Pyrazolopyridine compounds and uses thereof

Description

FIELD OF THE INVENTION

The disclosure provides compounds as well as their compositions and methods of use. The compounds modulate hematopoietic progenitor kinase 1 (HPK1) activity and are useful in the treatment of various diseases including cancer.

BACKGROUND OF THE INVENTION

Hematopoietic progenitor kinase 1 (HPK1) 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). HPK1 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).

HPK1 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-βR) (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 PGE₂receptors (EP2 and EP4) (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). As such, HPK1 regulates diverse functions of various immune cells.

HPK1 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).

HPK1 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, HPK1 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., Mol Med, 2005. 11(1-12): p. 21-9). Those observations suggested that attenuation of HPK1 activity may contribute to autoimmunity in patients. Furthermore, HPK1 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 HPK1 knockout mice as compared to wild-type mice (see US 2007/0087988). In addition, it was shown that adoptive transfer of HPK1 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 HPK1 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 HPK1 in hematopoietic cells and lack of effect on the normal development of immune cells, suggest that HPK1 may be an excellent drug target for enhancing antitumor immunity. Accordingly, there is a need for new compounds that modulate HPK1 activity.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

embedded image

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 HPK1 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 provides a compound of Formula (I):

embedded image

or a pharmaceutically acceptable salt thereof, wherein:

R¹is selected from C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^jR^k, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NOR^a)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)₂R^b, S(O)NR^cR^d, and S(O)₂NR^cR^d; wherein said C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

Cy^Ais 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more ring-forming carbon atoms and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a carbon atom of 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R²⁰; or

Cy^Ais phenyl fused with a 5-6 membered heterocycloalkyl ring; wherein the fused 5-6 membered heterocycloalkyl ring comprises ring-forming carbon atoms and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of the fused 5-6 membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group; wherein the fused 5-6 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R²¹; wherein the phenyl portion of Cy^Ais further optionally substituted with 1, 2 or 3 substituents independently selected from R²⁰; and wherein Cy^Ais attached to the pyrrazolopyridine core through the phenyl portion;

R²is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, OR^a7, SR^a7, C(O)R^b7, C(O)NR^c7R^d7, C(O)OR^a7, NR^c7R^d7, NR^c7C(O)R^b7, NR^c7C(O)OR^a7, NR^c7S(O)R^b7, NR^c7S(O)₂R^b7, NR^c7S(O)₂NR^c7R^d7, S(O)R^b7, S(O)NR^c7R^d7, S(O)₂R^b7, and S(O)₂NR^c7R^d7; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰;

each R¹⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, C(═NR^e1)R^b1, C(═NOR^a1)R^b1, C(═NR^e1)NR^c1R^d1NR^c1C(═NR^e1)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹;

or two R¹⁰substituents taken together with the carbon atom to which they are attached form a spiro 3-7-membered heterocycloalkyl ring, or a spiro C_3-6cycloalkyl 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 C_3-6cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹¹;

each R¹¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3S(O)R^b3NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹²;

each R¹²is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)OR^a5, NR^c5S(O)R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_6-10aryl, 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 R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NOR^a2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹;

or two R²⁰substituents taken together with the carbon atoms to which they are attached form a fused 4-7-membered heterocycloalkyl ring, or a fused C_4-6cycloalkyl ring; wherein each fused 4-7-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 fused 4-7-membered heterocycloalkyl ring or fused C_4-6cycloalkyl ring is optionally substituted by oxo to form a carbonyl group; and wherein the fused 4-7-membered heterocycloalkyl ring and fused C_4-6cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R²¹;

each R²¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²²;

or two R²¹substituents taken together with the carbon atom to which they are attached form a spiro 3-7-membered heterocycloalkyl ring, or a spiro C_3-6cycloalkyl 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 C_3-6cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R²²;

each R²²is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)OR^a6, NR^c6S(O)R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, and S(O)₂NR^c6R^d6; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 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 R³⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)OR^a8, NR^c8S(O)R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, and S(O)₂NR^c8R^d8; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 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^a, R^cand R^dis independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

or any R^cand R^dattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰;

R^bis selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

R^eis selected from H, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkylthio, C_1-6alkylsulfonyl, C_1-6alkylcarbonyl, C_1-6alkylaminosulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, aminosulfonyl, C_1-6alkylaminosulfonyl and di(C_1-6alkyl)aminosulfonyl;

R^jis selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

R^kis selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

each R^a1, R^c1and R^d1is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹;

or any R^c1and R^d1attached 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 R¹¹;

each R^b1is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹;

each R^e1is independently selected from H, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkylthio, C_1-6alkylsulfonyl, C_1-6alkylcarbonyl, C_1-6alkylaminosulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, aminosulfonyl, C_1-6alkylaminosulfonyl and di(C_1-6alkyl)aminosulfonyl;

each R^a2, R^c2and R^d2, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹;

or any R^c2and R^d2attached 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 R²¹;

each R^b2is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹;

each R^e2is independently selected from H, CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkylthio, C_1-6alkylsulfonyl, C_1-6alkylcarbonyl, C_1-6alkylaminosulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, aminosulfonyl, C_1-6alkylaminosulfonyl and di(C_1-6alkyl)aminosulfonyl;

each R^a3, R^c3and R^d3, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹²;

or any R^c3and R^d3attached 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 R¹²;

each R^b3is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹²;

each R^a4, R^c4and R^d4, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²²;

or any R^c4and R^d4attached 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 R²²;

each R^b4is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²²;

each R^a5, R^c5and R^d5, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^b5is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^a6, R^c6and R^d6is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^b6is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^a7, R^c7, and R^d7is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰;

or any R^c7and R^d7attached 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 R³⁰;

each R^b7is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰;

each R^a8, R^c8and R^d8, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 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;

or any R^c8and R^d8attached 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^g;

each R^b8is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 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; and

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-2alkylene, C_1-6alkoxy, C_1-6haloalkoxy, C_1-3alkoxy-C_1-3alkyl, C_1-3alkoxy-C_1-3alkoxy, HO—C_1-3alkoxy, HO—C_1-3alkyl, cyano-C_1-3alkyl, H₂N—C_1-3alkyl, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino;

provided that

1) R¹is other than CH═CH₂;

2) R^bis other than substituted piperidine;

3) R^bis other than unsubstituted or substituted propyl;

4) when R^bis phenyl, then R¹⁰is other than pyrrolidin-1-ylmethyl or dimethylamino; and

5) when Cy^Ais unsubstituted or substituted pyridinyl or unsubstituted quinolinyl, then R^bis other than cyclopropyl or cyclopentyl.

In some embodiments, R¹is selected from C_2-6alkynyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^jR^k, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)₂R^b, S(O)NR^cR^d, and S(O)₂NR^cR^d; wherein said C_2-6alkynyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰.

In some embodiments, R¹is selected from C_2-6alkynyl, CN, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^jR^k, NR^cC(O)R^b, and NR^cC(O)OR^a; wherein said C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, R¹is selected from C(O)NR^cR^d, C(O)OR^a, NR^jR^k, NR^cC(O)R^b, and NR^cC(O)OR^a.

In some embodiments, R¹is selected from C(O)NR^cR^dand NR^cC(O)R^b. For example, R¹is C(O)NR^cR^dsuch as C(O)NHR^d. In some examples, R¹is NR^cC(O)R^bsuch as NHC(O)R^b.

In some embodiments, each R^a, R^cand R^dis independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, each R^cand R^dis independently selected from H, C_1-6alkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R¹⁰.

In some embodiments, each R^cand R^dis independently selected from H and C_6-10aryl; wherein said C_6-10aryl is optionally substituted with 1 or 2 substituents independently selected from R¹⁰.

In some embodiments, R^bis selected from C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰.

In some embodiments, R^bis selected from C_6-10aryl and 5-10 membered heteroaryl; wherein said C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, R^bis C_6-10aryl; wherein said C_6-10aryl is optionally substituted with 1 or 2 substituents independently selected from R¹⁰.

In some embodiments, R^bis phenyl optionally substituted with 1 or 2 substituents independently selected from R¹⁰.

In some embodiments, each R¹⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1NR^c1C(O)R^b1, and NR^c1C(O)OR^a1; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰is independently selected from C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, NR^c1R^d1, NR^c1C(O)R^b1, and NR^c1C(O)OR^a1; wherein said C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰is independently selected from 4-10 membered heterocycloalkyl and NR^c1R^d1; wherein said 4-10 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R¹¹.

In some embodiments, R¹⁰is 4-10 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R¹¹.

In some embodiments, R¹⁰is NR^c1R^d1.

In some embodiments, each R^c1and R^d1is independently selected from H, C_2-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_2-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹.

In some embodiments, each R^c1and R^d1is independently selected from H, C_2-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_2-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹.

In some embodiments, each R^c1and R^d1is independently selected from H and C_2-6alkyl; wherein said C_2-6alkyl is optionally substituted with 1 or 2 substituents independently selected from R¹¹.

In some embodiments, R¹⁰is morpholinyl, 4-methylpiperazin-1-yl, 4-ethoxycarbonylpiperazin-1-yl, 4-methoxypiperidin-1-yl, 3-aminopiperidin-1-yl, 3-methoxypiperidin-1-yl, 1-propylamino, 2-methoxyethylamino, or 3-difluoropyrrolidin-1-yl.

In some embodiments, R¹⁰is 1-propylamino or 2-methoxyethylamino.

In some embodiments, each R¹¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3NR^c3R^d3, NR^c3C(O)R^b3, and NR^c3C(O)OR^a3; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹².

In some embodiments, each R¹¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, OR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3NR^c3R^d3, NR^c3C(O)R^b3, and NR^c3C(O)OR^a3.

In some embodiments, each R¹¹is independently selected from C_1-6alkyl, halo, OR^a3, C(O)OR^a3, and NR^c3R^d3.

In some embodiments, each R^a3, R^c3and R^d3is independently selected from H and C_1-6alkyl.

In some embodiments, R²is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, OR^a7, SR^a7, C(O)R^b7, C(O)NR^c7R^d7, C(O)OR^a7, NR^c7R^d7, NR^c7C(O)R^b7, and NR^c7C(O)OR^a7; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R³⁰.

In some embodiments, R²is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, and halo; wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R³⁰.

In some embodiments, R²is selected from H and C_1-6alkyl.

In some embodiments, R²is H.

In some embodiments, Cy^Ais 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more ring-forming carbon atoms and 1, 2, or 3 ring-forming N heteroatoms; wherein the N is optionally oxidized; wherein a carbon atom of 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from R²⁰.

In some embodiments, Cy^Ais pyridyl or pyrazolyl; wherein said pyridyl and pyrazolyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R²⁰.

In some embodiments, Cy^Ais 4-methylpyridin-3-yl, 1,5-dimethyl-1H-pyrazol-4-yl, or 4-methoxypyridin-3-yl. In some embodiments, Cy^Ais 4-methylpyridin-3-yl. In some embodiments, Cy^Ais 1,5-dimethyl-1H-pyrazol-4-yl. In some embodiments, Cy^Ais 4-methoxypyridin-3-yl.

In some embodiments, R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NOR^a2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹.

In some embodiments, each R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹.

In some embodiments, each R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, and NR^c2C(O)OR^a2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹.

In some embodiments, each R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, and OR^a2.

In some embodiments, each R²⁰is independently selected from C_1-6alkyl and OR^a2.

In some embodiments, each R²⁰is independently selected from methyl and methoxy.

In some embodiments, provide herein is a compound of Formula II:

embedded image

or a pharmaceutically acceptable salt thereof, wherein R¹and Cy^Aare as defined herein.

In some embodiments, provide herein is a compound of Formula III:

embedded image

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or 4; and R²⁰and R¹are as defined herein.

In some embodiments, provide herein is a compound of Formula IV:

embedded image

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or 4; and R²⁰and R¹are as defined herein.

In some embodiments, provide herein is a compound of Formula IIIa or Formula IIIb:

embedded image

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or 4; and R²⁰, R^b, R^c, and R^dare as defined herein.

In some embodiments, provide herein is a compound of Formula IVa or Formula IVb:

embedded image

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or 4; and R²⁰, R^b, R^c, and R^dare as defined herein.

In some embodiments: wherein:

R¹is selected from C_2-6alkynyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^jR^k, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NOR^a)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)₂R^b, S(O)NR^cR^d, and S(O)₂NR^cR^d; wherein said C_2-6alkynyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

Cy^Ais phenyl a fused with a 5-6 membered heterocycloalkyl ring; wherein the fused 5-6 membered heterocycloalkyl ring comprises ring-forming carbon atoms and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of the fused 5-6 membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group; wherein the fused 5-6 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R²¹; wherein the phenyl portion of Cy^Ais further optionally substituted with 1, 2 or 3 substituents independently selected from R²⁰; and wherein Cy^Ais attached to the pyrrazolopyridine core through the phenyl portion;

each R¹⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, C(═NR^e1)R^b1, C(═NOR^a1)R^b1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹²;

each R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NOR^a2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹;

each R³⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c(O)OR^a8, NR^c8S(O)R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, and S(O)₂NR^c8R^d8; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 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;

R^bis selected from C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

each R^a1, R^c1and R^d1is independently selected from H, C_2-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_2-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹;

In some embodiments:

R¹is selected from CN, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^jR^k, NR^cC(O)R^b, and NR^cC(O)OR^a;

Cy^Ais 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more ring-forming carbon atoms and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a carbon atom of 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from R²⁰;

R²is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, OR^a7, SR^a7, C(O)R^b7, C(O)NR^c7R^d7, C(O)OR^a7, NR^c7R^d7, NR^c7C(O)R^b7, and NR^c7C(O)OR^a7; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1 or 2;

each R¹⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, and NR^c1C(O)OR^a1; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹;

each R¹¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, NR^c3R^d3, NR^c3C(O)R^b3, and NR^c3C(O)OR^a3; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹²;

each R¹²is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, and NR^c5C(O)OR^a5;

each R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, and NR^c2C(O)OR^a2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R²¹;

each R²¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, and NR^c4C(O)OR^a4; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²²;

each R²²is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, NR^c6R^d6, NR^c6C(O)R^b6, and NR^c6C(O)OR^a6;

each R^a, R^cand R^dis independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰;

R^bis selected from C_6-10aryl and 5-10 membered heteroaryl; wherein said C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰;

R^jis selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

R^kis selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^a1, R^c1and R^d1is independently selected from H, C_2-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_2-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹;

each R^a2, R^c2and R^d2, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^b2is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^a3, R^c3and R^d3, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^b3is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^a4, R^c4and R^d4, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^b4is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^a5, R^cS and R^d5, is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl;

each R^b5is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl;

each R^a6, R^c6and R^d6is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl;

each R^b6is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^a7, R^c7, and R^d7is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; and

each R^b7is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl.

In some embodiments:

R¹is selected from C(O)R^b, C(O)NR^cR^d, C(O)OR^a, and NR^cC(O)R^b;

Cy^Ais 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more ring-forming carbon atoms and 1, 2, or 3 ring-forming N heteroatoms; wherein the N is optionally oxidized; wherein a carbon atom of 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R²⁰;

R²is selected from H, C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl;

each R¹⁰is independently selected from 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, NR^c1R^d1, and NR^c1C(O)R^b1; wherein said 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R¹¹;

each R¹¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, OR^a3, C(O)NR^c3R^d3, C(O)OR^a3, and NR^c3R^d3;

each R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, and OR^a2;

each R^a, R^cand R^dis independently selected from H, C_1-6alkyl, C_6-10aryl and 5-10 membered heteroaryl; wherein said C_1-6alkyl, C_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R¹⁰;

R^bis C_6-10aryl; wherein said C_6-10aryl is optionally substituted with 1 or 2 substituents independently selected from R¹⁰;

each R^c1and R^d1is independently selected from H and C_2-6alkyl; wherein said C_2-6alkyl is optionally substituted with 1 or 2 substituents independently selected from R¹¹;

each R^b1is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl;

each R^a2is independently selected from H and C_1-6alkyl; and

each R^a3, R^c3and R^d3, is independently selected from H and C_1-6alkyl.

In some embodiments:

R¹is selected from C(O)NR^cR^dand NR^cC(O)R^b;

Cy^Ais 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more ring-forming carbon atoms and 1 or 2 ring-forming N heteroatoms; wherein the N is optionally oxidized; wherein a carbon atom of 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R²⁰;

R²is H;

each R¹⁰is independently selected from 4-10 membered heterocycloalkyl and NR^c1R^d1; wherein said 4-10 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R¹¹;

each R¹¹is independently selected from C_1-6alkyl, halo, OR^a3, C(O)OR^a3, and NR^c3R^d3;

each R²⁰is independently selected from C_1-6alkyl and OR^a2;

each R^cand R^dis independently selected from H and C_6-10aryl; wherein said C_6-10aryl is optionally substituted with 1 or 2 substituents independently selected from R¹⁰;

R^bis C_6-10aryl; wherein said C_6-10aryl is optionally substituted with 1 or 2 substituents independently selected from R¹⁰;

each R^c1and R^d1is independently selected from H and C_2-6alkyl; wherein said C_2-6alkyl is optionally substituted with 1 or 2 substituents independently selected from R¹¹;

each R^a2is independently selected from H and C_1-6alkyl; and

each R^a3, R^c3and R^d3, is independently selected from H and C_1-6alkyl.

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 “C_1-6alkyl” is specifically intended to individually disclose (without limitation) methyl, ethyl, C₃alkyl, C₄alkyl, C₅alkyl and C₆alkyl.

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(CR′R″)_n-includes both —NR(CR′R″)_n— and —(CR′R″)_nNR— 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 C_1-4, C_1-6and 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-malkyl”, 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, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-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-malkenyl” 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, n-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-malkynyl” refers to an alkynyl group having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-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-malkylene” refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl, propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-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-malkoxy” refers to an alkoxy group, the alkyl group of which has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-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 —NH₂.

The term “carbonyl,” employed alone or in combination with other terms, refers to a —C(═O)— 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, Cl, 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-mhaloalkyl” refers to a C_n-malkyl group having n to m carbon atoms and from at least one up to {2(n to m)+1}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, CCl₃, CHCl₂, C₂Cl₅and 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 “C_n-mhaloalkoxy” 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 (═O) 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 71 (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-maryl” 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. Examples of N-oxide heteroaryl include pyridine N-oxide, pyrimidine N-oxide, pyrazine N-oxide, quinoline N-oxide, etc. In some embodiments, any ring-forming S in a heteroaryl moiety can be S(O) or S(O)₂, e.g., thiophene oxide, thiophene dioxide, etc. 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, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]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 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-mcycloalkyl” 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 C_3-6monocyclic 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[1.1.1]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(O)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-oxopiperazin-1-yl, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, piperazinonyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, tropanyl, benzodioxole, 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 α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on a 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 (R)-configuration. In other embodiments, the compounds have the (S)-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.

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” 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^thEd., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 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^thEd. (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., ¹H or ¹³C), 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 (Ia) (compounds of Formula I wherein R¹is C(O)NR^cR^d) can be prepared, using a process as illustrated in Scheme 1. In the process depicted in Scheme 1, compounds of formula 1-2 is formed after protection of the NH group of the compounds of formula 1-1 with a suitable protecting group (e.g. SEM or Boc). The chloro substituent in the compounds of formula 1-2 can be converted into Cy^Avia 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(0) 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. Th compounds of formula 1-6 are converted into compounds of formula 1-7 under Pd-catalyzed carbonylation conditions, such as in a presence of Pd catalyst (e.g., Pd(dppf)Cl₂*DCM) and base (e.g., triethylamine) under carbon monoxide atmosphere. Hydrolysis of the ester group under basic conditions, such as LiOH or NaOH, forms the compounds of formula 1-8. Compounds of the formula 1-8 can be coupled to an amine, HNR^cR^d, using standard amide coupling agents (e.g., HBTU, HATU or EDC) to give compounds of formula 1-9. 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 (Ia).

embedded image

Compounds of formula (Ib) (compounds of Formula I wherein R¹is NR^cC(O)R^b) can be prepared, using a process as illustrated in Scheme 2. In the process depicted in Scheme 2, compounds of formula 2-1 react which hydroxylamine hydrochloride to form oxime intermediates, which are further converted to compounds of formula 2-2 under the standart conditions (e.g. under treatment with cyanuric chloride). Cyclization upon treatment of the compounds of formula 2-2 with hydrazine hydrate results in compounds of formula 2-3. The NH group of the pyrazole ring of the compounds of formula 2-3 is protected with a suitable protecting group (e.g., Boc) to form compounds of formula 2-4. The halo substituent in the compounds of formula 2-4 can be further converted into Cy^Avia a number of different cross-coupling reactions, including Suzuki, Stille, and others, to give the compounds of formula 2-5. Compounds of formula 2-5 react with different acid chlorides in a presence of base, such as triethylamine or DIPEA, to form compounds of formula 2-6. 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 (Ib). Alternatively compounds of formula 2-6 can be alkylated or arylated and then deprotected to prepare amides wherein R^cis other than hydrogen.

embedded image

HPK1 Kinase

Extensive studies have established that HPK1 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). HPK1-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, HPK1 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, HPK1 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 HPK1 phosphorylates SLP-76 on Ser376 or BLNK on Thr152, 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 Cγ1, calcium flux, and NFAT activation), HPK1-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 HPK1 knockout mice showed higher expression of co-stimulatory molecules (e.g. CD80/CD86) and enhanced production of proinflammatory cytokines (IL-12, TNF-α 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 HPK1 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, HPK1 appears to be a positive regulator of suppressive functions of regulatory T cells (Treg) (Sawasdikosol, S. et al., The journal of immunology, 2012. 188 (supplement 1): p. 163). HPK1 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., The Journal of Immunology, 2012. 188 (supplement 1): p. 163). These data suggest that HPK1 is an important regulator of Treg functions and peripheral self-tolerance.

HPK1 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 HPK1 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 HPK1 deficient T cells was resistant to the suppressive effects of PGE2 (see US 2007/0087988). Therefore, PGE2-mediated activation of HPK1 may represent a novel regulatory pathway of modulating immune response.

Uses of the Compounds

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 promyelocytic 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, 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 promonocytic 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: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, 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, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio1347, INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib or 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. Inhibitors of c-Met such as onartumzumab, tivantnib, and INC-280. Inhibitors of BTK such as ibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus. Inhibitors of Raf, such as vemurafenib and dabrafenib. Inhibitors of MEK such as trametinib, selumetinib and GDC-0973. 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 CD27, CD28, CD39, CD40, CD122, 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, TIM3, 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, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 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-PD1 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-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 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 CSF1R, 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.

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 (Cytoxan™), 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, PAK1, PAK2, PAK3, PAK4, PDKi, 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 gp100, 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 (NRTIs), 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 NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC1-675451) 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 or injection 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 PH102™. 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 KOOLV™).

In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).

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.

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 labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating HPK1 protein in tissue samples, including human. Accordingly, the present invention includes HPK1 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 an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). 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). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. 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 ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. 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 HPK1 protein by monitoring its concentration variation when contacting with the HPK1, 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 HPK1 protein (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the HPK1 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 HPK1, 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 HPK1 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 separated compounds 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 μm particle size, 2.1×5.0 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™ C₁₈5 μm particle size, 19×100 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 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈5 μm particle size, 19×100 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 30×100 mm column was 60 mL/minute.

Example 1. N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide

embedded image

Step 1. 2-Bromo-5-fluoroisonicotinonitrile

embedded image

Hydroxylamine hydrochloride (2.73 g, 39.2 mmol) was added to a solution of 2-bromo-5-fluoroisonicotinaldehyde (Combi-Blocks, 2.0 g, 9.80 mmol) in 2-propanol (19.61 mL). The reaction mixture was refluxed for 2 h, then the solvent was removed in vacuo. The residue was redissolved in EtOAc. The organic phase was washed with saturated NaHCO₃solution, brine and was dried over sodium sulfate. The solvent was evaporated in vacuo to give the oxime.

Cyanuric chloride (2.41 g, 13.04 mmol) was slowly added to DMF (19.61 mL) at 0° C. After it was completely dissolved, obtained oxime was slowly added at 0° C. to this solution and the reaction was stirred at r.t. for 1 h. Then the reaction was quenched with water. The product was extracted with ethyl acetate and the organic phase was washed with brine. The organic phase was dried over sodium sulfate and the solvents were evaporated under reduced pressure. Obtained crude product was used in the next step without further purification (1 g, 51%).

Step 2. 5-Bromo-1H-pyrazolo[3,4-c]pyridin-3-amine

embedded image

Water solution of hydrazine (0.6 mL, 10 mmol) was added to a solution of 2-bromo-5-fluoroisonicotinonitrile (1.0 g, 4.98 mmol) in ethanol (15 mL). After stirring at reflux for 2 h, the solvent was evaporated and the obtained crude product was used in the next step without further purification. LCMS calculated for C₆H₆BrN₄(M+H)⁺ m/z=213.0; found 213.1.

Step 3. tert-Butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

embedded image

Di-tert-butyl dicarbonate (1.127 g, 5.16 mmol) was added to a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridin-3-amine (1.0 g, 4.69 mmol) and triethylamine (0.785 mL, 5.63 mmol) in CH₂Cl₂(15 mL). After stirring at r.t. for 1 h., water was added and product was extracted with DCM. The organic phase was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and obtained crude product was purified by Biotage Isolera™ (1.4 g, 87%). LCMS calculated for C₁₁H₁₄BrN₄O₂(M+H)⁺ m/z=313.0; found 313.0.

Step 4. tert-Butyl 3-amino-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

embedded image

tert-Butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.0 g, 3.19 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.05 g, 4.79 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (0.251 g, 0.319 mmol) and potassium phosphate (1.356 g, 6.39 mmol) were placed in a flask and the flask was evacuated and backfilled with nitrogen three times. Then dioxane (20 mL) and degassed water (2 mL) were added and reaction was stirred at 90° C. for 2 h. After cooling to r.t., the reaction mixture was diluted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure and obtained crude product was purified by Biotage Isolera™ (890 mg, 86%). LCMS calculated for C₁₇H₂₀N₅O₂(M+H)⁺ m/z=326.2; found 326.1.

Step 5. tert-Butyl 3-(4-bromobenzamido)-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

embedded image

4-Bromobenzoyl chloride (206 mg, 0.939 mmol) was added to a solution of tert-butyl 3-amino-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (278 mg, 0.854 mmol) and DIPEA (224 μL, 1.281 mmol) in THF (6 mL). The reaction mixture was stirred at 60° C. for 2 h. Then methanol (1 mL) was added and the solvents were evaporated in vacuo. Obtained crude product was purified by Biotage Isolera™ (204 mg, 47%). LCMS calculated for C₂₄H₂₃BrN₅O₃(M+H)⁺: m/z=508.1/510.1; Found: 508.1/510.1.

Step 6. N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide

embedded image

tert-Butyl 3-(4-bromobenzamido)-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (14 mg, 0.028 mmol), morpholine (3.62 mg, 0.042 mmol), cesium carbonate (18.1 mg, 0.055 mmol) and chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (RuPhos Pd G2, 2.2 mg, 2.77 μmol) were placed in a vial and the vial was evacuated and backfilled with nitrogen three times. Then dioxane (2 mL) was added and the reaction mixture was stirred at 100° C. for 2 h. Then it was cooled down to r.t., solids were filtered off and the solvent was evaporated in vacuo.

DCM (1 mL) and trifluoroacetic acid (1 mL) were added to the obtained residue and the reaction was stirred at r.t. for 1 h. The reaction mixture was then diluted with acetonitrile and was purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₃H₂₃N₆O₂(M+H)⁺: m/z=415.2; Found: 415.3.

1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.14 (d, J=1.1 Hz, 1H), 8.77 (s, 1H), 8.65 (s, 1H), 8.11-7.97 (m, 3H), 7.72 (d, J=5.2 Hz, 1H), 7.04 (d, J=9.0 Hz, 2H), 3.81-3.66 (m, 4H), 3.36-3.12 (m, 4H), 2.52 (s, 3H) ppm.

Example 2. 4-(4-Methylpiperazin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

embedded image

This compound was prepared according to the procedures described in Example 1, using 1-methylpiperazine instead of morpholine as starting material. LCMS calculated for C₂₄H₂₆N₇O (M+H)⁺: m/z=428.2; Found: 428.2.

Example 3. Ethyl 4-(4-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate

embedded image

This compound was prepared according to the procedures described in Example 1, using ethyl piperazine-1-carboxylate instead of morpholine as starting material. LCMS calculated for C₂₆H₂₈N₇O₃(M+H)⁺: m/z=486.2; Found: 486.2.

Example 4. 4-(4-Methoxypiperidin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

embedded image

This compound was prepared according to the procedures described in Example 1, using 4-methoxypiperidine instead of morpholine as starting material. LCMS calculated for C₂₅H₂₇N₆O₂(M+H)⁺: m/z=443.2; Found: 443.2.

Example 5. 4-(3-Aminopiperidin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

embedded image

This compound was prepared according to the procedures described in Example 1, using tert-butyl piperidin-3-ylcarbamate instead of morpholine as starting material. LCMS calculated for C₂₄H₂₆N₇O (M+H)⁺: m/z=428.2; Found: 428.2.

Example 6. N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide

embedded image

Step 1. tert-Butyl 3-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

embedded image

tert-Butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (Example 1, Step 3, 1.0 g, 3.19 mmol), 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.06 g, 4.79 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (0.251 g, 0.319 mmol) and potassium phosphate (1.356 g, 6.39 mmol) were placed in a flask and the flask was evacuated and backfilled with nitrogen three times. Then dioxane (20 mL) and degassed water (2 mL) were added and reaction was stirred at 90° C. for 2 h. After cooling to r.t., the reaction mixture was diluted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure and obtained crude product was purified by Biotage Isolera™ (809 mg, 77%). LCMS calculated for C₁₆H₂₁N₆O₂(M+H)⁺ m/z=329.2; found 329.2.

Step 2. tert-Butyl 3-(4-bromobenzamido)-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

embedded image

4-Bromobenzoyl chloride (206 mg, 0.939 mmol) was added to a solution of tert-butyl 3-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (281 mg, 0.854 mmol) and DIPEA (224 μL, 1.281 mmol) in THF (6 mL). The reaction mixture was stirred at 60° C. for 2 h. Then methanol (1 mL) was added and the solvents were evaporated in vacuo. Obtained crude product was purified by Biotage Isolera™ (204 mg, 38%). LCMS calculated for C₂₃H₂₄BrN₆O₃(M+H)⁺: m/z=511.1; Found: 511.1.

Step 3. N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide

embedded image

tert-Butyl 3-(4-bromobenzamido)-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (14 mg, 0.028 mmol), morpholine (3.62 mg, 0.042 mmol), cesium carbonate (18.1 mg, 0.055 mmol) and chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (RuPhos Pd G2, 2.2 mg, 2.77 μmol) were placed in a vial and the vial was evacuated and backfilled with nitrogen three times. Then dioxane (2 mL) was added and the reaction mixture was stirred at 100° C. for 2 h. Then it was cooled down to r.t., solids were filtered off and the solvent was evaporated in vacuo.

DCM (1 mL) and trifluoroacetic acid (1 mL) were added to the obtained residue and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was then diluted with acetonitrile and was purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₂H₂₄N₇O₂(M+H)⁺: m/z=418.2; Found: 418.3.

Example 7. N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

embedded image

This compound was prepared according to the procedures described in Example 6, using 1-methylpiperazine instead of morpholine as starting material. LCMS calculated for C₂₃H₂₇N₈O (M+H)⁺: m/z=431.2; Found: 431.3.

Example 8. Ethyl 4-(4-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate

embedded image

This compound was prepared according to the procedures described in Example 6, using ethyl piperazine-1-carboxylate instead of morpholine as starting material. LCMS calculated for C₂₅H₂₉N₈O₃(M+H)⁺: m/z=489.2; Found: 489.3.

Example 9. N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-meth oxypiperidin-1-yl)benzamide

embedded image

This compound was prepared according to the procedures described in Example 6, using 4-methoxypiperidine instead of morpholine as starting material. LCMS calculated for C₂₄H₂₈N₇O₂(M+H)⁺: m/z=446.2; Found: 446.3.

Example 10. N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(3-meth oxypiperidin-1-yl)benzamide

embedded image

This compound was prepared according to the procedures described in Example 6, using 3-methoxypiperidine instead of morpholine as starting material. LCMS calculated for C₂₄H₂₈N₇O₂(M+H)⁺: m/z=446.2; Found: 446.3.

Example 11. N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(propylamino)benzamide

embedded image

This compound was prepared according to the procedures described in Example 6, using propan-1-amine instead of morpholine as starting material. LCMS calculated for C₂₁H₂₄N₇O (M+H)⁺: m/z=390.2; Found: 390.3.

Example 12. N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(2-methoxyethylamino)benzamide

embedded image

This compound was prepared according to the procedures described in Example 6, using 2-methoxyethanamine instead of morpholine as starting material. LCMS calculated for C₂₁H₂₄N₇O₂(M+H)⁺: m/z=406.2; Found: 406.3.

Example 13. 4-(3,3-Difluoropyrrolidin-1-yl)-N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

embedded image

This compound was prepared according to the procedures described in Example 6, using 3,3-difluoropyrrolidine instead of morpholine as starting material. LCMS calculated for C₂₂H₂₂F₂N₇O (M+H)⁺: m/z=438.2; Found: 438.3.

Example 14. N-(5-(4-methoxypyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

embedded image

Step 1. tert-Butyl 3-amino-5-(4-methoxypyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

embedded image

tert-Butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (Example 1, Step 3, 50 mg, 0.160 mmol), 4-methoxypyridin-3-ylboronic acid (49 mg, 0.319 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (12 mg, 0.016 mmol) and potassium phosphate (85 mg, 0.40 mmol) were placed in a flask and the flask was evacuated and backfilled with nitrogen three times. Then dioxane (1 mL) and degassed water (0.2 mL) were added and reaction was stirred at 90° C. for 2 h. After cooling to r.t., the reaction mixture was diluted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure and obtained crude product was purified by Biotage Isolera™. LCMS calculated for C₁₇H₂₀N₅O₃(M+H)⁺ m/z=342.2; found 342.2.

Step 2. N-(5-(4-methoxypyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

embedded image

To a suspension of 4-(4-methylpiperazin-1-yl)benzoic acid (70.4 mg, 0.320 mmol) in DCM (800 μL) were added DMF (1.2 μL) and oxalyl chloride (28.0 μl, 0.320 mmol). The resulting orange suspension was stirred at r.t. for 1 hr. This solution was then added to a solution of tert-butyl 3-amino-5-(4-methoxypyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (52 mg, 0.152 mmol) and Hunig's base (84 μL, 0.479 mmol) in THF (800 μL).

The resulting mixture was heated to 70 degrees for 1 hr, then cooled to r.t., and quenched with water. The mixture was extracted with ethyl acetate and the organic layer dried over sodium sulfate and concentrated. The residue was then dissolved in DCM (1 mL) and TFA (1 mL), then stirred at r.t. for 30 mins, diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₄H₂₆N₇O₂(M+H)⁺ m/z=444.2; found 444.2.

Example 15. N-(4-(4-methylpiperazin-1-yl)phenyl)-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

embedded image

Step 1. 5-Chloro-3-iodo-1-((2-(trimethysilyl)ethoxy)methyl)-H-pyrazolo[3,4-c]pyridine

embedded image

To a suspension of 5-chloro-1H-pyrazolo[3,4-c]pyridine (1.5 g, 9.77 mmol) in acetonitrile (20 mL) was added NIS (2.2 g, 9.77 mmol) and the reaction mixture heated to 80° C. for 1 hour. It was then cooled to r.t. Hunig's base (3.41 mL, 19.54 mmol) and SEM-Cl (2.60 mL, 14.65 mmol) were added and the resulting reaction mixture was stirred at r.t. for 30 mins, then concentrated and purified by Biotage Isolera™ (0-75% ethyl acetate in hexanes) to provide the desired product as an orange solid. LCMS calculated for C₁₂H₁₈ClIN₃OSi (M+H)⁺: m/z=410.0; Found: 410.0.

Step 2. Ethyl 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

embedded image

5-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (3.157 g, 7.71 mmol) was dissolved in DMF (12 mL) and ethanol (8 mL). Triethylamine (3.22 mL, 23.12 mmol) was added followed by [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.629 g, 0.771 mmol). The reaction flask was evacuated and back filled with CO gas from a balloon. The resulting solution was then stirred at 80° C. overnight. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by Biotage Isolera™ (0-75% ethyl acetate in hexanes) to provide the desired product as a pale yellow oil. LCMS calculated for C₁₅H₂₃ClN₃O₃Si (M+H)⁺: m/z=356.1; Found: 356.1.

Step 3. 5-Chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

embedded image

To a mixture of ethyl 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (82 mg, 0.230 mmol) and 4-(4-methylpiperazin-1-yl)aniline (88 mg, 0.461 mmol) in THF (1.2 mL) was added potassium tert-butoxide solution (1 M in THF, 922 μl, 0.922 mmol) and the reaction mixture stirred at r.t. for 30 mins. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by Biotage Isolera™ (2-10% methanol in DCM) to provide the desired product as a brown oil. LCMS calculated for C₂₄H₃₄ClN₆O₂Si (M+H)⁺: m/z=501.2; Found: 501.2.

Step 4. N-(4-(4-methylpiperazin-1-yl)phenyl)-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

embedded image

To a mixture of 5-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (28 mg, 0.056 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (24.5 mg, 0.112 mmol), XPhos Pd G2 (4.40 mg, 5.59 μmol) and potassium phosphate, tribasic (23.72 mg, 0.112 mmol) were added 1,4-dioxane (0.5 mL) and water (0.1 mL). The resulting reaction mixture was evacuated, back filled with nitrogen, then stirred at 80 degrees overnight. The mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in methanol (1 mL) and 4N solution of HCl in dioxane (1 mL) and stirred at 80 degrees for 30 mins. The resulting mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₄H₂₆N₇O (M+H)⁺: m/z=428.2; Found: 428.2.

Example 16. 5-(4-Methoxypyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

embedded image

This compound was prepared according to the procedures described in Example 15, using 4-methoxypyridin-3-ylboronic acid as the coupling partner in step 4. LCMS calculated for C₂₄H₂₆N₇O₂(M+H)⁺: m/z=444.2; Found: 444.2.

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 μL 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 MgCl₂, 0.01% BSA, and 5 mM DTT. 5 μl 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 μl 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≤2000 nM.

TABLE 1

Example
HPK1 Ki, nM

1
+

2
+

3
+

4
+

5
+

6
+

7
+

8
+

9
+

10
+

11
+

12
+

13
+

14
+

15
+

16
+

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 3×10⁶cells/ml. The Jurkat cells (35 ul) are dispensed into each well in a 384 well plate. Test compounds are diluted with cell culture media for 40-fold dilution (adding 39 ul cell culture media into 1 ul compound). The Jurkat cells in the well plate are treated with the test compounds at various concentrations (adding 5 ul diluted compound into 35 ul Jurkat cells and starting from 3 uM with 1:3 dilution) for 1 hour at 37° C., 5% CO₂), followed by treatment with anti-CD3 (5 ug/ml, OKT3 clone) for 30 min. A 1:25 dilution of 100× blocking reagent (from p-SLP76 ser376HTRF kit) with 4× Lysis Buffer (LB) is prepared and 15 ul of the 4×LB buffer with blocking reagent is added into each well and incubated at room temperature for 45 mins with gentle shaking. The cell lysate (16 ul) is added into a Greiner white plate, treated with p-SLP76 ser376HTRF reagents (2 ul donor, 2 ul acceptor) and incubated at 4° C. for overnight. The homogeneous time resolved fluorescence (HTRF) is measured on a PHERAstar plate reader the next day. IC₅₀determination is performed by fitting the curve of percent inhibition versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.

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.

Claims

1. A compound of Formula I:
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is C(O)NRcRd.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is NRcC(O)Rb.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rb is phenyl optionally substituted with 1 or 2 substituents independently selected from R10.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein CyA is pyridyl or pyrazolyl; wherein said pyridyl and pyrazolyl are each optionally substituted with 1 or 2 substituents independently selected from R20.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R20 is independently selected from C1-6 alkyl.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R20 is ORa2.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R20 is independently selected from methyl and methoxy.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein CyA is 4-methylpyridin-3-yl, 1,5-dimethyl-1H-pyrazol-4-yl, or 4-methoxypyridin-3-yl.
10. The compound of claim 1 having Formula III:
11. The compound of claim 1 having Formula IV:
12. The compound of claim 1 having Formula Ma or Formula IIIb:
13. The compound of claim 1 having Formula IVa or Formula IVb:
14. The compound of claim 1 selected from: N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide;4-(4-Methylpiperazin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide;Ethyl 4-(4-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate;4-(4-Methoxypiperidin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide;4-(3-Aminopiperidin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide;N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide;N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide;Ethyl 4-(4-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate;N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methoxypiperidin-1-yl)benzamide;N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(3-methoxypiperidin-1-yl)benzamide;N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(propylamino)benzamide;N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(2-methoxyethylamino)benzamide;4-(3,3-Difluoropyrrolidin-1-yl)-N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide;N-(5-(4-methoxypyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide;N-(4-(4-methylpiperazin-1-yl)phenyl)-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; and5-(4-Methoxypyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
16. A method of inhibiting HPK1 activity, said method comprising administering to a patient a compound of claim 1, or a pharmaceutically acceptable salt thereof.

US Referenced Citations (105)

Number	Name	Date	Kind
5250534	Bell et al.	Oct 1993	A
6200980	Piazza et al.	Mar 2001	B1
6333330	Bunnage et al.	Dec 2001	B1
6458951	Bunnage et al.	Oct 2002	B1
6512002	Lee et al.	Jan 2003	B2
6670366	Bunnage et al.	Dec 2003	B1
6743799	Westbrook et al.	Jun 2004	B2
6756373	Allerton et al.	Jun 2004	B1
6770645	Denton et al.	Aug 2004	B2
6784185	Allerton et al.	Aug 2004	B2
6916927	Bunnage et al.	Jul 2005	B2
7105532	Rawlings	Sep 2006	B2
7166293	Teng et al.	Jan 2007	B2
7259165	Bernotas et al.	Aug 2007	B2
7345178	Nunes et al.	Mar 2008	B2
7576087	Bernotas et al.	Aug 2009	B2
7919487	Sun et al.	Apr 2011	B2
7968719	Zoller et al.	Jun 2011	B2
8106190	Kuramochi et al.	Jan 2012	B2
8450335	Singh et al.	May 2013	B2
8546403	Whitten et al.	Oct 2013	B2
8637507	Zhou et al.	Jan 2014	B2
8722691	He et al.	Mar 2014	B2
8987273	Rehwinkel et al.	Mar 2015	B2
9090593	Wang et al.	Jul 2015	B2
9260425	Do et al.	Feb 2016	B2
9284319	Eis et al.	Mar 2016	B2
9320737	Eis et al.	Apr 2016	B2
9718818	DeMong et al.	Aug 2017	B2
9730929	Eis et al.	Aug 2017	B2
10266530	Vechorkin et al.	Apr 2019	B2
10280164	Ye et al.	May 2019	B2
10435405	Vechorkin et al.	Oct 2019	B2
10722495	Vechorkin et al.	Jul 2020	B2
10745388	Vechorkin et al.	Aug 2020	B2
10752635	Sokolsky et al.	Aug 2020	B2
10800761	Vechorkin et al.	Oct 2020	B2
10899755	Hummel et al.	Jan 2021	B2
20020013327	Lee et al.	Jan 2002	A1
20030162782	Grossman et al.	Aug 2003	A1
20030186996	Teng et al.	Oct 2003	A1
20040063730	Eggenweiler et al.	Apr 2004	A1
20040077681	Rawlings et al.	Apr 2004	A1
20040147546	Tanaka et al.	Jul 2004	A1
20040157866	Takasugi et al.	Aug 2004	A1
20040167030	Bernotas et al.	Aug 2004	A1
20040204417	Perez et al.	Oct 2004	A1
20050070557	Fryburg et al.	Mar 2005	A1
20050075795	Pandit	Apr 2005	A1
20050119278	Teng et al.	Jun 2005	A1
20050137226	Ji et al.	Jun 2005	A1
20050208582	Ohi et al.	Sep 2005	A1
20050261339	Ohi et al.	Nov 2005	A1
20060106032	Kuo et al.	May 2006	A1
20070087988	Sawasdikosol et al.	Apr 2007	A1
20070161673	Barker et al.	Jul 2007	A1
20070185152	Yamashita et al.	Aug 2007	A1
20070270412	Bell et al.	Nov 2007	A1
20080280891	Kelly et al.	Nov 2008	A1
20100035891	Bunnage et al.	Feb 2010	A1
20100087464	Mi et al.	Apr 2010	A1
20100216798	Nakai et al.	Aug 2010	A1
20120129852	Duan et al.	May 2012	A1
20120225869	Liu et al.	Sep 2012	A1
20120295884	Altmann et al.	Nov 2012	A1
20130039906	Do et al.	Feb 2013	A1
20130040949	Gray et al.	Feb 2013	A1
20130281433	Babaoglu et al.	Oct 2013	A1
20140225073	Lee et al.	Aug 2014	A1
20140249135	Burger et al.	Sep 2014	A1
20140288045	Ren et al.	Sep 2014	A1
20140288069	Eis et al.	Sep 2014	A1
20140350017	Williams et al.	Nov 2014	A1
20140364605	Li et al.	Dec 2014	A1
20150038485	Eis et al.	Feb 2015	A1
20150191462	Hommel et al.	Jul 2015	A1
20150239868	Pais et al.	Aug 2015	A1
20150239889	Nakajima et al.	Aug 2015	A1
20150243908	Lee et al.	Aug 2015	A1
20150274639	Williams et al.	Oct 2015	A1
20150328188	Orlemans et al.	Nov 2015	A1
20160013427	Kim et al.	Jan 2016	A1
20160046648	Petrukhin et al.	Feb 2016	A1
20160068529	KC et al.	Mar 2016	A1
20160068547	KC et al.	Mar 2016	A1
20160068548	KC et al.	Mar 2016	A1
20160068551	KC et al.	Mar 2016	A1
20160200722	DeMong et al.	Jul 2016	A1
20180072718	Liu et al.	Mar 2018	A1
20180072719	Ye et al.	Mar 2018	A1
20180072720	Vechorkin et al.	Mar 2018	A1
20180072741	Vechorkin et al.	Mar 2018	A1
20180228786	Sokolsky	Aug 2018	A1
20190076401	Vechorkin et al.	Mar 2019	A1
20190106419	Vechorkin et al.	Apr 2019	A1
20190256500	Vechorkin et al.	Aug 2019	A1
20190256520	Sokolsky	Aug 2019	A1
20190315717	Hummel et al.	Oct 2019	A1
20190315743	Liu et al.	Oct 2019	A1
20190382380	Vechorkin et al.	Dec 2019	A1
20200048241	Hummel et al.	Feb 2020	A1
20200087301	Vechorkin et al.	Mar 2020	A1
20200172545	Vechorkin et al.	Jun 2020	A1
20200283434	Liu et al.	Sep 2020	A1
20210002288	Sokolsky	Jan 2021	A1

Foreign Referenced Citations (177)

Number	Date	Country
102206172	Oct 2011	CN
102503959	Jun 2012	CN
102516263	Jun 2012	CN
103570709	Feb 2014	CN
10 2004 054 666	May 2006	DE
2543372	Jan 2013	EP
2824099	Jan 2015	EP
187433	Apr 2002	IN
H03287584	Dec 1991	JP
2000-038350	Feb 2000	JP
2007-055940	Mar 2007	JP
2010-111624	May 2010	JP
2011-246389	Dec 2011	JP
963644	Feb 1996	KR
10 2014 0019055	Feb 2014	KR
9910322	Jul 2003	MX
146643	Sep 2012	MY
WO 1989008263	Sep 1989	WO
WO 2000043394	Jul 2000	WO
WO 2001019827	Mar 2001	WO
WO 2001019828	Mar 2001	WO
WO 2001021576	Mar 2001	WO
WO 2001046124	Jun 2001	WO
WO 2002000196	Jan 2002	WO
WO 2002016348	Feb 2002	WO
WO 2002019975	Mar 2002	WO
WO 2002050073	Jun 2002	WO
WO 2002090347	Nov 2002	WO
WO 2003037432	May 2003	WO
WO 2003049681	Jun 2003	WO
WO 2004072069	Aug 2004	WO
WO 2004096810	Nov 2004	WO
WO 2004108133	Dec 2004	WO
WO 2005004799	Jan 2005	WO
WO 2005011681	Feb 2005	WO
WO 2005028475	Mar 2005	WO
WO 2005051906	Jun 2005	WO
WO 2005066167	Jul 2005	WO
WO 2005073199	Aug 2005	WO
WO 2005073232	Aug 2005	WO
WO 2003101968	Sep 2005	WO
WO 2005085227	Sep 2005	WO
WO 2005085248	Sep 2005	WO
WO 2005085249	Sep 2005	WO
WO 2006013095	Feb 2006	WO
WO 2006028958	Mar 2006	WO
WO 2006038001	Apr 2006	WO
WO 2006045010	Apr 2006	WO
WO 2006050097	May 2006	WO
WO 2006053109	May 2006	WO
WO 2006053121	May 2006	WO
WO 2006053227	May 2006	WO
WO 2006074428	Jul 2006	WO
WO 2006105289	Oct 2006	WO
WO 2006128172	Nov 2006	WO
WO 2007019344	Feb 2007	WO
WO 2007019345	Feb 2007	WO
WO 2007019346	Feb 2007	WO
WO 2007019417	Feb 2007	WO
WO 2007020050	Feb 2007	WO
WO 2007023110	Mar 2007	WO
WO 2007023111	Mar 2007	WO
WO 2007023114	Mar 2007	WO
WO 2007030582	Mar 2007	WO
WO 2007056280	May 2007	WO
WO 2007063925	Jun 2007	WO
WO 2007065924	Jun 2007	WO
WO 2007080382	Jul 2007	WO
WO 2007093402	Aug 2007	WO
WO 2007112093	Oct 2007	WO
WO 2007114848	Oct 2007	WO
WO 2007137030	Nov 2007	WO
WO 2008008059	Jan 2008	WO
WO 2008008539	Jan 2008	WO
WO 2008012027	Jan 2008	WO
WO 2008045627	Apr 2008	WO
WO 2008070313	Jun 2008	WO
WO 2008089307	Jul 2008	WO
WO 2008089310	Jul 2008	WO
WO 2008113856	Sep 2008	WO
WO 2009019167	Feb 2009	WO
WO 2009024341	Feb 2009	WO
WO 2009032651	Mar 2009	WO
WO 2009038784	Mar 2009	WO
WO 2009058348	May 2009	WO
WO 2009100130	Aug 2009	WO
WO 2009139834	Nov 2009	WO
WO 2009152356	Dec 2009	WO
WO 2010029300	Mar 2010	WO
WO 2010035217	Apr 2010	WO
WO 2010035219	Apr 2010	WO
WO 2010035221	Apr 2010	WO
WO 2010046780	Apr 2010	WO
WO 2010080503	Jul 2010	WO
WO 2010104306	Sep 2010	WO
WO 2010107765	Sep 2010	WO
WO 2010107768	Sep 2010	WO
WO 2010111624	Sep 2010	WO
WO 2010118367	Oct 2010	WO
WO 2011019780	Feb 2011	WO
WO 2011031628	Mar 2011	WO
WO 2011050245	Apr 2011	WO
WO 2011051535	May 2011	WO
WO 2011062253	May 2011	WO
WO 2011078143	Jun 2011	WO
WO 2011082400	Jul 2011	WO
WO 2011082488	Jul 2011	WO
WO 2011107186	Sep 2011	WO
WO 2011133920	Oct 2011	WO
WO 2011139489	Nov 2011	WO
WO 2011141756	Nov 2011	WO
WO 2011147765	Dec 2011	WO
WO 2011153553	Dec 2011	WO
WO 2011157653	Dec 2011	WO
WO 2011158108	Dec 2011	WO
WO 2012048058	Apr 2012	WO
WO 2012049277	Apr 2012	WO
WO 2012078777	Jun 2012	WO
WO 2012080376	Jun 2012	WO
WO 2012109263	Aug 2012	WO
WO 2012130780	Oct 2012	WO
WO 2012141487	Oct 2012	WO
WO 2012143144	Oct 2012	WO
WO 2012158810	Nov 2012	WO
WO 2012163959	Dec 2012	WO
WO 2013007708	Jan 2013	WO
WO 2013021276	Feb 2013	WO
WO 2013024002	Feb 2013	WO
WO 2013024011	Feb 2013	WO
WO 2013042137	Mar 2013	WO
WO 2013064445	May 2013	WO
WO 2013123215	Aug 2013	WO
WO 2013130890	Sep 2013	WO
WO 2013146942	Oct 2013	WO
WO 2014003405	Jan 2014	WO
WO 2014024125	Feb 2014	WO
WO 2014047616	Mar 2014	WO
WO 2014055955	Apr 2014	WO
WO 2014151616	Sep 2014	WO
WO 2015026683	Feb 2015	WO
WO 2015037965	Mar 2015	WO
WO 2015038503	Mar 2015	WO
WO 2015058163	Apr 2015	WO
WO 2015061247	Apr 2015	WO
WO 2015089327	Jun 2015	WO
WO 2015089479	Jun 2015	WO
WO 2015090235	Jun 2015	WO
WO 2015091426	Jun 2015	WO
WO 2015104662	Jul 2015	WO
WO 2015117718	Aug 2015	WO
WO 2015164956	Nov 2015	WO
WO 2015192939	Dec 2015	WO
WO 2015193506	Dec 2015	WO
WO 2015193846	Dec 2015	WO
WO 2015200682	Dec 2015	WO
WO 2016040180	Mar 2016	WO
WO 2016040181	Mar 2016	WO
WO 2016041618	Mar 2016	WO
WO 2016057500	Apr 2016	WO
WO 2016083433	Jun 2016	WO
WO 2016090300	Jun 2016	WO
WO 2016124304	Aug 2016	WO
WO 2016144351	Sep 2016	WO
WO 2016144702	Sep 2016	WO
WO 2016164285	Oct 2016	WO
WO 2016174183	Nov 2016	WO
WO 2016205942	Dec 2016	WO
WO 2017009798	Jan 2017	WO
WO 2017009806	Jan 2017	WO
WO 2017023894	Feb 2017	WO
WO 2017023972	Feb 2017	WO
WO 2017027400	Feb 2017	WO
WO 2017045955	Mar 2017	WO
WO 2017058915	Apr 2017	WO
WO 2017108744	Jun 2017	WO
WO 2019164846	Aug 2019	WO
2003005330	Jul 2003	ZA

Non-Patent Literature Citations (173)

Entry
Marc Thiriet “Intracellular Signaling Mediators in the Circulatory and Ventilatory Systems” Springer: New York 2013, pp. 180-182.
Boomer “Functional Interactions of HPK1 With Adaptor Proteins” Journal of Cellular Biochemistry 95:34-44 (2005) 34-44.
Sawasdikosol and Burakoff. “A perspective on HPK1 as a novel immuno-oncology drug target” eLife 2020;9:e55122.
Wang “HPK1 Expression in Estrogen Receptor-Positive IDC-NOS” Molecular Medicine Reports 16: 4634-4642, 2017.
Bae, Cancer Targeted Drug Delivery, Springer: New York, 2013, p. v.
Hayat, M.A. Autophagy Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging vol. 5 Academic Press: Sand Diego, 2015, p. xxi.
Carlo C. Maley and Mel Greaves Frontiers in Cancer Research Springer: 2016, pp. 18-19.
Sharma “Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents” Nature Reviews Cancer Apr. 2010, vol. 10, 241-253.
Ocana, A. “Preclinical development of molecular targeted agents for cancer” Nat. Rev. Clin. Oncol. 2011, 8, 200-209.
Johnson, et al. “Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials.” British Journal of Cancer 2001, 84, 1424-1431.
Ledford “US cancer institute overhauls cell lines” Nature Feb. 25, 2016 vol. 530 p. 391.
Benz “The Jeremiah Metzger Lecture Cancer in the Twenty-First Century: An Inside View from an Outsider” Transactions of The American Clinical and Climatological Association, vol. 128, 2017, 275-297.
Dolgin “Lung Cancer Outlook” Nature \| vol. 587 \| Nov. 19, 2020 S16-S17.
Howington “Treatment of Stage I and II Non-small Cell Lung Cancer Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines” Chest 2013; 143(5)(Suppl):e278S-e313.
Socinski “Treatment of Stage IV Non-small Cell Lung Cancer Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guideline” Chest 2013; 143(5)(Suppl):e341S-e368S.
Jett Treatment of Small Cell Lung Cancer Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2013; 143(5)(Suppl):e400S-e419S.
Schober “New Advances in the Treatment of Metastatic Pancreatic Cancer” Digestion 2015;92:175-184.
Sanz-Garcia, “Current and advancing treatments for metastatic colorectal cancer” Expert Opinion on Biological Therapy, 16:1, 2016, 93-110.
Fattaneh A. Tavassoli and Peter Devilee “World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Breast and Female Genital Organs” Online “http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/BB4.pdf” accessed Nov. 4, 2016 lARCPress Lyon, 2003 pp. 1-112.
Gerratana “Do platinum salts fit all triple negative breast cancers?”Cancer Treatment Reviews 48 (2016) 34-41.
Garson “Models of ovarian cancer—Are we there yet?” Molecular and Cellular Endocrinology 239 (2005) 15-26.
Sale “Models of ovarian cancer metastasis: Murine models” Drug Discovery Today: Disease Models 2006, 3, 150-154.
Hudis “Triple-Negative Breast Cancer: An Unmet Medical Need” The Oncologist 2011; 16(suppl 1):1-11.
Wang et al., “Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors,” Boorg Med Chem Lett., 2014, 24(18):4546-4552.
Alzabin et al., “Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response,” Cancer Immunol Immunother, 2010, 59(3):419-429.
Alzabin et al., “Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation,” J Immunol, 2009, 182(10):6187-6194.
Anonymous, “Crystalline ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate,” IP.com #IPCQM000233229D, Dec. 3, 2019, 4 pages.
Anonymous, “Crystalline APX,” IP.com #IPCOM000233879, Dec. 25, 2013, 3 pages.
Antoine et al., “Efficient synthesis of novel disubstituted pyrido[3,4-b]pyrazines for the design of protein kinase inhibitors,” Med Chem Common., 2016, 6:224-229.
Antunes et al., “In silico prediction of novel phosphodiesterase type-5 inhibitors derived from Sildenafil, Vardenafil and Tadalafil,” Bioorg Med Chem., Aug. 15, 2008, 16(16):7599-7606.
Atzrodt et al., “The Renaissance of H/D Exchange,” Angew. Chem. Int. Ed., 2007, 7744-7765.
Ballell et al., “Fueling Open-Source Drug Discovery: 177 Small-Molecule Leads against Tuberculosis,” ChemMedChem., 2013, 8(2):313-321.
Balog et al., “The synthesis and evaluation of [2.2.1]-bicycloazahydantoins as androgen receptor antagonists,” Bioorg, Med. Chem., Lett., Dec. 20, 2004, 14(24):6107-6111.
Batliwalla et al., “Microarray analyses of peripheral blood cells identifies unique gene expression signature in psoriatic arthritis,” Mol Med, 2005, 11(1-12):21-29.
Berge et al., “Pharmaceutical Salsts,” J. Pharm. Sci., 1977, 66(1):1-19.
Blom et al., “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification,” J. Combi. Chem., 2003, 5:670.
Blom et al., “Preparative LC-MS Purification: Improved Compound Specific Method Optimization,” J. Combi. Chem., 2004, 6:874-883.
Blom et al., “Two-Pump at Column Dilution Configuration for Preparative LC-MS,” J. Combi. Chem., 2002, 4: 295.
Brioche et al., “Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component Aza-Diels—Alder Reactions of Aminopyrroles and Aminopyrazoles,” Advanced Synthesis & Catalysis, 2014, 356(8):1719-1724.
Chessari et al., “Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP,” J. Med. Chem., Jul. 18, 2015, 58(16):6574-6588.
Chinchilla and Najera, “Recent advances in Sonogashira reactions,” Chem. Soc. Rev., 2011, 40: 5084-5121.
Cheung et al., “A Parallel Synthesis Approach to the Identification of Novel Diheteroarylamide-Based Compounds Blocking HIV Replication: Potential Inhibitors of HIV-1 Pre-mRNA Alternative Splicing,” J Med Chem., Mar. 10, 2016, 59(5):1869-1879.
Choi et al., “In vitro metabolism of a novel phosphodiesterase-5 inhibitor DA-8159 in rat liver preparations using liquid chromatography/electrospray mass spectrometry,” Biomed Chromatogr., Sep. 2002, 16(6):395-399.
Cordovilla et al., “The Stille Reaction, 38 Years Later,” ACS Catalysis, 2015, 5: 3040-3053.
Devegowda et al., “Novel 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-one derivatives as potential anti-cancer agents,” BioorgMed Chem Lett., Mar. 1, 2010, 20(5):1630-1633.
Di Bartolo et al., “A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76,” J. Exp. Med., Mar. 2007, 204(3): 681-691.
Dong et al., “Pharmacophore identification, virtual screening and biological evaluation of prenylated flavonoids derivatives as PKB/Akt1 inhibitors,” Eur J Med Chem., Dec. 2011, 46(12):5949-5958.
Dong et al., “QSAR study of Akt/protein kinase B (PKB) inhibitors using support vector machine,” Eur J Med Chem., Oct. 2009, 44(10):4090-4097.
Dornow et al., “Syntheses of nitrogen-containing heterocycles. XXXVIII. Preparation and reaction of several substituted 3-nitropyridines,” Chemische Berichte, 1966, 99(1):244-253 (Machine Translation).
Dumestre-Toulet et al., “Last performance with VIAGRA: post-mortem identification of sildenafil and its metabolites in biological specimens including hair sample,” Forensic Sci Int., Mar. 28, 2002, 126(1):71-76.
El-Aziz et al., “Synthesis and in vitro anti-breast cancer activity of some novel 1,4-dihydropyridine derivatives,” Int J of Pharm Pharma Sci., 2013, 5(Suppl. 3):183-189.
El Sayed et al., “New route for the preparation of pyrazolo[4,3-c]pyridines,” Bulletin of the Chemical Society of Japan (1973), 46(6), 1801-1803.
Edmondson et al., “Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors,” Bioorg Med Chem Lett., Aug. 2009, 19(15):4097-4101.
Elgemeie et al., “A new general method for substituted 4-alkylthio-N-arylsulfonylamino-2-pyridones: Reaction of ketene-S,S-acetals with arylsulfonylhydrazides,” Phosphorus, Sulfur and Silicon and the Related Elements, 2001, 170:171-179.
Elgemeie et al., “Novel N-Substituted Amino-4-methylsulfanyl-2-pyridones and Deazapurine Analogues from Ketene Dithioacetals,” J Chem Res., 1998, 3:164-165.
Elgemeie et al., “Novel synthesis of N-aroylaminated pyridones via reaction of ketene dithioacetals with cyanoaceto-N-aroylhydrazides,” Synth Comm., 2003, 33(2):253-258.
Elgemeie et al., “Novel Nucleoside Analogues: First Synthesis of Pyridine-4-Thioglycosides and Their Cytotoxic Evaluation,” Nucleosides, Nucleotides and Nucleic Acids, Jun. 27, 2015, 34:659-673.
Elgemeie et al., “Synthesis of Novel Derivatives of 4-Methylthio-N-Aryl-2-Pyridone and Deazapurine Analogues: The Reaction of Ketene Dithioacetals with Substituted Acetanilides,” Phosphorus, Sulfur and Silicon, 2000, 164:189-197.
Erian, “2-Aryl-1,1-dicyano-3-phenylsulfonylpropenes in heterocyclic synthesis. A synthetic strategy towards heterocyclic sulfone,” Monatshefte fuer Chemie, Oct. 1998, 129(10):1049-1056.
Figueiredo et al., “A chemometric study of phosphodiesterase 5 inhibitors,” J Mol Graph Model., Jan. 2006, 24(4):227-232.
Gao, “Slidenafil” Handbook of Metabolic Pathways of Xenobiotics, 2014, 5:2151-2154.
Goodarzi et al., “Feature Selection and Linear/Nonlinear Regression Methods for the Accurate Prediction of Glycogen Synthase Kinase-3β Inhibitory Activities,” J. Chem. Inf. Model, 2009, 49(4):824-832.
Haas et al., “Recent Developments in Negishi Cross-Coupling Reactions,” ACS Catalysis, 2016, 6: 1540-1552.
Haning et al., “Comparison of different heterocyclic scaffolds as substrate analog PDE5 inhibitors,” Sep. 1, 2005, 15(17):3900-3907.
Hanson, “Diterpenoids of Terrestrial Origin”, National Product Reports, 2016, 33:1227-1238.
He et al., “Predicting the Genotoxicity of Polycyclic Aromatic Compounds from Molecular Structure with Different Classifiers,” Chemical Research in Toxicology (2003), 16(12):1567-1580.
Hu et al., “Discovery of 3,5-substituted 6-azaindazoles as potent pan-Pim inhibitors,” Bioorg Med Chem Lett., 2015, 25(22):5258-5264.
Hu et al., “Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade,” Genes Dev, 1996, 10(18): p. 2251-2264.
Ho et al., “Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors,” Boorg Med Chem Lett, 2013, 23(2):569-573.
Howard et al., “Identification of potent phosphodiesterase inhibitors that demonstrate cyclic nucleotide-dependent functions in apicomplexan parasites,” ACS Chem Biol., Apr. 17, 2015, 10(4):1145-1154.
Ikegami et al., “The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by lipopolysaccharide in C3H/HeN peritoneal macrophages,” J. Immunol., Apr. 2001, 166(7): 4689-4696.
International Search Report and Written Opinion in International Application No. PCT/US2017/048880, dated Nov. 2, 2017, 15 pages.
International Search Report and Written Opinion in International Application No. PCT/US2017/050669, dated Nov. 6, 2017, 16 pages.
International Search Report and Written Opinion in International Application No. PCT/US2017/050727, dated Nov. 2, 2017, 16 pages.
International Search Report and Written Opinion in International Application No. PCT/US2017/050737, dated Nov. 2, 2017, 16 pages.
International Search Report and Written Opinion in International Application No. PCT/US2017/050757, dated Nov. 10, 2017, 20 pages.
International Search Report and Written Opinion in International Application No. PCT/US2018/018205, dated Apr. 30, 2018, 16 pages.
International Search Report and Written Opinion in International Application No. PCT/US2018/049908, dated Nov. 7, 2018.
International Search Report and Written Opinion in International Application No. PCT/US2019/018609, dated May 13, 2019, 12 pages.
International Search Report and Written Opinion in International Application No. PCT/US2019/018608, dated Apr. 16, 2019, 14 pages.
International Preliminary Report on Patentability in International Application No. PCT/US2017/050669, dated Mar. 12, 2019, 8 pages.
International Preliminary Report on Patentability in International Application No. PCT/US2017/050737, dated Mar. 12, 2019, 8 pages.
International Preliminary Report on Patentability in International Application No. PCT/US2017/050727, dated Mar. 12, 2019, 8 pages.
International Preliminary Report on Patentability in International Application No. PCT/US2017/050757, dated Mar. 12, 2019, 10 pages.
International Preliminary Report on Patentability in International Application No. PCT/US2018/018205, dated Aug. 20, 2019, 10 pages.
Ivon et al., “Synthesis of a 2,5-Diazabicyclo[2.2.1]heptane-Derived α,β-Diamino Acid,” Synthesis, 2015, 47(8):1123-1130.
Karaman “Analyzing the efficiency in intramolecular amide hydrolysis of Kirby's N-alkylmaleamic acids—A computational approach,” Computational and Theoretical Chemistry, 2011, 974(1-3):133-142.
Katritzky et al., “QSAR modeling of the inhibition of Glycogen Synthase Kinase-3,” Bioorganic & Medicinal Chemistiy, 2006, 14(14):4987-5002.
Kerekes et al., “Aurora kinase inhibitors based on the imidazo[1,2-a]pyrazine core: fluorine and deuterium incorporation improve oral absorption and exposure,” J. Med. Chem., Jan. 2011, 54(1): 201-210.
Kiefer et al., “HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway,” EMBO. J., Dec. 1996, 15(24): 7013-7025.
Kim et al., “Reliable screening and confirmation of 156 multi-class illegal adulterants in dietary supplements based on extracted common ion chromatograms by ultra-high-performance liquid chromatography-quadrupole/time of flight-mass spectrometry,” J Chromatogr A., Mar. 31, 2017, 1491:43-56.
Kotha et al., “Recent applications of the Suzuki—Miyaura cross-coupling reaction in organic synthesis,” Tetrahedron, 2002, 58: 9633-9695.
Kumar et al., “3-(1H-Indol-2-yl)-1H-pyrazolo[4,3-b]pyridines as Wnt pathway modulators and their preparation,” retrieved from STN Database Accession No. 2017: 232331, Feb. 9, 2017, Chemical Abstracts Service, Columbus, Ohio, US, XP002775032.
Kumar et al., “3-(1H-Indol-2-yl)-1H-pyrazolo[4,3-b]pyridines as Wnt pathway modulators and their preparation,” retrieved from STN Database Accession No. 2017: 232415, Feb. 9, 2017, Chemical Abstracts Service, Columbus, Ohio, US, XP002775031.
Kumar et al., “3-(1H-Indol-2-yl)-1H-pyrazolo[4,3-b]pyridines as Wnt pathway modulators and their preparation,” retrieved from STN Database Accession No. 2017: 232564, Feb. 9, 2017, Chemical Abstracts Service, Columbus, Ohio, US, XP002775030.
Kumar et al., “3-(1H-Indol-2-y1)-1H-pyrazolo[4,3-b]pyridines as Wnt pathway modulators and their preparation,” retrieved from STN Database Accession No. 2017: 233013, Feb. 9, 2017, Chemical Abstracts Service, Columbus, Ohio, US, XP002775029.
Kumar et al., “3-(1H-Indol-2-yl)-1H-pyrazolo[4,3-b]pyridines as Wnt pathway modulators and their preparation,” retrieved from STN Database Accession No. 2017: 233418, Feb. 9, 2017, Chemical Abstracts Service, Columbus, Ohio, US, XP002775028.
Kumar et al., “3-(1H-Indol-2-yl)-1H-pyrazolo[4,3-b]pyridines as Wnt pathway modulators and their preparation,” retrieved from STN Database Accession No. 2017: 233427, Feb. 9, 2017, Chemical Abstracts Service, Columbus, Ohio, US, XP002775027.
Kumar et al., “3-(1H-Indol-2-yl)-1H-pyrazolo[4,3-b]pyridines as Wnt pathway modulators and their preparation,” retrieved from STN Database Accession No. 2017: 233436, Feb. 9, 2017, Chemical Abstracts Service, Columbus, Ohio, US, XP002775026.
Lebel et al., “A rapid, quantitative liquid chromatography-mass spectrometry screening method for 71 active and 11 natural erectile dysfunction ingredients present in potentially adulterated or counterfeit products,” J Chromatogr A., May 23, 2014, 1343:143-151.
Lee et al., “Comparative metabolism of sildenafil in liver microsomes of different species by using LC/MS-based multivariate analysis,” J of Chromato., Oct. 15, 2011, 879(28):3005-3011.
Li et al., “Metabolism of aildenafil in vivo in rats and in vitro in mouse, rat, dog, and human liver microsomes,” Drug Test Anal., Jun. 2014., 6(6):552-562.
Li et al., “A highly effective one-pot synthesis of quinolines from o-nitroarylcarbaldehydes,” Organic & Biomolecular Chemistry, 2007, 5(1):61-64.
Li et al., “One-pot Friedlander quinoline synthesis: scope and limitations,” Synthesis, 2010, 10:1678-1686.
Lim et al., “Discovery of 1-(1 H-Pyrazolo [4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers,” Journal of Medicinal Chemistry, Jul. 2016, 59(13): 6501-6511.
Lin et al., “2,3,4-Trisbustituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles,” Bioorganic & Medicinal Chemistry Letters, 2010, 20:679-683.
Lin et al., “Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines,” Bioorg Med Chem Lett. Jan. 15, 2010;20(2):684-688.
Liou et al., “HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1,” Immunity, Apr. 2000, 12(4): 399-408.
Liu et al., “Synthesis and SAR of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as novel, selective c-Jun N-terminal kinase inhibitors,” Bioorg Med Chem Lett, May 15, 2006, 16(10):2590-2594.
Michelotti et al., “Two Classes of p38a MAP kinase inhibitors having a common core but exhibiting devergent binding modes,” 2005, 15:5274-5279.
Miyazaki et al., “Design and effective synthesis of novel templates, 3,7-diphenyl-4-amino-thieno and furo-[3,2-c]pyridines as protein kinase inhibitors and in vitro evaluation targeting angiogenetic kinases,” Bioorg Med Chem Lett., Jan. 1, 2007, 17(1):250-254.
Muddassar et al., “Elucidation of binding mode and three dimensional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors,” J Mol Model., Feb. 2009, 15(2):183-192.
Mulvihill et al., “Novel 2-phenylquinolin-7-y1-derived imidazo[1,5-a]pyrazines as potent insulin-like growth factor-I receptor (IGF-IR) inhibitors,” Bioorg Med Chem Lett, Feb. 2008, 16(3):1359-1375.
Patel et al., “Selectivity criterion for pyrazolo[3,4-b]pyrid[az]ine derivatives as GSK-3 inhibitors: CoMFA and molecular docking studies,” European Journal of Medicinal Chemistry, 2008, 43: 949-957.
Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 1997, 74(11), 1297.
Piersanti et al., “Synthesis of Benzo[1,2-d;3,4-d′]diimidazole and 1H-Pyrazolo[4,3-b]pyridine as Putative A2A Receptor Antagonists,” Organic a& Biomolecular Chemistry, Jul. 13, 2007, 5:2567-2571.
Pitt et al., “Heteroaromatic rings of the future,” J Med Chem., May 14, 2009, 52(9):2952-2963.
Pozharskii et al., Heterocycles in Life and Society Wiley, 1997, pp. 1-6.
Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418.
Sawasdikosol et al., “HPK1 as a novel target for cancer immunotherapy,” Immunologic Research, Apr. 4, 2012, 54(1-3): 262-265.
Sawasdikosol et al., “Hematopoietic progenitor kinase 1 (HPK1) influences regulatory T cell functions,” The Journal of Immunology, 2012, 188(supplement 1): 163, English Abstract.
Shaughnessy et al., “Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles,” Organic Reactions, Chapter 1, 2014, 85: 1-668.
Shou et al., “Simple means to alleviate sensitivity loss by trifluoroacetic acid (TFA) mobile phases in the hydrophilic interaction chromatography-electrospray tandem mass spectrometric (HILIC-ESI/MS/MS) bioanalysis of basic compounds,” J Chromatogr B Analyt Technol Biomed Life Sci., Oct. 25, 2008, 825:186-192.
Shui et al., “Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses,” Nat. Immunol., Jan. 2007, 8(1): 84-91.
Smyth et al., “Synthesis and reactivity of 3-amino-1H-pyrazolo[4,3-c]pyridin-4(5H)-ones: development of a novel kinase-focussed library,” Tetrahedron, Apr. 2010, 66(15): 2843-2854.
Subramanyam et al., “6-(4-Pyridinyl)-1H-1,2,3-triazolo[4,5-d]-pyrimidin-4(5H)-one: A Structurally Novel Competitive AMPA Receptor Antagonist,” J Med Chem., 1995, 38(4):587-589.
Surry and Buchwald, “Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User's Guide,” Chem. Sci., 2011, 2(1): 27-50.
Taha et al., “Pharmacophore Modeling, Quantitative Structure-Activity Relationship Analysis, and in Silico Screening Reveal Potent Glycogen Synthase Kinase-3 Inhibitory Activities for Cimetidine, Hydroxychloroquine, and Gemifloxacin,” J. Med. Chem., 2008, 51(7):2062-2077.
Terrett et al., “Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction,” Bioorg & Med Chem Lett., Aug. 6, 1996, 6(15):1819-1824.
Vaclavik et al., “Single-Laboratory Validation Study of a Method for Screening and Identification of Phosphodiesterase Type 5 Inhibitors in Dietary Ingredients and Supplements Using Liquid Chromatography/Quadmpole-Orbital Ion Trap Mass Spectrometry: First Action Dec. 2015,” J AOAC Int., Jan.-Feb. 2016, 99(1):55-72.
Vymetalova et al., “5-Substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with anti-proliferative activity as potent and selective inhibitors of cyclin-dependent kinases,” Eur J Med Chem., Mar. 3, 2016, 110:291-301.
Waddell et al., “Benzothiazolylthio Carbapenems: Potent Anti-MRSA Agents,” Biorg & Med Chem Lett., 1995, 5(13):1427-1432.
Wang et al., “Activation of the hematopoietic progenitor kinase-1 (HPK1)-dependent, stress-activated c-Jun N-terminal kinase (JNK) pathway by transforming growth factor beta (TGF-beta)-activated kinase (TAK1), a kinase mediator of TGF beta signal transduction,” J. Biol. Chem., Sep. 1997, 272(36): 22771-22775.
Wang et al., “Down-regulation of B cell receptor signaling by hematopoietic progenitor kinase 1 (HPK-1)-mediated phosphorylation and ubiquitination of activated B cell linker protein (BLNK),” J. Biol. Chem., Mar. 2012, 297(14): 11037-11048.
Wang et al., “Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 1. Sildenafil analogs,” Bioorg Med Chem Lett., Apr. 1, 2012, 22(7):2579-2581.
Weinmann et al., “Identification of lorazepam and sildenafil as examples for the application of LC/ionspray-MS and MS-MS with mass spectra library searching in forensic toxicology,” Forensic Sci Int., Sep. 11, 2000, 113(1-3):339-344.
Witherington et al., “5-Aryl-pyrazolo[3,4-b]pyridazines: Potent Inhibitors of Glycogen Synthase Kinase-3 (GSK-3),” Bioorganic & Medicinal Letters, 2003, 13: 1577-1580.
Witherington et al., “5-Aryl-pyrazolo[3,4-b]pyridazines: Potent Inhibitors of Glycogen Synthase Kinase-3 (GSK-3),” Bioorganic & Medicinal Letters, 2003, 13: 1581-1584.
Wislicenus “Adolph Strecker's Short Textbook of Organic Chemistry,” 1881, Spottiswood, London, pp. 38-39.
Xu et al., “Design, synthesis and biological evaluation of euterated nintedanib for improving pharmacokinetic properties,” J. Labelled Comp. Radiopharm., Jun. 2015, 58(7): 308-312.
Yang et al., “Highly efficient synthesis of fused bicyclic 2,3-diaryl-pyrimidin-4(3H)-ones via Lewis acid assisted cyclization reaction,” Tetrahedron Letters, Mar. 10, 2008, 49(11):1725-1728.
Yeo et al., “New metabolites of hongdenafil, homosildenafil and hydroxyhomosildenafil,” J Pharm Biomed Anal., Feb. 5, 2018, 149:586-590.
Zhang et al., “Anti-angiogenic effects of novel cyclin-dependent kinase inhibitors with a pyrazolo[4,3-d]pyrimidine scaffold,” Br J Pharmacol., Sep. 2016, 173(17):2645-2656.
Zhou et al., “Hematopoietic progenitor kinase 1 is a component of transforming growth factor beta-induced c-Jun N-terminal kinase signaling cascade,” J. Biol. Chem., May 1999, 274(19): 13133-13138.
Zhu et al., “Design and Synthesis of Pyridine-pyrazolopyridine based inhibitors of protein kinase B/Akt,” Bioorganic and Medicinal Chemistry, Jan. 17, 2007, 15: 2441-2452.
Zhu et al., “Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry,” J Pharm Biomed Anal., Jan. 5, 2016, 117:217-226.
Zhu et al., “Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension,” J Med Chem., Jun. 28, 2007, 50(13):2990-3003.
Literature and Patent Chemical Structure Search, Science IP, The CAS Search Service, Jul. 1, 2016, 441 pages.
Literature and Patent Chemical Structure Search, Science IP, The CAS Search Service, Jun. 30, 2016, 200 pages.
Structure 4: Substance Search Patent and Non-Patent Databases, Science IP, The CAS Search Service, Jun. 8, 2016, 820 pages.
Structure 3: Substance Search Patent and Non-Patent Databases, Science IP, The CAS Search Service, Jun. 7, 2016, 512 pages.
Structure 2: Substance Search Patent and Non-Patent Databases, Science IP, The CAS Search Service, Jun. 7, 2016, 833 pages.
Structure 1: Substance Search Patent and Non-Patent Databases, Science IP, The CAS Search Service, Jun. 6, 2016, 583 pages.
STN Search Report dated Aug. 17, 2016, 157 pages.
STN Search Report dated Aug. 25, 2016, 25 pages.
STN Search Report dated Aug. 30, 2016, 31 pages.
STN Search Report dated Aug. 31, 2016, 32 pages.
STN Search Report dated Jan. 27, 2017, 94 pages.
STN Search Report dated Sep. 5, 2017, 26 pages.
STN Search Report dated Sep. 5, 2017, 5 pages.
STN Search Report dated Jan. 23, 2018, 26 pages.
STN Search Report dated Apr. 25, 2018, 19 pages.
STN Search Report dated Apr. 9, 2018, 7 pages.
STN Search Report dated May 9, 2018, 16 pages.
Eurasian Office Action in Eurasian Application No. 201990665, dated Feb. 17, 2020, 5 pages.
International Preliminary Report on Patentability in International Application No. PCT/US2018/049908, dated Mar. 10, 2020, 8 pages.
McMahon “VEGF Receptor Signaling in Tumor Angiogenesis,” The Oncologist, 2000, 5(suppl 1):3-10.
Pinedo et al., “Translational Research: The Role of VEGF in Tumor Angiogenesis,” The Oncologist, 2000, 5(suppl 1):1-2.
STN Search Report dated Jan. 22, 2018, 9 pages.
Indian Office Action in Indian Application No. 201917010977, dated Nov. 27, 2020, 5 pages.
International Search Report and Written Opinion in International Application No. PCT/2020/044919, dated Oct. 2, 2020, 14 pages.
International Preliminary Report on Patentability in International Application No. PCT/US2019/018609, dated Aug. 27, 2020, 7 pages.
International Preliminary Report on Patentability in International Application No. PCT/US2019/018608, dated Aug. 27, 2020, 8 pages.

Related Publications (1)

	Number	Date	Country
	20190343814 A1	Nov 2019	US

Provisional Applications (1)

	Number	Date	Country
	62459413	Feb 2017	US

Continuations (1)

	Number	Date	Country
Parent	15896867	Feb 2018	US
Child	16518366		US

Pyrazolopyridine compounds and uses thereof

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

Field of Search

CPC

International Classifications

Abstract

Description

Claims

US Referenced Citations (105)

Foreign Referenced Citations (177)

Non-Patent Literature Citations (173)

Related Publications (1)

Provisional Applications (1)

Continuations (1)