PROGENITOR KINASE 1 (HPKl) MODULATORS

FIELD OF THE INVENTION

The disclosure provides compounds as well as their compositions and methods of use. The compounds modulate hematopoietic progenitor kinase 1 (HPKl) activity and are useful in the treatment of various diseases including cancer.

BACKGROUND OF THE INVENTION

Hematopoietic progenitor kinase 1 (HPKl) originally cloned from hematopoietic progenitor cells is a member of MAP kinase kinase kinase kinases (MAP4Ks) family, which includes MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK (Hu, M.C., et al., Genes Dev, 1996. 10(18): p. 2251-64). HPKl is of particular interest because it is predominantly expressed in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Hu, M.C., et al, Genes Dev, 1996. 10(18): p. 2251-64; Kiefer, F., et al, EMBO J, 1996. 15(24): p. 7013-25). HPKl kinase activity has been shown to be induced upon activation of T cell receptors (TCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B cell receptors (BCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), transforming growth factor receptor (TGF- R) (Wang, W., et al, J Biol Chem, 1997. 272(36): p. 22771-5; Zhou, G., et al, J Biol Chem, 1999. 274(19): p. 13133-8), or G _s -coupled PGE ₂ receptors (EP2 and EP4) (Ikegami, R, et al, J Immunol, 2001. 166(7): p. 4689-96). As such, HPKl regulates diverse functions of various immune cells.

HPKl is important in regulating the functions of various immune cells and it has been implicated in autoimmune diseases and anti-tumor immunity (Shui, J.W., et al, Nat Immunol, 2007. 8(1): p. 84-91; Wang, X., et al, J Biol Chem, 2012. 287(14): p. 11037-48). HPKl knockout mice were more susceptible to the induction of experimental autoimmune encephalomyelitis (EAE) (Shui, J.W., et al., Nat Immunol, 2007. 8(1): p. 84-91). In human, HPKl was downregulated in peripheral blood mononuclear cells of psoriatic arthritis patients or T cells of systemic lupus erythematosus (SLE) patients (Batliwalla, F.M., et al., MolMed, 2005. 11(1-12): p. 21-9). Those observations suggested that attenuation of HPKl activity may contribute to autoimmunity in patients. Furthermore, HPKl may also control anti-tumor immunity via T cell-dependent mechanisms. In the PGE2-producing Lewis lung carcinoma tumor model, the tumors developed more slowly in HPKl knockout mice as compared to wild-type mice (see US 2007/0087988). In addition, it was shown that adoptive transfer of HPKl deficient T cells was more effective in controlling tumor growth and metastasis than wild-type T cells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p. 419-29). Similarly, BMDCs from HPKl knockout mice were more efficient to mount a T cell response to eradicate Lewis lung carcinoma as compared to wild-type BMDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). These data, in conjunction with the restricted expression of HPKl in hematopoietic cells and lack of effect on the normal development of immune cells, suggest that HPKl may be an excellent drug target for enhancing antitumor immunity. Accordingly, there is a need for new compounds that modulate HPKl activity.

SUMMARY

The present disclosure provide a compound of Formula (I):

I

or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein.

The present disclosure further provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

The present disclosure further provides methods of inhibiting HPKl activity, which comprises administering to an individual a compound of the disclosure, or a

pharmaceutically acceptable salt thereof.

The present disclosure further provides methods of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Compounds

The present disclosure provide Formula (I):

I

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl; wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; or

R ¹ is selected from pyridin-4-yl and pyrimidin-4-yl; wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ ;

Cy ^A is selected from C6-io aryl; wherein said C6-io aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ²⁰ ;

R ² is selected from H, D, OH, halo, Ci-3 alkyl, Ci-3 haloalkyl, and Ci-3 alkoxy;

each R ¹⁰ is independently selected from Ci-6 alkyl, C _2- 6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, NO2, OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , OC(0)NR ^cl R ^dl , NR ^cl R ^dl , NR ^cl C(0)R ^bl , NR ^cl C(0)OR ^al , NR ^cl C(0)NR ^cl R ^dl , C(=NR ^el )R ^bl , C(=NOR ^al )R ^bl , C(=NR ^el )NR ^cl R ^dl , NR ^cl C(=NR ^el )NR ^cl R ^dl , NR ^cl S(0)R ^bl , NR ^cl S(0) ₂ R ^bl , NR ^cl S(0) ₂ NR ^cl R ^dl , S(0)R ^bl ,

S(0)NR ^cl R ^dl , S(0) ₂ R ^bl , S(0) ₂ NR ^cl R ^dl , and BR ^hl R ⁿ ; wherein said Ci _-6 alkyl, C _2-6 alkenyl, C _2- 6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ; each R ¹¹ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, OR ^a3 , SR ^a3 , C(0)R ^b3 , C(0)NR ^c3 R ^d3 , C(0)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(0)R ^b3 , NR ^c3 C(0)OR ^a3 , NR ^c3 S(0)R ^b3 , NR ^c3 S(0) ₂ R ^b3 , NR ^c3 S(0) ₂ NR ^c3 R ^d3 , S(0)R ^b3 , S(0)NR ^c3 R ^d3 , S(0) ₂ R ^b3 , S(0) ₂ NR ^c3 R ^d3 , and BR ^h3 R ^l3 ; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-io cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, C6-10 aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

each R ¹² is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C6-io aryl, 5-10 membered heteroaryl, 4-7 membered

heterocycloalkyl, halo, D, CN, OR ^a5 , SR ^a5 , C(0)R ^b5 , C(0)NR ^c5 R ^d5 , C(0)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(0)R ^b5 , NR ^c5 C(0)OR ^a5 , NR ^c5 S(0)R ^b5 , NR ^c5 S(0) ₂ R ^b5 , NR ^c5 S(0) ₂ NR ^c5 R ^d5 , S(0)R ^b5 , S(0)NR ^c5 R ^d5 , S(0) ₂ R ^b5 , S(0) ₂ NR ^c5 R ^d5 , and BR ^h5 R ⁱ⁵ ; wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-io aryl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ¹⁵ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, NO2, OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , OC(0)NR ^cl R ^dl , C(=NR ^el )R ^bl , C(=NOR ^al )R ^bl C(=NR ^el )NR ^cl R ^dl , NR ^cl C(=NR ^el )NR ^cl R ^dl , S(0)R ^bl , S(0)NR ^cl R ^dl , S(0) ₂ R ^bl , S(0) ₂ NR ^cl R ^dl , and BR ^hl R ^l! ; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, C6-io aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

each R ²⁰ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, NO2, OR ^a2 , SR ^a2 , C(0)R ^b2 , C(0)NR ^c2 R ^d2 , C(0)OR ^a2 , OC(0)R ^b2 , OC(0)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(0)R ^b2 , NR ^c2 C(0)OR ^a2 , NR ^c2 C(0)NR ^c2 R ^d2 , C(=NR ^e2 )R ^b2 , C(=NOR ^a2 )R ^b2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 S(0)R ^b2 , NR ^c2 S(0) ₂ R ^b2 , NR ^c2 S(0) ₂ NR ^c2 R ^d2 , S(0)R ^b2 ,

S(0)NR ^c2 R ^d2 , S(0) ₂ R ^b2 , S(0) ₂ NR ^c2 R ^d2 , and BR^R ¹² ; wherein said Ci-e alkyl, C _2-6 alkenyl, C _2- 6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

each R ²¹ is independently selected from Ci-6 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, OR ^a4 , SR ^a4 , C(0)R ^b4 , C(0)NR ^c4 R ^d4 , C(0)OR ^a4 , NR ^c4 R ^f4 , NR ^c4 C(0)R ^b4 , NR ^c4 C(0)OR ^a4 , NR ^c4 S(0)R ^M , NR ^c4 S(0) ₂ R ^b4 , NR ^c4 S(0) ₂ NR ^c4 R ^d4 , S(0)R ^b4 , S(0)NR ^c4 R ^d4 , S(0) ₂ R ^M , S(0) ₂ NR ^c4 R ^d4 , and BR ^h4 R ^l4 ; wherein said Ci-6 alkyl, C _2- 6 alkenyl, C _2- 6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-io cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, C6-10 aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

or two R ²¹ substituents taken together with the carbon atom to which they are attached form a spiro 3-7-membered heterocycloalkyl ring, or a spiro C3-6 cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S; wherein a ring -forming carbon atom of each spiro 3-7-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ring and spiro C3-6 cycloalkyl ring are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

each R ²² is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR ^a6 , SR ^a6 , C(0)R ^b6 , C(0)NR ^c6 R ^d6 , C(0)OR ^a6 , NR ^c6 R ^d6 , NR ^c6 C(0)R ^b6 ,

NR ^c6 C(0)OR ^a6 , NR ^c6 S(0)R ^b6 , NR ^c6 S(0) ₂ R ^b6 , NR ^c6 S(0) ₂ NR ^c6 R ^d6 , S(0)R ^b6 , S(0)NR ^c6 R ^d6 , S(0) ₂ R ^b6 , S(0) ₂ NR ^c6 R ^d6 , and BR ^h6 R ⁱ⁶ ; wherein said Ci-e alkyl, C _2-6 alkenyl, C ₂ * alkynyl, C _3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ; each R ^al , R ^cl , and R ^dl is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -10 cycloalkyl, 4- 10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

or any R ^cl and R ^dl attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

each R ^bl is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

each R ^el is independently selected from H, CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkylthio, Ci-6 alkylsulfonyl, Ci-6 alkylcarbonyl, Ci-6 alkylaminosulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, aminosulfonyl, Ci-6 alkylaminosulfonyl, and di(Ci-6 alkyl)aminosulfonyl;

each R ^hl and R ¹¹ is independently selected from OH, and Ci-6 alkoxy;

or any R ^hl and R ¹¹ attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a2 , R ^c2 , and R ^d2 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -10 cycloalkyl, 4- 10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

or any R ^c2 and R ^d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

each R ^b2 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ; each R ^e2 is independently selected from H, CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkylthio, Ci-6 alkylsulfonyl, Ci-6 alkylcarbonyl, Ci-6 alkylaminosulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, aminosulfonyl, Ci-6 alkylaminosulfonyl, and di(Ci-6 alkyl)aminosulfonyl;

each R ¹¹² and R ^l2 is independently selected from OH and Ci-6 alkoxy;

or any R ^h2 and R ^l2 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a3 , R ^c3 , and R ^d3 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

or any R ^c3 and R ^d3 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R ¹² ;

each R ^b3 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered

heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

each R ^h3 and R ^l3 is independently selected from OH and Ci-6 alkoxy;

or any R ^h3 and R ^l3 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a4 , R ^c4 , and R ^d4 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R ²² ; each R ^M is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered

heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

each R ^f4 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered

heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

or R ^c4 and R ^f4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R ²² ;

each R ^h4 and R ^l4 is independently selected from OH and Ci-6 alkoxy;

or any R and R ^l4 attached to the same B atom are C2-3 dialkoxy and together with the

B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a5 , R ^c5 , and R ^d5 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci -e haloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^b5 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^h5 and R ^l5 is independently selected from OH and Ci-6 alkoxy;

or any R ^h5 and R ^l5 attached to the same B atom are C2-3 dialkoxy and together with the

B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a6 , R ^c6 , and R ^d6 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci -6 haloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^b6 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^h6 and R ^l6 is independently selected from OH and Ci-6 alkoxy; or any R ^h6 and R ^l6 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; and

each R ^g is independently selected from D, OH, NO2, CN, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C3-6 Cycloalkyl-Ci-2 alkylene, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-3 alkoxy-Ci-3 alkyl, Ci-3 alkoxy-Ci-3 alkoxy, HO-Ci-3 alkoxy, HO- Ci-3 alkyl, cyano-Ci-3 alkyl, H2N-Ci-3 alkyl, amino, Ci-6 alkylamino, di(Ci-6 alkyl)amino, thio, Ci-6 alkylthio, Ci-6 alkylsulfmyl, 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; provided that when R ¹ is phenyl substituted by one R ¹⁰ , then Cy ^A is substituted by one or more R ²⁰ .

In some embodiments, R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl; wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; or

R ¹ is selected from pyridin-4-yl and pyrimidin-4-yl; wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ .

In some embodiments, R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, and pyrimidin-5-yl; wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, and pyrimidin-5-yl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; or

R ¹ is selected from pyridin-4-yl and pyrimidin-4-yl; wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ .

In some embodiments, R ¹ is selected from pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl; wherein said pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In some embodiments, R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl; wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R ¹⁰ ; or

R ¹ is selected from pyridin-4-yl and pyrimidin-4-yl; wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1 or 2 substituents independently selected from R ¹⁵ .

In some embodiments, R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl; wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R ¹⁰ ; or R ¹ is pyridin-4-yl; wherein said pyridin-4-yl is optionally substituted with 1 or 2 substituents independently selected from R ¹⁵ .

In some embodiments, R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, and pyrimidin-5-yl; wherein said phenyl, pyridin-2-yl, pyridin-3-yl, and pyrimidin-5-yl are each optionally substituted with 1 or 2 substituents independently selected from R ¹⁰ ; or

R ¹ is pyridin-4-yl; wherein said pyridin-4-yl is optionally substituted with 1 or 2 substituents independently selected from R ¹⁵ .

In some embodiments, R ¹ is selected from pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl; wherein said pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R ¹⁰ .

In some embodiments, R ¹ is selected from phenyl and pyrazolyl; wherein said phenyl and pyrazolyl are each optionally substituted with 1 or 2 substituents independently selected from R ¹⁰ .

In some embodiments, R ¹ is selected from pyridin-2-yl and pyridin-3-yl, wherein said pyridin-2-yl and pyridin-3-yl are optionally substituted with 1 or 2 substituents independently selected from R ¹⁰ ; or

R ¹ is selected from pyridin-4-yl; wherein said pyridin-4-yl is optionally substituted with R ¹⁵ .

In some embodiments, each R ¹⁰ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, N0 ₂ , OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , OC(0)NR ^cl R ^dl , NR ^cl R ^dl , NR ^cl C(0)R ^bl , NR ^cl C(0)OR ^al ,

NR ^cl C(0)NR ^cl R ^dl , NR ^cl S(0)R ^bl , NR ^{c l} S(0) ₂ R ^bl , NR ^cl S(0) ₂ NR ^cl R ^dl , S(0)R ^bl , S(0)NR ^cl R ^dl , S(0) ₂ R ^bl , and S(0) ₂ NR ^cl R ^dl ; wherein said CM alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹

In some embodiments, each R ¹⁰ is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, C3-io cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C6-io aryl-Ci-3 alkylene, halo, OR ^al , C(0)NR ^cl R ^dl , NR ^cl R ^dl , NR ^cl C(0)R ^bl , and S(0) ₂ R ^bl ; wherein said Ci-e alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, and C6-io aryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹⁰ is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C6-io aryl-Ci-3 alkylene, halo, OR ^al , C(0)NR ^cl R ^dl , NR ^cl R ^dl , NR ^cl C(0)R ^bl , and S(0) ₂ R ^bl ; wherein said Ci _-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, and C6-io aryl-Ci-3 alkylene are each optionally substituted with 1 or 2 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹⁰ is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, halo, OR ^al ,

C(0)NR ^cl R ^dl , NR ^cl R ^dl , NR ^cl C(0)R ^bl , and S(0) ₂ R ^bl ; wherein said Ci-e alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and C6-10 aryl are each optionally substituted with 1 or 2 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹⁵ is independently selected from Ci-6 alkyl, C _2- 6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, N0 ₂ , OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , and OC(0)NR ^cl R ^dl ; wherein said Ci _-6 alkyl, C _2-6 alkenyl, C ₂ ^, alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹⁵ is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, halo, D, CN, N0 ₂ , OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , and OC(0)NR ^cl R ^dl ; wherein said Ci-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹⁵ is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, halo, D, CN, NO2, and OR ^al ; wherein said Ci-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹⁵ is Ci-6 alkyl optionally substituted with 1 or 2 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹¹ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, OR ^a3 , SR ^a3 , C(0)R ^b3 , C(0)NR ^c3 R ^d3 , C(0)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(0)R ^b3 , NR ^c3 C(0)OR ^a3 , NR ^c3 S(0)R ^b3 , NR ^c3 S(0) ₂ R ^b3 , and

NR ^c3 S(0) ₂ NR ^c3 R ^d3 ; wherein said Ci _-6 alkyl, C2-6 alkenyl, C ₂ ^, alkynyl, C3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R ¹² .

In some embodiments, each R ¹¹ is independently selected from Ci-6 alkyl, halo, CN,

OR ³³ , C(0)R ^b3 , and NR ^c3 R ^d3 ; wherein said Ci-e alkyl is optionally substituted with 1 or 2 substituents independently selected from R ¹² .

In some embodiments, R ¹ is optionally substituted with 1 or 2 substituents independently selected from: -Ct¼, -CH2CH3, -OCH3, cyclopropyl, -CH2CF3, 2- chlorophenyl, -CH(CH ₃ ) ₂ , -CH ₂ OH, -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -NHC(0)CH ₃ , -CF ₃ , - CH ₂ CN, -F, -SO2CH3, -C(CH ₃ ) ₂ CN, 1-cyanocyclopropyl, -C(0)NHCH(CH ₃ ) ₂ , -CI, - S02CH(CH3)2, 4-methylpiperazin-l-yl, moφholinyl, 4-acetylpiperazin-l-yl, tetrahydro-2H- pyran-4-yl, -C(CH3)20H, 3-fluoropyrrolidin-l-yl, 4-hydroxypiperidin-l-yl, - NHCH(CH3)CH2CH3, 3-(hydroxymethyl)azetidin-l-yl, and 3-(dimethylamino)pyrrolidin-l- yl.

In some embodiments, Cy ^A is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R ²⁰ .

In some embodiments, Cy ^A is phenyl; wherein phenyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R ²⁰ .

In some embodiments, Cy ^A is phenyl; wherein phenyl is substituted by 1, 2, 3, or 4 substituents independently selected from R ²⁰ .

In some embodiments, Cy ^A is phenyl; wherein phenyl is substituted by 1, 2, or 3 substituents independently selected from R ²⁰ . In some embodiments, each R ²⁰ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, N0 ₂ , OR ^a2 , SR ^a2 , C(0)R ^b2 , C(0)NR ^c2 R ^d2 , C(0)OR ^a2 , OC(0)R ^b2 , OC(0)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(0)R ^b2 , NR ^c2 C(0)OR ^a2 ,

NR ^c2 C(0)NR ^c2 R ^d2 , C(=NR ^e2 )R ^b2 , C(=NOR ^a2 )R ^b2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 S(0)R ^b2 , NR ^c2 S(0) ₂ R ^b2 , and NR ^c2 S(0) ₂ NR ^c2 R ^d2 ; wherein said Ci _-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ .

In some embodiments, each R ²⁰ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, N0 ₂ , OR ^a2 , SR ^a2 , C(0)R ^b2 , C(0)NR ^c2 R ^d2 , C(0)OR ^a2 , OC(0)R ^b2 , OC(0)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(0)R ^b2 , NR ^c2 C(0)OR ^a2 ,

NR ^c2 C(0)NR ^c2 R ^d2 , NR ^c2 S(0)R ^b2 , NR ^c2 S(0) ₂ R ^b2 , and NR ^c2 S(0) ₂ NR ^c2 R ^d2 ; wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ .

In some embodiments, each R ²⁰ is independently selected from Ci-6 alkyl, halo, and OR ^a2 ; wherein said Ci-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ .

In some embodiments, each R ²¹ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-io cycloalkyl-Ci-3 alkylene, 4-10 membered

heterocycloalkyl-Ci-3 alkylene, C6-10 aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, OR ^a4 , SR ^a4 , C(0)R ^b4 , C(0)NR ^c4 R ^d4 , C(0)OR ^a4 , NR ^c4 R ^f4 ,

NR ^c4 C(0)R ^M , NR ^c4 C(0)OR ^a4 , NR ^c4 S(0)R ^M , NR ^c4 S(0) ₂ R ^M , NR ^c4 S(0) ₂ NR ^c4 R ^d4 , S(0)R ^M , S(0)NR ^c4 R ^d4 , S(0) ₂ R ^b4 , S(0) ₂ NR ^c4 R ^d4 and BR ^h4 R ⁱ⁴ .

In some embodiments, each R ²¹ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, OR ^a4 , SR ^a4 , C(0)R ^b4 , C(0)NR ^c4 R ^d4 , C(0)OR ^a4 , NR ^c4 R ^f4 , NR ^c4 C(0)R ^M , NR ^c4 C(0)OR ^a4 , NR ^c4 S(0)R ^b4 , NR ^c4 S(0) ₂ R ^M , and

NR ^c4 S(0) ₂ NR ^c4 R ^d4 .

In some embodiments, each R ²¹ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci _-6 haloalkyl, halo, D, CN, OR ^a4 , SR ^a4 , C(0)R ^M , C(0)NR ^c4 R ^d4 , C(0)OR ^a4 , NR ^c4 R ^f4 , NR ^c4 C(0)R ^M , NR ^c4 C(0)OR ^a4 , NR ^c4 S(0)R ^M , NR ^c4 S(0) ₂ R ^M , and NR ^c4 S(0) ₂ NR ^c4 R ^d4 .

In some embodiments, each R ²⁰ is independently selected from Ci-6 alkyl, halo, and OR ^a2 ; wherein said Ci-6 alkyl is optionally substituted with NR ^c4 R ^f4 .

In some embodiments, Cy ^A is optionally substituted with 1, 2, or 3 substituents independently selected from -F, -CH3, -CH2NHCH3, and -OCH3.

In some embodiments, Cy ^A is phenyl; wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from -F, -CH3, -CH2NHCH3, and -OCH3.

In some embodiments, Cy ^A is phenyl; wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from -F, -CH3, and -CH2NHCH3.

In some embodiments, R ² is selected from H, D, OH, halo, and Ci-3 alkyl.

In some embodiments, R ² is selected from H, D, OH, and halo.

In some embodiments, R ² is selected from H and D.

In some embodiments, R ² is H.

In some embodiments, provided herein is a compound having Formula (Hal), Formula (IIa2), Formula (IIa3), Formula (IIa4), Formula (IIa5), Formula (IIa6), Formula

IIa7, IIa8, or IIa9,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A , R ¹⁰ , and R ¹⁵ are as defined herein.

In some embodiments, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.

In some embodiments, provided herein is a compound having Formula (Hal)

Hal,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁰ are as defined herein.

In some embodiments, p having Formula (IIa2)

IIa2,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁰ are as defined herein.

In some embodiments, p having Formula (IIa3)

IIa3,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula (IIa4)

IIa4,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁰ are as defined herein.

In some embodiments, p having Formula (IIa5)

IIa5,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula (IIa6)

IIa6,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula (IIa7)

IIa7,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula (IIa8)

IIa8,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula (IIa9)

IIa9,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and variables Cy ^A and R ¹⁵ are as defined herein.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, m is 2.

In some embodiments, m is 3.

In some embodiments, provided herein is a compound having Formula (Ilbl):

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, 4, or 5; and variables R ¹ and R ²⁰ are as defined herein.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

In some embodiments, provided herein is a compound having Formula (IIb2):

IIb2,

or a pharmaceutically acceptable salt thereof; and variables R ¹ and R ²⁰ are as defined herein.

In some embodiments, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl; wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; or

R ¹ is selected from pyridin-4-yl or pyrimidin-4-yl; wherein said pyridin-4-yl or pyrimidin-4-yl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ ;

Cy ^A is selected from C6-io aryl; wherein said C6-io aryl is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ²⁰ ;

R ² is selected from H, D, OH, halo, Ci-3 alkyl, Ci-3 haloalkyl, and Ci-3 alkoxy;

each R ¹⁰ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, NO2, OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , OC(0)NR ^cl R ^dl , NR ^cl R ^dl , NR ^cl C(0)R ^bl , NR ^cl C(0)OR ^al , NR ^cl C(0)NR ^cl R ^dl , C(=NR ^el )R ^bl , C(=NOR ^al )R ^bl , C(=NR ^el )NR ^cl R ^dl , NR ^cl C(=NR ^el )NR ^cl R ^dl , NR ^cl S(0)R ^bl , NR ^cl S(0) ₂ R ^bl , NR ^cl S(0) ₂ NR ^cl R ^dl , S(0)R ^bl ,

S(0)NR ^cl R ^dl , S(0) ₂ R ^bl , S(0) ₂ NR ^cl R ^dl , and BR ^hl R ⁿ ; wherein said Ci _-6 alkyl, C _2-6 alkenyl, C _2- 6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

each R ¹¹ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, OR ^a3 , SR ^a3 , C(0)R ^b3 , C(0)NR ^c3 R ^d3 , C(0)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(0)R ^b3 , NR ^c3 C(0)OR ^a3 , NR ^c3 S(0)R ^b3 , NR ^c3 S(0) ₂ R ^b3 , NR ^c3 S(0) ₂ NR ^c3 R ^d3 , S(0)R ^b3 , S(0)NR ^c3 R ^d3 , S(0) ₂ R ^b3 , S(0) ₂ NR ^c3 R ^d3 , and BR ^h3 R ^l3 ; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-io cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, C6-10 aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

each R ¹² is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C6-io aryl, 5-10 membered heteroaryl, 4-7 membered

heterocycloalkyl, halo, D, CN, OR ^a5 , SR ^a5 , C(0)R ^b5 , C(0)NR ^c5 R ^d5 , C(0)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(0)R ^b5 , NR ^c5 C(0)OR ^a5 , NR ^c5 S(0)R ^b5 , NR ^c5 S(0) ₂ R ^b5 , NR ^c5 S(0) ₂ NR ^c5 R ^d5 , S(0)R ^b5 , S(0)NR ^c5 R ^d5 , S(0) ₂ R ^b5 , S(0) ₂ NR ^c5 R ^d5 , and BR ^h5 R ⁱ⁵ ; wherein said Ci _-6 alkyl, C _2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-io aryl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ¹⁵ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, NO2, OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , OC(0)NR ^cl R ^dl , C(=NR ^el )R ^bl , C(=NOR ^al )R ^bl , C(=NR ^el )NR ^cl R ^dl , NR ^cl C(=NR ^el )NR ^cl R ^dl , S(0)R ^bl , S(0)NR ^cl R ^dl , S(0) ₂ R ^bl , S(0) ₂ NR ^cl R ^dl , and BR ^hl R ^l! ; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, C6-io aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ; each R ²⁰ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, NO2, OR ^a2 , SR ^a2 , C(0)R ^b2 , C(0)NR ^c2 R ^d2 , C(0)OR ^a2 , OC(0)R ^b2 , OC(0)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(0)R ^b2 , NR ^c2 C(0)OR ^a2 , NR ^c2 C(0)NR ^c2 R ^d2 , C(=NR ^e2 )R ^b2 , C(=NOR ^a2 )R ^b2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 S(0)R ^b2 , NR ^c2 S(0) ₂ R ^b2 , NR ^c2 S(0) ₂ NR ^c2 R ^d2 , S(0)R ^b2 ,

S(0)NR ^c2 R ^d2 , S(0) ₂ R ^b2 , S(0) ₂ NR ^c2 R ^d2 , and BR^R ¹² ; wherein said Ci _-6 alkyl, C _2-6 alkenyl, C _2- 6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

each R ²¹ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, Ce- io aryl-Ci-3 alkylene, 5-10 membered heteroaryl-Ci-3 alkylene, halo, D, CN, OR ^a4 , SR ^a4 , C(0)R ^b4 , C(0)NR ^c4 R ^d4 , C(0)OR ^a4 , NR ^c4 R ^f4 , NR ^c4 C(0)R ^b4 , NR ^c4 C(0)OR ^a4 , NR ^c4 S(0)R ^M , NR ^c4 S(0) ₂ R ^M , NR ^c4 S(0) ₂ NR ^c4 R ^d4 , S(0)R ^b4 , S(0)NR ^c4 R ^d4 , S(0) ₂ R ^b4 , S(0) ₂ NR ^c4 R ^d4 , and BR ^h4 R ^l4 ; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, C6-10 aryl-Ci-3 alkylene, and 5-10 membered heteroaryl-Ci-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

or two R ²¹ substituents taken together with the carbon atom to which they are attached form a spiro 3-7-membered heterocycloalkyl ring, or a spiro C3-6 cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S; wherein a ring -forming carbon atom of each spiro 3-7-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ring and spiro C3-6 cycloalkyl ring are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

each R ²² is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR ^a6 , SR ^a6 , C(0)R ^b6 , C(0)NR ^c6 R ^d6 , C(0)OR ^a6 , NR ^c6 R ^d6 , NR ^c6 C(0)R ^b6 , NR ^c6 C(0)OR ^a6 , NR ^c6 S(0)R ^b6 , NR ^c6 S(0) ₂ R ^b6 , NR ^c6 S(0) ₂ NR ^c6 R ^d6 , S(0)R ^b6 , S(0)NR ^c6 R ^d6 , S(0) ₂ R ^b6 , S(0) ₂ NR ^c6 R ^d6 , and BR ^h6 R ⁱ⁶ ; wherein said Ci-e alkyl, C _2-6 alkenyl, C ₂ * alkynyl, C _3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^al , R ^cl , and R ^dl is independently selected from H, Ci-6 alkyl, C _2- 6 alkenyl, C _2- 6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4- 10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -10 cycloalkyl, 4- 10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

or any R ^cl and R ^dl attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

each R ^bl is independently selected from Ci-6 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

each R ^el is independently selected from H, CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkylthio, Ci-6 alkylsulfonyl, Ci-6 alkylcarbonyl, Ci-6 alkylaminosulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, aminosulfonyl, Ci-6 alkylaminosulfonyl, and di(Ci-6 alkyl)aminosulfonyl;

each R ^hl and R ¹¹ is independently selected from OH and Ci-6 alkoxy;

or any R ^hl and R ¹¹ attached to the same B atom are C _2- 3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a2 , R ^c2 , and R ^d2 is independently selected from H, Ci-6 alkyl, C _2- 6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3 -10 cycloalkyl, 4- 10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3 -10 cycloalkyl, 4- 10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

or any R ^c2 and R ^d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ; each R ^b2 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

each R ^e2 is independently selected from H, CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkylthio, Ci-6 alkylsulfonyl, Ci-6 alkylcarbonyl, Ci-6 alkylaminosulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, aminosulfonyl, Ci-6 alkylaminosulfonyl, and di(Ci-6 alkyl)aminosulfonyl;

each R ¹¹² and R ^l2 is independently selected from OH and Ci-6 alkoxy;

or any R ^h2 and R ^l2 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a3 , R ^c3 , and R ^d3 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

or any R ^c3 and R ^d3 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R ¹² ;

each R ^b3 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered

heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

each R ^h3 and R ^l3 is independently selected from OH and Ci-6 alkoxy;

or any R ^h3 and R ^l3 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a4 , R ^c4 , and R ^d4 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R ²² ;

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

heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

each R ^f4 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered

heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

or R ^c4 and R ^f4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R ²² ;

each R ^h4 and R ^l4 is independently selected from OH and Ci-6 alkoxy;

or any R and R ^l4 attached to the same B atom are C2-3 dialkoxy and together with the

B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a5 , R ^c5 , and R ^d5 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci -6 haloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^b5 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^h5 and R ^l5 is independently selected from OH and Ci-6 alkoxy;

or any R ^h5 and R ^l5 attached to the same B atom are C2-3 dialkoxy and together with the

B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; each R ^a6 , R ^c6 , and R ^d6 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^b6 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^g ;

each R ^h6 and R ^l6 is independently selected from OH and Ci-6 alkoxy;

or any R ^h6 and R ^l6 attached to the same B atom are C2-3 dialkoxy and together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci-6 alkyl; and

each R ^g is independently selected from D, OH, NO2, CN, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-2 alkylene, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-3 alkoxy-Ci-3 alkyl, Ci-3 alkoxy-Ci-3 alkoxy, HO-Ci-3 alkoxy, HO- Ci-3 alkyl, cyano-Ci-3 alkyl, H2N-Ci-3 alkyl, amino, Ci-6 alkylamino, di(Ci-6 alkyl)amino, thio, Ci-6 alkylthio, Ci-6 alkylsulfmyl, Ci-6 alkylsulfonyl, carbamyl, Ci-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, Ci-6 alkylcarbonyl, Cus 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.

In some embodiments, provide a compound of Formula I:

I

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl; wherein said phenyl, pyridin-2-yl, pyridin- 3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R ¹⁰ ; or

R ¹ is selected from pyridin-4-yl and pyrimidin-4-yl; wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1, 2, or 3 substituents independently selected from R ¹⁵ ; Cy ^A is phenyl substituted with 1, 2, 3, or 4 substituents independently selected from

_R 20.

R ² is selected from H, D, OH, halo, and Ci-3 alkyl;

each R ¹⁰ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, 5-10 membered heteroaryl, halo, D, CN, N0 ₂ , OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , OC(0)NR ^cl R ^dl , NR ^cl R ^dl , NR ^cl C(0)R ^bl , NR ^cl C(0)OR ^al , NR ^cl C(0)NR ^cl R ^dl , S(0)R ^bl , S(0)NR ^cl R ^dl , S(0) ₂ R ^bl , and S(0) ₂ NR ^cl R ^dl ; wherein said C _w alkyl, C ₂ ^, alkenyl, C _2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R ¹¹ ;

each R ¹¹ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, D, CN, OR ³³ , SR ^a3 , C(0)R ^b3 , C(0)NR ^c3 R ^d3 , C(0)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(0)R ^b3 , NR ^c3 C(0)OR ^a3 , NR ^c3 S(0)R ^b3 , NR ^c3 S(0) ₂ R ^b3 , NR ^c3 S(0) ₂ NR ^c3 R ^d3 , S(0)R ^b3 , S(0)NR ^c3 R ^d3 , S(0) ₂ R ^b3 , and S(0)2NR ^c3 R ^d3 ; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R ¹² ;

each R ¹² is independently selected from Ci _-6 alkyl, halo, D, CN, OR ^a5 , SR ^a5 , C(0)R ^b5 , C(0)NR ^c5 R ^d5 , C(0)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(0)R ^b5 , and NR ^c5 C(0)OR ^a5 ;

each R ¹⁵ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, D, CN, N0 ₂ , OR ^al , SR ^al , C(0)R ^bl , C(0)NR ^cl R ^dl , C(0)OR ^al , OC(0)R ^bl , and OC(0)NR ^cl R ^dl ; wherein said Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R ¹¹ ;

each R ²⁰ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, D, CN, N0 ₂ , OR ³² , SR ^a2 , C(0)R ^b2 , C(0)NR ^c2 R ^d2 , C(0)OR ^a2 , OC(0)R ^b2 , OC(0)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(0)R ^b2 , NR ^c2 C(0)OR ^a2 , NR ^c2 C(0)NR ^c2 R ^d2 , and S(0) ₂ R ^b2 ; wherein said Ci _-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R ²¹ ;

each R ²¹ is independently selected from halo, D, CN, OR ^a4 , SR ^a4 , C(0)R ^M ,

C(0)NR ^c4 R ^d4 , C(0)OR ^a4 , NR ^c4 R ^f4 , NR ^c4 C(0)R ^b4 , and NR ^c4 C(0)OR ^a4 ;

each R ^al , R ^cl , and R ^dl is independently selected from H and Ci-6 alkyl;

each R ^bl is independently selected from Ci-6 alkyl;

each R ^a2 , R ^c2 , and R ^d2 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3 -10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; each R ^b2 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

each R ^a3 , R ^c3 , and R ^d3 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

each R ^b3 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered

heterocycloalkyl;

each R ^a4 , R ^c4 , and R ^d4 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl;

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

heterocycloalkyl;

each R ^f4 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered

heterocycloalkyl;

each R ^a5 , R ^c5 and R ^d5 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl; and

each R ^b5 is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl.

In some embodiments, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl; wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R ¹⁰ ; or

R ¹ is pyridin-4-yl; wherein said pyridin-4-yl is optionally substituted with R ¹⁵ ;

Cy ^A is phenyl substituted with 1, 2, or 3 substituents independently selected from R ²⁰ ;

R ² is selected from H, D, and Ci-3 alkyl;

each R ¹⁰ is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C3-10 cycloalkyl, 4- 10 membered heterocycloalkyl, Ce-io aiyl, halo, OR ^al , C(0)NR ^cl R ^dl , NR ^cl R ^dl , NR ^cl C(0)R ^bl , and S(0)2R ^{b l} ; wherein said Ci-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and C6-io aryl are each optionally substituted with 1 or 2 substituents independently selected from R»;

each R ¹¹ is independently selected from Ci-6 alkyl, halo, CN, OR ^a3 , C(0)R ^b3 , and NR ^c3 R ^d3 ; wherein said Ci-6 alkyl is optionally substituted with R ¹² ;

R ¹² is OR ³⁵ ;

R ¹⁵ is Ci-6 alkyl;

each R ²⁰ is independently selected from Ci-6 alkyl, halo, and OR ^a2 ; wherein said Ci-6 alkyl is optionally substituted with R ²¹ ;

_R 21 _ig NRc4 _R f4.

each R ^al , R ^cl , and R ^dl is independently selected from H and Ci-6 alkyl;

R ^bl is Ci-6 alkyl;

R ^a2 is independently selected from H and Ci-6 alkyl;

each R ^a3 , R ^c3 and R ^d3 is independently selected from H and Ci-6 alkyl;

R ^b3 is Ci-6 alkyl;

R ^c4 is selected from H and Ci-6 alkyl;

R ^f4 is Ci-6 alkyl; and

R ^a5 is selected from H and Ci-6 alkyl.

The floating R ² group is intended to be bound to either of the two unsubstituted positions on the benzene ring of the indazole.

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 (while the embodiments are intended to be combined as if written in multiply dependent form). 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. Thus, it is contemplated as features described as

embodiments of the compounds of Formula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci-6 alkyl" is specifically intended to individually disclose (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl.

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.

At various places in the present specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CRR") _n - includes both -NR(CR'R") _n - and -(CR'R") _n NR- and is intended to disclose each of the forms individually. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise indicated, refers to any level of substitution, e.g. , mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. 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.

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 C1-4, Ci-6 and the like. The term "alkyl" employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. The term "C _n -m alkyl", refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. 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. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, ^-propyl, isopropyl, «-butyl, fert-butyl, isobutyl, sec-butyl; higher homologs such as 2- methyl-1 -butyl, «-pentyl, 3-pentyl, «-hexyl, 1,2,2-trimethylpropyl, and the like.

The term "alkenyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term "C _n -m alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

Example alkenyl groups include, but are not limited to, ethenyl, «-propenyl, isopropenyl, n- butenyl, sec-butenyl, and the like.

The term "alkynyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term "C _n -m alkynyl" refers to an alkynyl group 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.

The term "alkylene", employed alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound. The term "C _n -m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-l,2-diyl, ethan-1, 1-diyl, propan-l,3-diyl, propan-l,2-diyl, propan-1, 1-diyl, butan-l,4-diyl, butan-l,3-diyl, butan-1,2- diyl, 2-methyl-propan-l,3-diyl, and the like.

The term "alkoxy", employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above. The term "C _n -m alkoxy" refers to an alkoxy group, the alkyl group of which has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g. , «-propoxy and isopropoxy), i-butoxy and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

The term "amino" refers to a group of formula -Nth.

The term "carbonyl", employed alone or in combination with other terms, refers to a -C(=0)- group, which also may be written as C(O).

The term "cyano" or "nitrile" refers to a group of formula -C≡N, which also may be written as -CN.

The terms "halo" or "halogen", used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, "halo" refers to a halogen atom selected from F, CI, or Br. In some embodiments, halo groups are F.

The term "haloalkyl" as used herein refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom. The term "C _n - _m haloalkyl" refers to a Cn-m alkyl group having n to m carbon atoms and from at least one up to {2(n to m)+l } halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCI3, CHCh, C2CI5, and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

The term "haloalkoxy", employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "Cn-m haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups may be optionally substituted by 1 or 2 oxo (=0) substituents.

The term "sulfido" refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C=S) when attached to carbon.

The term "aromatic" refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized π (pi) electrons where n is an integer). The term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings). The term "C _n -m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments aryl groups have 6 carbon atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

The term "heteroaryl" or "heteroaromatic," employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5- 14 ring atoms including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6- naphthyridine), indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[l,2-6]thiazolyl, purinyl, and the like. In some embodiments, the heteroaryl group is pyridone (e.g., 2-pyridone).

A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g. , 1, 2, or 3) ring atoms are independently selected from N, O, and S.

Exemplary five-membered ring heteroaryls include 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, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g. , 1, 2, or 3) ring atoms are independently selected from N, O, and S.

Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term "cycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term "C _n -m cycloalkyl" refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g. , having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, or 7 ring-forming carbons (C3-7) . In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3 -6 monocyclic cycloalkyl group. Ring- forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 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, e.g. , 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. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[l . l . l]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term "heterocycloalkyl" are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g. , having two fused or bridged rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g. , C(O), S(O), C(S) or S(0)2, N-oxide etc.) or a nitrogen atom can be quaternized. 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 heterocycloalkyl ring, e.g. , 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. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, l-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydronaphthyl, 2,3-dihydro-lH-inden-5-yl, isoindolinyl, tropanyl, and thiomorpholino.

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 an azetidin-3-yl ring is attached at the 3 -position.

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 invention 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 invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., 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.

In some embodiments, the compounds of the invention have the (^-configuration. In other embodiments, the compounds have the (^-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated.

Compounds of the invention 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, e.g., 1H- and 3H-imidazole, 1H-, 2H-, and 4H- 1,2,4- triazole, 1H- and 2H- isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas,New York, N.Y., Appleton- Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies such as NMR

spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. (A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

The term, "compound," as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.

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. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially isolated," it 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, e.g. , a composition enriched in the compounds of the invention. 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 of the invention, or salt thereof.

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 expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g. , a temperature from about 20 °C to about 30 °C.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "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 invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention 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 (MeCN) are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17 ^th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci. , 1977, 66(\), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms.

Synthesis

Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below.

The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates or products at the temperatures at which the reactions are carried out, e.g. , temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection and

deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g. , in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 ^th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ, 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. , ¾ or ¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.

Compounds of Formula (I) can be prepared, e.g. , using a process as illustrated in the schemes below.

Compounds of Formula (I) with a variety of substitution at position R ¹ (aryl or heteroaryl) can be prepared, using a process as illustrated in Scheme 1. In the process depicted in Scheme 1, compounds of formula 1-2 are formed after protection of the NH group of the compounds of formula 1-1 with a suitable protecting group (e.g. SEM or Boc) followed by cyanation reaction (e.g. Pd-catalyzed cyanation). The chloro substituent in the compounds of formula 1-2 can be converted into Cy ^A via a number of different cross- coupling reactions, including Suzuki (e.g. , in the presence of a palladium catalyst, such as Xphos Pd G2, and a base, such as potassium phosphate) or Stille (e.g. , in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), and others, to give the compounds of formula 1-3. Deprotection of the protecting group (e.g. , under acidic conditions, such as treatment with HCl or TFA) results in the formation of compounds of formula 1-4. These compounds can be further halogenated with one of the halogenation agents (e.g. , NIS or iodine) to form compounds of formula 1-5. The NH group of the pyrazole ring of the compounds of formula 1-5 is protected with a suitable protecting group, such as Boc or SEM, to form compounds of formula 1-6. The halogen substituent in the compounds of formula 1-6 can be converted into R ¹ via a number of different cross-coupling reactions, including Suzuki (Tetrahedron 2002, 58, 9633-9695), Negishi (ACS Catalysis 2016, 6, 1540- 1552), Stille (ACS Catalysis 2015, 5, 3040-3053) coupling and others, to give the compounds of formula 1-7. Finally, deprotection of the protecting group under acidic conditions (e.g. , treatment with HCl or TFA) results in the formation of the desired compounds of Formula (I).

Scheme 1

Alternatively, for the exploration of the substitution at position Cy ^A , compounds of formula (I) can be prepared, using a process as illustrated in Scheme 2. Deprotection of the protecting group in the compounds of formula 1-2 under acidic conditions (e.g., treatment with HCl or TFA), followed by iodination with one of the iodination agents, such as iodine or NIS, forms compounds of formula 2-2. The NH group of the pyrazole ring of the compounds of formula 2-2 is protected with a suitable protecting group (e.g. , Boc or SEM) to form compounds of formula 2-3. The iodo substituent in the compounds of formula 2-3 can be converted into R ¹ via a number of different cross-coupling reactions, including Suzuki, Negishi, Stille and others, to give the compounds of formula 2-4. The chloro substituent in the compounds of formula 2-4 can be further converted into Cy ^A via a number of different cross-coupling reactions, including Suzuki, Stille, and others, to give the compounds of formula 2-5. Finally, deprotection of the protecting group, e.g. under acidic conditions, such as treatment with HCl or TFA, results in the formation of the desired compounds of Formula (I)

Scheme 2

Suzuki, Stille, Negishi

(I) 2-5 2-4

HPKl Kinase

Extensive studies have established that HPKl is a negative regulator of T cell and B cell activation (Hu, M.C., et al, Genes Dev, 1996. 10(18): p. 2251-64; Kiefer, F., et al, EMBO J, 1996. 15(24): p. 7013-25). HPKl -deficient mouse T cells showed dramatically increased activation of TCR proximal signaling, enhanced IL-2 production, and hyper- proliferation in vitro upon anti-CD3 stimulation (Shui, J.W., et al., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPKl knockout B cells produced much higher levels of IgM and IgG isoforms after KLH immunization and displayed hyper-proliferation potentially as a result of enhanced BCR signaling. Wang, X., et al., J Biol Chem, 2012. 287(14): p. 11037-48. Mechanistically, during TCR or BCR signaling, HPKl is activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells) mediated-Tyr379 phosphorylation and its subsequent binding to adaptor protein SLP-76 (T cells) or BLNK (B cells) (Wang, X., et al, J Biol Chem, 2012. 287(14): p. 11037-48). Activated HPKl phosphorylates SLP-76 on Ser376 or BLNK on Thrl52, leading to the recruitment of signaling molecule 14-3-3 and ultimate ubiquitination- mediated degradation of SLP-76 or BLNK (Liou, J., et al., Immunity, 2000. 12(4): p. 399- 408; Di Bartolo, V., et al, J Exp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential for TCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cyl, calcium flux, and NFAT activation), HPKl -mediated downregulation of these adaptor proteins provide a negative feedback mechanism to attenuate signaling intensity during T cell or B cell activation (Wang, X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

The bone marrow-derived dendritic cells (BDMCs) from HPKl knockout mice showed higher expression of co-stimulatory molecules (e.g. CD80/CD86) and enhanced production of proinflammatory cytokines (IL-12, TNF-ot etc), and demonstrated superior ability to stimulate T cell proliferation in vitro and in vivo as compared to wild-type DCs (Alzabin, S., et al, J Immunol, 2009. 182(10): p. 6187-94). These data suggest that HPKl is also an important negative regulator of dendritic cell activation (Alzabin, S., et al., J

Immunol, 2009. 182(10): p. 6187-94). However, the signaling mechanisms underlying HPK-1 mediated negative regulation of DC activation remains to be elucidated.

In contrast, HPKl appears to be a positive regulator of suppressive functions of regulatory T cells (Treg) (Sawasdikosol, S. et al, J Immunol,, 2012. 188(supplement 1): p. 163). HPKl deficient mouse Foxp3+ Tregs were defective in suppressing TCR-induced effector T cell proliferation, and paradoxically gained the ability to produce IL-2 following TCR engagement (Sawasdikosol, S. et al., J Immunol,, 2012. 188(supplement 1): p. 163). These data suggest that HPKl is an important regulator of Treg functions and peripheral self- tolerance.

HPKl was also involved in PGE2 -mediated inhibition of CD4+ T cell activation

(Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). Studies published in US

2007/0087988 indicated that HPKl kinase activity was increased by exposure to

physiological concentrations of PGE2 in CD4+ T cells and this effect was mediated by PEG2 -induced PKA activation. The proliferation of HPKl deficient T cells was resistant to the suppressive effects of PGE2 (see US 2007/0087988). Therefore, PGE2-mediated activation of HPKl may represent a novel regulatory pathway of modulating immune response. The present disclosure provides methods of modulating (e.g. , inhibiting) HPK1 activity, said method comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to enhance, stimulate and/or increase immunity in cancer. For example, a method of treating a disease or disorder associated with inhibition of HPK1 interaction can include administering to a patient in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including cancers. For the uses described herein, any of the compounds of the disclosure, including any of the embodiments thereof, may be used.

Examples of cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T -cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g. , metastatic malignant melanoma), renal cancer (e.g. , clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma), and combinations of said cancers.

In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocyte leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma, and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney

(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),

cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma,

chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors

Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes

(carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple -negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancers, and thyroid and parathyroid cancers.

In some embodiments, HPK1 inhibitors may be used to treat tumors producing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73 and CD39 over-expressing tumors). Overexpression of Cox-2 has been detected in a number of tumors, such as colorectal, breast, pancreatic and lung cancers, where it correlates with a poor prognosis. Overexpression of COX-2 has been reported in hematological cancer models such as RAJI (Burkitt's lymphoma) and U937 (acute promonocyte leukemia) as well as in patient's blast cells. CD73 is up-regulated in various human carcinomas including those of colon, lung, pancreas and ovary. Importantly, higher expression levels of CD73 are associated with tumor neovascularization, invasiveness, and metastasis and with shorter patient survival time in breast cancer.

The terms "individual" or "patient," used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

The phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

As used herein, the term "treating" or "treatment" refers to one or more of (1) inhibiting the disease; e.g. , inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e. , arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g. , ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.

In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but does not yet experience or display the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signaling pathways.

Thus, it is useful to combine different enzyme/protein/receptor inhibitors, exhibiting different preferences in the targets which they modulate the activities of, to treat such conditions. Examples of agents that may be combined with compounds of the present disclosure include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, inhibitors of beta catenin pathway, inhibitors of notch pathway, inhibitors of hedgehog pathway, inhibitors of Pim kinases, and inhibitors of protein chaperones and cell cycle progression. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination with one or more other enzyme/protein/receptor inhibitors for the treatment of diseases, such as cancer. Examples of cancers include solid tumors and liquid tumors, such as blood cancers. For example, the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, TGF-βΡν, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFotR, PDGFpR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for treatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., AZD4547, BAY 1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, J J-42756493, Debiol347, INCB54828, INCB62079, and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib (INCB39110)), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872 and

INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selective inhibitor, a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as

OTX015, CPI-0610, INCB54329, and INCB57643), and an adenosine receptor antagonist or combinations thereof. Inhibitors of HDAC such as panobinostat and vorinostat can be combined with the compounds of the present disclosure. Inhibitors of c-Met such as onartumzumab, tivantnib, and capmatinib (INC-280) be combined with the compounds of the present disclosure. Inhibitors of BTK such as ibrutinib can be combined with the compounds of the present disclosure. Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus can be combined with the compounds of the present disclosure. Inhibitors of Raf, such as vemurafenib and dabrafenib can be combined with the compounds of the present disclosure. Inhibitors of MEK such as trametinib, selumetinib and GDC-0973 can be combined with the compounds of the present disclosure. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependent kinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases ( LGH447, INCB053914, and SGI-1776) can also be combined with compounds of the present disclosure.

Compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD27, CD28, CD39, CD40, CD 122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, ΉΜ3, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PD 1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD- 1 monoclonal antibody. In some embodiments, the anti-PD- 1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD 1 antibody is pembrolizumab. In some embodiments, the anti PD-1 antibody is SHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-Ll, e.g. , an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is

MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CSFIR, e.g., an anti- CSF1R antibody. In some embodiments, the anti- CSF1R antibody is IMC-CS4 or RG7155.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, IMP321 or GSK2831781.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, MK1248, BMS-986156, MEDI1873, or GWN323.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MEDI6469, MOXR0916, PF-04518600, or

GSK3174998. In some embodiments, the OX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is MBG-453. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g. , an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the compounds of the invention can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO l, TDO, or arginase. Examples of IDOl inhibitors include epacadostat and NGL919. An example of an arginase inhibitor is CB-1158.

The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD- 1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGF receptor.

Compounds of the present disclosure can be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include bendamustine, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or

pomalidomide (POM).

The compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumor- targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207

immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2 inhibitor and the like. The compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,

mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib, prednisone, procarbazine, quinacrine, rasburicase, regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

Other anti -cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples of antibodies to PD-1 and/or PD-L1 that can be combined with compounds of the present disclosure for the treatment of cancer or infections such as viral, bacteria, fungus, and parasite infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736, and SHR-1210.

Other anti -cancer agents include inhibitors of kinases associated cell proliferative disorder. These kinases include but not limited to Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, PAKl, PAK2, PAK3, PAK4, PDKl, PKA, PKC, Rsk, and SGK.

Other anti -cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4. The compounds of the present disclosure can further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants, or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gplOO, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself. In some embodiments, the compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

The compounds of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.

Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NPvTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; beta-L- FD4 (also called beta-L-D4C and named beta-L-2', 3'-dicleoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable N RTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP- 266); PNU-142721; AG-1549; MKC-442 (l-(ethoxy-methyl)-5-(l-methylethyl)-6-

(phenylmethyl)-(2,4(lH,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607.

When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents). Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. Thus the present disclosure provides a composition comprising a compound of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is indicated and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic, and to mucous membranes including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular orinjection or infusion; or intracranial, e.g. , intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose, or may be, e.g. , by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders.

Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, and the like may be necessary or desirable. This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified

microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and polyethylene oxide. In some

embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PHI 02™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M

Premier™) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1 105™).

In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.

The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the composition is preferably manufactured or formulated under Good Manufacturing Practice standards as defined in the applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and/or substantially isotonic and/or in full compliance with all Good

Manufacturing Practice regulations of the U. S. Food and Drug Administration.

The active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a

pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, e.g., about 0.1 to about 1000 mg of the active ingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, e.g. , liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g. , glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, e.g. , glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention. The topical formulations can be suitably packaged in tubes of, e.g., 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient and the like.

The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9, and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a

pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful in investigations of biological processes in normal and abnormal tissues. Thus, another aspect of the present invention relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds provided herein that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating HPKl protein in tissue samples, including human, and for identifying HPKl ligands by inhibition binding of a labeled compound.

Accordingly, the present invention includes HPKl binding assays that contain such labeled compounds.

The present invention further includes isotopically-substituted compounds of the disclosure. An "isotopically-substituted" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having the same atomic number but a different atomic mass or mass number. Compounds of the invention may contain isotopes in a natural abundance as found in nature. Compounds of the invention may also have isotopes in amounts greater to that found in nature, e.g., synthetically incorporating low natural abundance isotopes into the compounds of the invention so they are enriched in a particularly useful isotope (e.g., ² H and ¹³ C). It is to be understood that a "radio-labeled" compound is a compound that has incorporated at least one isotope that is radioactive (e.g., radionuclide), e.g., ³ H and ¹⁴ C. Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to ³ H (also written as T for tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ 0, ¹⁷ 0, ¹⁸ 0, ¹⁸ F, ³⁵ S, ³⁶ C1, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ^{13 !} I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. In some

embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ 1, ³⁵ S and ⁸² Br. For in vitro HPKl labeling and competition assays, compounds that incorporate ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I, or ³⁵ S will generally be most useful. For radio-imaging applications ⁿ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³ % ⁷⁵ Br, ⁷⁶ Br, or ⁷⁷ Br will generally be most useful. Synthetic methods for incorporating radio-isotopes into organic compounds are known in the art.

Specifically, a labeled compound of the invention can be used in a screening assay to identify and/or evaluate compounds. For example, a newly synthesized or identified compound (i.e. , test compound) which is labeled can be evaluated for its ability to bind a HPKl protein by monitoring its concentration variation when contacting with the HPKl, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a HPKl protein (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the HPKl protein directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g., in the treatment or prevention of diseases or disorders associated with the activity of HPKl, such as cancer or infections, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or any of the embodiments thereof. Such kits can further include one or more of various conventional pharmaceutical kit components, such as, e.g., containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non- critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples have been found to inhibit the activity of HPKl according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are provided below.

Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature. See e.g. , "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following conditions: Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ Cis 5 μπι particle size, 2.1 x 5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse- phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:

pH = 2 purifications: Waters Sunfire™ Cis 5 μπι particle size, 19 x 100 mm column, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem. , 6, 874-883 (2004)]. Typically, the flow rate used with the 30 x 100 mm column was 60 mL/minute. pH = 10 purifications: Waters XBridge Cis 5 μπι particle size, 19 x 100 mm column, eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [See "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem. , 6, 874-883 (2004)]. Typically, the flow rate used with 30 x 100 mm column was 60 mL/minute. Example la. Intermediate 1. tert-Butyi 3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzyl(methyl)carbamate

Step 1. 4-Bromo-3-fluoro-5-methylaniline

N-Bromosuccinimide ( 15.8 g, 89 mmol) was added to a solution of 3-fluoro-5- methylaniline (Combi-Blocks, 1 1 g, 88 mmol) in DMF (80 mL) cooled to 0 °C in an ice bath. The reaction mixture was stirred at 0 °C for 30 minutes. After warming to room temperature, the reaction was stirred for an additional 1 hour. Water and EtOAc were then added, and the organic phase was washed with saturated aqueous NaHCC and brine. The organic phase was then dried over magnesium sulfate and the solvents were evaporated under reduced pressure. The crude product was purified by Biotage Isolera™ (17.2 g, 96%). LCMS calculated for CyHsBrFN (M+H) ⁺ m/z = 203.9; found 204.0.

Step 2. 2-Bromo-l-fluoro-5-iodo-3-methylbenzene

To a solution of 4-bromo-3-fluoro-5-methylaniline (7.28 g, 36 mmol) in acetonitrile (190 mL) cooled to 0 °C in an ice bath was added sulfuric acid (4.75 mL, 89 mmol) dissolved in H2O (10 mL). After stirring for 5 minutes, a solution of sodium nitrite (4.92 g, 71.4 mmol) in water ( 10 mL) was added dropwise and the reaction mixture was stirred for an additional 15 minutes at 0 °C. Potassium iodide (23.7 g, 143 mmol) in water (20 mL) was then added, and the ice-bath was removed. After warming to room temperature the reaction was stirred for an additional 20 minutes before the reaction was quenched via the addition of aqueous Na2Si03. The mixture was then extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by Biotage Isolera™ (10.3 g, 94%). ^! H NMR (400 MHz, CDC1 ₃ ) δ 7.39 (br s, 1H), 7.29 (m, 1H), 2.38 (s, 3H) ppm.

Step 3. 2-Bromo-l-fluoro-3-methyl-5-vinylbenzene

To a solution of 2-bromo-l-fluoro-5-iodo-3-methylbenzene ( 10.3 g, 32.8 mmol) in 1,4-dioxane (80 mL) and water (13.3 mL) was added 4,4,5, 5-tetramethyl-2-vinyl-l, 3,2- dioxaborolane (Aldrich, 6.16 mL, 34.5 mmol), [l, l '-bis(diphenylphosphino)ferrocene]- dichloropalladium(II) (Pd(dppf)Ch) (2.40 g, 3.3 mmol), and potassium phosphate tribasic (13.9 g, 65.7 mmol). The reaction mixture was degassed with a nitrogen sparge and heated to 70 °C for 1 h. After cooling to room temperature, the reaction mixture was filtered over a pad of Celite, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by Biotage Isolera™ (5.46 g, 77%). 'H NMR (400 MHz, CDCh) δ 7.05 (br s, 1H), 7.01 (dd, J = 2.0, 9.4 Hz, 1H), 6.60 (dd, J = 10.9, 17.5 Hz, 1H), 5.75 (d, J= 17.5 Hz, 1H), 5.31 (d, J = 10.9 Hz, 1H), 2.42 (s, 3H) ppm.

Step 4. 4-Bromo-3-fluoro-5-methylbenzaldehyde

To a solution of 2-bromo-l-fluoro-3-methyl-5-vinylbenzene (5.46 g, 25.4 mmol) in acetone (46 mL) and water (4.6 mL) was sequentially added sodium periodate (21.7 g, 102 mmol) and a 4% aqueous solution of osmium tetroxide (8.07 mL, 1.27 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was then filtered over a pad of celite, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by Biotage Isolera™ (3.22 g, 58%). 'H NMR (400 MHz, CDCh) δ 9.93 (d, J = 1.8 Hz, lH), 7.55 (d, J= 1.8 Hz, 1H), 7.44 (dd, J = 1.8, 7.8 Hz, 1H), 2.52 (s, 3H) ppm. Step 5. l-(4-Bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine

In a 20 mL scintillation vial equipped with a magnetic stir bar, was charged with 4- bromo-3-fluoro-5-methylbenzaldehyde ( 1.46 g, 6.70 mmol) dissolved in MeOH (6.70 mL) and the reaction was placed under a nitrogen environment. The mixture was treated with a 33% solution of methanamine (3. 15 g, 33.5 mmol) in ethanol and titanium(IV) isopropoxide (0.982 mL, 3.35 mmol) and stirred at room temperature for 3 hours. Then, sodium borohydride ( 1.01 g, 26.8 mmol) was added to the reaction mixture portion wise and stirring was continued at room temperature for an additional 1.5 hours. At this time NH4OH (30% aqueous solution) was added to the reaction mixture and stirring continued for another 15 minutes. The reaction was then acidified with 1 N HCl and extracted with ethyl acetate. The aqueous phase was made basic and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford l-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g, 85%) as a light yellow oil. The crude product was used in the next step without further purification. LCMS calculated for C ₉ Hi ₂ BrFN (M+H) ⁺ m/z = 232.0; found 231.9.

Step 6. tert-Butyl 4-bromo-3-fluoro-5-methylbenzyl(methyl)carbamate

To a solution of l-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine ( 1.32 g, 5.67 mmol) and triethylamine (1.58 mL, 1 1.34 mmol) in THF (18.9 mL) was added di-tert- butyl dicarbonate ( 1.58 mL, 6.80 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phases were dried with magnesium sulfate and concentrated under reduced pressure. The crude product was purified by Biotage Isolera™ (1.42 g, 78%). LCMS calculated for CioHnBrFNOi (M+H-C ₄ H8) ⁺ m/z = 276.0; found 276.0.

Step 7. tert-Butyl 3-fluoro-5-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)benzyl(methyl)carbamate

An oven-dried 20 mL scintillation vial was charged with fert-butyl (4-bromo-3- fluoro-5-methylbenzyl)(methyl)carbamate (573 mg, 1.73 mmol) dissolved in THF (11.5 mL). The solution was cooled to -78 °C in a dry ice/acetone bath and «-BuLi (1.6 M solution in hexanes, 1.19 mL, 1.90 mmol) was added dropwise . The reaction mixture was allowed to stir for 3 minutes before 2-isopropyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (427 μί, 2.25 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for an additional 5 hours. The reaction was quenched by the addition of water, acidified to pH 5-6 using 1 N HCl, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to afford fert-butyl 3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)benzyl(methyl)carbamate. The crude product was used in the next step without further purification. LCMS calculated for Ci6H ₂₄ BrFN04 (M+H-C ₄ H ₈ ) ⁺ m/z = 324.2; found 324. 1. Example 1. 3-(l-Ethyl-lH-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

Step 1. tert-Butyl 6-bromo-5-chloro-lH-indazole-l-carboxylate

Boc-anhydride (5.00 g, 22.90 mmol) was added to a solution of 6-bromo-5-chloro- lH-indazole (5.3 g, 22.90 mmol) and DIPEA (4.00 ml, 22.90 mmol) in dioxane (25 ml). After stirring at room temperature for 1 h the reaction mixture was concentrated in vacuo and purified by Biotage Isolera™ (7.27 g, 96%). LCMS calculated for C nHnBrClNaNiOi (M+Na) ⁺ m/z = 353.0; found 353.0.

Step 2. tert-Butyl 5-chloro-6-cyano-lH-indazole-l-carboxylate

tert-Butyl 6-bromo-5-chloro-lH-indazole-l-carboxylate (5.5 g, 16.59 mmol), Pd ₂ (dba) ₃ (0.304 g, 0.332 mmol), Xantphos (0.384 g, 0.663 mmol) and zinc cyanide (2.3 g, 19.90 mmol) were charged in a flask and the flask was evacuated and backfilled with nitrogen three times. A solution of TMEDA (2.503 ml, 16.59 mmol) in DMF (100 ml) was added and the reaction mixture was heated at 110 ^° C for 3 h. After cooling to room temperature, Boc-anhydride (5.78 ml, 24.88 mmol) was added and the reaction mixture was stirred at room temperature for 30 mins. The reaction mixture was treated with water and extracted with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and obtained crude product was purified by Biotage Isolera™ (4.3 g, 93%). LCMS calculated for C13H13CIN3O2 (M+H) ⁺ m/z = 278.1 ; found 278.1. tert-Butyl 4-(6-cyano-lH-indazol-5-yl)-3-fluoro-5-methylbenzyl(methyl)c arbamate

Boc

A flask was charged with fert-Butyl 5-chloro-6-cyano-lH-indazole-l-carboxylate (2.0 g, 7.20 mmol), fert-butyl (3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2- yl)benzyl)(methyl)carbamate (2.73 g, 7.20 mmol, Intermediate 1), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl) [2-(2'-amino- 1, 1'- biphenyl)]palladium(II) (Pd XPhos G2) (0.500 g, 0.62 mmol) and potassium phosphate (1.5 g, 7.1 mmol). The flask was evacuated and backfilled with nitrogen three times. Then dioxane (50 mL) and water (10 mL) were added and the reaction mixture was stirred at 90 ^° C for 2h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with brine and the separated organic phase dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by

Biotage Isolera™ (310 mg, 1 1%). LCMS calculated for (M+Na) ⁺ m/z = 417.2; found 417.2.

Step 4. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-m ethylphenyl)- 6-cyano-3-iodo-lH-indazole-l-carboxylate

NIS (0.177 g, 0.786 mmol) was added to a solution of fert-butyl (4-(6-cyano-lH- indazol-5-yl)-3-fluoro-5-methylbenzyl)(methyl)carbamate (0.31 g, 0.786 mmol) in DMF (4 ml) and the reaction mixture was stirred at 70 ^° C for 2 h. The reaction mixture was cooled to room temperature and treated with triethylamine (0.14 ml, 1 mmol) followed by boc- anhydride (0.22 g, 1 mmol). After stirring for additional 2 h at room temperature, water was added and precipitated product was collected by filtration, dried and was used in the next step without further purification (220 mg, 46%). LCMS calculated for C27H3oFINaN404

(M+Na)+: m/z = 643.1; found 643.0.

Step 5. 3-(l-Ethyl-lH^yrazol-4-yl)-5-(2-fluoro-6-methyl-4-((methylam ino)methyl)phenyl)- lH-indazole-6-carbonitrile

A vial equipped with a magnetic stir bar was charged with fert-butyl 5-(4-(((tert- butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl )-6-cyano-3-iodo-lH- indazole-l-carboxylate (12.0 mg, 0.019 mmol), l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (5.58 mg, 0.025 mmol), chloro(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-l, l'-biphenyl)[2-(2'-amino-l, r-biphenyl)]palladium(II) (XPhos Pd G2, 2.3 mg, 3 umol) and potassium phosphate (8 mg, 0.039 mmol). The vial was sealed, evacuated and backfilled with nitrogen (this process was repeated a total of three times). Then 1,4-dioxane (2.00 ml) was added followed by water (200.0 μΐ). The reaction mixture was heated to 80 ^° C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was treated with CH2CI2 (1 mL) followed by TFA (1 mL). The mixture was stirred at room temperature for 15 min, and then concentrated under vacuum. The residue was purified using prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMS calculated C22H22FN6 (M+H)+: m/z = 389.2; found: 389.2.

Example 2. 3-(l-Cyclopropyl-lH-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )-lH-pyrazole instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-p yrazole as starting material. LCMS calculated for C23H22FN6 (M+H) ⁺ : m/z = 401.2; Found: 401.2.

Example 3. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(l-(2, 2,2- trifluoroethyl)-lH-pyrazol-4-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 -(2,2,2-trifluoroethyl)- IH-pyrazole instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-p yrazole as starting material. LCMS calculated for C22H19F4N6 (M+H) ⁺ : m/z = 443.2; Found: 443.2.

Example 4. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(lH-py razol-4-yl)- lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using lH-pyrazol-4-ylboronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C20H18FN6 (M+H) ⁺ : m/z = 361.2; Found: 361.1. Example 5. 3-(l-(2-Chlorophenyl)-lH-pyrazol-4-yl)-5-(2-fluoro-6-methyl- 4- ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using l-(2-chlorophenyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)-lH-pyrazole instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole as starting material. LCMS calculated for C ₂ 6H ₂ iClFN ₆ (M+H) ⁺ : m/z = 471.2; Found: 471.2.

Example 6. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(l-iso propyl-lH- pyrazol-4-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole instead of 1- ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyr azole as starting material. LCMS calculated for C23H24FN6 (M+H) ⁺ : m/z = 403.2; Found: 403.2. Example 7. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4- (hydroxymethyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)metha nol instead of l-ethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C24H22FN4O (M+H) ⁺ : m/z = 401.2; Found: 401.2.

Example 8. 4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)pheny l)-lH- indazol-3-yl)-/V-methylbenzamide

This compound was prepared according to the procedures described in Example 1, using 4-(methylcarbamoyl)phenylboronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C25H23FN5O (M+H) ⁺ : m/z = 428.2; Found: 428.3. Example 9. 4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phi

indazol-3-yl)-7V,7V-dimethylbenzamide

This compound was prepared according to the procedures described in Example 1, using 4-(dimethylcarbamoyl)phenylboronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C26H25FN5O (M+H) ⁺ : m/z = 442.2; Found: 442.2.

Example 10. 7V-(4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)p henyl)-lH- indazol-3-yl)phenyl)acetamide

This compound was prepared according to the procedures described in Example 1, using 4-acetamidophenylboronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C25H23FN5O

(M+H) ⁺ : m/z = 428.2; Found: 428.3. Example 11. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-/7-tol yl-lH- indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using p-tolylboronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole as starting material. LCMS calculated for C24H22FN4 (M+H) ⁺ : m/z = 385.2; Found: 385.3.

Example 12. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(3- methoxyphenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (3-methoxyphenyl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C24H22FN4O (M+H) ⁺ : m/z = 401.2; Found: 401.2. Example 13. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4- methoxyphenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-methoxyphenyl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C24H22FN4O (M+H) ⁺ : m/z = 401.2; Found: 401.2.

Example 14. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4- (trifluoromethyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-(trifluoromethyl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C24H19F4N4 (M+H) ⁺ : m/z = 439.2; Found: 439.2. Example 15. 3-(4-Cyclopropylphenyl)-5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-cyclopropylphenyl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C26H24FN4 (M+H) ⁺ : m/z = 411.2; Found: 411.2.

Example 16. 3-(4-(Cyanomethyl)phenyl)-5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-(cyanomethyl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C25H21FN5 (M+H) ⁺ : m/z = 410.2; Found: 410.2. Example 17. 4-(6-Cyano-5-(2-f luor o-6-methyl-4-((methylamino)methyl)phi

indazol-3-yl)-2-fluoro-/V-methylbenzamide

This compound was prepared according to the procedures described in Example 1, using (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C ₂ 5H ₂₂ F ₂ N5O (M+H) ⁺ : m/z = 446.2; Found: 446.2.

Example 18. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4- (methylsulfonyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-(methylsulfonyl)phenyl)boronic acid instead of 1 -ethyl -4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C24H22FN4O2S (M+H) ⁺ : m/z = 449.1; Found: 449.2. Example 19. 3-(4-(2-Cyanopropan-2-yl)phenyl)-5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-(2-cyanopropan-2-yl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-pyrazole as starting material. LCMS calculated for C27H25FN5 (M+H) ⁺ : m/z = 438.2; Found: 438.2.

Example 20. 3-(4-(l-Cyanocyclopropyl)phenyl)-5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)- -indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-(l-cyanocyclopropyl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-pyrazole as starting material. LCMS calculated for C27H23FN5 (M+H) ⁺ : m/z = 436.2; Found: 436.2. Example 21. 4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phi indazol-3-yl)-2-fluoro-7V,7V-dimethylbenzamide

This compound was prepared according to the procedures described in Example 1, using (4-(dimethylcarbamoyl)-3-fluorophenyl)boronic acid instead of l-ethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C ₂ 6H ₂ 4F ₂ N5O (M+H) ⁺ : m/z = 460.2; Found: 460.2.

Example 22. 3-Chloro-4-(6-cyano-5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)-lH-indazol-3-yl)-7V-isopropylbe nzamide

This compound was prepared according to the procedures described in Example 1, using (2-chloro-4-(isopropylcarbamoyl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C ₂ 7H ₂ 6CIFN5O (M+H) ⁺ : m/z = 490.2; Found: 490.2. Example 23. 3-(3-Fluoro-4-(methylsulfonyl)phenyl)-5-(2-fluoro-6-methyl-4 - ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (3-fluoro-4-(methylsulfonyl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C ₂ 4H ₂ 1F ₂ N4O ₂ S (M+H) ⁺ : m/z = 467.2; Found: 467.2.

Example 24. 3-(2-Chloro-4-(methylsulfonyl)phenyl)-5-(2-fluoro-6-methyl-4 - ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (2-chloro-4-(methylsulfonyl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C ₂ 4H ₂ 1CIFN4O ₂ S (M+H) ⁺ : m/z = 483.1; Found: 483.1. Example 25. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4- (isopropylsulfonyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (4-(isopropylsulfonyl)phenyl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-pyrazole as starting material. LCMS calculated for

C ₂ 6H ₂ 6FN4O ₂ S (M+H) ⁺ : m/z = 477.2; Found: 477.2.

Example 26. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(l-met hyl-lH- pyrazol-4-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole instead of 1- ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyr azole as starting material. LCMS calculated for C ₂ iH ₂ oFN ₆ (M+H) ⁺ : m/z = 375.2; Found: 375.2. Example 27. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-(4- methylpiperazin-l-yl)pyrimidin-5-yl)-lH-indazole-6-carbonitr ile

This compound was prepared according to the procedures described in Example 1, using 2-(4-methylpiperazin-l-yl)pyrimidin-5-ylboronic acid instead of l-ethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for CieHisFNs (M+H) ⁺ : m/z = 471.2; Found: 471.2. 1H NMR (600 MHz, DMSO-d6) δ 9.05 (s, 2H), 9.03 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 7.36 (d, J = 10.8 Hz, 2H), 4.23 (s, 2H), 3.67 - 3.01 (m, 8H), 2.85 (s, 3H), 2.63 (s, 3H), 2.15 (s, 3H) ppm.

Example 28. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6- morpholinopyridin-3-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)moφholine instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-p yrazole as starting material. LCMS calculated for CieHieFNeO (M+H) ⁺ : m/z = 457.2; Found: 457.2. Example 29. 7V-(5-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)p hi indazol-3-yl)pyridin-2-yl)acetamide

This compound was prepared according to the procedures described in Example 1, using N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)acetamide instead of 1- ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyr azole as starting material. LCMS calculated for C ₂ 4H ₂ 2FN ₆ 0 (M+H) ⁺ : m/z = 429.2; Found: 429.2.

Example 30. 3-(6-(4-Acetyl piper azin- l-yl)pyridin-3-yl)-5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 1 -(4-(5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin- 1 -yl)ethan- 1-one instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-p yrazole as starting material. LCMS calculated for C28H29FN7O (M+H) ⁺ : m/z = 498.2; Found: 498.3. Example 31. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-met hylpyridin- 4-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyri dine instead of l-ethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C23H21FN5 (M+H) ⁺ : m/z = 386.2; Found: 386.2.

Example 32. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(te trahydro- 2H-pyran-4-yl)pyridin-3-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 2-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-l,3,2-di oxaborolan-2-yl)pyridine instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-p yrazole as starting material. LCMS calculated for C27H27FN5O (M+H) ⁺ : m/z = 456.2; Found: 456.2. 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.98 (br, 1H), 8.44 (d, J = 0.6 Hz, 1H), 8.37 (dd, J = 8.2, 2.3 Hz, 1H), 8.26 - 8.14 (m, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.40 - 7.27 (m, 2H), 4.23 (t, J = 5.7 Hz, 2H), 3.98 (dt, J = 11.0, 3.0 Hz, 2H), 3.52 - 3.42 (m, 2H), 3.09 - 2.96 (m, lH), 2.64 (t, J = 5.2 Hz, 3H), 2.15 (s, 3H), 1.91 - 1.72 (m, 4H) ppm. Example 33. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(2- hydroxypropan-2-yl)pyridin-3-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)propan-2-ol instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-p yrazole as starting material. LCMS calculated for C ₂ 5H ₂ 5FN5O (M+H) ⁺ : m/z = 430.2; Found: 430.2. 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.91 (br, 1H), 8.44 (s, 1H), 8.40 (dd, J = 8.3, 2.3 Hz, 1H), 8.24 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.41 - 7.22 (m, 2H), 4.28 - 4.16 (m, 2H), 2.64 (t, J = 5.3 Hz, 3H), 2.16 (s, 3H), 1.49 (s, 6H) ppm.

Example 34. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-met hylpyridin- 3-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyri dine instead of l-ethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C23H21FN5 (M+H) ⁺ : m/z = 386.2; Found: 386.2. Example 35. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2- methoxypyrimidin-5-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using (2-methoxypyrimidin-5-yl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C22H20FN6O (M+H) ⁺ : m/z = 403.2; Found: 403.2.

Example 36. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(oxazo l-5-yl)-lH- indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)oxazole instead of l-ethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C ₂ 0H17FN5O (M+H) ⁺ : m/z = 362.1 ; Found: 362.1. Example 37. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(isoth iazol-4-yl)- lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using isothiazol-4-ylboronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C20H17FN5S (M+H) ⁺ : m/z = 378.1 ; Found: 378.1. 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.23 (s, 1H), 9.09 (br, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 7.46 - 7.27 (m, 2H), 4.22 (s, 2H), 2.63 (s, 3H), 2.16 (s, 3H) ppm.

Example 38. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(isoxa zol-4-yl)- lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole instead of l-ethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C ₂ 0H17FN5O (M+H) ⁺ : m/z = 362.1 ; Found: 362.1. Example 39. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(te trahydro- 2H-pyran-4-yl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 4,4,5 ,5 -tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)- 1 , 3 ,2-dioxaborolane instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole as starting material. LCMS calculated for C ₂ 8H ₂ 8FN ₄ 0 (M+H) ⁺ : m/z = 455.2; Found: 455.2.

Example 40. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-met hyloxazol- 5-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 1, using 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)oxaz ole instead of l-ethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C ₂ 1H19FN5O (M+H) ⁺ : m/z = 376.2; Found: 376.2. Example 41. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(( ₁ 5)-3- fluoropyrrolidin-l-yl)pyridin-3-yl)-lH-indazole-6-carbonitri le

Step 1. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-m ethylphenyl)- 6-cyano-3-(6-fluoropyridin-3-yl)-lH-indazole-l-carboxylate

This compound was prepared according to the procedures described in Example 1, using (6-fluoropyridin-3-yl)boronic acid instead of l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole as starting material. LCMS calculated for C28H26F2N5O4 (M- C ₄ H ₈ +H) ⁺ : m/z = 534.2; Found: 534.2.

Step 2. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-((S )-3-fluoropyrrolidin-l- yl)pyridin-3-yl)-lH-indazole-6-carbonitrile

(<S)-3-Fluoropyrrolidine (3 mg, 0.034 mmol) was added to a solution of fert-butyl 5- (4-(((ter^butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-me thylphenyl)-6-cyano-3-(6- fluoropyridin-3-yl)-lH-indazole-l-carboxylate (0.010 g, 0.017 mmol) in 2-methoxyethanol (0.5 ml) and the reaction mixture was stirred at 120 ^° C overnight. After cooling to room temperature TFA (1 ml) was added and the reaction mixture was stirred at room temperature for 30 mins. The reaction mixture was diluted with acetonitrile and purified using prep- LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMS calculated C26H25F2N6 (M+H)+: m/z = 459.2; found: 459.2.

Example 42. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(4- hydroxypiperidin-l-yl)pyridin-3-yl)-lH-indazole-6-carbonitri le

This compound was prepared according to the procedures described in Example 41, using piperidin-4-ol instead of (iS)-3-fluoropyrrolidine as starting material. LCMS calculated for C ₂ 7H ₂ 8FN ₆ 0 (M+H) ⁺ : m/z = 471.2; Found: 471.2.

Example 43. 3-(6-(((i?)-sec-Butyl)amino)pyridin-3-yl)-5-(2-fluoro-6-meth yl-4- ((methylamino)methyl)phenyl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 41, using (i?)-butan-2 -amine instead of (iS)-3-fluoropyrrolidine as starting material. LCMS calculated for C ₂ 6H ₂ 8FN ₆ (M+H) ⁺ : m/z = 443.2; Found: 443.2. Example 44. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(3- (hydroxymethyl)azetidin-l-yl)pyridin-3-yl)-lH-indazole-6-car bonitrile

This compound was prepared according to the procedures described in Example 41, using azetidin-3-ylmethanol instead of (5)-3-fluoropyrrolidine as starting material. LCMS calculated for CieHieFNeO (M+H) ⁺ : m/z = 457.2; Found: 457.2.

Example 45. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(4- hydroxypiperidin-l-yl)pyridin-2-yl)-lH-indazole-6-carbonitri le

Step 1. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-m ethylphenyl)- 6-cyano-3-(6-fluoropyridin-2-yl)-lH-indazole-l-carboxylate

A flask was charged with fert-Butyl 5-(4-(((tert- butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl )-6-cyano-3-iodo-lH- indazole-l-carboxylate (0.25 g, 0.403 mmol, Example 1, Step 4), triphenylphosphine palladium chloride (0.030 g, 0.043 mmol) and 2-fluoro-6-(tributylstannyl)pyridine (0.156 g, 0.403 mmol). The flask was evacuated and backfilled with nitrogen three times. The reaction mixture was treated with DMF (3 ml) and stirred at 1 10 ^° C overnight. After cooling to room temperature, the reaction mixture was treated with water andextracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and

concentrated under vacuum. The crude product was purified by Biotage Isolera™. LCMS calculated for CisHieFiNsC (M-C4H8+H) ⁺ m/z = 534.2; found 534.1. Step 2. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(4- hydroxypiperidin-l- yl)pyridin-2-yl)-lH-indazole-6-carbonitrile

This compound was prepared according to the procedures described in Example 42, using fert-butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-m ethylphenyl)- 6-cyano-3-(6-fluoropyridin-2-yl)-lH-indazole-l-carboxylate instead of fert-butyl 5-(4-((tert- butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl) -6-cyano-3-(6- fluoropyridin-3-yl)-lH-indazole-l-carboxylate as starting material. LCMS calculated for CivHisFNeO (M+H)+: m/z = 471.2; Found: 471.2.

Example 46. 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(4- methylpiperazin-l-yl)pyridin-2-yl)-lH-indazole-6-carbonitril e

This compound was prepared according to the procedures described in Example 45, using 1-methylpiperazine instead of piperidin-4-ol as starting material. LCMS calculated for C27H29FN7 (M+H) ⁺ : m/z = 470.2; Found: 457.2. Example 47. 3-(6-(( ₁ 5)-3-(Dimethylaniino)pyrrolidin-l-yl)pyridin-2-yl)-5-( 2-fluoro-6- methyl-4-((methylamino)methyl)phenyl)-lH-indazole-6-carbonit rile

This compound was prepared according to the procedures described in Example 45, using (5)-NN-dimethylpyrrolidin-3-amine instead of piperidin-4-ol as starting material. LCMS calculated for CisftiFNy (M+H) ⁺ : m/z = 484.3; Found: 484.3.

Example 48. 3-(l-Methyl-lH-pyr indazole-6-carbonitrile

Step 1. tert-Butyl 6-bromo-5-chloro-3-iodo-lH-indazole-l-carboxylate

NIS (0.972 g, 4.32 mmol) was added to a solution of 6-bromo-5-chloro-lH-indazole (1.0 g, 4.32 mmol) in DMF (10 ml) and stirred at 70 ^° C for 2 h. The reaction mixture was cooled to room temperature and treated with triethylamine (0.84 ml, 6 mmol) followed by boc-anhydride (1.32 g, 6 mmol). After stirring for additional 2 h at room temperature, water was added and the precipitated product was collected by filtration, dried and used in the next step without further purification (1.77 g, 90%). LCMS calculated for CsftBrClINiOi (M- C ₄ H ₈ +H)+: m/z = 400.8; found 400.8. tert-Butyl 6-bromo-5-chloro-3-(l -methyl-lH-pyrazol-4-yl)-lH-indazole-l -carboxylate

A flask was charged with fert-Butyl 6-bromo-5-chloro-3-iodo-lH-indazole-l- carboxylate (0.7 g, 1.53 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.125 g, 0.1 mmol), l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.318 g, 1.53 mmol) and potassium phosphate (0.325 g, 1.53 mmol). The flask was evacuated and backfilled with nitrogen three times. Then dioxane (5 ml) and water (0.5 ml) were added and the reaction mixture was stirred at 80 ^° C for 1 h. After cooling to room temperature water was added, the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by Biotage Isolera™ (0.35 g, 56%). LCMS calculated for CieHnBrClN^ (M+H) + m/z = 41 1.0; found 41 1.0.

Step 3. tert-Butyl 5-chloro-6-cyano- -(l-methyl-lH-pyrazol-4-yl)-lH-indazole-l-carboxylate

A flask was charged with fert-Butyl 6-bromo-5-chloro-3-(l-methyl- lH-pyrazol-4-yl)- lH-indazole-1 -carboxylate (0.3 g, 0.729 mmol), Pd ₂ (dba)3 (0.1 g, 0.1 mmol), Xantphos (0.12 g, 0.21 mmol) and zinc cyanide (200 mg, 1.7 mmol). The flask was evacuated and backfilled with nitrogen three times. A solution of TMEDA (0.25 ml, 1.7 mmol) in DMF (10 ml) was added and the reaction mixture was heated at 1 10 ^° C for 3 h. After cooling to room temperature water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by Biotage Isolera™ (4.3 g, 93%). LCMS calculated for C17H17CIN5O2 (M+H) ⁺ m/z = 358.1 ; found 358.1.

Step 4. 3-(l-Methyl-lH-pyrazol-4-yl)-5-o-tolyl-lH-indazole-6-carboni trile

A vial equipped with a magnetic stir bar was charged with fert-butyl 5-chloro-6- cyano-3-(l-methyl-lH-pyrazol-4-yl)-lH-indazole-l-carboxylate (10.0 mg, 0.03 mmol), o- tolylboronic acid (10 mg, 0.07 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl- l, r-biphenyl)[2-(2'-amino-l, r-biphenyl)]palladium(II) (XPhos Pd G2, 2.3 mg, 3 μιηοΐ) and potassium phosphate (8 mg, 0.039 mmol). The vial was sealed, evacuated and backfilled with nitrogen (this process was repeated a total of three times). Then 1,4-dioxane (2.00 ml) was added, followed by water (200.0 μΐ). The reaction mixture was heated to 80 ^° C for 2 h, cooled and concentrated under vacuum. The residue was treated with CH2CI2 (1 mL) followed by TFA (1 mL). The reaction mixture was stirred at room temperature for 15 min, and then concentrated under vacuum. The resulting residue was purified using prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMS calculated C19H16N5 (M+H)+: m/z = 314.1; found: 314.2.

Example 49. 5-(2-Fluorophenyl)-3-(l-methyl-lH-pyrazol-4-yl)-lH-indazole- 6- carbonitrile

This compound was prepared according to the procedures described in Example 48, using (2-fluorophenyl)boronic acid instead of o-tolylboronic acid as starting material. LCMS calculated for Ci ₈ Hi ₃ FN ₅ (M+H) ⁺ : m/z = 318.1; Found: 318.2.

Example 50. 5-(2-Fluoro-6-methoxyphenyl)-3-(l-methyl-lH-pyrazol-4-yl)-lH -indazole- 6-carbonitrile

This compound was prepared according to the procedures described in Example 48, using (2-fluoro-6-methoxyphenyl)boronic acid instead of o-tolylboronic acid as starting material. LCMS calculated for C19H15FN5O (M+H) ⁺ : m/z = 348.1; Found: 348.2.

Example 51. 5-(2-Fluoro-6-methylphenyl)-3-(l-methyl-lH-pyrazol-4-yl)-lH- indazole-6- carbonitrile

This compound was prepared according to the procedures described in Example 48, using (2- fluoro-6-methylphenyl)boronic acid instead of o-tolylboronic acid as starting material. LCMS calculated for C19H15FN5 (M+H) ⁺ : m/z = 332.1; Found: 332.1. Example A. HPK1 Kinase Binding Assay

A stock solution of 1 mM test compound was prepared in DMSO. The compound plate was prepared by 3-fold and 11 -point serial dilutions. 0.1 of the compound in DMSO was transferred from the compound plate to the white 384 well polystyrene plates. The assay buffer contained 50 mM HEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCh, 0.01% BSA, and 5 mM DTT. 5 μΐ of 4 nM active HPK1 (SignalChem M23- 11G) prepared in the buffer was added to the plate. The enzyme concentration given was based on the given stock concentration reported by the vender. 5 μΐ of 18 nM tracer 222 (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody (ThermoFisher PV5595) were added. After one hour incubation at 25 °C, the plates were read on a PHERAstar FS plate reader (BMG Labtech). Ki values were determined.

Compounds of the present disclosure, as exemplified in Examples, showed the Ki values in the following ranges: + = Ki < 100 nM; ++ = 100 nM < Ki < 500 nM; +++ = 500 nM < Ki < 5000 nM.

Table 1.

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+ 35 +

36 +

37 +

38 +

39 +

40 +

41 +

42 +

43 +

44 +

45 +

46 +

47 +

48 +

49 +

50 +

51 +

Example B. p-SLP76S376 HTRF Assay

One or more compounds of the invention can be tested using the p-SLP76S376 HTRF assay described as follows. Jurkat cells (cultured in RPMI1640 media with 10% FBS) are collected and centrifuged, followed by resuspension in appropriate media at 3 xlO ⁶ cells / ml. The Jurkat cells (35 μΐ) are dispensed into each well in a 384 well plate. Test compounds are diluted with cell culture media for 40-fold dilution (adding 39 μΐ cell culture media into 1 μΐ compound). The Jurkat cells in the well plate are treated with the test compounds at various concentrations (adding 5 μΐ diluted compound into 35 μΐ Jurkat cells and starting from 3 μΜ with 1:3 dilution) for 1 hour at 37 °C, 5% CO2), followed by treatment with anti-CD3

(5 μg/ml, OKT3 clone) for 30 min. A 1 :25 dilution of lOOx blocking reagent (from p-SLP76 ser376HTPvF kit) with 4xLysis Buffer(LB) is prepared and 15 μΐ of the 4xLB buffer with blocking reagent is added into each well and incubated at room temperature for 45 mins with gentle shaking. The cell lysate (16 μΐ) is added into a Greiner white plate, treated with p- SLP76 ser376HTRF reagents (2 μΐ donor, 2 μΐ acceptor) and incubated at 4 °C for overnight. The homogeneous time resolved fluorescence (HTRF) is measured on a PHERAstar plate reader the next day. IC50 determination is performed by fitting the curve of percent inhibition versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software. Example C. Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement

Blood samples are collected from healthy donors. CD4+ or CD8+ T cells are isolated by negative selection using CD4+ or CD8+ enrichment kits (lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells is determined by flow cytometry and is routinely >80%. Cells are cultured in RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics

(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkat cells or primary CD4+ or CD 8+ T cells are plated at 200 k cells/well and are stimulated for 24 h with anti- CD3/anti-CD28 beads in the presence or absence of testing compounds at various concentrations. 16 of supernatants are then transferred to a white detection plate and analyzed using the human IL2 or IFNy assay kits (Cisbio).

Example D. Treg Assay

One or more compounds can be tested using the Regulatory T-cell proliferation assay described as following. Primary CD4+/CD25- T-cells and CD4+/CD25+ regulatory T-cells are isolated from human donated Peripheral Blood Mononuclear Cells, using an isolated kit from Thermo Fisher Scientific (11363D). CD4+/CD25- T-cells are labeled with CFSE

(Thermo Fisher Scientific, C34554) following the protocol provided by the vendor. CFSE labeled T-cells and CD4+/CD25+ regulatory T-cells are re-suspended at the concentration of IX 106 cells/ml in RPMI-1640 medium. 100 μΐ of CFSE-labeled T-cells are mixed with or without 50 μΐ of CD4+/CD25+ regulatory T-cells, treated with 5 μΐ of anti-CD3/CD28 beads (Thermo Fisher Scientific, 11132D) and various concentrations of compounds diluted in 50μ1 of RPMI-1640 medium. Mixed populations of cells are cultured for 5 days (37 °C, 5% CO2) and proliferation of CFSE-labeled T-cells is analyzed by BD LSRFortessa X-20 using FITC channel on the 5th day. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including without limitation all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.