AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS

Abstract

This application relates to compounds of Formula (I): NR3 NH2 R4 X 1 R2 R5 HO R6 HO R7 R8 (I) or pharmaceutically acceptable salts thereof, which are inhibitors of PI3K-y which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. 20 24 20 39 16 07 J un 2 02 4 A B S T R A C T 0 7 J u n 2 0 2 4 X H O 2 0 2 4 2 0 3 9 1 6

Description

The present Application is a Divisional Application from Australian Patent Application No. 2019272342. The entire disclosures of Australian Patent Application No. 2019272342 and its corresponding International Patent Application No. PCT / US2019 / 021186 are incorporated herein by 5 reference. The Application claims priority to US 62 / 640,276 filed on 8 March 2018, US 62 / 702,230 filed on 23 July 2018, and US 62 / 745,873 filed on 15 October 2018, which are herein incorporated by reference in their entirety. TECHNICAL FIELD The present invention provides aminopyrazine diol compounds that modulate the activity of phosphoinositide 3-kinases-gamma (P13Ky) and are useful in the treatment of diseases related to the activity of P13Ky including, for example, autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. BACKGROUND The phosphoinositide 3-kinases (P13Ks) belong to a large family of lipid signaling kinases 15 that phosphorylate phosphoinositides at the D3 position of the inositol ring (Cantley, Science, 2002, 296(5573):1655-7). P13Ks are divided into three classes (class 1,11, and 111) according to their structure, regulation and substrate specificity. Class 1 P13Ks, which include P13Ka, PI3K0, P13Ky, and P13K5, are a family of dual specificity lipid and protein kinases that catalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate (PIP2) giving rise to phosphatidylinosito-3,4,5-trisphosphate 20      (PIP3). PIP3 functions as a second messenger that controls a number of cellular processes, including growth, survival, adhesion and migration. All four class 1 P13K isoforms exist as heterodimers composed of a catalytic subunit (pl 10) and a tightly associated regulatory subunit that controls their expression, activation, and subcellular localization. P13Ka, P13K0, and P13K5 associate with a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine 25 kinase-dependent mechanism (Jimenez, et al., J Biol Chern., 2002, 277(44):41556-62) whereas P13Ky associates with two regulatory subunits (p 101 and p84) and its activation is driven by the activation of G-protein-coupled receptors (Brock, et al., J Cell Biol., 2003, 160(1):89-99). P13Ka and P13KP are ubiquitously expressed. In contrast, P13Ky and P13K5 are predominantly expressed in leukocytes (Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204). 30             Expression of P13Ky is mainly restricted to hematopoietic system, although it can be also detected at lower level in endothelium, heart and brain. P13Ky knock-out or kinase dead knock in mice are normal and fertile and do not present any overt adverse phenotypes. Analysis at the cellular level indicates that P13Ky is required for GPCR ligand-induced PtdlNs (3,4,5)P3 production, chemotaxis and respiratory burst in neutrophils. P13Ky-null macrophages and dendritic cell exhibit 2024203916   07 Jun 2024 reduced migration towards various chemoattractants. T-cells deficient in P13Ky show impaired cytokine production in response to anti-CD3 or Con A stimulation. P13Ky working downstream of adenosine A3A receptor is critical for sustained 2024203916   07 Jun 2024 degranulation of mast cells induced by FCsRI cross-linking with IgE. PI3Ky is also essential for 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 P13Ky in various autoimmune and inflammatory disease models has been investigated with genetic 5 and pharmacological tools. In asthma and allergy models, PI3Ky' / _ mice or mice treated with PI3Ky inhibitor showed a defective capacity to mount contact hypersensitivity and delayed-■ypc hypersensitivity reactions. In these models, PI3Ky was shown to be important for recruitment of neutrophils and eosinopohils to airways and degranulation of mast cells (see e.g. Laffargue et al., Immunity, 2002, 16, 441-451; Prete et al., The EMBO Journal, 2004, 23, 10      3505-3515; Pinho et al., L. Leukocyte Biology, 2005, 77, 800-810; Thomas et al., Eur. J. Immunol. 2005, 35, 1283-1291; Doukas et al., J. Pharmacol. Exp Ther. 2009, 328, 758-765). In two different acute pancreatitis models, genetic ablation of PI3Ky significantly reduced the extent of acinar cell injury / necrosis and neutrophil infiltration without any impact on secretive function of isolated pancreatic acini (Lupia et al., Am. J. Pathology, 2004,165, 15      2003-2011). PI3Ky''' mice were largely protected in four different models of rheumatoid arthritis (CIA, a-CII-IA, K / BxN serum transfer and TNF transgenic) and PI3Ky inhibition suppressed the progression of joint inflammation and damage in the CIA and a-CII-IA models (see e.g., Camps et al., Nat. Medicine, 2005, 11, 939-943; Randis et al., Eur. J. Immunol, 2008, 38, 1215-1224; Hay er et al., FASBJ., 2009, 4288-4298). In the MRL- / / >r 20 mouse model of human systemic lupus erythematous, inhibition of PI3Ky reduced glomerulonephritis and prolonged life span (Barber et al., Nat. Medicine, 2005, 9, 933-935). There is evidence suggesting that chronic inflammation due to infiltration by myeloid-derived cells is a key component in the progression of neurodegeneration diseases, such as Alzheimer’s disease (AD) (Giri et al., Am. J. Physiol. Cell Physiol., 2005, 289, C264-25      C276; El Khoury et al., Nat. Med., 2007, 13, 432-438). In line with this suggestion, PI3Ky inhibition was shown to attenuate Ap(l-40)-induced accumulation of activated astrocytes and microglia in the hippocampus and prevent the peptide-induced congnitive deficits and synaptic dysfunction in a mouse model of AD (Passos et al., Brain Behav. Immun. 2010, 24, 493-501). PI3Ky deficiency or inhibition also was shown to delay onset and alleviate 30 symptoms in experimental autoimmune encephalomyelitis in mice, a mouse model of human multiple sclerosis, which is another form of neurodegeneration disease (see e.g, Rodrigues et al., J. Neuroimmtmol. 2010, 222, 90-94; Berod et al., Euro. J. Immunol. 2011, 41, 833-844; Comerford et al., PLOSone, 2012, 7, e45095; Li et al., Neuroscience, 2013, 253, 89-99). Chronic inflammation has been formally recognized as one of the hallmarks for many 35 different types of cancers. Accordingly, selective anti-inflammatory drugs represent a novel 2024203916   07 Jun 2024 class of anti-cancer therapies (Hanahan and Weinberg. Cell, 2011, 144, 646-674). Since PI3Ky is reported to mediate various inflammatory processes, its role as an immune oncology target has also been investigated. A recent study reported that PI3Ky deficiency suppressed tumor growth in the syngeneic models of lung cancer, pancreatic cancer and melanoma (LLC, 5 PAN02 and Bl6). PI3Ky deficiency or inhibition also inhibited tumor growth in a spontaneous breast cancer model (Schmid et al., Cancer Cell, 2011, 19, 715-727). A further study reported that PI3Ky deficiency could ameliorate inflammation and tumor growth in mice having colitis-associated coion cancer, (Gonzalez-Garcia et al., Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic analysis indicates that tmnor infiltration by CD1 lb+ 10 myeloid cells can cause protumorigenic inflammation at tumor sites and PI3Ky in the myeloid cells is critical in mediating signaling of various chemoattractants in bring the ceils to the tumor (Schmid et al., Cancer Cell, 2011, 19, 715-727). Other studies suggest that PI3Ky is also required for differentiation of naive myeloid cells into M2, macrophges at tumor sites. M2, macrophages promote tumor growth and progression by secreting immunosuppressive factors 15 such arginase 1, which depletes the tumor microenvironment of arginine, thereby promoting T-cell death and NK cell inhibition (Schmidt et al,, Cancer Res. 2012, 72 (Suppl 1: Abstract, 411; Kaneda et al.. Cancer Res., 74 (Suppl 19: Abstact 3650)). In addition to its potential role in promoting protumorigenic microenvironment, PI3Ky may play a direct role in cancer cells. PI3Ky is reported to be required for signaling 20 from the Kaposi’s sarcoma-associated herpevirus encoded vGPCR oncogene and tumor growth in a mouse model of sarcoma (Martin et al., Cancer Cell, 2011, 19, 805-813). P13Ky was also suggested to be required for growth of T-ALL (Subramanjam et al., Cancer Cell, 2012, 21, 459-472), PDAC and HCC cells (Falasca and Maffucci, Frontiers in Physiology, 2014, 5, 1 -10). Moreover, in a survey of driver mutations in pancreatic cancer, PI3Ky gene 25 was found to contain second highest scoring predicted driven mutation (R839C) among the set of genes not previously identified as a driver in pancreatic cancer (Carter et al., Cancer Biol. Ther. 2,010,10, 582-587). Finally, PI3Ky deficiency also has been reported to offer protection to experimental animals in different cardiovascular disease models. For examples, lack of PI3Ky would 30 reduce angiotension-evoked smooth muscle contraction and, therefore, protect mice from angiotension-induced hypertension (Vecchione et al., J. Exp. Med. 2005, 201, 1217-1228). In rigorous animal myocardial infarction models, PI3Ky inhibition provided potent cardioprotection, reducing infarct development and preserving myocardial function (Doukas etaLProc. Natl. Acad. Set. USA, 2006, 103, 19866-19871). 2024203916   07 Jun 2024 For these reasons, there is a need to develop new PI3Ky 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 need and others, SUMMARY 5             The present invention relates to, inter alia, compounds of Formula (I): or pharmaceutically acceptable salts thereof, wherein 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 10 pharmaceutically acceptable carrier. The present invention further provides methods of inhibiting an activity’ of PI3Ky kinase 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 a disorder 15      associated with abnormal PI3Ky kinase expression or activity 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. 20             The present invention further provides 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 Compounds 25             The present application provides, inter alia, compounds of Formula (I): R8                         (I) 2024203916   07 Jun 2024 or a pharmaceutically acceptable salt thereof; wherein: X! is N or CR1; R1 is selected from H, D, halo, Cm alkyd, Cm alkoxy, C2< alkenyl, C2-6 alkynyl, Cm haloalky 1, Ci-6 haloalkoxy, CN, OH, andNH2; 5             R2 is selected from H, D, halo, Cm alkyl, CMhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, Cy-Cm alkyl-, CN, NO2, ORaI, SRa!, NHORal, C(O)Rb!, C(O)NRCIRdl, C(O)NRe!(ORal), C(O)OR3i, OC(O)Rb!, OC(O)NRciRdi, NRclRdl, NR 'NR ;R". NRciC(O)Rb:i, NRc!C(O)ORal, NRclC(O)NRclRdl, C(=NRei)RbI, C(=NOH)Rbl, C(=NCN)RbI, C(=NRel)NRCIRdl, NRclC(-NRei)NRclRds,NRciC(=NOH)NRcSRds,NRciC(-NCN)NRc!Rd!,NRclCe=NRei)Rbl, 10      NR'S(O)NR‘:iRd\ NRc!S(O)Rbl, NRclS(O)2Rb5, \R':SsO)( \R' : ;R 1. NRc 1 S((d)2NRc 1 Rd’, S(O)Rbl, S(O)NRciRdi, S(O)2Rbi, S(O)2NRciRdi, OS(O)(=NRel)Rbl, OS(O)2Rbl, SF5, P(O)RI!Rs!, OP(O)(ORhl)(ORli), P(O)(ORh’)(ORi!), and BR IVwherein the Cm alkyl, C2-6 alkenyl, and C2-s alkynyl of R2 are each optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; 15             Cy is selected from (N-u and, C3- 14cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocvcloalkyl, each of which are 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, CN, OH, Cm alkyl, Ci-6haloalky 1, C2-6 alkenyl, C2-s alkynyl, Cm alkoxy, Ci-6haloalkoxy, cyano-CM alkyl, HO-20 Cm alkyl, Cm alkoxy-Cm alkyl, C3-6 cycloalkyl, amino, Cm alkylamino, di(CMalkyl)amino, and C(O)NRcRd, wherein the Cm alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; R6, R7 and R8 are each independently selected from H, D, Cm alkyl, Cm haloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C&-io ary 1-Cm alkyl-, C3-10cycloalkyl-CMalkyl-, (5-10 membered 25 heteroaryl)-CMalkyl-, (4-10 membered heterocycloalkyl)-CMalkyl-, C(O)Rb3, C(O)NRCJRdJ, CtOtNR3(ORa3), CtOORC C(=NR;:)R'3, C(=NOH)Rb3, Ct NCN ;R' . and C(=NRs3)NR“Rd3, wherein the Cm. alkyl, C2-6 alkenyl, C2-6 alkynyl, C&.10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aiyl-CM alky 1-, C3.10cycloalkyl-CM alky 1-, (5-10 membered heteroaryl)-CM alkyl-, and (4-10 membered 30      heterocycloalkyl)-Cmalkyl- of R6, R', and R8 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; and wherein the Cm haloalky 1 of R6, R' , or R8 is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, Cm alkyl, and Cm haloalky 1; 2024203916   07 Jun 2024 or Rb and R7 substituents, together with the ring atoms to which they are attached, form a C3..10 cycloalky 1 or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; or R7 and R8 substituents, together with the ring atoms to which they are attached, 5 form a C3-10 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Rc and R“ are each independently selected from H, Cpe, alkyl, Cm haloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cs-w ary l, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-C 1«alkyl-, C3.7cycloalky 1-C«alkyl-, (5-10 membered 10 heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C m alky 1-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C>-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-e alkyl-, (5-10 membered heteroand)-C 1-6 alkyl-, and (4-10 membered beterocycloalkyl)-C [-6 alkyl- of Rc and Rd, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; 15             each Ral, Rbi, Rc!, and Rai is independently selected from H, Cw alkyd, Cw haloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C&-io ary 1-Cm alkyl-, C3-10cycloalkyl-Cm alkyl-, (5-10 membered heteroaryl)-C-6 alkyl-, and (4-10 membered heterocycloalkyl)-Cj^ alkyl-, wherein the Cj^ alkyl, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 20 membered heterocvcloalkyl, C6-io aryl-C-ealkyd-, C3-10cycloalkyd-C 1-6 alkyd-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6alkyl- of Ral, RD1, Rci, and Rd!, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any Rci and attached to the same N atom, together with the N atom to which 25 they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocvcloalkyl 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 RA substituents; each Rel is independently selected from H, OH, CN, C1..6 alkyl, C1..6 alkoxy, Ci« 30 haloalky1, C^haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cft-so aryl, Cmo cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered hetereocycloalkyl, Ceuo ary 1-C1-6 alkyl-, C3.10 cycloalkyl-Cmalkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocy cloalky 1)-C 1 -s alky' 1-; each Rn and R8i is independently selected from H, Cm alkyl, Cm alkoxy, Cm 35 haloalkyl, Cm haloalkoxy', C2-6 alkenyl, Cm alkynyl, Cs-io aryl, €3-10 cycloalkyl, 5-10 2024203916   07 Jun 2024 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cg-io ary 1-Ci-g alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaiyl)-Ci.6 alkyl-, and (4-10 membered hetereocycloalkyl)-Cj-6 alkyl-; each Rhl and R1! is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 5 alkenyl, C2-6 alkynyl, Cwo aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cmo aryl-Cw alkyl-, C3-10 cycloalkyl-Cwalkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C]^ alkyl-; each Rjl and RKi is independently' selected from OH, Ci-g alkoxy, and Cj^haloalkoxy; or any Rji and Rkl attached to the same B atom, together with the B atom to which 10 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 Cm haloalky 1; each R3’, Rb3, Rc3, and R3’ is independently selected from H, C« alkyl, Chaloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cg-w ary l, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io ary 1-Ci-e alkyl-, C3-10cycloalkyl-Ci^alkyl-, (5-10 membered 15     heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C)^alkyl-, wherein the Ci-g alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryI-Ci-6 alkyl-, C3-10cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Cj.galkyl- of Ra3, Rbj, Rc3, and Rli3 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R" 20 substituents; or, any Rc3 and R“’, 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 25 selected RB substituents; each R63 is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci^ haloalkyl, C]-g haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cmd aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cg-w aiyl-Ci-g alkyl-, C3-10 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-g alkyl-, and (4-10 membered 30      hetereocycloalkyl)-Ci-6 alkyd-; each RA is independently selected from D, halo, Ci..g alkyl, Ci-g haloalkyl, C2.6 alkenyl, C2-6 alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-w aiyl-Ci^alkyl-, C3-7cycloalkyl-Ci-g alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, (4-10 membered heterocycioalkyl)-C«alkyl-, CN, NO2, ORa4, SR*4, 35 NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRC4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, 2024203916   07 Jun 2024 NR^4, NRc4NRc4Rd4, NRc4C(O)RM, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRs4)Rb4, C(==NOH)RM, C(==NCN)Rm Ct XR?iiXR'R18. XR 'C; XR:i'\R'Or) XRd) XRdlw NRc4C(=NOH)NRc4Rd4, NRc4C^          NRc4S(O)Rb4, NR^SONR^R134, NRc4S(O)2RM, NR"S(O)2NRc4Rd\ S(O)RM, S(OiNR"R34. S(O)2RM, S(O)2NRc4Rd4, 5 OS(O)(-NRe4)RM, OS(O)2Rb4, SF5, P(O)Rf4Rg4, 0P(0)(0RM)(0R14), P(O)(ORh4)(ORi4), and BRj4Rk4, wherein the Cm alkyl, C2-6 alkenyl, C2^ alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl. Cmo ary 1-Cmalkyl-, C3-7 cycloalkyl-Ci-salkyl-, (5-10 membered beteroaryl)-C 1-6alkyl-, and (4-10 membered beterocycloalkyl)-Ci-6 alkyl- of Ra is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD 10 substituents; each R13 is independently selected from D, halo, Ci^ alkyl, C1-6 haloalky 1, C2.e alkenyl, C2^, alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-to aryl-C)^ alkyl-, C3-7 cycloalky 1-Cw alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, (4-10 membered heterocycloalkyl)-C«alkyl-, CN, NO2, ORa2, SR32, 15 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, NR‘ 'C(O)OR'\ XiV GOiXR' R1 ’. Cf X R W". C(=NOH)Rb2, C(=NCN)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRe2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)2Rb2, X R3 ’StO) -X R Rd ’. S(O)Rb2, S(O)NRc2Rd2, S(O) Rb2, S(O)2NRc2Rd2, 20 OS(O)(=NRe2)Rb2. OS(O)2Rb2, SF5, P(O)Rf2R®2, OP(O)(OR112)(ORi2), P(O)(ORh2)(OR12), and BRl2Rk2, wherein the C1-6 alkyl, C2-s alkenyl, C2.s alkynyl, Ce-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-C walkyl-, C3-7 cycloalky 1-C1-6 alkyl-, (5-10 membered heteroaiy l)-Cj-6alkyl-, and (4-10 membered heterocycloalkyl)-Cj. 6 alkyl- of Rb is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM 25 substituents; each R3 / , Rb2, Rc2, and Rd2 is independently selected from H, Ci^ alkyl, C1-6 haloalkv 1, C2-6 alkenyl, C2-& alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky l)-Ci-6 alkyl-, wherein the Ci-6 30 alkyl, C2-6 alkenyl, C2-6 alkynyl, C&-w aryl, C3-7cycloalkyd, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C&-io ary 1-C« alkyl-,    cycloalkyl-Ci.6 alkyl-, (5-10 membered heteroaryl)-Ci^ alkyl-, and (4-10 membered heterocycloalkyl)-Ci^ 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; 2024203916   07 Jun 2024 or, any Rc2 and R“2 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 5 selected RM substituents; each Re / is independently selected from H, OH, CN, C.-6 alkyl, Ci-6 alkoxy, Ci-s haloalkyl, Ci^haloalkoxy, C2-6 alkenyl. C2-6 alkynyl, Cmd aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-k> ary l-Cj^alkyd-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered 10 hetereocycloalkyI)-Cj-6 alkyl-; each Re and Rg2 is independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci^ haloalkyl, C1-6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cs-io aiyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aryl-C 1-6 alkyl-, C3-7 cycloalky 1-C1..6alky 1-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered 15 hetereocycloalkyl)-C 1-6 alkyl-; each R112 and R’z is independently selected from H, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C&-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io ary l-Cj^alkyd-, C3-7 cycloalky 1-C [-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-Ci^ alkyl-; 20             each Rj2 and R',! is independently selected from OH, C]-&alkoxy, and C1-6 haloalkoxy; or any R'2 and RK 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 6¼ alky l and Ci-6haloalkyl; each Ra4, Rb4, Rc4, and Ra4 is independently selected from H, Ci..& alkyl, C 1..6haloalkyl, 25      C2-6 alkenyl, C2-s alkynyl, C&-W aryl, C3-7 cycloalkyl, 5-10 membered heteroary l, 4-10 membered heterocvcloalkyl, C6-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroand)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-ao atyl-C.-s alkyl-, C3-7 cycloalkyl-Ci-ealkyl-, (5-10 membered 30 heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R!) substituents; or, any Rc4 and Ra4 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 35 heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered 2024203916   07 Jun 2024 heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Ru substituents; each Re4 is independently selected from H, OH, CN, alkyl, alkoxy, C)^ haloalky 1, Cmhaloalkoxy, C2-6 alkenyl, C2< alkynyl, Cs-w aryl, C3-7 cycloalkyl, 5-10 5 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aiyl-Ci^, alkyl-, C3-7 cycloalkyl-Ci-ealkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyI)-C]-6 alkyl-; each Rf+ and Rs4 is independently selected from H, Cw alkyl, Cw alkoxy, C)^ haloalkyl, Ci-ehaloalkoxy, Cz-6 alkenyl, C2.6 alkynyl, Cs-io aryl, C3.7 cycloalkyl, 5-10 10 membered heteroaiyl, 4-10 membered hetereocy cloalkyl, C&-io aryl-Ci-6 alky 1-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-C 1-6alkyl-, and (4-10 membered hetereocy cloalky 1)-C 1-6 alky 1-; each Rh+ and R14 is independently selected from H, Cj^ alkyd, Cj.* haloalkyl, C2-6 alkenyl, C2.6 alkynyl, Cs-io ary l, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered 15 hetereocycloalkyl, Cs-io ary l-Cj^alkyd-, C3-7cycloalky 1-C[-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-Cj-6alkyl-; each R / 4 and Rk4 is independently selected from OH, Ci^alkoxy, and Ci-g haloalkoxy; or any 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 20 with 1, 2, 3, or 4 substituents independently selected from Cj-s alkyd and C)^haloalkyl; each Rd is independently selected from H, D, halo, Cm alkyl, Cm haloalkyl, C2-6 alkenyl, Cz^, alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci^alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, (4-10 membered heterocycloalkyl)-CiMalkyl-, CN, NO2, ORa5, SR3", 25 NHORa5, C(O)Rb5, C(O)NR R3". CiOtXR'dOR'"). C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NR=5NRc5Rd5> NRc5C(O)Rb5, NRc5C(O)OR35, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C( XOH jR3'. C(=NCN)Rb5, O NR 'iC NRo5C(=NRe5)NRc5Rd5, X iCX s X R3' X.b\ MVC( X()n!.\R''R:'. XIC'G XCXk\R'4Cb XR3N(()^ NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, StOiXR 'IC'. St ()) R X S(O)2NIOC 30 OS(OX=NRe5)Rb5, OS(O)2Rb5, SF5, PiOdX R OPCOXOR^OR15), P^XOR^XOR*), and BRJ’Rk’, wherein the C1..6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg.io aryl, C3.7 cycloalkyl, 5-10 membered heteroary l, 4-10 membered heterocycloalkyl, Cwo atyd-C alkyl-, C3-7 cy cloalky 1-C1-6alkyl-, (5-10 membered heteroaiyl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-Cj-6 alkyl- of Rd are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently 35 selected Re substituents; 2024203916   07 Jun 2024 each R35, Rfc5. Rc3, and Ra:' is independently selected from H, Ci^ alkyl. Ci^ haloalkyl, alkenyl, alkynyl, (Xio aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocvcloalkyl, Cs-.o aryl-CXs alkyl-, Cs-vcycloalkyl-Ci^ alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-C1-6 alkyl-, wherein the Ci-6 5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cwo aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocvcloalkyl, Cg-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl- of R3i, RX R05, and Rd' are each optional!}' substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independent!}' selected R: substituents; 10             or, any R05 and R® 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 heterocvcloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R" substituents; 15            each R" is independently selected from H, OH, CN, Cm alkyl, Cw alkoxy, Cb6 haloalkyl, Ci-6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered hetereocycloalkyl, C&-io aryl-Ci-6alkyl-, C3-7 cycloalkyl-C^ alkyl-, (5-10 membered heteroaryl)-C[-6 alkyl-, and (4-10 membered hetereocy cloalkyl)-Ci-6 alky 1-; 20             each Rb and Rg5 is independently selected from H, (Xs alkyl, C)-& alkoxy, (Xs haloalkyl, Ci^haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, CX10 aryl, C3-7 cycloalkvl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, CXw aiyl-Ci^ alkyd-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryd)-Ci-6 alkyl-, and (4-10 membered hetereocy cloalky l)-Ci-6 alkyl-; 25             each Rto and R15 is independently selected from H, Ci^ alkyd, C1-6 haloalkyl, C2-6 alkenyl, (Xs alkynyl, CX10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered hetereocycloalkyl, C&-io aryl-Ci-6alky!-, C3-7cycloalky 1-CWalkyd-, (5-10 membered heteroaryl)-Cj-6alkyl-, and (4-10 membered hetereocycloalkyl)-Ci-6 alkyl-; each Rj5 and RB' is independently selected from OH, Ci-6alkoxy, and Ci-e haloalkoxy; 30             or any 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 C1-6haloalkyl; each Rfc is independently selected from H, D, halo, alkyl, (Xs haloalkyl, C2-6 alkenyl, C2.S alkynyl, (X10 aryl, C3-7cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered 35 heterocycloalkyl, Cs-w aryl-Ci-6 alkyl-, C3-7 cycloalkyl-C)^ alkyl-, (5-10 membered 2024203916   07 Jun 2024 heteroaryl)-Cj-6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, ORab, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRcSRds, NRc6Rd6, XR'P RM NRcSC(O)RbS, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(==NRe6)Rbb, C(===NOH)Rb5, C(-NCN)Rb6s C(==NRs6)NRc6Rd6, XkT( 5 NR^CC^NR^Rh6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6, XR : St())Rb\ NR^S^NR^6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rbt S(O)NRc5Rd5, S(O)2Rc6, S(O)2NRc6Rd6, 08(0)(=-NRe6)Rbs, OS(O);R!". SR PiOMM OIWhOR ROR : r P(O)(ORhS)(OR16), and BRj6Rk6, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6 10 alkyl-, C3-7 cycloalkyl-C alkyl-, (5-10 membered heteroaryl)-Ci-6alky 1-, and (4-10 membered heterocycloalkyl)-C 1-6alkyl- of Rb are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Ru substituents; each RaS, Rb6, Rc6, and R“s is independently selected from H, C)-& alkyl, C)-&haloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 15 membered heterocycloalkyl, Cr-jo atyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci^alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci^ alkyl-, wherein the Cu alkyl, C2-6 alkenyl, C2-6 alkynyl, C&-]o aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cr-jo atyl-Ci-6 alkyl-, C3-7 cycloalkyl-C]^alkyl-, (5-10 membered heteroaryl)-Ci.R alkyl-, and (4-10 membered heterocycloalky 1)-C 1.6 alkyl- of Ra6, Rbs, RcS, and 20 Rdb are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R& substituents; or, any RcS and RaS attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryi or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered 25 heterocycloalkyl group is optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, Cw alkyl, Cw alkoxy, Ci-& haloalkyl, Ci^haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-7 cycloalkvl, 5-10 membered heteroaryi, 4-10 membered hetereocycloalkyl, Cs-io ary 1-Ci.r alkyl-, C3..7 30      cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-C]-6alkyl-, and (4-10 membered hetereocycloalky 1)-C].r alkyl-; each Rf6 and Rg6 is independently selected from H, C1-6 alkyl, Cwalkoxy, Ci-& haloalkyl, Ci^haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryi, 4-10 membered hetereocycloalkyl, Ceuo aryl-Ci-6alkyl-, C3.7 2024203916   07 Jun 2024 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocy cloalkyl)-Ci-6 alky 1-; each Rhs and R16 is independently selected from H, Cj^ alkyd, Cj.* haioalkyl, C2-6 alkenyl, C2.6 alkynyi, Cs-io ary l, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered 5 hetereocycloalkyl, Cmo ary 1-Ci^ alkyl-, C3-7 cycloalky 1-Cusalkyl-, (5-10 membered heteroaryi)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-Cj-6alkyl-; each RjD and R*6 is independently selected from OH, C^alkoxy, and C1-6 haloalkoxy; or any RJb and Rks 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 10 with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and Ci^ haioalkyl; each R& is independently selected from H, D, halo, CN, NO2, SF5, C1-6 alkyl, C1-6 alkoxy, Ci^haloalkyl, C2-6 alkenyl, C2-6 alkynyi, Cs-jo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-C1-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl; and 15             each Rm is independently selected from H, D, OH, NO2, CN, halo, Ci-6 alkyd, C2-6 alkenyl, C2-6 alkynyi, Cj-6 haioalkyl, cyano-Cj-6 alkyl, HO-C« alkyd, alkoxy-Cj-6 alkyl, Co-jo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyl-, C3-7cycloalkyl-Ci-6alkyd-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl, Ci-6 alkoxy, Ci..& haloalkoxy, amino, Ci^ alkylamino, 20 di(C)-6alkyd)ainino, thio, Cj^ alkylthio, C]< alkyl sulfinyl, Cj-6 alkylsulfonyl, carbamyl, Ci^ alkylcarbamyl, di(Ci^ aikyi)carbamyl, carboxy, Cm alkylcarbonyl, Cm alkoxycarbonyl, Ci^ alkylcarbonylamino, Ci-s alkylsulfonylamino, aminosulfonyl, C]-6alkylaminosulfonyl, di(Ci-6 alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbony lamino, C1-6 alkylaminocarbonylamino, and di(Ci-6 25 alkyl)aminocarbonylamino. In some embodiments: X' is N or CR5; R! is selected from H, D, halo, Cw alkyl, Cw alkoxy, C2-6 alkenyl, C2-6 alkynyi, Cjm haioalkyl, Ci-ehaloalkoxy, CN, OH, and NH2; 30              R2 is selected from H, D, halo, Cj^ alkyd, Ci-6 haioalkyl, C2-6 alkenyl, C2.6 alkyny i, Cy, Cy-Cwalkyl-, CN, NO2, ORai, SRal, NHORaI, C(O)Rbl, C(O)NRciRd!, C(O)NRcl(ORa!), C(O)OR31, OCtOdCk OC(O)NR'd^. NRciRdi, NR' NIC^R^, NRC1C(O)RW, XR':(iOiORJ XR^CtONR 'dC1, (4 XR :!Rh. C( XOH)Rbi. C( XCX !RH. C( XR':)XR;:RJI, NRt!CCNRb\iXRdRJL NR!jCNXOHbNRldRJL NR-CNXCNiNR^RtC NR:JC(-NRb!iRN. 35 NRciS(O)NRc!Rd!, NRciS(O)Rbi, NRciS(O)2Rb!, NRc!S(O)(=NRe!)Rb!, XR-'SsOjNR-'k!l. 2024203916   07 Jun 2024 S(O)Rbi, S(O)NRC*Rdi, S(O)2Rbl, S(O)2NRc!Rd!, 08(0)(=^)1^, OS(O)2Rbl, SF5, P(O)Rf!Rg!, OP(O)(ORhl)(ORi). P(O)(ORhl)(ORu), and BRjlRkl, wherein the Cw alkyl, C2-6 alkenyl, and C2.s alkynyl of R2 are each optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; 5             Cy is selected from C&.M and, C3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocvcloalkyl, each of which are 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, CN, OH, C).& alkyl, Ci<haloalky 1, C2-6 alkenyl, C2-6 alkynyl, 0¼ alkoxy, C-.6haloalkoxy, cyano-Ci-6 alkyl, HO- 10      C1-6 alkyl, C1-6 alkoxy-C  alkyl, C3-6 cycloalkyl, amino, C1-6 alkylainino, di(C 1 -&alkyl)amino, and C(O)NRCR“, wherein said Cw alkyl can be optionally substituted bv 1, 2, 3, 4, 5, or 6 D; R6, R'' and R8 are each independently selected from H, D, Cm alkyl, C.-6haloalky 1, C2-6 alkenyl, C2-6 alkynyl, CY-io ary l, C3-10 cycloalkyl, 5-10 membered heteroaryd, 4-10 membered heterocycloalkyl, C&-io ary 1-Ci-e alkyl-, C3-10cycloalkyl-Ci-6alkyl-, (5-10 membered 15 heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-C]-6 alkyl-, C(O)Rb3, C(O)NRCJRdJ, C(O)NRc3(ORa3), C(O)ORa3, C(=NRe3)Rb3, C(=NOH)Rb3, C(=NCN)Rb3, and C(=NRe3)NRc3Rd3, wherein the Ci-& alkyl, C2-& alkenyl, C2-6 alkynyl, Cg-io aryl, C3-10 cycloalkyd, 5-10 membered heteroaryd, 4-10 membered heterocycloalkyd, Ce-io aryd-Cj^alkyd-, C3.10cycloalkyl-Ci.6 alky 1-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered 20      heterocycloalkyd)-C 1-6alkyl- of R6, R', and R8 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; and wherein said Ci^haloalkyl of R6, R', or R8 is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, C1-6 alkyl, and C1-6 haloalky I; or R6 and R ' substituents, together with the ring atoms to which they are attached, 25 form a C3-10 cycloalkyl or 4-7 membered heterocycloalkyd, each of which is optionally' substituted with 1, 2, 3, or 4 independently selected R13 substituents; or R7 and R8 substituents, together with the ring atoms to which they are attached, form a C3-10 cycloalkyl or 4-7 membered heterocvcloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; 30             Rc and Ra are each independently selected from H, C)-& alkyl, C)-&haloalky1, C2< alkenyl, C2.6 alkynyl, Cs-io aryl, C3-7cycloalkyl, 5-10 membered heteroaryd, 4-10 membered heterocycloalkyl, Co-10 aryl-Cw alky 1-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyd)-Ciw alkyl-, wherein the Ciw alkyl, C2-6 alkenyl, C2< alkynyl, Cs-io aryl, C3-7cycloalkyl, 5-10 membered heteroaryd, 4-10 35 membered heterocvcloalkyl, Cr-io atyl-Ci-6 alkyd-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered 2024203916   07 Jun 2024 heteroaryl)-CM alkyl-, and (4-10 membered heterocycloalkyl)-CM alkyl- of Rc and Rd, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each RaI, Rd!, Rci, and Rd! is independently selected from H, Cm alkyd, Cmhaloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 5 membered heterocycloalkyl, Cg-io aryl-Ci-6alkyl-, C3-10 cycloalkyi-CMalkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-CM alkyl-, wherein the Cu alkyl, C2-6 alkenyl. C2-6 alkynyl, Cmo aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cr-jo aryl-CM alkyl-, Cs-iocycloalkyd-CMalkyd-, (5-10 membered heteroaryl)-CM alkyl-, and (4-10 membered heterocycloalky 1)-Cm alkyl- of R3i, Rbi, Rcl, and 10 Rdi, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any RC1 and Rai, 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 15 heterocycloalkyl group is optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; each Rel is independently selected from H, OH, CN, Cm alkyl, Cm alkoxy, Cm haloalkyl, Cm haloalkoxy', C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, Cmo cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cmo aryl-CM alkyl-, C3-10 20 cycloalkyl-CM alkyl-, (5-10 membered heteroaryl)-CM alkyl-, and (4-10 membered hetereocycloalkyl)-CM alkyl-; each Rfl and Rgi is independently selected from H, Cm alkyl, Cm alkoxy, Cm haloalkyl, Cm haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cs-io aiyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ceuo aryl-CM alkyl-, C3.10 25 cycloalkyl-CMalkyl-, (5-10 membered heteroaryl)-CMalkyl-, and (4-10 membered hetereocy cloalky 1)-C 1 -s alky' 1-; each Rw and R15 is independently selected from H, Cm alkyl, Cmhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cb-10 ary l, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io aryl-CM alkyl-, C3-10 cycloalkyl-CM alkyl-, (5-10 membered 30 heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-CM alkyl-; each RJ1 and Rk! is independently selected from OH, Cm alkoxy, and CMhaloalkoxy; or any R1 and Rki 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 Cm alkyl and Cmhaloalkyl; 2024203916   07 Jun 2024 each Ra3, Rb3, Rc3, and Ra3 is independently selected from H, Ci^ alkyl. Ci^haloalky 1, C2< alkenyl, C2< alkynyl, Cs-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Cw alkyl-, C3-10 cycloalky 1-C 1-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-C1-6 alkyl-, wherein the C1-6 5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cwo aryl, C3-10cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, Cs-io aryl-C«alkyl-, C3-Wcycloalkyl-Cwalkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl- of Ra3, Rb’, Rc3, and Rd3 are each optional!}' substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independent!}' selected RB substituents; 10             or, any R" and Ra’, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaiyl 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 RB substituents; 15            each R®3 is independently selected from H, OH, CN, Cm alkyl, Cw alkoxy, Cm haloalkyl, Cjmhaloalkoxy, C2^ alkenyl, C2^ alkynyl, Cs-io aiyl, C3-10 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered hetereocycloalkyl, C&-io aryl-C 1-6alkyl-, €3-10 cycloalkyl-Cj-e alkyl-, (5-10 membered heteroaryl)-C[-6alkyl-, and (4-10 membered hetereocy cloalky 1)-C 1-6 alky 1-; 20              each Ra is independently selected from D, halo, Ci-s alkyl, Ci-s haloalkyl, C2.& alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cvcloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-C alkyl-, C3-7 cycloalkyl-Cw alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, ORa4, SRa4, NHORa4, C(O)Rb4, C(0)NFRd’, C(O)NRa4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, 25    NR^4, NRc4NRc4Rd4, NRc4C(O)RM, NR^C^OR84, NRc4C(O)NRc4Rd4, C(=NRs4)Rb4, CC XOh)Rm, C(=NCN)Rb+, Ct XR'^XR'lCl XR'G XR':tXR!RXR :C( XR :!hb:. XR 'C( XOH iXR':Ri:. NRc4C(=NCN)NRc4Rd4, XR 'S(O)RH XR sStO)X R 'R'. NRc4S(O)2Rb4, XR;S(ObXR:R:;. S(O)Rb4, StOiX R :R11 S(O)2Rb4, S(O)2NRc4Rd4, OS(O)RNRe4)Rb4, OS(O)2Rm, SF5, P(O)RftRg4, OP(O)(ORh4)(OR14), P(O)(ORh4)(ORi4), and 30 BRj+Rk+, wherein the Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, Cg-io aryl-C 1.6alkyl-, C3..7 cycloalkyl-C1-6alkyl-, (5-10 membered heteroaryI)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl- of Ra is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; 2024203916   07 Jun 2024 each Rb is independently selected from D, halo, Cim alkyl, Ci-e haloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cr-io aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-w aryl-C)^ alkyl-, C3-7 cycloalky 1-Cwalkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, (4-10 membered heterocycloalkyl)-C«alkyl-, CN, NO2, OR32, SRa2, 5 NHORa2, C(O)Rb2, C(O)NRR:. GOiXR- sORh ). C(O)ORa2, OC(O)Rb2, (X (O)XR- ’R2 NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, XR2 (4OiXR’ R1C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C(=NRe2)NRc2Rd2, NR22C(=NRe2)NRc2Rd2, NRe2C(=NRe2)Rb2, NRc2C(=N0H)W^ NRc2C(=NCN)NRc2RcI2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, XR' S.OvR'X R2 Ss0 • -X R' R2 \ S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, S(O)2NRc2Rd2, 10 OS(O)(=NRe2)Rb2, OS(O)2Rb2, SF5, P(O)RaRs\ OP(O)(OR112)(ORi2), P(O)(ORh2)(OR12), and BR-l2Rk2, wherein the C1-6 alkyl, C2-s alkenyl, C2-s alkynyl, Ce-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-C walkyl-, C3-7 cycloalky 1-Cj-6 alkyd-, (5-10 membered heteroaryl)-Cj-& alkyd-, and (4-10 membered heterocycloalkyl)-Cj. 6 alkyl- of Rb is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM 15 substituents; each Ra / , Rb2, Rc2, and Rd2 is independently selected from H, Ci^ alkyl, C1-6 haloalkv 1, C2-6 alkenyl, C2-& alkynyl, Cwo aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cr-jo atyl-Ci-6 alkyd-, C3-7 cycloalky 1-Cimalkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky 1)-C 1.6 alkyl-, wherein the Ci-6 20 alkyl, C2-6 alkenyl, C2-6 alkynyl, C&-w aryl, C3-7 cycloalkyd, 5-10 membered heteroary l, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6 alky 1-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci^ alkyl-, and (4-10 membered heterocycloalkyl)-CiM alkyd- of Ra2, Rb2, Rc2, and Rd2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; 25             or, any Rc2 and R“2 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 heterocycloalky l group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; 30             each Re2 is independently selected from H, OH, CN, Cm alkyd, Cmalkoxy, C)^ haloalky 1, Cm haloalkoxy, C2-6 alkenyl, C2< alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aiyl-Ci^ alkyd-, C3-7 cycloalky I-C1-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocycloalky l)-Ci-6 alkyl-; 2024203916   07 Jun 2024 each Rg and R82 is independently selected from H, Cm alkyl, Cim alkoxy, Ci^ haloalkyl, Ci-ehaloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aryl-C 1-6 alkyl-, C3-7 cycloalky 1-C1..6alky 1-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered 5      hetereocycloalkyl)-C 1-6 alky 1-; each R112 and R’z is independently selected from H, Cj-e alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io ary 1-C alkyd-, C3-7 cycloalky 1-C 1.6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocycloalkyl)-Ci-6alkyl-; 10             each R'z and RK is independently selected from OH, Ci^alkoxy, and C1-6haloalkoxy; or any R-'2 and RK 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 alkyd and C)^haloalkyl; each Ra4, Rb4, Rc4, and Ra4 is independently selected from H, C1..& alkyl, C1-6 haloalkyl, 15      C2-6 alkenyl, C2-6 alkynyl, C&-W aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyi, C6-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io ary l, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyi, Cs-io aryl-C-.6 alkyl-, C3.7 cycloalkyl-C«alkyl-, (5-10 membered 20 heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R34, RM, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R° substituents; or, any Rc4 and Ra4 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 25 heterocycloalkyi group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyi group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each R84 is independently selected from H, OH, CN, 0¼ alkyl, C-.6 alkoxy, Cim haloalkyl, Ci^haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3.7 cycloalky 1, 5-10 30 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io aryl-C 1-6 alkyd-, C3-7 cycloalky 1-C 1..6alky 1-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocy cloalky 1)-C 1-6 alky 1-; each Rf4 and Rg4 is independently selected from H, C1-6 alkyl, C« alkoxy, Ci^ haloalkyl, Ci-6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7cycloalkyl, 5-10 35 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io ary 1-Cj^alkyd-, C3-7 2024203916   07 Jun 2024 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocy cloalkyl)-Ci-6 alky 1-; each Rh+ and R14 is independently selected from H, Cj^ alkyd, Cj.* haioalkyl, C2-6 alkenyl, C2-6 alkynyi, Cs-io ary l, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered 5 hetereocycloalkyl, Cmo ary 1-Ci^ alkyl-, C3-7 cycloalky 1-Calkyl-, (5-10 membered heteroaryi)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-Cj-6alkyl-; each R / 4 and Rk4 is independently selected from OH, Ci^alkoxy, and C1-6 haloalkoxy; or any 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 10 with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and Ci^ haioalkyl; each Rd is independently selected from H, D, halo, Cm alkyl, Cm haioalkyl, C2-6 alkenyl, C2-6 alkynyi, Cmo aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-w aryl-Cj-6 alkyl-, C3-7 cycloalky 1-Cw alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, (4-10 membered heterocycloalkyl)-CiMalkyl-, CN, NO2, ORa5, SR3", 15 NHORa5, C(OX0 (40)NRR':. GOR- 4ORh'). C(O)ORa5, (X4O)Rh' OC(O)NRc5Rd5, nrc5r®             NRc5C(O)Rb5, NRc5C(O)OR35, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(-NRe5)Rb5, XOibXR'T. NRc5C(=NCN)NRc5RdVNRc5S(O^^ NRc5S(O)2Rm, NRc5S(O)2NRc5Rd5, S(O)Rb5, StCoXR 'Rd'. S(O) itS(Ob\'RGfG 20 OS(O)(=NRe5)Rb5, OS(O)2Rb5, SF5, POR'R" OP(O)(ORM)(ORi5), P(O)(ORh5)(OR15), and BR-pRk’, wherein the C1-6 alkyl, C2-6 alkenyl, C2-s alkynyi, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-C alkyl-, C3-7 cycloalky 1-C1-6alkyl-, (5-10 membered heteroaiyl)-Cj-6alkyl-, and (4-10 membered heterocycloalkyl)-Cj. 6 alkyl- of Rd are each optionally substituted with 1, 2, 3, or 4 independently selected RE 25 substituents; each R35, Rb", R05, and Rd5 is independently selected from H, Ci^ alkyl, C1-6 haioalkyl, C2-& alkenyl, C2-& alkynyi, Cmo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky l)-Ci-6 alkyl-, wherein the Ci-6 30 alkyl, C2-6 alkenyl, C2-s alkynyi, Cg-w aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C&-io ary 1-Cim alkyl-, C3-7 cycloalkyl-C.-g alkyl-, (5-10 membered heteroaryl)-C;-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci^ alkyl- of Ra5, Rb0 Rc5, and Rd5 are each optionally substituted with 1, 2, 3, or 4 independently selected R" substituents; or, any R° and R® attached to the same N atom, together with the N atom to which 35 they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered 2024203916   07 Jun 2024 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 Rr substituents; each Rs5 is independently selected from H, OH, CN, C.-g alkyl, C-.6 alkoxy, Ci..g 5 haloalkyl, Cm haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cg-io aiyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cg-io aryl-Ci-g alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rb and Rg5 is independently selected from H, Ci« alkyl, Ci<alkoxy, Ci-6 10 haloalkyl, Ci^haloalkoxy, C2_g alkenyl, C2-6 alkynyl, Cmd aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cg-w aiyl-Cj-g alkyl-, C3-7 cycloalkyl-C]^alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-Ci-6 alkyl-; each Rto and R15 is independently selected from H, Ci-6 alkyl, Ci-6haloalkyl, C2-6 15 alkenyl, C2-6 alkynyl, Cg-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cg-io aryl-Ci-g alkyl-, C3-7 cycloalkyl-Ci^alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-Ci^ alkyl-; each Rp and R*5 is independently selected from OH, Cj-galkoxy, and C1-6 haloalkoxy; or any Rp and Rk5 attached to the same B atom, together with the B atom to which 20 they are attached, form a 5- or 6-membered heterocycloalkyd group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and Cmhaloalkyl; each Re is independently selected from H, D, halo, C]^ alkyl, C]^haloalkyl, C2-6 alkenyl, C2-g alkynyl, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.io ary I-C1-6 alkyl-, C3-7cycloalkyl-Ci« alkyl-, ¢5-10 membered 25 heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C).g alkyl-, CN, NO2, ORab, SRa5, NHORa5, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa5, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rds,      R’M’. NRPC(O;RC \ IV Vt O)OR‘ NRc6C(O)NRc6Rd6, C(-NRp;Rbb. C(=NOH)Rb6, C(-NCN)Rb6, C(            MV MV rMV'RV NR^CC—NR^Rh6, MM \OV\VV'. NR^C^NC^NR^R* NRc6S(O)Rb6, 30 NRcSS(O)NRc6Rd6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2RcS, S(O)2NRc6Rd6, OStOb MV:itVb. OS(O)2Rb6, SF5, P(O)Rf6Rg6, OP(O)(ORh6)(OR16), P(O)(OR^)(OR16), and BRj6Rk6, wherein the C« alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-10 aryl-Ci-g alky 1-, C3..7 cycloalkyl-Ci-6 alky 1-, (5-10 membered heteroaryl)-Ci-6alky 1-, and ¢4-10 2024203916   07 Jun 2024 membered heterocycloalky 1)-C--6 alkyl- of RE are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each RaS, Rb6, Rc6, and R“s is independently selected from H, C)-& alkyl, C)-6haloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 5 membered heterocycloalkyl, Ce-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-e alkyl-, (5-10 membered heteroaryi)-Ci-6 alkyl-, and (4-10 membered heterocycloaikyi)-C 1-6 alkyl-, wherein the Cu alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cr-jo aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Cwalkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky 1)-C 1.6 alkyl- of R36, Rb6, Rco, and 10 Rdo are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any Rco and R“6 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 RG 15 substituents; each Re6 is independently selected from H, OH, CN, Ci-6 alkyl, C1-6 alkoxy, Ci^ haloalkyl, C1-6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cg-m aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io aryl-Ci-s alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroatyl)-Ci-6 alkyl-, and (4-10 membered 20 hetereocycloalkyl)-Ci-6 alkyd-; each R® and Rs° is independently selected from H, Ci-6 alkyl, C1-6 alkoxy, Ci^ haloalkyl, Ci-6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cs-io aiyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aryl-Ci^ alkyl-, C3-7 cycloalky 1-Cuealky4-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered 25 hetereocycloalkyl)-C 1-6 alkyd-; each R116 and R16 is independently selected from H, Cj-e alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C&-M aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io aiy l-Cj-6 alkyl-, C3-7 cycloalky 1-C alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocycloalkyl)-Ci-6alkyl-; 30             each Rj6 and Rk6 is independently selected from OH, C]-&alkoxy, and C1-6haloalkoxy; or any R-Ib and Rkl5 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 0¼ alky l and Ci-6haloalkyl; each Rg is independently selected from H, D, halo, CN, NO2, SF5, Ci-6 alkyl, Ci-6 35 alkoxy, Cj^haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, C3-7 cycloalkyl, 5-10 membered 2024203916   07 Jun 2024 heteroaryl, 4-10 membered heterocycloalkyl, C&.10 ary 1-Cm alkyl-, C3-7 cycloalkyl-CM alkyl-, (5-10 membered heteroaryl)-CM alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6alkyl; and each Rm is independently selected from H, D, OH, NO?, CN, halo, Cm alkyl, C2-6 alkenyl, C2< alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Cm alkyl, CMalkoxy-Ci-6 alkyl, 5 Cmo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN-so aryl-Ci-6alkyl-, C3-7 cycloalkyl-CMalky 1-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalky 1)-0=-6alkyl, Ci-e,alkoxy, C1-6haloalkoxy, amino, C1-6 alkylamino, di(Ci-6alkyl)amino, thio, C1-6alkylthio, C m alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, Cm alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, Cm alkoxy carbonyl, Cm 10     alkylcarbonylamino, Cr alkylsulfonylamino, aminosulfonyl, Cm alkylaminosulfonyl, di(CM alkyl)aminosulfonyl, aminosulfonylamino, Cm alkylaminosulfonylamino, di(CM alkyl)aminosulfonylamino, aminocarbonylamino, Cm alkylaminocarbonylamino, and di(CM alky l)amin ocarbo ny lam in 0. In some embodiments, 15          X’isNorCR1; R1 is selected from H, D, halo, Cm alkyl, Cm alkoxy, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, Cm haloalkoxy, CN, OH, andNH?; R2 is selected from H, D, halo, Cm alkyd, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, Cy-Cm alkyl-, CN, NO?, ORai, SRa!, NHORal, C(O)Rb!, C(O)NRclRdl, C(O)NRc!(ORal), 20 C(O)ORal, OC(O)Rbl, OC(O)NRciRdi, NRclRdl, NRclNRclRdl, NRciC(O)Rbi, NRclC(O)ORal, NRc’C(O)NRclRdl, ( ( MC bRM. C( XOH)Rhl. C(=NCN)RM, C(=NRel)NRclRdl, NR^C^R^R^k NRclC(-NOH)NRciRd\ NRc!C(-NC^ NIC!S(O)NRC:iRdi, NRclS(O)RbI, NRclS(O)2Rbl, NRCIS(O)(=NReI)Rbl, NRclS(O)2NRclRdl, S(O)Rbi, SsOiXR'dCL S(O)2Rbi, S(O)2NRciRdi, OS(O)t NR'hX'l OS(O)?Rbl, SF5, 25 P(O)RflRsl, OPtOXOR^XOR1*), P(O)(ORM)(ORil), and BIC*Rk\ wherein the Cm alkyl, C2m alkenyl, and C2-6 alkynyl of R2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; Cy is selected from C6-14 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 30      8 independently selected RA substituents; RJ, R4 and R5 are each independently selected from H, D, halo, CN, OH, Cm alkyl, Cm haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cm alkoxy, Cm haloalkoxy, cyano-CM alkyl, HO-Cm alkyl, Cm alkoxy -Cm alkyl, C3-6 cycloalkyl, amino, Cm alky lamino, di(CMalkyl)ammo, and C(O)NReRd, wherein the Cm alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; 2024203916   07 Jun 2024 R6, R' and R8 are each independently selected from H, D, halo, Cm alkyl, C« alkoxy, €2« alkenyl, alkynyl, Ci-6 haloalkyl, Ci-ehaloalkoxy, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aryl-C)-&alkyl-, C3-7 cycloalkyl-C1-6alkyl-, (5-10 membered heteroaryI)-Ci-6alkyl-, (4-10 membered heterocycloalky l)-Ci-6 5 alkyl-, CN, NO •. OH, COOH and NH2; Rc and Ra are each independently selected from H and C1-6 alkyl; each Ra!, Rsl, Rci, and Rd! is independently selected from H, C]^ alkyl, Ci^ haloalkyl, C2-6 alkenyl, C2-s alkynyl, C&.w aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6 alkyl-, C3.10 cycloalky 1-Ci-salkyl-, (5-10 membered 10 heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6alkyl-, C3-10 cycloalky 1-Ci^alkyl-, (5-10 membered heteroand)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ral, Rw, Rc!, and Rdl, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA 15 substituents; or, any Rci and Ral, 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 20 selected RA substituents; each R81 is independently selected from H, OH, CN, 0¼ alkyl, C--6 alkoxy, Ci-6 haloalkyl, Cw, haloalkoxy, C2-6 alkenyl, C2-& alkynyl, Cs-io aiyl, €3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cmo ary 1-C« alkyl-, C3-10 cycloalky 1-C1..6alky 1-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered 25 hetereocycloalkyl)-C 1-6 alkyl-; each Rfl and Rgi is independently selected from H, C1-6 alkyl, C1-6 alkoxy, Cue haloalkyl, Ci^ haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cg-m aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io aiyl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered 30 hetereocycloalkyl)-Ci-6 alkyd-; each Rw and R1! is independently selected from H, Ci-s alkyl, Ci-shaloalkyl, C2-6 alkenyl, C2-& alkynyl, Cwo aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cmo aryl-Ci-6 alkyl-, C3-10cycloalkyl-Cwalkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyI)-Ci^ alkyl-; 35             each Rjl and RKi is independently selected from OH, Ci-6alkoxy, and Cj^haloalkoxy; 2024203916   07 Jun 2024 or any Rj! and Rkl attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalky i group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-s alkyd and Cj^haloalkyl; each Ra is independently selected from D, halo, Ci..e alkyl, Ci-e haloalky 1, C2.6 5 alkenyl, C2-6 alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci^alkyl-, C3-7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, OR*4, SR*4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORM), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, XR' :XR' Mt11 NRc4C(O)RM, NRc4C(O)OR*4, NRc4C(O)NRc4Rd4, ( t X R‘ 10 C(=NOH)Rb4, C(=NCN)Rb4, O X ik'XX kX<! 1 NRc4C(=NRe4)NRc4Rd4, X X s X Re: XR / :C( XO’hXIC^X XR4X1 XCXiXRXtX XR3M))RH X NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, StO) XR?’Rd t OS(OX=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, Cg-io aryl, C3.7 cycloalkyl, 5-10 15 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-Cwalkyl-, C3-7 cycloalkyl-C1-6 alkyl-, (5-10 membered heteroaryl)-Cj-6 alkyl-, and (4-10 membered heterocycloalkyl)-Cj. 6 alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Rb is independently selected from D, halo, Ci< alkyl, C1«haloalky 1, C2-6 20 alkenyl, C2-6 alkynyl, C&.W aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-w ary 1-Ci^ alkyl-, C3-7 cycloalkyl-Ci-s alkyl-, (5-10 membered heteroaryl)-Cj-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, OR*4, SR*2, NHORa2, C(O)Rb2, CtOiXR' R: . C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, Nr=2r<c NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, XR'"( (O;XR' Rd3. C(=NRe2)Rb2, 25 C(=NOH)Rb2, C(=NCN)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, XO XR dC . XRA( t X()H)XR'NR“S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, S(O)2.NRc2Rd2, OStOu XR")R:". OS(O)2Rb2, SFs, bOiR k ". OPOCOR^XOR12), PlOXOR^XOR2), and BR^R^2, wherein the Ci« alkyl, C2-6 alkenyl, C2.6 alkynyl, Cs-io and, C3-7 cycloalkyl, 5-10 30 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aryl-C)-&alkyl-, C3-7 cycloalkyl-C1-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalky 1)-Ci. 6 alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each R*2, Rb2, Rc2, and R“2 is independently selected from H, C1..6 alkyl, C1-6haloalky 1, 35      C2-6 alkenyl, C2-6 alkynyl, C&-io aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 2024203916   07 Jun 2024 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyd-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky 1)-C 1.6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg-w aryl, C3-7 cycloalkyd, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C&-io ary 1-Ci-e alkyl-, C3-7 cycloalkyl-Ci.6 alkyl-, (5-10 membered 5 heteroaryI)-C;-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-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 Rc2 and R“2 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 10 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, Cw alkyd, Cwalkoxy, C)^ haloalky 1, Cmhaloalkoxy, C2-6 alkenyl, CS-s alkynyl, Cg.io aryl, C3-7cycloalkyl, 5-10 15 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cg-io aryl-Cj-6 alkyl-, C3-7 cycloalky I-C1-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocycloalkyl)-Ci^ alkyd-; each Rg and R82 is independently selected from H, Cw alkyl, Cw alkoxy, C)^ haloalkyl, Ci-ehaloalkoxy, C2.6 alkenyl, C2.6 alkynyl, Cs-io aiyl, C3.7 cycloalkyl, 5-10 20 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aryd-C 1-6 alkyd-, C3-7 cycloalkyl-Ci-6alkyd-, (5-10 membered heteroaryl)-C 1-6alky 1-, and (4-10 membered hetereocycloalkyl)-C i-g alky 1-; each R112 and R12 is independently selected from H, Cj-e alkyl, C1-6haloalkyl, C2-6 alkenyl, C2.6 alkynyl, Cs-io ary l, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered 25 hetereocycloalkyl, Cg-io ary 1-Cjm alkyd-, C3-7 cycloalkyd-C [-6alkyl-, (5-10 membered heteroaryi)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyd)-Cj-6 alkyd-; each R-'2 and R:<2 is independently selected from OH, Cimalkoxy, and C1-6haloalkoxy; or any Rj2 and R!~ 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 30 with 1, 2, 3, or 4 substituents independently selected from (Xs alkyd and Cjmhaloalkyl; each Ra4, RM, Rc4, and Ra‘! is independently selected from H, Ci.g alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C&-]o aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocvcloalkyl, C6-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-C 1..6alkyl-, wherein the 35 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg-w ary l, C3-7 cycloalkyd, 5-10 membered heteroaryl, 4-10 2024203916   07 Jun 2024 membered heterocycloalkyl, Cg-io aryl-Ci-6 alkyd-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky 1)-C 1.6 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; 5             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; 10             each Re4 is independently selected from H, OH, CN, Cm alkyl, Cm alkoxy, Ci-& haloalkyl, C^haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-7 cycloalkvl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aiyl-Ci^ alkyd-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-C)-6alkyl-, and (4-10 membered hetereocy cloalky l)-Ci-6 alkyl-; 15             each Rf4 and Rg4 is independently selected from H, C ,.6 alkyl, Cw alkoxy, C)^ haloalkyl, Ci-6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered hetereocycloalkyl, C6-jo ary 1-C 1-6alkyl-, C3-7 cycloalkyl-Ci-ealkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocy cloalky 1)-C 1-6 alky 1-; 20             each Rh4 and R14 is independently selected from H, Cj^ alkyd, Cj.* haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cmo aryl-Cj-6 alkyl-, C3-7cycloalky 1-Calkyl-, (5-10 membered heteroaryi)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-Cj-6alkyl-; each Rj4 and Rk4 is independently selected from OH, C1.6alkoxy, and Ci-6haloalkoxy; 25             or any 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 heterocycloalky 1 group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl and Ci^ haloalkyl; each Rd is independently selected from H, D, halo, Cm alky l, Cm haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io ary l, C3-7 cycloalkyl, 5-10 membered heteroary l, 4-10 membered 30 heterocycloalkyl, Cs-w aryl-C)^ alkyd-, C3-7 cycloalky 1-C 1-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-CiMalkyl-, CN, NO2, ORa\ SR55, NHORa5, CtOdC C(O)N      C(O)NRC5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5,            NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(==NOH)Rb5, C^NCN)!^5, CC=NRe5)NR( R;i'. NRc5C(==NRe5)NRc5Rd5, NR^a-NR^R^, 35 X’CX s XOi hXIC'RMCC! XC\)\R "R b NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, 2024203916   07 Jun 2024 NRc5S(O)2Rb5, X R''S(O)A R" 'RS(O)Rb5, StOiX R*'R X SjOvR '. S(O)2NRc5Rd5, OS(OjtaXX-X. OS(O)-Rh'. SF5, P(O)RrR&\ ()P(O)(OR“XOR !. P(O)(OR'XOR'), and BrRr’X wherein the Ci-s alkyl, C2.6 alkenyl, C2.6 alkynyl, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io ary I-C 1.6 alkyl-, C3..7 cycloalkyl- 5 C[-6 alkyl-, (5-10 membered heteroaryll-CXs alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl- of Rd are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents; each R35, Rb5, R", and R03 is independently selected from H, Cw alkyl, Cw haloalky 1, C2< alkenyl, C2< alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 10 membered heterocycloalkyl, C&-io ary I-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Cj-6alkyI-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the Cj^ alkyl, C2.6 alkenyl, C2^, alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-.o aryl-CXs alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci..6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6alkyl- of R3i, R?”, R05, and 15 Rd5 are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; or, any Rc5 and Ra’ 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 Rr 20 substituents; each Rs5 is independently selected from H, OH, CN, C1-6 alkyd, C1-6alkoxy, Cue haloalkyl, Ci-6haloalkoxy, C2-6 alkenyl, C2-& alkynyl, CX10 aiyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io ary l-CXs alkyl-, C3-7 cycloalky 1-C 1..6alky 1-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered 25      hetereocycloalkyl)-C 1-6 alkyl-; each Rb and Rg5 is independently selected from H, C1-6 alkyl, C« alkoxy, Ci-6 haloalkyl, Ci^haloalkoxy, C2-s alkenyl, C2-6 alkynyl, Cmd aryl, C3-7 cycloalkyl, 5-10 membered heteroary l, 4-10 membered hetereocycloalkyl, Ce-io aiy 1-C 1-6 alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaiyl)-Ci.6 alkyl-, and (4-10 membered 30 hetereocycloalkyl)-Ci-6 alkyd-; each R1” and R15 is independently selected from H, Ci-6 alkyl, Ci-6haloalkyl, C2.s alkenyl, C2^, alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io ary 1-CW alkyl-, C3-7 cycloalkyl-Ci-ealkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered hetereocycloalkyl)-Ci-6 alkyl-; 35             each Rp and R*5 is independently selected from OH, Cs-6alkoxy, and C1-6haloalkoxy; 2024203916   07 Jun 2024 or any Rp and Rk3 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalky i group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cj-s alkyd and Cj^haloalky l; each Rb is independently selected from H, D, halo, Ci-6 alkyl, Ci-6 haloalky 1, C2-6 5 alkeny l, C2-6 alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aiyl-Ci^alkyl-, C3-7cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C alkyl-, CN, NO2, ORaS. SRa6, NHORa6, C(O)Rb6,             QO)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OCONR^R16, NRc5Rd6, NRc6NRc6Rd6, NRcSC(O)Rb6, NRc6C(O)ORa5, NRc6C(O)NRc6Rd6, 10 G \ RGC(=NOH)Rb6, C(=NCN)Rb6, G=NRe:)NRsRd6, X RGG XJGYs RGG. NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc5C(=NCN)NRc5Rd5, \R;G.tO)R.G NRc6S(O)NRc6Rds, X IGSt O) -R?". NRc6S(O)2NRc6Rdf>, S(O)Rb6, S(O)NRcf>Rdf>, S(O)2Rc6, S(O) XR' -rG OS(O)(=NRe6)Rb6, OS(O)2Rb6, SFs P(O)Rf6Rs6, OP(O)(ORb6)(ORi6), P(O)(ORI1S)(OR1R), and BRjSRks, wherein the Cm alkyl, C2-6 alkenyl, C2m alkynyl, Cs-io aryl, 15      C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered beterocycloalkyl, Cg-io aryl-Cj^ alkyl-, C3-7 cycloalky 1-C1-6alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6alkyl- of RE are each optionally substituted with 1, 2, 3, or 4 independently selected R° substituents; each RaS, Rb6, Rcf>, and RdS is independently selected from H, Ci< alkyl, C14 haloalky 1, 20      C2-6 alkenyl, C2-& alkynyl, Cg-w ary l, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-g alky l-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-CiM alkyl-, and (4-10 membered heterocycloalky 1)-Cim alkyl-, wherein the Ci-g, alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C&-io ary 1-Cim alkyl-, C3-7 cycloalkyl-C.-g alkyl-, (5-10 membered 25 heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C)M alkyl- of Ra6, Rbb, RcS, 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 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 30 heterocycloalkyl group is optionally' substituted with 1, 2, 3, or 4 independently selected RG substituents; each Reb is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy , C« haloalkyl, Cimhaloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ceuo ary 1-C1-6 alkyl-, C3.7 2024203916   07 Jun 2024 cycloalkyl-CMalkyl-, (5-10 membered heteroaryl)-CMalkyl-, and (4-10 membered hetereocy cloalkyl)-Ci-6 alky 1-; each Rfb and RgS is independently selected from H, Cm alkyl, Cm alkoxy, Cm haloalky 1, CMhaloalkoxy, C2-6 alkenyl, alkynyl, Cs-w aryl, C3-7 cycloalkyl, 5-10 5 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aiyl-CM alkyl-, C3-7 cycloalkyl-CM alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-CM alkyl-; each Rhb and R16 is independently' selected from H, Cm alkyd, Ci-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io ary l, C3.7 cycloalkyl, 5-10 membered heteroary l, 4-10 membered 10 hetereocycloalkyl, C&-io ary 1-Cm alkyl-, C3-7 cycloalkyl-CMalkyd-, (5-10 membered heteroaryl)-CM alkyl-, and (4-10 membered hetereocycloalkyl)-CM alkvl-; each Rj6 and Rte is independently selected from OH, C1-6alkoxy, and CMhaloalkoxy; or any RjS and Rkb 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 15 with 1, 2, 3, or 4 substituents independently selected from Cm alkyd and CMhaloalkyl; each Rg is independently selected from H, D, halo, CN, NO2, SF5, Cm alkyl, Cm alkoxy, CMhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, CXw aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-CM alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-CMalkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl; and 20             each Rm is independently selected from H, D, OH, NO2, CN, halo, C« alkyl, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, cyano-CM alkyl, HO-Cj^ alkyl, CMalkoxy-CM alkyd, Cmo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CXio ary I-Cmalkyl-, C3-7 cycloalkyl-CMalkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalky 1)-Cmalkyl, Ci-ealkoxy, CMhaloalkoxy, amino, Cmalkylamino, 25 di(C 1-6 alkyl)amino, thio, C1-6alkylthio, Cm alkylsulfinyl, Cm alkylsulfonyl, carbamyl, Cm alkylcarbamyl, di(C us alkyd)carbamyl, carboxy, Cm alkylcarbonyl, Cm alkoxycarbonyl, Cm alkylcarbonylamino, Cm alkylsulfonylamino, aminosulfonyl, Cm alkylaminosulfonyl, di(CM alkyl)aminosulfonyl, aminosulfonylamino, Cm alkylaminosulfonylamino, di(CM alkyl)aminosulfonylamino, aminocarbonylamino, Cm alkylaminocarbony lamino, and di(CM 30 alkyl)aminocarbonylamino. 2024203916   07 Jun 2024 In some embodiments, the compound of Formula (I) is a compound of Formula (II): (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (III): (HI) 10 or a pharmaceutically acceptable salt thereof. In some embodiments, R1 is H, D or Ci-6 alkyd. In some embodiments, R1 is H, D or methyl. In some embodiments, R! is H. 15 20 In some embodiments, R2 is selected from H, D, halo, Ci^ alkyl, Ci^haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (X14 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, Cs-14 ary 1-C 1-6 alkyd-, C3-14 cycloalkyl-Ci-6alkyl-, (5-14 membered heteroaryl)-Ci^ alkyl-, and (4-14 membered heterocycloalkyl)-Ci^ alkyl-, C(O)NRclRdl, C(O)ORal, CM, NO?, OH, COOH and NH2, wherein the Cj^ alkyd, C2-6 alkenyl, C2-6 alkynyl, Ce-i4 aryl, €3..1+cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, Ce-i4 aryl-Ci-s alkyl-, C3-14 cycloalkyl-C)^alkyl-, (5-14 membered heteroaryl)-C]<alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6alky1- of Rz are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R2 is selected from H, D, halo, Cs^ alkyd, Cs^haloalkyl, C2-s alkenyl, C2..6 alkynyl. Cy, Cy-Chalky 1-, C(O)NRc!Rd!, C(O)OR31, CN, NO2, OH, COOH and NH2, wherein the Cis alkyd, C2< alkenyl, C2.6 alkynyl, (Xu aryd, C3-14cycloalkyl, 5-14 membered heteroary l, 4-14 membered heterocycloalky l, CXu ary 1-C 1-6alkyl-, Cj-u cycloalky 1-C1-6alkyl-, (5-14 membered he•cromy I i-()..-. alky 1-, and (4-14 membered heterocycloalkyI)-Ci. 2024203916   07 Jun 2024 6 alkyl- of R2 are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R2 is selected from Cy, Cy-Cwalkyl, Cwhaloalky 1, C(O)NRclRal, and C(O)ORai; and Cy is selected from C3.14 cycloalkyl, 5-14 membered 5 heteroaryl, and 4-14 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; In some embodiments, R2 is C(O)NRclRdl or C(O)ORai. In some embodiments, R2 is Cy, C(O)NRclRdl or NRclC(O)Rbl. In some embodiments, R2 is C(O)NRclRdl or NRclC(O)Rbl. 10             In some embodiments, R2 is C(O)NRc!Rd!. In some embodiments, R2 is Cy. In some embodiments, R2 is C(O)NRelRdl or NRclC(O)Rbl, wherein RC1 is H; and RS1 and Rdi are each independently selected from C)-& alkyl, C3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C3-10 cycloalkyl-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 15 alkyl-, each of which is optionally substituted by 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R2 is C(O)NRe!Rd!, wherein Rc! is H; and Rdl is selected from Cue alkyd, C3-7 cycloalkyl, 4-10 membered heterocycloalkyd, C3-!ocycloalkyl-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, each of which is optionally substituted by 1, 2, 20      3, or 4 independently selected RA substituents. In some embodiments, R2 is C(O)NRc!Rd!; and each RC1 and RdI is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, Ce-io aryl-Ci-6alkyl-, C3-10 cycloalkyl-Ci-6alkvl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-C1-6alkyl-, wherein the C1-6 25 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalky], 4-10 membered heterocycloalkyd, Cr-jo aryl-C1-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci.6 alkyl- of RC1 and Rdl are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; or, any RC1 and Rai, attached to the same N atom, together with the N atom to which 30 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, or 4 independently selected RA substituents. In some embodiments, R2 is C(O)NRclRdl; each RC1 and Rdi is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.10cycloalkyl, 4-10 membered 35 heterocycloalkyl, Ce-so aryl-Ci-6 alkyl-, Cj-.o cycloalkyl-Ci-ealkyl-, (5-10 membered 2024203916   07 Jun 2024 heteroaryl)-Cj-6alkyl-, and (4-10 membered heterocydoalkyl)-Ci-6 alkyl-, wherein the Cj-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C&-io aryl-Cj-& alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C-.6alkyl- of RC1 and Ra! are each optionally substituted with 1, 5      2, 3, or 4 independently selected RA substituents; or, any Rci and Ral, 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 heterocycloalkyd group is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; and 10             each Ra is independently selected from D, halo, oxo, Cu& alkyl, C1-6 haloalky 1, C2-6 alkenyl, and C2-6 alkynyl, CN, NO2, and ORa4, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of RA is optionally substituted with 1, 2, or 3 independently selected RD substituents. In some embodiments, R2 is C(O)NRclRdl; each Rc! and Rai is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, CS-s alkynyl, C3.10 cycloalkyl, 4-10 membered 15 heterocycloalkyl, Cs-w aryd-Ci-s alkyl-, C3-10 cycloalkyd-Cxalkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci^ alkyl-, wherein the Cu alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-B3 cycloalkyl, 4-10 membered heterocycloalkyl, Ca-so aryl-Cu6alkyl-, Cj-iocycloalkyl-Cxalkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6alkyl- of Rc! and Ral are each optionally substituted with 1, 20      2, 3, or 4 independently selected RA substituents; or, any RC1 and Rd i, 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 heterocycloalky l group is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; 25             each Ra is independently selected from D, halo, oxo, Cw alkyl, C^haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, CN, NO2, and ORa4, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of RA is optionally substituted with 1, 2, or 3 independently selected RD substituents; each Ra+ is independently selected from H and Ci^ alkyl, wherein the Cj-g alkyl is optionally substituted CN, NO2, or OH; and 30             each Rd is OH. In some embodiments, R' is C(O)NRclRdl; and Rci is H; and Rdl is selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkvl, phenyl-Chalky 1-, and C3.7 cycloalky 1-Cm alkyl-, wherein the C1-6 alkyl, C3-7cycloalkyl, 4-7 2024203916   07 Jun 2024 membered heterocycloalkyl, phenyl-Ci-4 alkyl-, and C3-7 cycloalky 1-Cm alkyl- of RC1 and RdI are each optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rci and Ra!, 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-, 5      6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, Rz is C(O)NRclRdl; and RC1 is H; and Rdl is selected from ethyl, propyl, isopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, 10 bicyclofl.l.ljpentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl, and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclofl .l.ljpentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, 15 tetrahydrofuranvl, tetrahydropyranyl, pyrorolidinyl and thianyl of Ral are each optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rci and Ral, 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, 2, or 3 independently selected RA substituents. 20            In some embodiments, R2 is C(O)NRclRdl; and RC1 is H; and Rdl is selected from ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclof 1.1. l]pentanyl, bicyclo[2.1.1 ]hexanyl, bicyclo[2.2.1 ]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, 25 tetrahydropyranyl, pyrorolidinyl, and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclofl.l.ljpentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranvl, tetrahydropyranyl, pyrorolidinyl and thianyl of Ra! are each optionally substituted with 1, 2, or 3 independently selected RA substituents; 30             or, any Rci and Ra!, 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, 2, or 3 independently selected RA substituents. In some embodiments, R2 is C(O)NRclRdl; Rci is H; 2024203916   07 Jun 2024 Rdi is selected from Ci-s alkyl, C3-7 cycloalkyd, 4-7 membered heterocycloalkyl, pheny1-Cualkyl-, and C3-7cycloalkyl-C 14alkyl-, wherein the Ci< alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, pheny 1-Cm alkyl-, and C3-7 cycloalkyl-Cw alkyl- of Rc! and Rdi are each optionally substituted with 1 or 2 independently selected RA substituents; 5             or, any RC1 and Rdi, 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 or 2 independently selected RA substituents; and each RA is independently selected from oxo, Ci-6 alkyl, Ci-6haloalky 1, CN, and ORa+, 10 wherein the Ci-6 alkyl of RA is optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R2 is C(O)NRc,Rd); Rc! is H; Rd! is selected from ethyl, propyl, isopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, 15 bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]bexanyl, bicyclo[2.2.1]beptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, 20 tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of Rdi are each optionally substituted with 1 or 2 independently selected RA substituents; or, any RC1 and Rai, 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 25             each Ra is independently selected from oxo, methyl, CH2F, CHF2, CF3, -OCH3, - CFLOH, CN and OH. In some embodiments, R2 is C(O)NRclRdl; Rci is H; Rdl is selected from ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, 30 bicyclofl. l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclofl.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, 2024203916   07 Jun 2024 tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of Ra! are each optionally substituted with 1 or 2 independently selected RA substituents; or, any Rci and Ra!, 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 5 optionally substituted with 1 or 2, independently selected RA substituents; and each Ra is independently selected from oxo, methyl, CHjF, CHFj, CF3, -OCH3, -CH2OH, CN and OH. In some embodiments, R2 is C(O)NRclRdl; Rcl is H; and Rd! is selected from 4-hydroxybicy clo[2.2. l]heptany 1 and tetrahydropyranyl. 10             In some embodiments, R2 is Cy, C(O)NRciRdi or NRciC(O)Rbl, wherein RC1 is H; and Rbl and Rdi are each independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C3-10 cycloalkyl-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, each of which is optionally substituted by 1,2, 3, or 4 independent!}' selected RA substituents. 15             In some embodiments, each Ral, Rbi, Rci, and Rd5 is independently selected from H, C1-6 alkyl, C1-6haloalky 1, C2-6 alkenyl, Cj-s alkynyl, Cmo aryl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, Cmo aryI-C1-6alkyl-, C3-10 cycloalkyl-Ch-6alkyl-, (5-10 membered beteroaryl)-C 1-6alkyl-, and (4-10 membered beterocycloalkyl)-Ci-6alkyl-, wherein the Cm alkyl, C2.6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-7cycloalkyl, 5-10 20 membered heteroaryl, 4-10 membered beterocycloalkyl, Cg-io aryl-C)-&alkyl-, C3-10 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryI)-Ci-6 alkyl-, and (4-10 membered heterocycloaIkyl)-Ci-6alkyl-, of Rai, Rbl, Rel, and Rdl are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; and each RA is independently selected from OH, CN, halo, Ci-e alkyl, Ci-e haloalkyl, Ci< 25 alkoxy, Cj^baloalkoxy, amino, Ci^alkylamino, and di(C]^alky1)amino. In some embodiments, each RC1 and Rdi is independently selected from H, C]^ alkyl, Ci-f, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, Ce-io aiy l-Cj-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, wherein the C1..6 alkyl, C2.6 alkenyl, C2-6 30 alkynyl, C3-M cvcloalkyl, 4-10 membered heterocycloalkyl, Cg-io aryl-C)-6alkyl-, C3-10 cycloalky 1-Cuealky 1-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-CiMalkyl- of Rc5 and Rdi are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any Rci and Rdl, attached to the same N atom, together with the N atom to which 35 they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 2024203916   07 Jun 2024 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. In some embodiments, Cy is a Cs-ucycloalky 1 optionally substituted with I, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. 5             In some embodiments, Cy is a C3-10cycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a Cj-ecycloalkyl 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 10      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. 15             In some embodiments, Cy is a 5 membered heteroaryl optional!}' 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 20 with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. 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. 25             In some embodiments, Cy is a 5 membered heterocycloalkyl optional!}' substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is selected from: ^7                 a N-N ’   N-0 ’ N-S ’                                    each of which is optionally substituted by 1 or 2 independently selected RA substituents. 2024203916   07 Jun 2024 In some embodiments, R2 is selected from the following moieties: In some embodiments, Cy is selected from pyrazol-l-yl, pyrazol-4-yl, pyrazol-5-yl, isoxazol-5-yl, isothiazol-4-yl, isothizol-5-yl, oxazol-5-yl, thiazol-5-yI, 1,2,3-triazol-l-yl, 5 l,2,3-triazol-2-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, C1..& alkyl, Ci-shaloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cvcloalkyl, 5-10 membered heteroaryl, 410 membered heterocycloalkyl, Cs-io aryl-Ci-6 alkyl-, C3-7 cycloalky 1-Cj^ alkyl-, (5-10 membered heteroaryl)-Ci^, alkyl-, (4-10 membered heterocycloalky 1)-Cn&alkyl-, CN, NO?, 10     OR34, SR34, NHOR34, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC^NR^4, NRaRd4, NRNIX':R:. XR W NR‘X1(OiOR". 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)2Rb4, wherein the C?.s alkyl, C2.s alkenyl, C2.s alkynyl, C6. 10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io 15      aryl-Ci-6 alkyl-, C3-7 cycloalkyl-CMalkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each R34, Rb4, Rc4, and Ra4 is independently selected from H, C1..& alkyl, C1-6 haloalky 1, C2-6 alkenyl, C2-6 alkyny l, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaiyl, 4-7 membered 20 heterocycloalkyl, phenyl-Ci-salkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-6 membered heteroaryl)-Ci-s alky 1-, and (4-7 membered heterocycloalkyl)-Ci^ alkyl-, wherein the Ci-& alkyl, C2-6 alkenyl, C2-s alkynyl, phenyl, C3-7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci.6 alkyl-, C3.7cycloalky 1-C«alkyl-, (5-6 membered heteroaryl)-Ci-s alkyl-, and (4-7 membered heterocycloalky 1)-Cj^ alkyd- of Ra4, R“4. Rc4, and Rd4 each 25 optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Ru substituents; or, any Rc4 and Ra4 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 30 selected R° substituents; and 2024203916   07 Jun 2024 each Rd is independently selected from D, OH, NO2, CN, halo, Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, Cm haloalky 1, cyano-CM alkyl, HO-Cm alkyl, CMalkoxy-CM alkyl, C3-7 cycloalkyl, Cmalkoxy, C m haloalkoxy, amino, C m alkylamino, di(CMalkvl)amino, thio, Cmalkylthio, Ci-6alkylsulfinyl, Cmalkylsulfonyl, carbamyl, Cm alkylcarbamyl, di(CM 5 alkyl)carbamyl, carboxy, CMalkydcarbonyl, Cm alkoxycarbonyl, Cm alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Cm alkyiaminosulfonyl, di(CM alkyiaminosulfonyl, aminosulfonylamino, Cm alkylaminosulfonylamino, di(CM alky l)aminosulfony lam ino, aminocarbonylamino, Cm alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino. In some embodiments, each RA is independently selected from D, halo, Cm alkyl, Ci- 10      shaloalky1, Cm, alkenyl, C2^ alkynyl, CN, NO2, OR44. SRa4, X HOR! \ C(O)Rb4, C; O}X R-' RJ C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, XR :XR' dC1. NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRe4S(O)RM, NRa4S(O)NRc4Rd4, NRc4S(O)2Rm, NRc4S(O)2NRc4Rd4, S(O)RW, S^NR^4, S(O)2RM, S(O)2NRc4Rd4, and OS(O)2RM, wherein the Cm alkyl, C2-6 alkenyl, and C2.6 alkynyl of RA are each optionally 15 substituted with 1, 2, 3, or 4 independently selected RD substituents; each IC4, Rb4, Rc4, and Rd4 is independently selected from H, Cm alkyl, and Cm haloalky 1, wherein the Cm alkyl of Ra4, Rb4, Rc4, and Ra4 are each optionally substituted with 1,2, 3, or 4 independently selected RD substituents; and each RD is independently selected from D, OH, NO2, CN, halo, Ci-6 alkyl, Cm 20 alkenyl, C2-s alkynyl, Cm haloalkyl, cyano-CM alkyl, HO-Cm alkyd, CMalkoxy-CM alkyd, C3-7 cycloalkyl, Cm alkoxy, Cm haloalkoxy, amino, CMalkylamino, di(CMalkyl)amino, thio, Cm alkylthio, Cm alkylsulfmyl, Cm alkylsulfonyl, carbamyl, Cm alkylcarbamyl, di(CM alkyl)carbamyl, carboxy, Cm alkylcarbonyl, Cm alkoxycarbonyl, CMalkylcarbonylamino, Cj. 6alkylsulfonylamino, aminosulfonyl, Cmalkyiaminosulfonyl, di(CMalkyl)aminosulfony 1, 25 aminosulfonylamino, Cm alkylaminosulfonylamino, di(C j-& alkyl)aminosulfonylamino, aminocarbonylamino, Cm alkylaminocarbonylamino, and di(CMalkyl)aminocarbonylamino. In some embodiments, each RA is independently selected from D, halo, Cm, alkyl, Cu 6haloalkyl, CN, ORa4, and NRc4Ra4; wherein the Cm alkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra are each optionally substituted with 1, 2, 3, or 4 independently selected R1’ substituents; 30             each Ra4, Rc4, and Rd4 is independent!}' selected from H, Cm alkyl, Cm haloalkyl,wherein the Cm alkyl of Ra4, Rc4, and Ra4 are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; and each Rd is independently selected from D, OH, CN, halo, Cm alkyl, Cm haloalkyl, Cm alkoxy, Cm haloalkoxy, amino, Cm alkylamino, and di(Ci-6alkyl)amino. 2024203916   07 Jun 2024 In some embodiments, each RA is independently selected from D, halo, Ci-s alkyl, and Ci-6 haloalky 1, wherein the Ci-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, each RA is independently selected from methyl and CDs. In some embodiments, each RA is methyl. 5            In some embodiments, each RA is CDs. In some embodiments, R2 is selected from Ci^ alkyl, Ci-ehaloalkvl, C2-6 alkenyl, and Cs-e, alkynyl, wherein the Cm alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R2 is Ci..& alkyl, which is optionally substituted by 1, 2, or 3 10 independently selected RA groups. In some embodiments, Rz is C1-6 alkyl. In some embodiments, R2 is propyl. In some embodiments, R2 is C2-6 alkenyl, which is optional!}' substituted by 1, 2, or 3 independently selected RA groups. 15             In some embodiments, R2 is C2-6 alkenyl. In some embodiments, R2 is propenyl or butenyl. In some embodiments, Rz is prop-l-enyl or but-l-enyl. In some embodiments, R2 is C2-6 alkynyl, which is optionally substituted with 1, 2 or 3 independently selected RA substituents. 20             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 substituted 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-1-ynyl, wherein the ethynyl is substituted by RA, and the prop-l-ynyl, but-l-ynyl, and pent-125 ynyl are each optionally substituted by 1,2, or 3 independently selected RA groups. In some embodiments, R2 is selected from prop-l-ynyl, but-l-ynyl, and pent-1-ynyl, wherein the prop-l-ynyl, but-l-ynyl, and pent-l-ynyl are each optionally substituted by 1, 2, or 3 independently selected RA groups. In some embodiments, R2 is ethynyl, wherein the ethynyl is optionally substituted by 30      1, 2, or 3 independently selected RA groups. In some embodiments, each RA is independently selected from H, D, Ci-e alkyl, C1-6 haloalkyl, Cg-io and, C3-12 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, wherein the Cm alkyl, Cmo aryl, C3-12 cycloalkyl, 5-10 membered heteroaryl, and 4-12 membered heterocycloalkyl, are each optionally substituted with I, 2, 3, 35      4, or 5 independently selected RD substituents. 2024203916   07 Jun 2024 In some embodiments, each RA is independently selected from H, D, Ci-6 alkyl, Ci^ haloalky 1, Cs-io aryl, C3.12 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C6-w aryl-C)-6 alkyl-, Cj.^cycloalkyi-Cs-e alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-12 membered heterocycloalkyl)-Ci-6 alkyl-, wherein the Ci-6 5 alkyl, C&-io aryl, C3-12 cycloalkyl, 5-10 membered heteroaiyl, 4-12 membered heterocycloalkyl, Cs-io aryl-Ci-s alkyl-, C3-12 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-12 membered heterocycloalkyI)-Ci-6 alkyl- are each optionally substituted with 1,2, 3, 4, or 5 independently selected RD substituents, and wherein the connection of Cwo aryl-Ci-6 alkyl-, Cs-ncycloalkyl-Ci-ealkyl-, (5-10 membered heteroaryl)- 10 Ci-f, alkyl- and (4-12 membered heterocycloalkyl)-Ci-6 alkyl- groups to R2 (e.g., to an alkynyl group of Rz) may occur through the aforementioned ring or the Ci-6 alkyl group. In some embodiments, each RA is independently selected from D, halo, Cue, alkyl, Coin aryl, Cs-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, and OR34, wherein the C1-6 alkyl, Cs-io aryl, C3-10 cycloalky 1, 5-10 membered heteroaryl, 15 and 4-10 membered heterocycloalkyd of RA are each optionally substituted by I or 2 independently selected RiJ groups. In some embodiments, each R34 is independently selected from H and Cue, alkyl. In some embodiments, each RA is independently selected from D, halo, C)-& alkyl, Cs-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, CN, 20 NO2, and OR34, wherein the Ci-6 alkyd, Cs-w aryl, C3-10 cycloalkyl, 5-10 membered heteroaiyl, and 4-10 membered heterocycloalkyd of RA are each optionally substituted by 1 or 2 independently selected Rv groups; and each Ra4 is independently selected from H and Ci-6 alkyl. In some embodiments, each RA is independently selected from Ci.s alkyl, Cs-io aryl, 25      C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyd, and OR34, wherein the Ci-s alkyl, Cs-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaiyl, and 4-10 membered heterocycloalkyl of RA are each optionally substituted by 1 or 2, independently selected RD groups. In some embodiments, each RA is independently selected from methyl, cyclopropyl, 30 pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazopyrazinyl, hydroxyl, and methoxy, wherein the cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and imidazopyraziny l of RA are each optionally substituted by 1 or 2 independently selected R° groups. In some embodiments, each Rn is independently selected from halo, Ci-6 alkyl, CN, 35 cyano-Ci-6 alkyd, and ORa5. 2024203916   07 Jun 2024 In some embodiments, each Raa is independently selected from H and Ci^ alkyl. In some embodiments, each RJ is independently selected from halo, Ci-6 alkyl, CN, cyano-Ci-6 alkyl, and ORa'; and each Ra5 is independently selected from H and Ci-6 alkyl. 5             In some embodiments, each RA is independently selected from Ci-6 alkyl, Cs-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyd, and ORa4, wherein the Ci^ alkyl, Cs-k;. aryl, Cs-w 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 RJ is independently selected from halo, Ci..e alkyl, CN, cyano-10 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 the cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and imidazopyrazinyl of RA are each optionally substituted by 1 or 2 independently 15 selected RD groups; and each RD is independently selected from methyl, cyano, cyanomethvl, and methoxy . In some embodiments, Rz is C i-s haloalkyl. In some embodiments, R2 is trifluoromethyl. In some embodiments, R2 is selected from C3-6 cycloalkyl and 4-7 membered 20 heterocycloalkyl, wherein the C3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, each RA is independently selected from D, halo, oxo, Ci^ alkyl, Ce-io aryl, C3-6 cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4R”4, and S(O)2Rb4! wherein the Ci-e alkyl, Cs-io aryl, C34 cycloalkyl, and 5-10 25 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected R° substituents. In some embodiments, each Ra4, Rb4, R04, and Rd4 is independently selected from H, Ci-6 alkyl, phenyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the Ci-6 alkyl, phenyl, C3.6 cycloalkyl, 5-10 membered heteroaryl, 30 and 4-10 membered heterocycloalkyl of Ra4 and RM are each optionally substituted with 1 or 2 independently selected R:) substituents. In some embodiments, R04 and R~4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyd group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 35 or 2 independently selected R:) substituents. 2024203916   07 Jun 2024 In some embodiments, each RD is independently selected from OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6haloalky 1, 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 5 optionally substituted with 1, 2, or 3 independently selected RA substituents; and each Ra is independently selected from D, halo, oxo, Ci-6 alkyl, Cmo aryl, C3-6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)ORa4, C(O)NRc4Rd4 and S(O)2Rb4, wherein the Cm alkyl, Cs-w aryl, C3-6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RiJ substituents. 10             In some embodiments, Rz 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 independently selected RA substituents; and each Ra is independently selected from Cw alkyl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4 and S(O)2RM, wherein the C1.3 alkyl of RA are each optionally substituted with 1 or 2 15 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 are each optionally substituted with 1,2, or 3 independently selected RA substituents; each RA is independently selected from D, halo, oxo, Ci-s alkyl, C&.10 aryl, C3-6 20 cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4 and S(O)2RM, wherein the Ci-6 alkyd, Ce-io aryl, C3-6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected Rv substituents; and each Ra4, Rw, Rc4, and R“4 is independently selected from H, Ci^ alkyl, phenyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the Ci-6 25 alkyl, phenyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 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 are each 30 optionally substituted with 1, 2, or 3 independent!}' selected RA substituents; each Ra is independently selected from D, halo, oxo, Ci-6 alkyl, Ce-io aryl, C3-6 cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4, and S(O)zRb4, wherein the Ci-6 alkyl, Cs-io aryl, C3-6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected R1’ substituents; 2024203916   07 Jun 2024 each R34, R14. Rc4, and Ra4 is independently selected from H, Cim alkyl, phenyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1..6 alkyl, phenyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4, Rb4, Rj. and R;U are each optionally substituted with 1 or 2 5 independently selected R17 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, wherein the 4-, 5-, 6-, or 7membered heterocycloalkyl group is optionally substituted with 1 or 2 independent!}' selected RJ substituents; and 10             each Rd is independently selected from OH, CN, Cm alkyl, Cm alkoxy, Cim haloalky 1, and phenyl. In some embodiments, R2 is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-ajpyrazinyl, w'herein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl of R2 are each optionally substituted with 1, 2, or 3 15 independently selected RA substituents. In some embodiments, R2 is selected from azetidinyl and cyclobutyl, w'herein the azetidinyl and cyclobutyl of R2 are each optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R2 is selected from azetidinyl, cyclobutyl, piperazinyl, and 20 hexahydropyrrolo[l ,2-aJpyrazinyl, w'herein 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 Ra is independently selected from oxo, Ci-6 alkyd, phenyl, C3-6 cycloalkyl, 5-10 membered heteroaiyl, C(O)Rb4, C(O)OR34, C(O)NRc4R”4 and S(O)2RM, wherein the Ci-6 alkyl, 25 phenyl, C3-6 cycloalkyd, and 5-10 membered heteroaiyl, of RA are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, Rz is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropvrrolo[l,2-a]pyrazinyl, wherein the azetidiny l, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2-a]pyrazinyl of R2 are each optionally substituted with 1, 2, or 3 30 independently selected RA substituents; each Ra is independently selected from oxo, C1-6 alkyl, phenyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)OR34, C^NR^R04, and S(O)2R04, wherein the Cim alkyl, phenyl, C3-6 cycloalkyl, and 5-10 membered heteroaryl, of RA are each optionally substituted with 1 or 2 independently selected Rn substituents; and 2024203916   07 Jun 2024 each Ra4, RM, Rc4, and Ra4 is independently selected from H, Cm alkyl, phenyl, C3-6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the Ci-6 alkyl, C3-6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD 5 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; 10             each Ra is independently selected from Ci-3 alkyl, C(O)Rb4, C(O)ORa4, C(O)NRc4R~4, and S(O)2Rm, wherein the C1-3 alkyl of RA are each optionally substituted with 1 or 2 independently selected Rv substituents; each Ra4, Rw, Rc4, and Rd+ is independently selected from H, Cm alkyl, phenyl, C3-6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein die Cm 15 alkyl, C3-6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD substituents; or, any Rc4 and R“4 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-, 20      6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independent!}' selected RJ substituents; and each Rd is independently selected from OH, CN, Cm alkyl, Cm alkoxy, Cm haloalky 1, and phenyl. In some embodiments, Rz is selected from azetidinyl and cyclobutyl, wherein the 25 azetidinyl and cyclobutyl of R2 are each optionally substituted with 1, 2, or 3 RA substituents independently selected from (l-methyI-lH-pyrazol-4-yl)sulfonyl, ethylcarboxylate, oxo, cyclopropyl, butyl, acetyl, cyclopropanecarbonyl, phenyl, methylphenyl, dimethylphenyl, pyrindinyl, thiazolyl, trifluoromethylphenyl, cyanophenyl, hydroxyphenvl, hydroxymethyl, cyanoethyl, oxohexahydropyrrolo[l,2-a]pyrazine-2-yl, furan-2-carbonyl, cyanopyrazinyl, and 30 ethoxyphenyl. In some embodiments, R! is selected from H, D, halo, C1..6 alkyl, C1..6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Cmhaloalky 1, Cwhaloalkoxy, CN, OH, and XSty wherein Cm alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R’ is Cm alkyl, wherein Cm alkyl is optionally substituted 35 with 1, 2, or 3 D. 2024203916   07 Jun 2024 In some embodiments, RJ 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..g alkyl, Ci..g alkoxy, C2-6 5      alkenyl, C2-6 alkynyl, Ci^ haloalky 1, Cwhaloalkoxy, CN, OH, and NH2, wherein Ci^,alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R4 is H, D or Ci-g alkyl, wherein Cj^alkyl is optionally substituted with 1,2, or 3 D. In some embodiments, R4 is H. 10             In some embodiments, R4 is D. In some embodiments, R5 is selected from H, D, halo, Ci.g alkyl, C.-g alkoxy, C2-6 alkenyl, C2-6 alky nyl, Cw haloalky 1, Cwhaloalkoxy, CN, OH, and NH2, wherein Ci^,alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R" is H, D or Ci..6 alkyl, wherein Ci-6 alkyl is optionally 15 substituted with 1,2, or 3 D. In some embodiments, R5 is H. In some embodiments, R" is D. In some embodiments, R4 and R' are each H. In some embodiments, R6 is selected from H, D, halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 20 alkynyl, Cj^ haloalkyl, Cg-io aryl, C3-10cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered heterocycloalkyl, Cg.w aryl-Cus alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C].6 alkyl-, (4-10 membered heterocycloalky 1)-Ci^ alkyl-, CN, NO2, OH, COOH and NH2, wherein Ci-g alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R6 is selected from H, D, halo, C1..6 alkyl, C2-6 alkenyl, C2-6 25 alkynyl, C1-6 haloalkyl, CN, NO2, OH, COOH and NH2, wherein Cj-g alkyd is optionally substituted with 1, 2, or 3 D. In some embodiments, Rb is H, D or Ci-g alkyl, wherein Cj-g alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R6 is methyl. 30             In some embodiments, R6 is CD3. In some embodiments, R6 is H. In some embodiments, R6 is D. In some embodiments, R6 is Ci-6 haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein 2024203916   07 Jun 2024 each Y is independently selected from D, halo, Cj-6 alkyl, and Ci-s haloalkyl. In other embodiments, each Y is independently selected from halo and Ci-6 haloalkyl. In some embodiments, R6 is H, CH2F, CHF2 or CF3. In some embodiments, R6 is selected from CF3, CCI3, CF2H, CC12H, CF2Y, CC12Y, 5     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, Rs is C)-& haloalkyl, wherein each halogen is F. In some embodiments, R6 is Ci..& haloalkyl, wherein each halogen is Cl. 10             In some embodiments, Rb is selected from CH2F, CHF2, CF3, and CF2CF3. In some embodiments, R6 is CH2F, CHF2, or CF3. In some embodiments, R6 is CF3. In some embodiments, Rb is CH2F. In some embodiments, R6 is CHF2. 15             In some embodiments, R6 is CF2CF3. In some embodiments, R' is selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2.e alkynyl, C]^ haloalkyl, Co-10 and., C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-w aryl-C^alky!-, CYiocycloalkyl-Cs-ealkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, (4-10 membered heterocycloalky l)-Ci-6alkyl-, CN, NO2, OH, COOH 20 and NH2. In some embodiments, R' is selected from H, D, halo, Ci-s alkyl, C2-6 alkenyl, C2.6 alkynyl, CYs haloalkyl, CN, NO2, OH, COOH and NH2. In some embodiments, R7 is H, D or C1-6 alkyd. In some embodiments, R' is methyl or ethyl. 25             In some embodiments, R' is CD3. In some embodiments, R' is H. In some embodiments, R' is D. In some embodiments, R8 is selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, Cg-w aryl, C3.? cycloalky 1, 5-10 membered heteroaryl, 4-10 membered 30 heterocycloalkyl, C6-w aryl-C)-6alkyd-, C3-io cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, OH, COOH and NH2, wherein the C1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R8 is selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2.g alkynyl, Ci-6 haloalkyl, CN, NO2, OH, COOH and NH2, wherein the Ci-6 alkyl is optionally 35 substituted with 1,2, or 3 D. 2024203916   07 Jun 2024 In some embodiments, R8 is H, D or C.-6 alkyl, wherein the Ci^ alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R8 is methyl or ethyl. In some embodiments, R8 is CD3. 5             In some embodiments, R8 is H. In some embodiments, R8 is D. In some embodiments, R ' and R8 are each H. In some embodiments, R' and R8, together with the C atom to which they are attached, form a cyclopropyl or cyclobutyl. 10             In some embodiments, R ' and R8, together with the C atom to which they are attached, form a cyclopropyl. In some embodiments, each is independently selected from H, D, halo, Ci-6 alkyl, Cj-fthaloalkyl, Cb-s alkenyl, C2-6 alkynyl, Cr-jo and, C3-7 cycloalkyl, 5-10 membered heteroand, 4-10 membered heterocycloalkyl, Cs-io ary 1-C i-e alkyl-, C3.7 cycloalky l-Ci-6alkyl-, (5-10 15     membered heteroaryl)-C)-6 alkyl-, (4-10 membered heterocycloalkyl)-C)-6 alkyl-, CN, NO2, OR35, SR35, NHORa5, C(O)Rb5, C(O)NRc5R“5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5R® N R'X!(O)Rb5, NRc5C(O)OR35, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rby C(=NCN)Rb5, Cs XiVlXR-'RNRc5C(=NRe5)NRc5Rd5, XR'X s XR'dli1". NR-(d                                    X Rd'St our'. 20 XR- StOtXR-'Rd'. NR-"S(O).Rh' NRc5S(O). XR-'R< S(O)Rb5, S(O)NRc5Rd5, S(O)2Rc5, StOf-XR-R1'. OS(O)(=NRe5)Rb5, OS(O)2Rb5, SF5, P(O)R:'R OP(O)(ORte)(OR15), P(O)(ORn5)(ORi5), and BRjSRks, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C&-io aryl, C3-7 cycloalky l, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-Ci-s alky 1-, C3..7 cycloalky 1-Ci .6 alky 1-, (5-10 membered heteroaryl)-Ci-6 alky 1-, and (4-10 25     membered heterocycloalky l)-Ci-6alkyd- of RD are each optionally substituted with 1,2, 3, or 4 independently selected Rk substituents. In some embodiments, each Ra5, Rb5, R®, and Rd5 is independently selected from H, Ci-6 alkyl, C1-6haloalky 1, C2-6 alkenyl, C2-e alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Co-10 ary 1-C 1-6 alkyl-, C3-7 cycloalky l-Ci-6 alkyl-, 30      (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyd)-Ci-6 alky 1-, wherein the Ci« alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io and, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C&-io ary 1-C 1-6alky4-, Cs-rcycloalkyl-Ci^ alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R33, Rb5, and Rdi are each optionally substituted with 1, 2, 3, or 4 independently selected 35 Re substituents; 2024203916   07 Jun 2024 or, any Rc:' and R“5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryi 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 R" 5 substituents. In some embodiments, each R“ is independently selected from H, D, halo, Ci-6 alkyl, Cm haloalky 1,    alkenyl, C2-6 alkynyl, C&.10 aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyd, Cg-w aryl-Ci-6 alkyl-, Cs-vcycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, 10 NO2, ORa6, SRa6, NHORa6, C(O)Rb6, ( tO)XR- ’Rd \ C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rds, NRc5NRc6Rd6, NRc6C(O)Rb6, X )R NRc6C(O)NRc6R“6, C; vy-jR- C(-NOH)Rb6, C(=NCN)Rb6, C^NR^NR^R*6, NR^C^NR^NR^R* Xl^O XR^bR^ XR'cd XO’l)X^;'R:d NRc6C(=NCXW NRc6S(O)NRc6Rd6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rbs, St O)X R' -Rd \ S(O)2Rc6, 15 S(O)2NRc6Rds, OS(O)(=NRs6)Rb6, OS(O)2Rb6, SF5, P^R^R86, OP(O)(ORh6)(ORl6), P(O)(OR^)(ORi6), and BR-l0Rk0, wherein the Ci-g alkyl, C2-6 alkenyl, C2-g alkynyl, Cg-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-jo aryl-Ci-g alkyl-, C3-7 cycloalkyl-Cj-g alkyl-, (5-10 membered heteroaryl)-Ci-g alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6alkyl- of Rb are each optionally substituted with 1, 2, 3, or 4 20 independently selected R& substituents. In some embodiments, each Rao, Rb6, Rc6, and Rd6 is independently selected from H, C« alkyl, C«haloalky 1, C2-6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyd, Cg-io aiyl-Cj-g alky 1-, C3-7 cycloalky l-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky l)-Ci-6alkyl-, 25 wherein the Cm alkyl, C2.g alkenyl, C2.g alkynyl, Cg-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyd, Cg-10 aiyl-Cj-g alky 1-, C3-7 cycloalky l-Ci-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R*, Rb6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, or 4 independently selected Rg substituents; 30             or, any RcS and Rab 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 heteroaryi or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents. 2024203916   07 Jun 2024 In some embodiments, the compound is a compound of Formula (II): (II) or a pharmaceutically acceptable salt thereof. 5             In some embodiments, the compound is a compound of Formula (III): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (IV): 10 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Fo rmula (V7): 2024203916   07 Jun 2024 or a pharmaceutically acceptable salt thereof. In some embodiments, X1 is N or CR1; R1 is H, D or Cm alkyd; R2 is Cy, C(O)NRciRdl or NRclC(O)Rbl; 5              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 R" are each independently selected from H, D, halo, Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Cw haloalkyl, Ci-shaloalkoxy, CN, OH, andNH2, wherein Cmalkyl is optionally substituted with 1, 2, or 3 D; 10             R6, R7 and R8 are each independently selected from H, D, halo, Cm alkyl, C2-6 alkenyl, Cm alkynyl, Cm haloalkyl, CN, OH, and NH2, wherein Cm alkyl is optionally substituted with 1, 2, or 3 D; each Ra is independently selected from D, halo, Ci-s alkyl, Cm haloalkyl, C2-6 alkenyl, C2< alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered 15 heterocycloalkyl, Cs-w aryl-CM alkyl-, C3-7 cycloalkyl-C)^ alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalky 1)-Cm alkvl-, CN, NO2, OR84, SR84, NHORa4, CC(O)\R !rC!. C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NR^4, NRc4NRc4Rd4, NRc4C(O)RM, NR^C^OR84, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, 20 S(O)2NRc4Rd4, and OS(O)2RM, wherein the Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-w aryl, C3-7 cvcloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aryl-CM alkyl-, C3-7 cycloalky 1-Cmalkyl-, (5-10 membered heteroaryl)-CMalkyl-, and (4-10 membered heterocvcloalkyl)-CM alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Rn substituents; 25             each Rb!, Rcl, and Rd! is independently selected from H, Cm alkyl, Cj^> haloalkyl, C2< alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-CM alkyl-, Cs-rcycloalkyl-CM alkyl-, (5-6 membered heteroaryl)-Ci-6 alkyl-, and (4-7 membered heterocycloalkyl)-CM alkyl-, wherein the Cm alkyl, Cm alkenyl, C2< alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered 30     heterocycloalkyl, phenyl-C)^ alkyl-, Cs-vcycloalkyl-CMalkyl-, (5-6 membered heteroaryl)-Ci- 6 alky 1-, and (4-7 membered heterocycloalky 1)-Cm alkyl- of Rc!, Rcl, and Rdl are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; each Ra4, Rw, Rc4, and R44 is independently selected from H, Cm alkyl, Cm haloalkyl, C2-6 alkenyl, C2.6 alkynyl, phenyl, C3.7 cycloalky 1, 5-6 membered heteroaryl, 4-7 membered 35     heterocycloalkyl, phenyl-CM alkyl-, C3-7 cycloalkyl-CMalkyl-, (5-6 membered heteroaryl)-Ci- 2024203916   07 Jun 2024 6 alkyl-, and (4-7 membered heterocycloalky 1)-Cm alkyl-, wherein the Cm alkyl, C2-6 alkenyl, alkynyl, phenyl, C3.7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-CM alkyl-, Cs-vcycloalkyl-CMalkyl-, (5-6 membered heteroaryl)-C]. 6 alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6alkyl- of R34, Rb4, Rc4, and Rd4 are each 5 optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Ra4 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 beteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently 10 selected RD substituents; and each Rd is independently selected from D, OH, NO2, CN, halo, Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, cyano-CM alkyl, HO-Cm alkyl, Cm alkoxy -Cm alkyl, C3-7 cycloalkyl, Cm alkoxy, C m haloalkoxy, amino, C m alkylamino, di(C 1-6 alkyl)amino, thio, Cm alkylthio, Cm alkylsulfinyl, Cm alkylsulfonyl, carbamyl, Cm alkylcarbamyl, di(CM 15 alkyl)carbamyl, carboxy, Cm alkylcarbonyl, Cm alkoxycarbonyl, Cm alkylcarbonylamino, Ci-& alkylsulfonylamino, aminosulfonyl, Cm alkylaminosulfonyl, di(CM alkyl)aminosulfonyl, aminosulfonylamino, Cm alkylaminosulfonylamino, di(CM alky I)aminosulfonylamino, aminocarbonylamino, Cm alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino. In some embodiments, groups X1, R1, Rbi, Rci, Rdl, Cy, RA, R3, R4, R5, R6, R7, R8, R34, 20 Rb4, Rc4, Ra4, and RD are as defined above, and R2 is Cy. In some embodiments, groups X!, R1, Rbi, Rci, Rdi, Cy, RA, R3, R4, R5, R6, R7, R8, R34, Rb4, Rc4, Ra4, and RC are as defined above, and R2 is C(O)NRclRd!. In some embodiments, groups X1, R1, Rb!, Rc!, Rdl, Cy, RA, R3, R4, R5, R6, R7, R8, IC4, Rb4, Rc4, Rd4, and Rn are as defined above, and R2 is NRciC(O)Rbi. 25            In some embodiments, X! is N or CR1; R1 is H, D or Cm alkyl; R2 is Cy, C(O)NRciRdl or NRciC(O)RbI; Cy is 5-6 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 30 independently selected RA substituents; RJ, R4, and R' are each independently selected from H, D, halo, Cm alkyl, Cm alkoxy, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, Cm haloalkoxy, CN, OH, andNH2, wherein Cm alkyl is optionally substituted with 1, 2, or 3 D; 2024203916   07 Jun 2024 R6, R' and R8 are each independently selected from H, D, halo, Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci^ haloalkyl, CN, OH, and NH?, wherein Ci-salkyl is optionally substituted with 1, 2, or 3 D; each Ra is independently selected from D, halo, Cm alkyl, C« haloalkyl, C2.6 5 alkenyl, C2-6 alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aiyl-Ci^alkyl-, (XTcycloalkyl-Ci-b alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, ORa4, SR*4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORM), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)RM, NRc4C(O)OR*4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, 10      X R' St O ;X R-! RdX R :S(O b Rbl. XR- 'StO! XR- ’Rd S(C))Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, and OS(O)2R°4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-Ci^ alkyl-, C3-7 cycloalkyl-C [-6 alkyl-, (5-10 membered heteroaryl)-C 1-6alkyl-, and (4-10 membered heterocycloalkyl)-C.-6alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 15      6, 7, or 8 independently selected RD substituents; each Rbi, Rci, and Ra! is independently selected from H, Cue alkyl, Cuehaloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaiyl, 4-7 membered heterocycloalkyl, phenyl-Cwalkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-6 membered heteroaryl)-Ci-& alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl-, wherein the Ci-e alkyl, C2-6 alkenyl, 20      C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci^ alkyl-, C3-7 cycloalkyl-C 1-6alkyl-, (5-6 membered heteroaryl)-Ci-6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of Rbl, Rcl, and Rd! are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Ra4 is independently selected from H, C1..& alkyl, C1-6 haloalkyl, 25      C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci^alkyl-, C3-7 cycloalkyl-C 1-6alkyl-, (5-6 membered heteroaryl)-Ci-6 alkyl-, and (4-7 membered heterocycloalkyl)-Ci^ alkyl-, wherein the Ci-& alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryi, 4-7 membered heterocycloalkyl, phenyl-Ci.5 alkyl-, C3.7 cycloalky l-Ci-e alkyl-, (5-6 membered heteroaryl)-Ci-30 s alkyl-, and (4-7 membered heterocycloalkyl)-Cj^ alkyd- of Ra4, RD4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Ru 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 heteroaryi or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryi or 4-, 5-, 6-, or 7-membered 2024203916   07 Jun 2024 heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Ru substituents; and each Rd is independently selected from D, OH, NO?, CN, halo, C)-& alkyl, C2-6 alkenyl, alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-e alkyl, C«alkoxy-Ci.6 alkyl, 5      C3-7 cycloalkyl, Cw alkoxy, C1-6haloalkoxy, amino, Ci^alkylamino, di(Ci^ alkyl)amino, thio, C1-6 alkylthio, C1-6 alkyIsulfmyl, Ci-6alkylsulfonyl, carbamyl, Ci-6alkylcarbamyl, di(Ci^ alkyl)carbamyl, carboxy, CYs alkylcarbonyl, Cm alkoxycarbonyl, Ci-6alkylcarbonylamino, Cj. & alkylsulfonylamino, aminosulfonyl, C i-s alkylaminosulfonyl, di(Cw alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6alkyl)aminosulfonylamino, 10 aminocarbonylamino, C alkylaminocarbonylamino, and di(C]^ alkyl)aminocarbonylammo. In some embodiments, groups X!, R1, Rbi, Rci, Rdi, Cy, RA, R3, R \ R5, R6, R7, R8, Ra+, RM, R“4, Ra4, and R° are as defined above, and R2 is Cy. In some embodiments, groups X1, R1, Rd!, Rc!, RdI, Cy, RA, R-\ R4, R’, Rb, R', R8, R34, Rm, Rc4, Ra4 and Rn are as defined above, and R2 is C(O)NRciRdi. 15             In some embodiments, groups X1, R1, Roi, Rcl, Rdi, Cy, RA, R3, R4, R5, R6, R7, R8, R34, rc4 Ra4, anj rd are ag defined above, and R2 is NRc!C(O)Rbl. In some embodiments: X1 is N or CH; R2 is C(O)NRc!Rd!; 20              each Rci and Rdi is independently selected from H, C i-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyd, Ce-io aryl-C 1-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, Ce-io aryl-C 1«alley 1-, C3-10cycloalkyl-Ci-6alkyl-, 25      (5-10 membered heteroaryl)-C)-&alkyl-, and (4-10 membered heterocycloa1ky])-C)-6alkyl- of Rci and Ral are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; or, any Rc! and Rdi, 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-, 30      6-, or 7-membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected RA substituents; each Ra is independently selected from D, halo, oxo, C alkyl, C haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, and OR3'1, wherein the Ci^ alkyl, C2-6 alkenyl, and C2-6 alkynyl of RA is optionally substituted with 1, 2 or 3 independently selected R1’ substituents; 2024203916   07 Jun 2024 each R34 is independently selected from H and Ci^ alkyl, wherein the Ci-6 alkyl is optionally substituted by CN, NO2, or OH; each Rd is OH; each R!, R4 and R' is independently selected from H, D, halo, CN, OH, Clj alkyl, and 5 Ci-3 haloalkyl, wherein the Ci^ alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; and each R6, R', and R8 is independently selected from H, D, 0¼ alkyl and Ci-6haloalkyl. In some embodiments: X!isN; R2 is C(O)NRc!Rd!; 10               R' : isH; Rd! is selected from ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[ 1.1. l]pentanyI, bicyclo[2.1. Ijhexanyl, bicyclo[2.2. IJheptanyl, methy 1-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, etbyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, 15 cyclobutyl, cyclohexyl, bicyclo [l.l.l]pentanyl, bicyclo [2.1. Ijhexanyl, bicyclo[2.2. IJheptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropy ranyl, pyrorolidinyl and thianyl of Rai is optionally substituted with 1 or 2 independently selected RA substituents; or, any RC1 and Rai, attached to the same N atom, together with the N atom to which 20 they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected RA substituents; each Ra is independently selected from oxo, methyl, CH2F, CHF2, CF3, -OCH3, -Cl-LOH, CN, and OH; R3 is selected from H, methyl, and CD3. 25             R4 and R5 are each H; R6 is selected from CH2F, CHF2, and CF3; and R7 and R8 are each H. In some embodiments: X! is N or CH; 30              R2 is selected from C]< alkyl, Cj-e haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents; each Ra is independently selected from D, halo, Ci-6 alkyl, Ce-io aryl, C3-10 cycloalkvl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, and ORa4, wherein 35 the Ci-6 alkyd, Cs-w ary l, C3.io cycloalky l, 5-10 membered heteroaryl, and 4-10 membered 2024203916   07 Jun 2024 heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups; each R34 is independently selected from H and C]< alkyl; each Rd is independently selected from halo, Ci« alkyl, CN, cyano-Ci-6 alkyl, and 5      OR35; each R35 is independently selected from H and Ci-6 alkyl; each R’, R4 and R5 is independently selected from H, D, halo, CN, OH, C1-3 alkyl, and C1-3 haloalky], wherein the Cj^ alkyd is optionally substituted by 1,2, 3, 4, 5, or 6 D; and each R6, R', and R8 is independently selected from H, D, C.-g alkyl, and Ci-6 10      haloalky 1. In some embodiments: X! is N or CH; R2 is selected from C]< alkyl, C^haloalkyd, C2-6 alkenyl, and Cz-g alkynyl, wherein the Ci-6 alkyl, Cz-g alkenyl, and C2-6 alkynyl are each optionally substituted with 1 or 2 15 independently selected RA substituents; each Ra is independently selected from D, halo, Ci-g alky l, Cg-io aryl, C3-10 cycloalkvl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO?., and OR34, wherein the Ci-6 alkyd, Cg-w ary l, 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 20 groups; each Ra+ is independently selected from H and Ci-6 alkyl; each Rd is independently selected from halo, Ci-6 alkyl, CN, cyano-Cj-g alkyl, and OR35; each R35 is independently selected from H and Ci-6 alkyl; 25             R3 is selected from H and Ci-6 alkyd; R4 is selected from H and Ci-6 alky l; R5 is selected from H and Ci-6 alkyl; R6 is a C1-3 haloaikyd, wherein each halogen of the C1-3 haloalkyl is independently selected from F and Cl; and 30             each R' and R8 is independently selected from H, D, Cj.g alkyd, and Cj-ghaloalkyl. In some embodiments: X! is N; R2 is selected from trifluoromethyl, propyl, propenyl, ethynyl, propynvl, butynyl, and pentynyl, w'herein the ethynyl is optionally substituted by RA, and the propynyl, butynyl, and 2024203916   07 Jun 2024 pentynyl groups are each optionally substituted by 1, 2, or 3 independently selected RA groups; each Ra is independently selected from Ci-6 alkyl, Cg-w aryl, C3-W cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and ORa4, wherein the Ci-6 alkyl, Cg. 5 jo 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 R° groups; each Ra4 is independently selected from H and Ci^ alkyl; each Rd is independently selected from halo, Cw alkyl, CN, cyano-Ci-g alkyl, and ORa5; 10             each Ra5 is independently selected from H and Ci-g alkyl; R3 is Ci-g alkyl; R4 is H; R5 is H; RR is a C1-3 haloalky 1, wherein each halogen of the C1..3 haloalkyl is independently 15 selected from F and Cl; R? is H; and R8 is H. In some embodiments: X! is N; 20             R2 is selected from trifluoromethyl, propyl, propenyl, etbynyl, propynvl, butynyl, and pentynyl, wherein the ethynyl is optionally substituted by RA, and the propynvl, butynyl, and pentynyl groups are each optionally substituted by 1, 2, or 3 independently selected RA groups; each RA is independently selected from methyl, cyclopropyl, pyrazolyl, imidazolyl, 25 phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazopyrazinyl, hydroxyl, and 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; each Rd is independently selected from methyl, cyano, cyanomethyl, and methoxy; 30               R3 is Ci-g alkyl; R4 is H; R5 is H; R6 is CHF2 or CF3; R' is H; and 35              R8 is H, 2024203916   07 Jun 2024 In some embodiments: X! is N or CH; R2 is selected from C3-12 cycloalkyl and 4-12 membered heterocycloalkyl, wherein the C3-12 cycloalkyl and 4-12 membered heterocycloalky i are each optionally substituted with 1, 5      2, or 3 independently selected RA substituents; each Ra is independently selected from D, halo, oxo, C1-6 alkyl, Cmo aryl, C3-6 cycloalkyl, 5-10 membered heteroaryl, C(O)RM, C(O)ORa4, C(O)NRc4Rd4, and S(O)2RM, wherein the Cm alkyl, Cs-jo aryl, C3-6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RiJ substituents; 10              each Ra4, Rb4, R04 and Rd4 is independently selected from H, Calkyl, pheny l, C3-6 cycloalkyl, 5-10 membered heteroaryi, and 4-10 membered heterocycloalkyl, wherein the C1-6 alkyl, phenyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of‘ Ra4 and Rb4 are each optionally substituted with 1 or 2 independently selected substituents; 15             or, any Rc4 and R~4 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, w'herein the 4-, 5-, 6-, or 7-membered heterocycloalky l group is optionally substituted 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 20 Cj-3haloalkyl, wherein the Ci-6 alkyd is optionally substituted by 1, 2, 3, 4, 5, or 6 D; and each R6, R' and R8 is independently selected from H, D, 0¼ alkyl, and Cmhaloalkyl. In some embodiments: X1 is N or CH; R2 is selected from C3-6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the 25      C3-6 cycloalkyd and 4-7 membered heterocycloalkyd are each optionally substituted with 1, 2, or 3 Ra substituents; each Ra is independently selected from C1-3 alkyl, C(O)Rb4, C(O)ORa+, C(O)NRc4R~4, and S(O)2Rb4, wherein the C1-3 alkyl of RA are each optionally substituted with 1 or 2 independently selected Rv substituents; 30             each Ra4, Rb4, R04, and Rd4 is independently selected from H, C)^ alkyl, phenyl, C3-6 cycloalkyl, 5-7 membered heteroaryi, and 4-7 membered heterocycloalkyl, wherein die Ci-e alkyl, C3-6 cycloalkyl, 5-7 membered heteroaryi, and 4-7 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD substituents; 2024203916   07 Jun 2024 or, any Rc4 and R“4 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 or 2 independently selected substituents; 5             each Rd is independently selected from OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl and phenyl; R3 is selected from H, methyl and CO3; R4 and R5 are each H; R6 is selected from CH2F, CHF2, and CF3; and 10             R7 and R8 are each H. In some embodiments: X! is N; R2 is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l ,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[l,2- 15 ajpyrazinyl of"R2 are each optionally substituted with 1, 2, or 3 RA 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]pyrazine-2-yL furan-2-carbonyl, cyanopyrazinyl, and 20 etboxyphenyl; R3 is selected from H, methyl and CD3; R4 and R" are each H; R6 is selected from CH2F, CHF2, and CF3; and R' and R8 are each H. 25            In some embodiments, X! is N or CR1; R: is H; R2 is Cy, C(O)NRciRdl or NRciC(O)RbI; Cy is 5-membered heteroaryl, which is optionally substituted with 1, 2, or 3 30 independently selected RA substituents; R3, R4, and R' are each independently selected from H, D, halo, Ci.<, alkyl, Ci.<, alkoxy, C2^ alkenyl, C2^ alkynyl, Cm haloalkyl, C«haloalkoxy, CN, OH, andNH2, wherein Ci-6 alkyl is optionally substituted with 1, 2, or 3 D; 2024203916   07 Jun 2024 R6, R' and R8 are each independently selected from H, D, halo, Cm alkyl, C2-6 alkenyl, C2.6 alkynyl, Ci^ haloalkyl, CN, OH, and NH?, wherein Ci-salkyl is optionally substituted with 1, 2, or 3 D; each Ra is independently selected from D, halo, Cm alkyl, C« haloalkyl, C2.6 5 alkenyl, C2-6 alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aiyl-Ci^alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, ORa4, SR*4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORM), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)RM, NRc4C(O)OR*4, NRe4C(O)NRc4Rd4, NRc4S(O)Rb4, 10      X R' St O ;X R~! R4\ R:S(O)2Rh\ XR' 'StO! XR- ’R4 S(C))Rb4, StO)NR1 R;". S(O)2Rb4, S(O)2NRc4Rd4, and OS(O)2R°4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-Ci^ alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered heterocycloalkyl)-C.-6alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 15      6, 7, or 8 independently selected RD substituents; each Rbi, Rci, and Ra! is independently selected from H, Cue alkyl, Cuehaloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaiyl, 4-7 membered heterocycloalkyl, phenyl-Cwalkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-6 membered heteroaryl)-Ci-& alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl-, wherein the Ci-e alkyl, C2-6 alkenyl, 20      C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1.6 alkyl-, C3-7 cycloalkyl-C 1-6alkyl-, (5-6 membered heteroaryl)-Ci-6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6alkyl- of Rbl, Rcl, and Rd! are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Ra4 is independently selected from H, C1..6 alkyl, Ci-6 haloalkyl, 25      C2-6 alkenyl, 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-6 alkyl-, and (4-7 membered heterocycloalkyl)-Ci^ alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci.5 alkyl-, C3.7 cycloalky 1-Ci-e alkyl-, (5-6 membered heteroaryl)-Ci-30 s alkyl-, and (4-7 membered heterocycloalkyl)-Cj^ alkyd- of Ra4, RD4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Ru substituents; or, any Rc4 and R~4 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 2024203916   07 Jun 2024 heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Ru substituents; and each Rd is independently selected from D, OH, NO?, CN, halo, C)-& alkyl, C?-6 alkenyl, alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-e alkyl, C«alkoxy-Ci.6 alkyl, 5      C3-7 cycloalkyl, Cw alkoxy, C1-6haloalkoxy, amino, Ci^alkylamino, di(Ci^ alkyljamino, thio, C1-6 alkylthio, C1-6 alkyIsulfmyl, C1-6alkylsulfonyl, carbamyl, Ci-6alkylcarbamyl, di(Ci^ alkyl)carbamyl, carboxy, CYs alkylcarbonyl, Cm alkoxycarbonyl, Ci-6alkylcarbonylamino, Cj. & alkylsulfonylamino, aminosulfonyl, C i-s alkylaminosulfonyl, di(Cw alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6alkyl)aminosulfonylamino, 10 aminocarbonylamino, C alkylaminocarbonylamino, and di(C]^ alkyl)aminocarbonylamino. In some embodiments, groups X!, R1, Rbi, Rci, Rdi, Cy, RA, R3, R \ R5, R6, R7, R8, Ra+, RM, R“4, Ra4, and R° are as defined above, and R2 is Cy. In some embodiments, groups X1, R1, Rd!, Rc!, RdI, Cy, RA, R-\ R4, R’, Rb, R', R8, Ra4, Rm, Rc4, Ra4, and Rn are as defined above, and R2 is C(O)NRciRdi. In some embodiments, groups X1, R1, Roi, Rcl, Rdi, Cy, RA, R3, R4, R5, R6, R7, R8, R34, rc4 Ra4* anj rd are ag above, and R2 is NRc!C(O)Rbl. In some embodiments, the compound is a compound of Formula (V): (V) 20 or a pharmaceutically acceptable salt thereof, wherein: X! is N or CR1; R1 is H, D or Ci^ alkyl; Cy is 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; 25             R3, R4, and R5 are each independently selected from H, D, halo, Ci-a alkyl, Ci-a alkoxy, C?-6 alkenyl, C2-6 alkynyl, Ci^ haloalkyl, C1-6haloalkoxy, CN, OH, andNH?, wherein C1-6 alkyl is optionally substituted with 1, 2, or 3 D; R6, R7 and R8 are each independently selected from H, D, halo, C]< alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, CN, OH, and NH2, wherein Ci-6alkyl is optionally 30 substituted with 1, 2, or 3 D; 2024203916   07 Jun 2024 each Ra is independently selected from D, halo, Ci.g alkyl, Ci-ghaloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-w aryl-C)^ alkyl-, Cs-vcycloalkyl-Cw alkyl-, (5-10 membered heteroaryl)-Ci-6alkyl-, (4-10 membered heterocycloalkyl)-C«alkyl-, CN, NO2, OR34, SRa4, 5 NHORa4, C(O)Rb4, C(O)NR C(O)NRc4(ORM), C(O)ORa4, OC(O)Rb4, OCiOtXR- !Ri!. nrc+r^, nr<*Nrc4Rd4, NR<*C(0)Rm nr^C(O)ORX R'^CtOiX R'JR11 NRc4S(O)Rm, XR 'StO•XR 'dC. NRc4S(O)2RM NRc4S(O)2NRc4Rd4, S(O)RH S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, and OS(O)2RM, wherein the Cw alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg-w aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg.10 aryl-Ci.g 10 alkyl-, C3-7 cycloalkyl-Ci.g alkyl-, (5-10 membered heteroaryl)-Ci-6alky 1-, and (4-10 membered heterocycloalkyl)-C-.galkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RJ substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, Cj-g alkyl, Cj-g haloalky I, C2-6 alkenyl, C2.6 alkynyl, phenyl, C3.7 cycloalky 1, 5-6 membered heteroaryl, 4-7 membered 15 heterocycloalkyl, phenyl-Cwalkyl-, C3-7cycloalkyl-Ci-6alkyl-, (5-6 membered heteroaryl)-Ci-6alkyl-, and (4-7 membered heterocycioalkyl)-Ci-g alkyl-, wherein the Ci-g alkyl, C3-g alkenyl, C2-6 alkynyl, phenyl, C3-7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Cwalkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-6 membered heteroaryl)-Ci-g alkyl-, and (4-7 membered heterocycloalkyl)-Ci..g alkyl- of Ra4, R°4, Rc4, and Rd4 are each 20 optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and R“4 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 25 selected RD substituents; and each Rd is independently selected from D, OH, NO2, CN, halo, Ci-g alkyl, C2-6 alkenyl, C2-6 alkynyl, Cj-g haloalkyl, cyano-Cj-g alkyl, HO-Ci-g alkyl, C1-6 alkoxy-Ci^, alkyl, C3-7 cycloalkyl, Ci-g alkoxy, Ci-g haloalkoxy, amino, Ci-galkydamino, di(Ci-galkyl)amino, thio, Ci.galkylthio, Ci-galkylsulfmyl, Ci-galkylsulfonyl, carbamyl, Cj..galkylcarbamyl, di(Ci-g 30 alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, CMalkoxycarbonyl, C).g alkylcarbonylamino, Cu galkylsulfonylamino, aminosulfonyl, Ci.galkylaminosulfonyl, di(C..galkyl)aminosulfonyl, aminosulfonylamino, Ci-g alkylaminosulfonylamino, di(Ci^alkyd)aminosulfonylamino, aminocarbonylamino, Ci^alkylaminocarbonylamino, and di(Cj-galkyl)aminocarbonylamino. 2024203916   07 Jun 2024 In some embodiments, the compound is a compound of Formula (V): (VO or a pharmaceutically acceptable salt thereof, wherein: 5          X'isNorCR1; R! is H, D or Ci-6 alkyl; Cy is 5-6 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; RJ, R4, and R5 are each independently selected from H, D, halo, Ci-6 alkyl, Ci-6 10 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Cm haloalky 1, C«haloalkoxy, CN, OH, and NH2, wherein C1-6 alkyl is optionally substituted with 1, 2, or 3 D; RR, R' and R8 are each independently selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, OH, and NH2, wherein Ci-6 alkyl is optionally substituted with 1, 2, or 3 D; 15              each Ra is independently selected from D, halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io and-C us alkyl-, C3.7 cycloalky 1-C« alkyl-, (5-10 membered heteroaryl)-C 1-6alkyl-, (4-10 membered heterocycloalky 1)-Ci^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, 20 NRc4Rd4, NRc4NRc4Rd4, Nif 4C(O)Rb4, \ R'ViOjOR". NR' 'C(O)N R"sRd \ N w4S(O)Rb4, NR^S^NR^4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRe4Rd4, and OS(O)2R04, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CN-io aryl, C3-7 cvcloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-k> aryl-Cj^ alkyl-, C3-7cycloalkyI-C1-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 25      membered heterocycloalkyl)-Ci-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R° substituents; each R*4, Rb4, Rc4, and Rd4 is independently selected from H, C« alkyl, Chaloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6alkyl-, Cj-vcycloalkyl-Ci^alkyl-, (5-6 membered heteroaryl)-Ci. 30      6alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6alkyl-, wherein the Ci-e alkyl, C2-6 alkenyl, 2024203916   07 Jun 2024 C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryi, 4-7 membered heterocycloalkyl, phenyl-Ci-s alkyl-, C3.7 cycloalky 1-Cm alkyd-, (5-6 membered heteroaryl)-Ci-s alkyl-, and (4-7 membered heterocycloalkyl)-Cj-6 alkyd- of Ra4, R“!. Rc+, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Ru substituents; 5             or, any Rc4 and R~4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryi or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryi 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; and 10             each Rd is independently selected from D, OH, NO?, CN, halo, Cm, alkyl, C2-6 alkenyl, C?-6 alkynyl, Cm haloalkyl, cyano-Ci-s alkyl, HO-Cj^ alkyl, Ci-gaikoxy-Ci-s alkyd, C3-7 cycloalkyl, Cm alkoxy, Cmhaloalkoxy, amino, Cmalkylamino, di(CM alkyd)amino, thio, Cm alkydthio, Cm alkydsulfmyl, Cj.&alkydsulfonyl, carbamyl, Cmalkylcarbamyl, di(CM alkyl)carbamyl, carboxy, C1-6 alky learbonyl, Cm alkoxy carbonyl, Cm alkylcarbonylamino, Ci. 15      & alkydsulfonylamino, aminosulfonyl, C m alkylaminosulfonyl, di(CM alkyl)aminosulfon.yl, aminosulfonylamino, C« alkydaminosulfonylamino, di(C 1-s alkyd)aminosulfonylamino, aminocarbonylamino, C m alkylaminocarbonylamino, and di(CM alkyl)aminocarbonylamino. In some embodiments, the compound is a compound of Formula (V): 20                                                 (V) or a pharmaceutically acceptable salt thereof, wherein: X1 is N or CR!; R1 is H; Cy is 5-membered heteroaryi, which is optionally substituted with 1, 2, or 3 25 independently selected RA substituents; RJ, R4, and R' are each independently selected from H, D, halo, Cm alkyl, Cm alkoxy, C?^ alkenyl, C?-6 alkynyl, Cm haloalkyl, Cm haloalkoxy, CN, OH, andNH?, wherein Cm alkyd is optional!}' substituted with 1, 2, or 3 D; 2024203916   07 Jun 2024 R6, R' and R8 are each independently selected from H, D, halo, Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, OH, and NH?, wherein Ci-salkyl is optionally substituted with 1, 2, or 3 D; each Ra is independently selected from D, halo, Ci-e alkyl, C« haloalkyl, C2.6 5 alkenyl, C2-6 alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aiyl-Ci^alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, OR*4, SR*4, NHORa4, C(O)Rm, C(O)NRc4Rd4, C(O)NRc4(ORM), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)RM, NRc4C(O)OR*4, NRe4C(O)NRc4Rd4, NRc4S(O)Rb4, 10      X R' St () )X R~! R4\ R:S(O)2Rh\ XR' 'StO! XR- ’R4 S(C))Rb4, StO)NRc1 R;". S(O)2Rb4, S(O)2NRc4Rd4, and OSiQhR04, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-Ci^ alkyl-, C3-7 cycloalkyl-Cws alkyl-, (5-10 membered heteroaryl)-C 1-6alkyl-, and (4-10 membered heterocycloalkyl)-C.-6alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 15      6, 7, or 8 independently selected RD substituents; each R*4, Rw, Rc4, and R44 is independently selected from H, Ci^ alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Cwalkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-6 membered heteroaryl)-Ci-& alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl-, wherein the Ci-e alkyl, C2-6 alkenyl, 20      C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci^ alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-6 membered heteroaryl)-Ci-6 alkyl-, and (4-7 membered heterocycloalkyl)-Ci-6 alkyl- of R*4, R04, Re4, and R44 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R14 substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which 25 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 heteroaiyl 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; and each Rd is independently selected from D, OH, NO2, CN, halo, Ci« alkyl, C2-6 30 alkenyl, C2-s alkynyl, Cj^ haloalkyl, cyauo-Cj^ alkyl, HO-C1-6 alkyd, Ci-salkoxy-Ci-s alkyd, C3-7cycloalkyl, C«alkoxy, Ck haloalkoxy, amino, alkylamino, di(Ci-6alkyl)amino, thio, C1-6 alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carbamyl, Ci-salkylcarbamyl, di(Cj-6 alkyl)carbamyl, carboxy, Cu alkylcarbonyl, Cm alkoxycarbonyl, Ci^atkylcarbonylamino, Cj. 6alkylsulfonylamino, aminosulfonyl, C1..&alkylaminosulfonyl, di(Cj.6alkyl)aminosulfony 1, 2024203916   07 Jun 2024 aminosulfony lamino, Ci-6alkylaminosulfonylamino, di(Cj^alky l)ammosulfony lamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci^ alky l)aminocarbony lamino. In some embodiments, the compound is a compound of Formula (V): 5                                                 (V) or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from 5 membered heteroaryl, which is optionally substituted with 1, 2, or 3 independently selected RA substituents; RJ is Cu6 alkyl, which is optionally substituted with 1, 2, or 3 D; 10             R4 and R' are each independently H, D or Cm alkyl, wherein the Ci^ alkyl is optionally substituted with 1, 2, or 3 D; RR is H, D, Ci-6 alkyl or Ci-6 haloalkyl, wherein each halogen is F, wherein the haloalky] is optionally substituted with 1 or 2 independently selected Y substituents, wherein each Y substituent is independently selected from D, halo, C --6 alkyl, and C-.6 haloalkyl; 15             R7 and R8 are each independently H, D or Ci^ alkyl, wherein the Ci-6 alkyl is optionally substituted with 1, 2, or 3 D; each RA is independently selected from D, halo, Cj« alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, 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 20 NRc4C(O)Rb4, NRc4C(O)ORa4, XR- !C(O)X R' :R!X R'dS(( NR 4. X R' % (NX R':Rd s. NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)RW, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, and OS(O)2Rb4, wherein the Ci-6 alkyl, C2-6 alkenyl, and €2^ alkyny l of RA are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rw, Rc4, and Rd4 is independently selected from H, Ci-6 alkyl, and Ci« 25 haloalkyl, wherein the Ci-6 alkyl of Ra4, Rb4, R04, and Rd4 are each optionally substituted with 1, 2, 3, or 4 independently selected R:) substituents; and each Rd is independently selected from D, OH, NO2, CN, halo, Cw alkyl, C2-6 alkenyl, C2-6 alkynyl, Cj^ haloalkyl, cyano-Cj^ alkyl, HO-C1-6 alkyd, Ci-salkoxy-Ci-s alkyd, C3-7cycloalkyl, C« alkoxy, Ci-6haloalkoxy, amino, alkylamino, di(C«alkyl)amino, thio, 30 C1-6 alkyIthio, Ci-6 alkydsulfinyl, Ci-6alkydsulfonyl, carbamyl, Ci-s alkylcarbamyl, di(Ci-6 2024203916   07 Jun 2024 alkyl)carbamyl, carboxy, Cm alkylcarbonyl, Cm alkoxycarbonyl, Cm alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Cm alkylaminosulfonyl, di(CM alkyl)aminosulfonyl, aminosulfonylamino, Cm alkylaminosulfonylamino, di(C m alkyl)aminosulfonylamino, aminocarbonylamino, Cm alkylaminocarbonylamino, and di(CMalkyl)aminocarbonylamino. 5            In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from 5 membered heteroaryl, which is optionally substituted with 1, 2, 10 or 3 independently selected RA substituents; R3 is Cm alkyl, winch is optionally substituted with 1, 2, or 3 D; R4 and R5 are each 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 haioalkyi, wherein each halogen is F, wherein the 15 haioalkyi 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 haioalkyi; R' and R8 are each independently H, D or Cm alkyl, wherein the Cm alkyl is optionally substituted with 1, 2, or 3 D; each Ra is independently selected from D, halo, Cm alkyl, Cm haioalkyi, CN, ORa4, 20 and NRc4Rd4; wherein the Cm alkyl of RA are each optionally substituted with 1, 2, 3, or 4 independently selected RiJ substituents; each Ra4, Rc4, and Rd4 is independently selected from H, D, Cm alkyl, and Cm haioalkyi, wherein the Cm alkyd of Ra4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, or 4 independently selected R[) substituents; and 25             each Rd is independently selected from D, OH, CN, halo, Cm alkyl, Cm haioalkyi, Cm alkoxy', CMhaloalkoxy, amino, Cm alkylamino, and di(CMalkyl)amino. 2024203916   07 Jun 2024 In some embodiments, the compound is a compound of Formula (V): (VO or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from: , and N N , each of which is 10 optionally substituted by 1 or 2 independently selected RA substituents; R3 is methyl or CD3; R4 and R5 are each H: R° is Ci-6 haloalkyl, wherein each halogen is F; R' and R8 are each H; and each RA is methyl or CD3. In some embodiments, the compound is compound of Formula (VI), (VIb), or (Vic): 2024203916   07 Jun 2024 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound of Formula (VII), (Vllb), or (Vile): or a pharmaceutically acceptable salt thereof. In some embodiments, the compoimd is compound of Formula (VIII), (Vlllb), or (VlIIc): 10 (VIII), (Vlllb), 2024203916   07 Jun 2024 (VlIIc), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from: 2-(3-(5-Amino-6-(l-(methyl-d3)-l / / -pyrazol-5-yl)pyrazin-2-yl)-4-metbylphenyl)- 5 3,3,3-trifhioropropane-l,2-diol; 2-(3-(5-Amino-6-(l-methyl-l / f-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(l.f / -pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol; 10             2-(3-(5-Amino-6-(3-methylisoxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(isothiazol-4-v l)pyrazin-2-yl)-4-methylpheny 1)-3,3,3- trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(isothiazol-5-y l)pyrazin-2-yl)-4-methylpheny 1)-3,3,3 15      trifluoropropane-1,2-diol; 2-(3-(5-amino-6-(3-methylisothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol; 20             2-(3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(oxazol-5-yl)pyrazin-2-yl)-4-methylpheny 1)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(l / / -pyrazol-l-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- 25      trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(lH-l,2,3-triazol-l-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol; (2-(3-(5-Amino-6-(2 / M,2,3-ttiazol-2-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 30              2-(3-(5-Amino-6-(lZf-l, 2,4-triazol-l-y l)pyrazin-2-yl)-4-methylpheny 1)-3,3,3- trifluoropropane-l,2-diol; g. o & g. 6 G> Qi Ui !|Oip-j‘|-9UBdojdojonyifl-g‘g‘g-(jAU9i[d[Xip9ui-f7 -(|X-^-uizB.!Ad(|A-£-uipq9ZE([Xuoj|tis({A-£-[ozBjXd- / / [-|XqpiM-|))-{)-9-ouiim3-g)-£)-j; :9ppnExoqjB9-3"9mzBJAd(|A-p-utu£d” / f£<9ipAqB.ii9i) A;-(pA:oqd(p-z-iiu}rMqp;qpu:-£-\\orp^^                  l)-g-|Xqpui-j)-9-ouiuiB-£ d°’P" t‘Z“aEre?nq°J0sqjBx^      ‘ l‘ I g- 5’ WO 2019 / 226213                                                 PCT / US2019 / 021186 2024203916   07 Jun 2024 (S)-3-amino-A'X2-cyano-2-methyipropyi)-6-(2-(methyl-d3)-5-(l,l,l-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (<S)-3-amino-A,r-(4-hydroxybicyclo[2.2.1]heptan-l-yl)-6-(2-(methyl-d3)-5-(l,l ,1 -trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 5              3-amino-A?-((R)-l-hydroxypropan-2-yl)-6-(2-(metliyl-d3)-5-((S)-l,l,l-trifluoro-2,3- dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (5)-3 -ammo-j¥-(4-hy droxybicy clo [2.1. Ijhexan-1 -y l)~6-(2-(methy l-ds)-? -(1,1,1- trifluoro-2,3-dihydroxypropan-2-yl)pbenyl)pyrazme-2-carboxamide; 3 -amino-6-(5-((5)-1,1 -difluoro-2,3 -dihy droxypropan-2-y l)-2-(methy I-d3)phenyl) W- 10 ((lS',2S)-2-hydroxycyclohexyl)pyrazme-2-carboxamide; 3-amino-6-(5-((5)-l, l-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)^ ((ljR,2R)"2-hydroxycyc!ohexyl)pyrazine~2-carboxamide; (5)-3-amino-A'r-(4-cyanobicyclo[2.1. l]hexan-l-yl)-6-(5-(l, 1-difluoro-2,3- dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)pyrazine-2-carboxamide; 15             (5)-3-amino-6-(5-(l ,l-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)pbenyl)-N- (tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; (5)-3-animo-6-(5-(l, 1-difluoro-2,3-dihy droxypropan-2-yl)-2-methylphenyl)-Ar- (tetrabydro-2 / 7-pyran-4-yl)pyrazine-2-carboxamide; 3 -amino-6-(5-((5)-1,1 -difluoro-2,3 -dihy droxypropan-2-y l)-2-methylpheny l)-Ar-((5)-1 - 20 hydroxy propan-2-yl)pyrazine-2-carboxamide; 3 -amino-6-(5-(1,1 -difluoro-2,3 -dihy droxypropan-2-yl)-2-methylphenyl)-AA(4-hy droxybicy clo [2.2.1 jheptan-1 -y l)py razine-2-carboxamide; (3-ammo-6-(5-((S)-l,l-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazm-2-yl)((i?)-2-(hydroxymethyl)pyrrolidin-l-yl)methanone; 25             (5)-3-amino-6-(5-(l,l-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-iV- isopropylpyrazine-2-carboxamide; 3 -amino-Ar-(4-cyanobicy clo [2.1. l]hexan-l -yl)-6-(5-(1,1 -difluoro-2,3 -dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxamide; 3 -amino-6-(5-((5)-1,1 -difluoro-2,3 -dihy droxypropan-2-y l)-2-methy lphenyl)-N-(3 - 30      inethyltetrahydrofuran-3-yl)pyrazine~2-carboxamide; and 2-(3-(5-amino-6-(trifluoromethyl)pyrazin-2-yl)-4-methylpheny 1)-3,3,3-trifluoropropane-1,2-diol; or an enationmer, diastereomer or tautomer thereof; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 35 the (S)-enantiomer of one of the preceding com pounds, or a pharmaceutically acceptable salt 2024203916   07 Jun 2024 thereof. In some embodiments, the compound is the dRi-enantiomer of one of the preceding 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): or a pharmaceutically acceptable salt thereof; wherein: X1 is N or CR1; R* is selected from H, D, halo, Ci-6 alkyl, Ci-6 alkoxy, C2.6 alkenyl, Cz-s alkynyl, Cue haloalky], Ci-6 haloalkoxy, CN, OH, and NH2; 10              R2 is selected from ( i()XR : : R3, R4 and R5 are each independently selected from H, D, halo, CN, OH, C k, alkyl, C 1.6haloalky 1, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, C1-6 haloalkoxy, cyano-Cj-6 alkyl, HO-C1-6 alkyl, C1-6 alkoxy-Ci^ alkyl, C3-6 cycloalkyl, amino, Cw, alkylamino, di(CW6alkyl)amino, and C(O)NRcRa, wherein the Cj.& alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; 15             R°, R' and R8 are each independently selected from H, D, Ci-6 alkyl, Ci-6 haloalky 1, C2-6 alkenyl, C2-s alkynyl, C&-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocvcloalkyl, Cs-io aryl-C-.6 alkyl-, C3-W cycloalkyl-Cw alkyl-, (5-10 membered heteroatyl)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, C(O)Rb3, C(O)NRc’Rd’, C(O)NRc3(ORa3), C(O)ORa3, C(=NRe3)Rw, C(=NOH)Rb3, C(=NCN)Rb3, and 20 C(=NRe3)NRCJR<,J, wherein the Ci« alkyl, C2-6 alkenyl, C2.6 alkynyl, Co-10 ary l, C3-10 cycloalkyl, 5-10 membered heteroary l, 4-10 membered heterocycloalkyl, C6-m aryl-C w, alky 1-, C3-10cycloalky 1-Calkyl-, (5-10 membered heteroaryl)-Ci-6 alkvl-, and (4-10 membered heterocycloalkyl)-Ci-&alkyl- of RR, R', and R8 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; and wherein the Cj-ehaloalkyl of R6, R', 25 or R8 is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, Ch-6 alkyl, and Ci^ haloalkvl; or R6 and R' substituents, together with the ring atoms to which they are attached, form a C3-10 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; 2024203916   07 Jun 2024 or R7 and R8 substituents, together with the ring atoms to which they are attached, form a C3.10 cycloalky 1 or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Rc and R“ are each independently selected from H, Ci..& alkyl, C1-6 haloalky 1, C2-6 5 alkenyl, C2-6 alkynyl, Cwo aryl, C3-7 cy cloalky 1, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aiyl-Ci^alkyl-, C3-7 cycloalkyl-Ci.« alkyl-, (5-10 membered heteroand)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Calkyl-, wherein the Ci^ alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-w ary l, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6 alkyl-, C3.7 cycloalkyl-Ci-ealkyl-, (5-10 membered 10     heteroaryl)-Ci-6 alky 1-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R° and Rd, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Rcl and Rd! is independently selected from H, Ci-& alkyl, C1-6haloalky 1, C2-6 alkenyl, C2-6 alkynyl, CXw cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-6 alkyl-, Cs-iocycloalkyl-Ci-Aalkyl-, (5-10 memberedheteroaryl)-Ci-6alkyl-, and (4-10 membered 15      heterocycloalkyl)-C)-6alkyd-, wherein the Cj^ alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, Cwo ary 1-C1-6 alkyl-, C3-10cycloalkyl-Ci-salkyl-, (5-10 membered heteroaryl)-C 1-6alkyl-, and (4-10 membered heterocycloalky 1)-C 1-6alkyl- of Rc! and R“! are each optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected Ra substituents; 20             or, any Rci and Ral, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkvl 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 Ra3 is independently selected from H, Ci..& alkyl, C1-6 haloalky 1, 25      C2-6 alkenyl, C2-6 alkynyl, C&.w aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkvl, C6-io aryl-C-.6 alkyl-, C3-10 cycloalkyl-Ci-s alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkvl, Cs-io aryl-Ci-6alkyl-, C3.10 cycloalky l-Ci-6alkyl-, (5-10 membered 30 heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra3, Rb3, R00, and RdJ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; or, any RC5 and Ra3, 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 35 heterocycloalkyl group, wherein the 5- or 6-membered beteroaryl or 4-, 5-, 6-, or 7-membered 2024203916   07 Jun 2024 heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RH substituents; each ReJ is independently selected from H, OH, CN, Cw alkyl, Cwalkoxy, C)^ haloalky 1, Cmhaloalkoxy, C2-6 alkenyl, alkynyl, Cg-w aryl, C3-10 cycloalkyl, 5-10 5 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cg-io aiyl-Ci^ alkyl-, C3-10 cycloalkyl-Ci-ealkyl-, (5-10 membered heteroary l)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyI)-C]-6 alkyl-; each Ra is independently selected from D, halo, C]^ alkyd, Cs^haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cmo ary l, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered 10 heterocycloalkyl, Cg-to aryI-C1-6 alkyl-, C3-7 cycloalky 1-Ck, alkyl-, (5-10 membered heteroary l)-Ci-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, ORa4, SIC4, XHOR". C(O)Rb4, C(O)N R'dCf CtOiXRMOR1'1). C(O)ORa4, OC(O)Rb4, OC(O)XR 'RC NRc4R“4, NRc4NRc4Rd4, NR^CCOiR”4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)RM, C( XOH jR”. C(==NCN)Rb4, Ct XR1 jN R 'R11. NRc4C(==NRe4)NRc4Rd4, XCXi XRblfC 15 NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O)2Rm, NRc4S(O)2NRc4Rd4, S(O)RW, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, OS(¢)){ XR !    . OS(O)2Rb4, SF5, P(O)Rf4R®4, OP(O)(ORh4)(ORi4), P(O)(ORh4)(ORi4), and BRj4Rk4, wherein the C]^ alkyl, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cmo aryl-C i.galky 1-, C3.7 cycloalky 1 20      Cj-g alkyl-, (5-10 membered heteroary l)-Cj-g alkyl-, and (4-10 membered heterocycloalkyl)-Cj. 6 alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Rb is independently selected from D, halo, Ci-g alkyl, Ci-g haloalky 1, C2-6 alkenyl, Ci< alkynyl, Cg.10 aryl, C3-7 cycloalkyl, 5-10 membered heteroary!, 4-10 membered 25 heterocycloalkyl, Cg-w aryl-Cw alkyl-, C3-7 cycloalkyl-C)^ alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, (4-10 membered heterocycloalky l)-Ci-6 alkvl-, CN, NO2, OR82, SRa2, XHOR!\ C(O)Rb2, C(O)XRRC(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, X R' C(O)R!NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(==NOH)Rb2, C(==NCN)Rb2, Ci XC' iX•C IC2. NRc2C(==NRe2)NRc2Rd2, XR ('( XIC2iRh . 30 XR- ('( XO1 DMC iV. NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NR StO) IC2. NRc2S(O)2NRc2Rd2, S(O)Rb2, S(OiXR R!'. StOs -R \ S(OpXk2dC2. OS(O)rCJR2}R“2. OS(O)3Rb2, SF5, PtDiK 2R ", OP(O)(ORh2)(OR12), P(O)(OR112)(ORi2), and BRX-fV2, wherein the C^ alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroary 1, 4-10 membered heterocycloalkyl, Cg-w aryl-C 1.6alkyl-, C3..7 cycloalkyl- 35 Cugalkyl-, (5-10 membered heteroary 1)-C 1-6alkvl-, and (4-10 membered beterocycloalkyl)-Ci- 2024203916   07 Jun 2024 6 alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7. or 8 independently selected RM substituents; each R“, Rb2, Rc2, and R“2 is independently selected from H, C)^ alkyl, C)^haloalkv 1, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 5     membered heterocycloalkyl, Ce-io aryl-Ci-6alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryi)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci^ alkyl-, wherein the Cu alkyl, C2-6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cr-io atyd-Ci^alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky l)-Ci-6 alkyl- of R32, Rb2, Rc2, and 10 Rdz are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; or, any Rc2 and Ra2 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 15 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, Cw alkyl, Cw alkoxy, Ci-& haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aryl-Ci-6 alkyl-, C3..7 20      cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-C)-6alkyl-, and (4-10 membered hetereocycloalkyi)-Ci-6 alkyl-; each R° and Rg2 is independently selected from H, C1-6 alkyl, Cw alkoxy, Ci-& haloalkyl, Ci-6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io aryl-Ci-6alkyl-, C3.7 25      cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-C[-6alkyl-, and (4-10 membered hetereocy cloalky 1)-C 1 -s alky' 1-; each Rh2 and R12 is independently selected from H, Ci-6 alkyl, Ci-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io aryl-Ci-6 alkyl-, C3-7cycloalkyl-Ci-6alky 1-, (5-10 membered 30 heteroatyl)-C 1-6 alkyl-, and (4-10 membered betereocycloalkyl)-Cj^ alkyl-; each Rj2 and Rk2 is independently selected from OH, Ci-6alkoxy, and haloalkoxy; or any R2 and Rk2 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 Ci-6haloalkyl; 2024203916   07 Jun 2024 each R34, RM. Rc4, and Ra4 is independently selected from H, Ch alkyl. Chhaloalky 1, alkenyl, alkynyl, Cs-io aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocvcloalkyl, Cs-.o aryl-Ch alkyl-, C3-7 cycloalkyl-Chalkyl-, (5-10 membered heteroaryl)-Ch alkyl-, and (4-10 membered heterocycloalky 1)-Chalkyl-, wherein the Ch 5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cwo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocvcloalkyl, C6-io aryl-Ch alkyl-, C3-7 cycloalkyl-Ch alkyl-, (5-10 membered heteroatyl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ch alkyl- of R34, R04, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R:) substituents; 10             or, any Rc4 and Ra4 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 heteroaiyl or 4-, 5-, 6-, or 7-membered heterocycloalkyd group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected substituents; 15            each Re4 is independently selected from H, OH, CN, Cm alkyd, Ch alkoxy, Ch haloalkyl, Ch haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cg-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered hetereocycloalkyl, C&-io aryl-Ch alkyl-, C3-7 cycloalkyl-Ch alkyl-, (5-10 membered heteroaiyl)-Chalkyl-, and (4-10 membered hetereocy cloalkyl)-Ch alky 1-; 20             each Rf4 and Rg4 is independently selected from H, Ch alkyl, Ch alkoxy. Ch haloalkyl, Chhaloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cb-10 aryl, C3-7 cycloalkvl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cg-w ary 1-Ch alkyl-, C3-7 cycloalky1-Chalkyl-, (5-10 membered heteroaryl)-Ch alkyl-, and (4-10 membered hetereocy cloalky 1)-Ch alkyl-; 25             each Rm and R14 is independently selected from H, Ch alkyd. Chhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaiyl, 4-10 membered hetereocycloalkyl, C6-jo aryl-Chalkyl-, C3-7 cycloalkyl-Ch alkyl-, (5-10 membered heteroaryl)-Ch alkyl-, and (4-10 membered hetereocycloalkyl)-Ch alkvl-; each Rj4 and Rk4 is independently selected from OH, Ch alkoxy, and Ch haloalkoxy; 30             or any 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 Ch alkyl and Chhaloalkyl; each Rd is independently selected from H, D, halo, Ch alkyl, Chhaloalkyl, C2-6 alkenyl, C2.6 alkynyl, Cs-io ary l, C3-7cycloalkyl, 5-10 membered heteroary l, 4-10 membered 35 heterocycloalkyl, Cs-w aiyl-Ch alkyl-, C3-7 cycloalkyl-Ch alkyl-, (5-10 membered 2024203916   07 Jun 2024 heteroaryl)-Cj-6 alkyl-, (4-10 membered heterocycloalkyl)-Ci-6 alkyl-, CN, NO2, OR35, SR35, NHORa5, C(O)Rb5, C(O)NRc5R®, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5R“5, NR^NR^R®. NRc5C(O)Rb5, NRc5C(O)OR35, XR'GONR'I^ C(=NRe5)Rb5, C( X()H jRb\ C(=NCN)Rb5, Ct XRjXR'~Rd\ ; XO\Cr. NRX ! XRXk1". 5 XR'X t XC)H)XR''R X NRc5C(-NCN)NRc5Rd5, NRc5S(O)Rb5, XR-'StO)XR'-RX XlC'SiO!2R1”, NR StOi XR R . S(O)Rb5, SfOjXR 'Rx S(O)2Rc5, StOyXk'R OSi())( XR- ';Rb\ OS(O)2Rb5, SF5, PtOsR'k". OP(O)(ORb5)(ORX PtOROK'btOR ). and BR^'R1”, wherein tlie Cs-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Cmo aiyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalky i, Cmo aryl-C 1.5 alky 1-, C3.7 cycloalky I- 10      Ci-6 alkyl-, (5-10 membered heteroaryl)-C1-6alkyl-, and (4-10 membered heterocycloalkyl)-Ci- 6 alkyl- of Rd are each optionally substituted with 1, 2, 3, or 4 independently selected Rfc substituents; each R35, Rb3, Rc5, and R“5 is independently selected from H, C)^ alkyl, C)^haloalkv 1, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3.7 cycloalkyl, 5-10 membered heteroaryl, 4-10 15 membered heterocycloalkyl, Cr-jo atyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-R alkyl-, wherein the Cu alkyl, C2-6 alkenyl, C2-6 alkynyl, C&-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cr-jo atyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalky 1)-C 1.6 alkyl- of R35, Rba, R~ '. and 20 Rd5 are each optionally substituted with 1, 2, 3, or 4 independently selected Rc substituents; or, any Rc’ and R“5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroary l 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 R" 25 substituents; each Re5 is independently selected from H, OH, CN, Ci-6 alkyl, Ct-6 alkoxy, C1-6 haloalkyl, Ci^haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cmo aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Ce-io aiyl-C 1-6 alkyl-, C3-7 cycloalkyl-Ci-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered 30 hetereocycloalkyl)-Ci-6 alkyd-; each Rf5 and Rg’ is independently selected from H, Ci-e alkyl, Ci-6 alkoxy, Ci« haloalkyl, Ci-6haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, Cs-io aiyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io ary 1-Ci-r alkyl-, C3-7 cycloalky 1-C1-6alky 1-, (5-10 membered heteroaryl)-Ci-6alkyl-, and (4-10 membered 35 hetereocycloalkyl)-C i-r alkyl-; 2024203916   07 Jun 2024 each Rto and R15 is independently selected from H, alkyl, Ci^haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aryl-C 1-6 alkyl-, C3-7cycloalkyl-C)-6alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyI)-Ci^ alkyl-; 5             each Rj5 and R*5 is independently selected from OH, Ci-salkoxy, and C1-6haloalkoxy; or any Rj5 and RK 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 alkyd and Cushaloalkyl; each Rfc is independently selected from H, D, halo, Ci-6 alkyl, Ci-6 haloalky 1, C2.6 10 alkenyl, C2-6 alkynyl, C&-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-w aryl-C 1-6 alkyl-, C3-7 cycloalkyl-Ci-s alkyl-, (5-10 membered heteroaryl)-Cj-6 alkyl-, and (4-10 membered heterocy cloalky l)-Ci-6 alkyl-, CN, NO?, ORa6, SRaS, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORaS, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rds, \R ' \NR-;C(O)Rbf'. NRc6C(O)OR36, XJVaC(O!\ IVdbN 15 C(=NRe6)Rbs, C(=NOH)Rb6, C(=NCN)Rbs, C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc5C(=NRe5)Rb5, NRc6C(=NOH)NRc5Rd5, NRc6C(=NCN)NRc6Rd6, NRc5S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O)2Rb6, NRC6S(Oi \ R 'Rd\ S(O)Rb6, Ss O)XR' 'R1 \ SiObRN S(O)2NRc6Rd6, OS(O)(=NRe6)Rb5, OS(O)2Rbs, SF5, P(O)RfsRgS, OP(O)(ORh6)(ORl6), P(O)(ORn6)(OR’6), and BRJRRkn, wherein the C1..6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, 20      C3-7 cycloalkyd, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6 alkyl-, C3-7 cycloalky I-C1-6alkyd-, (5-10 membered heteroaryl)-C 1-6alky 1-, and (4-10 membered heterocycloalkyl)-Ci-6 alkyl- of RE are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; each Ra6, Rbs, RCR, and RaS is independently selected from H, C1..& alkyl, Ci-6 haloalky I, 25      C2-6 alkenyl, C2-s alkynyl, Cs-w aryl, C3-7cycloalkyd, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs-io aryl-C.-s alkyl-, C3.7 cycloalkyl-Ci-s alky 1-, (5-10 membered 30 heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-s alkyl- of R®6, RbS, Rcb, and Rd6 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; or, any Rc6 and Rao 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 35 heterocycloalky l group, wherein the 5- or 6-membered beteroaryd or 4-, 5-, 6-, or 7-membered 2024203916   07 Jun 2024 heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; each ReS is independently selected from H, OH, CN, Cm alkyl, Cmalkoxy, Cm haloalky 1, Cmhaloalkoxy, C2-6 alkenyl,    alkynyl, Cs-w aryl, C3-7 cycloalkyl, 5-10 5 membered heteroaryl, 4-10 membered hetereocycloalkyl, Cs-io aiyl-CM alkyl-, C3-7 cycloalkyd-CM alkyl-, (5-10 membered heteroaryd)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-CM alkyl-; each Rfs and Rgb is independently selected from H, Cm alkyl, Cm alkoxy, Cm haloalkyl, CMhaloalkoxy, Cz-s alkenyl, C2.6 alkynyl, Cs-io aryl, C3.7 cycloalkyl, 5-10 10 membered heteroaiyl, 4-10 membered hetereocy cloalkyl, Ca-jo aryl-Ci-6 alky 1-, C3-7 cycloalkyl-CMalkyl-, (5-10 membered heteroaryl)-C 1-6 alkyd-, and (4-10 membered hetereocy cloalky 1)-C 1-6 alky 1-; each Rhs and R16 is independently selected from H, Cm alkyd, Cj.*haloalkyl, C2-6 alkenyl, Cz-s alkynyl, Cs-io ary l, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered 15 hetereocycloalkyl, Cs-io aryd-CM alkyd-, C3-7 cycloalky 1-C malkyl-, (5-10 membered heteroaryl)-Ci-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C1-6 alkyl-; each RjD and R*6 is independently selected from OH, Cmalkoxy, and Ci-ghaloalkoxy; or any RJb and Rks 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 20 with 1, 2, 3, or 4 substituents independently selected from Cm alkyd and Cmhaloalkyl; each R& is independently selected from H, D, halo, CN, NOz, SFs, C1-6 alkyl, Cm alkoxy, CMhaloalkyl, Cm alkenyl, C2-6 alkyny l, Cs-jo and., C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyd, Ce-io aiyl-CM alky 1-, C3-7 cycloalky 1-Cm alkyl-, (5-10 membered heteroaryd)-CM alkyl-, and (4-10 membered heterocycloalkyl)-Ci-6alkyl; and 25             each Rm is independently selected from H, D, OH, NO?., CN, halo, Cm alkyd, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, cyano-Ci-6 alkyl, HO-Cm alkyd, C« alkoxy-C1-6 alkyl, C&-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cg-io aryl-Ci-6alkyl-, C3-7 cycloalkyd-Cwalkyl-, (5-10 membered heteroaryd)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-CM alkyl, Cm alkoxy, Cmhaloalkoxy, amino, Cm alkylamino, 30 di(CMalkyl)amino, thio, Cm alkylthio, Cm alkyl sulfinyl, Cj-s alkylsulfonyl, carbamyl, Cm alkylcarbamyl, di(C m alky l)carbamyl, carboxy, Cm alkylcarbonyl, Cm alkoxy carbonyl, Cm alkylcarbonylamino, Cm alkydsulfonylamino, aminosulfonyl, Cm alkylaminosulfonyl, di(CM alkyl)aminosulfonyl, aminosulfonylamino, Cm alkylaminosulfonylamino, di(CM alkyl)aminosulfonylamino, aminocarbonylamino, Cm alkylaminocarbonylamino, and di(CM 35 alkyl)aminocarbonylamino. 2024203916   07 Jun 2024 It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any 5 suitable subcombination. At various places in the present specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent include both the forward and backward forms of the lurking substituent. For example, -NR(CR’R”)n- includes both -NR(CR’R”)n- and -(CR’R”)nNR-. Where the structure clearly requires a linking group, 10 the Markush variables listed for that group are understood to be linking groups. The term “n-membered” where n is an integer typically describes the number of ringforming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocvcloalkyd ring, pyrazolyl is an example of a 5-membered heteroary l ring, pyridyl is an example of a 6-membered heteroaryl ring, and 15      1,2,3,4-tetrahydro-naphthalene is an example of" a 10-membered cycloalkyd group. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can 20 replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency. As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as wherein “at each occurrence ‘variable’ is selected from.” Throughout the definitions, the term “Cr..m” indicates a range which includes the 25 endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-3, C1-4, C1-6, and the like. As used herein, the term “Cn-m alkyd”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, havmg n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups 30 such as methyl (Me), ethyl (Et), n-propyl (w-Pr), isopropyl (iPr), u-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l-butyl, w-pentyl, 3-pentyl, w-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double 35 carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not 2024203916   07 Jun 2024 limited to, ethenyl, n-propenyl, isopropenyl, w-butenyl, sec-butenvl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, “Ctwn alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not 5 limited to, ethynd. propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term “Cn-m alkoxy", employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n- 10 propoxy and isopropoxy), butoxy (e.g., / ?~butoxy and te / d-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 formula -NH?. As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., 15 having 2, 3 or 4 fused rings). The term “Cn.mand” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 5 to 14 carbon atoms. In some embodiments, the and group has from 5 to 10 carbon atoms, hi some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, die and is phenyl. 20             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. In some embodiments, a halo is Cl. As used herein, “Cn-mhaloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF3 and OCHF2. In some 25 embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or I to 3 carbon atoms. As used herein, the term “Cn-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl 30 group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCI3, CHCE, C2CI5 and the like. 2024203916   07 Jun 2024 As used herein, the term “Cn-m alkvlamino” refers to a group of formula -NH(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 “Cn.m alkoxy carbonyl” refers to a group of formula -C(O)O-5 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 “Cn-n> alkylcarbonyl” refers to a group of formula -C(O)-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. 10             As used herein, the term “Cn-m alkylcarbonylamino” refers to a group of formula -NHC(O)-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 “Cn.m alkoxy carbonylamino” refers to a group of formula -NHC(O)O(Cn-m alkyl), wherein the alkyl group has n to m carbon atom. In some 15 embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfonylamino” refers to a group of formula -NHS(O)2-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 “aminosulfonyl” refers to a group of formula -S(O)2NH2. 20             As used herein, the term “Cn.malkylaminosulfonyl” refers to a group of formula -S(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)aminosulfonyl” refers to a group of formula -S(O)2N(alkyI)2, wherein each alkyl group independently has n to m carbon atoms. In 25 some embodiments, each alkyl group has, independently, I to 6, I to 4, or 1 to 3 carbon atoms. As used herein, the term “aminosulfonylamino” refers to a group of formula -MlStO).Mb. As used herein, the term “Cn-malkylaminosulfonylamino” refers to a group of formula 30 -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-malkyI)aminosulfonylamino” refers to a group of formula -NHS(O)2N(alkyI)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 35 carbon atoms. 2024203916   07 Jun 2024 As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2. As used herein, the term “Cn-m alkylaminocarbonylamino” refers to a group of formula -NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some 5 embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(C1M1 alkyl)aminocarbonylammo” refers to a group of formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyd group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. 10             As used herein, the term “Cn-malkylcarbamyl” refers to a group of formula -C(O)- NH(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 “thio" refers to a group of formula -SH. As used herein, the term “Cn.m alkylthio” refers to a group of formula -S-alkyl, 15 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 “Cn-m alkylsulfiny l” refers to a group of formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, I to 4, or 1 to 3 carbon atoms. 20             As used herein, the term “Cn-malkydsulfonyr refers to a group of formula -S(O)2- 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 “carbamyl” to a group of formula -C(O)NH2. As used herein, the term “carbonyl”, employed alone or in combination with other 25 terms, refers to a -C(O)- group. As used herein, the term “cyano-Ci-6 alkyl” refers to a group of formula -(Ci^ alkylene)-CN. As used herein, the term “HO-Ci-6 alkyl” refers to a group of formula -(Calkylene)-OH. 30             As used herein, the term “HOC us alkyl” refers to a group of formula -(Ci-3 alkylene)- OH. As used herein, the term “Cue alkoxy-Ci^ alkyl” refers to a group of formula ~(Cu6 alky lene)-O(C i-3 alkyl). As used herein, the term “Ci-6 alkoxy -Ci-3 alkyl” refers to a group of formula -(Ci-6 35 alkylene)-O(Ci-3 alkyd). 2024203916   07 Jun 2024 As used herein, the term “carboxy” refers to a group of formula -C(O)OH. As used herein, the term “di(C)WB-alkyl)amino” refers to a group of formula -N(a1kyl)2, wherein the two alkyl groups each has, independently, 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. 5             As used herein, the term “di(Cn.m-alkyl)carbamyl” refers to a group of formula - C(O)N(alkyl)2, wherein the two alkyl groups each has, independently, 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 “aminocarbonyloxy” refers to a group of formula -OC(O)NH2. 10             As used herein, the term “Cj-3 alkylcarbonyloxy” refers to a group of formula - OC(O)(Ci-3 alkyl). As used herein, the term “C1-3 alkylaminocarbonyloxy” refers to a group of formula ■OC(O)NH(Ci-3 alkyl). As used herein, the term “di(Ci-3 alkyl)aminocarbonyloxy” refers to a group of 15 formula -OC(O)N(Ci-3 alkyl)2, wherein the two alkyl groups each has, independently, 1 to 3 carbon atoms. As used herein, “cycloalky I” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused rings) groups, spirocycles, and bridged rings (e.g., a bridged 20 bicycloalkyl group). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring 25 can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring-forming carbons (i.e., C3-14). In some embodiments, the cycloalkyl is a C3-14 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4.7 monocyclic cycloalkyl. In some embodiments, the 30 cycloalkyl is a C4-10 spirocycle or bridged cycloalkyl (e.g, a bridged bicvcloalkyl group). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpmyl, norcamyl, cubane, adamantane, bicyclo[l.l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.l]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and 2024203916   07 Jun 2024 the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopenty l, or cyclohexyl. As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from 5 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 heteroatom ring members independently selected from N, O, S and B. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently 10 selected from N, O, S and B. In some embodiments, the heteroaryl is a 5-14 membered monocyclic, bicyclic heteroaryl, or tricyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1,2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 15     5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S and B. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl ring. 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 20 or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Example 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, 25 benzisoxazole, imidazo[l, 2-b]thiazole, purine, triazine, thieno[3,2-b]pyridine, imidazo[l,2-a]pyridme, 1,5-naphthyridine, lB-pyrazoio[4,3-6]pyridine and the like. A five-membered heteroaiyl is a heteroaryl group having five 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 or B. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, 30 imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-fhiadiazolyI, 1,3,4-oxadiazolyl and l,2-dihydro-l,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 2024203916   07 Jun 2024 selected from N, O, S and B. Exemplary' 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 5     more of the ring-forming carbon atoms is replaced by a heteroatom selected from N, O, S and B, and wherein the ring-forming carbon atoms and heteroatoms can 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 (e.g., having 2, 3, or 4 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3-14- or 4-14- or 3-12- or 4-12-, or 3-10-, or 10      4-10- or 3-7- or 4-7- or 5-6-membered heterocycloalkyl groups. Heterocycloalkyl groups can also 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 can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 15      3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A 20 heterocycloalkyl group containing a fused aromatic ring can be attached through any ringforming atom including 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 ringforming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has I to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 25 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 monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S and B and having one or more oxidized 30 ring members. Example heterocycloalkyl groups include pyrrolidin-2-one, l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidmyl, isoxazohdinyl, isothiazolidinyl, pyrazolidinyL oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, 1,2,3,4 35 tetrahydroisoquinoline, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1 .OJhexanyl, 2024203916   07 Jun 2024 oxabicyclo[2.1. l]hexanyl, azabicyclo[2.2. l]heptanyl, diazabicyclo[2.2. l]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2Joctanyl, azaadamantanyL diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl, 5 diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl, azaspiro[2.5Joctanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5jdecanyl, diazaspiro[4.5Jdecanyl, diazaspiro[4.4]nonanyl, oxa-diazaspiro[4.4]nonanyl and the like. 10             As used herein, “Co-p cycloalky l-C^m alkyl-” refers to a group of formula cycloalkyl alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. As used herein “Cop aryl-C^m alkyl-” refers to a group of formula aryl-alkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon 15 atoms. As used herein, “heteroaiyl-Cn-m alkyl-” refers to a group of formula heteroarylalkylene-, wherein alkylene linking group has n to m carbon atoms. As used herein “beterocycloalkyl-CIMn alkyl-" refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms. 20              At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position. 25             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=O or C(O)), or attached 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, e.g., RM or RA, are independently selected at each occurrence 30 from the applicable list. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on 35 how to prepare optically active forms from optically inactive starting materials are known in 2024203916   07 Jun 2024 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 be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are 5 described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the / Rj-configuration. In some embodiments, the cosnpound has the (^-configuration. The Formulas (e.g., Formula (I), etc.) provided herein include stereoisomers of the compounds. Resolution of racemic mixtures of compounds can be carried out by any of numerous 10 methods known in the art. An example method includes fractional recrystallizaion using 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 optically active camphorsulfonic acids such as P 15 camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomericallv pure forms of a-methylbenzylamine (e.g., S andR 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 column packed 20 with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are 25 isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone --- enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine -- imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H- 30 pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated. 2024203916   07 Jun 2024 In some embodiments, preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts. In some embodiments, the compounds provided herein, or salts thereof, are 5 substantially isolated. By “substantially isolated’’ is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include coinpositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 10 about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric 15 forms unless otherwise specified. The phrase “pharmaceutically acceptable” is employed herein to refer to those cosnpounds, materials, coinpositions, and / or dosage forms which are, within the scope of sound 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 20 complication, commensurate with a reasonable benefit / risk ratio. The present application also includes pharmaceutically acceptable salts of the compounds described herein. The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent 25 compound is modified by converting an existing acid 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 acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for 30 example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains 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 base or acid in water or in an organic solvent, or in a mixture of the two; 35 generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso- 2024203916   07 Jun 2024 propanol, 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 herein by reference in its entirety. 5 Synthesis As will be appreciated bv those skilled in the art, the compounds provided herein, including salts and stereoisomers thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. Compounds of Formula (I) can be prepared as shown in Scheme 1. Suitable starting 10 materials 1-1, where Y1 and Yz are independently a halogen (e.g., CI, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be converted to an appropriate substituted metal 1-2 (e.g., M1 is BtOH i . Bpin, BILK. SnfBuh, 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(II), or 15 bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex 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 OMs) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dicMorobis(triphenylphosphine)palladium(II), or [1, T- 20 bis(diphenylphospbmo)ferrocene]dichloropalladium (II), 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 letrakis(triphenylphosphine)palladium(0) or [ 1,1'25 bis(diphenylphosphino)ferrocene] dichloropalladium (11)) to give 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 re-oxidant such as N-methylmorpholineW-oxide, or AD-mix a or AD-mix P). Intermediate 1-5 can be converted to an appropriate substituted metal 1-6 (e.g., M2 is B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn) under 30 standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II), bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, or Pd2(dba)3 and a ligand (such as 2-dicyclohexylpbosphino-2',4',6'-tri-iso-propyl-l ,T-biphenyl) and a base, such as potassium acetate) and then coupled to 1-7 where Y’ and Y7 are 35 independently a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under 2024203916   07 Jun 2024 standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetralds(iriphenylphosphine)palladium(0) or [1,1'- bis(diphenylphospbino)ferrocene]dicbloropalladium (II), complex with dichlorometbane and a base (e.g., a carbonate base, such as sodium carbonate or potassium carbonate)) or standard 5 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)palladinm(0) or [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (11)) to give to give compound 1-8. Intermediate 1-8 can be converted to compounds of Formula (I) by cross-coupling 10 with an appropriate metal R2-M (where M 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,r-bis(diphenylpbosphino)ferrocene]dichloropalladium (II), complex with dichlorometbane and a base (e.g., a carbonate base such as sodium carbonate or potassium carbonate)) or 15 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(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)). Alternatively, compounds of Formula (I) can be prepared from intermediate 1-8 by reacting with a nucleophile under 20 SNAr conditions (e.g., 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 also be prepared by reversing the order of the last two steps of Scheme 1. Beginning with a suitably substituted intermediate 1-7, where Y3 and Y7 are independently a halogen (e.g, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), coupling to install R7 can be perfomed before coupling 25 w’ith intermediate 1-6, to afford compounds of Formula (I). 2024203916   07 Jun 2024 Scheme 1. R8 Suzuki, Stille metalation HO HO or Negishi 1-7 Suzuki, Stille or Negishi dihydroxylation orR2-H SNAr R2-M Suzuki, Stille or Negishi io 15 20 Compounds of Formula (1) can be prepared as shown in Scheme 2. Beginning with an appropriately substituted 1,4-dibromobenzene 2-1, sequential reaction with strong base (e.g., wBuLi) at low temperature (e.g., -78 °C), followed by reaction with a carboxylic acid derivative R6C(O)-L!, such as an ester (methyl or ethyl ester) (e.g., methyl trifluoroacetate or ethyl trifluoroacetate) or a Weinreb amide (e.g., 2,2-difluoro-Ar-methoxy-Ar-methylacetamide), followed by in situ treatment with a second equivalent of strong base (e.g., wBuLi) at low temperature (e.g., -78 °C), followed by a second electrophile R’-L2 (wherein L2 is a suitable leaving group (e.g., halogen, such as Cl, Br or I or a mesylate or tosylate)) affords ketone intermediate 2-2. It will be appreciated by one skilled in the art that the order of the two steps can be reversed and the two steps can also be performed separately, stepwise. Intermediate 2-2 can be halogenated by exposure to halogenating conditions to introduce Y2 (e.g., bromine in the presence of AlCh and mild heating), or A-halo-succinimide (e.g., N-bromosuccinimide) and sulfuric acid in acetic acid at elevated temperature (e.g., 80 °C)) to afford intermediate 2-3. Intermediate 2-3 can be olefinated to afford intermediate 2-5 under standard conditions for olefination (e.g., Wittig conditions with an ylide such as 2-4, where Y9 can be a phenyl, generated by reacting a phosphonium salt with a strong base (e.g., w-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., in situ generation of methylenetriphenylphosphorane from the rhodium(I)-catalyzed decomposition of trimethvlsilyldiazomethane in the presence of tripbenylphosphine and 2-propanol)). 2024203916   07 Jun 2024 Intermediate olefin 2-5 can be converted to compounds of Formula (I) by the methods outlined in Scheme 1. Scheme 2. Formuta ! 5            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 / Buh, 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 10 tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or [l,r~bis(diphenylphosphino)ferrocene]dichloropalladium (II), 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(triphenylpbosphine)panadium(0)) or standard Negishi conditions (e.g., in the 15 presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) optionally in the presence of an additive such as copper(l)iodide) to afford intermediate 3-2. Intermediate 3-2 can then be halogenated by reaction with a reagent suitable for introducing the halogen Y ' (e.g., N-halosuccinimide such as Y-iodosuccinimide, A’-bromosuccinimide or A-chlorosuccinimide). 20 Intermediate 3-3 bearing a suitable halogen Y' (e.g., Cl, Br or I) can be elaborated to provide compounds of Formula (I) as shown in Scheme 1. 2024203916   07 Jun 2024 Scheme 3. nh2 HzN^N^ r2.m H2N          halogenation H2N N Scheme! Y^X1^         R^X1*             R^X’^Y7 3-1                         3'2                               3-3 Compounds of Formula (I) wherein R / ' is an amide or a heterocycle can also be prepared as shown in Scheme 4. The group Y3 of halo-substituted intermediate 4-1 (wherein 5 Y3 is Cl, Br or I) can be converted to a nitrile group via 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 as tetrakis(triphenylphosphine)palladium(0) or [LT-bis(diphenylphosphino)ferrocene]dichloropalladium (II)) to afford intermediate 4-2. The 10 nitrile substituent of intermediate 4-2 can be converted to heterocycle-substituted compounds of Formula (I) by methods known to one skilled in the art (e.g., heating an appropriately substituted acyl hydrazide in the presence of an alkoxide base in an alcoholic solvent (e.g., NaOMe in MeOH or NaOEt in EtOH) to form a triazole; heating with an azide source such as NaN3 to form a tetrazole). Nitrile containing intermediates 4-2 can also be converted to amide 15 intermediates 4-4 (compounds of Formula (I) wherein Rz 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 using standard amide coupling conditions (e.g., HATU). The group Y3 of halo-substituted intermediate 4-1 (wherein Y3 is Cl, Br or I) can be converted to an ester intermediate 4-3 under standard conditions for carbonylation (e.g., in the 20 presence of a palladium catalyst, such as [1,T-bis(diphenylphosphino)ferrocene]dichloropalladium, carbon monoxide, and an alcohol RaiOH such as methanol or ethanol). Ester 4-3 can be converted to amide 4-4 (compounds of Formula (I) wherein R2 is an amide group) using amination conditions (e.g., by reacting with an amine such as RciRdiNH in the presence of AIMe3). Alternatively, ester 4-3 can be 25 converted to amide 4-4 under standard conditions for hydrolysis, such as exposure to hydroxide base (e.g., LiOH, NaOH, KOH in water and a cosolvent such as THF, MeOH or EtOH) to furnish a carboxy lic acid, followed by coupling of the resulting acid with RclRdlNH using standard amide coupling conditions (e.g., HATU). Alternatively, the group Y3 of halo-substituted intermediate 4-1 can be converted directly to an amide 4-4 under standard 30 conditions for carbonylation (e.g., in the presence of a palladium catalyst, such as [1,1'- 2024203916   07 Jun 2024 10 bis(diphenylphosphino)ferrocene]dichloropalladium, carbon monoxide, and an amine r^r^nr). Suitable amides 4-4 can be converted to compounds of Formula (I) wherein R2 is a heterocycle by methods known to one skilled in the art (e.g., when amide 4-4 is a hydrazide, it may be reacted with ^-(triphenylphosphoranylidene^socyanamide or with p-toluenesulfonic acid and an orthoester (e.g., triethylorthoformate) to form an 1,3,4-oxadiazole; an appropriately substituted amide can be reacted with an a-halocarbonyl compound (e.g., chloracetaldehyde) to afford an oxazole; an appropriately substituted amide can be reacted with IJ-dimethoxy-A’.A’-dimethylmethanamine and bydroxylamine to form an 1,2,4-oxadiazole; conversion of the amide to a thioamide (e.g., using P2S5 or Lawesson’s reagent) before subjecting to the aforementioned reagents, would result in the corresponding thiadiazoles or thiazoles rather than oxadsazoles and oxazoles). Scheme 4. As shown in Scheme 5. the steps of Scheme 4 can be performed on appropriate starting materials 5-1 prior to coupling with intermediate 1-6 from Scheme 1. This also affords intermediates useful in the preparation of compounds of Formula (I) wherein R2 is an amide or a heterocycle. Carboxylic acid intermediate 5-4 (e.g., Ral=H and Y'=an appropriate halogen such as Cl, Br or I) can be converted to amide intermediate 5-5 by reacting with an 95 2024203916   07 Jun 2024 10 15 amine (RclRdlNH) under standard conditions for amide formation (e.g., using a coupling reagent such as HATU, in the presence of a base, such as diisopropylethylamine). Scheme 5. M2 5-4                                   5-5 Compounds of Formula (I) can be prepared as shown in Scheme 6. Suitable starting materials 6-1, wherein Y3 and Y? are suitable halogen atoms (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs), can be converted to intermediate 6-3 by coupling with an organozinc species formed from a suitable optionally protected halide 6-2 wherein Y! is a halogen (e.g., Cl, Br, or I) under standard Negishi conditions (e.g., 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, (e.g., dichloro[ 1,1’-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct and copper (I)iodide)). Intermediate 6-3 wherein Y' is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with an appropriately substituted metal 6-4 (e.g., M~ is B(OH)2, Bpin, BF3K, SnIBuh, or Zn) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(ll), or [ 1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 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 [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to give compounds 6-5, which 2024203916   07 Jun 2024 themselves may be compounds of Formula (I), or if protected (with a protecting group P, e.g., Boc), may be deprotected to afford compounds 6-6 using conditions suitable for removal of the protecting group which are also suitable in terms of compatibility with other functional groups that may be present in the molecule. Intermediates 6-6 may optionally be reacted with 5 an electrophile RA-L5 (wherein L1 is a leaving group (e.g., halogen, such as Cl, Br or I or a mesylate or tosylate), or Ra-L' may be a carboxylic acid activated by exposure to a coupling reagent (e.g., DCC, EDC or HATU)) in the presence of a base (e.g.. diisopropylethylamine or triethylamine) to furnish compounds of Formula (I). Scheme 6. R.3 R? 6-3                                                6-5 •> Q                             6-6                                                FormuSa (B Compounds of Formula (I) can be prepared as shown in Scheme 7. Suitable starting materials 7-1, wherein Y'' is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be converted to intermediates 7-3 by coupling with an appropriately substituted metal 7-2 (e.g., M2 is B(OH)i, Bpin, BF3K, Sn(Bu)3, or Zn) under standard Suzuki conditions 15      (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)pailadium(0), dichlorobis(triphenylphosphine)palladium(II), or [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 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 2024203916   07 Jun 2024 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 [1,1'-bis(diphenylphospbino)ferrocene]dicbloropalladium(Il)). Halogen-containing intermediate 74 can be prepared by reacting intermediate 7-3 with a reagent suitable for introducing the 5 halogen Y3 (e.g., N-halosuccinimide such as Ar-iodosuccinimide, A'-bromosuccinimide or A-chlorosuccinimide). Intermediate 7-4 bearing a suitable halogen Y’ (e.g., Cl, Br or I) can be coupled with an organozinc derived from a suitable starting material 7-5 wherein Y’ is a suitable halogen (e.g., Br or I) under standard Negishi conditions (e.g., in the presence of Zn (which can be activated by agents such as 1,2-dibromoethane and TMSC1) and in the presence 10 of a suitable palladium catalyst, (e.g., [l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylideue](3-chloropyridyl)palladium(II) dichloride)) to furnish compounds of Formula (I). Scheme 7. Formula (I) Compounds of Formula (I) can be prepared as shown in Scheme 8. Intermediates 8 15      1 which contain an ester (e.g., R is methyl or ethyl) can be hydrolyzed by exposure to 2024203916   07 Jun 2024 15 hydroxide base (e.g., LiOH, NaOH, KOH in water and a cosolvent such as THF, MeOH or EtOH) to furnish carboxylic acid intermediates 8-2. Carboxylic acid containing intermediates can be coupled with an amine 8-3 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 furnish compounds of Formula (I). Alternatively, ester containing intermediates can be converted drrectlv to amide-containing compounds of Formula (I) by reaction at elevated temperature (e.g.. 80 °C) with an am ine 8-3 in the presence of a Lewis acid catalyst (e.g., AlMes). Scheme 8. Lewis acid Compounds of Formula (1) can be prepared as shown in Scheme 9. Diol-containing intermediate 9-4 can be elaborated to carboxylic acid intermediate 9-1 by reaction with a suitable oxidizing agent (e.g., by reaction with oxygen or air over a metal, such as Pt). Carboxylic acid containing intermediate 9-1 can be subjected io conditions for esterification (e.g., refluxing in an alcoholic solvent such as methanol or ethanol in the presence of an acid, such as sulfuric acid) to provide ester intermediate 9-2. Exposure of 9-2 to an organometallic reagent R7-M! (e.g., a Grignard reagent such as methylmagnesium bromide) can provide substituted diol intermediate 9-3. Alternatively, 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 periodinane). Exposure of aldehyde 95 to an appropriate nucleophile (e.g,. an organometallic reagent R'-M1 such as a Grignard reagent (e.g., methylmagnesium bromide) or reagents providing a source of a fluorinated carbon nucleophile (e.g., an appropriately substituted silane such as trimethyl(trifluoromethyl)silane or trimethyl(difhtoromethyl)silane in the presence of TBAF)) 2024203916   07 Jun 2024 can provide substituted diol intermediate 9-6. Intermediate 9-6 can be oxidized to ketone 9-7 by reaction with an appropriate oxidizing agent (e.g., Dess Martin periodinane or PCC) and the product ketone 9-7 can be reacted with an appropriate nucleophile (e.g,. an organometallic reagent R8-M2 such as a Grignard reagent (e.g., methylmagnesium bromide) or reagents providing a source of a fluorinated carbon nucleophile (e.g., an appropriately substituted silane such as trimethyl(trifluoromethyl)silane or trimethyl(difluoromethyl)silane in the presence of TBAF)) to provide substituted diol-containing intermediate 9-8. Intermediates 93, 9-6, and 9-8 are useful for the synthesis of compounds of Formula (I) according to the 10 methods of Scheme 1. Scheme 9. Compounds of Formula (I) can be prepared as shown in Scheme 10. Appropriate starting material 10-1, wherein Y! and Y2 are independently suitable halogens (e.g., Cl, Br or I) or pseudohalogens (e.g., OTf), can be converted to ketone intermediate 10-2 by formation 15 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!j, 2024203916   07 Jun 2024 wherein L1 is a suitable leaving group (e.g, R6CO-L! is a Weinreb amide (L1 = -NMeOMe), such as 2,2-difluoro-Ar-methoxy-Ar-methylacetamide). Intermediate 10-2 can be converted to an appropriately substituted olefin 10-3 via known methods (e.g, by reaction with trimethylsilyldiazomethane in the presence of a catalyst such as tris(triphenylphosphme)rhodium(I) chloride and triphenylphosphine in a mixture containing 2-propanol; or via Peterson olefmation, e.g., reaction with ((trimethylsilyl)methyl)magnesium chloride followed by reaction with trimethylsilyl trifluoromethaneesulfonate)). Intermediate 10-3 can be converted to compounds of Formula (I) as shown in Scheme 1. Scheme 10. Y2 10-1 1) Mg. (CH2Br)2 2) ^CO-L1 10 Formula I 15 20 The reactions for preparing compounds described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, (e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature ). / 4 given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. The expressions, “ambient temperature” or “room temperature” or “rt” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C. 2024203916   07 Jun 2024 Preparation of compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. 5 Wirts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999). 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., or i3C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high 10 performance li quid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). 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 15             The compounds, salts or stereoisomers thereof described herein inhibit activity of PBKy kinase. Accordingly, the compounds, salts or stereoisomers described herein can be used in methods of inhibiting PBKy kinase by contacting the kinase with any 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 activity of PBKy in an 20 individual / patient in need of the inhibition by administering an effective amount of a compound or salt of described herein. In some embodiments, modulating is inhibiting. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is ex vivo. Advantageously, the compounds as described herein demonstrate better efficacy and favorable safety and toxicity profiles in animal studies. 25             In some embodiments, the PBKy 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 can be present in the kinase domain of the PBKy. In some embodiments, the compound or salt further inhibits PI3K8. The compounds or salts described herein can be selective. By “selective” is meant 30 that the compound binds to or inhibits PBKy 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 PBKy over PI3K5, PI3Ka, and PI3Kp. In some embodiments, the compounds of the disclosure are selective inhibitors of PBKy over PBKa and PI3Kp. In some embodiments, selectivity can be at least about 2-fold, 3-fold, 5-fold, 10-fold, at or 20 35 fold over P13K8 as measured by the assays described herein. In some embodiments, 2024203916   07 Jun 2024 selectivity can be tested at the 2 pM ATP concentration of each enzyme. In some embodiments, the selectivity of compounds of the disclosure can be determined by cellular assays associated with particular PI3K kinase activity. Another aspect of the present disclosure pertains to methods of treating a kinase 5 PI3Ky-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 disclosure or a pharmaceutical composition thereof. A PI3Ky-associated disease or disorder can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the PI3Ky, including overexpression and / or 10 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, 15 prostate cancer, liver cancer, color cancer, endometrial cancer, bladder cancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer, or sarcoma. In some embodiments, the sarcoma is Askin’s tumor, sarcoma botry oides, chondrosarcoma, Ewing’s sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, 20 desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic 25 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 30 monocytic leukemia), small lymphocyctic lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, T-cell actute lymphoblasic leukemia (T-ALL), cutaneous T-cell lymphoma, large granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm (PTCL), anaplastic large ceil lymphoma (ALCL), or lymphoblastic lymphoma. In some embodiments, the mature (peripheral) t-ceil neoplasm 35 (PTCL) is T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive 2024203916   07 Jun 2024 NK-cell leukemia, mycosis fungoides / Sezary syndrome, naplastic large cell lymphoma (T-cell type), enteropathy type T-cell lymphoma, adult T-cell leukemia / lymphoma, or angioimmunoblastic T-cell lymphoma In some embodiments, the anaplastic large cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL. 5             In some embodiments, the disease or disorder is Burkitt's ly mphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, xenoderoma pigmentosum, keratoctanthoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, 10     prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary7 effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma (aka asymptomatic myeloma), monoclonal 15 gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma. In some embodiments, the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, hairy7 ceil leukemia, Mantie cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, 20 Waldenstrom’s macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma (aka asymptomatic myeloma), 25 monoclonal gammopathy of undetermined significance (MGU S), or diffuse large B cell lymphoma. MDSC (myeloid-derived suppressor cells) are a heterogenous group of immune cells from the myeloid lineage (a family of cells that originate from bone marrow stem cells). MDSCs strongly expand in pathological situations such as chronic infections and cancer, as a 30      result of an altered haematopoiesis. MDSCs are discriminated from other myeloid cell types in which they possess strong immunosuppressive activities rather than immunostimulatory7 properties. Similar to other myeloid cells, MDSCs interact with other immune cell types 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 2024203916   07 Jun 2024 methods realted to cancer tissue (e.g., tumors) with high infiltration of MDSCs, including Solid tumors with high basal level of macrophage and / or MDSC infiltration. In some embodiments, the non-Hodgkin’s lymphoma (NHL) is relapsed NHL, refractory' NHL, recucurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL 5 taMU.i In some embodiments, the diffuse large B cell lymphoma is activated B-cell like (ABC) diffuse large B cell lymphoma, or germinal center B cell (GCB) diffuse large B cell lymphomaln some embodiments, the Burkitt’s lymphoma is endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like lymphoma. 10             In some embodiments, the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, 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, Sjogren’s syndrome, osteoarthritis, restenosis, or 15 atherosclerosis. In some embodiments, the disease or disorder is heart hypertropy, cardiac myocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, or pure red cell anemia), bacterial infection, 20 viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneic or xenogeneic transplantation, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), idiopathic pulmonary fibrosis, autoimmune hemolytic anemia, vasculitis, lupus nephritis, pemphigus, or membranous nephropathy. 25             In some embodiments, disease or disorder is heart hypertropy, cardiac myocyte dysfunction, chronic obstructive pulmonary' disease (COPD), elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, or pure red cell anemia), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, 30 angiogenesis, sepsis, graft rejection, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, 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. 2024203916   07 Jun 2024 In some embodiments, the idiopathic thrombocytopenic purpura (ITP) is relapsed ITP or refractory ITP. In some embodiments, the vasculitis is Behcet's disease, Cogan’s syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease 5 (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cry oglobulinemia vasculitis (essential or hepatitis C virus (HCV)-induced), Henoch-Schonlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener’s granulomatosis, or anti-neutrophil cytoplasm antibody associated (ANC / k) systemic vasculitis (AASV). 10             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 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. 15              As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a PI3K with a compound of the disclosure includes the administration of a compound of the present disclosure to an individual or patient, such as a human, having a PI3K, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or 20 purified preparation containing the P13K. It is believed that compounds of provdied herein (e.g., compounds of Formula (I), or pharmaceutically acceptable salts thereof) or any of the embodiments thereof, may possess satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility, and 25 permeability’. It will be understood that determination of appropriate biopharmaceutical properties is within the knowledge of a person skilled in the art, e.g., determination of cytotoxicity in cells or inhibition of 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, swine, 30 cattle, 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 that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. 2024203916   07 Jun 2024 As used herein, the term “treating” or “treatment” can refer to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology); and 5      (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e.. reversing the pathology and / or symptomatology) such as decreasing the severity of disease. In some embodiments, the compounds of the invention are useful in preventing or 10 reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology7 of the disease. Combination Therapies 15             Cancer ceil growth and survival can be impacted by multiple signaling pathways. Thus, it is useful to combine different enzyme / protein / receptor inhibitors, exhibiting different preferences in the targets which they modulate the activities of, to treat such conditions. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell 20 population, and / or reduce the toxicity of treatment. The compounds of the present disclosure can be used in combmatron with one or more other enzyme / protein / receptor inhibitors or one or more therapies for the treatment of diseases, such as cancer. Examples of diseases and indications treatable with combination therapies include those as described herein. Examples of cancers include solid tumors and 25 liquid tumors, such as blood cancers. One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as Bcr-Abl, Fit-3, EGFR, HER2, 30 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 can be used in combination with the compounds of the present disclosure for treatment of diseases, disorders, or conditions, particularly PI3K-associated diseases, disorders, or conditions. The one or more additional pharmaceutical agents can be administered to a patient 35 simultaneously or sequentially. 2024203916   07 Jun 2024 For example, the compounds as disclosed herein can 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, 5 PDGFaR, PDGFpR, CSFIR, KIT, FLK-II, KDR FI K-L FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFRTlt2,1^114, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lek, Fgr, 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 disclosure for treatment of cancer and other diseases and disorders 10 described herein include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAKI 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 CSFIR inhibitor, 15 a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643) and an adenosine receptor antagonist or combinations thereof. 20             In some embodiments, the compound or salt described herein is administered with a PI3K8 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 JAKI inhibitor. 25 In some embodiments, the compound or salt described herein is administered with a JAKI inhibitor, which is selective over JAK2. Example 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), 30 Rituxan (anti-CD20) and antibodies directed to c-MET. One or more of the following agents may be used in combination with the compounds of the present disclosure 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, methoxtrexate, temozolomide, 35 cyclophosphamide, SCH 66336, RI 15777, L778,123, BMS 214662, IRESSA™(gefitinib), 2024203916   07 Jun 2024 TARCEVA™ (erlotinib), antibodies to EGFR, GLEEVEC™ (imatinib mesylate), intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiopbosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 5 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXAT1N™ (oxaliplatin), pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone, megestrolacetate, 10 methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTIN™ 15 (trastuzumab), BEXXAR™ (tositumomab), VELCADE™ (bortezomib),ZEV ALIN™ (ibritumomab tiuxetanj, TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, 20 tezacitabine, Smll, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731. The compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumortargeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of 25 immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, Toll receptor agonists, STING agonists, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1 / 2 inhibitor and the like. The compounds can be administered in combination with one or more anti-cancer drugs, such as a 30 chemotherapeutics. Example chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, 35 cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, 2024203916   07 Jun 2024 decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, 5 histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon aifa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate, 10 panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, rucaparib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, tbioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, niraparib, 15 veliparib, talazoparib and zoledronate. Additional examples of chemotherapeutics include proteosome inhibitors ie.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like. Example steroids include corticosteroids such as dexamethasone or prednisone. 20             Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other example suitable Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04 / 005281, and U.S. Ser. No. 60 / 578,491. 25              Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and their pharmaceutically acceptable salts. Other example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03 / 037347, WO 03 / 099771, and WO 04 / 046120. 30             Example suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and their pharmaceutically acceptable salts. Other example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00 / 09495 and WO 05 / 028444. Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, 35     BI853520, and GSK2256098,and their pharmaceutically acceptable salts. Other example 2024203916   07 Jun 2024 suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed 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 disclosure can be used in combination 5 with one or more other kinase inhibitors including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors. In some embodiments, the c ompounds of the disclos ure can be used in combination with a chemotherapeutic in the treatment of cancer, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its 10 toxic effects. In some embodiments, the compounds of the disclosure can be used in combination with a chemotherapeutic provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma 15 include 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 an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfUzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the 20 immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). Additive or synergistic effects are desirable outcomes of combining a PI3K inhibitor of the present disclosure with an additional agent. In some embodiments, PI3Ky inhibitors provided herein can be used in combination with one or more immune checkpoint inhibitors for the treatment of cancer as described 25 herein. In one embodiment, the combination with one or more immune checkpoint inhibitors as described herein can be used for the treatment of melanoma. Compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD28, CD40, CD 122, CD96, CD73, CD47, GITR, CSF1R, JAK, 30 PI3K delta, PI3K gamma, TAM, arginase, HPKI, CD 137 (also known as 4-IBB), 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, OX40, GITR and CD 13 7. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, 35     B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, T1M3, TIGIT and VISTA. In some 2024203916   07 Jun 2024 embodiments, the compounds of the disclosure provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors. In some embodiments, the PI3Ky inhibitors provided herein can be used in 5 combination with one or more agonists of immune checkpoint molecules, e.g., OX40, CD27, OX40, GITR, and CD137 (also known as 4-1BB). In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PDl antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor 10 of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab (Imfmzi®), 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 15 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 anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g. urelumab, utomilumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor 20 of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll 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 MED1473 6. In some embodiments, the PI3Ky inhibitors provided herein can be used alone, or in 25 combination an anti-PD-1, for the treatmem melanoma (PD-1 refractor}'), NSCLC (PD-1 refractory'), HNSCC (PD-1 refractory), triple negative breast cancer (PD-1 naive), mesothelioma, adrenocarcinoma or tumors with high level of MDSC. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, e.g., an anti-PD-l / PD-Ll monoclonal antibody. In some embodiments, 30 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 an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab AGENI884, or CP-675,206. 2024203916   07 Jun 2024 In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., 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 an inhibitor 5 of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INC AGX23W. MBG453, or TSR-022. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of G1TR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or 10     MEDI1873. In some embodiments, the inhibitor of an immune checkpoint molecule is an agonist of OX40, e.g., OX40 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. 15             In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab. The compound s of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, 20 PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGF0 receptor. In some embodiments, PI3K-gamma inhibitors provided herein can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, BMS-986205, PF-06840003, IOM2983, RG-70099, 25     LY338196, and NGL919. In some embodiments, the compounds of the disclosure can be used in combination with an inhibitor of JAK or PI3K8. The agents can be combined with the present compound in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate 30 dosage forms. The compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infections. Examples of infections include viral infections, bacterial infections, fungus infections or parasite infections. 2024203916   07 Jun 2024 In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the compounds of the disclosure where the dexamethasone is administered intermittently as opposed to continuously. The compounds of Formula (I) or any of the formulas as described herein, a 5 compound as recited in any of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of 10 gplOO, MAGE antigens, Trp-2, MARTI and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF. The compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, 15 the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor 20 tissue itself. In some embodiments, the compounds of" Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses. The compounds of the present disclosure can be used in combination with bispecific 25 macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells. The compounds of the present disclosure can also be combmed with macrocyclic peptides that activate host immune responsiveness. In some further embodiments, combinations of the compounds of the disclosure with other therapeutic agents can be administered to a patient prior to, during, and / or after a bone 30 marrow transplant or stem cell transplant. The compound s of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin. The compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in 35 combination with vaccines, to stimulate the immune response to pathogens, toxins, and self 2024203916   07 Jun 2024 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, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, 5 Staphylococcus aureus, Pseudomonas Aeruginosa. Viruses causing infections heatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome vims, ebola virus, measles virus, herpes vims (e.g., VZV, HSV-1, HAV-6, HSV-II, and 10 CMV, Epstein Barr vims), flavivimses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis vims. Pathogenic bacteria causing infections treatable by methods of the disclosure include, 15 but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria. Pathogenic fungi causing infections treatable by methods of the disclosure include, 20 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 causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, 25 Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongyhis brasiliensis. Methods for the safe and effective administration of most of these chemotherapeutic 30 agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians’ Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety. 2024203916   07 Jun 2024 As provided throughout, the additional compounds, inhibitors, agents, etc. can be combined with the present compound in a single or continuous dosage form, or they can be administered simultaneously or sequential!}' as separate dosage forms. Pharmaceutical Formulations and Dosage Forms 5             When employed as pharmaceuticals, the compounds of the disclosure 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 upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, 10 ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery'), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can 15 be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. 20             This disclosure also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the disclosure or a pharmaceutically acceptable salt thereof, in combination with one or snore 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, 25 diluted by an excipient or enclosed w'ithin such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a 30 liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound 35 is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active 2024203916   07 Jun 2024 compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. The compounds of the disclosure may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other 5 formulation types. Finely divided (nanoparticulate) preparation s of the compound s of the disclosure can be prepared by processes known in the art, e.g., see International App. No. WO 2002 / 000196. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium 10 silicate, microcrystalline cellulose, poly vinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the disclosure can be formulated so as to provide quick, 15 sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary 20 dosages for human subjects and other mammals, each unit containing a predetermined quantity 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 having ordinary skill in the art will appreciate that 25 this einbodies compositions containing 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 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 having ordinary skill in the art will appreciate that 30 this embodies compositions containing 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 about 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 having ordinary skill in the art will appreciate 35 that this embodies compositions containing about 500 to about 550, about 550 to about 600, 2024203916   07 Jun 2024 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 may be used of the compounds described herein in the methods and 5 uses of the disclosure. The active compound can 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 actually- administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen 10 route of administration, the actual compound administered, the age, weight, and response of the individual patient, tire severity of the patient's symptoms, and the like. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. When referring to these 15 preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly 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 from, for example, about 0.1 to about 1000 mg of the active ingredient of the 20 present disclosure. The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged ac tion. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric 25 layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. 30             The liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. 2024203916   07 Jun 2024 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 supra. In some embodiments, the compositions are administered by the oral or 5 nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner. 10             Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g. glycerinemonostearate, PEG- 15 glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combmation 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 wt % of the compound of the disclosure. The topical formulations can be 20 suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition. The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In 25 therapeutic applications, compositions can 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 by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. 30             The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 35 II, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use 2024203916   07 Jun 2024 of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. The therapeutic dosage of a compound of the present disclosure can vary according to, for example, the particular use for which the treatment is made, the manner of 5 administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the disclosure in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity’), and the route of administration. For example, the compounds of the disclosure can be provided in an aqueous physiological buffer solution 10 containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 pg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg kg of body weight per day. The dosage is likely’ to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the 15 relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. The compositions of the disclosure can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory’ compound, or 20 immunosuppressant, examples of which are listed herein. Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to labeled compounds of the disclosure (radro-labeled, fluorescent-labeled, etc.) that would be useful not only ...

Claims

1. A compound, selected from:2-(3-(5-amino-6-(l-(methyl-d3)-l / / -pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3 -trifluoropropane-1,2-diol;2-(3 -(5 -amino-6-( 1 -methyl-1 / / -py razol -4-y I )py raz i n-2-y I )-4-mcthy I phony 1)-3,3,3-trifluoropropane-1,2-diol;2-(3-(5-amino-6-(l / / -pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;2-(3-(5-amino-6-(3-methylisoxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;2-(3 -(5 -amino-6-(isothiazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3 -trifluoropropane-1,2-diol;2-(3 -(5 -amino-6-(isothiazol-5 -yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3 -trifluoropropane-1,2-diol;2-(3 -(5 -amino-6-(3 -methylisothiazol-5 -yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3 -trifluoropropane-1,2-diol;2-(3 -(5 -amino-6-(2-methyloxazol-5 -yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;2-(3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;2-(3-(5-amino-6-(oxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;2-(3-(5-amino-6-(l / / -pyrazol-l-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;2-(3 -(5 -amino-6-( 1 / / -1,2,3 -triazol-1 -yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3 -trifluoropropane-1,2-diol;2-(3-(5-amino-6-(2 / / -l,2,3-triazol-2-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;2-(3-(5-amino-6-(l / / -l,2,4-triazol-l-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;2-(3-(5-amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-(methyl-d3)phenyl)-3,3,3-trifluoropropane-1,2-diol;2024203916   07 Jun 20242-(3-(5-amino-6-(3-mcthyl-l / / -pyrazol-4-yl)pyrazin-2-yl)-4-(mcthyl-d3 (phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol;2-(3-(5-amino-6-(3-mcthyl-l / / -pyrazol-4-yl)pyrazin-2-yl)-4-(mcthyl-d3 (phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol;2-(3 -(5 -amino-6-( 1-((1 -methyl-1 / / -py razol-3 -yl)sulfonyl)azetidin-3-yl)pyrazin-2-yl)-4-methylpheny 1)-3,3,3 -trifluoropropane-1,2-diol;(3-(3-amino-6-(2-methyl-5-(l, 1,1 -trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazin-2-yl)cyclobutyl)(3 -hydroxyazetidin-1 -yl)methanone; and2-(3-(5-amino-6-(trifluoromethyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

3. A method of treating a disease or disorder in a patient, wherein the disease or disorder is associated with abnormal expression or activity of PI3Ky kinase, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder in a patient, wherein the disease or disorder is associated with abnormal expression or activity of PI3Ky kinase.

5. The method of claim 3 or the use of claim 4, wherein the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease.

6. The method of claim 3 or the use of claim 4, wherein the disease or disorder is lung cancer, melanoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, colon cancer, endometrial cancer, bladder cancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer, seminoma, teratocarcinoma, astrocytoma, neuroblastoma, glioma, or sarcoma.2024203916   07 Jun 20247.     The method or use of claim 6, wherein the disease or disorder is sarcoma selectedfrom Askin’s tumor, sarcoma botryoides, chondrosarcoma, Ewing’s sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangiosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

8. The method of claim 3 or the use of claim 4, wherein the disease or disorder is acute myeloid leukemia, acute monocytic leukemia, small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma, large granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), and lymphoblastic lymphoma.

9. The method or use of claim 8, wherein the disease or disorder is mature (peripheral) T-cell neoplasm (PTCL) selected from T-cell pro lymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, mycosis fungoides / Sezary syndrome, anaplastic large cell lymphoma (T-cell type), enteropathy type T-cell lymphoma, adult T-cell leukemia / lymphoma, and angioimmunoblastic T-cell lymphoma.

10. The method or use of claim 8, wherein the anaplastic large cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.

11. The method of claim 3 or the use of claim 4, wherein the disease or disorder isBurkitt’s lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, xeroderma pigmentosum, keratoacanthoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom’s2024203916   07 Jun 2024macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma (aka asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma.

12. The method or use of claim 11, wherein the disease or disorder is non-Hodgkin’s lymphoma (NHL) selected from relapsed NHL, refractory NHL, recurrent follicular NHL, indolent NHL (iNHL), and aggressive NHL (aNHL).

13. The method or use of claim 11, wherein the disease or disorder is diffuse large B cell lymphoma selected from activated B-cell like (ABC) diffuse large B cell lymphoma, and germinal center B cell (GCB) diffuse large B cell lymphoma.

14. The method or use of claim 11, wherein the disease or disorder is Burkitt’s lymphoma selected from endemic Burkitt’s lymphoma, sporadic Burkitt’s lymphoma, or Burkitt’s-like lymphoma.

15. The method of claim 3 or the use of claim 4, wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, asthma, allergy, allergic rhinitis, pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease, thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjogren’s syndrome, osteoarthritis, restenosis, or atherosclerosis.

16. The method of claim 3 or the use of claim 4, wherein the disease or disorder is heart hypertrophy, cardiac myocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemiareperfusion, vasoconstriction, 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 transplantation, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic2024203916   07 Jun 2024purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, or membranous nephropathy.

17. The method or use of claim 16, wherein the disease or disorder is idiopathic thrombocytopenic purpura (ITP) selected from relapsed ITP and refractory ITP.

18. The method or use of claim 16, wherein the disease or disorder is vasculitis selected from Behcet’s disease, Cogan’s syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu’s arteritis, Buerger’s disease (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential or hepatitis C virus (HCV)-induced), Henoch-Schonlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener’s granulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV).

19. The method of claim 3 or the use of claim 4, wherein the disease or disorder is Alzheimer’s disease, central nervous system trauma, or stroke.