Diolic aminopyrazine compounds as p13K-γ inhibitors

Abstract

Claim 1: A compound of formula (1), or a pharmaceutically acceptable salt thereof; wherein: X¹ is N or CR¹; R¹ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN, OH and NH₂; R² is C(O)NRᶜ¹Rᵈ¹; R³, R⁴ and R⁵ are each independently selected from H, D, halo, CN, OH, C₁₋₆, alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₆ alkyl, HO-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino and C(O)NRᶜRᵈ, wherein the C₁₋₆ alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; R⁶, R⁷, and R⁸ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆, alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆, alkyl-, C(O)Rᵇ³, C(O)NRᶜ³Rᵈ³, C(O)NRᶜ³(ORᵃ³), C(O)ORᵃ³, C(=NRᵉ³)Rᵇ³, C(=NOH)Rᵇ³, C(=NCN)Rᵇ³ and C(=NRᵉ³)NRᶜ³Rᵈ³, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁶, R⁷ and R⁸ are each optionally substituted with independently selected 1, 2, 3, 4, 5, 6, 7 or 8 RB substituents; and wherein the C₁₋₆ haloalkyl of R⁶, R⁷, or R⁸ is optionally substituted by 1, 2, 3, or 4 independently selected substituents Y; each Y is independently selected from D, halo, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; or the substituents R⁶ and R⁷, together with the ring atoms to which they are attached,form a 4-7 membered C₃₋₁₀ cycloalkyl or heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; or the R⁷ and R⁸ substituents, together with the ring atoms to which they are attached, form a 4-7 membered C₃₋₁₀ cycloalkyl or heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Rᶜ and Rᵈ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of Rᶜ and Rᵈ, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected RM substituents; each Rᶜ¹ and Rᵈ¹ is independently selected from H, C₁₋₆ alkyl, C₁₋₆, haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of Rᶜ¹ and Rᵈ¹ are each optionally substituted with 1,2, 3, 4, 5, 6, 7 or 8 independently selected RA substituents; or, any Rᶜ¹ and Rᵈ¹, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected RA substituents; Each Rᵃ³, Rᵇ³, Rᶜ³ and Rᵈ³ is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (heterocycloalkyl 4-10 membered)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆, alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of Rᵃ³, Rᵇ³, Rᶜ³ and Rᵈ³ are each optionally substituted with independently selected 1, 2, 3, 4, 5, 6, 7 or 8 RB substituents; or, any Rᵉ³ and Rᵈ³, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with independently selected 1, 2, 3, 4, 5, 6, 7, or 8 RB substituents; each Rᵉ³ is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; Each RA is selected independently from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, ORᵃ⁴, SRᵃ⁴, NHORᵃ⁴, C(O)Rᵇ⁴, C(O)NRᶜ⁴Rᵈ⁴, C(O)NRᶜ⁴(ORᵇ⁴), C(O)ORᵃ⁴, OC(O)Rᵇ⁴, OC(O)NRᶜ⁴Rᵈ⁴, NRᶜ⁴Rᵈ⁴, NRᶜ⁴NRᶜ⁴Rᵈ⁴, NRᶜ⁴C(O)Rᵇ⁴, NRᶜ⁴C(O)ORᵃ⁴, NRᶜ⁴C(O)NRᵃ⁴Rᵈ⁴, C(=NRᵉ⁴)Rᵇ⁴, C(=NOH)Rᵇ⁴, C(=NCN)Rᵇ⁴, C(=NRᵉ⁴)NRᶜ⁴Rᵈ⁴, NRᶜ⁴C(=NRᶜ⁴)NRᶜ⁴Rᵈ⁴, NRᶜ⁴C(=NRᵉ⁴)Rᵇ⁴, NRᶜ⁴C(=NOH)NRᶜ⁴Rᵈ⁴, NRᶜ⁴C(=NCN)NRᶜ⁴Rᵈ⁴, NRᶜ⁴S(O)Rᵇ⁴, NRᶜ⁴S(O)NRᶜ⁴Rᵈ⁴, NRᶜ⁴S(O)₂Rᵇ⁴, NRᶜ⁴S(O)₂NRᶜ⁴Rᵈ⁴, S(O)Rᵇ⁴, S(O)NRᶜ⁴Rᵈ⁴, S(O)₂Rᵇ⁴, S(O)₂NRᶜ⁴Rᵈ⁴, OS(O)(=NRᵉ⁴)Rᵇ⁴, OS(O)₂Rᵇ⁴, SF₅, P(O)Rᶠ⁴Rᵍ⁴, OP(O)(ORʰ⁴)(ORⁱ⁴), P(O)(ORʰ⁴)(ORⁱ⁴) and BRʲ⁴Rᵏ⁴,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected RD substituents; each RB is selected independently from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆, alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, ORᵃ², SRᵃ², NHORᵃ², C(O)Rᵇ², C(O)NRᶜ²Rᵈ², C(O)NRᶜ²(ORᵇ²), C(O)ORᵃ², OC(O)Rᵇ², OC(O)NRᶜ²Rᵈ², NRᶜ²Rᵈ², NRᶜ²NRᶜ²Rᵈ², NRᶜ²C(O)Rᵇ², NRᶜ²C(O)ORᵃ², NRᶜ²C(O)NRᶜ²Rᵈ², C(=NRᵉ²)Rᵈ²,C(=NOH)Rᵇ², C(=NCN)Rᵇ², C(=NRᵉ²)NRᶜ²Rᵈ², NRᶜ²C(=NRᵉ²)NRᶜ²Rᵈ², NRᶜ²C(=NRᵉ²)Rᵇ², NRᶜ²C(=NOH)NRᶜ²Rᵈ², NRᶜ²C(=NCN)NRᶜ²Rᵈ², NRᶜ²S(O)Rᵇ², NRᶜ²S(O)NRᶜ²Rᵈ², NRᶜ²S(O)₂Rᵇ², NRᶜ²S(O)₂NRᶜ²Rᵈ², S(O)Rᵇ², S(O)NRᶜ²Rᵈ², S(O)₂Rᵇ², S(O)₂NRᶜ²Rᵈ², OS(O)(=NRᵉ²)Rᵇ², OS(O)₂Rᵇ², SF₅, P(O)Rᶠ²Rᵍ², OP(O)(ORʰ²)(ORⁱ²), P(O)(ORʰ²)(ORⁱ²) and BRʲ²Rᵏ², wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, heteroaryl of 5-10 membered, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of RB is optionally substituted with independently selected 1, 2, 3, 4, 5, 6, 7 or 8 RM substituents; each Rᵃ², Rᵇ², Rᶜ² and Rᵈ² is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of Rᵃ², Rᵇ², Rᶜ² and Rᵈ² are each optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected RM substituents; or, any Rᵉ² and Rᵈ² attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6- or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6- or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6,7 or 8 independently selected RM substituents; each Rᵉ² is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; Each R₠₲ and Rₐ₲ is independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each Rʰ² and Rⁱ² is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆, alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆, alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each Rʲ² and Rᵏ² is independently selected from OH, C₁₋₆ alkoxy and C₁₋₆ haloalkoxy; or any Rʲ² and Rᵏ² attached to the same atom B, together with the atom B to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected C₁₋₆ alkyl and C₁₋₆ haloalkyl substituents; each Rᵃ⁴, Rᵇ⁴, Rᶜ⁴ and Rᵈ⁴ is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆, alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of Rᵃ⁴, Rᵇ⁴, Rᶜ⁴ and Rᵈ⁴ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected RD substituents; or, any Rᶜ⁴ and Rᵈ⁴ attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6- or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6- or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6,7 or 8 independently selected RD substituents; each Rᵉ⁴ is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each Rᶠ⁴ and Rᵍ⁴ is independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl members)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each Rʰ⁴ and Rⁱ⁴ is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each Rʲ⁴ and Rᵏ⁴ is independently selected from OH, C₁₋₆ alkoxy and C₁₋₆ haloalkoxy; or any Rʲ⁴ and Rᵏ⁴ attached to the same atom B, together with the atom B to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected C₁₋₆ alkyl and C₁₋₆ haloalkyl substituents; Each RD is independently selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN,NO₂, ORᵃ⁵, SRᵃ⁵, NHORᵃ⁵, C(O)Rᵇ⁵, C(O)NRᶜ⁵Rᵈ⁵, C(O)NRᵉ⁵(ORᵇ⁵), C(O)ORᵃ⁵, OC(O)Rᵇ⁵, OC(O)NRᶜ⁵Rᵈ⁵, NRᶜ⁵Rᵈ⁵, NRᶜ⁵NRᶜ⁵Rᵈ⁵, NRᶜ⁵C(O)Rᵇ⁵, NRᶜ⁵C(O)ORᵃ⁵, NRᶜ⁵C(O)NRᶜ⁵Rᵈ⁵, C(=NRᵉ⁵)Rᵇ⁵, C(=NOH)Rᵇ⁵, C(=NCN)Rᵇ⁵, C(=NRᵉ⁵)NRᶜ⁵Rᵈ⁵, NRᶜ⁵C(=NRᵉ⁵)NRᶜ⁵Rᵈ⁵, NRᶜ⁵C(=NRᵉ⁵)Rᵇ⁵, NRᶜ⁵C(=NOH)NRᶜ⁵Rᵈ⁵, NRᶜ⁵C(=NCN)NRᶜ⁵Rᵈ⁵, NRᶜ⁵S(O)Rᵇ⁵, NRᵉ⁵S(O)NRᶜ⁵Rᵈ⁵, NRᶜ⁵S(O)₂Rᵇ⁵, NRᶜ⁵S(O)₂NRᶜ⁵Rᵈ⁵, S(O)Rᵇ⁵, S(O)NRᶜ⁵Rᵈ⁵, S(O)₂Rᵉ⁵, S(O)₂NRᶜ⁵Rᵈ⁵, OS(O)(=NRᵉ⁵)Rᵇ⁵, OS(O)₂Rᵇ⁵, SF₅, P(O)Rᶠ⁵Rᵍ⁵, OP(O)(ORʰ⁵)(ORⁱ⁵), P(O)(ORʰ⁵)(ORⁱ⁵) and BRʲ⁵Rᵏ⁵, where the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of RD are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; each Rᵃ⁵, Rᵇ⁵, Rᶜ⁵ and Rᵈ⁵ is selected independently of H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of Rᵃ⁵, Rᵇ⁵, Rᶜ⁵ and Rᵈ⁵ are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; or, any Rᶜ⁵ and Rᵈ⁵ attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6- or 7-membered heterocycloalkyl group,wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6- or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; each Rᵉ⁵ is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each Rᶠ⁵ and Rᵍ⁵ is selected independently,

Description

AMINOPYRAZINE DIOL COMPOUNDS AS ΡΙ3Κ-γ INHIBITORS TECHNICAL FIELD The present invention provides aminopyrazine diol compounds that modulate the activity of phosphoinositide 3-kinases-gamma (ΡΙ3Κγ) and are useful in the treatment of diseases related to the activity of ΡΙ3Κγ including, for example, autoimmune diseases, cancer, cardiovascular diseases and neurodegenerative diseases. BACKGROUND OF THE INVENTION Phosphoinositide 3-kinases (PI3K) belong to a large family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring (Cantley, Science, 2002, 296(5573):1655-7). PI3Ks are divided into three classes (class I, Π and ΠΙ) according to their structure, regulation and substrate specificity. Class I PI3Ks, which include PI3K.cc, ΡΙ3Κβ, ΡΙ3Κγ, and ΡΙ3Κδ, are a family of dual lipid- and protein-specific kinases that catalyze the phosphorylation of phosphatidylinositol-4,5-bisphosphate (ΡΠ>2) to give instead to phosphatidylinositol3,4,5-trisphosphate (PIP3). PIP3 functions as a second messenger that controls a series of cellular processes, including growth, survival, adhesion, and migration. The four class I PI3K isoforms exist as heterodimers composed of a catalytic subunit (pl 10) and a closely associated regulatory subunit that controls their expression, activation, and subcellular localization. PI3Kot, ΡΙ3Κβ, and ΡΙ3Κδ are associated with a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine kinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002, 277(44) :41556-62) while ΡΙ3Κγ is associated with two regulatory subunits (pl01 and p84) and its activation is directed by the activation of G protein-coupled receptors (Brock, et al., J Cell Biol., 2003, 160(1) :89-99). ΡΙ3Κα and ΡΙ3Κβ are ubiquitously expressed. In contrast, PI3Ky and ΡΙ3Κδ are predominantly expressed in leukocytes (Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204). The expression of ΡΙ3Κγ is mainly restricted to the hematopoietic system, although it can also be detected at a lower level in endothelium, heart and brain. Mice with ΡΙ3Κγ gene knockout or gene replacement and kinase inactivation are normal and fertile and do not have any obvious adverse phenotype. Analysis at the cellular level indicates that ΡΙ3Κγ is required for GPCR ligand-induced PtdIN (3,4,5)P3 production, chemotaxis, and respiratory burst in neutrophils. ΡΙ3Κγ-null macrophages and dendritic cells exhibit reduced migration toward various chemoattractants. ΡΙ3Κγ-deficient T cells show impairment of cytokine production in response to stimulation with anti-CD3 or Con A. The action of ΡΙ3Κγ downstream of the adenosine A3 A receptor is critical for sustained mast cell degranulation induced by the cross-linking of FCsRI with IF-2019-19254930-APN-ANP#INpi Page 1 of 170 IgE. ΡΙ3Κγ is also essential for the survival of eosinophils (Ruckle et al., Nat. Rev. Drug Discovery, 2006, 5, 903-918) Given its unique expression pattern and cellular functions, the potential role of ΡΙ3Κγ in various autoimmune and inflammatory disease models has been investigated with genetic and pharmacological tools. In asthma and allergy models, PI3Ky mice or ΡΙ3Κγ inhibitor-treated mice showed impaired ability to mount contact hypersensitivity and delayed-type hypersensitivity reactions. In these models, PI3Ky was shown to be important for the recruitment of neutrophils and eosinophils to the airways and the degranulation of mast cells (see for example Laffargue et al., Immunity, 2002, 16, 441451; Prete et al., The EMBO Journal , 2004, 23, 3505-3515; Pinho et al., L. Leukocyte Biology, 2005, 77, 800-810; Pharmacol. Exp Ther. 2009, 328, 758-765). In two different models of acute pancreatitis, genetic ablation of ΡΙ3Κγ significantly reduced the degree of acinar cell injury / necrosis and neutrophil infiltration without any impact on the secretory function of isolated pancreatic acini (Lupia et al., Am. J . Pathology, 2004, 165, 2003-2011). ΡΒΚγ7' mice were largely protected in four different rheumatoid arthritis models (CIA, α-CII-IA, K / BxN serum transfer, and NET transgenic) and inhibition of ΡΙ3Κγ suppressed the progression of inflammation and damage in the joints in the CIA and α-CII-IA models (see for example, Camps et al., Nat. Medicine, 2005, 11, 939-943; Randis et al., Eur. J. Immunol, 2008, 38, 1215 -1224; Hayer et al., FASB J., 2009, 4288-4298). In the MRL-Zpr mouse model of human systemic lupus erythematosus, inhibition of ΡΙ3Κγ reduced glomerulonephritis and prolonged lifespan (Barber et al., Nat. Medicine, 2005, 9, 933-935). There is evidence to suggest that chronic inflammation due to the infiltration of cells of myeloid origin is a fundamental component in the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) (Giri et al., Am. J. Physiol. Cell Physiol., 2005, 289, C264-C276; El Khoury et al., Nat. Med., 2007, 13, 432-438). Consistent with this suggestion, inhibition of ΡΙ3Κγ was shown to attenuate Αβ(1-40)-induced accumulation of activated astrocytes and microglia in the hippocampus and prevent peptide-induced cognitive deficits and synaptic dysfunction in the AD model. mouse (Passos et al., Brain Behav. Immun. 2010, 24, 493-501). Deficiency or inhibition of ΡΙ3Κγ was further shown to delay the onset and alleviate symptoms in experimental autoimmune encephalomyelitis in mice, a mouse model of human multiple sclerosis, which is another form of neurodegenerative disease (see e.g. Rodrigues et al. , J. Neuroimmunol. 2010, 222, 90-94; Euro. J. Immunol. 2011, 41, 833-844; 2013, 253, 89-99). IF-2019-19254930-APN-ANP#INpi Page 2 of 170 Chronic inflammation has been formally recognized as one of the hallmarks for many different types of cancer. Consequently, selective anti-inflammatory drugs represent a novel class of anticancer therapies (Hanahan and Weinberg, Cell, 2011, 144, 646-674). Since ΡΙ3Κγ has been reported to be a mediator of several inflammatory processes, its role as an immune oncological target has also been investigated. A recent study reported that ΡΙ3Κγ deficiency suppressed tumor growth in syngeneic models of lung cancer, pancreatic cancer, and melanoma (LLC, PAN02, and B16). PI3Ky deficiency or inhibition also inhibited tumor growth in a spontaneous breast cancer model (Schmid et al., Cancer Cell, 2011, 19, 715-727). An additional study reported that ΡΙ3Κγ deficiency could improve inflammation and tumor growth in mice that have colitis-associated colon cancer, (Gonzalez-Garcia et al., Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic analysis indicates that tumor infiltration of CD1 lb+ myeloid cells can cause protumorigenic inflammation at tumor sites and ΡΙ3Κγ in myeloid cells is critical in mediating the signaling of various chemoattractants that deliver cells to the tumor (Schmid et al. , Cancer Cell, 2011, 19, 715-727). Other studies suggest that ΡΙ3Κγ is also required for the differentiation of naïve myeloid cells to M2 macrophages at tumor sites. M2 macrophages promote tumor growth and progression by secreting immunosuppressive factors such as arginase 1, which deprives the tumor microenvironment of arginase, thereby promoting T cell death and NK cell inhibition (Schmidt et al. , Cancer Res. 2012, 72 (Suppl 1: Summary, 411; Kaneda et al., Cancer Res., 74 (Suppl 19: Summary 3650)). In addition to its potential role in promoting a protumorigenic microenvironment, PI3Ky may play a direct role in cancer cells. PI3Ky is reported to be required for Kaposi's sarcoma-associated herpesvirus vGPCR oncogene signaling and tumor growth in a mouse sarcoma model (Martin et al., Cancer Cell, 2011, 19, 805813). It was further suggested that PI3Ky is required for the growth of T-ALL cells (Subramanjam et al., Cancer Cell, 2012, 21, 459-472), PDAC and HCC (Falasca and Maffucci, Frontiers in Physiology, 2014, 5, 1 -10). Furthermore, in a search for causal mutations in pancreatic cancer, the ΡΙ3Κγ gene was found to contain the second highest-scoring predicted causal mutation (R839C) among the set of genes not previously identified as causal in pancreatic cancer (Carter and others, Cancer Biol. Ther. 2010,10, 582-587). Finally, ΡΙ3Κγ deficiency has also been reported to offer protection to experimental animals in different models of cardiovascular disease. For example, lack of ΡΙ3Κγ could reduce angiotensin-evoked smooth muscle contraction and therefore protect mice against angiotensin-induced hypertension (Vecchione et al., J. Exp. Med. 2005, 201, 1217 -1228). In strict animal models of myocardial infarction, inhibition of PI3Ky provided potent cardioprotection, with reduction in the development of infarctions and IF-2019-19254930-APN-ANP#INpi Page 3 of 170 preservation of myocardial function (Doukas et al., Proc. Natl. Acad. Sci. USA, 2006, 103, 1986619871). For these reasons, there is a need to develop new ΡΙ3Κγ inhibitors that can be used for the treatment of diseases such as cancer, autoimmune disorders, and inflammatory and cardiac diseases. This application is directed to this and other needs. BRIEF DESCRIPTION OF THE INVENTION The present invention relates, inter alia, to compounds of Formula (I): R= <nYNH2 R5^y HO--R6 HO-|—R7 R8(I) or pharmaceutically acceptable salts thereof, wherein the constituent members are defined herein. The present invention further provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention further provides methods for inhibiting a ΡΙ3Κγ kinase activity comprising contacting the kinase with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The present invention further provides methods of treating a disease or disorder associated with abnormal expression or activity of ΡΙ3Κγ kinase in a patient by administering to a patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein. The present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. DETAILED DESCRIPTION OF THE INVENTION Compounds The present application provides, inter alia, compounds of Formula (I): IF-2019-19254930-APN-ANP#INpi Page 4 of 170 (I) or a pharmaceutically acceptable salt thereof; where: X1isNoCR1; R1 is selected from H, D, halo, Ci.6alkyl, Ci.6alkoxy, C2-6alkenyl, C2.6alkynyl, Ci.6haloalkyl, Ci.6haloalkoxy, CN, OH, and NH2; R2 is selected from H, D, halo, Ci-6 alkyl, Cue haloalkyl, C2.6 alkenyl, C2.6 alkynyl, Cy, Cy-C,.6 alkyl-, CN, NO2, ORal, SRal, NHORal, C( O)Rbl, C(O)NRclRdl, C(O)NRcl(ORal), C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclNRclRdl, NRclC(O)Rbl, NRclC(O )ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NOH)Rbl, C(=NCN)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclC(=NOH)NRclRdl , NRclC(=NCN)NRcIRdl, NRclC(=NRel)Rbl, NRclS(O)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)(=NRel)Rbl, NRclS(O)2NRclRdl, S (O)Rbl, S(O)NRclRdl, S(O)2Rbl, S(O)2NRclRdl, OS(O)(=NRel)Rbl, OS(O)2Rbl, SF5, P(O)RflR81, ΟΡζΟχΟ^' χΟ^1), P(O)(ORhl)(OR''), and BRjlRkl, where each of Cue alkyl, C2.6 alkenyl, and C2.6 alkynyl of R is optionally substituted with 1, 2, 3 , 4, 5, 6, 7, or 8 independently selected R substituents; Cy is selected from Cg.14 aryl, C3.14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; Each of R3, R4 and R5 is independently selected from H, D, halo, CN, OH, Ci.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 alkoxy, Ci.g haloalkoxy, cyano-C|.6 alkyl, HO-Ci-6 alkyl, Ci.6 alkoxy-Ci.6 alkyl, C3.6 cycloalkyl, ammo, Ci.6 alkylamino, di(Ci.6 alkyl)amino, and C(O )NRcRd, wherein the Ci.6 alkyl is optionally replaced by 1, 2, 3, 4, 5, or 6 D; Each of R6, R7 and R8 is independently selected from H, D, Ci.6 alkyl, Ci.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, Cé.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C6.io aryl-Ci^ alkyl-, C3.10 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-C|.6 alkyl-, (4-membered heterocycloalkyl 10 members)-C1.6 alkyl-, C(O)Rb3, C(O)NRc3Rd3, C(O)NRc3(ORa3), C(O)ORa3, C(=NRe3)Rb3, C(=NOH)Rb3 , C(=NCN)Rb3, and C(=NRe3)NRc3Rd3, where each of Ci_6 alkyl, C2.6alkenyl, C2.6alkynyl, C6.io anlo, C3-10 cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, C6.io anlo-Ci.6alkyl-, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)- C1.6alkyl- of R6, R7, and R8 is optionally replaced with 1, IF-2019-19254930-APN-ANP#INpi Page 5 of 170 2, 3, 4, 5, 6, 7, or 8 RBindependently selected substituents; and wherein the Ci-6 haloalkyl of R6, R7, or R8 is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, Ci-6 alkyl, and C|.6 haloalkyl; or the substituents R6 and R7, together with the ring atoms to which they are attached, form a C3.10cycloalkyl or a 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 RB substituents independently selected; or the substituents R7 and R8, together with the ring atoms to which they are attached, form a C3. io cycloalkyl or a 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Each of Rcy Rd is independently selected from H, Ci-6 alkyl, Ci-β haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.10aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cé-ιο aryl-Cj^ alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-, in where each of C1.6 alkyl, C2.g alkenyl, C2.g alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl-C^e alkyl -, C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-C|.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Rcy Rd, optionally substituted with 1 , 2, 3, 4, 5, 6, 7, or 8 independently selected Rmin substituents; each Ral, Rbl, Rcl, and Rdl is independently selected from H, Ci-6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.g alkynyl, Cg.io aryl, C3.io cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-g alkyl-, C3.io cycloalkyl-Ci-e alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-membered heterocycloalkyl 10 members)-Ci_6alkyl-, wherein each of Ci-6 alkyl, C2.g alkenyl, C2.§ alkynyl, C^io aryl, C3.io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C6.io aryl-Ci.6alkyl-, C3.io cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- Ral, Rbl, Rcl, and Rdl, are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any of Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Relse independently selected from H, OH, CN, Cpe alkyl, C1.6 alkoxy, C1.6 haloalkyl, C1.6 haloalkoxy, C2.6 alkenyl, C2.g alkynyl, Ce-io aryl, C3.io cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyl-, C3.io cycloalkyl-Ci-6 IF-2019-19254930-APN-ANP#INpi Page 6 of 170 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each R and Rgl is independently selected from H, C].6alkyl, C].6alkoxy, Ci.6 haloalkyl, Cpg haloalkoxy, C2.6 alkenyl, C2-6 alkynyl, Ce-io aryl, C3.10 cycloalkyl, 5-heteroaryl 10-membered, 4-10-membered heterocycloalkyl, C6.10aryl-Ci.6alkyl-, C3.10cycloalkyl-Ci.6alkyl-, (5-10-membered heteroaryl)-Ci.6alkyl-, and (4-10-membered heterocycloalkyl members)-Ci.6alkyl-; each Rhly R11 is independently selected from H, C[.g alkyl, Ci-β haloalkyl, C2-6 alkenyl, C2.6alkynyl, C6-io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, C^io aryl-Ci.g alkyl-, C3.10 cycloalkyl-C]^ alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci. 6alkyl-; each Rjly Rkl is independently selected from OH, Ci.6alkoxy, and Ci_6haloalkoxy; or any of Rj and Rklunified to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and Ci-6 haloalkyl; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, Ci-6 alkyl, Ci-β haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, Cg.10 aryl-Cj-g alkyl-, C3.10 cycloalkyl-Ci-s alkyl-, (5-10 membered heteroaryl)-C|.6alkyl-, and (4-membered heterocycloalkyl -10 membered)-Ci.6alkyl-, wherein each of C|.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 members, C6.io aryl-Ci.6alkyl-, C3-10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C ,.6alkyl- of Ra3, Rb3, Rc3, and R113 is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; or, any of Rc3 and Rd3, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, where the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Re3 is independently selected from H, OH, CN, C1.6 alkyl, Cue alkoxy, C1.6 haloalkyl, Ci_6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, C3_10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.10aryl-C|.6alkyl-, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl) -Ci.6alkyl-; each Rase independently selects from D, halo, C].6alkyl, Ci_6haloalkyl, C2.6 alkenyl, C2.6alkynyl, C^o aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg -io aryl-Ci.^ alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 heteroaryl IF-2019-19254930-APN-ANP#INpI Page 7 of 170 members)-Ci.6alkyl-, (4-10 membered heterocycloalkyl)-Ci.6alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C( O)NRc4(ORM), C(O)ORa4, OC(O)RM, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rm, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(= NRe4)Rb4, C(=NOH)RM, C(=NCN)Rm, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4C(=NRe4)RM, NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN )NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O)2RM, NRc4S(O)2NRc4Rd4, S(O)RM, S(O)NRc4Rd4, S(O)2Rm, S(O)2NRc4Rd4 , OS(O)(=NRe4)RM, OS(O)2RM, SF5, P(O)Rf4Rg4, OP(O)(ORh4)(OR'4), P(O)(ORh4)(ORi4), and BRj4Rk4, wherein Cj.6alkyl, C2.6alkenyl, C2.6alkynyl, C6.)0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.,0aryl-C,.6alkyl- , C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkylj-C,^ alkyl- of RA is optionally substituted with 1, 2, 3, 4 , 5, 6, 7, or 8 RDindependently selected substituents; each Rbse independently selected from D, halo, Ci.g alkyl, Ci-6 haloalkyl, C2.g alkenyl, C2.6 alkynyl, C6.i0 aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10-membered, Cg.io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, (4-10 membered heterocycloalkyl)-Ci .6 alkyl-, CN, NO2, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC( O)NRc2Rd2, NR^, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C( =NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O)2Rb2 , NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, YES^NR^R02, OS(O)(=NRe2)Rb2, OS(O)2Rb2, SF5, P (O)RGRg2, OPIOXOR^XOR12), PtOXOR'^XOR12), and BR^R12, wherein C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C6-io aryl, C3.7cycloalkyl, 5-heteroaryl 10-membered, 4-10-membered heterocycloalkyl, Cg-io aryl-Ci.g alkyl-, C3.7cycloalkyl-Ci.g alkyl-, (5-10-membered heteroaryl)-Ci-6 alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Ra2, Rb2, Rc2, and R^ is independently selected from H, Ci-6 alkyl, C,.6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-heteroaryl 10-membered, 4-10-membered heterocycloalkyl, Cg-io anlo-Ci-g alkyl-, C3.7cycloalkyl-Ci.g alkyl-, (5-10-membered heteroaryl)-Ci.6alkyl-, and (4-membered heterocycloalkyl -10 membered)-Ci.6alkyl-, wherein each of Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10-membered, C6.|0aryl-Ci-6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci. 6alkyl- of Ra2, Rb2, Rc2, and R'12 is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; or, any of Rc2 and R02 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl IF-2019-19254930-APN-ANP#INpi 8 of 170 members are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Re2 is independently selected from H, OH, CN, Ci.g alkyl, Cj.6 alkoxy, Cpe haloalkyl, Cue haloalkoxy, C2-6 alkenyl, C2.6 alkynyl, Ce-io aryl, C3.7 cycloalkyl, 5-heteroaryl -10 membered, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl-; each Rgy R®2 is independently selected from H, C1.6 alkyl, C1.6 alkoxy, C1.6 haloalkyl, C1.6 haloalkoxy, C2-6 alkenyl, C2.6 alkynyl, Ce-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci_6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl-; each R112 and R12 is independently selected from H, Ci-6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6.,or aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, C^io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-^ alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl -; each Rj2y Rtíis independently selected from OH, Ci_6alkoxy, and Ci.6haloalkoxy; or any of Rj2 and R152 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C|.e alkyl and C1.6 haloalkyl; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, Cj.6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2.6alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl members)-Ci.6alkyl-, wherein each of Ci.$ alkyl, C2.6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, C6.10aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroarylj-Cue alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra4 , RM, Rc4, and Rd4 are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any of Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 RDindependently selected substituents; each Re4 is independently selected from H, OH, CN, Ci-6 alkyl, Ci.$ alkoxy, C|.g haloalkyl, Ci-6 haloalkoxy, C2.6 alkenyl, C2-6 alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci^ alkyl-, C3.7 cycloalkyl-Ci-6 IF-2019-19254930-APN-ANP#INpi Page 9 of 170 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each Rf4 and Rg4 is independently selected from H, Ci.6 alkyl, Ci.g alkoxy, Cpg haloalkyl, C,_6haloalkoxy, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroanl, heterocycloalkyl 4-10 membered, C6.io aryl-Ci.6alkyl-, C3.7cycloalkyl-Ci_6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl -; each Rh4 and R14 is independently selected from H, Cg-ιο, Cg-ιο aryl-C|.6alkyl-, C3.7cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-C,.6alkyl-; each Rj4 and Rk4 is independently selected from OH, Ci.6 alkoxy, and C].6 haloalkoxy; or any of Rj4 and Rk4 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and C|.6 haloalkyl; each Rd is independently selected from H, D, halo, Ct.6 alkyl, Ci-β haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C^io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered, Cg-io aryl-Ci.6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl) -Ci.6 alkyl-, CN, NO2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C (=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O) 2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rc5, S(O)2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O)2Rb5, SF5, P(O)RBRg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(OR'5), and BRj5Rk5, where each of Ci.6 alkyl, C2.6alkenyl, C2.6alkynyl . C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7cycloalkyl-C,.6alkyl-, (5-10 membered heteroaryl )-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RD is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents REindependently selected; each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, Ci.6alkyl, C].6haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.ioaryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, C6.io aryl-Cpe alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl -, wherein each of Ci-6 alkyl, C2.6 alkenyl, C2.g alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- Ci.6alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-C,.6 alkyl-, and (4-10 membered heterocycloalkyl IF-2O19-1925493O-APN-ANP#INPI Page 10 of 170 members)-Ci-6alkyl- of Ra5, Rb5, Rc5, and Rd5 is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 REindependently selected substituents; or, any of Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 REindependently selected substituents; each Re5 is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci.g haloalkyl, C|.6 haloalkoxy, C2-6 alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci.6 alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocyclicalkyl)-Ci.6alkyl-; each R® and Rg5 is independently selected from H, C|.6 alkyl, C1.6 alkoxy, Ci-6 haloalkyl, C|.g haloalkoxy, C2.6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-10 aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocyclicalkyl)-Ci.6alkyl-; each Rh5 and R15 is independently selected from H, Ci.g alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, Cg-io aryl-Ci.^ alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci. 6alkyl-; each RÍ5 and R10 is independently selected from OH, Ci-6 alkoxy, and Ci-6 haloalkoxy; or any of Rj5 and Rk5 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cj.6 alkyl and Cj.6 haloalkyl; each Rese independently selected from H, D, halo, C|.g alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, C^o aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, Cg-io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci-e alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl members)-Ci.6 alkyl-, CN, NO2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O) Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rbé, C(=NCN)Rb6 , C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6> NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S( O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rc6, S(O)2NRc6Rd6, OS(O)(=NRe6)Rb6, OS(O)2Rb6, SF5, P(O)RKRg6, OP(O)(ORh6)(ORi6), P(O)(ORh6)(ORi6), and BRj6Rk6, where each of Ci.6 alkyl, C2-6 alkenyl, C2. 6 alkynyl, C6.i0aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (heteroaryl of 5-10 members)-Ci-6 IF-2019-19254930-APN-ANP#INfI Page 11 of 170 alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RE is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RGindependently selected; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, Ci-β alkyl, Ci_6haloalkyl, C2-6alkenyl, C2.6alkynyl, C6-io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, Cg-io aryl-Ci-6alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci_6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- , wherein each of C1.6 alkyl, C2.g alkenyl, C2.g alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C^io aryl- Ci.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra6, Rb6, Rc6, and Rd6 is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; or, any of Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Re6 is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, C1.6 haloalkyl, C1.6 haloalkoxy, C2.g alkenyl, C2.6 alkynyl, Ce-10 aryl, C3.7 cycloalkyl , 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-C|.6alkyl-, (5-10 membered heteroaryl)-C,.6alkyl- , and (4-10 membered heterocycloalkyl)-C,.6alkyl-; each Rf6 and Rg6 is independently selected from 5-10 membered, 4-10 membered heterocycloalkyl, C6.i0aryl-C|.6alkyl-, C3.7 cycloalkyl-Ci_6alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (4-membered heterocycloalkyl -10 membersj-C^ alkyl-; each Rh6 and R'6 is independently selected from H, C1.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6.,or aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, Cg-io aryl-Ci.g alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)- Ci.6alkyl-; each Rj6y Rtóis independently selected from OH, Ci.6alkoxy, and Ci.6haloalkoxy; or any of Rj6 and Rk6 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and Ci-6 haloalkyl; each Rg is independently selected from H, D, halo, CN, NO2, SF5, Ci_6alkyl, Ci.6alkoxy, C|-6 haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.7 cycloalkyl, heteroaryl of 5 -10 membered, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci.6IF-2019-19254930-APN-ANP#INfI Page 12 of 170 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl; and each Rm is independently selected from H, D, OH, NO2, CN, halo, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C].6haloalkyl, cyano-Ci-6 alkyl, HO-Ci.6alkyl , Ci_6alkoxy-Ci-6 alkyl, C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci-6 alkyl-, C3.7cycloalkyl-Cpe alkyl-, (5-10 membered heteroaryl)-Cwalkyl-, (4-10 membered heterocycloalkyl)-C|.6 alkyl, Ci.g alkoxy, Cj.g haloalkoxy, amino, Ci.g alkylamino, di(C,_6alkyl) amino, thio, C,.6alkylthio, Ci.6alkylsulfinyl, Ci.6alkylsulfonyl, carbamyl, Ci.6alkylcarbamyl, di(C,.6alkyl)carbamyl, carboxy, Ci.6alkylcarbonyl, CMalkoxycarbonyl, C|.6alkylcarbonylamino, Ci.6alkylsulfonylamino, aminosulfonyl, C].6alkylaminosulfonyl, di(Ci.6alkylaminocarbonylamino, aminosulfonylamino, Cpe alkylaminosulfonylamino, di(Ci_6alkylaminocarbonylamino, aminocarbonylamino, Cb6alkylaminocarbonylamino, and di(Ci.6alkylaminocarbonylamino. In some modalities: X1isNoCR1; R1 is selected from H, D, halo, Ci-6 alkyl, C|.g alkoxy, C2-6 alkenyl, C2.6 alkynyl, Ci.g haloalkyl, C1.6 haloalkoxy, CN, OH, and NH2; R2 is selected from H, D, halo, C1.6 alkyl, C|.g haloalkyl, C7.6 alkenyl, C2-6 alkynyl, Cy, Cy-Ci.6 alkyl-, CN, NO2, ORal, SRal, NHORal, C(O)Rbl, C(O)NRc,Rdl, C(O)NRcl(ORal), C(O)ORal, OC(O)Rbl, OC(O)NRc'Rdl, NRclRdl, NRclNRclRdl, NRclC(O )Rbl, NRclC(O)ORaI, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NOH)Rbl, C(=NCN)Rbl, C(=NRel)NRclRdl, NRc,C(=NRel) NRclRdl, NRclC(=NOH)NRclRdl, NRclC(=NCN)NRclRdl, NRclC(=NRel)Rbl, NRc,S(O)NRc,Rdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)( =NRel)Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRc,Rdl, S(O)2Rbl, S(O)2NRclRdl, OS(O)(=NRe')Rbl, OS( O)2Rbl, SF5, P(O)RflRgl, OP(O)(ORhl)(ORil), P(O)(ORhl)(ORn), and BRjlRkl, where each of Ci_6 alkyl, C2.6 alkenyl, and C2.6alkynyl of R2 is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; Cy is selected from C6.i4 aryl, C3.]4cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; Each of R3, R4, and R5 is independently selected from H, D, halo, CN, OH, Ci_6 alkyl, C3.6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1.5 alkoxy, C1.6 haloalkoxy, cyano- Ci-6 alkyl, HO-Ci.6 alkyl, Ci.6 alkoxy-C,.6 alkyl, C3.6 cycloalkyl, amino, Ci.6 alkylamino, di(Ct.6 alkyl)amino, and C(O)NRcRd , wherein said Ci.6 alkyl may optionally be substituted by 1, 2, 3, 4, 5, or 6 D; Each of R6, R7 and R8 is independently selected from H, D, C].6alkyl, Cy.6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.io cycloalkyl, 5-10 membered heteroaryl, IF-2019-19254930-APN-ANP#INpi Page 13 of 170 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-g alkyl-, C3.10 cycloalkyl-Cj-e alkyl-, (5-10 membered heteroaryl)-C1.6alkyl-, (heterocycloalkyl 4-10 members)-Ci.6alkyl-, C(O)Rb3, CiOjNRV, C(O)NRc3(ORa3), C(O)ORa3, C(=NRe3)Rb3, C(=NOH)Rb3, C( =NCN)Rb3, and C(=NRe3)NRc3Rd3, wherein each of Ci.6alkyl, C2-6 alkenyl, C2-6 alkynyl, C6.io aryl, C3.|0cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, C6.io aryl-Ci.6alkyl-, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (4-10 membered heterocycloalkyl) -Ci.6alkyl- of R6, R7, and R8 is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; and wherein said Ci-6 haloalkyl of R6, R7, or R8 is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, Cj.6 alkyl, and Ci.g haloalkyl; or the substituents R6 and R7, together with the ring atoms to which they are attached, form a C3. cycloalkyl or a 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; or the substituents R7 and R8, together with the ring atoms to which they are attached, form a C3. [q cycloalkyl or a 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Each of Rcy Rd is independently selected from H, Ct.6 alkyl, C|_6haloalkyl, C2. 6alkenyl, C2.6alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-C|.g alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-, where each of C1.6 alkyl, C2.g alkenyl, C2.g alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.10aryl-C^ alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-membered heteroaryl -10 membered)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6alkyl- of Rcy Rd, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents Rmin independently selected; each Ral, Rbl, Rcl, and Rdl is independently selected from H, Ci.g alkyl, Ci^ haloalkyl, C2.6 alkenyl, C2.§ alkynyl, Cg-io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-e alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl members)-Ci.6alkyl-, wherein each of Ci.g alkyl, C2.6 alkenyl, C2.6 alkynyl, Ce. 10 aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, C6.io aryl-Ci.6alkyl-, C3.10 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci. 6alkyl- of Ral, Rbl, Rcl, and Rdl, is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any of Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl IF-2019-19254930 -APN-ANP#INpi Page 14 of 170 members, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R substituents independently selected; each Relse independently selected from H, OH, CN, Ci-6 alkyl, Ci.6alkoxy, Ci-6 haloalkyl, Ci.6haloalkoxy, C2-6 alkenyl, C2.6alkynyl, C6.io aryl, C3.10 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (heterocycloalkyl 4-10 members)-C|.6alkyl-; each Rñy Rgl is independently selected from H, Ci.6alkyl, Ci.6alkoxy, C(.6 haloalkyl, Ci-6 haloalkoxy, C2.6 alkenyl, C2.6 alkynyl, C6.to ayl, C3.10 cycloalkyl, heteroaryl of 5 -10 membered, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-membered heterocycloalkyl -10 members)-Ci.6alkyl-; each Rhly R11 is independently selected from H, C].6alkyl, Ci.6haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6.i0aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ^io aryl-Ci-e alkyl-, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each Rjly Rkl is independently selected from OH, Ci.6alkoxy, and C|.6haloalkoxy; or any of Rj and Rklunted to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C|.e alkyl and C1.6 haloalkyl; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, Ci.6alkyl, Cy.6haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, C6.|0aryl-Ci-6 alkyl-, C3.10 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)- Ci.6alkyl-, wherein each of C|.g alkyl, C2.g alkenyl, C2.g alkynyl, C§.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C6.10aryl-Ci.6alkyl-, C3.10 cycloalkyl-Cue alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra3, Rb3, Rc3, and Rd3 are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; or, any of Rc3 and Rd3, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, where the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; each Re3 is independently selected from H, OH, CN, C1.6 alkyl, C(.6 alkoxy, Cj.6 haloalkyl, Ci 6 haloalkoxy, C2.6 alkenyl, C2.6alkynyl, Cg-io aryl, C3.10 cycloalkyl, IF-2019-19254930-APN-ANP#INfI heteroaryl Page 15 of 170 5-10 membered, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-g alkyl-, C3.10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and ( 4-10 membered heterocycloalkyl)-C].6 alkyl-; each Rase independently selects from D, halo, C1.6 alkyl, C1.6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, C6.i0 aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10-membered, Cg.io aryl-Ci.6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C|.6 alkyl-, (4-10 membered heterocycloalkyl)- Ci.6 alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORM), C(O)ORa4, OC(O)RM, OC (O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)Rb4, C(=NOH)RM, C(=NCN)Rb4, C( =NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4C(=NRe4)Rb4, NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O)2RM , NRc4S(O)2NRc4Rd4, S(O)RM, S(O)NRc4Rd4, S(O)2Rm, S(O)2NRc4Rd4, OS(O)(=NRe4)RM, OS(O)2RM, SF5, P (O)Rf4Rg4, OP(O)(ORh4)(OR'4), P(O)(ORb4)(ORi4), and BRj4Rk4, where Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, C6.i0aryl , C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.10aryl-C,.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-C[. 6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RDindependently selected; each Rbse independently selected from D, halo, C|_g alkyl, C|.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, Ce-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, Cg-io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Cpg alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci. 6 alkyl-, CN, NO2, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O )NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C(=NRe2 )NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O)2Rb2, NR ^YES^NR^R02, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, S(O)2NRc2Rd2, OS(O)(=NRe2)Rb2, OS(O)2Rb2, SF5, P (O)RGRg2, OP(O)(ORh2)(ORi2), P(O)(ORh2)(ORi2), and BR^R12, where C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C6. io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cé.io aryl-Ci-e alkyl-, C2.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl) -Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R independently selected substituents; each Ra2, Rb2, Rc2, and R02 is independently selected from H, C1.6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6-io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, Cg-io aryl-Ci-6 alkyl-, C3J7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl) -Ci.6alkyl-, wherein each of Ci.g alkyl, C2.6 alkenyl, C2.g alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg .io aryl-Ci-6 alkyl-, C3.7IF-2019-19254930-APN-ANP#IN£I Page 16 of 170 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C,.6alkyl- of Ra2, Rb2, Rc2, and Rd2se optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RMin substituents; or, any of Rc2 and R42 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Re2 is independently selected from H, OH, CN, C|_g alkyl, Ci-6 alkoxy, Ci.g haloalkyl, Ci.6 haloalkoxy, C2.6 alkenyl, C2.6 alkynyl, C6.|0aryl, C3.7 cycloalkyl , 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.)0aryl-Ci.6alkyl-, C3.7cycloalkyl-C|.6alkyl-, (5-10 membered heteroaryl)-Cu6alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl-; each Rgy Rg2 is independently selected from H, Ci.6alkyl, Cj.6alkoxy, Ci_6haloalkyl, Cj.6 haloalkoxy, C2.6 alkenyl, C2.6 alkynyl, Cg-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ch6alkyl-, C3.7 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci .6alkyl-; each R112and R'2 is independently selected from H, C].6alkyl, Ci.6haloalkyl, C2.6 alkenyl, C2.6 alkynyl, Ce-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10-membered, Cg-io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci^ alkyl-, (5-10 membered heteroaryl)-C,.6 alkyl-, and (4-10 membered heterocycloalkyl)- Cb6alkyl-; each Rj2y Rtíis independently selected from OH, Ci.6alkoxy, and Ci.6haloalkoxy; or any of Rj2 and R1'2 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cpé alkyl and Ομβ haloalkyl; each Ra4, RM, Rc4, and Rd4 is independently selected from H, C|.6 alkyl, C^6 haloalkyl, C2-6 alkenyl, C2.6alkynyl, C6.,0aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C6.io aryl-Cb6alkyl-, C3.7 cycloalkyl-Cb6alkyl-, (5-10 membered heteroaryl)-Cu6alkyl-, and (4-10 membered heterocycloalkyl)-Ch6alkyl-, in where each of C^6 alkyl, C2.6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0anlo-C^ alkyl -, C3.7 cycloalkyl-C|.6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra4, RM, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any of Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached form a 5- or 6-membered heteroaryl group or a 4, 5, 6, or 7' heterocycloalkyl IF-2019-19254930- APN-ANP#INpi Page 17 of 170 members, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R substituents independently selected; each Re4 is independently selected from H, OH, CN, alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci.g haloalkoxy, C2.6 alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, C^io aryl-Ci_6 alkyl-, C3-7 cycloalkyl-Ci-e alkyl-, (5-10 membered heteroarylj-Cué alkyl-, and (4-membered heterocycloalkyl 10 members)-Ci.6alkyl-; each Rf4 and Rg4 is independently selected from H, C1.6 alkyl, Ci-6 alkoxy, C1.6 haloalkyl, C |_¿ haloalkoxy, C2.6 alkenyl, C2.6 alkynyl, C^io aryl, C3.7 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-e alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each Rh4 and R14 is independently selected from H, Ci.$ alkyl, Ci-β haloalkyl, C2.6 alkenyl, C2-6alkynyl, Ce-io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 I rent-; each RÍ4 and Rk4 is independently selected from OH, Cj.6 alkoxy, and C1.6 haloalkoxy; or any of R^4 and Rk4 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1- 6 alkyl and C1.6 haloalkyl; each Rd is independently selected from H, D, halo, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.,o aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, Ce-io aryl-Ci-e alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl )-Ci.6 alkyl-, CN, NO2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5 , OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5> NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O )2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rc5, S(O)2NRc5Rd5, OS(O)(=NRe5)Rb5> OS(O)2Rb5, SF5 , P(O)RBRg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(OR15), and BRj5Rk5, where each of Ci_6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C6.j0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Cj-g alkyl-, (5-10 membered heteroaryl members)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RD is optionally substituted with 1, 2, 3, or 4 substituents REindependently selected; each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1.6 alkyl, C]_6 haloalkyl, C2 6 alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, IF-2019-19254930-APN-ANP#INpi Page 18 of 170 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-g alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (heterocycloalkyl 4-10 membered)-Ci.6alkyl-, wherein each of Ci-s alkyl, C2.6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-C1.6alkyl-, and (4-10 membered heterocycloalkyl) -Ci.6 alkyl- of Ra5, Rb5, Rc5, and Rd5 is optionally substituted with 1, 2, 3, or 4 independently selected substituents; or, any of Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 REindependently selected substituents; each Re5 is independently selected from H, OH, CN, Ci-6 alkyl, C1.6 alkoxy, Cj.6 haloalkyl, C|.6 haloalkoxy, C2-6 alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cé-ιο aryl-C|.6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci. 6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each Rby Rs5 is independently selected from H, C1.6 alkyl, C|.g alkoxy, C1.6 haloalkyl, Ci.6haloalkoxy, C2.6alkenyl, C2-6alkynyl, C6.10aryl, C3.7 cycloalkyl, heteroaryl from 5-10 members, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-C|.6 alkyl-, (5-10 membered heteroaryl)-C1.6alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl-; each Rh5 and R'5 is independently selected from H, Ci-6 alkyl, C].6haloalkyl, C2-6 alkenyl, C2.6alkynyl, C^o aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-C).6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl -; each Rj5 and Rk5 are independently selected from OH, C1.6 alkoxy, and C1.6 haloalkoxy; or any of Rj5 and Rk5 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cj.6 alkyl and Ci-6 haloalkyl; each Rese independently selected from H, D, halo, C1.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6alkynyl, C^o aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, Cg.io aryl-Ci.6 alkyl-, C3.7 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, and (4-10 membered heterocycloalkyl) -Ci.6alkyl-, CN, NO2, ORa6, SR , NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC (O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rb6, C(=NCN)Rb6, C( =NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, ' IF-2019-19254930-APN-ANP#INpi Page 19 of 170 NRc6C(=NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rc6, S (O)2NRc6Rd6, OS(O)(=NRe6)Rb6, OS(O)2Rb6, SF5, P(O)Rf6Rg6, OP(O)(ORh6)(OR'6), P(O)(ORh6)( OR16), and BRj6Rk6, wherein each of Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, C6.ioaryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl- C,.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C,.6alkyl- of RE is optionally substituted with 1 , 2, 3, or 4 independently selected RG substituents; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, Ci.6 alkyl, C|.6 haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.i0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered, Cg-io aryl-Ci.6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Cl.6alkyl-, and (4-10 membered heterocycloalkyl)- Ci.6alkyl-, wherein each of C|.6 alkyl, C2.g alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6 .io aryl-Ci.6alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl- of Ra6 , Rb6, Rc6, and Rd6 are optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any of Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, Q.6 alkyl, Cj.6 alkoxy, Ci.6 haloalkyl, Ci.6haloalkoxy, C2.6alkenyl, C2.6alkynyl, C6.,or aryl, C3.7cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci.^ alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl-; each Rf6 and Rg6 is independently selected from 5-10 membered, 4-10 membered heterocycloalkyl, Cg-io aryl-Cpe alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (5-10 membered heterocycloalkyl) 4-10 members)-Ci.6 alkyl-; each Rh6 and R'6 is independently selected from H, Cy.6alkyl, Cy.6haloalkyl, C2.6alkenyl, C2.6alkynyl, C^o aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ^.io aryl-Ci-6 alkyl-, C3.7cycloalkyl-C|-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl -; each R-i6 and Rk6 is independently selected from OH, Ci.6 alkoxy, and Cj.6 haloalkoxy; IF-2019-19254930-APN-ANP#INpi Page 20 of 170 or any of R?6 and Rk6 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and C|.g haloalkyl; each Rg is independently selected from H, D, halo, CN, NO2, SF5, Cpg alkyl, Ci-6 alkoxy, C|-6 haloalkyl, C2.g alkenyl, C2.g alkynyl, Cg.io aryl, C3.7 cycloalkyl , 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci.^ alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl- , and (4-10 membered heterocycloalkyl)-Ci.6alkyl; and each Rm is independently selected from H, D, OH, NO2, CN, halo, C|.6alkyl, C2.g alkenyl, C2.6alkynyl, Ci.6haloalkyl, cyano-Ci.6alkyl, HO-Ci.6alkyl, Ci. 6alkoxy-Ci.6alkyl, C6.io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, (4-10 membered heterocycloalkyl)-Ci.6 alkyl, Cj.g alkoxy, C|.g haloalkoxy, amino, Ci.g alkylamino, di(C, .6alkyl)amino, thio, C,.6alkylthio, Ci.6alkylsulfinyl, C^ alkylsulfonyl, carbamyl, C].6alkylcarbamyl, di(Ci.6alkyl)carbamyl, carboxy, C].6alkylcarbonyl, CMalkoxycarbonyl, Ci.6alkylcarbonylamino, Cb6alkylsulfonylamino, aminosulfonyl, C,.6alkylaminosulfonyl, di(Ci.g alkyl)aminosulfonyl, aminosulfonylamino, Ci.g alkylaminosulfonylamino, di(C|.g alkyl)aminosulfonylamino, aminocarbonylamino, C|.g alkylaminocarbonylamino, and di(Ci-6 alkylaminocarbonylamino. In some modalities, X1isNoCR1; R1 is selected from H, D, halo, Ci-6 alkyl, Ci-6 alkoxy, C2.g alkenyl, C2.g alkynyl, C1.6 haloalkyl, Ci.6haloalkoxy, CN, OH, and NH2; R2 is selected from H, D, halo, Ci.g alkyl, C1.6 haloalkyl, C2.g alkenyl, C2.g alkynyl, Cy, Cy-C,.6 alkyl-, CN, NO2, ORal, SRal, NHORal, C(O)Rbl, C(O)NRclRdl, C(O)NRcl(ORal), C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclNRclRdl, NRclC(O)Rbl, NRclC (O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NOH)Rbl, C(=NCN)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclC(=NOH )NRclRdl, NRclC(=NCN)NRclRdl, NRclC(=NRel)Rbl, NRclS(O)NRc,Rdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)(=NRel)Rbl, NRclS(O )2NRclRdl, S(O)Rbl, S(O)NRc,Rdl, S(O)2Rbl, S(O)2NRclRdl, OS(O)(=NRel)Rbl, OS(O)2Rbl, SF5, P(O )RflRgl, OP(O)(ORhl)(OR¡1), 2 PtOXORh'XOR”), and BRjlRkl, wherein each of the Ci.6 alkyl, C2.6alkenyl, and C2.6alkynyl of R is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; Cy is selected from C6-i4aryl, C3.14cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; IF-2019-19254930-APN-ANP#INpi Page 21 of 170 Each of R3, R4 and R5 is independently selected from H, D, halo, CN, OH, Ci.6 alkyl, Ci-β haloakyl, C2-6 alkenyl, C2-6 alkynyl, C1.6 alkoxy, C1.6 haloalkoxy, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci.6 alkoxy-Ci.6 alkyl, C3.6 cycloalkyl, amino, C].6 alkylamino, di(Ci.6 alkyl)amino, and C(O )NRcRd, wherein the C,.6 alkyl is optionally replaced by 1, 2, 3, 4, 5, or 6 D; Each of R6, R7 and R8 is independently selected from H, D, halo, Cj.6 alkyl, C1.6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ci.g haloaikil, C|.g haloalkoxy, Cg-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl-Ci.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci. 6alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, OH, COOH and NH2; Each of Rcy Rdse independently selected from H and Cj.6alkyl; each Ral, Rbl, Rcl, and Rdl is independently selected from H, C,.6 alkyl, Cj.g haloakyl, C2-6 alkenyl, C2-6 alkynyl, C6.i0aryl, C3.,or cycloalkyl, 5-10 heteroaryl members, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3.io cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C].6alkyl-, and 4-10 members)-Ci.6alkyl-, wherein each of C|.e alkyl, C2-6 alkenyl, C2-6 alkynyl, C^iq aryl, C3.io cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, Cg.io aryl-Cpe alkyl-, C3.io cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C1 .6alkyl- of Ral, Rbl, Rcl, and Rdl, is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any of Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Relse independently selected from H, OH, CN, Ci-6 alkyl, Cpe alkoxy, C|.6 haloakyl, Cj.6 haloalkoxy, C2.6 alkenyl, C2-6 alkynyl, Ce-io aryl, C3.io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C$.1 or aryl-Ci.6 alkyl-, C3.io cycloalkyl-Ci.s alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl -, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each R and Rgl is independently selected from 10-membered, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-e alkyl-, C3.io cycloalkyl-Ci-e alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (5-10 membered heterocycloalkyl) 4-10 membersj-C,.6alkyl-; each Rhly R11 is independently selected from H, C1.6 alkyl, C1.6 haloakyl, C2.6 alkenyl, C2.6alkynyl, C6.,0aryl, C3.!0cycloalkyl, 5-10 membered heteroaryl, APN-ANP#INpi Page 22 of 170 4-10 membered heterocycloalkyl, C^-io aryl-Ci-e alkyl-, C3.10 cycloalkyl-Ci-e alkyl-, (5-10 membered heteroarylj-C^e alkyl-, and ( 4-10 membered heterocycloalkyl)-Ci.6alkyl-; each R*1 and Rkl is independently selected from OH, Ci.g alkoxy, and C1.6 haloalkoxy; or any of R^1 and Rklunted to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci^ alkyl and C(.6 haloalkyl; each Rase independently selects from D, halo, C[.6 alkyl, Ci.g haloalkyl, C2.6 alkenyl, C2.g alkymyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroanyl, 4-membered heterocycloalkyl -10 membered, Cg.io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci.^ alkyl-, (5-10 membered heteroaryl)-C|.6 alkyl-, (4-10 membered heterocycloalkyl) -Ci.6 alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rm, NRc4C(O)OR34, NRc4C(O)NRc4Rd4, C(=NRe4)Rb4, C(=NOH)RM, C(=NCN)Rb4, C (=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4C(=NRe4)Rb4, NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O) 2RM, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rm, S(O)2NRc4Rd4, OS(O)(=NRe4)Rb4, OS(O)2RM, SF5, P(O)Rf4Rg4, OP(O)(ORh4)(ORi4), P(O)(ORh4)(ORi4), and BRj4Rk4, where Cue alkyl, C2.6alkenyl, C2.6alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ίο aryl-Cue alkyl-, C3.7 cycloalkyl-Cue alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl -, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RDindependently selected; each Rb is independently selected from D, halo, C|.6 alkyl, C|.6 haloalkyl, C2.6 alkenyl, C2.g alkynyl, Cg-ιο aryl, C3.7 cycloalkyl, 5-10 membered heteroanyl, 4-10 membered, Cg-io aryl-Ci.g alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl) -Ci.6 alkyl-, CN, NO2, OR32, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRC2NRc2Rd2, NRc2C(O)Rb2jNRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C(= NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O)2Rb2, NR^YES^R02, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, S(O)2NRc2Rd2, OS(O)(=NRe2)Rb2, OS(O)2Rb2, SF5, P( O)RGRg2, OPIOXOR^XOR'2), PODXOR^XOR'2), and BR^R12, where C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C6.j0aryl, C3.7cycloalkyl, heteroaryl of 5-10 membered, 4-10 membered heterocycloalkyl, C6.i0aryl-Ci.6alkyl-, C3.7cycloalkyl-C^ alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (4-membered heterocycloalkyl -10 membered)-Ci.6alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each R32, Rb2, Rc2, and R02 is independently selected from H, Ci-6 alkyl, C1.6 haloalkyl, C2.6alkenyl, C2.6alkynyl, CMo aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl. 10 members, Cg-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, IF-2019-19254930-APN-ANP#INpi Page 23 of 170 (5-10 membered heteroaryl)-C|.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-, where each of Ci-g alkyl, C2.§ alkenyl, C2 .g alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (heteroaryl 5-10 membered)-^ alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of R32, Rb2, Rc2, and Rd2 are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RMin substituents; or, any of Rc2 and R02 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Re2 is independently selected from H, OH, CN, Cj.6 alkyl, C].6alkoxy, C|.g haloalkyl, C|.g haloalkoxy, C2.g alkenyl, C2,g alkynyl, Cg.io aryl, C3. 7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-C|.6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl -, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each Rgy Rs2 is independently selected from H, Ci.g alkyl, Cí.g alkoxy, C1.6 haloalkyl, C|.g haloalkoxy, C2.g alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyl-, C3.7cycloalkyl-C|.g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C|.6alkyl-; each R112 and R'2 is independently selected from H, C|.g alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6alkynyl, C^io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10-membered, Cg.io aryl-Ci^ alkyl-, C3.7cycloalkyl-Ci.g alkyl-, (5-10 membered heteroarylj-C,^ alkyl-, and (4-10 membered heterocycloalkyl)-C|. 6alkyl-; each Rj2 and R^ is independently selected from OH, Ci.g alkoxy, and Cj.6 haloalkoxy; or any of R*2 and Rti attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci. g alkyl and C|.g haloalkyl; each Ra4, RM, Rc4, and Rd4 is independently selected from H, C]_6alkyl, Ci-6 haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, Cg.io aryl-Ci-e alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci .6alkyl-, wherein each of C|.g alkyl, C2.g alkenyl, C2.g alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg. io aryl-Ci.6 alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl IF-2019-19254930-APN-ANP#INpi Page 24 of 170 j-C^ alkyl- members of Ra4, RM, Rc4, and Rd4 are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any of Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Re4 is independently selected from H, OH, CN, C1.6alkyl, C16 alkoxy, C1-6 haloalkyl, C16 haloalkoxy, C2-6 alkenyl, C2.6 alkynyl, Cg-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci_6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl-; each Rf4 and Rg4 are independently selected from 5-10 membered, 4-10 membered heterocycloalkyl, C^io aryl-Ci.^ alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and ( 4-10 membered heterocycloalkyl)-C,.6alkyl-; each Rh4 and R14 is independently selected from H, Ci-6 alkyl, C1.6 haloalkyl, C2-6 alkenyl, C2.6alkynyl, Ce-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , Cg-io aryl-Ci-g alkyl-, C3.7 cycloalkyl-C|.6 alkyl-, (5-10 membered heteroaryl)-C|.6 alkyl-, and (4-10 membered heterocycloalkyl)- Ci.6alkyl-; each Rj4 and Rk4 is independently selected from OH, C1.6 alkoxy, and C)_6 haloalkoxy; or any of Rj4 and Rk4 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cue alkyl and Ci -6 haloalkyl; each Rd is independently selected from H, D, halo, C1.6 alkyl, Ct.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, Ce-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered, Cg-io aryl-Ci.^ alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C,.6 alkyl-, (4-10 membered heterocycloalkyl )-Ci.6 alkyl-, CN, NO2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5 , OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5> NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O )2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rc5, S(O)2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O)2Rb5, SF5 , P(O)RcRg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(ORi5), and BRj5Rk5, where each of Ci.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C6.i0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl members)-Ci.6 IF-2019-19254930-APN-ANP#INpi Page 25 of 170 alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RD is optionally substituted with 1, 2, 3, or 4 substituents REindependently selected; each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, Ct.6 alkyl, Ci^ haloalkyl, C2-6 alkenyl, C2.6alkynyl, C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, Cg-io aryl-Ci.6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)- Ci.6alkyl-, wherein each of C|.g alkyl, C2.g alkenyl, C2.6 alkynyl, Cg-io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6 .io aryl-Ci.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C,.6alkyl- of Ra5 , Rb5, Rc5, and Rd5 are optionally substituted with 1, 2, 3, or 4 independently selected substituents; or, any of Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R substituents; each Re5is independently selected from H, OH, CN, Cj.g alkyl, C|.g alkoxy, Ci-6 haloalkyl, Ci.6 haloalkoxy, C2.e alkenyl, C2.§ alkynyl, Cg.io aryl, C3.7cycloalkyl , 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-C|.6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl- , and (4-10 membered heterocycloalkyl)-C|.6alkyl-; each Rf3 and Rg5 is independently selected from H, Cj.6 alkyl, C|.6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2.g alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-e alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl-; each Rh5 and R'5 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6.i0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , Cg-io aryl-Ci-g alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl -; each Rj5 and Rk5 are independently selected from OH, Ci-6 alkoxy, and Ci-6 haloalkoxy; or any of Rj5 and Rk5 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and C[.6haloalkyl; each Rese independently selected from H, D, halo, Ci-6 alkyl, Ci.6 haloalkyl, C2.g alkenyl, C2.6alkynyl, C^io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10 members, C^io aryl-Ci-6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 heteroaryl IF-2019-19254930-APN-ANP#INpi Page 26 of 170 members)-Ci-6alkyl-, and (4-10 membered heterocyclicalkyl)-Ci.6alkyl-, CN, NO2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C (O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C( =NRe6)Rb6, C(=NOH)Rb6, C(=NCN)Rb6, C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(= NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rc6, S(O) 2NRc6Rd6, OS(O)(=NRe6)Rb6, OS(O)2Rb6, SF5, P(O)Rf6Rg6, OP(O)(ORh6)(ORi6), P(O)(ORb6)(OR'6), and BRj6Rk6, wherein each of Cy.6alkyl, C2.6alkenyl, C2.6 alkynyl, C6.10aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.10aryl-C, .6alkyl-, C3.7 cycloalkyl-C^ alkyl-, (5-10 membered heteroaryl)-C^ alkyl-, and (4-10 membered heterocycloalkyl)-^.6alkyl- of RE is optionally substituted with 1, 2 , 3, or 4 independently selected RGin substituents; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C|.6 alkyl, C1.6 haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.|0aryl-Ci.6alkyl-, C3.7 cycloalkyl-C].6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl )-Ci-6alkyl-, wherein each of C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6 .io aryl-Ci-e alkyl-, C3.7 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-C|.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6 alkyl - of Ra6, Rb6, Rc6, and Rd6 is optionally substituted with 1, 2, 3, or 4 independently selected Rgin substituents; or, any of Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci.6haloalkoxy, C2.6alkenyl, C2.6alkynyl, C6-io aryl, C3.7 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, C6.i0aryl-Cpe alkyl-, C3.7 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (4-membered heterocycloalkyl -10 membersj-C^ alkyl-; each Rrey Rg6 is independently selected from H, Ci.6alkyl, C|.g alkoxy, C1.6 haloalkyl, C1.6 haloalkoxy, C2.6 alkenyl, C2.6alkynyl, Cg-io aryl, C3.7 cycloalkyl, heteroaryl -10 membered, 4-10 membered heterocycloalkyl, C6.i0aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-^ alkyl-, and (4-10 membered heterocycloalkyl members)-Ci.6alkyl-; each Rh6y R'6is independently selected from H, Ci-6 alkyl, Cpg haloalkyl, C2.6 alkenyl, C2 6alkynyl, C^o aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl IF-2019-19254930- APN-ANP#INpi Page 27 of 170 4-10 membered, Cg-io aryl-Ci^ alkyl-, C3.7 cycloalkyl-Cbg alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl members)-CUg alkyl-; each Rj6 and Rk6 is independently selected from OH, C^g alkoxy, and Cbg haloalkoxy; or any of Rj6 and Rk6 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci.g alkyl and Q.g haloalkyl; each Rg is independently selected from H, D, halo, CN, NO2, SF5, C^g alkyl, Q.g alkoxy, Cbg haloalkyl, C2.g alkenyl, C2.g alkynyl, Cg-io aryl, C3.7 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-g alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroarylj-C^g alkyl-, and ( 4-10 membered heterocycloalkyl)-Cb6alkyl; and each Rm is independently selected from H, D, OH, NO2, CN, halo, C|.g alkyl, C2.g alkenyl, C2.6alkynyl, C^g haloalkyl, cyano- C|.g alkyl, HO-C^g alkyl, C^g alkoxy-C^g alkyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.10 aryl-C|.g alkyl-, C3.7cycloalkyl-Q-g alkyl-, (5-10 membered heteroaryl)-C|.6alkyl-, (4-10 membered heterocycloalkyl)-Ci.g alkyl, C¡.g alkoxy, C(.g haloalkoxy, amino, C,.g alkylamino, di(Ci.g alkyljamino, thio, C^g alkylthio, C,.6alkylsulfmyl, Ch6alkylsulfonyl, carbamyl, Cb6alkylcarbamyl, di(Ci_6alkyljcarbamyl, carboxy, Cb6alkylcarbonyl, CMalkoxycarbonyl C, In some embodiments, the compound of Formula (I) is a compound of Formula (Π): H.O. H.O. N<vxNH2 N R2(Π) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (ΙΠ): IF-2019-19254930-APN-ANP#INpi Page 28 of 170 HO--R6 HO-|—R7 R8(IH) or a pharmaceutically acceptable salt thereof. In some embodiments, R1 is H, D or Cpg alkyl. In some embodiments, R1 is H, D or methyl. In some embodiments, R1 is H. In some embodiments, R2 is selected from H, D, halo, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.g alkynyl, C5.14 aryl, C344 cycloalkyl, 5-14 membered heteroaryl, 5-14 membered heterocycloalkyl. 4-14 members, Cg.i4 aryl-C 1.6 alkyl-, C3.14 cycloalkyl-Ci.6 alkyl-, (5-14 membered heteroaryl)-Ci.6 alkyl-, and (4-14 membered heterocycloalkyl) -Ci.6 alkyl-, C(O)NRclRdl, C(O)ORal, CN, NO2, OH, COOH and NH2, where C].6alkyl, C2.6alkenyl, C2.6alkynyl, C6.i4aryl, C3 -14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6.i4 arylCi-6 alkyl-, C3.14 cycloalkyl-Ci.6alkyl-, (5-14 membered heteroaryl)-^ alkyl-, and (4-14 membered heterocycloalkyl)-Ct.6alkyl- of R2 each is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R2 is selected from H, D, halo, Ci-β alkyl, Cp6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, Cy, Cy-Cj.6alkyl-, C(O)NRclRdl, C(O) ORal, CN, NO2, OH, COOH and NH2, where Ci-6 alkyl, C2.g alkenyl, C2.g alkynyl, Cg.i4 aryl, C3-14 cycloalkyl, 514-membered heteroaryl, 4-14-membered heterocycloalkyl members, Cg.14 aryl-C 1.6 alkyl-, C3.14 cycloalkyl-Ci-6 alkyl-, (5-14 membered heteroaryl)-Ci-6 alkyl-, and (4-14 membered heterocycloalkyl)-C| .6 alkyl- of R each is optionally substituted with 1, 2, 3, or 4 independently selected R substituents. In some embodiments, R2 is selected from Cy, Cy-Ci.6 alkyl, Ci.6 haloalkyl, C(O)NRclRdl, and C(O)ORal; and Cy is selected from C3.14cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RAindependently selected; In some embodiments, R2 is C(O)NRclRdlo C(O)ORal. In some embodiments, R2 is Cy, C(O)NRclRdlo NRclC(O)Rb. In some embodiments, R2 is C(O)NRclRdlo NRclC(O)Rbl. In some embodiments, R2 is C(O)NRclRdl. In some embodiments, R2 is Cy. IF-2019-19254930-APN-ANP#INpi Page 29 of 170 In some embodiments, R2 is C(O)NRclRdlo NRclC(O)Rb, where R is H, and R and R are each independently selected from C].6 alkyl, C3.7 cycloalkyl, 410-membered heterocycloalkyl, C3. iocycloalkyl-C,.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-, each of which is optionally substituted by 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R2 is C(O)NRclRdl, where Rcles H; and Rdl is selected from Ci.6alkyl, C3.7 cycloalkyl, 4-10 membered heterocycloalkyl, C3-10 cycloalkyl-C.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, each of which are optionally replaced by 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R2 is C(O)NRclRdl; and each Rcly Rdl is independently selected from H, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci.6 alkyl-, C3.iocycloalkyl -C 1.6 alkyl-, (5-10 membered heteroaryl)-C 1.6 alkyl-, and (4-10 membered heterocycloalkyl)-C|.6alkyl-, wherein Cy.6alkyl, C2.6alkenyl, C2.6alkynyl , C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.i0aryl-C 1.6 alkyl-, C3.10 cycloalkyl-C,.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (heterocycloalkyl 4-10 membered)-C,.6alkyl- of Rcly Rdleach is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6, or 7-membered heterocycloalkyl group, wherein the 4, 5, 6-membered heterocycloalkyl group , or 7-membered is optionally substituted with 1, 2, 3, or 4 independently selected R substituents. In some embodiments, R2 is C(O)NRclRdl; each Rcly Rdl is independently selected from H, Ci.g alkyl, C2.g alkenyl, C2-6 alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, Cg-io aryl-Cí.g alkyl-, Cs-iocycloalkyl -Ci-g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C,.6alkyl-, wherein Ci.6alkyl, C2.6alkenyl, C2. 6alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci-6 alkyl-, C3.10 cycloalkyl-C,.6alkyl-, (5-10 membered heteroaryl)-^ alkyl-, and (4-10 membered heterocycloalkyl)-C^ alkyl- of Rcly Rdleach is optionally substituted with 1, 2, 3, or 4 RAindependently selected substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6, or 7-membered heterocycloalkyl group, wherein the 4, 5, 6-membered heterocycloalkyl group , or 7-membered is optionally substituted with 1, 2, 3, or 4 independently selected R substituents; and each Rase independently selects from D, halo, oxo, C|.g alkyl, C|.g haloalkyl, C2-6 alkenyl, and C2.6 alkynyl, CN, NO2, and ORa4, where the C,.6 alkyl Rase, C2.6alkenyl, and C2.6alkynyl are optionally substituted with 1, 2, or 3 independently selected RD substituents. IF-2019-19254930-APN-ANP#INpi Page 30 of 170 In some embodiments, R2 is C(O)NRclRdl; each R and R is independently selected from H, Ci.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, Cg.io aryl-C 1.6 alkyl-, C3.iocycloalkyl -C|.6 alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-, wherein Ci.6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.i0aryl-Ci.6alkyl-, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroarylj-Cpe alkyl-, and ( 4-10 membered heterocycloalkyl)-C,.6alkyl- of Rcly Rdleach is optionally substituted with 1, 2, 3, or 4 substituents RAindependently selected; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6, or 7-membered heterocycloalkyl group, wherein the 4, 5, 6-membered heterocycloalkyl group , or 7-membered is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; each Rase independently selects from D, halo, oxo, C|.e alkyl, C|.g haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, CN, NO2, and ORa4, where the Ci-6 alkyl, C2 -6 alkenyl, and C2.6 Rase alkynyl optionally substituted with 1, 2, or 3 independently selected RD substituents; each Ra4 is independently selected from H and alkyl, wherein the C]6alkyl is optionally substituted with CN, NO2, or OH; and each Rdes OH. In some embodiments, R2 is C(O)NRclRdl; and RC1is H; and Rdl is selected from Ci.6alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, phenylCMalkyl-, and C3.7 cycloalkyl-CMalkyl-, wherein C,.6alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl , phenyl-Ci.4 alkyl-, and C3.7 cycloalkyl-Ci.4 alkyl- of R and R each is optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6, or 7-membered heterocycloalkyl group, wherein the 4, 5, 6-membered heterocycloalkyl group , or 7-membered is optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R2 is C(O)NRclRdl; and Rcles H; and Rdl is selected from ethyl, propyl, isopropyl, butyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methylcyclopbutyl, methyl-phenyl , ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and tianyl, wherein ethyl, propyl, isopropyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2 .1]heptanyl, methylcyclopropyl, methylcyclopbutyl, methylphenyl, ethylphenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and IF-2019-19254930-APN-ANP#INfI Page 31 of 170 Rdl thianyl each is optionally substituted with 1, 2, or 3 RAindependently selected substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form nn azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl are optionally substituted with 1, 2, or 3 RA independently selected substituents. In some embodiments, R2 is C(O)NRclRdl; and RC1is H; and Rdl is selected from ethyl, propyl, isopropyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methylcyclopbutyl, methyl-phenyl, ethyl -phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and thianyl, where ethyl, propyl, isopropyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1 ]heptanyl, methyl-cyclopropyl, methylcyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and tianyl of Rdl are each optionally substituted with 1, 2, or 3 RA independently selected substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl are optionally substituted with 1, 2, or 3 RA independently selected substituents. In some embodiments, R2 is C(O)NRclRdl; RC1is H; Rdl is selected from Ci.6alkyl, C3.7cycloalkyl, 4-7 membered heterocycloalkyl, phenylCMalkyl-, and C3.7cycloalkyl-CMalkyl-, wherein C,.6alkyl, C3.7cycloalkyl, 4-7 membered heterocycloalkyl, phenyl- Ci.4 alkyl-, and C3.7cycloalkyl-Ci-4 alkyl- of Rcly R are each optionally substituted with 1 or 2 RAindependently selected substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6, or 7-membered heterocycloalkyl group, wherein the 4, 5, 6-membered heterocycloalkyl group , or 7-membered is optionally substituted with 1 or 2 independently selected RA substituents; and each Rase independently selects from oxo, Cpg alkyl, C1.6 haloalkyl, CN, and OR, wherein the Ci.6alkyl of RAse is optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R2 is C(O)NRclRdl; RC1is H; Rdl is selected from ethyl, propyl, isopropyl, butyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methylcyclopbutyl, methyl-phenyl , ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and IF-2019-19254930-APN-ANP#INPI Page 32 of 170 tianyl, where ethyl, propyl, isopropyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methylcyclopbutyl Rdl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrolidinyl and tianyl are each optionally substituted with 1 or 2 RA independently selected substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected RA substituents; and each Rase independently selects from oxo, methyl, CH2F, CHF2, CF3, -OCH3, CH2OH, CN and OH. In some embodiments, R2 is C(O)NRclRdl; RC1is H; Rdl is selected from ethyl, propyl, isopropyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methylcyclopbutyl, methyl-phenyl, ethyl -phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and tianyl, where ethyl, propyl, isopropyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1] heptanyl, methyl-cyclopropyl, methylcyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and thianyl of Rdl are each optionally substituted with 1 or 2 RA independently selected substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected RA substituents; and each Rase independently selects from oxo, methyl, CH2F, CHF2, CF3, -OCH3, CH2OH, CN and OH. In some embodiments, R2 is C(O)NRclRdl; Rcles H; and Rdl is selected from 4hydroxybicyclo[2.2.1]heptanyl and tetrahydropyranyl. In some embodiments, R2 is Cy, C(O)NRclRdlo NRclC(O)R, where R is H, and R and Rdl are each independently selected from Ci-6 alkyl, C3.7cycloalkyl, 4-10 membered heterocycloalkyl, C3 .iocycloalkyl-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C|_6alkyl-, each of which is optionally substituted by 1, 2, 3, or 4 RA independently selected substituents. In some embodiments, each Ral, Rbl, Rcl, and Rdl is independently selected from H, Cj.6alkyl, Ci.e haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.10 aryl, Ce-io aryl, C3.7cycloalkyl. , 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aryl-Cue alkyl-, C3.io cycloalkyl-Ci.6alkyl-, (5-10 membered heteroarylj-C^ alkyl-, and (heterocycloalkyl 4-10 members)-Ci-6alkyl-, wherein Page 33 of 170 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci-6 alkyl, C3.10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)- Ci.6alkyl-, and (410-membered heterocycloalkyl)-Ci.6alkyl-, of Ral, Rbl, RcI, and Rdleach are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 RA substituents independently selected; and each Rase independently selects from OH, CN, halo, C1.6 alkyl, C1.6 haloalkyl, C]. 6alkoxy, Ci-6 haloalkoxy, amino, C1.6 alkylamino, and di(Ci-6alkyl)amino. In some embodiments, each Rcly Rdl is independently selected from H, Ci.6alkyl, Ci-6haloalkyl, C2.6alkenyl, C2.6alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, Ce-io aryl-Ci.6alkyl, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C].6 alkyl-, wherein Ci.g alkyl, C2 .6 alkenyl, C2.g alkynyl, C3.10cycloalkyl, 4-10 membered heterocycloalkyl, C6.10aryl-Ci.6alkyl-, C3.10cycloalkyl-C].6 alkyl-, (5-10 membered heteroaryl)- Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6alkyl- of Rcly Rdl are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 RA independently selected substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6, or 7-membered heterocycloalkyl group, wherein the 4, 5, 6-membered heterocycloalkyl group , or 7-membered is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents. In some embodiments, Cy is a C3.14 cycloalkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. In some embodiments, Cy is a C3.10 cycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a C3.6cycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. In some embodiments, Cy is a 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 5-6 membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 5-membered heteroaryl optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, Cy is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. In some embodiments, Cy is a 4-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. IF-2019-19254930-APN-ANP#INÍI Page 34 of 170 In some embodiments, Cy is a 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 5-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is selected from: each of which is optionally substituted by 1 or 2 independently selected RA substituents. In some embodiments, R2 is selected from the following portions: In some embodiments, Cy is selected from pyrazol-l-yl, pyrazol-4-yl, pyrazol-5-yl, isoxazol-5-yl, isothiazol-4-yl, isotizol-5-yl, oxazol-5-yl, thiazol-5-yl, 1,2,3-triazol-l-yl, 1,2,3-triazol2-yl, and 1,2,4-triazol-l-yl, each of which is substituted by 1 RA substituent. In some embodiments, each RA is independently selected from D, halo, Ci.6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.§ alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io anl-Cpé alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, (4-10 membered heterocycloalkyl) -Ci.6 alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)RM, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)RM, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)RM, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rm, NRc4S(O)NRc4Rd4> NRc4S(O)2RM, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2RM, S(O)2NRc4Rd4, and OS(O)2Rm, where C,_6alkyl, C2.6alkenyl, C2.6alkynyl, Ce- io ardo, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ίο aryl-Ci-6 alkyl, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl) -Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of R are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RDindependently selected; . each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, Ci.6alkyl, C 1.6haloalkyl, C2.6alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-6-membered heteroarylj-Ci.g IF-2019-19254930-APN-ANP#INpi Page 35 of 170 alkyl-, and (4-7 membered heterocycloalkyl)-C1.6alkyl-, wherein Cy.6alkyl, C2.6alkenyl, C2-6 alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl , 4-7 membered heterocycloalkyl, phenyl-Ci.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-6 membered heteroaryl j-C|.6alkyl-, and (4-7 membered heterocycloalkyl)-Cj. 6alkyl of Ra4, Rb4, Rc4, and Rd4 each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the heteroaryl group 5- or 6-membered or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 RDindependently selected substituents; and each Rd is independently selected from D, OH, NO2, CN, halo, Ci-6 alkyl, C2.6 alkenyl, C2.6alkynyl, Ci.6haloalkyl, cyano-Ci-6 alkyl, HO-Ci.6alkyl, Ci.6alkoxy -Ci.6alkyl, C3.7cycloalkyl, Ci.6alkoxy, Ci.6haloalkoxy, amino, Ci.6alkylamino, di(C|.6alkyljamino, thio, C,.6alkylthio, Ci_6alkylsulfmil, Ci.6alkylsulfonyl, carbamyl, Ci_6alkylcarbamyl, di( C|_6alkylcarbamyl, carboxy, Ci_6alkylcarbonyl, CMalkoxycarbonyl, Ci_6alkylcarbonylamino, Ci_6alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci-6 alkyljaminosulfonyl, aminosulfonylamino, Ci.6alkylaminosulfonylamino, di(Ci-6 alkyljaminosulfonylamino, aminocarbonylamino, .6alkylaminocarbomlarnino, and di( Ci.6alkyl)aminocarbonylamino. In some embodiments, each RA is independently selected from D, halo, C|.6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORm), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4NRc4C(O)RM, NRc4C(O)ORa4, NRc4C(O )NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rm, S(O)NRc4Rd4, S(O)2RM, S(O)2NRc4Rd4 , and OS(O)2RM, wherein the C^ alkyl, C2.6alkenyl, and C2.6alkynyl of R are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, Ci-6 alkyl, and Ci-6 haloalkyl, wherein the Ci.6alkyl of Ra4, RM, Rc4, and Rd4 are each optionally replaced with 1, 2, 3 , or 4 independently selected RD substituents; and each Rd is independently selected from D, OH, NO2, CN, halo, Cj-e alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, cyano-Ct.6 alkyl, HO-C|_6alkyl, Ci .galkoxy-C^ alkyl, C3.7 cycloalkyl, C|.6 alkoxy, C].6haloalkoxy, amino, Ci-6 alkylamino, di(Ci-6 alkyljamino, thio, C].6alkylthio, Ci.6alkylsulfmyl, Cj. 6 alkylsulfonyl, carbamyl, Ci_6alkylcarbamyl, di(Ci_6alkylcarbamyl, carboxy, Ci.6alkylcarbonyl, CMalkoxycarbonyl, Ci_6alkylcarbonylamino, C].6alkylsulfonylamino, aminosulfonyl, Ci_6alkylaminosulfonyl, di(Ci.6alkyljaminosulfonyl, aminosulfonylamino, Ci.6alkylaminosulfonyl onylamino, di(C|.§ alkyljaminosulfonylamino , aminocarbonylamino, Ci.6alkylaminocarbonylamino, and di(Ci-6alkyl)aminocarbonylamino. IF-2019-19254930-APN-ANP#INpi Page 36 of 170 In some embodiments, each RA is independently selected from D, halo, C|.6 alkyl, C|_6haloakyl, CN, ORa4, and NRc4Rd4; wherein the Cj.6 alkyl, C2.6alkenyl, and C2.6alkynyl of R are each optionally substituted with 1, 2, 3, or 4 R independently selected substituents; each Ra4, Rc4, and Rd4 is independently selected from H, Ci.6alkyl, C].6haloakyl, wherein the C].6alkyl of Ra4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, or 4 RD substituents independently selected; and each Rd is independently selected from D, OH, CN, halo, Ci-6 alkyl, Ci-6 haloakyl, Cj.6alkoxy, C|.6haloalkoxy, amino, Ci.6alkylamino, and di(Ci.6alkyl)amino. In some embodiments, each RA is independently selected from D, halo, Ci.6alkyl, and Ci-6 haloakyl, wherein the Ci.6alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, each RA is selected independently of methyl and CD3. In some embodiments, each RA is methyl. In some embodiments, each RA is CD3. In some embodiments, R2 is selected from Cj.g alkyl, Ci.g haloakyl, C2.g alkenyl, and C2.6 alkynyl, wherein Ci-6 alkyl, C2.6 alkenyl, and C2.6 alkynyl are each substituted. optionally with 1, 2, or 3 independently selected RA substituents. . In some embodiments, R2 is C].6alkyl, which is optionally replaced by 1, 2, or 3 independently selected Rain groups. In some embodiments, R2 is C|.6alkyl. In some embodiments, R2 is propyl. In some embodiments, R2 is C2.6alkenyl, which is optionally replaced by 1, 2, or 3 independently selected Rain groups. In some embodiments, R2 is C2.6 alkenyl. In some embodiments, R2 is propendene or butenyl. In some embodiments, R2 is prop-l-enyl or but-l-enyl. In some embodiments, R2 is C2.6alkynyl, which is optionally substituted with 1, 2 or 3 RAindependently selected substituents. In some embodiments, R2 is ethynyl, propynyl, butynyl, or pentynyl, wherein the ethynyl is optionally substituted by RA, and the propynyl, butynyl, and pentynyl groups are each optionally replaced by 1, 2, or 3 independently selected RA groups. In some embodiments, R2 is selected from ethynyl, prop-l-ynyl, but-l-ynyl, and pent-l-ynyl, wherein ethynyl is replaced by RA, and prop-l-ynyl is replaced by but-l-ynyl. , and pent-l-ynyl are each optionally replaced by 1, 2, or 3 independently selected RA groups. In some embodiments, R2 is selected from prop-l-ynyl, but-l-ynyl, and pent-l-ynyl, wherein prop-l-ynyl, but-l-ynyl, and pent-l-ynyl are each Optionally substitutes 1, 2, or 3 independently selected Rain groups. IF-2019-19254930-APN-ANP#INpi Page 37 of 170 In some embodiments, R2 is ethynyl, wherein the ethynyl is optionally replaced by 1, 2, or 3 independently selected Rain groups. In some embodiments, each RA is independently selected from H, D, Ci.6alkyl, Ci.6haloalkyl, C6.10aryl, C3.12 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, wherein Ci.$ alkyl, Cg-ιο aryl, C3.12 cycloalkyl, 5-10 membered heteroaryl, and 4-12 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected RD substituents. In some embodiments, each RA is independently selected from H, D, Cj.6 alkyl, Ci.6 haloalkyl, C6.i0 aryl, C3.)2 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6. i0 aryl-C,.6 alkyl-, C3.12 cycloalkyl-Cue alkyl-, (5-10 membered heteroaryl)-C,.6 alkyl-, and (4-12 membered heterocycloalkyl)-Ci.6 alkyl- , where I alkyl them, C6.io aryl, C3. 12 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, Ce-io aryl-Ci-6 alkyl-, C3.12 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci. 6 alkyl-, and (4-12 membered heterocycloalkyl)-Ci_6 alkyl- each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rdin substituents, and wherein the connection of the C6.io aryl- groups Ci.6alkyl-, C3.12cycloalkyl-Cus alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl- and (4-12 membered heterocycloalkyl)-Ci-6 alkyl- to R2(e.g. to a group alkynyl of R2) can occur through the aforementioned ring or the C|.g alkyl group. In some embodiments, each RA is independently selected from D, halo, Ci.6 alkyl, C6.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, and ORa4, in where the Ci.6 alkyl, C6.i0aryl, C3.,ocycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups. In some embodiments, each Ra4 is selected independently of H and Ci.6alkyl. In some embodiments, each RA is independently selected from D, halo, Ci.6 alkyl, C6.io aryl, C3.io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, and ORa4, in where the C].6 alkyl, C6.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups; and each Ra4se independently selects from H and C1.6 alkyl. In some embodiments, each RA is independently selected from Ci.6 alkyl, C6-io aryl, C3.io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and ORa4, wherein the C,.6 alkyl, C6.io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RAeach are optionally substituted by 1 or 2 independently selected RD groups. In some embodiments, each RA is independently selected from methyl, cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazopyrazinyl, hydroxyl, and IF-2019-19254930-APN-ANP#INpi Page 38 of 170 methoxy, wherein the cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and imidazopyrazinyl of RA are each optionally substituted by 1 or 2 independently selected RD groups. In some embodiments, each RD is independently selected from halo, Ci-6alkyl, CN, cyano-Ci-6 alkyl, and ORa5. In some embodiments, each Ra5 is selected independently of H and Ci.6alkyl. In some embodiments, each RD is independently selected from halo, Cj.6alkyl, CN, cyano-Ci.6alkyl, and ORa5; and each Ra5se independently selected from H and Ci.6 alkyl. In some embodiments, each RA is independently selected from Ci-6 alkyl, C6.i0 aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and ORa4, wherein the Ci.6 alkyl, C6 -io aryl» C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RAeach is optionally substituted by 1 or 2 independently selected RD groups; and each RD is independently selected from halo, Ci-6alkyl, CN, cyano-Ci-6 alkyl, and ORa5. In some embodiments, each RA is independently selected from methyl, cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazopyrazinyl, hydroxyl, and methoxy, wherein cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and R imidazopyrazinyl is each optionally substituted by 1 or 2 independently selected R groups; and each RD is independently selected from methyl, cyano, cyanomethyl, and methoxy. In some embodiments, R2 is C|.6 haloalkyl. In some embodiments, R2 is trifluoromethyl. In some embodiments, R2 is selected from C3.6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C3.6 cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 RA independently selected substituents. In some embodiments, each RA is independently selected from D, halo, oxo, Ci.6 alkyl, C6.i0 aryl, C3.6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)ORa4, C (O)NRc4Rd4, and S(O)2Rm, wherein the C].6alkyl, C^io aryl, C3.6cycloalkyl, and 5-10 membered heteroaryl of RAeach are optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, each Ra4, RM, Rc4, and Rd4 is independently selected from H, Ci.6alkyl, phenyl, C3.6cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1.6alkyl , phenyl, C3.g cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4 and Rb4 are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the group IF-2019-19254930-APN- ANP#INpi Page 39 of 170 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, each RD is independently selected from OH, CN, Ci-6alkyl, Ci-6 alkoxy, C 1.6 haloalkyl, and phenyl. In some embodiments, R2 is selected from C3.12 cycloalkyl and 4-12 membered heterocycloalkyl, wherein the C3.12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 RA independently selected substituents; and each Rase independently selects from D, halo, oxo, Ct.6 alkyl, C6.i0 aryl, C3.6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)ORa4, C(O) NRc4Rd4y S(O)2Rb4, wherein the C1.6 alkyl, C6.io aryl, C3.6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R2 is selected from C3.6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C3.6 cycloalkyl and 4-7 membered heterocycloalkyl of R2 are each optionally substituted with 1, 2, or 3 RA independently selected substituents; and each Rase independently selects from C1.3 alkyl, C(O)RM, C(O)ORa4, C(O)NRc4Rd4 and S(O)2Rm, wherein the C1.3 alkyl of RAeach is optionally substituted with 1 or 2 independently selected RDin substituents. In some embodiments, R2 is selected from C3.6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C3.6 cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 RA independently selected substituents; each Rase independently selects from D, halo, oxo, C1.6 alkyl, C6.io aryl, C3.6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)ORa4, C(O)NRc4Rd4y S(O)2RM, wherein the C,.6 alkyl, C6.io aryl, C3.6cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RD substituents; and each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C].6alkyl, phenyl, C3.6cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein Cj.6 alkyl, phenyl , C3.6cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4, Rm, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R2 is selected from C3.6cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C3.6cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 RA independently selected substituents; each Rase independently selects from D, halo, oxo, C1.6 alkyl, C6.io aryl, C3.6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)ORa4, C(O)NRc4Rd4 , and S(O)2RM, wherein the C,-6 alkyl, C6.io aryl, C3.6cycloalkyl, and 5-10 membered heteroaryl of RAeach are optionally substituted with 1 or 2 RIndependently selected substituents, IF-2019-19254930-APN-ANP#IN(PI Page 40 of 170 each Ra4, RM, Rc4, and Rd4 is independently selected from H, Cy.6alkyl, phenyl, C3.6cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the Cy.6alkyl, phenyl, C3.6cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4, Rm, Rc4, and Rd4 each optionally substituted with 1 or 2 independently selected RD substituents; Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, where the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RD substituents; and each Rdse is independently selected from OH, CN, Ci.g alkyl, Ci.6 alkoxy, Ci-6 haloalkyl, and phenyl. In some embodiments, R2 is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl of R2 are each optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R2 is selected from azetidinyl and cyclobutyl, wherein the azetidinyl and cyclobutyl of R2 are each optionally substituted with 1, 2, or 3 independently selected R substituents. In some embodiments, R2 is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl of R2 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; and each Rase independently selects from oxo, C|.6 alkyl, phenyl, C3.6 cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4, and S(O)2Rb4 , wherein the Cj.6 alkyl, phenyl, C3.6 cycloalkyl, and 5-10 membered heteroaryl, of R are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R2 is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl of R2 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; each Rase independently selects from oxo, Ci-β alkyl, phenyl, C3.6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)ORa4, C(O)NRc4Rd4, and S(O)2RM , wherein the Cj-é alkyl, phenyl, C3.6cycloalkyl, and 5-10 membered heteroaryl, of R are each optionally substituted with 1 or 2 independently selected RD substituents; and each Ra4, RM, Rc4, and Rd4 is independently selected from H, Cj.6 alkyl, phenyl, C3.6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein Ci-6 alkyl, C3.6cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl of Ra4, IF-2019-19254930-APN-ANP#INfI Page 41 of 170 Rb4, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD substituents. ' In some embodiments, R2 is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl of R2 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; each Rase independently selects from Ci.3 alkyl, C(O)RM, C(O)ORa4, C(O)NRc4Rd4, and S(O)2RM, wherein the Ci.3alkyl of RAeach is optionally substituted with 1 or 2 independently selected RDin substituents; each Ra4, RM, Rc4, and Rd4 is independently selected from H, Ci.6alkyl, phenyl, C3.6cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein Ci.6alkyl, C3.6cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl of Ra4, Rm, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group 7 members are optionally replaced with 1 or 2 independently selected RD substituents; and each Rdse is independently selected from OH, CN, Ci_6alkyl, Ci-6 alkoxy, Ci.6 haloalkyl, and phenyl. In some embodiments, R2 is selected from azetidinyl and cyclobutyl, wherein the azetidinyl and cyclobutyl of R2 are each optionally substituted with 1, 2, or 3 R substituents independently selected from (l-methyl-lH-pyrazol-4-yl)sulfonyl, ethylcarboxylate, oxo, cyclopropyl, butyl, acetyl, cyclopropanecarbonyl, phenyl, methylphenyl, dimethylphenyl, pyrindinyl, thiazolyl, trifluoromethylphenyl, cyanophenyl, hydroxyphenyl, hydroxymethyl, cyanoethyl, oxohexahydropyrrolo[l,2-a]pyrazin-2-yl, fiiran-2- carbonyl, cyanopyrazinyl, and ethoxyphenyl. In some embodiments, R3 is selected from H, D, halo, Cj-6 alkyl, C|.§ alkoxy, C2.6 alkenyl, C2.g alkynyl, C|.g haloalkyl, C|.g haloalkoxy, CN, OH, and NH2, wherein C].6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R3 is Ci-6 alkyl, wherein C|.6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R3 is methyl or CD3. In some embodiments, R3 is methyl. In some embodiments, R3 is CD3. In some embodiments, R4 is selected from H, D, halo, Ci-6 alkyl, C|.g alkoxy, C2.6 alkenyl, C2.6 alkynyl, C|.g haloalkyl, C|_6 haloalkoxy, CN, OH, and NH2, where Ci.g alkyl is optionally substituted with 1, 2, or 3 D. IF-2019-19254930-APN-ANP#INpi Page 42 of 170 In some embodiments, R4 is H, D or C¡.g alkyl, wherein Ci-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R4 is H. In some embodiments, R4 is D. In some embodiments, R5 is selected from H, D, halo, Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2.6alkynyl, C,.6haloalkyl, Q.6 haloalkoxy, CN, OH, and NH2, in where C].6alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R5 is H, D or C|.g alkyl, wherein Ci.g alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R5 is H. In some embodiments, R5 is D. In some embodiments, R4 and R5 are each H. In some embodiments, R6 is selected from H, D, halo, C|.g alkyl, C2.g alkenyl, C2.g alkynyl, C,.6haloalkyl, C6.io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, Cg.io aryl-Ci.6 alkyl-, C3.iocycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl members)-Ci.6alkyl-, CN, NO2, OH, COOH and NH2, where Ci_6alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R6 is selected from H, D, halo, C|.g alkyl, C2.g alkenyl, C2.g alkynyl, C¡_6 haloalkyl, CN, NO2, OH, COOH and NH2, where Cj.6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R6 is H, D, or C|.g alkyl, wherein Cpg alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R6 is methyl. In some embodiments, R6 is CD3. In some embodiments, R6 is H. In some embodiments, R6 is D. In some embodiments, R6 is C|.g haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein each Y is independently selected from D, halo, C].6 alkyl, and Ci-6 haloalkyl. In other embodiments, each Y is independently selected from halo and C|.6 haloalkyl. In some embodiments, R6 is H, CH2F, CE1F2, or CF3. In some embodiments, R6 is selected from CF3, CCI3, CF2H, CC12H, CF2Y, CC12Y, CFH2, CC1H2, CFHY, CC1HY, CF(Y)2, and CC1(Y)2. In some embodiments, R6 is selected from CF3, CF2H, CF2Y, CFH2, CFHY, and CF(Y)2. In some embodiments, R6 is C1.6 haloalkyl, where each halogen is F. In some embodiments, R6 is C¡.g haloalkyl, where each halogen is Cl. In some embodiments, R6 is selected from CH2F, CHF2, CF3, and CF2CF3. IF-2019-19254930-APN-ANP#INpi Page 43 of 170 In some embodiments, R6 is CH2F, CHF2, or CF3. In some embodiments, R6 is CF3. In some embodiments, R6 is CH2F. In some embodiments, R6 is CHF2· In some embodiments, R6 is CF2CF3. In some embodiments, R7 is selected from H, D, halo, Cpg alkyl, C2.6 alkenyl, C2.6 alkynyl, C,.6haloalkyl, C6.10aryl, C3.10cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl. 10-membered, Cg-ιο aryl-C 1-6 alkyl-, C3.iocycloalkyl-C|.5 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, (4-10 membered heterocycloalkyl)-Ci .6alkyl-, CN, NO2, OH, COOH and NH2. In some embodiments, R7 is selected from H, D, halo, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, CN, NO2, OH, COOH and NH2. In some embodiments, R7 is H, D or C|.g alkyl. In some embodiments, R7 is methyl or ethyl. In some embodiments, R7 is CD3. In some embodiments, R7 is H. In some embodiments, R7 is D. In some embodiments, R8 is selected from H, D, halo, C|.g alkyl, C2-6 alkenyl, C2.6 alkynyl, C,.6haloalkyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, Cg.io aryl-C 1-6 alkyl-, C3-ioCÍcloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C 1.6 alkyl-, (4-10 membered heterocycloalkyl members)-Ci.6alkyl-, CN, NO2, OH, COOH and NH2, wherein the Ci.6alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R8 is selected from H, D, halo, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C(.6haloalkyl, CN, NO2, OH, COOH and NH2, where the C^ alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R8 is H, D or C|.g alkyl, wherein the C|.g alkyl is optionally replaced with 1, 2, or 3 D. In some embodiments, R8 is methyl or ethyl. In some embodiments, R8 is CD3. In some embodiments, R8 is H. In some embodiments, R8 is D. In some embodiments, R7 and R8 are each H. In some embodiments, R7 and R8, together with the C atom to which they are attached, form a cyclopropyl or cyclobutyl. In some embodiments, R7 and R8, together with the C atom to which they are attached, form a cyclopropyl. IF-2019-19254930-APN-ANP#INpi Page 44 of 170 In some embodiments, each RD is independently selected from H, D, halo, Ci.6 alkyl, Ci.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.10 aryl, C3.7 cycloalkyl, 5-10 heteroaryl members, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci.g alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, (4-membered heterocycloalkyl -10 membersj-Cj-e alkyl-, CN, NO2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O )Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN) Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S (O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rc5, S(O)2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O)2Rb5 , SF5, P(O)RBRg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(ORl5), and BRj5Rk5, where C,.6 alkyl, C2.6alkenyl, C2.6alkynyl , C6.]0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyl-, C3.7cycloalkyl-Ci.g alkyl-, (5-membered heteroaryl 10-membered)-Ci.6alkyl-, and (4-10-membered heterocycloalkyl)-C|.6alkyl- of RD are each optionally substituted with 1, 2, 3, or 4 REindependently selected substituents. In some embodiments, each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, Cp6alkyl, C,.6haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.ioaryl, C3.7cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, Cg-io aryl-Cj-e alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl) -Cy.6alkyl-, wherein C,.éalkyl, C2.6alkenyl, C2.6alkynyl, C6.,or anlo, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cé-io aryl -Ci-e alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra5, Rb5 , Rc5, and Rd5 are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; or, any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the heteroaryl of 5- or 6-membered or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 REindependently selected substituents. In some embodiments, each RE is independently selected from H, D, halo, C].6 alkyl, Ci-6haloalkyl, C2.g alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 heteroaryl members, 4-10 membered heterocycloalkyl, C^-io aryl-Cj.g alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6 alkyl-, CN, NO2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rb6, C( =NCN)Rb6, C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O) NRc6Rd6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rc6, S(O)2NRc6Rd6, IF-2019-19254930-APN-ANP#INpi Page 45 of 170 OS(O)(=NRe6)Rb6, OS(O)2Rb6, SF5j P(O)RKRg6, OP(O)(ORh6)(ORi6), P(O)(ORh6)(ORi6), and BRj6Rk6, where The Cy.6alkyl, C2.6alkenyl, C2.6alkynyl, C6.i0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-e alkyl-, C3.7cycloalkyl- Ci.g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of R each optionally substituted with 1, 2, 3, or 4 independently selected R substituents. In some embodiments, each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, alkyl, Ci.g haloalkyl, C2.g alkenyl, C2.g alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, Cg.io aryl-Cj.g alkyl-, C3.7cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (4-membered heterocycloalkyl Cg. or aryl-Ci.g alkyl-, C3.7cycloalkyl-Ci.g alkyl-, (5-10 membered heteroarylj-C]^ alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra6, Rb6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which it is attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the heteroaryl group 5- or 6-membered or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents. In some embodiments, the compound is a compound of Formula (II): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (ΠΙ): IF-2019-19254930-APN-ANP#INpi Page 46 of 170 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (IV): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (V): . / N. ,NH2 I í Ύ r41 i Λ Ίιι^Ν Cy R5^^ HO--R6 HO-|—R7 R8(V) or a pharmaceutically acceptable salt thereof. In some embodiments, X1 is N or CR1; R1 is H, D or Ci-β alkyl; R2es Cy, C(O)NRc,Rdlo NRclC(O)Rbl; Cy is 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; R3, R4, and R5 are each independently selected from H, D, halo, Ci.6alkyl, Ci.6alkoxy, C2-6 alkenyl, C2.6alkynyl, C,.6haloaikil, C,.6haloalkoxy, CN, OH, and NH2 , where Ci_6alkyl is optionally substituted with 1, 2, or 3 D; R6, R7, and R8 are each independently selected from H, D, halo, Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, Ci.6haloaikil, CN, OH, and NH2, where Ci.6alkyl is optionally substituted with 1, 2 , or 3 D; each Rase independently selects from D, halo, Ci.g alkyl, Cpe haloakyl, C2.6 alkenyl, C2.6 alkynyl, Ce-ίο aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , Cg.io aryl-Ci.6 alkyl-, C3.7 cycloalkyl-Ci.^ alkyl-, (5-10 membered heteroaryl)Ci.6 alkyl-, (4-10 membered heterocycloalkyl)-Ci.6 alkyl -, CN, NO2, ORa4, SRa4, NHORa, C(O)Rm, C(O)NRc4Rd4> C(O)NRc4(ORm), C(O)ORa4, OC(O)RM, OC(O)NRc4Rd4 , NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O )RM, S(O)NRc4Rd4, S(O)2RM, S(O)2NRc4Rd4, and OS(O)2RM, in IF-2019-19254930-APN-ANP#INpi Page 47 of 170 where Ci.6 alkyl, C2.6 alkenyl, C2.g alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl- Ci.g alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of R are each substituted optionally with 1, 2, 3, 4, 5, 6, 7, or 8 RDindependently selected substituents; each Rbl, Rcl, and Rdl is independently selected from H, C1.6 alkyl, Ci.6haloalkyl, C2.6 alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-e alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-6 membered heteroaryl)-Ci-6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl-, in where C|.e alkyl, C2.g alkenyl, C2.g alkynyl, phenyl, C3.7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci.6 alkyl-, C3.7 cycloalkyl-C|.6alkyl-, (5-6 membered heteroaryl)-Ci.6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of Rbl, Rcl, and Rdleach optionally substituted with 1 , 2, 3, or 4 RDindependently selected substituents; each Ra4, RM, Rc4, and Rd4 is independently selected from H, Cj.g alkyl, C|.ghaloalkyl, C2.6alkenyl, C2.6alkynyl, phenyl, C3.7 cycloalkyl, 5-6 membered heteroaryl, 4-membered heterocycloalkyl 7-membered, phenyl-Ci-e alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-6 membered heteroaryl)-Ci-6 alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl-, wherein C3.7 cycloalkyl-Ci.g alkyl-, (5-6 membered heteroanlo)-Ci.§ alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of Ra4, RM, Rc4, and Rd4each one is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the heteroaryl group 5- or 6-membered or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; and each Rdse independently selected from D, OH, NO2, CN, halo, Ci-6 alkyl, C2.6 alkenyl, C2.6alkynyl, Ci.6haloalkyl, cyano-C^ alkyl, HO-Ci.6alkyl, Ci.6alkoxy- Ci.6alkyl, C3.7 cycloalkyl, Ct.6alkoxy, Ci.6haloalkoxy, amino, C,.6alkylamino, di(Ci_6alkyl)amino, thio, Ci.6alkylthio, C].6alkylsulfonyl, C].6alkylsulfonyl, carbamyl, Ci. 6alkylcarbamyl, di(Ci.6alkyl)carbamyl, carboxy, Cj.g alkylcarbonyl, C14 alkoxycarbonyl, C|.g alkylcarbonylamino, C|.g alkylsulfonylamino, aminosulfonyl, C).6alkylaminosulfonyl, di(Ci_6alkyl)aminosulfonyl, aminosulfonylammo, C¡. 6 alkylaminosulfonylamino, di(Ci.§ alkyl)anonesulfonylamino, aminocarbonylamino, C1.6 alkylaminocarbonylamino, and di(Ci-6 alkyljaminocarbonylamino. In some embodiments, the groups . IF-2019-19254930-APN-ANP#INpi Page 48 of 170 In some embodiments, the groups C(O)NRclRdl. In some embodiments, the groups NRclC(O)Rbl. In some modalities, X1isNoCR1; R1 is H, D or Ci-6 alkyl; R2is Cy, C(O)NRclRdlo NRclC(O)Rbl; Cy is 5-6 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; R3, R4, and R5 are each independently selected from H, D, halo, Ci_6alkyl, Ci_6alkoxy, C2.6 alkenyl, C2.6alkynyl, haloalkyl, C,_6haloalkoxy, CN, OH, and NH2, where C,.6alkyl is optionally substituted with 1, 2, or 3 D; R6, R7 and R8 are each independently selected from H, D, halo, C].6alkyl, C2.6alkenyl, C2.6alkynyl, Ci_6haloalkyl, CN, OH, and NH2, where C].6alkyl is optionally substituted with 1,2 , or 3 D; each Rase independently selects from D, halo, Ci-6 alkyl, C|.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.10 aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 members, C6.i0 aryl-Ci.6 alkyl-, C3.7cycloalkyl-C|_6 alkyl-, (5-10 membered heteroaryl)Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci. 6 alkyl-, CN, NO2, ORa4, SRa4, NHORa, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)RM, OC(O )NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O)2Rm, NRc4S(O)2NRc4Rd4, S (O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, and OS(O)2Rb4, where Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3. 7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl- , and (4-10 membered heterocycloalkyl)-Ci.6alkyl- deRA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Rbl, Rcl, and Rdl is independently selected from H, C].6 alkyl, Ci-βhaloalkyl, C2.e alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl , phenyl-Ci.6alkyl-, C3.7cycloalkyl-Cl.6alkyl-, (5-6 membered heteroaryl)-Ci.6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6alkyl-, where Ci.g alkyl, C2_g alkenyl, C2.g alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci.6 alkyl-, C3.7cycloalkyl-C,.6alkyl -, (5-6 membered heteroaryl)-C,.6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of Rbl, Rcl, and Rdl each optionally substituted with 1, 2, 3, or 4 independently selected RDin substituents; IF-2019-19254930-APN-ANP#INpi Page 49 of 170 each Ra4, RM, Rc4, and Rd4 is independently selected from H, C|.g alkyl, C 1.6 haloalkyl, C2-6 alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci.6 alkyl-, (5-6 membered heteroaryl)-Ci.6 alkyl-, and (4-7 membered heterocycloalkyl) -Ci.6alkyl-, wherein Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci.6alkyl-, C3 .7 cycloalkyl-C,.6alkyl-, (5-6 membered heteroaryl)-C,.6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of Ra4, RM, R, and R each one is optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the heteroaryl group 5- or 6-membered or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; and each Rd is independently selected from D, OH, NO2, CN, halo, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C].6haloalkyl, cyano-Ci.6 alkyl, HO-Ci.6alkyl, C ^alkoxy-Ci-e alkyl, C3.7 cycloalkyl, Ci.6alkoxy, Ci-6haloalkoxy, amino, Ci.6alkylamino, di(Ci.6alkyljamino, thio, C,.6 alkylthio, Ci.6alkylsulfinyl, C|.6alkylsulfonyl, carbamyl, Ci.6alkylcarbamyl, di(Ci.6alkyljcarbamyl, carboxy, C,.6alkylaminosulfonyl, CMalkoxycarbonyl, C,.6alkylcarbonylamino, Ci.6alkylsulfonylamino, aminosulfonyl, Ci.6alkylaminosulfonyl, di(C].6alkyljaminosulfonyl, aminosulfonylamino, C1.6 alkylaminosulfonylamino, di(Ci.6alkyljaminosulfonylamino, aminocarbonylamino, Ci.salkylaminocarbonylamino, and di(C|.6alkyl)aminocarbonylamino. In some embodiments, the groups . In some embodiments, the groups (O)NRc,Rdl. In some embodiments, the groups (O)Rbl. In some modalities: X1is N or CH; R2is C(O)NRclRdl; each RC1y Rdl is independently selected from H, Ct.6alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.10 cycloalkyl-Ci- 6 alkyl-, (5-10 membered heteroaryl)-C,.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6 alkyl-, wherein C|.g alkyl, C2.6 alkenyl, C2 -6 alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, Cg-io aryl-C 1.6 alkyl-, C3.iocycloalkyl-C|.6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl- , and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Rcly Rdleach optionally substituted with 1, 2, 3, or 4 independently selected RA substituents, IF-2019-19254930-APN-ANP#INpi Page 50 of 170 or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-membered heterocycloalkyl group , 5, 6, or 7 members are optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; each Rase independently selects from D, halo, oxo, Ci-β alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, CN, NO2, and ORa4, where the C,.6 alkyl, C2.6alkenyl , and C2.6alkynyl of Rase optionally substituted with 1, 2 or 3 independently selected RD substituents; each Ra4 is independently selected from H and C|.6 alkyl, wherein the Cj.6 alkyl is optionally replaced by CN, NO2, or OH; each Rdes OH; each R3, R4, and R5 is independently selected from H, D, halo, CN, OH, Ci.3alkyl, and Ci.3haloalkyl, wherein Ci.6alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D ; and each R6, R7, and R8 is independently selected from H, D, Ci-6 alkyl and C].6 haloalkyl. In some modalities: X1is N; R2es C(O)NRc'Rdl; RC1is H; Rdl is selected from ethyl, propyl, isopropyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methylcyclopbutyl, methyl-phenyl, ethyl -phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and tianyl, where ethyl, propyl, isopropyl, tere-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1] heptanyl, methyl-cyclopropyl, methylcyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and Rdl thianyl are optionally substituted with 1 or 2 RA independently selected substituents; or, any Rcly Rdl, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 RA independently selected substituents; each Rase independently selects from oxo, methyl, CH2F, CHF2, CF3, -OCH3, CH2OH, CN, and OH; . R3 is selected from H, methyl, and CD3. R4 and R5 are each H; R6 is selected from CH2F, CHF2, and CF3; and R7 and R8 are each H. In some modalities: X1is N or CH; IF-2019-19254930-APN-ANP#INpi Page 51 of 170 R2 is selected from Ci.6 alkyl, Ci-ghaloalkyl, C2-6 alkenyl, and C2.g alkynyl, wherein Ci.6 alkyl, C2.6alkenyl, and C2.6alkynyl are each optionally substituted with 1, 2, or 3 RAindependently selected substituents; each Rase independently selects from D, halo, Ci-6 alkyl, C6.i0 aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, and ORa4, where the C] .6 alkyl, C6.i0aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RAeach are optionally substituted by 1 or 2 independently selected RD groups; each Ra4se independently selected from H and Ci^ alkyl; each Rdse independently selected from halo, C1.6 alkyl, CN, cyano-Ci-6 alkyl, and ORa5; each Ra5 is independently selected from H and Ci.6alkyl; each R3, R4, and R5 is independently selected from H, D, halo, CN, OH, C1.3 alkyl, and C1.3 haloalkyl, wherein Ci.6alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; and · each R6, R7, and R8 is independently selected from H, D, Ci.6alkyl, and C 1.6haloalkyl. In some modalities: X1is N or CH; R2 is selected from Ci-6 alkyl, C1.6 haloalkyl, C2.g alkenyl, and C2.6 alkynyl, wherein Ci-6alkyl, C2.6alkenyl, and C2.6alkynyl are each optionally substituted with 1 or 2 substituents RAindependently selected; each Rase independently selects from D, halo, Cj.6 alkyl, C6.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, and ORa4, where Ci. 6 alkyl, C6.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RAeach are optionally substituted by 1 or 2 independently selected RD groups; each Ra4se independently selected from H and C^ alkyl; each Rdse independently selected from halo, C1.6 alkyl, CN, cyano-Ci-6 alkyl, and ORa5; each Ra5 is independently selected from H and C1.6 alkyl; R3 is selected from H and C1.6 alkyl; R4 is selected from H and Cp6 alkyl; R5 is selected from H and C1.6 alkyl; R6 is a C1.3 haloalkyl, wherein each halogen of the C1.3 haloalkyl is independently selected from F and Cl; and each R7 and R8 is independently selected from H, D, C1.6 alkyl, and C1.6 haloalkyl. In some modalities: X1esN; IF-2019-19254930-APN-ANP#INPI Page 52 of 170 R2 is selected from trifluoromethyl, propyl, propendend, ethynyl, propynyl, butynyl, and pentynyl, wherein ethynyl is optionally substituted by RA, and the propynyl, butynyl, and pentynyl groups are each optionally substituted by 1, 2, or 3 groups. R independently selected, each Rase independently selects from Ci.6 alkyl, C6.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and ORa4, wherein Ci.6 alkyl, C6 .io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RaEach is optionally substituted by 1 or 2 independently selected RD groups, each Ra4 is independently selected from H and Ci.g alkyl; each Rdse independently selected from halo, Ci.g alkyl, CN, cyano-Ci.6alkyl, and ORa5; each Ra5is selected independently from H and C].6alkyl; R3is Ci-6 alkyl; R4is H; R5is H; R6 is a C1.3 haloalkyl, wherein each halogen of the C1.3 haloalkyl is independently selected from F and Cl; R7is H; and R8es H. In some modalities: X1is N; R2 is selected from trifluoromethyl, propyl, propendeno, ethynyl, propynyl, butynyl, and pentynyl, wherein the ethynyl is optionally substituted by RA, and the propynyl, butynyl, and pentynyl groups are each optionally substituted by 1, 2, or 3 groups. RAindependently selected, each Rase independently selects from methyl, cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazopyrazinyl, hydroxyl, and methoxy, wherein cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and imidazopyrazinyl of Raeach is optionally replaced by 1 or 2 independently selected RD groups, each Rd is independently selected from methyl, cyano, cyanomethyl, and methoxy; R3es Cj.6 alkyl; ' R4is H; R5is H; R6 is CHF2 or CF3; R7is H; and R8es H. In some modalities: X1is N or CH; IF-2019-19254930-APN-ANP#INpi Page 53 of 170 R2 is selected from C3.12 cycloalkyl and 4-12 membered heterocycloalkyl, wherein C3. 12 cycloalkyl and 4-12 membered heterocycloalkyl each optionally substituted with 1, 2, or 3 RA independently selected substituents; each Rase independently selects from D, halo, oxo, Cj.6 alkyl, Cg.io aryl, C3.6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)ORa4, C(O)NRc4Rd4 , and S(O)2RM, wherein the C,.6 alkyl, C6.,0aryl, C3.6cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RD substituents; each Ra4, RM, Rc4, and Rd4 is independently selected from H, Ci-6 alkyl, phenyl, C3.6cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein Ct.6alkyl, phenyl, C3.6cycloalkyl , 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4y RM are each optionally substituted with 1 or 2 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group 7 members are optionally replaced with 1 or 2 independently selected RD substituents; each R3, R4, and R5 is independently selected from H, D, halo, CN, OH, C1.3 alkyl, and C1.3 haloalkyl, wherein the C]6alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; and each R6, R7, and R8 is independently selected from H, D, C1.6 alkyl, and C 1.6 haloalkyl. In some modalities: X1is N or CH; R2 is selected from C3.6cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C3.6cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 RA substituents; each Rase independently selects from C1.3 alkyl, C(O)RM, C(O)ORa, C(O)NR R, and S(O)2RM, where the C,.3 alkyl of RAeach is optionally substituted with 1 or 2 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, Cj.6 alkyl, phenyl, C3.6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein Ci.6alkyl, C3. 6cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl of Ra4, Rm, Rc4, and Rd4 each are optionally substituted with 1 or 2 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group 7 members are optionally replaced with 1 or 2 independently selected RD substituents; IF-2019-19254930-APN-ANP#INpi Page 54 of 170 each Rdse is independently selected from OH, CN, Cj.6 alkyl, Cí.6 alkoxy, Cj.6 haloalkyl and phenyl; R3 is selected from H, methyl and CD3; R4 and R5 are each H; R6 is selected from CH2F, CHF2, and CF3; and R7 and R8 are each H. In some modalities: X1is N; R2 is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl of R2 are each optionally substituted with 1, 2, or 3 RA substituents independently selected from (1-methyllH-pyrazol-4-yl)sulfonyl, ethylcarboxylate, oxo, cyclopropyl, butyl, acetyl, cyclopropanecarbonyl, phenyl, methylphenyl, dimethylphenyl, pyrindinyl, thiazolyl, trifluoromethylphenyl, cyanophenyl, hydroxyphenyl, hydroxymethyl, cyanoethyl , oxohexahydropyrrolo[l,2-a]pyrazin-2-yl, furan-2-carbonyl, cyanopyrazinyl, and ethoxyphenyl; R3 is selected from H, methyl and CD3; R4 and R5 are each H; R6 is selected from CH2F, CHF2, and CF3; and R7 and R8 are each H. In some modalities, X1isNoCR1; R1is H; R2is Cy, C(O)NRclRdlo NRclC(O)Rbl; Cy is a 5-membered heteroaryl, which is optionally substituted with 1, 2, or 3 independently selected RA substituents; R3, R4, and R5 are each independently selected from H, D, halo, C1.6 alkyl, C|.g alkoxy, C2-6 alkenyl, C2.6alkynyl, Ci.6haloalkyl, C].6haloalkoxy, CN, OH, and NH2, wherein Ci.6alkyl is optionally substituted with 1, 2, or 3 D; R6, R7, and R8 are each independently selected from H, D, halo, Ci.6alkyl, C2.6 alkenyl, C2-6 alkynyl, C|.6 haloalkyl, CN, OH, and NH2, wherein C1.6 alkyl is substituted optionally with 1, 2, or 3 D; each Rase independently selects from D, halo, C1.6 alkyl, Cj.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.i0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , Cg-io aryl-Ci.6 alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci.6alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORm), C(O)ORa4, OC(O)RM, OC(O)NRc4Rd4, NRc4Rd4 , NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, IF-2019-19254930-APN-ANP#INpi Page 55 of 170 NRc4S(O)2RM, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2RM, S(O)2NRc4Rd4, and OS(O)2Rb4, where the C(.6alkyl , C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci.g alkyl-, C3.7 cycloalkyl-Ci .g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-^ R alkyl- each optionally substituted with 1, 2, 3, 4, 5, 6 , 7, or 8 RDindependently selected substituents; each Rbl, Rcl, and Rdl is independently selected from C 1-6 alkyl-, C3.7 cycloalkyl-Ci-g alkyl-, (5-6 membered heteroaryl)-Ci-6 alkyl-, and (4-7 membered heterocycloalkylj-C,^ alkyl-, where The Ci.6alkyl, C2.6alkenyl, C2-6 alkynyl, phenyl, C3.7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci.6 alkyl-, C3.7 cycloalkyl-Ci. 6alkyl-, (5-6 membered heteroaryl)-Ci.6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of Rbl, Rcl, and Rdl each optionally substituted with 1, 2, 3, or 4 independently selected RDin substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, Ci.g alkyl, C|.6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3.7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered, phenyl-Ci.g alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-6 membered heteroaryl)-Ci-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1.6 alkyl-, where Cue alkyl, C2.6 alkenyl, C2.6 alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C|.g alkyl-, C3 -7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-Ci.f, alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of Ra4, RM, Rc4, and Rd4 is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the heteroaryl group 5- or 6-membered or 4-, 5-, 6-, or 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; and each Rd is independently selected from D, OH, NO2, CN, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C).6haloalkyl, cyano-Ci_6alkyl, HO-Ci.6alkyl, Ci-6alkoxy- Ci.6alkyl, C3.7 cycloalkyl, Ci.6alkoxy, C,.6haloalkoxy, amino, Cue alkylamino, di(Ci.6alkyljamino, thio, C].6alkylthio, Ci.6alkylsulfmyl, Cí.6alkylsulfonyl, carbamyl, Cu6alkylcarbamyl, di (C,.6alkyljcarbamyl, carboxy, Cue alkylcarbonyl, Cm alkoxycarbonyl, Ci.g alkylcarbonylamino, Cue alkylsulfonylamino, aminosulfonyl, Ci.6alkylaminosulfonyl, di(Ci_6alkyljaminosulfonyl, aminosulfonylamino, Cue alkylaminosulfonylamino, di(Ci.g alkyljaminosulfonylamino, aminocarbonylamino, Ci. galkylaminocarbonylamino, and di(Ci.§alkyl)aminocarbonylamino. In some embodiments, the groups . IF-2019-19254930-APN-ANP#INpi Page 56 of 170 In some embodiments, the groups C(O)NRclRdl. In some embodiments, the groups (O)Rbl. In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: X1isNoCR1; R1 is H, D or Ci-6 alkyl; Cy is a 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; Each of R3, R4, and R5 is independently selected from H, D, halo, Ci.6alkyl, Ci.6alkoxy, C2-6 alkenyl, C2.6alkynyl, C^ haloalkyl, Cj.6haloalkoxy, CN, OH, and NH2, wherein Cy.6alkyl is optionally substituted with 1, 2, or 3 D; Each of R6, R7, and R8 is independently selected from H, D, halo, Ci-6 alkyl, C2.6alkenyl, C2.6alkynyl, Ci.6haloalkyl, CN, OH, and NH2, where Ci.6alkyl is optionally substituted with 1 , 2, or 3 D; each Rase independently selects from D, halo, Ci.6 alkyl, Cb6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , Cg.io aryl-Ci-e alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, (4-10 membered heterocycloalkyl)-Ci.6 alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)RM, OC(O) NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rm, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O)2Rm, NRc4S(O)2NRc4Rd4, S( O)RM, S(O)NRc4Rd4, S(O)2RM, S(O)2NRc4Rd4, and OS(O)2RM, where each of Ci.g alkyl, C2.6 alkenyl, C2.6 alkynyl, Cg .io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7cycloalkyl-Ci_6alkyl-, (5-10 membered heteroaryl)-Ci. 6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Ra4, RM, Rc4, and Rd4 is independently selected from H, Ci.6 alkyl, Cj.6haloalkyl, C26 alkenyl, C26 alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, heterocycloalkyl'. IF-2019-19254930-APN-ANP#INpi Page 57 of 170 7 membered)-Ci.6alkyl-, wherein each of Cm alkyl, C2.6alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-CM alkyl- , C3.7cycloalkyl-Ci.g alkyl-, (5-6-membered heteroaryl)-Ci-6 alkyl-, and (4-7-membered heterocycloalkyl)-CM alkyl- of R, R, R, and R is substituted optionally with 1, 2, 3, 4, 5, 6, 7, or 8 RDindependently selected substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which it is attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R substituents independently selected; and each Rd is independently selected from D, OH, NO2, CN, halo, Ci.6 alkyl, C2.6 alkenyl, C2.6alkynyl, Cm haloalkyl, cyano-Ci.6alkyl, HO-Cm alkyl, Cm alkoxy-C]. 6alkyl, C3.7cycloalkyl, Ci.6alkoxy, C,.6haloalkoxy, amino, Cm alkylamino, di(Ci.6alkyl)amino, thio, C,.6alkylthio, Cm alkylsulfinyl, Ci.6alkylsulfonyl, carbamyl, Ci.6alkylcarbamyl, di( Ci.6alquil) carbamil, carboxy, cm alkarbonil, cm alcoxicarbonil, cm alkcabonylamine, cm alklocying, aminosulfonil, cm alkylaminefilosulfonil, di (ci.6alquil) aminosulfonil, aminosulfonilamino, cm alkylaminosulfonilamino, di (ci.6alquil) aminosulfonilamino, aminocarbon Bonilamino , and di(C।_g alkyljaminocarbonylamino. In some embodiments, the compound is a compound of Formula (V): N Cy R5HO HO (V) or a pharmaceutically acceptable salt thereof, wherein: X1isNoCR1; R1 is H, D or Cm alkyl; Cy is a 5-6 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; Each of R3, R4, and R5 is independently selected from H, D, halo, Cm alkyl, Cm alkoxy, C2.6alkenyl, C2.6alkynyl, Cm haloalkyl, Cm haloalkoxy, CN, OH, and NH2, where Cm alkyl is optionally substituted with 1, 2, or 3 D; IF-2019-19254930-APN-ANP#INpi Page 58 of 170 Each of R6, R7, and R8 is independently selected from H, D, halo, Cus alkyl, C2-6 alkenyl, C2.6alkynyl, C^ haloalkyl, CN, OH, and NH2, where Ci.6alkyl is optionally substituted with 1, 2, or 3 D; each Rase independently selects from D, halo, Ci.g alkyl, Cí.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C^io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, Cg-io aryl-Ci-e alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C 1.6 alkyl-, (4-10 membered heterocycloalkyl)-Ci .6 alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORM), C(O)ORa4, OC(O)RM, OC( O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rm, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O)2Rm, NRc4S(O)2NRc4Rd4> S(O)RM, S(O)NRc4Rd4, S(O)2RM, S(O)2NRc4Rd4, and OS(O)2RM, where each of Ci-6 alkyl, C2.g alkenyl, C2.6 alkynyl , Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Cp6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl )-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C|.6alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RDindependently selected; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, Ci.6alkyl, Cj.6 haloalkyl, C2-6alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl , phenyl-Ci.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-6 membered heteroaryl)-Ci.6alkyl-, and (4-7 membered heterocycloalkyl)-C|.6alkyl-, where each one of Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl -, (5-6 membered heteroaryl)-C].6 alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of Ra4, RM, Rc4, and Rdse optionally substituted with 1, 2, 3 , 4, 5, 6, 7, or 8 RDindependently selected substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which it is attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R substituents independently selected; and each Rd is independently selected from D, OH, NO2, CN, halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Cj.6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci^alkoxy-Ci.g alkyl, C3.7cycloalkyl, Ci.6alkoxy, C).6haloalkoxy, amino, C].6alkylamino, di(Ci.6alkyljamino, thio, Ci.6alkylthio, Ci-6 alkylsulfinyl, alkylsulfonyl, carbamyl, Cj.6 alkylcarbamyl, di(Ci-6 alkyljcarbamyl, carboxy, Ci.g alkylcarbonyl, Cm alkoxycarbonyl, Ci-6 alkylcarbonylamino, Ci.g alkylsulfonylamino, aminosulfonyl, Ci.6alkylaminosulfonyl, di(Ci.6alkyljaminosulfonyl, aminosulfonylamino, C1.6 alkylaminosulfonyl , di(Ci.g alkyljaminosulfonylamino, aminocarbonylamino, Ci.g alkylaminocarbonylamino, and di(Ci-6alkyl)aminocarbonylamino. In some embodiments, the compound is a compound of Formula (V): IF-2019-19254930-APN-ANP#INpi Page 59 of 170 (V) or a pharmaceutically acceptable salt thereof, wherein: X1isNoCR1; R1is H; Cy is a 5-membered heteroaryl, which is optionally substituted with 1, 2, or 3 independently selected RA substituents; Each of R3, R4, and R5 is independently selected from H, D, halo, Ci.6alkyl, C].6alkoxy, C2.6 alkenyl, C2.6alkynyl, C].6haloalkyl, C^ haloalkoxy, CN, OH, and NH2, wherein Ci.6alkyl is optionally substituted with 1, 2, or 3 D; Each of R6, R7, and R8 is independently selected from H, D, halo, Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, Ci-β haloalkyl, CN, OH, and NH2, where Ci-6alkyl is optionally substituted. with 1, 2, or 3 D; each Rase independently selects from D, halo, C1.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C^o aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, Cg-io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-C,.6 alkyl-, (4-10 membered heterocycloalkyl) -Ci.6 alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rm, C(O)NRc4R“4, C(O)NRc4(ORm), C(O)ORa4, OC(O) RM, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O)2Rb4, NRc4S( O)2NRc4Rd4, S(O)RM, S(O)NRc4Rd4, S(O)2RM, S(O)2NRc4Rd4, and OS(O)2RM, where each of C1.6 alkyl, C2.6 alkenyl , C2.g alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (heteroaryl 5-10 membered)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R substituents independently selected; each Ra4, RM, Rc4, and Rd4 is independently selected from H, Cj.6alkyl, C].6haloalkyl, C2.6alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl , phenyl-Ci-6 alkyl-, C3.7cycloalkyl-Ci.g alkyl-, (5-6 membered heteroaryl)-C|. 6 alkyl-, and (4-7 membered heterocycloalkyl)-Ci.g alkyl-, where each of C|.g alkyl, C2.6alkenyl, C2.6alkynyl, phenyl, C3.7cycloalkyl, 5-6heteroaryl members, 4-7 membered heterocycloalkyl, phenyl-C,.6alkyl-, C3.7cycloalkyl-C^ alkyl-, (5-6 membered heteroaryl)-C,.6 IF-2019-19254930-APN-ANP#INpi Page 60 of 170 alkyl-, and (4-7-membered heterocycloalkyl)-CM alkyl- of Ra4, RM, Rc4, and Rd4 are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 RD substituents independently selected; . or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which it is attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R substituents independently selected; and each Rd is independently selected from D, OH, NO2, CN, halo, Ci.6 alkyl, C2.g alkenyl, C2.6 alkynyl, Cm haloalkyl, cyano-CM alkyl, HO-Ci.6alkyl, Cm alkoxy-Ci. 6 alkyl, C3.7 cycloalkyl, Ci.6alkoxy, Ci.6haloalkoxy, amino, C].6alkylamino, di(Ci.6alkyljamino, uncle, Ci.6alkylthio, Ci.6alkylsulfmyl, Ci.6alkylsulfonyl, carbamyl, Ci.6alkylcarbamyl, di (Ci.6alkyljaminosulfonyl, Cm chylaminocarbonylamino, and di(Ci-6alkyl)aminocarbonylamino. In some embodiments, the compound is a compound of Formula (V): R5HO HO (V) or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from a 5-membered heteroaryl, which is optionally substituted with 1, 2, or 3 independently selected RA substituents; R3 is Cm alkyl, which is optionally substituted with 1, 2, or 3 D; Each of R4 and R5 is independently H, D or Cm alkyl, wherein the Cm alkyl is optionally substituted with 1, 2, or 3 D; R6 is H, D, Cm alkyl or Cm haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein each Y substituent is independently selected from D, halo, Cm alkyl, and Cm haloalkyl; Each of R7 and R8 is independently H, D or Cm alkyl, wherein the Cm alkyl is optionally substituted with 1, 2, or 3 D; each Rase independently selects from D, halo, Cm alkyl, Cm haloalkyl, Cm alkenyl, C26alkynyl, CN, NO2, ORa4, SRa4, NHORa4, C(O)RM, C(O)NRc4Rd4, C(O)NRc4(ORM) , IF-2019-19254930-APN-ANP#INpi Page 61 of 170 C(O)ORa4, OC(O)RM, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4> NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O)2Rb4! NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rm, S(O)2NRc4Rd4, and OS(O)2RM, where each of Ci.6alkyl, C2.6alkenyl, and C2.6alkynyl of RA is optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 are independently selected from H, Ci.6alkyl, and Ci.6haloalkyl, where each of the Ci.g alkyl of Ra4, RM, Rc4, and Rd4 is optionally substituted with 1, 2, 3, or 4 independently selected RDin substituents; and each Rd is independently selected from D, OH, NO2, CN, halo, Ci.g alkyl, C2.g alkenyl, C2.g alkynyl, C|.g haloalkyl, cyano-C|.g alkyl, HO-Cí. 6 alkyl, Ci^alkoxy-Ci-g alkyl, C3.7cycloalkyl, Ci.6alkoxy, Cb6haloalkoxy, amino, Ομ6alkylamino, di(C|.6alkyl)amino, uncle, Cj.6alkylthio, Ομ6alkylsulfinyl, Ομ6alkylsulfonyl, carbamyl, Ομ6alkylcarbamyl, di (Ci.6alkyl)carbamyl, carboxy, Ci.g alkylcarbonyl, C1-4 alkoxycarbonyl, C|.g alkylcarbonylamino, C|.g alkylsulfonylamino, aminosulfonyl, Ομ6alkylaminosulfonyl, di(C].6alkyl)aminosulfonyl, aminosulfonylamino, Ομ6alkylaminosulfonylamino, di( Ci.6alkyl)aminosulfonylamino, aminocarbonylamino, Ci-galkylaminocarbonylammo, and di(Ci-6alkyl)aminocarbomlamino. In some embodiments, the compound is a compound of Formula (V): R8(V) or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from a 5-membered heteroaryl, which is optionally substituted with 1, 2, or 3 independently selected RA substituents; R3 is C1.6 alkyl, which is optionally substituted with 1, 2, or 3 D; Each of R4 and R5 is independently H, D or C16alkyl, wherein the C16alkyl is optionally substituted with 1, 2, or 3 D; R6 is H, D, C1.6 alkyl or C,.6haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein each Y substituent is independently selected from D, halo , Ci.6alkyl, and Ci.6haloalkyl; Each of R7 and R8 is independently H, D or C|.6alkyl, wherein the Q.g alkyl is optionally substituted with 1, 2, or 3 D; IF-2019-19254930-APN-ANP#INpi Page 62 of 170 each Rase independently selects from D, halo, Cb6 alkyl, Ci.ghaloalkyl, CN, ORa, and NRc4Rd4; wherein each of the Cj.6 alkyl of RA is optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rc4, and Rd4 are independently selected from H, D, Ci.6alkyl, and C].6haloalkyl, wherein each of the Cj.6alkyl of Ra4, Rc4, and Rd4 is optionally replaced with 1, 2, 3, or 4 independently selected RDin substituents; and each Rd is independently selected from D, OH, CN, halo, Ci.6 alkyl, Ci.6 haloalkyl, Ci-6 alkoxy, C 1.6 haloalkoxy, amino, Ci.6alkylamino, and di(Ci.6alkyl)amino. In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from: N=N each of which is optionally substituted by 1 or 2 independently selected RA substituents; R3 is methyl or CD3; Each of R4 and R5 is H; R6 is Ci-6 haloalkyl, where each halogen is F; Each of R7and R8is H; and each Raes methyl or CD3. In some embodiments, the compound is the compound of Formula (VI), (VIb), or (VIc): (SAW), IF-2019-19254930-APN-ANP#INpi Page 63 of 170 n^nh2 R°1 (VIb), ν^νη2 N Ra(Vic), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound of Formula (VII), (VHb), or (VIIc): (VII) (VHb), (VIIc), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound of Formula (VIII), (VlUb), or (Vfflc): (HIV), IF-2019-19254930-APN-ANP#INpi Page 64 of 170 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from: 2-(3-(5-Amino-6-(l-(methyl-d3)-17 / -pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3trifluoropropane-1, 2-diol; 2-(3-(5-Amino-6-(1-methyl-1#-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane1,2-diol; 2-(3-(5-Amino-6-(127-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2-diol; 2-(3-(5-Amino-6-(3-methylisoxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2diol; 2-(3-(5-Amino-6-(isothiazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2-diol; 2-(3-(5-Amino-6-(isothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2-diol; 2-(3-(5-amino-6-(3-methylisothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2diol; 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2diol; 2-(3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2-diol; 2-(3 ​​-(5 -Amino-6-(oxazol-5 -yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2-diol; 2-(3-(5-Amino-6-(l / Z-pyrazol-l-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2-diol; 2-(3-(5-Amino-6-(l / f-l,2,3-triazol-l-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2diol ; (2-(3-(5-Amino-6-(2 / f-l, 2,3-triazol-2-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l, 2diol; 2-(3-(5-Amino-6-(177-l ,2,4-triazol-l -yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l ,2diol ; 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-(methyl-d3)phenyl)-3,3,3-trifluoropropane1,2-diol; IF-2019-19254930-APN-ANP#INfI Page 65 of 170 3-amino-6-(2-(methyl-d3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)feml)-A-(tetrahydro-2Hpyran-4-yl) pyrazine-2-carboxamide; 3-amino-6-(5-(l,l-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)-A-(4hydroxybicyclo[2.2.1]heptan-l- il)pyrazine-2-carboxamide; 3-amino-6-(2-(methyl-d3)-5-(1,1,1-trifluoro-2,3-dihydroxybutan-2-yl)phenyl)-A-(tetrahydro-2Hpyran-4-yl) pyrazine-2-carboxamide; 2-(3 ​​-(5 -amino-6-(3 -methyl-1 tf-pyrazol-4-yl)pyrazin-2-yl)-4-(methyl-d3)phenyl)-1,1,1,4 ,4,4hexafluorobutane-2,3-diol; 2-(3-(5-amino-6-(3-methyl-l / Z-pyrazol-4-yl)pyrazin-2-yl)-4-(methyl-d3)phenyl)-l, 1,1, 4,4,4hexafluorobutane-2,3-diol; 3-amino-6-(2-methyl-5-(l,l,l-trifluoro-2,3-dihydroxy-3-methylbutan-2-yl)phenyl)-iV-(tetrahydro-2 / fpyran-4- il)pyrazine-2-carboxamide; 2-(3-(5-amino-6-(l-((l-methyl-l / 7-pyrazol-3-yl)sulfonyl)azetidin-3-yl)pyrazin-2-yl)-4methylphenyl)-3 ,3,3-trifluoropropane-1,2-diol; (3-(3 -amino-6 -(2 -methyl-5 -(1,1,1 -trifluoro-2,3 -dihydroxypropan-2-yl)phenyl)pyrazin-2yl)cyclobutyl)(3-hydroxyazetidin-l -yl)methanone; 3-amino-A-((ls,37?)-3-cyanocyclobutyl)-6-(2-(methyl-d3)-5-((S)-l,l,l-trifluoro-2,3dihydroxypropan-2 -yl)phenyl)pyrazine-2-carboxamide; 3-amino-7V-((lS,2S)-2-hydroxycyclohexyl)-6-(2-(methyl-d3)-5-((S)-l,l,l-trifluoro-2,3dihydroxypropan-2- yl)phenyl)pyrazine-2-carboxamide; 3-amino-7V-((Zran5)-3-hydroxytetrahydro-2 / / -pyran-4-yl)-6-(2-(methyl-d3)-5-((S)-l, 1,1 - trifluoro2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-7V-((15.37?)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-6-(2-(methyl-d3)-5-((S)-l,l,ltrifluoro- 2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-aminoW-((ls,3R)-3-hydroxy-l -methylcyclobutyl)-6-(2-(methyl-d3)-5-((S)-l ,1,1 -trifluoro-2,3dihydroxypropane- 2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-A-(4-(hydroxymethyl)bicyclo[2.1.1 ]hexan-1 -yl)-6-(2-(methyl-d3)-5 -(1,1,1 -trifluoro2 ,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino W-(3-(hydroxymethyl)bicyclo[l. 1.1 ]pentan-l -11)-6-(2-(methyl-d3)-5-(1,1,1 -trifluoro2, 3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-y-((S)-l-hydroxypropan-2-11)-6-(2-(methyl-d3)-5-((S)-l,l,l-trifluoro-2,3dihydroxypropan- 2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-7V-(2-cyano-2-methylpropyl)-6-(2-(methyl-d3)-5-(l,l,l-trifluoro-2,3-dihydroxypropan2-yl) phenyl)pyrazine-2-carboxamide; (Sj-3-amino- / V-(4-hydroxybicyclo[2.2.1 ]heptan-l -yl)-6-(2-(methyl-d3)-5-(l, 1,1 -trifluoro-2, 3dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; IF-2019-19254930-APN-ANP#IN£I Page 66 of 170 3-amino-7V-((7?)-l-hydroxypropan-2-yl)-6-(2-(methyl-d3)-5-((S)-l, 1,1 -trifluoro-2,3dihydroxypropan -2-yl)phenyl)pyrazine-2-carboxainide; (5)-3-amino-A-(4-hydroxybicyclo[2.1.1]hexan-l -yl)-6-(2-(methyl-d3)-5-(l, 1,1 -trifluoro-2, 3dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; . 3-amino-6-(5 -((5)-1,1 -difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)-7V-(( 15.25)- 2hydroxycyclohexyl)pyrazine-2-carboxamide; 3-amino-6-(5-((5)-l,l-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)-A-((17?,27? )-2hydroxycyclohexyl)pyrazine-2-carboxamide; (5)-3-amino-A-(4-cyanobicyclo[2.1.1]hexan-l-yl)-6-(5-(l,l-difluoro-2,3-dihydroxypropan-2-yl)2- (methyl-d3)phenyl)pyrazine-2-carboxamide; (5)-3-amino-6-(5-(l, l-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)feml)-N-(tetrahydro-2Hpyran-4- il)pyrazine-2-carboxamide; (5)-3-amino-6-(5-(l,l -difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)W-(tetrahydro-2Z7pyran-4-yl)pyrazine-2- carboxaniide; 3-amino-6-(5-((5)-l, 1-difluoro-2,3-dihydroxypropan-2-yl)-2 -methylphenyl)-A-((5)-lhydroxypropan-2-yl)pyrazine -2-carboxamide; 3-amino-6-(5-(l,l-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-JV-(4hydroxybicyclo[2.2.1 ]heptan-l -yl)pyrazine-2 -carboxamide; (3-amino-6-(5-((5)-l,l-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazin-2-yl)((7?)-2( hydroxymethyl)pyrrolidin-1-yl)methanone; (5)-3-amino-6-(5-(l,l-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-A-isopropylpyrazine-2carboxamide; 3-amino-A-(4-cyanobicyclo[2.1.1]hexan-l -11)-6-(5-(1, 1-difluoro-2,3-dihydroxypropan-2-yl)-2methylphenyl)pyrazine-2 -carboxamide; 3-amino-6-(5-((5)-l, 1 -difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(3methyltetrahydrofuran-3-yl)pyrazine-2-carboxamide ; and 2-(3-(5-amino-6-(trifluoromethyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-l,2-diol; or an enantiomer, diasteromer or tautomer thereof; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the (S)-enantiomer of one of the above compounds, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the (R)-enantiomer of one of the above compounds, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention includes all stereoisomers of the aforementioned compounds. In some embodiments, the compound is a compound of Formula (I): IF-2019-19254930-APN-ANP#INpi Page 67 of 170 R8(I) or a pharmaceutically acceptable salt thereof; where: X'isNoCR'; R1 is selected from H, D, halo, C|.g alkyl, Cj.g alkoxy, C2.g alkenyl, C2.g alkynyl, C|.g haloalkyl, Cj.6 haloalkoxy, CN, OH, and NH2; R2 is selected from C(O)NRclRdl; Each of R3, R4 and R5 is independently selected from H, D, halo, CN, OH, C|.g alkyl, C|.g haloalkyl, C2.¿ alkenyl, C2.g alkynyl, C|.§ alkoxy, C, .6 haloalkoxy, cyano-Ci-g alkyl, HO-Ci.6 alkyl, C|.6 alkoxy-Ci.6 alkyl, C3.6 cycloalkyl, amino, Ci.6 alkylamino, di(Ci.6 alkyljamino, and C (O)NRcRd, wherein the Ci.6 alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; Each of R6, R7 and R8 is independently selected from H, D, Ci.6 alkyl, Ci.g haloalkyl, C2.g alkenyl, C2.g alkynyl, Cg.io aryl, C3.io cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-g alkyl-, C3.io cycloalkyl-Ci-g alkyl-, (5-10 membered heteroaryl)-C).6 alkyl-, (4-membered heterocycloalkyl -10 members)-Ci.6 alkyl-, C(O)Rb3, C(O)NRc3Rd3, C(O)NRc3(ORa3), C(O)ORa3, C(=NRe3)Rb3, C(=NOH) Rb3, C(=NCN)Rb3, and C(=NRe3)NRc3Rd3, wherein each of Ci.6 alkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.,or cycloalkyl, 5-heteroaryl 10-membered, 4-10-membered heterocycloalkyl, C6.|0aryl-Ci.6alkyl-, C3.I0cycloalkyl-Ci.6alkyl-, (5-10-membered heteroaryl)-Ci.6alkyl-, and . (4-10 membered heterocycloalkyl)-Ci.6alkyl- of R6, R7, and R8 is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; and wherein the Cy.6haloalkyl of R6, R7, or R8 is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, C|.g alkyl, and C].g haloalkyl; or the substituents R6 and R7, together with the ring atoms to which they are attached, form a C3. ίο cycloalkyl or a 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; or the substituents R7 and R8, together with the ring atoms to which they are attached, form a C3. io cycloalkyl or a 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; IF-2019-19254930-APN-ANP#INpi Page 68 of 170 Each of Rc and Rd is independently selected from H, Ci-6 alkyl, C].6haloalkyl, C2. alkenyl, C2.¿ alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci.g alkyl-, C3.7 cycloalkyl-Ci-g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-, where each of C1-6 alkyl, C2.g alkenyl, C2.g alkynyl, Cj.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-g alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (heteroaryl 5-10 membered)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Rcy Rd, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RMindependently selected; each Rcly Rdl is independently selected from H, C1.6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, Ce. 10 aryl-Ci.6alkyl-, C3.10 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C].6alkyl-, where each of C|.6alkyl, C2.6alkenyl, C2.6 alkynyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3.10 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl )-C,.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Rcly Rdl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RAindependently selected; or, any Rcly Rdl, bonded to the same N atom, together with the N atom to which it is bonded, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-membered heterocycloalkyl group. , 5-, 6-, or 7-membered is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; . each Ra3, Rb3, Rc3, and R is independently selected from H, C1.6 alkyl, C|.6 haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, Cg-ιο aryl-Ci-6 alkyl-, C3.10 cycloalkyl-Ci-g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-membered heterocycloalkyl 10 membered)-Ci.6alkyl-, wherein each of C1.6 alkyl, C2.g alkenyl, C2.g alkynyl, Ce-10 aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10 members, Cg-io aryl-C 1.6 alkyl-, C3.iocycloalkyl-C). 6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra3, Rb3, Rc3, and Rd3 are optionally substituted with 1, 2, 3, 4 , 5, 6, 7, or 8 independently selected R substituents; or, any Rc3 and Rd3, bonded to the same N atom, together with the N atom to which it is bonded, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl. members, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents R independently selected; each Re3 is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, C1.6 haloalkyl, C 1.6 haloalkoxy, C2.6 alkenyl, C2.g alkynyl, Cg-io aryl, C3.10 cycloalkyl, heteroaryl of IF-2Q19-1925493Q-APN-ANP#IN(PI Page 69 of 17Q 5-10 membered, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci.6 alkyl-, C3.10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and ( 4-10 membered heterocycloalkyl)-Ci.6alkyl-; each Rase independently selects from D, halo, C].6 alkyl, C1.6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, Ce-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, Cg.io aryl-Ci.g alkyl-, ¢3.-7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-C 1.6 alkyl-, (4-10 membered heterocycloalkyl) -Ci.6 alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORM), C(O)ORa4, OC(O)RM, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rm, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)RM, C(=NOH)RM, C(=NCN)Rm, C (=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4C(=NRe4)RM, NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN)NRc4Rd4, NRc4S(O)RM, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rm, S(O)2NRc4Rd4, OS(O)(=NRe4)RM, OS(O)2RM, SF5, P(O)Rf4Rg4, OP(O)(ORh4)(ORi4), P(O)(ORh4)(ORi4), and BRj4Rk4, where Cb6alkyl, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3 .7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.ioaryl-C,.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl- , and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents RDindependently selected; each Rbse independently selected from D, halo, Ci.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, Ce-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10-membered, Cg-io aryl-Ci-e alkyl-, C3.7 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6 alkyl-, (4-10 membered heterocycloalkyl)-Ci .6 alkyl-, CN, NO2, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC( O)NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C(= NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, S(O)2NRc2Rd2, OS(O)(=NRe2)Rb2, OS(O)2Rb2, SF5, P( O) RGRg2, OPtOXOR ^ 4-10 membered, Cg-io anlo-Ci-e alkyl-, C3.7cycloalkyl-C 1.5 alkyl-, (5-10 membered heteroaryl)-C|.6 alkyl-, and (4-10 membered heterocycloalkyl )-Ci.6alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R substituents; each Ra2, Rb2, Rc2, and R02 is independently selected from H, C1.6 alkyl, C]_6 haloalkyl, C2-6 alkenyl, C2.6alkynyl, C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci.g alkyl-, C3-7 cycloalkyl-Ci-g alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl members)-Ci.6alkyl-, wherein each of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, Cg.io aryl-Ci^ alkyl-, C3.7 cycloalkyl-Ci-6 IF-2019-19254930-APN-ANP#INpi Page 70 of 170 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C^ alkyl- of Ra2, Rb2, Rc2, and R^ is optionally replaced with 1 , 2, 3, 4, 5, 6, 7, or 8 independently selected RMin substituents; or, any Rc2 and R02 attached to the same N atom, together with the N atom to which it is attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R substituents independently selected; each Re2 is independently selected from H, OH, CN, Ci.6alkyl, C,.6 alkoxy, Cj.6 haloalkyl, Cj.6 haloalkoxy, C2.6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.7 cycloalkyl , 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each R*2 and R82 is independently selected from H, Ci-6 alkyl, Ci.g alkoxy, C1.6 haloalkyl, Cj.$ haloalkoxy, C2.6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7 cycloalkyl-Ci.6alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and ( 4-10 membered heterocycloalkyl)-Ci.6alkyl-; each R^ and R'2 is independently selected from H, C1.6 alkyl, C|.g haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, Cg.io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-C|.6 alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl members)-Ci.6alkyl-; each Rj2 and R^ is independently selected from OH, C|.g alkoxy, and C1.6haloalkoxy; or any Rj2 and R^ attached to the same B atom, together with the B atom to which it is attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci .6alkyl and Ci.6haloalkyl; each Ra4, RM, Rc4, and Rd4 is independently selected from H, C1.6 alkyl, C 1.6 haloalkyl, C2.6alkenyl, C2.6alkynyl,. C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-C|.g alkyl-, (heteroaryl 5-10 members)-C 1.6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, where each of Ci.g alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg. io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl-Cí.6alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl) -Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra4, RM, Rc4, and Rd4 are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 RD substituents independently selected; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which it is attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, IF-2019-19254930-APN-ANP#INpi Page 71 of 170 wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RDin substituents; each Re4 is independently selected from H, OH, CN, Ci-6 alkyl, Ci.6 alkoxy, Ci.6 haloalkyl, Cj.6haloalkoxy, C2.6alkenyl, C2.6alkynyl, C6.io aryl, C3.7cycloalkyl, heteroaryl of 5 -10 membered, 4-10 membered heterocycloalkyl, C6.i0aryl-Ci-6 alkyl-, C3_7cycloalkyl-C|_6alkyl-, (5-10 membered heteroaryl)-C|.6 alkyl-, and (4-membered heterocycloalkyl 10 members)-Ci.6alkyl-; each Rf4 and Rg4 is independently selected from H, Cj.6 alkyl, Ci-6 alkoxy, Q.g haloalkyl, C).6haloalkoxy, C2.6alkenyl, C2.6alkynyl, C6.10aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, Ce-io aryl-Cpe alkyl-, C3.7cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci .6alkyl-; each Rh4 and R'4 is independently selected from H, Ci.6 alkyl, Ci.g haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.i0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl members, C6.10aryl-Ci.6alkyl-, C3.7cycloalkyl-C|.6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl -; each Rj4 and Rk4 are independently selected from OH, C|.6alkoxy, and Ομβ haloalkoxy; or any Rj4 and Rk4 attached to the same B atom, together with the B atom to which it is attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C|. 6alkyl and C|.6 haloalkyl; each Rd is independently selected from H, D, halo, C|.g alkyl, Ci-6 haloalkyl, C2.g alkenyl, C2.g alkynyl, C6.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, C6.io aryl-Ci.6 alkyl-, C3.7 cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl )-Ci.6 alkyl-, CN, NO2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5 , OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O )2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rc5, S(O)2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O)2Rb5, SF5 , P(O)RRRg5, OP(O)(ORh5)(OR'5), P(O)(ORh5)(ORi5), and BRj5Rk5, where each of C].6 alkyl, C2.6alkenyl, C2 .6 alkynyl, C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-Ci.6alkyl-, C3.7cycloalkyl-Ci.6alkyl-, (5-membered heteroaryl -10 membered)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RD is optionally substituted with 1, 2, 3, or 4 substituents REindependently selected; each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, Ci.g alkyl, Ct.6 haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6-io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, IF -2019-19254930-APN-ANP#INPI Page 72 of 170 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.éalkyl-, and (heterocycloalkyl 4-10 membered)-C,.6alkyl-, wherein each of C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-e alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C).6alkyl-, and (4-membered heterocycloalkyl 10-membered)-Ci.6alkyl- of Ra5, Rb5, Rc5, and Rd5 is optionally substituted with 1, 2, 3, or 4 REindependently selected substituents; or, any Rc5 and Rd5 attached to the same N atom, together with the N atom to which it is attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 REindependently selected substituents; each Re5 is independently selected from H, OH, CN, Cpg alkyl, C1.6 alkoxy, C|.g haloalkyl, C,.6haloalkoxy, C2.6alkenyl, C2.6alkynyl, C6-io aryl, C3.7 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, C^-io aryl-Ci-g alkyl-, C3.7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-C|.6alkyl-; each Rf5 and Rg5 are independently selected from H, C,.6 alkyl, C|.6 alkoxy, Cj.6 haloalkyl, Ci.6haloalkoxy, C2.6alkenyl, C2.6alkynyl, C6.,oaryl, C3.7 cycloalkyl, heteroaryl -10 membered, 4-10 membered heterocycloalkyl, Cg.io aryl-Ci-6 alkyl-, C3.7cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-C|.6alkyl-, and (heterocycloalkyl 4-10 members)-Ci.6alkyl-; each Rh5 and R'5 is independently selected from H, C1.6 alkyl, C|_6haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , Cé-io aryl-Cpe alkyl-, C3.7cycloalkyl-C|.6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl -; each Rj5 and Rk5 are independently selected from OH, C1.6 alkoxy, and C[.g haloalkoxy; or any R*5 and Rk5 attached to the same B atom, together with the B atom to which it is attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1 .6 alkyl and C[.6haloalkyl; each Rese independently selected from H, D, halo, Ci-6 alkyl, C|.6 haloalkyl, C2.6 alkenyl, C2.6alkynyl, C6.i0aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl -10 membered, Cé.io aryl-Ci.6 alkyl-, C3.7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)- C 1.6 alkyl-, CN, NO2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC( O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6> NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rb6, C(=NCN)Rb6, C(= NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, IF-2019-19254930-APN-ANP#INpi Page 73 of 170 S(O)NRc6Rd6, S(O)2Rc6, S(O)2NRc6Rd6> OS(O)(=NRe6)Rb6, OS(O)2Rb6, SF5, P(O)Rf6Rg6, OP(O)(ORh6)( OR'6), P(O)(ORh6)(ORi6), and BRj6Rk6, where each of Cm alkyl, C2.6alkenyl, Cm alkynyl, C^o aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-CM alkyl-, C3.7cycloalkyl-CM alkyl-, (5-10 membered heteroaryl)-CM alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl - from RE is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, Cm alkyl, Cm haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.i0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C^qo aryl-CM alkyl-, C3.7cycloalkyl-CM alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-, where each Cm alkyl, Cm alkenyl, Cm alkynyl, Cg.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl-CM alkyl-, C3.7cycloalkyl-CM alkyl-, ( 5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of Ra6, Rb6, Rc6, and Rd6 is optionally substituted with 1, 2, 3, 4, 5, 6 , 7, or 8 independently selected RGin substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which it is attached, form a 5- or 6-membered heteroaryl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R substituents independently selected; each Re6 is independently selected from H, OH, CN, Cm alkyl, Cm alkoxy, Cm haloalkyl, Cm haloalkoxy, Cm alkenyl, C2.6alkynyl, Ce-ιο aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl 10-membered, C6.io aryl-CM alkyl-, C3.7cycloalkyl-CM alkyl-, (5-10 membered heteroaryl)-CM alkyl-, and (4-10 membered heterocycloalkyl)-C,.6 alkyl-; each Rf6 and Rg6 is independently selected from H, Cm alkyl, Cm alkoxy, Cm haloalkyl, Cm haloalkoxy, Cm alkenyl, C2.6alkynyl, Cé-io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.io aryl-CM alkyl-, C3.7cycloalkyl-CM alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each Rh6 and R'6 is independently selected from H, Cm alkyl, Cm haloalkyl, Cm alkenyl, C2.6alkynyl, C6.i0aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl-CM alkyl-, C3.7cycloalkyl-CM alkyl-, (5-10 membered heteroaryl)-Ci.6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl-; each Rj6 and Rk6 is independently selected from OH, Cm alkoxy, and Cm haloalkoxy; IF-2O19-1925493O-APN-ANP#INPI Page 74 of 170 or any Rj6y Attached to the same B atom, together with the B atom to which it is attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected substituents of C(.6 alkyl and Ci.6 haloalkyl; each Rg is independently selected from H, D, halo, CN, NO2, SF5, C|.6alkyl, C|.6alkoxy, Ci-6haloalkyl, C2.6alkenyl, C2.6alkynyl, C6.,oaryl, C3.7cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, Cg.io anlo-C].6 alkyl-, C3.7cycloalkyl-Ci-e alkyl, (5-10 membered heteroaryl)-Ci.6alkyl-, and (heterocycloalkyl 4-10 members)-Ci_6alkyl; and each Rm is independently selected from H, D, OH, NO2, CN, halo, C|.6 alkyl, C2.6 alkenyl, C2.g alkynyl, Ci-6 haloalkyl, cyano-Ci.6alkyl, HO-Ci-β alkyl, Ci.salkoxy-Ci-6 alkyl, C6.io aryl, C3.7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6.i0aryl-Ci-6 alkyl-, C3.7cycloalkyl-Ci. 6alkyl-, (5-10 membered heteroarylj-C,^ alkyl-, (4-10 membered heterocycloalkyl)-Ci.6 alkyl, Ci-6 alkoxy, Ci.6 haloalkoxy, amino, Ci-6 alkylan-lino, di(Cj_6 alkyljamino, thio, Ci.^alkylthio, Ci^alkylsulfinyl, Ci^alkylsulfonyl, carbamyl, C|-6alkylcarbamyl, di(C,.6alkyljcarbamyl, carboxy, C,.6alkylcarbonyl, CMalkoxycarbonyl, Ci.6alkylcarbonylamino, Cj.g alkylsulfonylamino, aminosulfonyl, Ci.g alkylaminosulfonyl, di(C|.g alkyljaminosulfonyl, aminosulfonylamino, Ci.g alkylaminosulfonylamino, di(Ci-6 alkyljaminosulfonylamino, aminocarbonylamino, Ci.6 alkylaminocarbonylamino, and di(Ci-6 alkyljaminocarbonylamino. It is further appreciated that certain features of the invention, which are described, for clarity, in the context of the separate embodiments, may further be provided in combination with a single embodiment. Rather, various features of the invention that are summarized, for brevity, in the context of a single embodiment, may further be provided separately or in any suitable subcombination. In several places herein, divalent linking substituents are described. It is specifically noted that each divalent linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR’R”)n- includes both NR(CR’R”)n- and -(CR’R”)nNR-. When the structure clearly requires a link group, the Markush variables listed for that group are understood to be link groups. The term “n-membered” when n is an integer typically describes the number of ring-forming atoms in a portion when the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3, 4-Tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are selected independently, and the substitution can be at any chemically accessible position. As used herein, the term IF-2019-19254930-APN-ANP#INpi Page 75 of 170 “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, for example oxo, can replace two hydrogen atoms. It should be understood that substitution on a given atom is limited by valence. As used herein, the phrase “each ‘variable is selected independently of’” means substantially the same as where “at each occurrence the ‘variable’ is selected from.” In all definitions, the term “Cn.m” indicates a range that includes extreme values, where n and m are integers and indicate the number of carbons. Examples include C1.3, CM, Ci.6, and the like. As used herein, the term "Cn.malkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), nbutyl, / ere-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l-butyl, w-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, “Cn.malkenyl” refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbons. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2a 6, 2a 4, or 2 to 3 carbon atoms. As used herein, “Cn.malkinyl” refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2a 6, 2a 4, or 2a3 carbon atoms. As used herein, the term "Cn.malkoxy", used alone or in combination with other terms, refers to a group of the formula -O-alkyl, wherein the alkyl group has n to m carbons. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and Zerc-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "amino" refers to a group of the formula -NH2. As used herein, the term “aryl,” used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). ). The term Cn.maryl refers to an aryl group having n to m carbon atoms in the ring. Aryl groups include, for example, IF-2019-19254930-APN-ANP#INpi Page 76 of 170 phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, the aryl groups have 5 to 14 carbon atoms. In some embodiments, the aryl group has 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl. As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In some embodiments, a halo is F, Cl, or Br. embodiments, a halo is F. In some embodiments, a halo is Cl. As used herein, “Cn.mhaloalkoxy” refers to a group of the formula -O-haloalkyl having n to m carbon atoms. Examples of haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn.mhaloalkyl,” used alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms that may be the same or different, where “s” is the number of carbon atoms in the alkyl group, where the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CC13, CHC12, C2C15and the like. As used herein, the term “Cn.malkylamino” refers to a group of the formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 3 carbon atoms. As used herein, the term “Cn.malkoxycarbonyl” refers to a group of the formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term “Cn.malkylcarbonyl” refers to a group of the formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term “Cn.malkylcarbonylamino” refers to a group of the formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term “Cn.malkoxycarbonylamino” refers to a group of the formula -NHC(O)O(Cn.malkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term "Cn-malkylsulfonylamino" refers to a group of the formula -NHS(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 3 carbon atoms. IF-2019-19254930-APN-ANP#INpi Page 77 of 170 As used herein, the term “aminosulfonyl” refers to a group of the formula -S(O)2NH2. As used herein, the term “Cn-malkylaminosulfonyl” refers to a group of the formula -S(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn.malkyl)aminosulfonyl” refers to a group of the formula -S(O)2N(alkyl)2, where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminosulfonylamino” refers to a group of the formula -NHS(O)2NH2· As used herein, the term “Cn.malkylaminosulfonylamino” refers to a group of the formula -NHS(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6.1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn.m alkyl)aminosulfonylamino” refers to a group of the formula -NHS(O)2N(alkyl)2, where each alkyl group independently has n to m carbon atoms . In some embodiments, each alkyl group independently has 6, 4, or 1 to 3 carbon atoms. As used herein, the term "aminocarbonylamino", used alone or in combination with other terms, refers to a group of the formula -NHC(O)NH2. As used herein, the term “Cn.malkylaminocarbonylamino” refers to a group of the formula -NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn.malkyl)aminocarbonylamino” refers to a group of the formula -NHC(O)N(alkyl)2, where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 4, or 3 carbon atoms. As used herein, the term “Cn.malkylcarbamyl” refers to a group of the formula -C(O)-NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term "thio" refers to a group of the formula -SH. As used herein, the term “Cn.malkylthio” refers to a group of the formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 3 carbon atoms. IF-2019-19254930-APN-ANP#INpi Page 78 of 170 As used herein, the term “Cn.malkylsulfinyl” refers to a group of the formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term “Cn.malkylsulfonyl” refers to a group of the formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 6, 4, or 1 to 3 carbon atoms. As used herein, the term “carbamyl” refers to a group of the formula -C(O)NH2. As used herein, the term “carbonyl,” used alone or in combination with other terms, refers to the -C(O)- group. As used herein, the term “cyano-Ci-6 alkyl” refers to a group of the formula -(Ci.6 alkylene)-CN. As used herein, the term “HO-Cj.6 alkyl” refers to the group of the formula -(Ci-6 alkylene)-OH. As used herein, the term “HO-C1.3 alkylene” refers to the group of the formula -(C1.3 alkylene)-OH. As used herein, the term “C].6alkoxy-Ci.6alkyl” refers to the group of the formula -(C|.6alkylene)-O(C|.3alkyl). As used herein, the term “C].6alkoxy-Ci.3alkyl” refers to the group of the formula -(C|.6alkylene)-O(Ci-3alkyl). As used herein, the term "carboxy" refers to a group of the formula -C(O)OH. As used herein, the term “di(Cn.m-alkyl)amino” refers to a group of the formula -N(alkyl)2, wherein the two alkyl groups each independently have n to m atoms. carbon. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn.m-alkyl)carbamyl” refers to a group of the formula -C(O)N(alkyl)2, wherein the two alkyl groups each have, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 6, 4, or 3 carbon atoms. As used herein, the term “aminocarbonyloxy” refers to the group of the formula -OC(O)NH2. As used herein, the term “C1.3 alkylcarbonyloxy” refers to a group of the formula -OC(O)(Ci-3 alkyl). As used herein, the term “C1.3 alkylaminocarbonyloxy” refers to a group of the formula -OC(O)NH(Ci-3 alkyl). IF-2019-19254930-APN-ANP#INpi Page 79 of 170 As used herein, the term “di(Ci.3alkyl)aminocarbonyloxy” refers to a group of the formula -OC(O)N(Ci.3alkyl^, wherein the two alkyl groups each, independently, have , 1 to 3 carbon atoms. As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons that include cyclized alkyl and alkenyl groups. Cycloalkyl groups may include mono- or polycyclic groups (e.g., having 2, 3, or 4 fused rings), spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group). The ring-forming carbon atoms of a cycloalkyl group may optionally be substituted by oxo or sulfide (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties having one or more aromatic rings fused (i.e., having a bond in common) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring may be joined by any ring-forming atom that includes a ring-forming atom of the fused aromatic ring. Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (i.e., C3.i4). In some embodiments, the cycloalkyl is a monocyclic or bicyclic C3.i4 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic C3.7cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic C4.7cycloalkyl. In some embodiments, the cycloalkyl is a C4.i0spirocycle or bridged cycloalkyl (e.g., a bridged bicycloalkyl group). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, Cuban, adamantane, bicyclo[l.l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[ 2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle (e.g., having 2, 3, or 4 fused rings) having at least one ring member of heteroatoms selected from N, O , S and B, wherein any ring-forming N is optionally an N-oxide group. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 ring members of heteroatoms independently selected from N, O, S, and B. In some embodiments, any ring-forming N in a heteroaryl moiety may be a dioxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 ring members of heteroatoms independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-14 membered monocyclic, bicyclic, or tricyclic heteroaryl having 1, 2, 3, or 4 ring members of heteroatoms independently selected from N, O, and S. In some embodiments, the heteroaryl is a monocyclic heteroaryl or 5-10 membered bicyclic having 1, 2, 3, or 4 ring members of heteroatoms independently selected from N, O, and S. In some embodiments, the IF-2Q19-1925493Q-APN-ANP#IN(PI Page 8Q of 17Q heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 ring members of heteroatoms independently selected from N, O, S and B. In some embodiments, the heteroaryl is a five membered or six membered heteroaryl ring. members. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When the heteroaryl group contains more than one ring member of heteroatoms, the heteroatoms may be the same or different. Examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole, thiadiazole, quinoline, isoquinoline , indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l,2-b]thiazole, purine, triazine, thieno[3,2-¿>]pyridine, imidazo[l,2-a]pyridine, 1,5-naphthyridine, l / / -pyrazolo[4,3-Z>]pyridine and the like. A five-membered heteroaryl is a heteroaryl group having five ring-forming atoms where one or more (e.g., 1, 2, or 3) of the ring-forming atoms are independently selected from N, O, S, or B. Illustrative five-membered ring heteroaryls are tindo, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3 -oxadiazolyl, 1,2,4-triazolyl, 1,2,4thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and 1 ,2-dihydro1,2-azaborine. A six-membered heteroaryl is a heteroaryl group with a ring having six ring-forming atoms wherein one or more (e.g., 1, 2, or 3) of the ring-forming atoms are independently selected from N, O, S and B. The six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. As used herein, "heterocycloalkyl" refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated), wherein one or more of the ring-forming carbon atoms are replaced by a heteroatom selected from N, O, S and B, and wherein the ring-forming heteroatoms and carbon atoms may be optionally substituted by one or more oxo or sulfide (e.g., C(O), S(O), C( S), or S(O)2, etc.). Heterocycloalkyl groups include monocyclic and polycyclic systems (e.g., having 2, 3, or 4 fused rings). Included in heterocycloalkyl are the heterocycloalkyl groups of 3-14- or 4-14- or 3-12- or 4-12-, or 3-10-, or 4-10- or 3-7- or 4-7- or 5-6monocyclic and polycyclic members. Heterocycloalkyl groups may further include spirocycles and bridged rings (e.g., a 5-14 membered bridged biheterocycloalkyl ring optionally substituted with 0 to 2 additional heteroatoms independently selected from N, O, S and B). The heterocycloalkyl group may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some modalities, the group IF-2019-19254930-APN-ANP#INpi Page 81 of 170 heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused (i.e. having a bond in common) to the non-aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring may be joined by any ring-forming atom that includes a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a 4-10 membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. Examples of heterocycloalkyl groups include pyrrolidin-2-one, l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, azepanyl, benzazapene, 1,2,3,4diazabicyclo[3.1.0]hexanyl. diazabicyclo[2.2.1]heptanyl. azabicyclo[3.2.1 joctanyl. ,2.2]octanyl, azaadamantanil. thiazolidinyl, imidazolidinyl, azabicyclo[3.1.0]hexanyl, azabicyclo[2.2.1 ]heptanyl, diazabicyclo[3.1.1 ]heptanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2 pyrazolidinyl, oxazolidinyl, tetrahydroisoquinoline, oxabicyclo[2.1. l]hexanyl, azabicyclo[3.1.1 ]heptanyl, diazabicyclo[3.2.1 Joctanyl, diazaadamantanil, oxa-adamantanil, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxa azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxaazaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxa diazaspiro[4.4]nonanyl and the like. As used herein, “C0.pcycloalkyl-Cn.malkyl-” refers to a group of the formula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. carbon. As used herein "C0.paryl-Cn-malkyl-" refers to a group of the formula aryl-alkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms . As used herein, “heteroaryl-Cn.malkyl-” refers to a group of the formula heteroaryl-alkylene-, wherein the alkylene linking group has n to m carbon atoms. IF-2019-19254930-APN-ANP#INPI Page 82 of 170 As used herein, “heterocycloalkyl-Cn.malkylene-” refers to a group of the formula heterocycloalkyl-alkylene-, wherein the alkylene linking group has n to m carbon atoms. In certain places, the definitions or embodiments refer to specific rings (for example, an azetidine ring, a pyridine ring, etc.). Unless otherwise noted, these rings can be attached to any ring member as long as the valence of the atom is not exceeded. For example, an azetidine ring can bind at any position on the ring, while a pyridin-3-yl ring binds at the 3-position. As used herein, the term “oxo” refers to an oxygen atom (i.e., =0) as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=0 or C(0)), or binds to a nitrogen or sulfur heteroatom forming a nitroso, sulfinyl, or sulfonyl group. As used herein, the term “independently selected from” means that each occurrence of a variable or substituent, for example, RMo RA, is independently selected at each occurrence from the applicable list. The compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also occur in the compounds described herein, and all of these stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as separate isomeric forms. In some embodiments, the compound has the (R)- configuration. In some embodiments, the compound has the (S) configuration. The Formulas (e.g., Formula (I), etc.) provided herein include the stereoisomers of the compounds. The resolution of racemic mixtures of compounds can be carried out by any of the numerous methods known in the art. An exemplary method includes fractional recrystallization through the use of a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various camphorsulfonic acids. optically active such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include forms IF-2019-19254930-APN-ANP#INfI Page 83 of 170 stereoisomerically pure α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a packed column with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine). One skilled in the art can determine the composition of the appropriate elution solvent. The compounds provided herein further include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactime pairs, enamine-imine pairs, and ring forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3Himidazole. , 1H-, 2H- and 4H-l,2,4-triazole, 1H- and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2Hpyrazole. Tautomeric forms can be in equilibrium or sterically locked in one form by appropriate substitution. All compounds, and their pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (for example, hydrates and solvates) or can be found isolated. In some embodiments, the preparation of compounds may involve the addition of acids or bases to effect, for example, the catalysis of a desired reaction or the formation of salt forms such as acid addition salts. In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By “substantially isolated” means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. The partial separation may include, for example, a composition enriched in the compounds provided in the present description. Substantial separation may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% by weight of the compounds provided herein, or a salt thereof. Methods for isolating compounds and their salts are routine in the art. The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures represented. Compounds identified herein by name or structure as a form IF-2019-19254930-APN-ANP#IN£I Page 84 of 170 tautomeric forms in particular are intended to include other tautomeric forms unless otherwise specified. The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of human beings. and animals without excessive toxicity, irritation, allergic response or other problem or complication, consistent with a reasonable risk / benefit ratio. The present application further includes pharmaceutically acceptable salts of the compounds described herein. The present description further includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the described compounds wherein the parent compound is modified by converting an existing acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acid residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present description can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate acid or base in water or in an organic solvent, or in a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g. methanol, ethanol, isopropanol or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated in its entirety herein by reference. Synthesis As those skilled in the art will appreciate, the compounds provided herein, including salts and stereoisomers thereof, can be prepared by use of known organic synthesis techniques and can be synthesized according to any of the numerous possible synthetic approaches. The compounds of Formula (I) can be prepared as shown in Scheme 1. Suitable starting materials 1-1, where Y1 and Y2 are independently a halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs), can be converted to an appropriate substituted metal 1-2 (e.g., M1es B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a reagent diboron such as bis(pinacolato)diboron, a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium (Π), or IF-2019-19254930-APN-ANP#INfI Page 85 of 170 bis(diphenylphosphino)ferrocene]dichloropalladium (Π), complexed with dichloromethane and a base, such as potassium acetate, and then coupled to 1-3 where Y6 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OM) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium (Π), or [ l,r-bis(diphenylphosphmo)ferrocene]dichloropalladium (Π), complexed with dichloromethane and a base (e.g., a carbonate base, such as sodium carbonate or potassium carbonate) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (Π)) to give compound 1-4. Intermediate 1-4 can be converted to diol-containing intermediate 1-5 by exposure to reagents for dihydroxylation (e.g., osmium tetroxide and a reoxidant such as N-methylmorpholine-N-oxide, or AD-mix a or AD -mixp). The intermediate 1-5 can be converted to an appropriate substituted metal 1-6 (e.g., M2es B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium (Π), bis(diphenylphospho)ferrocene]dichloropalladium (Π), complexed with dichloromethane, or Pd2(dba)3 and a ligand (such as 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-l,l'-biphenyl) and a base, such as potassium acetate) and then couples to 1-7 where Y3e Y7are independently a halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (Π), complexed with dichloromethane and a base (e.g., a carbonate base, such as sodium carbonate or potassium carbonate) or standard Stille conditions (e.g. for example, in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine) palladium(0) or [Ι,Γbis(diphenylphospho)ferrocene]dichloropalladium(II)) to give compound 1-8. Intermediate 1-8 can be converted to compounds of Formula (I) by cross-coupling with an appropriate metal R2-M (where M is B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn) under standard conditions from Suzuki (for example, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium (Π), complex with dichloromethane and a base (e.g., a carbonate base such as sodium carbonate or potassium carbonate) or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine) palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [Ι,ΓIF-2019-19254930-APN-ANP#INpi Page 86 of 170 bis(diphenylphospho)ferrocene]dichloropalladium (II)). Alternatively, compounds of Formula (I) can be prepared from intermediate 1-8 by reacting with a nucleophile under SNAr conditions (for example, by heating in the presence of a carbonate base, such as Cs2CO3). One skilled in the art would recognize that compounds of Formula (I) can be further prepared by reversing the order of the last two steps of Scheme 1. By starting with a suitably substituted intermediate 1-7, where Y3 and Y7 are independently a halogen (e.g. For example, Cl, Br, or I) or pseudohalogen (for example, OTf or OMs), coupling to install R2 can be performed prior to coupling with intermediate 1-6, to provide compounds of Formula (I). Scheme 1. R5 1-1 Suzuki, Stille or Negishi Formula I Compounds of Formula (I) can be prepared as shown in Scheme 2. By starting with a suitably substituted 2-1 1,4-dibromobenzene, sequential reaction with a strong base (e.g., nBuLi) at low temperature (e.g. example, -78 °C), followed by reaction with a carboxylic acid derivative R6C(O)-L', such as an ester (methyl or ethyl ester) (for example, methyl trifluoroacetate or ethyl trifluoroacetate) or a Weinreb amide (e.g. 2,2difluoro-N-methoxy-A-methylacetamide), followed by in situ treatment with a second strong base equivalent (e.g. mBuLI) at low temperature (e.g. -78°C ), followed by a second electrophile R3-L2 (where L2 is a suitable leaving group (e.g., halogen, such as Cl, Br or I or a mesylate or tosylate)), provides the ketone intermediate 2-2. One skilled in the art will appreciate that the order of the two steps can be reversed and the two steps can also be performed separately, step by step. Intermediate 2-2 can be halogenated by exposure to halogenation conditions to introduce Y2 (e.g. bromine in the presence of A1C13 and gentle heating), or IF-2019-19254930-APN-ANP#INPI Page 87 of 170 IV-halo-succinimide (e.g. A-bromosuccinimide) and sulfuric acid in acetic acid at elevated temperature (e.g. 80°C) to obtain intermediate 2-3. Intermediate 2-3 can be olefined to obtain intermediate 2-5 under standard conditions for olefination (e.g., Wittig conditions with a ylide such as 2-4, where Y9 may be a phenyl, generated by reacting a phosphonium salt with a strong base (e.g. m-BuLi, potassium tert-butoxide or NaHMDS) or generated by a method similar to that found in Organic Letters, Vol.4, No. 10, 1671-1674, 2002 (e.g. generation in situ of methylenetriphenylphosphorane from rhodium(I) the catalyzed decomposition of trimethylsilyldiazomethane in the presence of triphenylphosphorane and 2propanol)). The intermediate define 2-5 can be converted to compounds of Formula (I) by the methods described in Scheme 1. Scheme 2. Formula I Compounds of Formula (I) can also be prepared as shown in Scheme 3. Appropriate starting materials 3-1, where Y3 is a halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs ), can be coupled with an appropriately substituted metal R2-M (where M is B(OH)2, Bpin, BF3K, Sn(Bu)3, Zn or ZnX (where X is a halogen such as iodide) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II)), or [1,1'bis(diphenylphosphine)ferrocene]dichloropalladium (Π), complex with dichloromethane and a base (e.g., a carbonate base such as sodium carbonate or potassium carbonate) or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium (0) or standard Negishi conditions (for example, in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [Ι,Γbis(diphenylphospho)ferrocene]dichloropalladium (II) optionally in the presence of an additive such as copper (I) iodide to obtain intermediate 3-2. Intermediate 3-2 can then be halogenated by reacting with a suitable reagent to introduce the halogen Y7 (for example, Nhalosuccinimide such as W-iodosuccinimide, W-bromosuccinimide or TV-chlorosuccinimide). He IF-2019-19254930-APN-ANP#INpi Page 88 of 170 Intermediate 3-3 carrying a suitable halogen Y7 (e.g., Cl, Br or I) can be worked up to provide compounds of Formula (I) as shown in Scheme 1. Scheme 3. HjN H2N R halogenation 3-2 H2N 3-1 3-3 Scheme 1 Compounds of Formula (I) where R2 is an amide or a heterocycle can also be prepared as shown in Scheme 4. The Y3 group of the halosubstituted intermediate 4-1 (where Y3 is Cl, Br or I) can be converted to a nitrile group by nucleophilic displacement with a cyanide source (e.g. heating in the presence of NaCN) or by coupling with a cyanide source under standard Negishi conditions (e.g. heating with Zn(CN)2 in the presence of a palladium catalyst, such such as tetrakis(triphenylphosphine)palladium(0) or [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (Π)) to provide intermediate 4-2. The nitrile substituent of intermediate 4-2 can be converted to heterocycle-substituted compounds of Formula (I) by methods known to those skilled in the art (e.g., by heating an appropriately substituted acyl hydrazide) in the presence of an alkoxide base. in an alcoholic solvent (for example, NaOMe in MeOH or NaOEt in EtOH) to form a triazole; heat with an azide source such as NaN3 to form a tetrazole). Nitrile-containing 4-2 intermediates can further be converted to amide 4-4 intermediates (compounds of Formula (I) where R2 is an amide group) by hydrolysis (e.g., heating in the presence of aqueous acid; or with KOH in tBuOH). followed by coupling of the resulting acid with RclRdlNH by using standard amide coupling conditions (e.g., HATU). The Y3 group of the 4-1 halosubstituted intermediate (where Y3 is Cl, Br or I) can be converted to a 4-3 ester intermediate under standard conditions for carbonylation (for example, in the presence of a palladium catalyst, such as [l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium, carbon monoxide and an alcohol RalOH such as methanol or ethanol). Ester 4-3 can be converted to amide 4-4 (compounds of Formula (I) where R2 is an amide group) by using amination conditions (for example, by reacting with an amine such as R R NH in the presence of AlMe3 ). Alternatively, the 4-3 ester can be converted to 4-4 amide under standard conditions for hydrolysis, such as exposure to a hydroxide base (e.g., LiOH, NaOH, KOH in water and a cosolvent such as THF, MeOH or EtOH to provide a carboxylic acid, followed by coupling of the resulting acid with RclRdlNH by using conditions of IF-2019-19254930-APN-ANP#INpi Page 89 of 170 standard amide coupling (e.g. HATU). Alternatively, the Y3 group of the 4-1 halosubstituted intermediate can be converted directly to a 4-4 amide under standard conditions for carbonylation (e.g., in the presence of a palladium catalyst, such as [1,1'bis(diphenylphosphino)ferrocene] dichloropalladium, carbon monoxide and an amine RclRdlNH). Suitable amides 4-4 can be converted to compounds of Formula (I) where R2 is a heterocycle by methods known to those skilled in the art (for example, when knot 4-4 is a hydrazide, it can react with A-(triphenylphosphoranylidene )isocyanamide or with ptoluenesulfonic acid and an orthoester (e.g., triethyl orthoformate) to form a 1,3,4-oxadiazole; an appropriately substituted amide can be reacted with an a-halocarbonyl compound (e.g., chloracetaldehyde) to produce a oxazole; an appropriately substituted amide can be reacted with 1,1-dimethoxy-A,A-dimethylmethanamine and hydroxylamine to form a 1,2,4oxadiazole; Lawesson reagent) before subjecting the reagents mentioned above, would give rise to the corresponding thiadiazoles or tlazoles instead of oxadiazoles and oxazoles). Scheme 4. As shown in Scheme 5, the steps of Scheme 4 can be performed on the appropriate starting materials 5-1 prior to coupling with the intermediate 1-6 of Scheme 1. This further provides useful intermediates in the preparation of compounds. of IF-2019-19254930-APN-ANP#INpi Page 90 of 170 Formula (I) where R2 is an amide or a heterocycle. The 5-4 carboxylic acid intermediate (e.g., Ral=H and Y7=an appropriate halogen such as Cl, Br or I) can be converted to the 5-5 amide intermediate by reacting with an amine (RclRdlNH) under standard conditions for the formation of amides (for example, by using a coupling reagent such as HATU, in the presence of a base, such as diisopropylethylamine). Compounds of Formula (I) can be prepared as shown in Scheme 6. Suitable starting materials 6-1, wherein Y3 and Y7 are suitable halogen atoms (e.g. Cl, Br or I) or pseudohalogens (e.g. OTf or OMs), can be converted to the intermediate 6-3 by coupling with an organozinc species formed from a suitable protected halide optionally6-2 where Y1 is a halogen (e.g., Cl, Br or I) under standard conditions of Negishi (for example, in the presence of Zn (which can be activated by agents such as 1,2-dibromoethane and TMSC1) and in the presence of a suitable palladium catalyst (for example, dichloro[l,l'-bis(diphenylphospho )ferrocene]palladium (Π) adduct of dichloromethane and copper (I) iodide). The 6-3 intermediate where Y7 is a halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with an appropriately 6-4 substituted metal (e.g., M2 is B(OH)2 , Bpin, BF3K, Sn(Bu)3, or Zn) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II) , or [l,l'-bis(diphenylphospho)ferrocene]dichloropalladium(II), complexed with dichloromethane and a base (e.g., a carbonate base such as sodium carbonate or potassium carbonate) or standard Stille conditions (e.g. , in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0). 0) or [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (Π) to give compounds 6-5, which themselves IF-2019-19254930-APN-ANP#INfI Page 91 of 170 protecting group that are also suitable in terms of compatibility with other functional groups that may occur in the molecule. Intermediates 6-6 can optionally react with an electrophile Ra-L! (where L1 is a leaving group (for example, halogen, such as Cl, Br or I or a mesylate or tosylate, or Ra-L' can be an acid carboxylic acid activated by exposure to a coupling reagent (for example, DCC, EDC or HATU) in the presence of a base (for example, diisopropylethylamine or triethylamine) to provide compounds of Formula (I). Compounds of Formula (I) can be prepared as shown in Scheme 7. Suitable starting materials 7-1, wherein Y7 is a halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs ), can be converted to 7-3 intermediates by coupling with an appropriately 7-2 substituted metal (e.g., M2es B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn) under standard Suzuki conditions (e.g. For example, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane and a base (for example, a carbonate base, such as sodium carbonate or potassium carbonate) or standard conditions of Stille (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a IF-2019-19254930-APN-ANP#INpi Page 92 of 170 palladium(O) catalyst, such as tetrakis(triphenylphosphe)palladium(0) or [1,1'bis(diphenylphosphe)ferrocene]dichloropalladium(II)). The halogen-containing intermediate 7-4 can be prepared by reacting the intermediate 7-3 with a suitable reagent to introduce the halogen Y3 (for example, A-halosuccinimide such as A-iodosuccinimide, A-bromosuccinimide or N-chlorosuccinimide). Intermediate 7-4 carrying a suitable halogen Y3 (e.g. Cl, Br or I) can be coupled with an organozinc derived from a suitable starting material 7-5 where Y is a suitable halogen (e.g. Br or I ) under standard Negishi conditions (for example, in the presence of Zn (which can be activated by agents such as 1,2-dibromoethane and TMSC1)) and in the presence of a suitable palladium catalyst, (for example, dichloride [ 1,3-bis(2,6diisopropylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II))) to provide compounds of Formula (I). Formula (I) Compounds of Formula (I) can be prepared as shown in Scheme 8. Intermediates 8-1 containing an ester (e.g., R is methyl or ethyl) can be hydrolyzed by exposure to a hydroxide base (e.g., LiOH , NaOH, KOH in water and a cosolvent such as THF, MeOH or EtOH) to provide 8-2 carboxylic acid intermediates. IF-2019-19254930-APN-ANP#INpi Page 93 of 170 Carboxylic acid-containing intermediates can be coupled with an 8-3 amine in the presence of an amide coupling reagent (e.g., DCC, EDC, and HATU) and in the presence of a suitable base (e.g., diisopropylethylamine or triethylamine) to provide compounds of Formula (I). Alternatively, ester-containing intermediates can be converted directly to amide-containing compounds of Formula (I) by reaction at elevated temperature (e.g., 80 °C) with an 8-3 amine in the presence of a Lewis acid catalyst (e.g. , AlMe3). Scheme 8. The compounds of Formula (I) can be prepared as shown in Scheme 9. The diol-containing intermediate compound 9-4 can be made to obtain the carboxylic acid intermediate 9-1 by reaction with a suitable oxidizing agent (for example, by reaction with oxygen or air on a metal, such as Pt). The 9-1 carboxylic acid-containing intermediate can be subjected to conditions for esterification (for example, reflux in an alcoholic solvent such as methanol or ethanol in the presence of an acid, such as sulfuric acid) to provide a 9-2 ester intermediate. Exposure of 9-2 to an R7-M* organometallic reagent (e.g., a Grignard reagent such as methylmagnesium bromide) can provide a substituted diol intermediate 9-3. Alternatively, the diol-containing intermediate 9-4 can be converted to an aldehyde intermediate 9-5 by treatment with an appropriate oxidizing agent (e.g., sulfur trioxide-pyridine complex or Dess-Martin periodinan). Exposure of the 9-5 aldehyde to an appropriate nucleophile (e.g., an R7-M organometallic reagent such as a Grignard reagent (e.g., methylmagnesium bromide) or reagents that provide a source of a fluorinated carbon nucleophile (e.g. For example, an appropriately substituted silane such as trimethyl(trifluoromethyl)silane or trimethyl(difluoromethyl)silane in the presence of TBAF)) can provide a 9-6 substituted diol intermediate. Intermediate 9-6 can be oxidized to ketone 9-7 IF-2019-19254930-APN-ANP#INpi Page 94 of 170 by reaction with an appropriate oxidizing agent (e.g., Dess Martin periodinane or PCC) and the ketone product 9-7 can react with an appropriate nucleophile (e.g., an R8-M2 organometallic reagent such as a Grignard reagent ( for example, methylmagnesium bromide) or reagents that provide a source of a fluorinated carbon nucleophile (for example, an appropriately substituted silane such as trimethyl(trifluoromethyl)silane or trimethyl(difluoromethyl)silane in the presence of TBAF) to provide an intermediate compound containing diol 9-8. Intermediates 9-3, 9-6 and 9-8 are useful for the synthesis of compounds of Formula (I) according to the methods of Scheme 1. Scheme 9. Compounds of Formula (I) can be prepared as shown in Scheme 10. The appropriate starting material 10-1, wherein Y1 and Y2 are independently suitable halogens (e.g., Cl, Br or I) or pseudohalogens (e.g., OTf ), can be converted to the ketone intermediate 10-2 by formation of a Grignard reagent (e.g., by reacting 10-1 with magnesium in the presence of dibromoethane), and reaction of the Grignard reagent with a suitable electrophile (R6CO -L'), where L1 is a suitable leaving group (for example, R6CO-L* is a Weinreb amide (L1= -NMeOMe), such as 2,2-difluoro-7V-methoxy-A-methylacetamide). Intermediate 10-2 can be converted to an appropriately substituted define 10-3 by known methods IF-2019-19254930-APN-ANP#INpi Page 95 of 170 (e.g., by reaction with trimethylsilyldiazomethane in the presence of a catalyst such as tris(triphenylphosphine)rhodium(I) chloride and triphenylphosphine in a mixture containing 2-propanol, or by Peterson olefination, e.g., reaction with ((trimethylsilyl)methyl)magnesium chloride followed by reaction with trimethylsilyl trifluoromethanesulfonate)). Intermediate 10-3 can be converted to compounds of Formula (I) as shown in Scheme 1. Scheme 10. Formula 1 Reactions to prepare compounds described herein can be carried out in suitable solvents that can be easily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with starting materials (reactants), intermediates or products at the temperatures at which the reactions are carried out (for example, temperatures that may vary from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, those skilled in the art can select solvents suitable for a particular reaction step. The terms, “ambient temperature” or “room temperature” or “rt” as used herein, are understood in the art and generally refer to a temperature, for example, a reaction temperature, which is approximately the temperature of the room in which the reaction is carried out, for example, a temperature of about 20°C to about 30°C. The preparation of the compounds described herein may involve the protection and deprotection of various chemical groups. One skilled in the art can determine IF-2019-19254930-APN-ANP#INpi Page 96 of 170 easily the need for protection and deprotection, and the selection of appropriate protective groups. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999). The reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 'HO13C), infrared spectroscopy, spectrophotometry (e.g., UV visible), mass spectrometry, or by chromatographic methods such as such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). The compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography. Methods of use The compounds, salts or stereoisomers thereof described herein inhibit the activity of ΡΙ3Κγ kinase. Accordingly, the compounds, salts or stereoisomers described herein can be used in methods for inhibiting ΡΙ3Κγ kinase by contacting the kinase with one or more of the compounds, salts or compositions described herein. In some embodiments, the compounds or salts can be used in methods of inhibiting ΡΙ3Κγ activity in an individual / patient in need of inhibition by administering an effective amount of a compound or salt thereof described herein. In some embodiments, the modulation is inhibitory. In some embodiments, the contact is in vivo. In some modalities, the contact is ex vivo. Advantageously, the compounds as described herein demonstrate improved efficacy and favorable safety and toxicity profiles in animal studies. In some embodiments, the ΡΙ3Κγ includes a mutation. A mutation can be a replacement of one amino acid for another, or a deletion of one or more amino acids. In such embodiments, the mutation may occur in the kinase domain of ΡΙ3Κγ. In some embodiments, the compound or salt further inhibits PI3K5. The compounds or salts described herein may be selective. By "selective" is meant that the compound binds or inhibits ΡΙ3Κγ with greater affinity or potency, respectively, compared to at least one other kinase. In some embodiments, the compounds of the disclosure are selective inhibitors of ΡΙ3Κγ rather than PI3K5, PI3Ka and ΡΙ3Κβ. In some embodiments, the compounds of the disclosure are selective inhibitors of ΡΙ3Κγ rather than PI3Ka and ΡΙ3Κβ. In some embodiments, the selectivity may be at least about 2 times, 3 times, 5 times, 10 times, or 20 times more than ΡΙ3Κδ as measured by the assays described herein. In some embodiments, selectivity can be tested at the ATP 2 μΜ concentration of each enzyme. In some embodiments, the selectivity of the compounds of the description IF-2019-19254930-APN-ANP#INpi Page 97 of 170 can be determined by cellular assays associated with the activity of the PI3K kinase in particular. Another aspect of the present disclosure relates to methods of treating a ΡΙ3Κγ kinase-associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of one or more compounds of the present description or a pharmaceutical composition thereof. A ΡΙ3Κγ-associated disease or disorder may include any disease, disorder or condition that is directly or indirectly related to the expression or activity of ΡΙ3Κγ, including overexpression and / or abnormal activity levels. In some embodiments, the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease. In some embodiments, the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer, head and neck squamous cell carcinoma, prostate cancer, liver cancer. , colon cancer, endometrial cancer, bladder cancer, skin cancer, uterine cancer, kidney cancer, gastric cancer, or sarcoma. In some embodiments, the sarcoma is Askin's tumor, botryoid sarcoma, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft tissue sarcoma, angiosarcoma, phyllodes cystosarcoma, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small cell tumor. round, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangiosarcoma, Kaposi sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma. In some embodiments, the disease or disorder is mesothelioma or adrenocarcinoma. In some embodiments, the disease or disorder is mesothelioma. In some embodiments, the disease or disorder is adrenocarcinoma. In some embodiments, the disease or disorder is acute myeloid leukemia (e.g., acute monocytic leukemia), small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML). , multiple myeloma, T-cell lymphocytic leukemia (T-ALL), cutaneous T-cell lymphoma, large granular lymphocytic leukemia, mature t (peripheral) cell neoplasia (PTCL), Anaplastic large cell lymphoma (ALCL) or lymphoblastic lymphoma. In some embodiments, mature T-cell (peripheral) neoplasia (PTCL) is T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, mycosis fungoides / Sezary syndrome, anaplastic large cell lymphoma (of T-cell type), enteropathy associated with T-cell lymphoma, adult T-cell leukemia / lymphoma or IF-2019-19254930-APN-ANP#INpi Page 98 of 170 angioimmunoblastic T-cell lymphoma. In some embodiments, anaplastic large cell lymphoma (ALCL) is a systemic ALCL or a primary cutaneous ALCL. In some embodiments, the disease or disorder is Burkitt lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, pigmentous xenoderoma , keratoctantoma, lymphoplasmic lymphoma, extranodal marginal zone lymphoma, Waldenstrom macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (tunica) large B-cell lymphoma, lymphomatous granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, indolent myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse cell lymphoma B big. In some embodiments, the disease or disorder is Burkitt lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmic lymphoma , extranodal marginal zone lymphoma, Waldenstrom macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (tunic) large B-cell lymphoma, lymphomatous granulomatosis , splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, indolent myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS) English) or diffuse large B-cell lymphoma. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells of the myeloid lineage (a family of cells that originate from bone marrow stem cells). MDSCs expand strongly in pathological situations such as chronic infections and cancer, as a result of altered hematopoiesis. MDSCs are discriminated from other myeloid cell types in that they possess strong immunosuppressive activities rather than immunostimulatory properties. Similar to other myeloid cells, MDSCs interact with other types of immune cells, including T cells, dendritic cells, macrophages, and natural killer cells to regulate their functions. In some embodiments, the compounds, etc., described herein can be used in methods related to cancerous tissue (e.g., tumors) with high MDSC infiltration, including solid tumors with high basal level of macrophages and / or infiltration from MDSC. In some embodiments, non-Hodgkin lymphoma (NHL) is relapsed NHL, refractory NHL, recurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL). IF-2019-19254930-APN-ANP#INpi Page 99 of 170 In some embodiments, diffuse large B-cell lymphoma is diffuse large B-cell (ABC) lymphoma or diffuse germinal center B-cell (GCB) lymphoma. In some embodiments, Burkitt lymphoma is endemic Burkitt lymphoma, sporadic Burkitt lymphoma, or Burkitt-like lymphoma. In some embodiments, the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, asthma, allergy (e.g., allergic rhinitis), pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjógren's syndrome, osteoarthritis, restenosis or atherosclerosis. In some embodiments, the disease or disorder is cardiac hypertropia, cardiac myocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (for example, hemolytic anemia, aplastic anemia, or pure red blood cell anemia), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneic or xenogeneic transplant, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), idiopathic pulmonary fibrosis, autoimmune hemolytic anemia, vasculitis, lupus nephritis, pemphigus, or membranous nephropathy. In some embodiments, the disease or disorder is cardiac hypertropia, cardiac myocyte dysfunction, chronic obstructive pulmonary disease (COPD), elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, or anemia). pure red blood cells), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft rejection, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenia idiopathic (ITP), autoimmune hemolytic purpura, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus or membranous nephropathy. In some embodiments, the disease or disorder is Alzheimer's disease, central nervous system trauma, or stroke. In some embodiments, idiopathic thrombocytopenic purpura (ITP) is a relapsed ITP or a refractory ITP. In some embodiments, the vasculitis is Behqet's disease, Cogan syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu arteritis, Buerger's disease (thromboangiitis obliterans), central nervous system vasculitis , Kawasaki disease, cryoglobulinemia vasculitis disease (essential or induced by hepatitis C virus (HCV)), Henoch-Schonlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis or systemic vasculitis IF-2019-19254930-APN-ANP#INpi Page 100 of 170 associated with antineutrophil cytoplasmic antibody (AASV). The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein. The present disclosure further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. As used herein, the term “contacting” refers to the attachment of the indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3K with a compound of the disclosure includes administering a compound of the present disclosure to an individual or patient, such as a human, who has a PI3K, as well as, for example, introduction of a compound of the description into a sample containing a cellular or purified preparation containing PI3K. It is believed that the compounds provided in the present description (for example, compounds of Formula (I), or their pharmaceutically acceptable salts) or any of their embodiments, may possess a satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility and permeability. It should be understood that determining appropriate biopharmaceutical properties is within the knowledge of one skilled in the art, for example, determining cytotoxicity in cells or inhibiting certain targets or channels to determine potential toxicity. As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows. , sheep, horses or primates, and most preferably, humans. As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response sought in a tissue, system, animal, individual or human by a researcher. , veterinarian, medical doctor or other clinician. As used herein, the term “treat” or “treatment” may refer to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who experiences or displays the pathology or symptomatology of the disease, condition or disorder (i.e., stopping further development of the pathology and / or symptomatology); and (2) improve the disease; for example, improving a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology), such as decreasing the severity of the disease . IF-2019-19254930-APN-ANP#JNfI Page 101 of 170 In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases referred to in the present description; for example\, prevents or reduces the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but who does not yet experience or exhibit the pathology or symptomatology of the disease. Combined Therapies The growth and survival of cancer cells can be affected by multiple signaling pathways. Therefore, it is useful to combine different enzyme / protein / receptor inhibitors, which exhibit different preferences in the targets of which they modulate the activities, to treat such conditions. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) can reduce the likelihood of drug resistance emerging in a cell population and / or reduce treatment toxicity. The compounds of the present disclosure may be used in combination with one or more enzyme / protein / receptor inhibitors or one or more therapies for the treatment of diseases, such as cancer. Examples of diseases and indications that can be treated with combination therapies include those described herein. Examples of cancers include solid tumors and liquid tumors, such as blood cancers. One or more additional pharmaceutical agents such as, for example, chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, immune oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors and phosphatase inhibitors, as well as targeted therapies such such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF and FAK kinase inhibitors such as, for example, those described in WO 2006 / 056399. Other agents, such as therapeutic antibodies, may be used in combination with the compounds of the present disclosure for the treatment of diseases, disorders or conditions, particularly diseases, disorders or conditions associated with PI3K. The one or more additional pharmaceutical agents may be administered to a patient simultaneously or sequentially. For example, compounds as described herein may be combined with one or more inhibitors of the following kinases for the treatment of cancer and other diseases or disorders described herein: Aktl, Akt2, Akt3, TGF-pR, PKA , PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR, PDGFpR, CSFIR, KIT, FLK- II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Mar, TRKA, TRKB, TRKC, FLT3, VEGFR / FU2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fe, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. Non-limiting examples of inhibitors that can be combined with the compounds of the present description for the treatment of cancer and other diseases and IF-2019-19254930-APN-ANP#INPI Page 102 of 170 disorders described herein include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat, NLG919, or BMS-986205), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a Pim inhibitor, a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), a histone deacetylase (HDAC) inhibitor such as a HDAC8 inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor, inhibitors of bromine and extra terminal family members (for example, bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643) and an adenosine receptor antagonist or combinations thereof. In some embodiments, the compound or salt described herein is administered with a PI3K5 inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK inhibitor. In some embodiments, the compound or salt described herein is administered with a JAKI or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor. In some embodiments, the compound or salt described herein is administered with an inhibitor of JAK1, which is selective rather than JAK2. Examples of antibodies for use in combination therapy include, but are not limited to, Trastuzumab (e.g., anti-HER2), Ranibizumab (e.g., anti-VEGF-A), Bevacizumab (trade name Avastin, e.g., anti- VEGF, Panitumumab (e.g., anti-EGFR), Cetuximab (e.g., anti-EGFR), Rituxan (anti-CD20), and antibodies targeting c-MET. One or more of the following agents may be used in combination with the compounds of the present description and are presented as a non-limiting list: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel , epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies against EGFR, GLEEVEC™ (imatinib mesylate) , intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormetine, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenediophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, citrabine, 6-mercaptopurine, 6- thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitomycin-C, Lasparaginase, teniposide, 17-alpha- ethinyl estradiol, diethylethylbestrol, testosterone, prednisone, phhioxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, IF-2019-19254930-APN-ANP#INpi Page 103 of 170 hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsaziin, procarbazine, mitoxantrone, levamisole, navel, anastrazole, letrazol, capecitabine, reloxafine, droloxafine, hexa methylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™ (tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa , altretamine, melphalan, trastuzumab, lerozole, fiilvestrant, exemestane, ifosfomide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, afidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Smll, fludarabine, pentostatin, triapine, didox , trimidox, amidox, 3-AP and MDL-101,731. The compounds of the present disclosure may additionally be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumor-directed therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include treatment with cytokines (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibodies, adoptive transfer of T cells, agonists of Toll receptor, STING agonists, oncolytic virotherapy and small immunomodulatory molecules, including thalidomide or JAK.1 / 2 inhibitor and the like. The compounds may be administered in combination with one or more anticancer drugs, such as chemotherapeutics. Examples of chemotherapeutic agents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi and bortezomib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladnbine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dro propionate mostanolone, eculizumab , epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, amide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, fenpropionate nandrolone, nelarabine, nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate, panitumumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, rucaparib, sorafenib, sunitinib maleate sunitinib, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, niraparib, veliparib, talazoparib and zoledronate. IF-2019-19254930-APN-ANP#fNpi Page 104 of 170 Additional examples of chemotherapeutics include proteasome inhibitors (e.g., bortezomib), thalidomide, revlimid and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine and the like. Examples of steroids include corticosteroids such as dexamethasone or prednisone. Examples of Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib and ponatinib, and pharmaceutically acceptable salts. Other examples of suitable Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species described in US Patent No. 5,521,184, WO 04 / 005281, and US Ser. United 60 / 578,491. Examples of suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and pharmaceutically acceptable salts thereof. Other examples of suitable Flt-3 inhibitors include compounds and their pharmaceutically acceptable salts, as described in WO 03 / 037347, WO 03 / 099771 and WO 04 / 046120. Examples of suitable RAF inhibitors include dabrafenib, sorafenib and vemurafenib, and pharmaceutically acceptable salts thereof. Other examples of suitable RAF inhibitors include compounds and their pharmaceutically acceptable salts, as described in WO 00 / 09495 and WO 05 / 028444. Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS6063, BI853520 and GSK2256098, and pharmaceutically acceptable salts thereof. Other examples of suitable FAK inhibitors include compounds and pharmaceutically acceptable salts thereof, as described in WO 04 / 080980, WO 04 / 056786, WO 03 / 024967, WO 01 / 064655, WO 00 / 053595 and WO 01 / 014402. In some embodiments, the compounds of the invention may be used in combination with one or more additional kinase inhibitors, including imatinib, particularly to treat patients resistant to imatinib or other kinase inhibitors. In some embodiments, the compounds of the invention may be used in combination with a chemotherapeutic agent in the treatment of cancer, and may improve the response to the treatment compared to the response to the chemotherapeutic agent alone, without exacerbating its toxic effects. In some embodiments, the compounds of the invention may be used in combination with the chemotherapeutic agent provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma may include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Additional agents used in the treatment of multiple myeloma include the Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In IF-2019-19254930-APN-ANP#INpi Page 105 of 170 some modalities, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). Additive or synergistic effects are desirable results of combining a PI3K inhibitor of the present disclosure with an additional agent. In some embodiments, the ΡΙ3Κγ inhibitors provided herein may be used in combination with one or more immune checkpoint inhibitors for the treatment of cancer as described herein. In one embodiment, the combination with one or more immune checkpoint inhibitors as described herein can be used for the treatment of melanoma. The compounds of the present disclosure may be used in combination with one or more immune checkpoint inhibitors. Illustrative immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1 , CD 137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT and VIEW. In some embodiments, the compounds of the description provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors. . In some embodiments, the PI3Ky inhibitors provided herein may be used in combination with one or more agonists of immune checkpoint molecules, for example, 0X40, CD27, 0X40, GITR and CD137 (also known as 4-1BB). In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. In some embodiments, the inhibitor of an immune checkpoint molecule is a PD-1 inhibitor, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®), pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122 or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab or pembrolizumab. In some embodiments, the anti-PDl antibody is MGA012. In some embodiments, the anti-PDl antibody is nivolumab. In some embodiments, the anti-PDl antibody is pembrolizumab. In some embodiments, the anti-PDl antibody is SHR-1210. Other anticancer agent(s) include antibody therapies such as 4-1BB (e.g., urelumab, utomilumab). IF-2019-19254930-APN-ANP#fNpi Page 106 of 170 In some embodiments, the inhibitor of an immune checkpoint molecule is a PD-L1 inhibitor, for example, an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A or MEDI4736. In some embodiments, the ΡΙ3Κγ inhibitors provided herein may be used alone, or in combination with an anti-PD-1, for the treatment of melanoma (PD-1 refractory), NSCLC (PD-1 refractory), HNSCC (PD-1 refractory), triple negative breast cancer (PD-1 naïve), mesothelioma, adrenocarcinoma, or high MDSC tumors. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, for example, an anti-PD-1 / PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 / PD-L1 is MCLA-136. In some embodiments, the inhibitor is MCLA-145. In some embodiments, the inhibitor of an immune checkpoint molecule is a CTLA-4 inhibitor, for example, an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab AGEN1884 or CP-675,206. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525 or INCAGN2385. In some embodiments, the inhibitor of an immune checkpoint molecule is a T1M3 inhibitor, for example, an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453 or TSR-022. In some embodiments, the inhibitor of an immune checkpoint molecule is a GITR inhibitor, for example, an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323 or MEDI1873. In some embodiments, the inhibitor of an immune checkpoint molecule is an 0X40 agonist, for example, 0X40 agonist antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383. In some embodiments, the inhibitor of an immune checkpoint molecule is a CD20 inhibitor, for example, an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab. The compounds of the present description can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets the PD-1, PD-L1, CTLA-4, GITR, 0X40, TIM3, LAG3, CD137, ICOS, CD3 or TGFp receptor. In some embodiments, the PI3K-gamma inhibitors provided herein may be used in combination with one or more metabolic enzyme inhibitors. In IF-2019-19254930-APN-ANP#INpi Page 107 of 170 In some embodiments, the metabolic enzyme inhibitor is an IDO1, TDO or arginase inhibitor. Examples of IDO1 inhibitors include epacadostat, BMS-986205, PF-06840003, IOM2983, RG-70099, LY338196, and NGL919. In some embodiments, the compounds of the disclosure may be used in combination with a JAK or ΡΙ3Κδ inhibitor. The agents may be combined with the present compound in a single or continuous dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms. The compounds of the present disclosure may be used in combination with one or more inhibitors or one or more therapies for the treatment of infections. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections. In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the compounds of the invention, where the dexamethasone is administered intermittently rather than continuously. The compounds of Formula (I) or any of the formulas as described in the present description, a compound as mentioned in any of the claims and in the present description, or salts thereof, can be combined with another immunogenic agent, such as cancer cells, purified tumor antigens (11 including recombinant proteins, peptides and carbohydrate molecules, cells and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of immoral vaccines that can be used include melanoma antigen peptides, such as gplOO peptides, MAGE, Trp-2, MARTI and / or tyrosinase antigens, or tumor cells transfected to express the cytokine GM-CSF. Compounds of Formula (I) or any of the formulas as described in the present description, a compound as mentioned in any of the claims and described in the present description, or salts thereof, can be used in combination with a protocol vaccination for cancer treatment. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as Human Papillomaviruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). , for its acronym in English). In some embodiments, the compounds of the present disclosure may be used in combination with a tumor-specific antigen such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, compounds of Formula (I) or any of the formulas as described in the present description, a compound as mentioned in any of the claims and described in the present description, or salts thereof, may be combined with immunization of dentic cells to activate potent antitumor responses. IF-2019-19254930-APN-ANP#fNpi Page 108 of 170 The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that direct effector cells expressing the Fe alpha or Fe gamma receptor to tumor cells. The compounds of the present description can also be combined with macrocyclic peptides that activate the immune response capacity of the host. In some additional embodiments, combinations of the compounds of the disclosure with other therapeutic agents may be administered to a patient before, during, and / or after a bone marrow transplant or a stem cell transplant. The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of a variety of tumors of hematopoietic origin. The compounds of Formula (I) or any of the formulas described in the present description, a compound as mentioned in any of the claims and in the present description, or salts thereof, can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, hepatitis (A, B and C), influenza, herpes, Giardia, malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa. Viruses that cause infections treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza virus, hepatitis A, B, C or D, adenovirus, poxvirus, herpes simplex virus, cytomegalovirus. human, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-Π and CMV, Epstein Barr virus), flavivirus, echovirus, rhinovirus , coxsackie virus, comovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus. Pathogenic bacteria that cause infections treatable by the methods of the disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, tetanus, botulism, anthrax, plague, leptospirosis and Lyme disease bacteria. Pathogenic fungi that cause infections treatable by the methods of the disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor , absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum. Pathogenic parasites that cause infections treatable by the methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambía, Cryptosporidium sp., Pneumocystis carinii, IF-2019-19254930-APN -ANP#INpi Page 109 of 170 Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi and Nippostrongylus brasiliensis. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, its administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in Physicians' Desk Reference (PDR, e.g. 1996 edition, Medical Economics Company, Montvale, NJ), the description of which is incorporated in its entirety herein by reference. . As provided throughout the description, additional compounds, inhibitors, agents, etc., may be combined with the present compound in a single or continuous dosage form, or may be administered simultaneously or sequentially as separate dosage forms. Pharmaceutical Formulations and Dosage Forms When used as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and on the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal administration), pulmonary (for example, by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal) , oral or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, for example, intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be, for example, by means of a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, aerosols, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. This description further includes pharmaceutical compositions containing, as the active ingredient, the compound of the description or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions of the disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Therefore, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, IF-2019-19254930-APN-ANP#fNpi Page 110 of 170 pads, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard capsules of gelatin, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, the active compound can be ground to provide the appropriate particle size before combining it with the other ingredients. If the active compound is substantially insoluble, it may be milled to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation. For example, approximately 40 mesh. The compounds of the invention can be milled by using known milling procedures such as wet milling to obtain a particle size appropriate for tableting and for other types of formulation. Finely divided preparations (nanoparticles) of the compounds of the disclosure can be prepared by processes known in the art, for example, see International Application No. WO 2002 / 000196. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying agents and suspending agents; preservative agents such as methyl and propylhydroxyl benzoates; sweetening agents; and flavoring agents. The compositions of the disclosure can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient using methods known in the art. The compositions may be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more generally, about 100 to about 500 mg, of the active ingredient. The term unit dosage forms refers to physically separate units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some embodiments, the compositions of the disclosure contain from about 5 to about 50 mg of the active ingredient. One skilled in the art will appreciate that this embodiment of compositions contain about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to IF-2019-19254930-APN-ANP#INPI Page 111 of 170 about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient. In some embodiments, the compositions of the disclosure contain from about 50 to about 500 mg of the active ingredient. One skilled in the art will appreciate that these embodiments of compositions contain about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to approximately 500 mg of the active ingredient. In some embodiments, the compositions of the disclosure contain from about 500 to about 1000 mg of the active ingredient. One skilled in the art will appreciate that these embodiments of compositions contain about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient. Similar dosages of the compounds described herein may be used in the methods and uses of the disclosure. The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound currently administered will generally be determined by a physician, in accordance with the relevant circumstances, including, the condition being treated, the route of administration chosen, the compound currently administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. For the preparation of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present description. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically equally uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. . This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from about 0.1 to about 1000 mg of the active ingredient of the present description. The tablets or pills of the present description may be coated or otherwise compounded to provide a dosage form that provides the advantage of a Page 112 of 170 prolonged action. For example, the tablet or pill may comprise an internal dosage and an external dosage component, the latter may be in the form of a shell over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or be delayed in release. For such enteric layers or coatings a variety of materials can be used, such materials include a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. Liquid forms into which the compounds and compositions of the present disclosure may be incorporated for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils such as seed oil. cotton, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions can be nebulized through the use of inert gases. Nebulized solutions can be inhaled directly from the nebulizer device or the nebulizer device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. The solution, suspension or powder compositions may be administered orally or nasally from devices that deliver the formulation in a suitable manner. Topical formulations may contain one or more conventional carriers. In some embodiments, the ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petroleum jelly, and the like. Cream carrier compositions may be based on water in combination with glycerol and one or more other components, for example, glycerol monostearate, PEG-glycerol monostearate and cetylstearyl alcohol. The gels may be formulated through the use of isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of the compound. the description. Topical formulations may be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the selected indication, for example psoriasis or other skin condition. IF-2019-19254930-APN-ANP#|Npi Page 113 of 170 The amount of compound or composition administered to a patient will vary depending on what is administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the mode of administration, and the like. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as the judgment of the physician treating the patient depending on factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. . The compositions administered to a patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterilized by filtration. Aqueous solutions can be packaged for use as such, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier before administration. The pH of compound preparations will typically be between 3 and 11, most preferably 5 to 9 and most preferably 7 to 8. It should be understood that the use of certain excipients, carriers or stabilizers above will result in the formation of pharmaceutical salts. The therapeutic dosage of a compound of the present description may vary according to, for example, the particular use for which the treatment is made, the method of administration of the compound, the health and condition of the patient, and the judgment of the physician who administers the compound. prescribes. The proportion or concentration of a compound of the disclosure in a pharmaceutical composition may vary depending on a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the invention may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 pg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage is likely to depend on variables such as the type and degree of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. The compositions of the invention may further include one or more additional pharmaceutical agents such as a chemotherapeutic, a steroid, an anti-inflammatory compound, or an immunosuppressant, examples of which are listed herein. Labeled Compounds and Test Methods Another aspect of the present description is related to the labeled compounds of the description (radiolabeled, fluorescently labeled, etc.) that would be useful not only in IF-2019-19254930-APN-ANP#INpi Page 114 of 170 imaging techniques, but also in assays, both in vitro and in vivo, to localize and quantify PI3K in tissue samples, including humans, and to identify PI3K ligands by inhibiting the binding of a marked compound. The substitution of one or more of the atoms of the compounds of the present description may also be useful in the generation of differentiated ADME (adsorpt...

Claims

1. A compound characterized in that it is of Formula (I): FORMULA 1, or a pharmaceutically acceptable salt thereof; wherein: X1 is N; R2 is C(O)NR c1 R d1; R3, R4 and R5 are each independently selected from H and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by 1, 2 or 3 D; R6, R7 and R8 are each independently selected from H, D, C1-6 alkyl and C1-6 haloalkyl; each Rc1 and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-10 cycloalkyl and 5-6 membered heterocycloalkyl of Rc1 and Rd1 are each optionally substituted with 1, 2 or 3 independently selected RA substituents; or, Rc1 and Rd1, together with the N atom to which they are attached, form a 5 membered heterocycloalkyl group, wherein the 5 membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RA substituents;Each RA is independently selected from C1-6 alkyl, C1-6 haloalkyl, wherein the C1-6 alkyl of RA is optionally substituted with 1, 2 or 3 independently selected RD substituents; each R a4 is H; each RD is OR a5; and each R a5 is H. 55 Claims follow;