat:ClaimNumber> <pat:ClaimText>29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Z is -OH or -CN. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00030"> <pat:ClaimNumber>30< / pat:ClaimNumber> <pat:ClaimText>30. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is <semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics> alkynylene and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is phenylene. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00031"> <pat:ClaimNumber>31< / pat:ClaimNumber> <pat:ClaimText>31. The compound of any one of claims 1-27 and 30, or a pharmaceutically acceptable salt thereof, wherein <semantics>Z3<annotation encoding="application / x-tex">Z^3< / annotation>< / semantics> is a 5-6 membered monocyclic heteroarylene having 1-3 ring heteroatoms independently selected from N, O, and S. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00032"> <pat:ClaimNumber>32< / pat:ClaimNumber> <pat:ClaimText>32. The compound of any one of claims 1-27 and 30-31, or a pharmaceutically acceptable salt thereof, wherein <semantics>Z4<annotation encoding="application / x-tex">Z^4< / annotation>< / semantics> 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00033"> <pat:ClaimNumber>33< / pat:ClaimNumber> <pat:ClaimText>33. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Z is <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> monocyclic cycloalkyl or <semantics>−S(C1−4 alkyl)<annotation encoding="application / x-tex">-S(C_{1-4} \text{ alkyl})< / annotation>< / semantics>, wherein the <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00034"> <pat:ClaimNumber>34< / pat:ClaimNumber> <pat:ClaimText>34. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Z is <semantics>−NR11R12<annotation encoding="application / x-tex">-NR^{11}R^{12}< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00035"> <pat:ClaimNumber>35< / pat:ClaimNumber> <pat:ClaimText>35. The compound of any one of claims 1-27 and 34, or a pharmaceutically acceptable salt thereof, wherein Z is -NR11R12, wherein one of R11 and R12 is H and the other of R11 and R12 is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from -OH, halogen, and -CN. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00036"> <pat:ClaimNumber>36< / pat:ClaimNumber> <pat:ClaimText>36. The compound of any one of claims 1-27 and 34, or a pharmaceutically acceptable salt thereof, wherein Z is -NR11R12, wherein one of R11 and R12 is H and the other of R11 and R12 is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy and <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, and wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy is optionally substituted with one <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00037"> <pat:ClaimNumber>37< / pat:ClaimNumber> <pat:ClaimText>37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein the C1-6 alkyl is substituted with one group selected from -OH, methoxy, -OCH2CH2OCH3, or <semantics>−N(C1−3 alkyl)2<annotation encoding="application / x-tex">-N(C_{1-3} \text{ alkyl})_2< / annotation>< / semantics>, wherein each <semantics>C1−3 alkyl<annotation encoding="application / x-tex">C_{1-3} \text{ alkyl}< / annotation>< / semantics> may be the same or different. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00038"> <pat:ClaimNumber>38< / pat:ClaimNumber> <pat:ClaimText>38. The compound of any one of claims 1-27 and 34, or a pharmaceutically acceptable salt thereof, wherein Z is <semantics>−NR11R12<annotation encoding="application / x-tex">-NR^{11}R^{12}< / annotation>< / semantics>, wherein one of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is H and the other of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl is substituted with 1-3 groups independently selected from <semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics> 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, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl, and <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00039"> <pat:ClaimNumber>39< / pat:ClaimNumber> <pat:ClaimText>39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl of <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> and <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00040"> <pat:ClaimNumber>40< / pat:ClaimNumber> <pat:ClaimText>40. The compound of any one of claims 1-27 and 34, or a pharmaceutically acceptable salt thereof, wherein Z is -NR11R12, wherein NR11R12 is [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00041"> <pat:ClaimNumber>41< / pat:ClaimNumber> <pat:ClaimText>41. The compound of any one of claims 1-27 and 34, or a pharmaceutically acceptable salt thereof, wherein Z is -NR11R12, wherein 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00042"> <pat:ClaimNumber>42< / pat:ClaimNumber> <pat:ClaimText>42. The compound of any one of claims 1-27, 34, and 41, or a pharmaceutically acceptable salt thereof, wherein Z is -NR11R12, wherein 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00043"> <pat:ClaimNumber>43< / pat:ClaimNumber> <pat:ClaimText>43. The compound of any one of claims 1-27, 34, and 41-42, or a pharmaceutically acceptable salt thereof, wherein Z is -NR11R12, wherein 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 <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkoxy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00044"> <pat:ClaimNumber>44< / pat:ClaimNumber> <pat:ClaimText>44. The compound of any one of claims 1-27, 34, and 41-43, or a pharmaceutically acceptable salt thereof, wherein Z is -NR11R12, wherein -NR11R12 is [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00045"> <pat:ClaimNumber>45< / pat:ClaimNumber> <pat:ClaimText>45. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00046"> <pat:ClaimNumber>46< / pat:ClaimNumber> <pat:ClaimText>46. The compound of any one of claims 1-27 and 45, or a pharmaceutically acceptable salt thereof, wherein Z is phenyl optionally substituted 1-3 groups independently selected from halogen, -C(O)NR6R6, morpholinyl, or piperazinyl, wherein the morpholinyl and piperazinyl are each optionally substituted with one <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00047"> <pat:ClaimNumber>47< / pat:ClaimNumber> <pat:ClaimText>47. The compound of any one of claims 1-27 and 45-46, or a pharmaceutically acceptable salt thereof, wherein Z is [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00048"> <pat:ClaimNumber>48< / pat:ClaimNumber> <pat:ClaimText>48. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein 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 R13 groups and each have 1-3 ring heteroatoms independently selected from N, O, and S. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00049"> <pat:ClaimNumber>49< / pat:ClaimNumber> <pat:ClaimText>49. The compound of any one of claims 1-27 and 48, or a pharmaceutically acceptable salt thereof, wherein 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 R13 groups and each have 1-3 ring heteroatoms independently selected from N, O, and S. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00050"> <pat:ClaimNumber>50< / pat:ClaimNumber> <pat:ClaimText>50. The compound of any one of claims 1-27 and 48-49, or a pharmaceutically acceptable salt thereof, 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 1-3 ring heteroatoms independently selected from N, O, and S, wherein at least one ring heteroatom is a nitrogen. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00051"> <pat:ClaimNumber>51< / pat:ClaimNumber> <pat:ClaimText>51. The compound of any one of claims 1-27, 48, and 50, or a pharmaceutically acceptable salt thereof, wherein 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00052"> <pat:ClaimNumber>52< / pat:ClaimNumber> <pat:ClaimText>52. The compound of any one of claims 1-27 and 48, or a pharmaceutically acceptable salt thereof, wherein Z is [Image disponible dans le document PDF, Image available in the PDF document] 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00053"> <pat:ClaimNumber>53< / pat:ClaimNumber> <pat:ClaimText>53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein Ring <semantics>Za<annotation encoding="application / x-tex">Z^{a}< / annotation>< / semantics> is optionally substituted with 1-2 <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> groups. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00054"> <pat:ClaimNumber>54< / pat:ClaimNumber> <pat:ClaimText>54. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein Ring Za is [Image disponible dans le document PDF, Image available in the PDF document] each of which is optionally substituted with 1-3 R13 groups. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00055"> <pat:ClaimNumber>55< / pat:ClaimNumber> <pat:ClaimText>55. The compound of any one of claims 1-27 and 48-54, or a pharmaceutically acceptable salt thereof, wherein each R13 is independently oxo, -OH, halogen, -CN, C1-4 alkyl, C1-4 alkoxy, <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, <semantics>−C(O)R10NR6R6<annotation encoding="application / x-tex">-C(O)R^{10}NR^6R^6< / annotation>< / semantics>, <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> 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 <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> monocyclic or fused bicyclic aryl is optionally substituted with 1-3 <semantics>R14<annotation encoding="application / x-tex">R^{14}< / annotation>< / semantics> 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00056"> <pat:ClaimNumber>56< / pat:ClaimNumber> <pat:ClaimText>56. The compound of any one of claims 1-27 and 48-55, or a pharmaceutically acceptable salt thereof, wherein each R13 is independently oxo, -OH, halogen, methyl, ethyl, isopropyl, <semantics>−NR6R6<annotation encoding="application / x-tex">-NR^6R^6< / annotation>< / semantics>, <semantics>−C(O)R10NR6R6<annotation encoding="application / x-tex">-C(O)R^{10}NR^6R^6< / annotation>< / semantics>, <semantics>−C(O)NR6R6<annotation encoding="application / x-tex">-C(O)NR^6R^6< / annotation>< / semantics>, <semantics>−C(O)R8<annotation encoding="application / x-tex">-C(O)R^8< / annotation>< / semantics>, 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00057"> <pat:ClaimNumber>57< / pat:ClaimNumber> <pat:ClaimText>57. The compound of any one of claims 1-27 and 48-56, or a pharmaceutically acceptable salt thereof, wherein each R14 is independently halogen, C1-4 alkyl, or 5-6 membered monocyclic heteroaryl, wherein the <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00058"> <pat:ClaimNumber>58< / pat:ClaimNumber> <pat:ClaimText>58. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein <semantics>R14<annotation encoding="application / x-tex">R_{14}< / annotation>< / semantics> is imidazolyl optionally substituted with -CH2OCH2CH2Si(CH3)3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00059"> <pat:ClaimNumber>59< / pat:ClaimNumber> <pat:ClaimText>59. The compound of any one of claims 1-27 and 48-56, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently H or C1-4 alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00060"> <pat:ClaimNumber>60< / pat:ClaimNumber> <pat:ClaimText>60. The compound of any one of claims 1-27 and 48-56, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently H or methyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00061"> <pat:ClaimNumber>61< / pat:ClaimNumber> <pat:ClaimText>61. The compound of any one of claims 1-27 and 48-56, or a pharmaceutically acceptable salt thereof, wherein <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> is <semantics>−CH(CH3)2<annotation encoding="application / x-tex">-CH(CH_3)_2< / annotation>< / semantics>-. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00062"> <pat:ClaimNumber>62< / pat:ClaimNumber> <pat:ClaimText>62. The compound of any one of claims 1-27 and 48-56, or a pharmaceutically acceptable salt thereof, wherein <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> is <semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics> alkoxy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00063"> <pat:ClaimNumber>63< / pat:ClaimNumber> <pat:ClaimText>63. The compound of any one of claims 1, 3-5, and 7-8, wherein the compound is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] ) ) , [Image disponible dans le document PDF, Image available in the PDF document] _ _ [Image disponible dans le document PDF, Image available in the PDF document] 1 . , [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. 1 , [Image disponible dans le document PDF, Image available in the PDF document] , , [Image disponible dans le document PDF, Image available in the PDF document] _ [Image disponible dans le document PDF, Image available in the PDF document] , , [Image disponible dans le document PDF, Image available in the PDF document] 2 [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 0 [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] , , [Image disponible dans le document PDF, Image available in the PDF document] _ , or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00064"> <pat:ClaimNumber>64< / pat:ClaimNumber> <pat:ClaimText>64. A compound that is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] _ _ , [Image disponible dans le document PDF, Image available in the PDF document] , or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00065"> <pat:ClaimNumber>65< / pat:ClaimNumber> <pat:ClaimText>65. A pharmaceutical composition comprising a compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00066"> <pat:ClaimNumber>66< / pat:ClaimNumber> <pat:ClaimText>66. The pharmaceutical composition of claim 65, further comprising one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00067"> <pat:ClaimNumber>67< / pat:ClaimNumber> <pat:ClaimText>67. Use of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 65 or 66, for treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00068"> <pat:ClaimNumber>68< / pat:ClaimNumber> <pat:ClaimText>68. Use of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 65 or 66, for the manufacture of a medicament for treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00069"> <pat:ClaimNumber>69< / pat:ClaimNumber> <pat:ClaimText>69. The use of claim 67 or 68, in combination with of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00070"> <pat:ClaimNumber>70< / pat:ClaimNumber> <pat:ClaimText>70. The use of claim 69, wherein 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 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00071"> <pat:ClaimNumber>71< / pat:ClaimNumber> <pat:ClaimText>71. The use of claim 69 or 70, wherein 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00072"> <pat:ClaimNumber>72< / pat:ClaimNumber> <pat:ClaimText>72. The use of any one of claims 69-71, wherein 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00073"> <pat:ClaimNumber>73< / pat:ClaimNumber> <pat:ClaimText>73. The use of any one of claims 69-72, wherein 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00074"> <pat:ClaimNumber>74< / pat:ClaimNumber> <pat:ClaimText>74. A compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 65 or 66, for use in treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00075"> <pat:ClaimNumber>75< / pat:ClaimNumber> <pat:ClaimText>75. The compound or pharmaceutical composition for use of claim 74, for use in combination with of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00076"> <pat:ClaimNumber>76< / pat:ClaimNumber> <pat:ClaimText>76. The compound or pharmaceutical composition for use of claim 75, wherein the one or more additional therapeutic agents is selected from: 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 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00077"> <pat:ClaimNumber>77< / pat:ClaimNumber> <pat:ClaimText>77. The compound or pharmaceutical composition for use of claim 75 or 76, wherein the one or more additional therapeutic agents is selected from 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00078"> <pat:ClaimNumber>78< / pat:ClaimNumber> <pat:ClaimText>78. The compound or pharmaceutical composition for use of any one of claims 75-77, wherein the one or more additional therapeutic agents is selected from 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00079"> <pat:ClaimNumber>79< / pat:ClaimNumber> <pat:ClaimText>79. The compound or pharmaceutical composition for use of any one of claims 75-78, wherein the one or more additional therapeutic agents is selected from 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. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>