FIELD OF THE INVENTION

The present invention provides tertiary alcohol compounds that modulate the activity of phosphoinositide 3-kinases-gamma (ΡΙ3Κγ) and are useful in the treatment of diseases related to the activity of ΡΙ3Κγ including, for example, autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

BACKGROUND

The phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring (Cantley, Science, 2002, 296(5573): 1655-7). PI3Ks are divided into three classes (class I, II, and III) according to their structure, regulation and substrate specificity. Class I PI3Ks, which include ΡΙ3Κα, ΡΙ3Κβ, ΡΙ3Κγ, and ΡΙ3Κδ, 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 (PIP3). PIP3 functions as a second messenger that controls a number of cellular processes, including growth, survival, adhesion and migration. All four class I PI3K isoforms exist as heterodimers composed of a catalytic subunit (pi 10) and a tightly associated regulatory subunit that controls their expression, activation, and subcellular localization. ΡΙ3Κα, ΡΙ3Κβ, and PI3K8 associate with a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine kinase- dependent mechanism (Jimenez, et al., J Biol Chem., 2002, 277(44):41556-62) whereas

ΡΙ3Κγ associates with two regulatory subunits (plOl and p84) and its activation is driven by the activation of G-protein-coupled receptors (Brock, et al., J Cell Biol., 2003, 160(l):89-99). PI3Koc and ΡΙ3Κβ are ubiquitously expressed. In contrast, ΡΙ3Κγ and PI3K8 are

predominantly expressed in leukocytes (Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4): 194-204).

Expression of ΡΙ3Κγ is mainly restricted to hematopoietic system, although it can be also detected at lower level in endothelium, heart and brain. ΡΙ3Κγ 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 ΡΙ3Κγ is required for GPCR ligand-induced PtdlNs (3,4,5)P3 production, chemotaxis and respiratory burst in neutrophils. ΡΒΚγ-null macrophages and dendritic cell exhibit reduced migration towards various chemoattractants. T-cells deficient in ΡΙ3Κγ show impaired cytokine production in response to anti-CD3 or Con A stimulation. ΡΙ3Κγ working downstream of adenosine A3A receptor is critical for sustained degranulation of mast cells induced by FCsRI cross-linking with IgE. ΡΙ3Κγ 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 ΡΙ3Κγ in various autoimmune and inflammatory disease models has been investigated with genetic and pharmacological tools. In asthma and allergy models, ΡΙ3Κγ ^_/" mice or mice treated with ΡΙ3Κγ inhibitor showed a defective capacity to mount contact hypersensitivity and delayed- type hypersensitivity reactions. In these models, ΡΙ3Κγ 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, 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 ΡΙ3Κγ 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, 2003-2011). ΡΙ3Κγ ^_/" mice were largely protected in four different models of rheumatoid arthritis (CIA, oc-CII-IA, K/BxN serum transfer and TNF transgenic) and ΡΙ3Κγ inhibition suppressed the progression of joint inflammation and damage in the CIA and oc-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; Hayer et al., FASB J., 2009, 4288-4298). In the MKL-lpr mouse model of human systemic lupus erythematous, inhibition of ΡΙ3Κγ 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- C276; El Khoury et al., Nat. Med., 2007, 13, 432-438). In line with this suggestion, ΡΙ3Κγ 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). ΡΙ3Κγ deficiency or inhibition also was shown to delay onset and alleviate 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. Neuroimmunol. 2010, 222, 90-94; Berod et al., Euro. J. Immunol. 2011, 41, 833-844; Comerford et al., PLOS one, 2012, 7, e45095; Li et al., Neuroscience, 2013, 253, 89-99).

Chronic inflammation has been formally recognized as one of the hallmarks for many different types of cancers. Accordingly, selective anti-inflammatory drugs represent a novel class of anti-cancer therapies (Hanahan and Weinberg, Cell, 2011, 144, 646-674). Since ΡΙ3Κγ is reported to mediate various inflammatory processes, its role as an immune oncology target has also been investigated. A recent study reported that ΡΙ3Κγ deficiency suppressed tumor growth in the syngeneic models of lung cancer, pancreatic cancer and melanoma (LLC, PAN02 and B16). ΡΙ3Κγ 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 ΡΙ3Κγ deficiency could ameliorate inflammation and tumor growth in mice having colitis-associated colon cancer, (Gonzalez-Garcia et al., Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic analysis indicates that tumor infiltration by CDl lb ⁺ myeloid cells can cause protumorigenic inflammation at tumor sites and ΡΙ3Κγ in the myeloid cells is critical in mediating signaling of various chemoattractants in bring the cells to the tumor (Schmid et al., Cancer Cell, 2011, 19, 715-727). Other studies suggest that ΡΙ3Κγ 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 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, ΡΙ3Κγ may play a direct role in cancer cells. ΡΙ3Κγ is reported to be required for signaling 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). ΡΙ3Κγ 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, ΡΙ3Κγ gene 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. 2010, 10, 582-587).

Finally, ΡΙ3Κγ deficiency also has been reported to offer protection to experimental animals in different cardiovascular disease models. For examples, lack of ΡΙ3Κγ would 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, ΡΙ3Κγ inhibition provided potent

cardioprotection, reducing infarct development and preserving myocardial function (Doukas et al., Proc. Natl. Acad. Sci. USA, 2006, 103, 19866-19871). For these reasons, there is a need to develop new ΡΙ3Κγ inhibitors that can be used for the treatment of diseases such as cancer, autoimmune disorders, and inflammatory and cardiac diseases. This application is directed to this need and others.

SUMMARY

The present invention relates to, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt 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

pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting an activity of ΡΙ3Κγ 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 associated with abnormal ΡΙ3Κγ kinase expression or activity in a patient by administering to the patient a therapeutically effective amount of a compound of Formula (I), or a

pharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

The present invention further provides 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.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows an XRPD pattern for crystalline Form I of Example PL

Figure 2 shows the results of a DSC experiment for crystalline Form I of Example PI.

Figure 3 shows the results of a TGA experiment for crystalline Form I of Example

PL Figure 4 shows an XRPD pattern for crystalline Form II of Example P2.

Figure 5 shows the results of a DSC experiment for crystalline Form II of Example

P2.

Figure 6 shows the results of a TGA experiment for crystalline Form II of Example

P2.

Figure 7 shows an XRPD pattern for crystalline Form III in Example P3.

Figure 8 shows the results of a DSC experiment for crystalline Form III of Example

P3.

Figure 9 shows the results of a TGA experiment for crystalline Form III of Example

P3.

Figure 10 shows an XRPD pattern for crystalline Form I of Example P4.

Figure 11 shows the results of a DSC experiment for crystalline Form I of Example

P4.

Figure 12 shows an XRPD pattern for crystalline Form I of Example P5.

Figure 13 shows the results of a DSC experiment for crystalline Form I of Example

P5.

Figure 14 shows an XRPD pattern for crystalline Form II of Example P6.

Figure 15 shows the results of a DSC experiment for crystalline Form II of Example

P6.

Figure 16A shows the asymmetric crystalline unit of the hydrobromic acid salt, methanol solvent form of Example P7, with thermal ellipsoids drawn to the 30% probability level.

Figure 16B shows a crystalline unit of the hydrobromic acid salt of Example P7, with thermal ellipsoids drawn to the 30% probability level.

DETAILED DESCRIPTION

Compounds

The present application provides, inter alia, compounds of Formula (I):

harmaceutically acceptable salt thereof; wherein: X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is N or CR ⁷ ;

provided that X ⁴ , X ⁵ , and X ⁶ are not all N;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F or CI, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y ² substituents;

R ¹ is selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6- 10 membered aryl, C ₃ -iocycloalkyl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^a , SR ^a , NHOR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , OC(0)R ^a , OC(0)NR ^a R ^a , NR ^a R ^a , NR ^a NR ^a R ^a , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , NR ^a C(=NR')NR ^a R ^a , NR ^a C(=NOH)NR ^a R ^a , NR ^a C(=NCN)NR ^a R ^a , NR ^a S(0)R ^a , NR ^a S(0) ₂ R ^a , NR ^a S(0)(=NR ^I )R ^a , NR ^a S(0) ₂ NR ^a R ^a , S(0)R ^a , S(0)NR ^a R ^a , S(0) ₂ R ^a , OS(0)(=NR ^I )R ^a , SF ₅ , P(0)R ^a R ^a ,

P(0)(OR ^a )(OR ^a ), B(OR ^a ) ₂ , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ¹ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, halo, C1-5 alkyl, Ci-6 alkoxy, C2-5 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C ₃ - ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl, OH, NO2, amino, Ci-6 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, Ci-6 alkylsulfinyl, Ci-6 alkylsulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci- ₆ alkyl)carbamyl, carboxy, Ci-6 alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci-6 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci-6 alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents;

R ⁸ is selected from H, D, Ci-s alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, NO ₂ , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , SF ₅ , -P(0)R ^a R ^a , - P(0)(OR ^a )(OR ^a ), B(OR ^a ) ₂ , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, Ci _-6 alkoxy, C ₂ - ₆ alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or any two R ⁴ , R ⁵ , R ⁶ and R ⁷ substituents, together with the ring atoms to which they attached form a 4-, 5-, 6-, or 7-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-,

6- , or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

each R ¹ is independently selected from H, CN, OH, C1-4 alkyl, and alkoxy;

each Y ² is independently selected from OH, NO2, CN, halo, Ci-6 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C3-10 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, Ci-6 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci-6 alkoxy carbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^a is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-5 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered heterocycloalkyl-Ci- ₆ alkyl- of R ^a is each optionally substituted with 1, 2, 3, or 4

independently selected R ^b substituents;

each R ^b is independently selected from D, halo, Ci-s alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^c , SR ^C , NHOR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , C(=NR')R ^C , C(=NR ^I )NR ^C R ^C , NR ^C C(=NR ^I )NR ^C R ^C ,

NR ^c C(=NOH)NR ^c R ^c , NR ^C C(=NCN)NR ^C R ^C , NR ^c S(0)R ^c , NR ^c S(0) ₂ R ^c , NR ^c S(0) ₂ NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , SF ₅ , -P(0)R ^c R ^c , -P(0)(OR ^c )(OR ^c ), B(OR ^c ) ₂ , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^b is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ⁹ is independently selected from D, halo, C1-5 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, N0 ₂ , OR ^k , SR ^k , NHOR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , OC(0)R ^k , OC(0)NR ^k R ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , C(=NR')R ^k , C(=NR ¹ )NR ^k R ^k , NR ^k C(=NR')NR ^k R ^k ,

NR ^k C(=NOH)NR ^k R ^k , NR ^k C(=NCN)NR ^k R ^k , NR ^k S(0)R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0)R ^k , S(0)NR ^k R ^k , S(0) ₂ R ^k , SF ₅ , -P(0)R ^k R ^k , -P(0)(OR ^k )(OR ^k ), B(OR ^k ) ₂ , and S(0) ₂ NR ^k R ^k , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^c is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered heterocycloalkyl-Ci- ₆ alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

or two R ^c substituents, together with the nitrogen atom to which they attached form a 4-, 5-, 6-, or 7-membered heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ^d is independently selected from D, halo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^e , SR ^e , NHOR ^e , C(0)R ^e , C(0)NR ^e R ^e , C(0)OR ^e , OC(0)R ^e , OC(0)NR ^e R ^e , NR ^e R ^e , NR ^e C(0)R ^e , NR ^e C(0)OR ^e , NR ^e C(0)NR ^e R ^e , C(=NR')R ^e , C(=NR ¹ )NR ^e R ^e , NR ^e C(=NR ¹ )NR ^e R ^e ,

NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , NR ^e S(0)R ^e , NR ^e S(0) ₂ R ^e , NR ^e S(0) ₂ NR ^e R ^e , S(0)R ^e , S(0)NR ^e R ^e , S(0) ₂ R ^e , SF ₅ , -P(0)R ^e R ^e , -P(0)(OR ^e )(OR ^e ), B(OR ^e ) ₂ , and S(0) ₂ NR ^e R ^e , wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^e is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-s alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^e is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^f is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^s , SR ^S , NHOR ^s , C(0)R ^s , C(0)NR ^s R ^s , C(0)OR ^s , OC(0)R ^s , OC(0)NR ^s R ^s , NR ^S R ^S , NR ^s C(0)R ^s , NR ^s C(0)OR ^s , NR ^s C(0)NR ^s R ^s , C(=NR ^I )R ^S , C(=NR ^I )NR ^S R ^S , NR ^S C(=NR ^I )NR ^S R ^S , NR ^s C(=NOH)NR ^s R ^s , NR ^S C(=NCN)NR ^S R ^S , NR ^s S(0)R ^s , NR ^s S(0) ₂ R ^s , NR ^s S(0) ₂ NR ^s R ^s , S(0)R ^s , S(0)NR ^s R ^s , S(0) ₂ R ^s , SF ₅ , -P(0)R ^s R ^s , -P(0)(OR ^s )(OR ^s ), B(OR ^s ) ₂ , and S(0) ₂ NR ^s R ^s , wherein the Ci _-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^f is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^s is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^s is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^h is independently selected from OH, NO2, CN, halo, C1-5 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-s haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents;

each R ^q is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^m , SR ^m , NHOR ^m , C(0)R ^m , C(0)NR ^m R ^m , C(0)OR ^m , OC(0)R ^m , OC(0)NR ^m R ^m , NHR ^m , NR ^m R ^m , m C(0)R ^m , NR ^m C(0)OR ^m , NR ^m C(0)NR ^m R ^m , C(=NR')R ^m , C(=NR ¹ )NR ^m R ^m ,

NR ^m C(=NR ¹ )NR ^m R ^m , NR ^m C(=NOH)NR ^m R ^m , NR ^m C(=NCN)NR ^m R ^m , NR ^m S(0)R ^m , NR ^m S(0) ₂ R ^m , NR ^m S(0) ₂ NR ^m R ^m , S(0)R ^m , S(0)NR ^m R ^m , S(0) ₂ R ^m , SF ₅ , -P(0)R ^m R ^m , - P(0)(OR ^m )(OR ^m ), BCOR^z, and S(0) ₂ NR ^m R ^m , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C _2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^q is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ^m is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^m is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ⁿ is independently selected from D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,

Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ⁰ , SR°, NHOR ⁰ , C(0)R°, C(0)NR°R°, C(0)OR°, OC(0)R°, OC(0)NR°R°, NR°R°, NR°C(0)R°, NR°C(0)OR°, NR°C(0)NR°R°, C(=NR ^I )R°, C(=NR ^I )NR°R°, NR°C(=NR ^I )NR°R°, NR°C(=NOH)NR°R°, NR°C(=NCN)NR°R°, NR°S(0)R°, NR°S(0) ₂ R°, NR°S(0) ₂ NR°R°, S(0)R°, S(0)NR°R°, S(0) ₂ R°, and S(0) ₂ NR°R°, wherein the Ci _-6 alkyl, C ₂ -s alkenyl, C _2-6 alkynyl, Ci _-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ⁿ is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents; and

each R° is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R° is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents.

In some embodiments: X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is N or CR ⁷ ;

provided that X ⁴ , X ⁵ , and X ⁶ are not all N;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F or CI, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y ² substituents;

R ¹ is selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6- 10 membered aryl, C ₃ -iocycloalkyl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^a , SR ^a , NHOR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , OC(0)R ^a , OC(0)NR ^a R ^a , NR ^a R ^a , NR ^a NR ^a R ^a , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , NR ^a C(=NR')NR ^a R ^a , NR ^a C(=NOH)NR ^a R ^a , NR ^a C(=NCN)NR ^a R ^a , NR ^a S(0)R ^a , NR ^a S(0) ₂ R ^a , NR ^a S(0)(=NR ^I )R ^a , NR ^a S(0) ₂ NR ^a R ^a , S(0)R ^a , S(0)NR ^a R ^a , S(0) ₂ R ^a , OS(0)(=NR ^I )R ^a , SF ₅ , P(0)R ^a R ^a ,

P(0)(OR ^a )(OR ^a ), B(OR ^a ) ₂ , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ¹ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, CD ₃ , halo, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C ₃ - ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl, OH, NO2, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, C1-5 alkylsulfinyl, C1-5 alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci- ₆ alkyl)carbamyl, carboxy, C ₁ -5 alkylcarbonyl, Ci- ₆ alkoxycarbonyl, C ₁ -5 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci-6 alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, C1-5 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents;

R ⁸ is selected from H, D, Ci-s alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, NO ₂ , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , SF ₅ , -P(0)R ^a R ^a , - P(0)(OR ^a )(OR ^a ), B(OR ^a ) ₂ , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, Ci _-6 alkoxy, C ₂ - ₆ alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or any two R ⁴ , R ⁵ , R ⁶ and R ⁷ substituents, together with the ring atoms to which they attached form a 4-, 5-, 6-, or 7-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-,

6- , or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

each R ¹ is independently selected from H, CN, OH, C1-4 alkyl, and alkoxy;

each Y ² is independently selected from OH, NO2, CN, halo, Ci-6 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C3-10 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, Ci-6 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci-6 alkoxy carbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^a is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-5 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered heterocycloalkyl-Ci- ₆ alkyl- of R ^a is each optionally substituted with 1, 2, 3, or 4

independently selected R ^b substituents;

each R ^b is independently selected from D, halo, Ci-s alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^c , SR ^C , NHOR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , C(=NR')R ^C , C(=NR ^I )NR ^C R ^C , NR ^C C(=NR ^I )NR ^C R ^C ,

NR ^c C(=NOH)NR ^c R ^c , NR ^C C(=NCN)NR ^C R ^C , NR ^c S(0)R ^c , NR ^c S(0) ₂ R ^c , NR ^c S(0) ₂ NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , SF ₅ , -P(0)R ^c R ^c , -P(0)(OR ^c )(OR ^c ), B(OR ^c ) ₂ , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^b is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ⁹ is independently selected from D, halo, C1-5 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, N0 ₂ , OR ^k , SR ^k , NHOR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , OC(0)R ^k , OC(0)NR ^k R ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , C(=NR')R ^k , C(=NR ¹ )NR ^k R ^k , NR ^k C(=NR')NR ^k R ^k ,

NR ^k C(=NOH)NR ^k R ^k , NR ^k C(=NCN)NR ^k R ^k , NR ^k S(0)R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0)R ^k , S(0)NR ^k R ^k , S(0) ₂ R ^k , SF ₅ , -P(0)R ^k R ^k , -P(0)(OR ^k )(OR ^k ), B(OR ^k ) ₂ , and S(0) ₂ NR ^k R ^k , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^c is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered heterocycloalkyl-Ci- ₆ alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

or two R ^c substituents, together with the nitrogen atom to which they attached form a 4-, 5-, 6-, or 7-membered heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ^d is independently selected from D, halo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^e , SR ^e , NHOR ^e , C(0)R ^e , C(0)NR ^e R ^e , C(0)OR ^e , OC(0)R ^e , OC(0)NR ^e R ^e , NR ^e R ^e , NR ^e C(0)R ^e , NR ^e C(0)OR ^e , NR ^e C(0)NR ^e R ^e , C(=NR')R ^e , C(=NR ¹ )NR ^e R ^e , NR ^e C(=NR ¹ )NR ^e R ^e ,

NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , NR ^e S(0)R ^e , NR ^e S(0) ₂ R ^e , NR ^e S(0) ₂ NR ^e R ^e , S(0)R ^e , S(0)NR ^e R ^e , S(0) ₂ R ^e , SF ₅ , -P(0)R ^e R ^e , -P(0)(OR ^e )(OR ^e ), B(OR ^e ) ₂ , and S(0) ₂ NR ^e R ^e , wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^e is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-s alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^e is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^f is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^s , SR ^S , NHOR ^s , C(0)R ^s , C(0)NR ^s R ^s , C(0)OR ^s , OC(0)R ^s , OC(0)NR ^s R ^s , NR ^S R ^S , NR ^s C(0)R ^s , NR ^s C(0)OR ^s , NR ^s C(0)NR ^s R ^s , C(=NR ^I )R ^S , C(=NR ^I )NR ^S R ^S , NR ^S C(=NR ^I )NR ^S R ^S , NR ^s C(=NOH)NR ^s R ^s , NR ^S C(=NCN)NR ^S R ^S , NR ^s S(0)R ^s , NR ^s S(0) ₂ R ^s , NR ^s S(0) ₂ NR ^s R ^s , S(0)R ^s , S(0)NR ^s R ^s , S(0) ₂ R ^s , SF ₅ , -P(0)R ^s R ^s , -P(0)(OR ^s )(OR ^s ), B(OR ^s ) ₂ , and S(0) ₂ NR ^s R ^s , wherein the Ci _-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^f is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^s is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^s is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^h is independently selected from OH, NO2, CN, halo, C1-5 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-s haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents;

each R ^q is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^m , SR ^m , NHOR ^m , C(0)R ^m , C(0)NR ^m R ^m , C(0)OR ^m , OC(0)R ^m , OC(0)NR ^m R ^m , NHR ^m , NR ^m R ^m , m C(0)R ^m , NR ^m C(0)OR ^m , NR ^m C(0)NR ^m R ^m , C(=NR')R ^m , C(=NR ¹ )NR ^m R ^m ,

NR ^m C(=NR ¹ )NR ^m R ^m , NR ^m C(=NOH)NR ^m R ^m , NR ^m C(=NCN)NR ^m R ^m , NR ^m S(0)R ^m , NR ^m S(0) ₂ R ^m , NR ^m S(0) ₂ NR ^m R ^m , S(0)R ^m , S(0)NR ^m R ^m , S(0) ₂ R ^m , SF ₅ , -P(0)R ^m R ^m , - P(0)(OR ^m )(OR ^m ), BCOR^z, and S(0) ₂ NR ^m R ^m , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C _2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^q is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ^m is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^m is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ⁿ is independently selected from D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,

Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ⁰ , SR°, NHOR ⁰ , C(0)R°, C(0)NR°R°, C(0)OR°, OC(0)R°, OC(0)NR°R°, NR°R°, NR°C(0)R°, NR°C(0)OR°, NR°C(0)NR°R°, C(=NR ^I )R°, C(=NR ^I )NR°R°, NR°C(=NR ^I )NR°R°, NR°C(=NOH)NR°R°, NR°C(=NCN)NR°R°, NR°S(0)R°, NR°S(0) ₂ R°, NR°S(0) ₂ NR°R°, S(0)R°, S(0)NR°R°, S(0) ₂ R°, and S(0) ₂ NR°R°, wherein the Ci _-6 alkyl, C ₂ -s alkenyl, C _2-6 alkynyl, Ci _-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ⁿ is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents; and

each R° is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R° is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents.

In some embodiments: X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is N or CR ⁷ ;

provided that X ⁴ , X ⁵ , and X ⁶ are not all N;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F or CI, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y ² substituents;

R ¹ is selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6- 10 membered aryl, C ₃ -iocycloalkyl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^a , SR ^a , NHOR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , OC(0)R ^a , OC(0)NR ^a R ^a , NR ^a R ^a , NR ^a NR ^a R ^a , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , NR ^a C(=NR')NR ^a R ^a , NR ^a C(=NOH)NR ^a R ^a , NR ^a C(=NCN)NR ^a R ^a , NR ^a S(0)R ^a , NR ^a S(0) ₂ R ^a , NR ^a S(0)(=NR ^I )R ^a , NR ^a S(0) ₂ NR ^a R ^a , S(0)R ^a , S(0)NR ^a R ^a , S(0) ₂ R ^a , OS(0)(=NR ^I )R ^a , SF ₅ , P(0)R ^a R ^a ,

P(0)(OR ^a )(OR ^a ), B(OR ^a ) ₂ , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ¹ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, CD ₃ , halo, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C ₃ - ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl, OH, NO2, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, C1-5 alkylsulfinyl, C1-5 alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci- ₆ alkyl)carbamyl, carboxy, C ₁ -5 alkylcarbonyl, Ci- ₆ alkoxycarbonyl, C ₁ -5 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci-6 alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, C1-5 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents;

R ⁸ is selected from H, D, Ci-s alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, NO ₂ , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , SF ₅ , -P(0)R ^a R ^a , - P(0)(OR ^a )(OR ^a ), B(OR ^a ) ₂ , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, Ci _-6 alkoxy, C ₂ - ₆ alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or any two R ⁴ , R ⁵ , R ⁶ and R ⁷ substituents, together with the ring atoms to which they attached form a 4-, 5-, 6-, or 7-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-,

6- , or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

each R ¹ is independently selected from H, CN, OH, C1-4 alkyl, and alkoxy;

each Y ² is independently selected from OH, NO2, CN, halo, Ci-6 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C3-10 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, Ci-6 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci-6 alkoxy carbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^a is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-5 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered heterocycloalkyl-Ci- ₆ alkyl- of R ^a is each optionally substituted with 1, 2, 3, or 4

independently selected R ^b substituents;

each R ^b is independently selected from D, halo, Ci-s alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^c , SR ^C , NHOR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , C(=NR')R ^C , C(=NR ^I )NR ^C R ^C , NR ^C C(=NR ^I )NR ^C R ^C ,

NR ^c C(=NOH)NR ^c R ^c , NR ^C C(=NCN)NR ^C R ^C , NR ^c S(0)R ^c , NR ^c S(0) ₂ R ^c , NR ^c S(0) ₂ NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , SF ₅ , -P(0)R ^c R ^c , -P(0)(OR ^c )(OR ^c ), B(OR ^c ) ₂ , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^b is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ⁹ is independently selected from D, halo, C1-5 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, N0 ₂ , OR ^k , SR ^k , NHOR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , OC(0)R ^k , OC(0)NR ^k R ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , C(=NR')R ^k , C(=NR ¹ )NR ^k R ^k , NR ^k C(=NR')NR ^k R ^k ,

NR ^k C(=NOH)NR ^k R ^k , NR ^k C(=NCN)NR ^k R ^k , NR ^k S(0)R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0)R ^k , S(0)NR ^k R ^k , S(0) ₂ R ^k , SF ₅ , -P(0)R ^k R ^k , -P(0)(OR ^k )(OR ^k ), B(OR ^k ) ₂ , and S(0) ₂ NR ^k R ^k , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^c is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered heterocycloalkyl-Ci- ₆ alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

each R ^d is independently selected from D, halo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^e , SR ^e , NHOR ^e , C(0)R ^e , C(0)NR ^e R ^e , C(0)OR ^e , OC(0)R ^e , OC(0)NR ^e R ^e , NR ^e R ^e , NR ^e C(0)R ^e , NR ^e C(0)OR ^e , NR ^e C(0)NR ^e R ^e , C(=NR')R ^e , C(=NR ¹ )NR ^e R ^e , NR ^e C(=NR ¹ )NR ^e R ^e ,

NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , NR ^e S(0)R ^e , NR ^e S(0) ₂ R ^e , NR ^e S(0) ₂ NR ^e R ^e , S(0)R ^e , S(0)NR ^e R ^e , S(0) ₂ R ^e , SF ₅ , -P(0)R ^e R ^e , -P(0)(OR ^e )(OR ^e ), B(OR ^e ) ₂ , and S(0) ₂ NR ^e R ^e , wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^e is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-s alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^e is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^f is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^s , SR ^S , NHOR ^s , C(0)R ^s , C(0)NR ^s R ^s , C(0)OR ^s , OC(0)R ^s , OC(0)NR ^s R ^s , NR ^S R ^S , NR ^s C(0)R ^s , NR ^s C(0)OR ^s , NR ^s C(0)NR ^s R ^s , C(=NR ^I )R ^S , C(=NR ^I )NR ^S R ^S , NR ^S C(=NR ^I )NR ^S R ^S , NR ^s C(=NOH)NR ^s R ^s , NR ^S C(=NCN)NR ^S R ^S , NR ^s S(0)R ^s , NR ^s S(0) ₂ R ^s , NR ^s S(0) ₂ NR ^s R ^s , S(0)R ^s , S(0)NR ^s R ^s , S(0) ₂ R ^s , SF ₅ , -P(0)R ^s R ^s , -P(0)(OR ^s )(OR ^s ), B(OR ^s ) ₂ , and S(0) ₂ NR ^s R ^s , wherein the Ci _-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^f is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents; each R ^s is independently selected from H, D, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^s is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^h is independently selected from OH, NO2, CN, halo, C1-5 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents;

each R ^q is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^m , SR ^m , NHOR ^m , C(0)R ^m , C(0)NR ^m R ^m , C(0)OR ^m , OC(0)R ^m , OC(0)NR ^m R ^m , NHR ^m , NR ^m R ^m , m C(0)R ^m , NR ^m C(0)OR ^m , NR ^m C(0)NR ^m R ^m , C(=NR')R ^m , C(=NR ¹ )NR ^m R ^m ,

NR ^m C(=NR ¹ )NR ^m R ^m , NR ^m C(=NOH)NR ^m R ^m , NR ^m C(=NCN)NR ^m R ^m , NR ^m S(0)R ^m ,

NR ^m S(0) ₂ R ^m , NR ^m S(0) ₂ NR ^m R ^m , S(0)R ^m , S(0)NR ^m R ^m , S(0) ₂ R ^m , SF ₅ , -P(0)R ^m R ^m , - P(0)(OR ^m )(OR ^m ), BCOR^z, and S(0) ₂ NR ^m R ^m , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci- ₆ alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^q is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ^m is independently selected from H, D, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocy cloalkyl-Ci-6 alkyl- of R ^m is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ⁿ is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocy cloalky l-Ci _-6 alkyl-, CN, N0 ₂ , OR ⁰ , SR°, NHOR ⁰ , C(0)R°, C(0)NR°R°, C(0)OR°, OC(0)R°, OC(0)NR°R°, NR°R°, NR°C(0)R°, NR°C(0)OR°, NR°C(0)NR°R°, C(=NR ^I )R°, C(=NR ^I )NR°R°, NR°C(=NR ^I )NR°R°, NR°C(=NOH)NR°R°, NR°C(=NCN)NR°R°, NR°S(0)R°, NR°S(0) ₂ R°, NR ⁰ S(0) ₂ NR ⁰ R°, S(0)R°, S(0)NR°R°, S(0) ₂ R°, and S(0) ₂ NR°R°, wherein the Ci _-6 alkyl, C ₂ * alkenyl, C ₂ - ₆ alkynyl, Ci _-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocy cloalkyl-Ci-6 alkyl- of R ⁿ is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents; and

each R° is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cy cloalky l-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocy cloalky l-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cy cloalky l-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocy cloalkyl-Ci-6 alkyl- of R° is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ; X ⁶ is N or CR ⁶ ;

X ⁷ is N or CR ⁷ ;

provided that X ⁴ , X ⁵ , and X ⁶ are not all N;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F or CI, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y ² substituents;

R ¹ is selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6- 10 membered aryl, C ₃ -iocycloalkyl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^a , SR ^a , NHOR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , OC(0)R ^a , OC(0)NR ^a R ^a , NR ^a R ^a , NR^R^ ³ ,

NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , NR ^a C(=NR')NR ^a R ^a , NR ^a C(=NOH)NR ^a R ^a , NR ^a C(=NCN)NR ^a R ^a , NR ^a S(0)R ^a , NR ^a S(0) ₂ R ^a , NR ^a S(0)(=NR ^I )R ^a , NR ^a S(0) ₂ NR ^a R ^a , S(0)R ^a , S(0)NR ^a R ^a , S(0) ₂ R ^a , OS(0)(=NR ^I )R ^a , SF ₅ , P(0)R ^a R ^a ,

P(0)(OR ^a )(OR ^a ), B(OR ^a ) ₂ , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ¹ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, halo, Ci-6 alkyl, Ci-6 alkoxy, C2-5 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C ₃ -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl, OH, NO2, amino, Ci-6 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, Ci-6 alkylsulfinyl, Ci-6 alkylsulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci- ₆ alkyl)carbamyl, carboxy, Ci-6 alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci-6 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci-6 alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl,

4- 10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents; R is selected from H, D, Ci-s alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl,

4- 10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, NO ₂ , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , SF ₅ , -P(0)R ^a R ^a , -

P(0)(OR ^a )(OR ^a ), B(OR ^a ) ₂ , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, Ci _-6 alkoxy, C ₂ - ₆ alkenyl, C2-5 alkynyl, Ci-s haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or any two R ⁴ , R ⁵ , R ⁶ and R ⁷ substituents, together with the ring atoms to which they attached form a 4-, 5-, 6-, or 7-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-,

6- , or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

each R ¹ is independently selected from H, CN, OH, C1- alkyl, and CI alkoxy;

each Y ² is independently selected from OH, NO2, CN, halo, Ci-s alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-s haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C3-10 cycloalkyl, C1-5 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci-6 alkylcarbonyl, C1-5 alkoxy carbonyl, Ci-6 alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^a is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, 3, or 4

independently selected R ^b substituents; each R ^b is independently selected from D, halo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^c , SR ^C , NHOR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , C(=NR')R ^C , C(=NR ^I )NR ^C R ^C , NR ^C C(=NR ^I )NR ^C R ^C ,

NR ^c C(=NOH)NR ^c R ^c , NR ^C C(=NCN)NR ^C R ^C , NR ^c S(0)R ^c , NR ^c S(0) ₂ R ^c , NR ^c S(0) ₂ NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , SF ₅ , -P(0)R ^c R ^c , -P(0)(OR ^c )(OR ^c ), B(OR ^c ) ₂ , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^b is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ⁹ is independently selected from D, halo, C1-5 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, N0 ₂ , OR ^k , SR ^k , NHOR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , OC(0)R ^k , OC(0)NR ^k R ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , C(=NR')R ^k , C(=NR ¹ )NR ^k R ^k , NR ^k C(=NR')NR ^k R ^k ,

NR ^k C(=NOH)NR ^k R ^k , NR ^k C(=NCN)NR ^k R ^k , NR ^k S(0)R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k ,

S(0)R ^k , S(0)NR ^k R ^k , S(0) ₂ R ^k , SF ₅ , -P(0)R ^k R ^k , -P(0)(OR ^k )(OR ^k ), B(OR ^k ) ₂ , and S(0) ₂ NR ^k R ^k , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^c is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents; each R ^d is independently selected from D, halo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^e , SR ^e , NHOR ^e , C(0)R ^e , C(0)NR ^e R ^e , C(0)OR ^e , OC(0)R ^e , OC(0)NR ^e R ^e , NR ^e R ^e , NR ^e C(0)R ^e , NR ^e C(0)OR ^e , NR ^e C(0)NR ^e R ^e , C(=NR')R ^e , C(=NR ¹ )NR ^e R ^e , NR ^e C(=NR ¹ )NR ^e R ^e ,

NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , NR ^e S(0)R ^e , NR ^e S(0) ₂ R ^e , NR ^e S(0) ₂ NR ^e R ^e , S(0)R ^e , S(0)NR ^e R ^e , S(0) ₂ R ^e , SF ₅ , -P(0)R ^e R ^e , -P(0)(OR ^e )(OR ^e ), B(OR ^e ) ₂ , and S(0) ₂ NR ^e R ^e , wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^e is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-s alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^e is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^f is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^s , SR ^S , NHOR ^s , C(0)R ^s , C^NR ^S R ⁸ , C(0)OR ^s , OC(0)R ^s , OC^NR ^S R ⁸ , NR ^S R ^S , NR ^s C(0)R ^s , NR ^s C(0)OR ^s , NR ^s C(0)NR ^s R ^s , C(=NR ^I )R ^S , C(=NR ^I )NR ^S R ^S , NR ^S C(=NR ^I )NR ^S R ^S , NR ^s C(=NOH)NR ^s R ^s , NR ^S C(=NCN)NR ^S R ^S , NR ^s S(0)R ^s , NR ^s S(0) ₂ R ^s , NR ^s S(0) ₂ NR ^s R ^s , S(0)R ^s , S(0)NR ^s R ^s , S(0) ₂ R ^s , SF ₅ , -P(0)R ^s R ^s , -P(0)(OR ^s )(OR ^s ), B(OR ^s ) ₂ , and S(0) ₂ NR ^s R ^s , wherein the Ci _-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^f is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^s is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-s alkyl, C2-6 alkenyl, C ₂ - 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^s is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^h is independently selected from OH, NO2, CN, halo, C1-5 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-ehaloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents;

each R ^q is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^m , SR ^m , NHOR ^m , C(0)R ^m , C(0)NR ^m R ^m , C(0)OR ^m , OC(0)R ^m , OC(0)NR ^m R ^m , NHR ^m , NR ^m R ^m , m C(0)R ^m , NR ^m C(0)OR ^m , NR ^m C(0)NR ^m R ^m , C(=NR')R ^m , C(=NR ¹ )NR ^m R ^m ,

NR ^m C(=NR ¹ )NR ^m R ^m , NR ^m C(=NOH)NR ^m R ^m , NR ^m C(=NCN)NR ^m R ^m , NR ^m S(0)R ^m ,

NR ^m S(0) ₂ R ^m , NR ^m S(0) ₂ NR ^m R ^m , S(0)R ^m , S(0)NR ^m R ^m , S(0) ₂ R ^m , SF ₅ , -P(0)R ^m R ^m , - P(0)(OR ^m )(OR ^m ), BCOR^z, and S(0) ₂ NR ^m R ^m , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^q is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ^m is independently selected from H, D, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocy cloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocy cloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocy cloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocy cloalkyl-Ci-6 alkyl- of R ^m is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ⁿ is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocy cloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ⁰ , SR°, NHOR ⁰ , C(0)R°, C(0)NR°R°, C(0)OR°, OC(0)R°, OC(0)NR°R°, NR°R°, NR°C(0)R°, NR°C(0)OR°,

NR°C(0)NR°R°, C(=NR ^I )R°, C(=NR ^I )NR°R°, NR°C(=NR ^I )NR°R°, NR°C(=NOH)NR°R°, NR°C(=NCN)NR°R°, NR°S(0)R°, NR°S(0) ₂ R°, NR ⁰ S(0) ₂ NR ⁰ R°, S(0)R°, S(0)NR°R°, S(0) ₂ R°, and S(0) ₂ NR°R°, wherein the Ci _-6 alkyl, C ₂ * alkenyl, C ₂ - ₆ alkynyl, Ci _-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocy cloalkyl-Ci-6 alkyl- of R ⁿ is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents; and

each R° is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocy cloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocy cloalkyl-Ci-6 alkyl- of R° is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ; X ⁷ is N or CR ⁷ ;

provided that X ⁴ , X ⁵ , and X ⁶ are not all N;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F or CI, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y ² substituents;

R ¹ is selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-

10 membered aryl, C ₃ -iocycloalkyl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^a , SR ^a , NHOR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , OC(0)R ^a , OC(0)NR ^a R ^a , NR ^a R ^a , NR^R^ ³ , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , NR ^a C(=NR')NR ^a R ^a , NR ^a C(=NOH)NR ^a R ^a , NR ^a C(=NCN)NR ^a R ^a , NR ^a S(0)R ^a , NR ^a S(0) ₂ R ^a , NR ^a S(0)(=NR ^I )R ^a , NR ^a S(0) ₂ NR ^a R ^a , S(0)R ^a , S(0)NR ^a R ^a , S(0) ₂ R ^a , OS(0)(=NR ^I )R ^a , and S(0) ₂ NR ^a R ^a , wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ¹ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, halo, C1-5 alkyl, Ci-6 alkoxy, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, C 1-6 haloalkoxy, 6-10 membered aryl, C ₃ - ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-,

4- 10 membered heterocycloalkyl-Ci-6 alkyl, OH, NO2, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, C1-5 alkylsulfinyl, C1-5 alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci- ₆ alkyl)carbamyl, carboxy, C ₁ -5 alkylcarbonyl, Ci- ₆ alkoxycarbonyl, C ₁ -5 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci-6 alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, C1-5 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents;

R ⁸ is selected from H, D, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, C 1-6 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, 6-10 membered aryl-Ci- ₆ alkyl-, C3-iocycloalkyl-Ci- ₆ alkyl-,

5- 10 membered heteroaryl-Ci- ₆ alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, NO ₂ , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , and S(0) ₂ NR ^a R ^a , wherein the Ci- 6 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-5 alkynyl, C1-5 haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C3- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or any two R ⁴ , R ⁵ , R ⁶ and R ⁷ substituents, together with the ring atoms to which they attached form a 4-, 5-, 6-, or 7-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-,

6- , or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

each R ¹ is independently selected from H, CN, OH, C1- alkyl, and CI alkoxy;

each Y ² is independently selected from OH, NO2, CN, halo, Ci-s alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-s haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C3-10 cycloalkyl, C1-5 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci-6 alkylcarbonyl, C1-5 alkoxy carbonyl, Ci-6 alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^a is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, 3, or 4

independently selected R ^b substituents;

each R ^b is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci- ₆ alkyl-, 4-10 membered heterocycloalkyl-Ci- ₆ alkyl-, CN, NO ₂ , OR ^c , SR ^C , NHOR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , C(=NR')R ^C , C(=NR ^I )NR ^C R ^C , NR ^C C(=NR ^I )NR ^C R ^C ,

NR ^c C(=NOH)NR ^c R ^c , NR ^C C(=NCN)NR ^C R ^C , NR ^c S(0)R ^c , NR ^c S(0) ₂ R ^c , NR ^c S(0) ₂ NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the Ci _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^b is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ⁹ is independently selected from D, halo, Ci-6 alkyl, C _2- 6 alkenyl, C2-6 alkynyl,

Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, N0 ₂ , OR ^k , SR ^k , NHOR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , OC(0)R ^k , OC(0)NR ^k R ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , C(=NR')R ^k , C(=NR ¹ )NR ^k R ^k , NR ^k C(=NR')NR ^k R ^k ,

NR ^k C(=NOH)NR ^k R ^k , NR ^k C(=NCN)NR ^k R ^k , NR ^k S(0)R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0)R ^k , S(0)NR ^k R ^k , S(0) ₂ R ^k , and S(0) ₂ NR ^k R ^k , wherein the Ci _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^c is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

or two R ^c substituents, together with the nitrogen atom to which they attached form a 4-, 5-, 6-, or 7-membered heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ^d is independently selected from D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci- ₆ alkyl-, 5-10 membered heteroaryl-Ci- ₆ alkyl-, 4-10 membered heterocycloalkyl-Ci- ₆ alkyl-, CN, NO ₂ , OR ^e , SR ^e , NHOR ^e , C(0)R ^e , C(0)NR ^e R ^e , C(0)OR ^e , OC(0)R ^e , OC(0)NR ^e R ^e , NR ^e R ^e , NR ^e C(0)R ^e , NR ^e C(0)OR ^e , NR ^e C(0)NR ^e R ^e , C(=NR')R ^e , C(=NR ¹ )NR ^e R ^e , NR ^e C(=NR ¹ )NR ^e R ^e ,

NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , NR ^e S(0)R ^e , NR ^e S(0) ₂ R ^e , NR ^e S(0) ₂ NR ^e R ^e , S(0)R ^e , S(0)NR ^e R ^e , S(0) ₂ R ^e , and S(0) ₂ NR ^e R ^e , wherein the Ci _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^e is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^e is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^f is independently selected from D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-74 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^s , SR ^S , NHOR ^s , C(0)R ^s , C(0)NR ^s R ^s , C(0)OR ^s , OC(0)R ^s , OC(0)NR ^s R ^s , NR ^S R ^S , NR ^s C(0)R ^s , NR ^s C(0)OR ^s , NR ^s C(0)NR ^s R ^s , C(=NR ^I )R ^S , C(=NR ^I )NR ^S R ^S , NR ^S C(=NR ^I )NR ^S R ^S , NR ^s C(=NOH)NR ^s R ^s , NR ^S C(=NCN)NR ^S R ^S , NR ^s S(0)R ^s , NR ^s S(0) ₂ R ^s , NR ^s S(0) ₂ NR ^s R ^s , S(0)R ^s , S(0)NR ^s R ^s ,

S(0) ₂ R ^s , and S(0) ₂ NR ^s R ^s , wherein the Ci _-6 alkyl, C ₂ -s alkenyl, C _2-6 alkynyl, Ci _-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^f is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^s is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^s is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^h is independently selected from OH, NO2, CN, halo, C1-5 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents;

each R ^q is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^m , SR ^m , NHOR ^m , C(0)R ^m , C(0)NR ^m R ^m , C(0)OR ^m , OC(0)R ^m , OC(0)NR ^m R ^m , NHR ^m , NR ^m R ^m , ΝΙΤΟ^ΙΤ, NR ^m C(0)OR ^m , NR ^m C(0)NR ^m R ^m , C(=NR')R ^m , C(=NR ¹ )NR ^m R ^m ,

NR ^m C(=NR ¹ )NR ^m R ^m , NR ^m C(=NOH)NR ^m R ^m , NR ^m C(=NCN)NR ^m R ^m , NR ^m S(0)R ^m ,

NR ^m S(0) ₂ R ^m , NR ^m S(0) ₂ NR ^m R ^m , S(0)R ^m , S(0)NR ^m R ^m , S(0) ₂ R ^m , and S(0) ₂ NR ^m R ^m , wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^q is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ^m is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-s alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^m is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ⁿ is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalky l-Ci _-6 alkyl-, CN, N0 ₂ , OR ⁰ , SR°, NHOR ⁰ , C(0)R°, C(0)NR°R°, C(0)OR°, OC(0)R°, OC(0)NR°R°, NR°R°, NR°C(0)R°, NR°C(0)OR°, NR°C(0)NR°R°, C(=NR ^I )R°, C(=NR ^I )NR°R°, NR°C(=NR ^I )NR°R°, NR°C(=NOH)NR°R°, NR°C(=NCN)NR°R°, NR°S(0)R°, NR ⁰ S(0) ₂ R°, NR ⁰ S(0) ₂ NR ⁰ R°, S(0)R°, S(0)NR°R°, S(0) ₂ R°, and S(0) ₂ NR°R°, wherein the Ci _-6 alkyl, C ₂ * alkenyl, C ₂ - ₆ alkynyl, Ci _-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ⁿ is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents; and

each R° is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalky l-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R° is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is N or CR ⁷ ;

provided that X ⁴ , X ⁵ , and X ⁶ are not all N;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F or CI; R ¹ is independently selected from H, D, halo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^a , SR ^a , NHOR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , OC(0)R ^a , OC(0)NR ^a R ^a , NR ^a R ^a , NR ^a NR ^a R ^a ,

NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , NR ^a C(=NR')NR ^a R ^a , NR ^a C(=NOH)NR ^a R ^a , NR ^a C(=NCN)NR ^a R ^a , NR ^a S(0)R ^a , NR ^a S(0) ₂ R ^a , NR ^a S(0)(=NR ^I )R ^a , NR ^a S(0) ₂ NR ^a R ^a , S(0)R ^a , S(0)NR ^a R ^a , S(0) ₂ R ^a , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 memberedaryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl- C1-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ¹ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, halo, C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl, OH, NO2, amino, Ci-6 alkylamino, di(Ci-6 alkyl)amino, thio, Ci- ₆ alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci- ₆ alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents;

R ⁸ is selected from H, D, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl,

4- 10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, NO ₂ , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , and S(0) ₂ NR ^a R ^a , wherein the Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci- ₆ alkyl-, 5-10 membered heteroaryl-Ci- ₆ alkyl-, and 4-10 membered heterocycloalkyl-Ci- ₄ alkyl- of R ⁸ are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

each R ¹ is independently selected from H, CN, OH, Ci-4 alkyl, and alkoxy;

each R ^a is independently selected from H, D, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, 3, or 4

independently selected R ^b substituents;

each R ^b is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO2, OR ^c , SR ^C , NHOR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , C(=NR')R ^C , C(=NR ^I )NR ^C R ^C , NR ^C C(=NR ^I )NR ^C R ^C ,

NR ^c C(=NOH)NR ^c R ^c , NR ^C C(=NCN)NR ^C R ^C , NR ^c S(0)R ^c , NR ^c S(0) ₂ R ^c , NR ^c S(0) ₂ NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ^b is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ⁹ is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^k , SR ^k , NHOR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , OC(0)R ^k , OC(0)NR ^k R ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , C(=NR')R ^k , C(=NR ¹ )NR ^k R ^k , NR ^k C(=NR')NR ^k R ^k ,

NR ^k C(=NOH)NR ^k R ^k , NR ^k C(=NCN)NR ^k R ^k , NR ^k S(0)R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0)R ^k , S(0)NR ^k R ^k , S(0) ₂ R ^k , and S(0) ₂ NR ^k R ^k , wherein the Ci _-6 alkyl, C _2-6 alkenyl, C ₂ - ₆ alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^c is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

or two R ^c substituents, together with the nitrogen atom to which they attached form a

4-, 5-, 6-, or 7-membered heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ^d is independently selected from D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, N0 ₂ , OR ^e , SR ^e , NHOR ^e , C(0)R ^e , C(0)NR ^e R ^e , C(0)OR ^e , OC(0)R ^e , OC(0)NR ^e R ^e , NR ^e R ^e , NR ^e C(0)R ^e , NR ^e C(0)OR ^e , NR ^e C(0)NR ^e R ^e , C(=NR')R ^e , C(=NR ¹ )NR ^e R ^e , NR ^e C(=NR ¹ )NR ^e R ^e ,

NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , NR ^e S(0)R ^e , NR ^e S(0) ₂ R ^e , NR ^e S(0) ₂ NR ^e R ^e , S(0)R ^e , S(0)NR ^e R ^e , S(0) ₂ R ^e , and S(0) ₂ NR ^e R ^e , wherein the Ci _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^e is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-;

each R ^h is independently selected from OH, N0 ₂ , CN, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; and

each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is N or CR ⁷ ;

provided that X ⁴ , X ⁵ , and X ⁶ are not all N;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F or CI, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y ² substituents;

R ¹ is selected from H, D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6- 10 membered aryl, C ₃ -iocycloalkyl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^a , SR ^a , NHOR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , OC(0)R ^a , OC(0)NR ^a R ^a , NR ^a R ^a , NR^R^ ³ , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , NR ^a C(=NR')NR ^a R ^a , NR ^a C(=NOH)NR ^a R ^a , NR ^a C(=NCN)NR ^a R ^a , NR ^a S(0)R ^a , NR ^a S(0) ₂ R ^a , NR ^a S(0)(=NR ^I )R ^a , NR ^a S(0) ₂ NR ^a R ^a , S(0)R ^a , S(0)NR ^a R ^a , S(0) ₂ R ^a , OS(0)(=NR ^I )R ^a , and S(0) ₂ NR ^a R ^a , wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ¹ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, halo, C1-5 alkyl, Ci-6 alkoxy, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci- ₆ alkyl-, C3-io cycloalkyl-Ci- ₆ alkyl-, 5-10 membered heteroaryl-Ci- ₆ alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl, OH, NO2, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, C1-5 alkylsulfinyl, C1-5 alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci- ₆ alkyl)carbamyl, carboxy, C ₁ -5 alkylcarbonyl, Ci- ₆ alkoxycarbonyl, C ₁ -5 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci-6 alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, C1-5 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl,

4- 10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents;

R ⁸ is selected from H, D, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, C 1-6 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl,

4- 10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, NO ₂ , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , and S(0) ₂ NR ^a R ^a , wherein the Ci- 6 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-5 alkynyl, C1-5 haloalkyl, C1-5 haloalkoxy, 6-10 membered aryl, C3- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or any two R ⁴ , R ⁵ , R ⁶ and R ⁷ substituents, together with the ring atoms to which they attached form a 4-, 5-, 6-, or 7-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-,

6- , or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

each R ¹ is independently selected from H, CN, OH, C 1- alkyl, and CI alkoxy;

each Y ² is independently selected from OH, NO2, CN, halo, Ci-s alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-s haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C3-10 cycloalkyl, C1-5 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, C1-5 alkylsulfinyl, C1-5 alkylsulfonyl, carbamyl, Ci-s alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, Ci-s alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^a is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, 3, or 4

independently selected R ^b substituents;

each R ^b is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^c , SR ^C , NHOR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , C(=NR')R ^C , C(=NR ^I )NR ^C R ^C , NR ^C C(=NR ^I )NR ^C R ^C ,

NR ^c C(=NOH)NR ^c R ^c , NR ^C C(=NCN)NR ^C R ^C , NR ^c S(0)R ^c , NR ^c S(0) ₂ R ^c , NR ^c S(0) ₂ NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^b is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ⁹ is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^k , SR ^k , NHOR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , OC(0)R ^k , OC(0)NR ^k R ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , C(=NR')R ^k , C(=NR ¹ )NR ^k R ^k , NR ^k C(=NR')NR ^k R ^k ,

NR ^k C(=NOH)NR ^k R ^k , NR ^k C(=NCN)NR ^k R ^k , NR ^k S(0)R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0)R ^k , S(0)NR ^k R ^k , S(0) ₂ R ^k , and S(0) ₂ NR ^k R ^k , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^c is independently selected from H, D, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

each R ^d is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^e , SR ^e , NHOR ^e , C(0)R ^e , C(0)NR ^e R ^e , C(0)OR ^e , OC(0)R ^e , OC(0)NR ^e R ^e , NR ^e R ^e , NR ^e C(0)R ^e , NR ^e C(0)OR ^e , NR ^e C(0)NR ^e R ^e , C(=NR')R ^e , C(=NR ¹ )NR ^e R ^e , NR ^e C(=NR ¹ )NR ^e R ^e ,

NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , NR ^e S(0)R ^e , NR ^e S(0) ₂ R ^e , NR ^e S(0) ₂ NR ^e R ^e , S(0)R ^e , S(0)NR ^e R ^e , S(0) ₂ R ^e , and S(0) ₂ NR ^e R ^e , wherein the Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^e is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-s alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^e is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^f is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^s , SR ^S , NHOR ^s , C(0)R ^s , C(0)NR ^s R ^s , C(0)OR ^s , OC(0)R ^s , OC(0)NR ^s R ^s , NR ^S R ^S , NR ^s C(0)R ^s , NR ^s C(0)OR ^s , NR ^s C(0)NR ^s R ^s , C(=NR ^I )R ^S , C(=NR ^I )NR ^S R ^S , NR ^S C(=NR ^I )NR ^S R ^S , NR ^s C(=NOH)NR ^s R ^s , NR ^S C(=NCN)NR ^S R ^S , NR ^s S(0)R ^s , NR ^s S(0) ₂ R ^s , NR ^s S(0) ₂ NR ^s R ^s , S(0)R ^s , S(0)NR ^s R ^s , S(0) ₂ R ^s , and S(0) ₂ NR ^s R ^s , wherein the Ci _-6 alkyl, C ₂ -s alkenyl, C _2-6 alkynyl, Ci _-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^f is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^s is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^s is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

each R ^h is independently selected from OH, N0 ₂ , CN, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, Ci-6 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6

alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci-6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^k is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10

membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents;

each R ^q is independently selected from D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci- ₆ alkyl-, 5-10 membered heteroaryl-Ci- ₆ alkyl-, 4-10 membered heterocycloalkyl-Ci- ₆ alkyl-, CN, NO ₂ , OR ^m , SR ^m , NHOR ^m , C(0)R ^m , C(0)NR ^m R ^m , C(0)OR ^m , OC(0)R ^m , OC(0)NR ^m R ^m , NHR ^m , NR ^m R ^m , m C(0)R ^m , NR ^m C(0)OR ^m , NR ^m C(0)NR ^m R ^m , C(=NR')R ^m , C(=NR ¹ )NR ^m R ^m ,

NR ^m C(=NR ¹ )NR ^m R ^m , NR ^m C(=NOH)NR ^m R ^m , NR ^m C(=NCN)NR ^m R ^m , NR ^m S(0)R ^m ,

NR ^m S(0) ₂ R ^m , NR ^m S(0) ₂ NR ^m R ^m , S(0)R ^m , S(0)NR ^m R ^m , S(0) ₂ R ^m , and S(0) ₂ NR ^m R ^m , wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl- of R ^q is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ^m is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^m is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents;

each R ⁿ is independently selected from D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ⁰ , SR°, NHOR ⁰ , C(0)R°, C(0)NR°R°, C(0)OR°, OC(0)R°, OC(0)NR°R°, NR°R°, NR°C(0)R°, NR°C(0)OR°, NR°C(0)NR°R°, C(=NR ^I )R°, C(=NR ^I )NR°R°, NR°C(=NR ^I )NR°R°, NR°C(=NOH)NR°R°, NR°C(=NCN)NR°R°, NR°S(0)R°, NR°S(0) ₂ R°, NR°S(0) ₂ NR°R°, S(0)R°, S(0)NR°R°, S(0) ₂ R°, and S(0) ₂ NR°R°, wherein the Ci _-6 alkyl, C ₂ -s alkenyl, C _2-6 alkynyl, Ci _-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ⁿ is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents; and

each R° is independently selected from H, D, Ci-6 alkyl, C _2- 6 alkenyl, C _2- 6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C _2- 6 alkenyl, C _2- 6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl- and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R° is each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is N or CR ⁷ ;

provided that X ⁴ , X ⁵ , and X ⁶ are not all N;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F or CI;

R ¹ is independently selected from H, D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci _-6 alkyl-, CN, N0 ₂ , OR ^a , SR ^a , NHOR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , OC(0)R ^a , OC(0)NR ^a R ^a , NR ^a R ^a , NR^R^ ³ , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , NR ^a C(=NR')NR ^a R ^a , NR ^a C(=NOH)NR ^a R ^a , NR ^a C(=NCN)NR ^a R ^a , NR ^a S(0)R ^a , NR ^a S(0) ₂ R ^a , NR ^a S(0)(=NR ^I )R ^a , NR ^a S(0) ₂ NR ^a R ^a , S(0)R ^a , S(0)NR ^a R ^a , S(0) ₂ R ^a , and S(0) ₂ NR ^a R ^a , wherein the C _w alkyl, C ₂ - ₆ alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl- C1-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ¹ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, halo, C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl, OH, NO2, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, Ci- ₆ alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci- ₆ alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the Ci-s alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents;

R ⁸ is selected from H, D, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl,

4- 10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-,

5- 10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, NO ₂ , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , C(=NR')R ^a , C(=NR')NR ^a R ^a , and S(0) ₂ NR ^a R ^a , wherein the Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-,

6- , or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

each R ¹ is independently selected from H, CN, OH, C1- alkyl, and CI alkoxy;

each R ^a is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, 3, or 4

independently selected R ^b substituents;

each R ^b is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, NO ₂ , OR ^c , SR ^C , NHOR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , C(=NR')R ^C , C(=NR ^I )NR ^C R ^C , NR ^C C(=NR ^I )NR ^C R ^C ,

NR ^c C(=NOH)NR ^c R ^c , NR ^C C(=NCN)NR ^C R ^C , NR ^c S(0)R ^c , NR ^c S(0) ₂ R ^c , NR ^c S(0) ₂ NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the Ci _-6 alkyl, C _2-6 alkenyl, C ₂ - ₆ alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ^b is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ⁹ is independently selected from D, halo, Ci-6 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, N0 ₂ , OR ^k , SR ^k , NHOR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , OC(0)R ^k , OC(0)NR ^k R ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , C(=NR')R ^k , C(=NR ¹ )NR ^k R ^k , NR ^k C(=NR')NR ^k R ^k ,

NR ^k C(=NOH)NR ^k R ^k , NR ^k C(=NCN)NR ^k R ^k , NR ^k S(0)R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0)R ^k , S(0)NR ^k R ^k , S(0) ₂ R ^k , and S(0) ₂ NR ^k R ^k , wherein the Ci _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^c is independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl- and 4-10 membered

heterocycloalkyl-Ci-6 alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

each R ^d is independently selected from D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-io cycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, 4-10 membered heterocycloalkyl-Ci-6 alkyl-, CN, N0 ₂ , OR ^e , SR ^e , NHOR ^e , C(0)R ^e , C(0)NR ^e R ^e , C(0)OR ^e , OC(0)R ^e , OC(0)NR ^e R ^e , NR ^e R ^e , NR ^e C(0)R ^e , NR ^e C(0)OR ^e , NR ^e C(0)NR ^e R ^e , C(=NR')R ^e , C(=NR ¹ )NR ^e R ^e , NR ^e C(=NR ¹ )NR ^e R ^e ,

NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , NR ^e S(0)R ^e , NR ^e S(0) ₂ R ^e , NR ^e S(0) ₂ NR ^e R ^e , S(0)R ^e , S(0)NR ^e R ^e , S(0) ₂ R ^e , and S(0) ₂ NR ^e R ^e , wherein the Ci _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -io cycloalkyl-Ci- ₆ alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-4 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^e is independently selected from H, D, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C ₃ -7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-;

each R ^h is independently selected from OH, NO2, CN, halo, C1-5 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-s haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-ehaloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-6 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; and

each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C3-iocycloalkyl-Ci-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl-.

In some embodiments, X ² is N

In some embodiments, X ² is CR ² .

In some embodiments, R ² is selected from H, D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-5 haloalkyl.

In some embodiments, R ² is selected from H, D, and C1-5 alkyl.

In some embodiments, R ² is H.

In some embodiments, X ² is N or CH.

In some embodiments, R ³ is H or D.

In some embodiments, R ³ is H.

In some embodiments, X ⁴ is CR ⁴ .

In some embodiments, R ⁴ is selected from H, D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-5 haloalkyl.

In some embodiments, R ⁴ is selected from H, D, halo and C1-5 alkyl.

In some embodiments, R ⁴ is selected from H, D, fluoro, methyl, and CD ₃ .

In some embodiments, R ⁴ is selected from H, fluoro, methyl, and CD ₃ . In some embodiments, R ⁴ is selected from H, fluoro, and methyl.

In some embodiments, X ⁴ is N.

In some embodiments, X ⁵ is CR ⁵ .

In some embodiments, R ⁵ is selected from H, D, halo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-5 haloalkyl.

In some embodiments, R ⁵ is selected from H, D, and C1-5 alkyl.

In some embodiments, R ⁵ is H.

In some embodiments, X ⁵ is N.

In some embodiments, X ⁵ is N or CH.

In some embodiments, X ⁶ is CR ⁶ .

In some embodiments, R ⁶ is selected from H, D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-5 haloalkyl.

In some embodiments, R ⁶ is selected from H, D, and halo.

In some embodiments, R ⁶ is selected from H and halo.

In some embodiments, R ⁶ is selected from H and fluoro.

In some embodiments, X ⁶ is N.

In some embodiments, X ⁷ is CR ⁷ .

In some embodiments, R ⁷ is selected from H, D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-5 haloalkyl.

In some embodiments, R ⁷ is selected from H, D, and C1-5 alkyl.

In some embodiments, R ⁷ is H.

In some embodiments, X ⁷ is N.

In some embodiments, X ⁷ is N or CH.

In some embodiments, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from

H, D, halo, Ci-6 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, CN, OR ^a , and SR ^a , wherein the C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl and C1-5 haloalkoxy of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with

I, 2, 3, or 4 independently selected R ^h substituents.

In some embodiments, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, halo, CN, Ci-s alkyl, and C1-5 haloalkyl.

In some embodiments, R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each independently selected from H, D, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-5 haloalkyl.

In some embodiments, R ² , R ³ , R ⁵ , and R ⁷ are each H.

In some embodiments, R ³ , R ⁵ , and R ⁷ are each H. In some embodiments, any two R ⁴ , R ⁵ , and R ⁶ substituents, together with the ring atoms to which they attached form a 4-, 5-, 6-, or 7-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents.

In some embodiments, R ¹ is optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents

In some embodiments, R ¹ is selected from H, D, halo, Ci-s alkyl, C _2- 6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , NR ^a R ^a , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , NR ^a S(0) ₂ NR ^a R ^a , NR ^a S(0) ₂ R ^a , S(0) ₂ R ^a , and S(0) ₂ NR ^a R ^a , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents.

In some embodiments, R ¹ is selected from H, D, halo, C1-5 alkyl, C1-5 haloalkyl, 6-10 membered aryl, C3- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR ^a , C(0)NR ^a R ^a , and C(0)OR ^a , wherein the Ci _-6 alkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents.

In some embodiments, R ¹ is selected from H, C1-5 alkyl, C1-5 haloalkyl, phenyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl,

C(0)NR ^a R ^a , and C(0)OR ^a , wherein the C1-5 alkyl, phenyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ^b substituents.

In some embodiments, R ¹ is selected from H, C1-5 alkyl, C1-5 haloalkyl, phenyl, 5-6 membered heteroaryl, C(0)NR ^a R ^a , and C(0)OR ^a , wherein the C1-5 alkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R ^b substituents.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4- triazolyl, and piperidinyl, wherein the phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl are each optionally substituted by 1 or 2 independently selected R ^b substituents.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl, wherein the phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl are each optionally substituted by 1 or 2 independently selected R ^b substituents.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4- triazolyl, and piperidinyl, wherein the phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl are each optionally substituted by 1 or 2 independently selected R ^b substituents; and each R ^a is selected from H, Ci-s alkyl, isoxazol-5-ylmethyl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, 5,6-dihydro- 4H-pyrrolo[l,2-b]pyrazol-3-yl, wherein said isoxazol-5-ylmethyl, tetrahydrofuran-3-yl, and tetrahydro-2H-pyran-4-yl are each optionally subsituted by 1 or 2 substituents independently selected from methyl, trifluoromethyl, and cyclopropyl, and wherein said Ci-s alkyl is optionally substituted by OH.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4- triazolyl, and piperidinyl, wherein the phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl are each optionally substituted by 1 or 2 independently selected R ^b substituents; and each R ^a is selected from H, Ci-s alkyl, and isoxazol-5-ylmethyl; wherein said isoxazol-5-ylmethyl is substituted by methyl and said Ci-s alkyl is optionally substituted by OH.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl, wherein the phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl are each optionally substituted by 1 or 2 independently selected R ^b substituents; and each R ^a is selected from H, Ci-s alkyl, and isoxazol-5-ylmethyl; wherein said isoxazol-5-ylmethyl is substituted by methyl and said Ci-s alkyl is optionally substituted by OH.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl, wherein the phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl are each optionally substituted by 1 or 2 independently selected R ^b substituents; and each R ^a is selected from H, Ci-s alkyl, isoxazol-5-ylmethyl, tetrahydrofuran- 3-yl, tetrahydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl, wherein said isoxazol-5-ylmethyl, tetrahydrofuran-3-yl, and tetrahydro-2H-pyran-4-yl are each optionally subsituted by 1 or 2 substituents independently selected from methyl, trifluoromethyl, and cyclopropyl, and wherein said Ci-s alkyl is optionally substituted by OH. In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, cyclopropyl, thiazol-5-yl, thiazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-5-yl, pyrimidin-5-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-5-yl, 1,2,4-triazol-l-yl, and piperidin-l-yl, wherein the phenyl, thiazol-5-yl, thiazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-5-yl, pyrimidin-5-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-5-yl, 1,2,4- triazol-l-yl, and piperidin-l-yl are each optionally substituted by 1 or 2 independently selected R ^b substituents; and each R ^a is selected from H, Ci-s alkyl, and isoxazol-5-ylmethyl; wherein said isoxazol-5-ylmethyl is substituted by methyl and said Ci-s alkyl is optionally substituted by OH.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, thiazol-5-yl, thiazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-5-yl, pyrimidin-5-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-5-yl, and 1,2,4-triazol-l-yl, wherein the phenyl, thiazol-5-yl, thiazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-5-yl, pyrimidin-5-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-5-yl, and 1,2,4-triazol-l-yl are each optionally substituted by 1 or 2 independently selected R ^b substituents; and each R ^a is selected from H, Ci- ₆ alkyl, and isoxazol-5-ylmethyl; wherein said isoxazol-5-ylmethyl is substituted by methyl and said Ci-s alkyl is optionally substituted by OH.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OCH ₃ , C(0)NHCH ₃ , C(0)NHCH ₂ -(3-methylisoxazol-5-yl), C(0)NHCH ₂ C(CH ₃ ) ₂ OH, 4-fluorobenzamide-3-yl, 2- cyclopropylthiazol-5-yl, 5-methoxythiazol-2-yl, 2-(hydroxymethyl)pyridin-4-yl, l-(methyl- d ₃ )-lH-pyrazol-5-yl, 2-methyloxazol-5-yl, l-methyl-lH-pyrazol-5-yl, pyrimidin-3-yl, 2- methoxypyridin-3-yl, 2-methylthiazol-5-yl, 3-fluoro-2-methylpyridin-4-yl, 1,5-dimethyl-lH- pyrazol-4-yl, 1 -methyl- lH-pyrazol-4-yl, l,3-dimethyl-lH-pyrazol-4-yl, 3,5-dimethyl-lH- pyrazol-4-yl, lH-pyrazol-4-yl, l,3-dimethyl-lH-pyrazol-5-yl, l,4-dimethyl-lH-pyrazol-5-yl, l-methyl-lH-pyrazol-3-yl, 6-(hydroxymethyl)pyridin-3-yl, 3-methyl-lH-pyrazol-4-yl, 3- methylisoxazol-5-yl, 1H- 1,2,4-triazol-l-yl, 4-cyanopiperidin-l-yl, 4-hydroxypiperidin-l-yl, l-(methyl-d ₃ )-lH-pyrazol-5-yl, oxazol-5-yl, l-(hydroxymethyl)cycloprop-2-yl, 1- (ethoxycarbonyl)cycloprop-2-yl, l-(N-methylaminocarbonyl)cycloprop-2-yl, l-(4- methylpiperazin-l-yl)cycloprop-2-yl, and l-( -(2-hydroxy-l, l- dimethylethyl)aminocarbonyl)cycloprop-2-yl.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OCH ₃ , C(0)NHCH ₃ , C(0)NHCH ₂ -(3-methylisoxazol-5-yl), C(0)NHCH ₂ C(CH ₃ ) ₂ OH, 4-fluorobenzamide-3-yl, 2- cyclopropylthiazol-5-yl, 5-methoxythiazol-2-yl, 2-(hydroxymethyl)pyridin-4-yl, l-(methyl- d ₃ )-lH-pyrazol-5-yl, 2-methyloxazol-5-yl, l-methyl-lH-pyrazol-5-yl, pyrimidin-3-yl, 2- methoxypyridin-3-yl, 2-methylthiazol-5-yl, 3-fluoro-2-methylpyridin-4-yl, 1,5-dimethyl-lH- pyrazol-4-yl, 1 -methyl- lH-pyrazol-4-yl, l,3-dimethyl-lH-pyrazol-4-yl, 3,5-dimethyl-lH- pyrazol-4-yl, lH-pyrazol-4-yl, l,3-dimethyl-lH-pyrazol-5-yl, l,4-dimethyl-lH-pyrazol-5-yl, l-methyl-lH-pyrazol-3-yl, 6-(hydroxymethyl)pyridin-3-yl, 3-methyl-lH-pyrazol-4-yl, 3- methylisoxazol-5-yl, lH-l,2,4-triazol-l-yl, 3-cyclopropyltetrahydrofuran-3-yl, 2,3- dimethyltetrahydrofuran-3-yl, 4-(trifluoromethyl)tetrahydro-2H-pyran-4-yl, and 5,6-dihydro- 4H-pyrrolo[l,2-b]pyrazol-3-yl.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , C(0)OCH ₃ , C(0)NHCH ₃ , C(0)NHCH ₂ -(3-methylisoxazol-5-yl), C(0)NHCH ₂ C(CH ₃ ) ₂ OH, 4-fluorobenzamide-3-yl, 2- cyclopropylthiazol-5-yl, 5-methoxythiazol-2-yl, 2-(hydroxymethyl)pyridin-4-yl, l-(methyl- d ₃ )-lH-pyrazol-5-yl, 2-methyloxazol-5-yl, l-methyl-lH-pyrazol-5-yl, pyrimidin-3-yl, 2- methoxypyridin-3-yl, 2-methylthiazol-5-yl, 3-fluoro-2-methylpyridin-4-yl, 1,5-dimethyl-lH- pyrazol-4-yl, 1 -methyl- lH-pyrazol-4-yl, l,3-dimethyl-lH-pyrazol-4-yl, 3,5-dimethyl-lH- pyrazol-4-yl, lH-pyrazol-4-yl, l,3-dimethyl-lH-pyrazol-5-yl, l,4-dimethyl-lH-pyrazol-5-yl, l-methyl-lH-pyrazol-3-yl, 6-(hydroxymethyl)pyridin-3-yl, 3-methyl-lH-pyrazol-4-yl, 3- methylisoxazol-5-yl, and lH-l,2,4-triazol-l-yl.

In some embodiments, R ¹ is selected from H, methyl, CF ₃ , and

C(0)NHCH ₂ C(CH ₃ ) ₂ OH, .

In some embodiments, R ¹ is CF ₃ .

In some embodiments, R ¹ is C(0)NHCH ₂ C(CH ₃ ) ₂ OH.

In some embodiments, Y ¹ is C1-5 haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y ² substituents.

In some embodiments, Y ¹ is selected from CF ₃ , CCI3, CF ₂ H, CC1 ₂ H, CF ₂ Y ² , CC1 ₂ Y ² , CFH ₂ , CC1H ₂ , CFHY ² , CC1HY ² , CF(Y ² ) ₂ and CC1(Y ² ) ₂ .

In some embodiments, Y ¹ is selected from CF ₃ , CF ₂ H, CF ₂ Y ² , CFH ₂ , CFHY ² , and CF(Y ² ) ₂ .

In some embodiments, Y ¹ is C1-5 haloalkyl, wherein each halogen is F.

In some embodiments, Y ¹ is C1-5 haloalkyl, wherein each halogen is CI.

In some embodiments, Y ¹ is selected from CH ₂ F, CHF ₂ , CF ₃ , and CF ₂ CF ₃ .

In some embodiments, Y ¹ is CF ₃ .

In some embodiments, Y ¹ is CH ₂ F.

In some embodiments, Y ¹ is CHF ₂ .

In some embodiments, Y ¹ is CF ₂ CF ₃ .

In some embodiments, Y ² is selected from D, halo, C1-5 alkyl, and C1-5 haloalkyl.

In some embodiments, Y ² is selected from halo and Ci-s haloalkyl.

In some embodiments, at least one of R ¹ and Y ¹ is CF ₃ . In some embodiments, R ¹ is selected from H, methyl, CF ₃ , and C(0)NHCH ₂ C(CH ₃ ) ₂ OH, and Y ¹ is selected from CH ₂ F, CHF ₂ , CF ₃ , and CF ₂ CF ₃ .

In some embodiments, R ¹ is selected from H, methyl, and CF ₃ , and Y ¹ is selected from CH ₂ F, CHF ₂ , CF ₃ , and CF ₂ CF ₃ .

In some embodiments, R ¹ is CF ₃ and Y ¹ is selected from CH ₂ F, CHF ₂ , CF ₃ , and

CF ₂ CF ₃ .

In some embodiments, R ¹ is C(0)NHCH ₂ C(CH ₃ ) ₂ OH and Y ¹ is selected from CH ₂ F, CHF ₂ , CF ₃ , and CF ₂ CF ₃ .

In some embodiments, R ⁸ is selected from H, D, Ci-s alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C _3- io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and C(0)NR ^a R ^a , wherein the C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 membered aryl, C _3- io cycloalkyl, 5- 10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents.

In some embodiments, R ⁸ is selected from H, D, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl,

C2-6 alkynyl, Ci-6 haloalkyl, 6-10 membered aryl, C _3- io cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-ehaloalkoxy, 6-10 memberedaryl, C _3- io cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents.

In some embodiments, R ⁸ is selected from H, C1-5 alkyl, 6-10 membered aryl, C _3- io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and C(0)NR ^a R ^a , wherein the C1-5 alkyl, 6-10 membered aryl, C _3- io cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents.

In some embodiments, R ⁸ is selected from H, C1-5 alkyl, 6-10 membered aryl, C _3- io cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1-5 alkyl, 6-10 membered aryl, C _3- io cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents.

In some embodiments, R ⁸ is selected from H, C1-5 alkyl, phenyl, C ₃ -6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and C(0)NH ₂ , wherein the C1-5 alkyl, phenyl, C _3- 6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ⁹ substituents. In some embodiments, R is selected from H, Ci-s alkyl, phenyl, C3-5 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C1-5 alkyl, phenyl, C3- 6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ⁹ substituents.

In some embodiments, R ⁸ is selected from H, C1-5 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and C(0)NH ₂ , wherein the C1-5 alkyl, C3-6 cycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R ⁹ substituents.

In some embodiments, R ⁸ is selected from H, C1-5 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the C1-5 alkyl, C3-6 cycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R ⁹ substituents.

In some embodiments, R ⁸ is selected from H, methyl, hydroxy methyl, ethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2-aminoethyl, 2-( -methylamino)ethyl, 2-(N-{tetrahydro-2H- pyran-4-yl}amino)ethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxpropyl, cyclopropyl, 1- methyl-lH-tetrazol-5-yl, and aminocarbonyl.

In some embodiments, R ⁸ is selected from H, methyl, hydroxy methyl, ethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2-aminoethyl, 2-( -methylamino)ethyl, 2-(N-{tetrahydro-2H- pyran-4-yl}amino)ethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxpropyl, cyclopropyl, and 1 -methyl- lH-tetrazol-5-yl.

In some embodiments, R ⁸ is selected from H, methyl, ethyl, 2-hydroxyethyl, 2- aminoethyl, 2-(N-methylamino)ethyl, 2-(N-{tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, l-methyl-lH-tetrazol-5-yl, and aminocarbonyl.

In some embodiments, R ⁸ is selected from H, methyl, ethyl, 2-hydroxyethyl, 2- aminoethyl, 2-(N-methylamino)ethyl, 2-(N-{tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, and l-methyl-lH-tetrazol-5-yl.

In some embodiments, R ⁸ is selected from H, methyl, hydroxymethyl, ethyl, 2- hydroxyethyl, 2-(N-methylamino)ethyl, 2-(N-{tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, l-methyl-lH-tetrazol-5-yl, and amino carbonyl.

In some embodiments, R ⁸ is selected from H, methyl, hydroxymethyl, ethyl, 2- hydroxyethyl, 2-(N-methylamino)ethyl, 2-(N-{tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, and l-methyl-lH-tetrazol-5-yl.

In some embodiments, R ⁸ is selected from H, methyl, ethyl, 2-hydroxyethyl, 2-(N- methylamino)ethyl, 2-(N-{tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, 1-methyl-lH- tetrazol-5-yl, and aminocarbonyl. In some embodiments, R is selected from H, methyl, ethyl, 2-hydroxyethyl, 2-(N- methylamino)ethyl, 2-(N-{tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, and 1-methyl- lH-tetrazol-5-yl.

In some embodiments, Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl group which is optionally substituted by 1 or 2 independently selected halo substituents.

In some embodiments, Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from CI and F.

In some embodiments, Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from CI and F.

In some embodiments, Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 2-fluorocyclopentyl group.

In some embodiments, each R ⁹ is independently selected from halo, Ci-s alkyl, Ci-s haloalkyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-Ci-3 alkyl-, C3-6 cycloalkyl-Ci-3 alkyl-, 5-6 membered heteroaryl-Ci-3 alkyl-, 4-6 membered heterocycloalkyl-Ci _-3 alkyl-, CN, OR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0) ₂ R ^k , and S(0) ₂ NR ^k R ^k , wherein the C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-Ci-3 alkyl-, C3-6 cycloalkyl-Ci-3 alkyl-, 5-6 membered heteroaryl-Ci-3 alkyl-, and 4-6 membered heterocycloalkyl-Ci-3 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents.

In some embodiments, each R ⁹ is independently selected from halo, C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, OR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , and NR ^k R ^k , wherein the Ci _-6 alkyl, Ci _-6 haloalkyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R ⁹ is each optionally substituted with 1 or 2 independently selected R ^q substituents.

In some embodiments, each R ⁹ is independently selected from halo, C1-5 alkyl, C1-5 haloalkyl, CN, OR ^k , and NR ^k R ^k ; wherein the C1-5 alkyl of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents.

In some embodiments, each R ⁹ is independently selected from halo, C1-5 alkyl, C1-5 haloalkyl, CN, OR ^k , and NR ^k R ^k ; wherein the C1-5 alkyl of R ⁹ is each optionally substituted with 1, or 2 independently selected R ^q substituents. In some embodiments, each R ⁹ is independently selected from Ci-s alkyl, OR ^k , and

NR ^k R ^k .

In some embodiments, each R ⁹ is independently selected from methyl, OH, N- methylamino, and N-(tetrahydropyran-4-yl)amino.

In some embodiments, each R ^a is independently selected from H, D, Ci-s alkyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the Ci-s alkyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroary l-Ci-6 alkyl-, and 4-7 membered

heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, or 3 independently selected R ^b substituents.

In some embodiments, each R ^a is independently selected from H, C1-5 alkyl, C1-5 haloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C1-5 haloalkyl, phenyl- Ci-s alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, or 3 independently selected R ^b substituents.

In some embodiments, each R ^a is independently selected from H, C1-5 alkyl, C1-5 haloalkyl, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C1-5 haloalkyl, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1 or 2 independently selected R ^b substituents.

In some embodiments, each R ^a is selected from H, C1-5 alkyl, and isoxazol-5- ylmethyl; wherein said isoxazol-5-ylmethyl is substituted by methyl.

In some embodiments, each R ^a is H.

In some embodiments, each R ^b is independently selected from halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 memberedaryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents.

In some embodiments, each R ^b is independently selected from halo, C1-5 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, OR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , and NR ^C R ^C , wherein the Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents.

In some embodiments, each R ^b is independently selected from halo, C1-5 alkyl, C3-6 cycloalkyl, OR ^c , and C(0)NR ^c R ^c , wherein the C1-5 alkyl and C3-6 cycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents selected from D, C1-5 alkyl and OH; and each R ^c group is independently selected from H and C1-5 alkyl.

In some embodiments, each R ^b is independently selected from fluoro, methyl, CD ₃ , hydroxymethyl, methoxy, C(0)NH ₂ , cyclopropyl, and 3-methylisoxazol-5-yl.

In some embodiments:

each R ^c is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C ₃ -7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-4 alkyl-, C3-7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci-4 alkyl-, wherein the Ci-s alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C ₃ -7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-4 alkyl-, C3-7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci-4 alkyl- of R ^c is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents;

each R ^d is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl-, OH, NO2, CN, halo, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, Ci-6 alkylsulfinyl, Ci-e alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, C1-5 alkoxycarbonyl, C1-5 alkylcarbonylamino, C1-5 alkylsulfonylamino, aminosulfonyl, Ci- ₆ alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci- e alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents; and

each R ^f is independently selected from OH, NO2, CN, halo, Ci-s alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-s haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, Ci-s alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino.

In some embodiments, each R ^c is independently selected from H, C1-5 alkyl, and C1-5 haloalkyl, wherein the C1-5 alkyl and C1-5 haloalkyl of R ^c is each optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents; and each R ^d is independently selected from D, halo, Ci-6 alkyl, C1-5 haloalkyl, OH, CN, Ci-6 alkoxy, Ci-e haloalkoxy, amino, C1-5 alkylamino, and di(Ci-6 alkyl)amino.

In some embodiments, each R ^c group is independently selected from H and C1-5 alkyl; and each R ^d is independently selected from selected from D, C1-5 alkyl and OH.

In some embodiments, two R ^c substituents, together with the nitrogen atom to which they attached form a 4-, 5-, 6-, or 7-membered heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ^d substituents.

In some embodiments, two R ^c substituents, together with the nitrogen atom to which they attached form a 5- or 6-membered heteroaryl or heterocycloalkyl group optionally substituted with 1 or 2 independently selected R ^d substituents.

In some embodiments, two R ^c substituents, together with the nitrogen atom to which they attached form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1 or 2 independently selected R ^d substituents.

In some embodiments, two R ^c substituents, together with the nitrogen atom to which they attached form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1 or 2 independently selected R ^d substituents selected from D and C 1-5 alkyl.

In some embodiments, two R ^c substituents, together with the nitrogen atom to which they attached form a 5- or 6-membered heterocycloalkyl group optionally substituted with methyl.

In some embodiments:

each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-4 alkyl-, C3-7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci-4 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-4 alkyl-, C3-7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci- ₄ alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^q is independently selected from D, halo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl-, OH, NO2, CN, halo, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, Ci-6 alkylsulfinyl, Ci-e alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci- ₆ alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci- e alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^q is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents; and

each R ⁿ is independently selected from OH, NO2, CN, halo, C1-5 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci-6 alkylsulfinyl, Ci-6 alkylsulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino.

In some embodiments:

each R ^k is independently selected from H, C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, alkyl-, C ₃ -7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered

heterocycloalkyl-Ci-4 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 4 alkyl-, C ₃ -7 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci-4 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents; and

each R ^q is independently selected halo, C1-5 alkyl, C1-5 haloalkyl, OH, CN, C1-5 alkoxy, C 1-6 haloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, Ci-6 alkylsulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, C1-5 alkoxycarbonyl, Ci-e alkylcarbonylamino, C1-5 alkylsulfonylamino, aminosulfonyl, C1-5 alkylaminosulfonyl, and di(Ci- ₆ alkyl)aminosulfonyl.

In some embodiments, each R ^k is independently selected from H, C1-5 alkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, wherein the C1-5 alkyl, C3-7 cycloalkyl, and 4- 7 membered heterocycloalkyl of R ^k is each optionally substituted with 1 or 2 independently selected C1-5 alkyl groups.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is N or CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is N or CR ⁷ ;

Y ¹ is Ci-6 haloalkyl, wherein each halogen is F;

R ¹ is selected from H, D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-

10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, OR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , NR ^a R ^a , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , S(0)R ^a , S(0) ₂ R ^a , and S(0) ₂ NR ^a R ^a , wherein the Ci _-6 alkyl, C ₂ * alkenyl, C ₂ - ₆ alkynyl, 6-10 membered aryl, C ₃ -10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, halo, C1-5 alkyl, Ci-6 alkoxy, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, CN, OR ^a , and SR ^a , wherein the C1-5 alkyl, C1-5 alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, and C1-5 haloalkyl of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3, or 4 independently selected R ^h substituents;

R ⁸ is selected from H, D, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C ₃ -10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the Ci-s alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, 6-10 membered aryl, C ₃ -10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl group which is optionally substituted by 1 or 2 independently selected R ⁹ groups; each R ⁹ is independently selected from halo, Ci-s alkyl, C1-5 haloalkyl, CN, OR ^k , and NR ^k R ^k ; wherein the C1-5 alkyl of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^b is independently selected from halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, phenyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents;

each R ^c is independently selected from H, C1-5 alkyl, and C1-5 haloalkyl, wherein the Ci-6 alkyl and C1-5 haloalkyl of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

each R ^d is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl-, OH, NO2, CN, halo, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, Ci-6 alkylsulfinyl, Ci-e alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, C1-5 alkoxycarbonyl, C1-5 alkylcarbonylamino, C1-5 alkylsulfonylamino, aminosulfonyl, Ci- ₆ alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci- e alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino;

each R ^e is independently selected from H, D, C1-5 alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, Ci-6 haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl-Ci-6 alkyl-, C ₃ -10 cycloalkyl- C1-6 alkyl-, 5-10 membered heteroaryl-Ci-6 alkyl-, and 4-10 membered heterocycloalkyl-Ci-6 alkyl;

each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-4 alkyl-, C3-7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci-4 alkyl-;

each R ^q is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl-, OH, NO2, CN, halo, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, Ci-6 alkylsulfinyl, Ci-e alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci- ₆ alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci- e alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is CR ⁵ or N;

X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

Y ¹ is a Ci-6 haloalkyl, wherein each halogen is selected from F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y ² substituents;

R ¹ is selected from H, D, halo, C1-5 alkyl, C1-5 haloalkyl, C5-10 membered heteroaryl, Cs-io membered heteroaryl-Ci _-6 alkyl-, C(0)NR ^a R ^a , and C(0)OR ^a , wherein the C1-5 alkyl, Ci-s haloalkyl, C5-10 membered heteroaryl, C5-10 membered heteroaryl-Ci-6 alkyl- of R ¹ are each optionally substituted with 1, 2, 3 or 4 independently selected R ^b substituents,

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from H, D, halo, C1-5 alkyl and Ci-6 haloalkyl, wherein the C1-5 alkyl and C1-5 haloalkyl of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each optionally substituted with 1, 2, 3 or 4 independently selected R ^h substituents;

or Y ¹ and R ⁸ form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents; and

R ⁸ is selected from H, C1-5 alkyl, C3-10 cycloalkyl, C5-10 membered heteroaryl, C5-10 membered heteroaryl-Ci-6 alkyl-, wherein the C1-5 alkyl, C3-10 cycloalkyl, C5-10 membered heteroaryl, C5-10 membered heteroaryl-Ci-6 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3 or 4 independently selected R ⁹ substituents.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is CH or N;

X ⁶ is N or CR ⁶ ;

X ⁷ is CH;

Y ¹ is CF ₃ , CF ₂ H, CFH ₂ , CF ₂ CF ₃ , CFHY ² or CF(Y ² ) ₂ ; Y ² is D or Ci-6 alkyl;

R ¹ is selected from H, D, halo, Ci-s alkyl, C1-5 haloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-Ci _-6 alkyl-, C(0)NR ^a R ^a , and C(0)OR ^a , wherein the C1-5 alkyl, Ci-s haloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-Ci-6 alkyl- is optionally substituted with 1, 2, 3 or 4 independently selected R ^b substituents;

or Y ¹ and R ⁸ form a 4-, 5-, 6-, or 7-membered cycloalkyl heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents;

R ² is H;

R ³ is H;

R ⁴ is H or halo;

R ⁶ is H or halo; and

R ⁸ is selected from H, C1-5 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-Ci-6 alkyl-, wherein the C1-5 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-Ci-6 alkyl- of R ⁸ are each optionally substituted with 1, 2, 3 or 4 independently selected R ⁹ substituents.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

wherein 0 or 1 of X ⁵ and X ⁶ are N;

R ² is H, halo, CN, C1-5 alkyl, or C1-5 haloalkyl;

R ³ is H, halo, CN, C1-5 alkyl, or C1-5 haloalkyl;

R ⁴ is H, halo, CN, Ci _-6 alkyl, or C« haloalkyl;

R ⁵ is H, halo, CN, C1-5 alkyl, or C1-5 haloalkyl;

R ⁶ is H, halo, CN, C1-5 alkyl, or C1-5 haloalkyl;

R ⁷ is H, halo, CN, C1-5 alkyl, or C1-5 haloalkyl;

R ¹ is selected from H, D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6- 10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, OR ^a , C(0)R ^a , C(0)NR ^a R ^a , C(0)OR ^a , NR ^a R ^a , NR ^a C(0)R ^a , NR ^a C(0)OR ^a , NR ^a C(0)NR ^a R ^a , NR ^a S(0) ₂ NR ^a R ^a , NR ^a S(0) ₂ R ^a , S(0) ₂ R ^a , and S(0) ₂ NR ^a R ^a , wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ^b substituents; Y ¹ is Ci-6 haloalkyl, wherein each halo is independently selected from CI and F; R ⁸ is selected from H, D, Ci-s alkyl, Ci-s alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C ₃ - ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the Ci-s alkyl, C1-5 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, Ci-e haloalkoxy, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents; or

Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from CI and F;

each R ⁹ is independently selected from halo, C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-Ci-3 alkyl-, C3-6 cycloalkyl-Ci-3 alkyl-, 5-6 membered heteroaryl-Ci-3 alkyl-, 4-6 membered heterocycloalkyl- C1-3 alkyl-, CN, OR ^k , C(0)R ^k , C(0)NR ^k R ^k , C(0)OR ^k , NR ^k R ^k , NR ^k C(0)R ^k , NR ^k C(0)OR ^k , NR ^k C(0)NR ^k R ^k , NR ^k S(0) ₂ R ^k , NR ^k S(0) ₂ NR ^k R ^k , S(0) ₂ R ^k , and S(0) ₂ NR ^k R ^k , wherein the C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-5 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-Ci-3 alkyl-, C3-6 cycloalkyl-Ci-3 alkyl-, 5-6 membered heteroaryl-Ci-3 alkyl-, and 4-6 membered heterocycloalkyl-Ci-3 alkyl- of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^a is independently selected from H, D, C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered

heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, or 3 independently selected R ^b substituents;

each R ^b is independently selected from halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C ₃ - ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, phenyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents;

each R ^d is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl-, OH, NO2, CN, halo, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alky lthio, Ci-6 alkylsulfinyl, Ci-e alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci- ₆ alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci- 6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^d is each optionally substituted with 1, 2, 3 or 4 independently selected R ^f substituents;

each R ^f is independently selected from OH, NO2, CN, halo, Ci-s alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci-6 alkylsulfinyl, Ci-6 alkylsulfonyl, carbamyl, Ci-s alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino; each R ^k is independently selected from H, D, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-4 alkyl-, C3-7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci-4 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-4 alkyl-, C3-7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci-4 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^q is independently selected from D, halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-s haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered

heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl-, OH, NO2, CN, halo, Ci-6 alkoxy, C1-5 haloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, thio, C 1-6 alkylthio, Ci-6 alkylsulfinyl, Ci-e alkylsulfonyl, carbamyl, C1-5 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonylamino, C1-5 alkylsulfonylamino, aminosulfonyl, Ci- ₆ alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, Ci- 6 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, Ci-s alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino, wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, 4-7 membered heterocycloalkyl-Ci-6 alkyl- of R ^q is each optionally substituted with 1, 2, 3 or 4 independently selected R ⁿ substituents; and

each R ⁿ is independently selected from OH, NO2, CN, halo, C1-5 alkyl, C2-6 alkenyl, C2-5 alkynyl, Ci-6 haloalkyl, cyano-Ci-6 alkyl, HO-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkyl, C3-7 cycloalkyl, Ci-6 alkoxy, Ci-e haloalkoxy, amino, Ci-6 alkylamino, di(C 1-6 alky l)amino, thio, C1-5 alkylthio, Ci- ₆ alkylsulfinyl, Ci- ₆ alkylsulfonyl, carbamyl, Ci-e alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci- ₆ alkylcarbonyl, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylcarbonylamino, Ci- 6 alkylsulfonylamino, aminosulfonyl, C ₁ -5 alkylaminosulfonyl, di(Ci- ₆ alkyl)aminosulfonyl, aminosulfonylamino, C1-5 alkylaminosulfonylamino, di(Ci-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-5 alkylaminocarbonylamino, and di(Ci-6 alkyl)aminocarbonylamino.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

wherein 0 or 1 of X ⁵ and X ⁶ are N;

R ² is H;

R ³ is H;

R ⁴ is H, halo, or Ci-s alkyl;

R ⁵ is H;

R ⁶ is H or halo;

R ⁷ is H;

R ¹ is selected from H, C1-5 alkyl, Ci-6 haloalkyl, phenyl, 5-6 membered heteroaryl, C(0)NR ^a R ^a , and C(0)OR ^a , wherein the C1-5 alkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R ^b substituents;

Y ¹ is Ci-6 haloalkyl, wherein each halo is F;

R ⁸ is selected from H, C1-5 alkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1-5 alkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents; or

Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered cycloalkyl group which is optionally substituted by 1 or 2 F;

each R ⁹ is independently selected from halo, Ci-s alkyl, Ci-s haloalkyl, CN, OR ^k , and

NR ^k R ^k ; wherein the Ci-s alkyl of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^a is independently selected from H, Ci-s alkyl, C1-5 haloalkyl, phenyl-Ci-6 alkyl- , C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocy cloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C1-5 haloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered

heterocy cloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, or 3 independently selected R ^b substituents;

each R ^b is independently selected from halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, phenyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents;

each R ^c is independently selected from H, C1-5 alkyl, and C1-5 haloalkyl, wherein the Ci-s alkyl and C1-5 haloalkyl of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents;

each R ^d is independently selected from D, halo, C1-5 alkyl, C1-5 haloalkyl, OH, CN, Ci-6 alkoxy , C1-5 haloalkoxy , amino, C1-5 alky lamino, and di(Ci-6 alkyl)amino;

each R ^k is independently selected from H, C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, alkyl-, C ₃ -7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered

heterocy cloalkyl-Ci-4 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 4 alkyl-, C ₃ -7 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocy cloalkyl-Ci-4 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents; and

each R ^q is independently selected halo, C1-5 alkyl, C1-5 haloalkyl, OH, CN, C1-5 alkoxy, C 1-6 haloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, Ci-6 alkylsulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, C1-5 alkoxycarbonyl, Ci-e alkylcarbonylamino, C1-5 alkylsulfonylamino, aminosulfonyl, C1-5 alkylaminosulfonyl, and di(Ci- ₆ alkyl)aminosulfonyl.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

wherein 0 or 1 of X ⁵ and X ⁶ are N;

R ² is H;

R ³ is H;

R ⁴ is H, halo, or Ci-s alkyl;

R ⁵ is H;

R ⁶ is H or halo;

R ⁷ is H;

R ¹ is selected from H, Ci _-6 alkyl, Ci-s haloalkyl, C(0)OR ^a , C(0)NR ^a R ^a , phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl; wherein said Ci- ₆ alkyl, Ci-e haloalkyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl are each optionally substituted by 1, 2, 3, or 4 independently selected R ^b substituents;

Y ¹ is Ci-6 haloalkyl, wherein each halo is F;

R ⁸ is selected from H, C1-5 alkyl, C3-5 cycloalkyl, 5-6 membered heteroaryl, wherein the Ci-6 alkyl, C3-6 cycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R ⁹ substituents; or

Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4- 5-, or 6-membered cycloalkyl group which is optionally substituted by one F;

each R ⁹ is independently selected from Ci-s alkyl, OR ^k , and NR ^k R ^k ;

each R ^a is selected from H, C1-5 alkyl, and isoxazol-5-ylmethyl; wherein said isoxazol-5-ylmethyl is substituted by methyl and said C1-5 alkyl is optionally substituted by OH;

each R ^b is independently selected from halo, C1-5 alkyl, C3-6 cycloalkyl, OR ^c , and C(0)NR ^c R ^c , wherein the C1-5 alkyl and C3-6 cycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents;

each R ^c group is independently selected from H and C1-5 alkyl; each R ^d is independently selected from D, Ci-s alkyl and OH; and

each R ^k is independently selected from H, Ci-s alkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, wherein the Ci-s alkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl of R ^k is each optionally substituted with 1 or 2 independently selected C1-5 alkyl groups.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

wherein 0 or 1 of X ⁵ and X ⁶ are N;

R ² is H;

R ³ is H;

R ⁴ is H, F, or methyl;

R ⁵ is H;

R ⁶ is H or F;

R ⁷ is H;

Y ¹ is CF ₃ , CHF ₂ , CH ₂ F, or CF ₂ CF ₃ ;

R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl, wherein the phenyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, and 1,2,4-triazolyl are each optionally substituted by 1 or 2 independently selected R ^b substituents;

R ⁸ is selected from H, methyl, ethyl, 2-hydroxyethyl, 2-( -methylamino)ethyl, 2-(N- {tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, and l-methyl-lH-tetrazol-5-yl;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 2- flourocyclopentyl ring;

each R ^a is independently selected from H, methyl, 2-hydroxy-2-methylpropyl, and (3- methylisoxazol-5-yl)methyl; and

each R ^b is independently selected from fluoro, methyl, CD ₃ , hydroxymethyl, methoxy, C(0)NH ₂ , and cyclopropyl.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is N or CR ⁵ ; X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

wherein 0 or 1 of X ⁵ and X ⁶ are N;

R ² is H;

R ³ is H;

R ⁴ is H, F, or methyl;

R ⁵ is H;

R ⁶ is H or F;

R ⁷ is H;

Y ¹ is CF ₃ , CHF ₂ , CH ₂ F, or CF ₂ CF ₃ ;

R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, thiazol-5-yl, thiazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-5-yl, pyrimidin-5-yl, pyridin-3- yl, pyridin-4-yl, isoxazol-5-yl, and 1,2,4-triazol-l-yl, wherein the phenyl, thiazol-5-yl, thiazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-5-yl, pyrimidin-5-yl, pyridin-3- yl, pyridin-4-yl, isoxazol-5-yl, and 1,2,4-triazol-l-yl are each optionally substituted by 1 or 2 independently selected R ^b substituents;

R ⁸ is selected from H, methyl, ethyl, 2-hydroxyethyl, 2-( -methylamino)ethyl, 2-(N- {tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, and l-methyl-lH-tetrazol-5-yl;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 2- flourocyclopentyl ring;

each R ^a is independently selected from H, methyl, 2-hydroxy-2-methylpropyl, and (3- methylisoxazol-5-yl)methyl; and

each R ^b is independently selected from fluoro, methyl, CD ₃ , hydroxymethyl, methoxy, C(0)NH ₂ , and cyclopropyl.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

wherein 0 or 1 of X ⁵ and X ⁶ are N;

R ² is H;

R ³ is H;

R ⁴ is H, halo, or Ci-6 alkyl;

R ⁵ is H; R ⁶ is H or halo;

R ⁷ is H;

R ¹ is selected from H, Ci-s alkyl, Ci-6 haloalkyl, phenyl, 3-6 membered cycloalkyl, 5- 6 membered heteroaryl, 5-6 membered heterocycloalkyl, C(0)NR ^a R ^a , and C(0)OR ^a , wherein the Ci-6 alkyl, phenyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ^b substituents;

Y ¹ is Ci-6 haloalkyl, wherein each halo is F;

R ⁸ is selected from H, Ci-s alkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C ₁ -5 alkyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered

heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ⁹ substituents; or

Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered cycloalkyl group which is optionally substituted by 1 or 2 F;

each R ⁹ is independently selected from halo, C1-5 alkyl, C1-5 haloalkyl, CN, OR ^k , and NR ^k R ^k ; wherein the C1-5 alkyl of R ⁹ is each optionally substituted with 1, 2, 3, or 4 independently selected R ^q substituents;

each R ^a is independently selected from H, C1-5 alkyl, C1-5 haloalkyl, phenyl-Ci-6 alkyl- , C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered heterocycloalkyl-Ci-6 alkyl-, wherein the C1-5 alkyl, C1-5 haloalkyl, phenyl-Ci-6 alkyl-, C3-7 cycloalkyl-Ci-6 alkyl-, 5-6 membered heteroaryl-Ci-6 alkyl-, and 4-7 membered

heterocycloalkyl-Ci-6 alkyl- of R ^a is each optionally substituted with 1, 2, or 3 independently selected R ^b substituents;

each R ^b is independently selected from halo, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, 6-10 membered aryl, C3- ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR ^c , C(0)R ^c , C(0)NR ^c R ^c , C(0)OR ^c , OC(0)R ^c , OC(0)NR ^c R ^c , NR ^C R ^C , NR ^c C(0)R ^c , NR ^c C(0)OR ^c , NR ^c C(0)NR ^c R ^c , S(0)R ^c , S(0)NR ^c R ^c , S(0) ₂ R ^c , and S(0) ₂ NR ^c R ^c , wherein the C1-5 alkyl, C2-5 alkenyl, C2-6 alkynyl, 6-10 membered aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents;

each R ^c is independently selected from H, C1-5 alkyl, and C1-5 haloalkyl, wherein the Ci-s alkyl and C1-5 haloalkyl of R ^c is each optionally substituted with 1, 2, 3, or 4

independently selected R ^d substituents; each R ^d is independently selected from D, halo, Ci-s alkyl, C1-5 haloalkyl, OH, CN, Ci-e alkoxy, Ci-ehaloalkoxy, amino, C 1-6 alky lamino, and di(Ci-6 alkyl)amino;

each R ^k is independently selected from H, C1-5 alkyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, alkyl-, C3-7 cycloalkyl-Ci-4 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered

heterocycloalkyl-Ci-4 alkyl-, wherein the C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-5 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 4 alkyl-, C3-7 alkyl-, 5-6 membered heteroaryl-Ci-4 alkyl-, and 4-7 membered heterocycloalkyl-Ci-4 alkyl- of R ^k is each optionally substituted with 1, 2, 3, or 4

independently selected R ^q substituents; and

each R ^q is independently selected halo, C1-5 alkyl, C1-5 haloalkyl, OH, CN, C1-5 alkoxy, Ci-ehaloalkoxy, amino, C1-5 alkylamino, di(Ci-6 alkyl)amino, Ci-6 alkylsulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C1-5 alkylcarbonyl, C1-5 alkoxycarbonyl, Ci-e alkylcarbony lamino, C1-5 alky lsulfony lamino, aminosulfonyl, C1-5 alkylaminosulfonyl, and di(Ci- ₆ alkyl)aminosulfonyl.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

wherein 0 or 1 of X ⁵ and X ⁶ are N;

R ² is H;

R ³ is H;

R ⁴ is H, halo, or Ci-s alkyl;

R ⁵ is H;

R ⁶ is H or halo;

R ⁷ is H;

R ¹ is selected from H, Ci _-6 alkyl, C^ haloalkyl, C(0)OR ^a , C(0)NR ^a R ^a , phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl; wherein said C 1-5 alkyl, C1-5 haloalkyl, phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl are each optionally substituted by 1, 2, 3, or 4 independently selected R ^b substituents;

Y ¹ is Ci-6 haloalkyl, wherein each halo is F; R is selected from H, Ci-s alkyl, C3-5 cycloalkyl, 5-6 membered heteroaryl, wherein the Ci-6 alkyl, C3-6 cycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R ⁹ substituents; or

Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 4- 5-, or 6-membered cycloalkyl group which is optionally substituted by one F;

each R ⁹ is independently selected from Ci-s alkyl, OR ^k , and NR ^k R ^k ;

each R ^a is selected from H, C1-5 alkyl, and isoxazol-5-ylmethyl; wherein said isoxazol-5-ylmethyl is substituted by methyl and said C1-5 alkyl is optionally substituted by OH;

each R ^b is independently selected from halo, C1-5 alkyl, C3-6 cycloalkyl, OR ^c , and C(0)NR ^c R ^c , wherein the C1-5 alkyl and C3-6 cycloalkyl are each optionally substituted with 1 or 2 independently selected R ^d substituents;

each R ^c group is independently selected from H and C1-5 alkyl;

each R ^d is independently selected from D, C1-5 alkyl and OH; and

each R ^k is independently selected from H, C1-5 alkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, wherein the Ci-s alkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl of R ^k is each optionally substituted with 1 or 2 independently selected C1-5 alkyl groups.

In some embodiments:

X ² is N or CR ² ;

X ⁴ is CR ⁴ ;

X ⁵ is N or CR ⁵ ;

X ⁶ is N or CR ⁶ ;

X ⁷ is CR ⁷ ;

wherein 0 or 1 X ⁵ and X ⁶ are N;

R ² is H;

R ³ is H;

R ⁴ is H, F, methyl, or CD ₃ ;

R ⁵ is H;

R ⁶ is H or F;

R ⁷ is H;

Y ¹ is CF ₃ , CHF ₂ , CH ₂ F, or CF ₂ CF ₃ ;

R ¹ is selected from H, methyl, CF ₃ , C(0)OR ^a , C(0)NR ^a R ^a , phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperindinyl, wherein the phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl are each optionally substituted by 1 or 2 independently selected R ^b substituents;

R ⁸ is selected from H, methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-(N- methylamino)ethyl, 2-(N-{tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, and 1-methyl- lH-tetrazol-5-yl;

or Y ¹ and R ⁸ , together with the carbon atom to which they are attached, form a 2- flourocyclopentyl ring;

each R ^a is independently selected from H, methyl, 2-hydroxy-2-methylpropyl, and (3- methylisoxazol-5-yl)methyl; and

each R ^b is independently selected from fluoro, methyl, CD ₃ , hydroxymethyl, methoxy, C(0)NH ₂ , and cyclopropyl.

In some embodiments, the compound of Formula (I) is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , R ² , R ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , R ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I) In some embodiments, the compound of Formula (I) is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein variables X ⁴ , X ⁵ , X ⁶ , X ⁷ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula (VII):

or a pharmaceutically acceptable salt thereof, wherein variables X ⁴ , X ⁵ , X ⁶ , X ⁷ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula

(VIII):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , and R ⁸ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula

(Villa):

(villa)

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , and R ⁸ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , and R ⁸ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula

(IXa):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , and R ⁸ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula (X):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , R ⁴ , R ⁶ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , R ⁴ , R ⁶ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula (XII):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , R ⁴ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

In some embodiments, the compound of Formula (I) is a compound of Formula

(XIII):

or a pharmaceutically acceptable salt thereof, wherein variables R ¹ , X ⁴ , X ⁶ , R ⁸ , and Y ¹ are defined according to the definitions provided herein for compounds of Formula (I).

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 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 linking substituent. For example, -NR(CR'R") _n - includes both -NR(CR'R") _n - and -(CR'R") _n NR-. Where the structure clearly requires a linking group, 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 ring- forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as wherein "at each occurrence 'variable' is selected from."

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 replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

Throughout the definitions, the term "C _n - _m " indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include Ci-4, Ci-s, and the like.

As used herein, the term "C _n - _m alkyl", employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), ra-propyl («-Pr), isopropyl (iPr), ra-butyl, /er/-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l -butyl, ra-pentyl, 3-pentyl, ra-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, "C _n - _m alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, ra-propenyl, isopropenyl, ra-butenyl, seobutenyl, 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, "C _n - _m 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 limited to, ethynyl, 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 "C _n - _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- propoxy and isopropoxy), butoxy (e.g., ra-butoxy and /ert-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 ₂ .

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 poly cyclic (e.g., having 2, 3 or 4 fused rings). The term "C _n -maryi" 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, the aryl group has from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.

As used herein, "halo" refers to F, CI, Br, or I. In some embodiments, a halo is F, CI, or Br. In some embodiments, a halo is F or CI. In some embodiments, a halo is CI.

As used herein, "C _n - _m haloalkoxy" refers to a group of formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF ₃ and OCHF ₂ . In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "C _n - _m haloalkyl", 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 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 CF ₃ , C2F5, CHF ₂ , CH ₂ F, CCI3, CHCI2, C2CI5 and the like.

As used herein, the term "C _n - _m alkylamino" 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 "C _n -malkoxycarbonyl" refers to a group of formula -C(0)0- 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 "C _n -malkylcarbonyl" 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.

As used herein, the term "C _n - _m alkylcarbonylamino" refers to a group of

formula -NHC(0)-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 "C _n - _m alkylsulfonylamino" refers to a group of

formula -NHS(0) 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(0)2NH ₂ .

As used herein, the term "C _n -malkylaminosulfonyl" refers to a group of

formula -S(0) ₂ 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 "di(C _n - _m alkyl)aminosulfonyl" refers to a group of formula -S(0)2N(alkyl) 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 carbon atoms.

As used herein, the term "aminosulfonylamino" refers to a group of formula - NHS(0) ₂ NH ₂ .

As used herein, the term "Cn- _m alkylaminosulfonylamino" refers to a group of formula -NHS(0) ₂ 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 "di(Cn- _m alkyl)aminosulfonylamino" refers to a group of formula -NHS(0)2N(alkyl) 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 carbon atoms.

As used herein, the term "aminocarbonylamino", employed alone or in combination with other terms, refers to a group of formula -NHC(0)NH ₂ .

As used herein, the term "C _n - _m alkylaminocarbonylamino" refers to a group of formula -NHC(0)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 "di(C _n - _m alkyl)aminocarbonylamino" refers to a group of formula -NHC(0)N(alkyl) 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 carbon atoms.

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, 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 "C _n -malkylsulfinyl" refers to a group of formula -S(0)-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 "C _n -malkylsulfonyl" refers to a group of formula -S(0)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(0)NH ₂ .

As used herein, the term "carbonyl", employed alone or in combination with other terms, refers to a -C(O)- group.

As used herein, the term "cyano-Ci-3 alkyl" refers to a group of formula -(Ci-s alkylene)-CN.

As used herein, the term "HO-Ci-6 alkyl" refers to a group of formula -(Ci-s alkylene)-

OH.

As used herein, the term "HO-C1-3 alkyl" refers to a group of formula -(C1-3 alkylene)-

OH.As used herein, the term "Ci-6 alkoxy-Ci-6 alkyl" refers to a group of formula -(C1-5 alkylene)-0(Ci- ₆ alkyl).

As used herein, the term "C1-3 alkoxy-Ci-3 alkyl" refers to a group of formula -(C1-3 alkylene)-0(Ci-3 alkyl). As used herein, the term "carboxy" refers to a group of formula - C(0)OH.

As used herein, the term "di(C _n -m-alkyl)amino" refers to a group of formula - 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 "di(C _n -m-alkyl)carbamyl" refers to a group of formula - C(0)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, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic

(e.g., having 2 fused rings) groups, spirocycles, and bridged rings (e.g. , a bridged 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 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, or 10 ring-forming carbons (C3-10) . In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cycloalkyl which is optionally substituted by CH ₂ F, CHF ₂ , CF ₃ , and CF ₂ CF ₃ . In some embodiments, the cycloalkyl is a C3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-10 spirocycle or bridged cycloalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[l. l . l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from N, O, S or 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 selected from N, O, S and B. In some embodiments, the heteroaryl is a 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 5-6 monocyclic heteroaryl ring having 1 or 2 heteroatom ring members independently selected from N, O or S. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring- forming heteroatom. When the heteroaryl group contains more than one 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, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l, 2- b]thiazole, purine, triazine , thieno[3,2-£]pyridine, imidazo[l,2-a]pyridine, 1,5-naphthyridine, li/-pyrazolo[4,3-£]pyridine and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ring-forming atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, S and B. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and l,2-dihydro-l,2-azaborine.

A six-membered heteroaryl ring is a heteroaryl group having six ring-forming atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently 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 ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S and B, and wherein the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(0)2, etc.). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5-10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom 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 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 heterocycloalkyl group containing a fused aromatic ring can be attached through any ring- forming atom including a ring-forming atom of the fused aromatic ring. In some

embodiments, the heterocycloalkyl group contains 3 to 10 ring-forming atoms, 4 to 10 ring- forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some

embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members.

Example heterocycloalkyl groups include pyrrolidin-2-one, l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, 1,2,3,4- tetrahydroisoquinoline, azabicyclo[3. l.OJhexanyl, diazabicyclo[3. l.OJhexanyl,

oxabicyclo[2.1. l]hexanyl, azabicyclo[2.2. l]heptanyl, diazabicyclo[2.2. l]heptanyl, azabicyclo[3.1. l]heptanyl, diazabicyclo[3.1. l]heptanyl, azabicyclo[3.2. l]octanyl, diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl,

azaadamantanyl, diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl,

diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl,

diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl,

diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa- azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxa-diazaspiro[4.4]nonanyl and the like.

As used herein, "C ₀ - _P cycloalkyl-Cn-malkyl-" 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 "C ₀ - _p aryl-C _n - _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 atoms.

As used herein, "heteroaryl-C _n - _m alkyl-" refers to a group of formula heteroaryl- alkylene-, wherein alkylene linking group has n to m carbon atoms.

As used herein "heterocycloalkyl-C _n - _m alkyl-" refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms.

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.

As used herein, the term "oxo" refers to an oxygen atom (i.e., =0) as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=0 or C(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 are independently selected at each occurrence 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 how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also 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 described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R) -configuration. In some embodiments, the compound has the (Si-configuration. The Formulas (e.g. , Formula (I), (II), etc.) provided herein include stereoisomers of the compounds.

Formulas (I)-(XIII) herein include stereoisomers of the compounds. In some embodiments, the carbon atom to which R ⁸ and Y ¹ are attached is in the (R)-configuration. In some embodiments, the carbon atom to which R ⁸ and Y ¹ are attached is in the (S)- configuration.

Resolution of racemic mixtures of compounds can be carried out by any of numerous 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 β- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed 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 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- 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.

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.

Example acids can be inorganic or organic acids and include, but are not limited to, strong and weak acids. Some example acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, ^-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium bicarbonate. Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, zso-propyl, n-butyl, /ert-butyl, trimethylsilyl and cyclohexyl substituted amides. In some embodiments, the compounds provided herein, or salts thereof, are 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 compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or 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 forms unless otherwise specified.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, 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 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 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 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;

generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso- 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.

Synthesis

As will be appreciated by 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 from optionally protected (e.g., P = acetyl or p-methoxybenzyl) bicycles 1-1 where Y ⁹ is halogen (e.g., CI, Br, or I) or pseudohalogen (e.g., OTf or OMs) as shown in Scheme I. Bicycle 1-1 can be coupled with 1-2, where M ¹ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [ 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 1-3. After coupling, optionally chosen protecting groups can be removed under conditions suitable for their removal that are also compatible with the functionality present in 1-3 (e.g., exposure to aqueous HC1 or trifluoroacetic acid) to afford the resulting compounds of Formula (I).

Alternatively, the Y ⁹ group can be converted to an appropriate substituted metal 1-4 (e.g., M ² is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) and then coupled to 1-5 where W is halogen (e.g., CI, Br, or I) or pseudohalogen (e.g., OTf or OMs) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base)) 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(tripheny lphosphine)palladium(O) or [ 1 , l'-bis(dipheny lphosphino)ferrocene] dichloropalladium (II)) to give to give compound 1-3. After coupling, optionally chosen protecting groups can be removed under conditions suitable for their removal that are also compatible with the functionality present in 1-3 (e.g., exposure to aqueous HC1 or trifluoroacetic acid) to afford the resulting compounds of Formula (I). Scheme I.

1 -1 Suzuki, Stille, or Negishi

Intermediates for making compounds provided herein can be prepared as shown in Scheme II. For example, ketone 2-1 can be converted to tertiary alcohol 2-3 (Y ¹ = e.g., CF ₃ , CF ₂ H) with silane 2-2 where Z ¹ is a halogen (e.g., F or Br or H) under standard conditions (e.g., in the presence of TBAF or PPh ₃ andDMPU). The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 2-3 can be converted to an appropriate substituted metal 2-4 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu) ₃ , or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichloro[bis(triphenylphosphoranyl)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 2-4 using the methods described in Scheme I.

Scheme II.

2-1 2-3 2-4

Intermediates for making compounds provided herein can be prepared as shown in

Scheme III. For example, aldehyde 3-1 can be reacted with a nucleophile (e.g., a Grignard reagent or alkyllithium reagent) to afford secondary alcohol 3-2. The secondary alcohol 3-2 can be oxidized to ketone 3-3. Ketone 3-3 can be converted to tertiary alcohol 3-5 (Y ¹ = e.g., CF ₃ or CF ₂ H) with silane 3-4 where Z ¹ is a halogen (e.g., F or Br or H) under standard conditions (e.g., in the presence of TBAF or PPh ₃ and DMPU). The Y ² halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 3-5 can be converted to an appropriate substituted metal 3-6 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu) ₃ , or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichloro[bis(triphenylphosphoranyl)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 3-6 using the methods described in Scheme I.

Scheme III.

3-1 3-2 3-3

— S—\— F

3-4

3-6 3-5

Intermediates for making compounds provided herein can be prepared as shown in Scheme IV. For example, aldehyde 4-1 can be converted to secondary alcohol 4-3 (Y ¹ = e.g., CF ₃ or CF ₂ H) with silane 4-2 where Z ¹ is a halogen (e.g., F or Br or H) under standard conditions (e.g., in the presence of TBAF or PPh ₃ and DMPU). The secondary alcohol 4-3 can be oxidized to ketone 4-4. Ketone 4-4 can be reacted with a nucleophile (e.g., a Grignard reagent or alkyllithium reagent) to afford tertiary alcohol 4-5. The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 4-5 can be converted to an appropriate substituted metal 4-6 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu) ₃ , or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichloro[bis(triphenylphosphoranyl)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 4-6 using the methods described in Scheme I. Alternatively the W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 4-3 can be converted to an appropriate substituted metal 4-6 wherein R ⁸ is H (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as

dichloro [bis(tripheny lphosphorany l)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 4-6 using the methods described in Scheme I.

Scheme IV.

4-1 4-3 4-4

R ⁸ -MgX

Metalation or

R ⁸ -Li

M1 W

Metalation X ⁷ X ⁴

■ R8 I "

R ⁸ „X ⁵

HO ^' HO' y. _|

_Y 1

4-6 4-5

Intermediates for making compounds provided herein can be prepared as shown in Scheme V. For example, acid 5-1 can be converted to Weinreb amide 5-2. Weinreb amide 5- 2 can be reacted with a nucleophile (e.g., a Grignard reagent or alkyllithium reagent) to afford ketone 5-3. Ketone 5-3 can be converted to tertiary alcohol 5-5 (Y ¹ = e.g., CF ₃ or CF ₂ H) with silane 5-4 where Z ¹ is a halogen (e.g., F or Br or H) under standard conditions (e.g., in the presence of TBAF or PPh ₃ and DMPU). The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 5-5 can be converted to an appropriate substituted metal 5-6 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu) ₃ , or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichloro [bis(tripheny lphosphorany l)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 5-6 using the methods described in Scheme I.

5-1 5-2 5-3

— S — F

I T

5-4

5-6 5-5

Compounds of Formula (I) can also be prepared as shown in Scheme VI. For example, heteroaromatic amine 6-1, where Y ⁴ is a halogen (e.g., CI, Br, or I), can be reacted with alpha-halo carbonyl derivative 6-2 where Y ⁵ is a halogen (e.g., CI or Br), to give heterocycle 6-3. The amino group of 6-3 can be optionally protected with a suitable protecting group P, (e.g., acetyl), under standard conditions (e.g., in the presence of acetyl chloride or acetic anhydride, a base (e.g., triethylamine), and optionally a catalyst (e.g., 4- dimethylaminopyridine)) to give the protected amine 6-4. Compound 6-4 can be halogenated with suitable reagents, such as N-chlorosuccinimide, N-bromosuccinimide, or N- iodosuccinimide, to give halide 6-5 where Y ⁹ is a halo group (e.g., CI, Br, or I). Halide 6-5 can be selectively coupled with 1-2, where M ¹ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a carbonate base)) 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 catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 6-6. Compound 6-6 can be coupled with 6-7, where M ⁴ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropa lladium(II) and a base (e.g., a carbonate base or cesium fluoride)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 6-8. The optionally chosen protecting group can be removed according to Scheme I to afford the resulting compounds of Formula (I).

Alternatively, halide 6-5 can be selectively coupled with 6-7, where M ⁴ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu) ₃ or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with

dichloromethane or bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) and a base (e.g., a carbonate base or cesium fluoride)) 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 catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 6-9, which can be further coupled according to Scheme I to afford the resulting compounds of Formula (I).

Scheme VI.

6-6

R -M ⁴ R -M ⁴

6-7 6-7

Suzuki, Suzuki,

Stille, Stille, or Negishi or Negishi

Compounds of Formula (I) can also be prepared as shown in Scheme VII. For example, hetereoaromatic amine 7-1, where Y ⁴ and Y ⁶ are halo groups, can be reacted with alpha-halo carbonyl derivatives 6-2 where Y ⁵ is a halogen (e.g., CI or Br), to give heterocycle 7-2. Halogenation of heterocycle 7-2 with suitable reagents, such as N-chlorosuccinimide, N- bromosuccinimide, or N-iodosuccinimide can give halide 7-3 where Y ⁹ is a halo group (e.g., CI, Br, or I). Nucleophilic aromatic substitution of the halide of 7-3 with amine 7-4 (e.g., NH ₃ or p-methoxybenzylamine) can provide halide 7-5. Halide 7-5 can be selectively coupled with 1-2, where M ¹ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a carbonate base)) 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 catalyst, such as

tetrakis(tripheny lphosphine)palladium(O) or [ 1 , 1 '-bis(dipheny lphosphino)ferrocene] dichloropalladium (II)), to give compound 7-6. Compound 7-6 can be coupled with 7-7, where M ⁴ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropa lladium(II) and a base (e.g., a carbonate base or cesium fluoride)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1, 1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II)), followed by removal of the protecting group according to Scheme I can afford the resulting compounds of Formula (I).

Alternatively, selective coupling of halide 7-5 with 7-7, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropa lladium(II) and a base (e.g., a carbonate base or cesium fluoride)) 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 catalyst, such as

tetrakis(tripheny lphosphine)palladium(O) or [ 1 , l'-bis(dipheny lphosphino)ferrocene] dichloropalladium (II)), can afford compound 7-8, which can be further reacted according to Scheme I to afford the resulting compounds of Formula (I).

Scheme VII.

7-6

R ¹ -M ⁴ R ¹ -M ⁴

7-7 7-7

Suzuki, Suzuki,

Stille, Stille, or Negishi or Negishi

Formula (I)

Compounds of Formula (I) can also be prepared as shown in Scheme VIII. For example, hetereoaromatic amine 8-1, where Y ⁶ is a halogen group, can be reacted with alpha- halo carbonyl derivatives 6-2 where Y ⁵ is a halogen (e.g., CI or Br), to give heterocycle 8-2. Halogenation of heterocycle 8-2 with suitable reagents, such as N-chlorosuccinimide, N- bromosuccinimide, or N-iodosuccinimide, can give halide 8-3 where Y ⁹ is a halo group (e.g., CI, Br, or I). Nucleophilic aromatic substitution of the halide 8-3 with amine 8-4 (e.g., NH ₃ or p-methoxybenzylamine) can provide halide 8-5 with an optionally protected amine. Halide 8- 5 can be further reacted according to Scheme I to afford the resulting compounds of Formula (I). Scheme VIII.

Formula (I)

Compounds of Formula (I) can also be prepared as shown in Scheme IX. Preparation of intermediate 9-5 from imidazole 9-1 can be achieved by methods analogous to those described in International App. No. WO 2016/183094, the disclosure of which is incorporated herein by reference in its entirety. Amination of 9-1 (e.g., R ¹² can be alkyl) under standard conditions (e.g., in the presence of an NH ₂ -transfer agent such as chloramine, O- (diphenylphosphinyl)hydroxylamine, or 0-(4-nitrobenzoyl)hydroxylamine and a base such as sodium hydride, lithium hexamethyldisilazane, or potassium tert-butoxide) and then condensation with an alkyl chloroformate CICO2R ¹³ , where R ¹³ can be an alkyl group, under standard conditions (e.g., treatment with an appropriate base such as pyridine or sodium bicarbonate) can give compound 9-2. Cyclization of 9-2 in the presence of a suitable ammonia source (e.g., NH ₃ or NH4OH) can provide bicycle 9-3. The bicycle 9-3 can be halogenated with suitable reagents, such as N-chlorosuccinimide, N-bromosuccinimide, or N- iodosuccinimide, to give a halide 9-4 where Y ⁹ is a halo group (e.g., CI, Br, or I). Dehydrative halogenation (e.g., by treating with a reagent such as POCI3 or POBr ₃ ) can afford compound 9-5, where Y ⁴ and Y ⁶ are each halogens (e.g., CI or Br). Nucleophihc aromatic substitution of the halide of 9-5 with amine 9-6 (e.g., NH ₃ or p-methoxybenzylamine) can provide intermdediate 9-7 with an optionally protected amine.

Intermediate 9-7 can be selectively coupled with 1-2, where M ¹ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a carbonate base)) 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 catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to give compound 9-8. Coupling of compound 9-8 with 9-9, where M ⁴ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropa lladium(II) and a base (e.g., a carbonate base or cesium fluoride)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II)), followed by removal of the optional protecting group according to Scheme I can afford the resulting compounds of Formula (I), wherein X ² is N.

9-5 9-7

9-8 Formula (I) Intermediates for making compounds provided herein can be prepared as shown in Scheme X. Bis-halogenation of heteroaromatic amine 10-1 with suitable reagents, such as N- chlorosuccinimide, N-bromosuccinimide, Br ₂ , or N-iodosuccinimide can give halide 10-2 where Y ⁴ and Y ⁶ are each halogens (e.g., CI, Br, or I). Nucleophilic aromatic substitution of halide 10-2 with amine 10-3 (e.g., NH ₃ or p-methoxybenzylamine) can provide compound 10- 4 with an optionally protected amine. Compounds provided herein can be synthesized from intermediates 10-2 and 10-4 using the methods described in Scheme VII and Scheme VI, respectively.

Scheme X.

10-1 1 0-2 10-4

Intermediates for making compounds provided herein can be prepared as shown in Scheme XI. For example, ketone 11-1 can be converted to alkene 11-3 under standard olefination conditions such as reactions with ylides 11-2 (e.g.,

inethylenetripbenylphosphorane). Alkene 11-3 can be converted to the fluorinated alcohol 11- 4 with a reagent such as Selectfluor ^® and water. The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 11-4 can be converted to an appropriate substituted metal 11-5 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichloro [bis(tripheny lphosphorany l)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 11-5 using the methods described in Scheme I.

Intermediates for making compounds provided herein can be prepared as shown

Scheme XII. Nucleophilic aromatic substitution of halide 12-1, where Y ⁸ is a halogen (e

CI or Br), with ammonia can provide heteroaromatic amine 12-2. Halogenation of heteroaromatic amine 12-2 with suitable reagents, such as N-chlorosuccinimide, N- bromosuccinimide, Br ₂ , or N-iodosuccinimide, optionally in the presence of a base, such sodium bicarbonate or sodium carbonate, can give compound 12-3, where Y ⁶ is a halo group (e.g., CI, Br, or I). Nucleophilic aromatic substitution of compound 12-3 with amine 12-4 (e.g., NH ₃ or p-methoxybenzylamine)can provide compound 12-5 with an optionally protected amine. Compounds provided herein can be synthesized from intermediates 12-3 and 12-5 using the methods described in Scheme VII and Scheme VI, respectively.

Scheme XII.

12-5

Intermediates for making compounds provided herein can be prepared as shown in Scheme XIII. For example, boron reagent 13-1 (e.g., R ^p can be alkyl) can be coupled with haloalkene 13-7 (where Y ⁵ is a halogen and Y ¹ can be CF ₃ ) to give alkene 13-2.

Dihydroxylation of alkene 13-2 using reagents suitable for dihydroxylation (e.g., osmium tetroxide and a re-oxidant such as Af-methylmorpholine- -oxide, or AD-mix a or AD-mix β), can afford diol-containing intermediate 13-3. Diol 13-3 can be converted to epoxide 13-4 using tosyl chloride and a suitable base (e.g., triethylamine). Epoxide 13-4 can be treated with a variety of amines (e.g., R ^m and R ⁿ can be R ^b or R ^c ) to give amino alcohols 13-5. The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 13-5 can be converted to an appropriate substituted metal 13-6 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu) ₃ , or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichloro[bis(triphenylphosphoranyl)] palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 13-6 using the methods described in Scheme I. Scheme XIII.

13-1 13-2 13-3

TsCI

13-6 13-5 13^t

Diol-containing compounds of Formula (I) can be prepared as shown in Scheme 13b. For example, boron reagent 13b-l (e.g., R ^p can be alkyl) can be coupled with haloalkene 13b-2 (where Y ⁵ is a halogen and Y ¹ can be CF ₃ ) to give alkene 13b-3 (e.g., wherein R ¹⁰ and R ⁿ can each be R ⁹ ). Dihydroxylation with an appropriate oxidizing agent (e.g., osmium tetroxide and a re-oxidant such as A ^f -methylmorpholine- -oxide, or AD-mix a or AD-mix β) can afford diol 13b-4. The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of diol 13b-4 can be converted to an appropriate substituted metal 13b-5 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as

dichloro[bis(triphenylphosphoranyl)] palladium or bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 13b-5 using the methods described in Scheme I or Scheme VI.

Scheme XHIb.

Formula (I)

Intermediates for making compounds provided herein can be prepared as shown in Scheme XIV. For example, nitrile 14-1 can be converted to ketone 14-2 (e.g., wherein R ^b can be R ⁹ ) with addition of a Grignard reagent. Ketone 14-2 can be brominated (e.g., Br ₂ ) to give bromoketone 14-3. The bromine of 14-3 can be displaced with a variety of amines to give 14- 4. Ketone 14-4 (e.g., wherein R ^m and R ⁿ can each be R ^k ) can be converted to tertiary alcohol 14-5 (Y ¹ = e.g., CF ₃ or CF ₂ H) with silane 14-7 where Z ¹ is a halogen (e.g., F or Br or H) under standard conditions (e.g., in the presence of TBAF or PPh ₃ and DMPU). The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 14-5 can be converted to an appropriate substituted metal 14-6 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu) ₃ , or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichloro[bis(triphenylphosphoranyl)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 14-6 using the methods described in Scheme I.

Scheme XIV.

14-6 14-5 14-4

Intermediates for making compounds provided herein can be prepared as shown in Scheme XV. For example, aryl bishalide 15-1 where Y ⁹ is halogen (e.g., CI, Br, or I) and W is halogen (e.g., CI, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be selectively lithiated and treated with Weinreb amide 15-5 to give ketone 15-2. Ketone 15-2 can be converted to tertiary alcohol 15-3 (Y ¹ = e.g., CF ₃ or CF ₂ H) with silane 15-6 where Z ¹ is a halogen (e.g., F or Br or H) under standard conditions (e.g., in the presence of TBAF or PPh ₃ andDMPU). The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 15-3 can be converted to an appropriate substituted metal 15-4 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu) ₃ , or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as

dichloro [bis(tripheny lphosphorany l)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 15-4 using the methods described in Scheme I.

Scheme XV.

15-4 15-3

Compounds of Formula (I) can be prepared as shown in Scheme XVI. For example, ketone 4-4 can be reacted with a nucleophile (e.g., a Grignard reagent or alkyllithium reagent) to afford tertiary alcohol 16-1. The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 16-1 can be converted to an appropriate substituted metal 16-2 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as

dichloro [bis(tripheny lphosphorany l)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Bicycle 16-6 (where Y ⁹ is halogen (e.g., CI, Br, or I) or pseudohalogen (e.g., OTf or OMs)) can be coupled with 16-2 (where M ¹ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3 or Zn) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 16-3.

Deprotection of acetal 16-3 under acidic conditions (e.g., aqueous HC1) can give aldehyde 16- 4. Aldehyde 16-4 can undergo reductive amination with a variety of amines (e.g., R ^m and R ⁿ can each be R ^k ) under standard conditions (e.g., methylamine) to give compounds 16-5.

Scheme XVI.

16-6

Suzuki, Stille, or Negishi

16-5 16-1 16-3

Compounds of Formula (I) can also be prepared as shown in Scheme XVII. For example, halide Y ⁴ in 17-1 can be converted to ester 17-2 via carbonylation conditions (e.g., in the presence of a palladium catalyst, such as [Ι, Γ- bis(diphenylphosphino)ferrocene]dichloropalladium, carbon monoxide, and an alcohol such as methanol). Ester 17-2 can be converted to amides 17-4 (e.g., wherein R ^m and R ⁿ can each be R ^a ) using amination conditions (e.g., AlMe3) with appropriate amines. Alternatively, ester 17-2 can be hydrolyzed to acid 17-3 under standard conditions, (e.g., LiOH) and coupling of acid 17-3 with amines (e.g., methylamine) using standard amide coupling conditions (e.g., HATU or HO At) can afford amides 17-4.

17-4 1 7-3

Intermediates for making compounds provided herein can be prepared as shown in Scheme XVIII. For example, halide 18-1 (e.g., Y ⁴ is CI, Br, or I) can be coupled with cyclic alkene 18-2 where M ² is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [ 1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 18-3. Cyclic alkene 18-3 can be converted to the fluorinated alcohol 18-4 with a reagent such as Selectfluor ^® and water. The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 18-4 can be converted to an appropriate substituted metal 18-5 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as

dichloro[bis(triphenylphosphoranyl)] palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates 18-5 using the methods described in Scheme I.

18-1 18-3 18-4 18-5 Compounds of Formula (I) can also be prepared as shown in Scheme XIX.

Compound 19-1, where Y ⁴ is a halogen (e.g., CI, Br, or I), can be coupled with 19-2, where M ⁵ is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [l, l '-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane and a base (e.g., a carbonate base) or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) to give compound 19-3, where R ^bl , R ^b2 , and R ^b3 can be independently H or R ^b . Cyclopropanation in the presence of diazo compound 19-4, where R ¹⁴ is an alkyl group (e.g., ethyl or /er/-butyl) and R ^b4 can be H or R ^b , and optionally an appropriate catalyst (e.g., Rh ₂ (OAc)4, Rh ₂ (S- DOSP)4, Cu(OTf , or cobalt(II) meso-tetraphenylpoφhine) can give compound 19-5. Ester 19-5 can be hydrolyzed to acid 19-6 under standard conditions (e.g., aqueous NaOH), and coupling of acid 19-6 with amines 19-7, where R ^cl and R ^c2 can be independently R ^c , using standard amide coupling conditions (e.g., HATU or HOAt in the presence of an amine base such as AyV-diisopropylethylamine) can afford amides 19-8. Alternatively, reduction of ester 19-5 with a suitable reagent (e.g., LiAlH ₄ or LiAlD ₄ ) can afford alcohols 19-9, where V ¹ can be H or D.

19-9

Compounds of Formula (I) can also be prepared as shown in Scheme XX. The alcohol moiety of general structure 20-1 can be protected with a suitable protecting group (P ² ), such as a silyl protecting group (e.g. /er/-butyldimethylsilyl) to afford the protected alcohol 20-2. The nitrogen of the imidazo[l,2-a]pyrazin-8-amine core can be protected with a suitable protecting group, such as a mono- or di-Boc group to afford 20-3. The C-N bond of 20-4 (e.g., wherein R ^m and R ⁿ can each be R ^a ) could be constructed using metal catalyzed cross-coupling conditions, such as Buchwald-Hartwig coupling conditions (Buchwald, S. L., Ruiz-Castillo, P. Chem. Rev. 2016, 116, 12564.; Messaoudi, S., et al. ACS Catal. 2015, 5 (2), 1386.). For example, 20-3 could be coupled with an amine, aniline, heteroaniline, or amide in the presence of a base (CS2CO3, NaO/-Bu, etc.) and a catalyst, such as palladium in combination with a Buchwald ligand or the use of a Buchwald pre-catalyst system. Following C-N coupling, the protecting groups can be removed using standard conditions either sequentially or in one pot, such as TFA/DCM or 4 N HCl in 1,4-dioxane for removal of a silyl protected alcohol and Boc-protected heteroaniline. Scheme XX.

20-1 20-2

20-3 20-4

Intermediates 1-1 (Scheme I) useful for preparing compounds of Formula (I), such as wherein X ² is N and of varying substitution at R ¹ , can be prepared via the method shown in Scheme Y. Condensation of Y-l with an amidine at elevated temperature (e.g., 80 to 95 °C) in a suitable solvent (e.g., EtOH) affords bicyclic intermediate Y-2. Alternatively, Y-l can be treated with a nitrile and acid (e.g., HC1) in a suitable solvent (e.g., dioxane) at elevated temperature (e.g., 100 to 110 °C) to afford Y-2. In some cases of cyclization the use of nitriles requires that the reaction mixture is made basic in the second step to facilitate cyclization. Intermediate Y-2 can be halogenated with suitable reagents, such as N-chlorosuccinimide, N- bromosuccinimide, Br ₂ or N-iodosuccinimide to afford halide Y-3 where Y ⁹ is a halo group (e.g., CI, Br, or I). Dehydrative halogenation (e.g., by treating with a reagent such as POCI3 or POBr ₃ ) can afford compound Y-4 where Y ⁶ is a halogen (e.g., CI or Br). Nucleophilic aromatic substitution of the halide of Y-4 with ammonia (e.g., using aq. NH ₄ OH solution) can provide intermediates Y-5, useful for preparing compounds of Formula (I). Alternatively, intermediate Y-3 can be condensed with an amine R ¹⁷ NH ₂ (e.g., p-methoxybenzylamine) with a coupling reagent (e.g., BOP) to give intermediate Y-6. Deprotection of Y-6 (e.g., using TFA) can give Y-5.

I l l Scheme Y.

halogen ation

Y-3 Υ-4

coupling ΝΗ,ΟΗ

Alternatively, intermediates 1-1 (Scheme I) useful for preparing compounds of Formula (I), such as wherein X ² is N and of varying substitution at R ¹ , can be prepared via the method shown in Scheme Y-B. Condensation of Y-7 with an amidine at elevated temperature (e.g., 80 to 95 °C) in a suitable solvent (e.g., EtOH) affords bicyclic intermediate Y-8.

Alternatively, Y-7 can be treated with a nitrile and acid (e.g., HC1) in a suitable solvent (e.g., dioxane) at elevated temperature (e.g., 100 to 110 °C) to afford Y-8. In some cases of cyclization the use of nitriles requires that the reaction mixture is made basic in the second step to facilitate cyclization. Intermediate Y-8 can be halogenated with suitable reagents, such as N-chlorosuccinimide, N-bromosuccinimide, Br ₂ or N-iodosuccinimide to afford intermediates Y-5, useful for preparing compounds of Formula (I).

Scheme Y-B.

Substituents at R ³ may be introduced following the procedure shown in Scheme Z.

Intermediate Z-l can be halogenated with suitable reagents, such as N-chlorosuccinimide, N- bromosuccinimide, Br ₂ or N-iodosuccinimide to afford halide Z-2 where Y ⁹ is a halo group

(e.g., CI, Br, or I). The Y ⁹ halo group of Z-2 can be coupled to R ³ -M (Z-3) (e.g., M is

B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu Zn or Al) under standard conditions for Suzuki, Stille, Negishi and the like, in the presence of a palladium catalyst, and where appropriate, a base, to afford compounds of Formula (I).

Scheme Z.

Z-1 Z-2 Formula (I)

Substituents at R ⁴ may be introduced following the procedure outlined in Scheme Q. Intermediate Q-1 can be selectively coupled with Q-2 bearing a halogen substituent Y ⁴ (e.g., CI) to afford intermediate Q-3. The Y ⁴ halo group of Q-3 can be coupled to R ⁴ -M (Q-4) (e.g., M is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, Zn or Al) under standard conditions for Suzuki, Stille, Negishi and the like, in the presence of a palladium catalyst and where appropriate, a base, to afford compounds of Formula (I), wherein X ⁴ is CR ⁴ .

Scheme Q.

Formula (I)

Q-2

Intermediates for making compounds provided herein can be prepared as shown in Scheme Yl. Suitable starting materials Yl-1, where Y ⁸ is a halogen (e.g., CI, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be converted with silane Yl-2 where Z ¹ is a halogen (e.g., F or Br or H) under standard conditions (e.g., in the presence of TBAF or PPh ₃ and DMPU) to give secondary alcohol Yl-3 (e.g., Y ¹ is CF ₃ or CHF ₂ ). Oxidation of secondary alcohol Yl-3 under standard conditions (e.g., Swern oxidation or Dess-Martin oxidation) can give ketone Yl-4. Ketone Yl-4 can be converted to cyanohydrin Yl-5 under standard conditions (e.g., in the presence of KCN, TMSCN, and 18-crown-6). Cyanohydrin Yl-5 can be converted to carboxylic acid Yl-6 under standard acidic hydrolysis conditions (e.g., HC1 or HBr in water (Org. Syn. Coll. Vol. 1 1941, 289 and 131)) or standard basic hydrolysis conditions (e.g., NaOH in water (Org. Syn. Coll. Vol. 1 1941, 321)). Carboxylic acid Yl-6 can be coupled with amine Yl-7 under standard amide formation conditions (e.g., conversion of acid Yl-6 to the acid chloride (e.g., with oxalyl chloride) and condensing with amine Yl- 7) to give amide Yl-8. Alternatively, cyanohydrin Yl-5 can be converted directly to primary amide Yl-8 (where R ^k is H) with concentrated HC1 and HC1 gas (J. Med. Chem. 2003, 46, 2494-2501). The Y ⁸ group of Yl-8 can be converted to an appropriately substituted metal Yl-9 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane, and a base, such as potassium acetate). Compounds provided herein can be synthesized from intermediates Y3-6 using the methods described in the schemes herein (e.g., Scheme I).

Y1 -6 Y1 -8 Y1 -9

Compounds of Formula (I) can also be prepared as shown in Scheme Y2.

Cyanohydrin Yl-5 (from Scheme Yl) can be converted to aldehyde Y2-1 upon reduction (e.g., in the presence of a reducing agent such as DIBAL-H (for a review see Synthesis 1975, 10, 617-630)). Aldehyde Y2-1 can be converted to amine Y2-3 under standard reductive amination conditions with amine Y2-2 and an appropriate reducing agent (e.g., sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride). Alternatively, cyanohydrin Yl-5 can be reduced directly to amine Y2-3 where R ^k is hydrogen under standard conditions (e.g., LiAlH ₄ in Et20). The Y ⁸ group of Y2-3 can be converted to an appropriately substituted metal Y2-4 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane, and a base, such as potassium acetate) and then coupled to Y2-5 where Y ⁹ is a halogen (e.g., CI, 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), dichlorobis(triphenylphosphine)palladium(II), or [Ι,Γ- 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 [Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to give Y2-6. Amine Y2-6 can be coupled with carboxylic acid Y2-7 under standard amide formation conditions (e.g., in the presence of a coupling reagent, such as HATU, and amine, such as diisopropylethylamine) to give compounds of Formula (I).

Scheme Y2.

Formula (I)

Intermediates for making compounds provided herein can be prepared as shown in Scheme Y3. Keto-ester Y3-1 can be halogenated with suitable reagents, such as N- chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide to give Y3-2 where W is a halo group (e.g., CI, Br, or I). Ketone Y3-2 can be converted to tertiary alcohol Y3-4 with silane Y3-3 where Z ¹ is a halogen (e.g., F or Br or H) under standard conditions (e.g., in the presence of TBAF or PPh ₃ and DMPU). In some instances Z ¹ can be H wherein a CHF ₂ group (Y ¹ ) can be formed. Ester Y3-4 can be converted to primary amide (Y3-5, R ^k is hydrogen) under standard conditions (e.g., ammonia in methanol and optionally a base, such as cesium carbonate) or secondary and tertiary amides (Y3-5) under standard conditions (e.g., AlMe3 and an appropriate amine NHR ^k R ^k , wherein each R ^k can be R ^a ). The W group of Y3-5 can be converted to an appropriately substituted metal Y3-6 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron; a base, such as potassium acetate; a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0); and optionally a ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl). Compounds provided herein can be synthesized from intermediates Y3-6 using the methods described in the schemes herein (e.g., Scheme I).

Y3-4

Intermediates for making compounds provided herein can be prepared as shown in Scheme XXI. Diol 13-3 where W is a halogen (e.g., CI, Br, or I) or pseudohalogen (e.g. , OTf or OMs) can be oxidized under standard conditions (e.g. , in the presence of a transition metal catalyst, such as platinum on carbon in the presence of an oxygen source, such as air) to give a-hydroxy carboxylic acid 21-1. Coupling of acid 21-1 with amine 21-2 where R ^al and R ^a2 can be independently R ^a using standard amide coupling conditions (e.g. , formation of the acid chloride with an appropriate reagent, such as oxalyl chloride, and subsequent in situ quenching with amine 21-2) can afford amide 21-3. The W group of 21-3 can be converted to an appropriately substituted metal 21-4 (e.g. , M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g. , in the presence of a diboron reagent such as

bis(pinacolato)diboron; a base, such as potassium acetate; a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0); and optionally a ligand, such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl). Compounds provided herein can be synthesized from intermediates 21-4 using the methods described in the schemes herein (e.g., Scheme I).

Scheme XXI.

21-4

Compounds of Formula (I) can also be prepared as shown in Scheme XXII.

Hydrolysis of amide 22-1 where R ^al and R ^a2 can be independently R ^a under standard conditions (e.g., heating in the presence of aqueous HC1) can give acid 22-2. Coupling of acid 22-2 with amine 22-3 where R ^a3 and R ^a4 can be independently R ^a using standard amide coupling conditions (e.g. , formation of the acid chloride with an appropriate reagent, such as oxalyl chloride, and subsequent in situ quenching with amine 22-3) can afford amide 22-4. Scheme XXII.

Compounds of Formula (I) can also be prepared as shown in Scheme XXIII.

Ketone 23-1 where W is halogen (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) can be converted to alcohol 23-3 via standard Reformatsky conditions (e.g., in the presence of a metal, such as zinc or indium, and an a-haloester 23-2 where W ² is halogen (e.g., CI, Br, or I) and R ^z is a Ci-6 alkyl group). The W halo (e.g., CI, Br, or I) or pseudohalo group (e.g., OTf or OMs) of alcohol 23-3 can be converted to an appropriate substituted metal 23-4 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as

dichloro [bis(tripheny lphosphorany l)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate). Optionally protected (e.g., P = acetyl, tert- butoxycarbonyl, or p-methoxybenzyl) bicycle 6-5 can be coupled with metal 23-4 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 23-5. In some cases, subsequent hydrolysis of the ester (-C02R ² ) under standard conditions (e.g., in the presence of a base such as sodium hydroxide or an acid such as HC1 or trifluoracetic acid) may be required to give acid 23-5. Coupling of acid 23-5 with amines 23-6 where R ^a5 and R ^a6 can be independently R ^a using standard amide coupling conditions (e.g., in the presnce of a peptide coupling reagent, such as A ^r N,N,N-tetramethyl-0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate, and an amine base, such as N-diisopropylethylamine) can afford amide 23-7. Compound 23-7 can be coupled with metal 23-8 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 23-9.

Alternatively, compound 23-5 can be coupled with metal 23-8 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base)) 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 catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or [ 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give compound 23-10. Coupling of acid 23-10 with amine 23-6 using standard amide coupling conditions (e.g., in the presnce of a peptide coupling reagent, such as A ^r N,N,N-tetramethyl-0-(7-azabenzotriazol-l- yl)uronium hexafluorophosphate, and an amine base, such as A^N-diisopropylethylamine) can afford amide 23-9.

After coupling, optionally chosen protecting groups can be removed under conditions suitable for their removal that are also compatible with the functionality present in 23-9 (e.g., exposure to aqueous HC1 or trifluoroacetic acid) to afford the resulting compound 23-10.

Scheme XXIII.

R ¹ - ⁴ R ¹ - ⁴

23-8 23-8

Suzuki, Suzuki, Stille, Stille, or Negishi or Negishi

Intermediates for making compounds provided herein can be prepared as shown Scheme XXIV. Ester 23-3 where W is a halogen (e.g., CI, Br, or I) or pseudohalogen (e. OTf or OMs) can be reduced with a suitable reagent (e.g., NaBH ₄ or NaBD ₄ ) to afford alcohol 24-2 where V ² can be H or D. The W group of 24-2 can be converted to an appropriately substituted metal 24-3 (e.g., M ¹ is B(OH) ₂ , Bpin, BF ₃ K, Sn(Bu) ₃ , or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron; a base, such as potassium acetate; and a palladium catalyst, such as

dichloro [bis(tripheny lphosphorany l)]palladium or

bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane). Compounds provided herein can be synthesized from intermediates 24-3 using the methods described in the schemes herein (e.g., Scheme I).

23-3 24-2 24-3

Intermediates for making compounds provided herein can be prepared as shown in Scheme XXV. For example, bromide 25-1 can be converted to vinyl ether 25-3 under standard conditions for Suzuki or Negishi coupling (e.g., in the presence of a palladium catalyst, such as [l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium, and a organoborane or organozinc such as 25-2). Vinyl ether 25-3 can be converted to aldehyde 25- 4 under acid treatment (e.g., in the presence of HCl in THF). Aldehyde 25-4 can be converted to carboxylic acid 25-5 under standard Pinnick oxidation condition (e.g., in the presence of NaC102 and 2-methyl-2-butene). Acid 25-5 can be converted to amide 25-7 using standard amide synthesis conditions (e.g., coupling of 25-5 with amine 25-6 using coupling reagent such as HATU). Aldehyde 25-4 can also be converted to alcohol 25-9 utilizing nucleophilc addition (e.g., in the presence of organomagnesium or organolithium such as Grignard reagent). Aldehyde 25-4 can also be converted to amine 25-11 under standard conditions for reductive amination (e.g., in the presence of amine such as 25-10, and reducing reagent such as NaBH(OAc) ₃ ).