EA048980B1 - HPK1 REGULATORS BASED ON PYRAZOLOPYRIDINE DERIVATIVES AND THEIR APPLICATION FOR CANCER TREATMENT - Google Patents

Abstract

This document discloses compounds of formula (I), methods of using the compounds to inhibit HPK1 activity, and pharmaceutical compositions containing such compounds. The compounds are useful in the treatment, prevention, and amelioration of diseases or disorders associated with HPK1 activity, namely cancer.

Description

Field of invention

The invention provides compounds, as well as compositions based on them and methods of use. The compounds regulate the activity of hematopoietic progenitor kinase 1 (HPK1) and are suitable for the treatment of various diseases, including cancer.

State of the art

Hematopoietic progenitor kinase 1 (HPK1), originally cloned from hematopoietic stem cells, is a member of the MAP kinase kinase kinase kinase family (MAP4Ks), 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 mainly expressed in hematopoietic cells, namely 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 stimulated by activation of T-cell receptors (TCRs) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B-cell receptors (BCRs) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), transforming growth factor receptors (TGF-betaR) (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-PEG2-protein-coupled receptors (EP 2 and EP4) (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). Therefore, HPK1 regulates diverse functions of different immune cells.

HPK1 is important in regulating the functions of various immune cells and is involved in autoimmune diseases and antitumor 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 are more susceptible to the stimulation of experimental autoimmune encephalomyelitis (EAE) (Shui, J.W., et al., Nat Immunol, 2007. 8(1): p. 84-91). In humans, HPK1 activity was reduced in peripheral blood mononuclear cells from patients with psoriatic arthritis or in T cells from patients with systemic lupus erythematosus (SLE) (Batliwalla, F. M., et al., Mol Med, 2005. 11(1-12): p. 21-9). These observations imply that regulation of HPK1 activity influences autoimmunity in patients. Additionally, HPK1 also controls antitumor immunity through T cell-dependent mechanisms. In a PEG2-producing Lewis lung carcinoma model, tumors develop more slowly in HPK1 knockout mice compared to wild-type mice (see US 2007/0087988). Additionally, adoptive transfer of HPK1-deficient T cells has been shown to be more effective in controlling tumor growth and metastasis compared to wild-type T cells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p. 419-29). Similarly, HPK1 knockout mouse BMDCs are more effective in mediating a T cell response to kill Lewis lung carcinoma compared to wild-type BMDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). These data, coupled with the restricted expression of HPK1 in hematopoietic cells and its lack of influence on normal immune cell development, suggest that HPK1 represents an excellent drug target for improving antitumor immunity. Accordingly, there is a need for new compounds to inhibit HPK1 activity.

The essence of the invention

The present invention provides, among others, a compound of formula (I):

R ² R ¹ is sADD or a pharmaceutically acceptable salt thereof, with the variable components being as defined herein.

The present invention further provides a pharmaceutical composition for inhibiting hematopoietic progenitor kinase 1 (HPK1) activity, comprising a compound according to the disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

The present invention further provides methods for inhibiting HPK1 activity, which comprise administering to an individual a compound of the disclosure or a pharmaceutically acceptable salt thereof.

The present invention further provides methods for treating a disease or disorder associated with inhibition of HPK1 interaction 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

Connections.

The present invention provides a compound of formula (I):

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I or its pharmaceutically acceptable salt, wherein

R ¹ is Cy ¹ ;

Cy ¹ is selected from C _3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C _6-10 aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein the ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein each O _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ ;

Cy ^A is C _6-10 aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²⁰ ;

R ² is H;

each R ¹⁰ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halogen, CN, NO2, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , C(=NR ^e1 )R ^b1 , C(=NOR ^a1 ) R ^b1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 ) NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O)2R ^b1 , NR ^c1 S(O)2NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O)2R ^b1 and S(O)2NR ^c1 R ^d1 ; wherein each said C1-6αalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, _C6-10 aryl, 5-10 membered heteroaryl, _C3-10 cycloalkylC1-3 alkylene, 4-10 membered heterocycloalkyl- _C1-3 alkylene, _C6-10 aryl- _{C1-3 alkylene} and 5-10 membered heteroaryl- _C1-3 alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R11 ;

or two R ¹⁰ substituents, together with the carbon atoms to which they are attached, form a 3-7 membered heterocycloalkyl spiro ring or a C _3-6 cycloalkyl spiro ring; wherein each 3-7 membered heterocycloalkyl spiro 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 the ring-forming carbon atom of each 3-7 membered heterocycloalkyl spiro ring is optionally substituted with oxo to form a carbonyl group; and wherein each 3-7 membered heterocycloalkyl ring and C _3-6 cycloalkyl spiro ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

each R ¹¹ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halogen, CN, OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O)2R ^b3 , NR ^c3 S(O)2NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O)2R ^b3 and S(O)2NR ^c3 R ^d3 ; wherein each said C1-6αalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, _C6-10 aryl, 5-10 membered heteroaryl, _C3-10 cycloalkyl- _C1-3 alkylene, 4-10 membered heterocycloalkyl- _C1-3 alkylene, _C6-10 aryl- _C1-3 alkylene and 5-10 membered heteroaryl- _C1-3 alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R12 ;

each R ¹² is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halogen, CN, OR ^a5 , SR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , NR ^c5 C(O)OR ^a5 , NR ^c5 S(O)R ^b5 , NR ^c5 S(O)2R ^b5 , NR ^c5 S(O)2NR ^c5 R ^d5 , S(O)R ^b5 , S(O)NR ^c5 R ^d5 , S(ObR ^b5 and S(O)2NR ^c5 R ^d5 ; wherein each said C1-6αalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, _C6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ²⁰ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , C(=NR ^e2 )R ^b2 , C(=NOR ^a2 )R ^b2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C (=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; wherein each said C _1-6 αalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C _6-10 aryl, 5-10-membered heteroaryl, C _3-10 cycloalkyl

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_C1.3alkylene , 4-10 _- membered heterocycloalkyl- _C1.3alkylene , _C6-10 -membered heteroaryl- _C1-3alkylene and 5-10-membered heteroaryl- _C1-3alkylene are optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R21 ;

or two adjacent ^R20 substituents on the ^CyA ring, together with the atoms to which they are attached, form a _C3.7 cycloalkyl fused ring; wherein the ring-forming carbon atom _{of the C3.7} cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein the _{C3_7 cycloalkyl} fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from ^R21 ;

each R ²¹ is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, C3_10 cycloalkyl-C1.3 alkylene, 4-10 membered heterocycloalkyl-C1.3 alkylene, C6.10 aryl-C1.3 alkylene, 5-10 membered heteroaryl-C1_3 alkylene, halogen, CN, OR ^a4 , SR ^a4 , C(O) ^RM , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O) ^RM , NR ^c4 C(O)OR ^a4 , NR ^c4 S(O) ^RM , NR ^c4 S(O)2R ^b4 , NR ^c4 S(O)2NR ^c4 R ^d4 , S(O) ^RM , S(O)NR ^c4 R ^d4 , S(O)2R ^b4 and S(O)2NR ^c4 R ^d4 ; wherein each said _C1.6 alkyl, _C2.6 alkenyl, _{C2.6 alkynyl, C3.10 cycloalkyl} , _4- to 10-membered heterocycloalkyl, _C6-10 aryl, 5- to 10-membered heteroaryl, _C3.10 cycloalkyl- _{C1.3 alkylene} , 4- to ₁₀ - _membered heterocycloalkyl- _{C1.3 alkylene} , _{C6_10} aryl- _C1 . ₃ alkylene and 5-10 membered heteroaryl-C ₁ . ₃ alkylene optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ;

or two R ²¹ substituents together with the carbon atom to which they are attached form a C ₃ . ₇ cycloalkyl spiro ring; wherein the ring-forming carbon atom of the C ₃ . ₇ cycloalkyl spiro ring is optionally substituted with oxo to form a carbonyl group; and wherein the C ₃ . ₇ cycloalkyl spiro ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ;

each R ²² is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C3.6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halogen, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)OR ^a6 , NR ^c6 S(O)R ^b6 , NR ^c6 S(O)2R ^b6 , NR ^c6 S(O)2NR ^c6 R ^d6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O)2R ^b6 and S(O)2NR ^c6 R ^d6 ; wherein each said C1_ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C ₁ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₁ _ ₆ haloalkyl, C ₃ _ ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ _ ₁₀ aryl and 5- to 10-membered heteroaryl; wherein each said C ₁ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ _ ₁₀ aryl and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ;

or any R ^c1 and R ^d1 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ;

each R ^b1 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ;

each R ^e1 is independently selected from H, CN, C _{1_6} alkyl, C _1.6 haloalkyl, C _{1.6 alkylthio} , C _{1.6 alkylsulfonyl} , C _{1.6 alkylcarbonyl} , C _1.6 alkylaminosulfonyl, carbamyl, _{C 1.6 alkylcarbamyl ,} di(C _{1.6 alkyl} )carbamyl, aminosulfonyl, C _1.6 alkylaminosulfonyl, and _{di(C 1.6 alkyl ) aminosulfonyl ;}

each R ^a2 , R ^c2 and R ^d2 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ;

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

each R ^b2 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ;

each R ^e2 is independently selected from H, CN, _{C1.6 alkyl} , _C1.6 haloalkyl, _C1.6 alkylthio, _C1.6 alkylsulfonyl, _C1.6 alkylcarbonyl, _C1.6 alkylaminosulfonyl, carbamyl, _{C1.6 alkylcarbamyl ,} di( _{C1.6 alkyl )} carbamyl, aminosulfonyl, _C1.6 alkylaminosulfonyl, _and di _{( C1.6 alkyl )} aminosulfonyl _;

each R ^a3 , R ^c3 and R ^d3 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl;

- 3 048980 than each said C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, ^^cycloalkyl, phenyl, 5-6-membered heteroaryl and 4-7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ;

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

each R ^b3 is independently selected from C _1-6 αalkyl, C _2-6 αalkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5-6-membered heteroaryl, and 4-7-membered heterocycloalkyl; wherein each said C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5-6-membered heteroaryl, and 4-7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ;

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

each R ^b4 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

each R ^a5 , R ^c5 and R ^d5 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ _ ₆ alkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^b5 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl and C ₁ _ ₆ haloalkyl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ _ ₆ αalkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^a6 , R ^c6 and R ^d6 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₁ _ ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl and C ₂ . ₆ alkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^b6 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ αalkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^g is independently selected from OH, NO ₂ , CN, halogen, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkyl-C ₁ . ₂ alkylene, Cl . ₆ αalkyloxy, C ₁ . ₆ haloalkoxy, C ₁ _ ₃ alkoxy-C ₁ _ ₃ alkyl, C ₁ . ₃ alkoxy-C ₁ _ ₃ αalkoxy, HO-C ₁ _ ₃ alkoxy, HO-C ₁ _ ₃ αalkyl, cyano-C ₁ . ₃ alkyl, H ₂ NC ₁ _ ₃ αalkyl, amino, C ₁ . ₆ alkylamino, di(C ₁ _ ₆ alkyl)amino, thio, C ₁ . ₆ alkylthio, C ₁ . ₆ alkylsulfinyl, C ₁ . ₆ alkylsulfonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di(C ₁ _ ₆ alkyl)carbamyl, carboxy, C ₁ _ ₆ αalkylcarbonyl, C ₁ . ₆ alkyloxycarbonyl, C ₁ . ₆ αalkylcarbonylamino, C ₁ . ₆ alkylsulfonylamino, aminosulfonyl, C ₁ . ₆ alkylaminosulfonyl, di(C ₁ . ₆ alkyl)aminosulfonyl, aminosulfonylamino, C ₁ . ₆ alkylaminosulfonylamino, di(C ₁ . ₆ alkyl)aminosulfonylamino, aminocarbonylamino, C ₁ . ₆ alkylaminocarbonylamino and di(C ₁ . ₆ αalkyl)aminocarbonylamino, wherein said heteroaryl groups comprise carbon atoms and 1-4 heteroatoms independently selected from N, O and S, and said heterocycloalkyl groups comprise carbon atoms and 1-4 heteroatoms independently selected from N, O and S; and wherein the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group may be oxidized to form a carbonyl, N-oxide or sulfonyl group.

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

In some embodiments, each R ²⁰ is independently selected from C1.6 alkyl, C2.6 α alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1.3 alkylene, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; wherein each said _C1.6 alkyl, _C2.6 alkenyl, _{C2.6 alkynyl} , _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl, _4-10 membered heterocycloalkyl- _C1.3 alkylene, _{C6.10 aryl} and 5-10 membered heteroaryl is optionally substituted with ₁ , 2 or 3 substituents independently selected from ^R21 ; or two adjacent R ²⁰ substituents in a CyA ring, together with the atoms to which they are attached, form a C ₃ . ₇ cycloalkyl fused ring; the ring-forming carbon atom of each

- 4 048980

C ₃ . ₇ cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein each C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ .

In some embodiments, each R ²⁰ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; wherein each said _C1.6 alkyl, _C2.6 alkenyl, _C2.6 alkynyl, _C3.10 cycloalkyl, _4- to 10-membered heterocycloalkyl, C6.10 aryl and _5- to 10-membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on a ^C3A _ring , together with the atoms to which they are attached, form a _C3.7 cycloalkyl fused ring; wherein the ring-forming carbon atom of each _C3 . ₇ cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein each C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ .

In some embodiments, each R ²⁰ is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1.3 alkylene, C6.10 aryl, 5-10 membered heteroaryl, halogen, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , and NR ^c2 C(O)NR ^c2 R ^d2 ; wherein each said _{C1_6} alkyl, _{C2.6 alkenyl} , _{C2.6 alkynyl} , _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl- _C1.3 alkylene, _C6.1 oaryl and 5-10 membered heteroaryl is optionally substituted with 1, ₂ or 3 substituents independently selected from ^R21 ; or two adjacent ^R20 substituents on a ^CyA ring, together with the atoms to which they are attached, form a _C3.7 cycloalkyl fused ring; wherein the _ring -forming carbon atom of each _{C3.7 cycloalkyl} fused ring is optionally substituted with oxo to form a carbonyl group; and wherein each _C3 . ₇ The cycloalkyl fused ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ .

In some embodiments, each R ²⁰ is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.1 () aryl, 5-10 membered heteroaryl, halogen, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 and NR ^c2 C(O)OR ^a2 ; wherein each said C1_ ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ _ ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ - ₁₀ aryl and 5- to 10-membered heteroaryl are optionally substituted with 1, 2, or 3 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on a CyA ring, together with the atoms to which they are attached, form a C ₃ . ₇ cycloalkyl fused ring; wherein the ring-forming carbon atom of each C ₃ . ₇ cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein each C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ .

In some embodiments, each R ²⁰ is independently selected from C1.6 alkyl, C1.6 haloalkyl, C3.10 cycloalkyl, halogen, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1_3 alkylene, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , and _NR ^c2 C(O)NR ^c2 R ^d2 ; wherein each said C1.6 alkyl, _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl and 4-10 membered heterocycloalkyl-C ₁ . ₃ alkylene is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on the Cy ^A ring, together with the atoms to which they are attached, form a C ₃ . ₇ cycloalkyl fused ring; and wherein each C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ .

In some embodiments, each R ²⁰ is independently selected from C alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, halogen, and OR ^a2 ; wherein each said C 1-6 alkyl and _{C 3-10 cycloalkyl} is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on a C ^{2 A} ring, together with the atoms to which they are attached, form a C ₃₇ cycloalkyl fused ring; and wherein each C _3-7 cycloalkyl fused ring is optionally substituted with 1, ₂ , 3, or 4 substituents independently selected from R ²¹ .

In some embodiments, each R ²⁰ is independently selected from methyl, trifluoromethyl, cyclopropyl substituted with methanamine, fluoro, chloro, hydroxy, methoxy, ethoxy, C(O)NH(CH ₂ ) ₂ OCH ₃ , CO-(3-methoxyazetidin-1-yl), NHC(O)-cyclobutyl, NHC(O)-benzyl, methylamino, dimethylamino, NHC(O)CH ₂ -(pyrrolidin-1-yl), NHC(O)-(1-methyl-1H-pyrazol-4-yl), NH(CO)CH ₂ (cyclopentyl), NHC(O)CH ₂ -(pyridin-3-yl), NHC(O)CH ₂ -(7-azabicyclo[2.2.1]heptan-7-yl), NHC(O)-(7-oxa-2-azaspiro[3.5]nonan-2-yl), NHC(O)CH(Ch ₃ )-(pyrrolidin-1-yl), NHC(O)NH(CH ₂ ) ₂ oCh ₃ ,

NHC(O)CH ₂ -(azetidin-1-yl), NHC(O)CH ₂ -(3,3-dimethylazetidin-1-yl), NHC(O)O-(1-methylpiperidin-4-yl), NнC(O)Сн ₂ -(dimethylamino), NHc(O)CH ₂ -((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl), NHC(O)(CH ₂ ) ₂ (dimethylamino), NHC(O)CH ₂ CN, (methylamino)methyl, azetidin-1-ylmethyl, CH ₂ NH-(tetrahydro-2Н

- 5 048980 pyran-4-yl), (isopropylamino)methyl, cyclobutyl-NHCH(CH ₃ ) ₂ , (methylamino)ethyl, (CH ₂ ) ₂ NH(tetrahydro-2H-pyran-4-yl), (CH ₂ ) ₂ NH-(1-isopropylazetidin-3-yl), OCH ₂ -(azetidin-2-yl), tetrahydro2H-pyran-4-yloxy, OCH ₂ -(pyridin-4-yl), OC(O)N(CH ₃ ) ₂ , OC(O)-(morpholin-4-yl), CH^H-(pyridin-5yl), CH ₂ NH-(1-methyl-1H-pyrazol-3-yl), CH ₂ NH(CH ₂ ) ₂ OH, CH ₂ NH-cyclopropyl, (3-methoxypiperidin1-yl)methyl, (ethylamino)methyl, pyrrolidin-1-ylmethyl, 3-methoxyazetidin-1-ylmethyl, pyrrolidin2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl, CH ₂ NHCH ₂ CF ₃ , CH ₂ NH-(3-cyclobutan-1-ol), (1-pyrrolidin-3-ol)methyl, CH ₂ NHCH ₂ C(CH ₃ ) ₂ OH, CH ₂ NHCH ₂ -(1-methyl-1H-imidazol-4-yl), CH2NHCH2(oxazol-4-yl), CH ₂ NHCH ₂ CN, CH(CH ₃ )NH(CH ₃ ) , CH ₂ NHC(O)CH ₃ , CH ₂ NHC(O)O (CH ₃ ), difluoromethoxy, cyanomethyl, aminomethyl, (hydroxyl)methyl, amino, CH ₂ (3,3-dimethylazetidin-1-yl), CH ₂ NH-(3methoxycyclobutyl), CH ₂ NHCH ₂ -(1-methylcyclopropyl) and morpholinyl.

In some embodiments of the invention, each R ²⁰ is independently selected from methyl, trifluoromethyl, cyclopropyl substituted with methanamine, fluoro, chloro, hydroxy, methoxy, and ethoxy.

In some embodiments of the invention, each R ²⁰ is independently selected from methoxy or fluoro.

In some embodiments of the invention, Cy ^A is selected from 2-fluoro-6-methoxyphenyl, 1[1-(3-fluoro-5-phenyl)cyclopropyl]methanamine, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2,4,6-trifluorophenyl, 2-chloro-6-fluorophenyl, 1-hydroxy-3,5-difluorophen-4-yl, 2-fluoro-6-methylphenyl, 2-ethoxy-6-fluorophenyl, 2-chloro-6-methoxyphenyl, and 2-fluoro-6-(trifluoromethyl)phenyl.

In some embodiments of the invention, Cy ¹ is selected from 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one cyclic ring-forming carbon atom and 1, 2, 3 or 4 cyclic ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein a cyclic ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein each 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ .

In some embodiments, Cy ¹ is thiazolyl, isoxazolyl, piperazinonyl, 1,2,3,4-tetrahydroisoquinolyl, piperazinyl, phenyl, pyrazolyl, pyridinyl, imidazolyl, or pyrimidinyl; each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In some embodiments, Cy ¹ is thiazolyl, isoxazolyl, piperazinonyl, 1,2,3,4-tetrahydroisoquinolyl, piperazinyl, or phenyl; each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In some embodiments, R ¹⁰ is independently selected from C1.6 alkyl, C2.6 α alkenyl, C2.6 α alkenyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O)2R ^b1 , NR ^c1 S(O)2NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O)2R ^b1 and S(O)2NR ^c1 R ^d1 ; wherein each said _C1.6 alkyl, _{C2.6 αalkenyl} , _{C2.6 alkynyl, C3.10 cycloalkyl} , _4-10 -membered heterocycloalkyl, _{C6.10 aryl} and 5-10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ .

In some embodiments, R ¹⁰ is independently selected from C1.6αalkyl, C2.6alkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10 membered heterocycloalkyl, C6.10aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , NR ^c1 R ^d1 , and NR ^c1 C(O)R ^b1 ; wherein each _C1.6αalkyl , _C2.6alkenyl , _C2.6alkynyl , _{C3.10cycloalkyl} , _{4-10 membered heterocycloalkyl} , _C6 . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹⁰ is independently selected from C1.6 alkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a1 , C(O)NR ^c1 R ^d1 , and NR ^c1 R ^d1 ; wherein each said _C1.6 alkyl, _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl, _{C6.10 aryl} and 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹⁰ is independently selected from C1.6 alkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, and OR ^a1 ; wherein each said _C1.6 alkyl, _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl, _{C6.10 aryl} , and 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from R ¹¹ .

In some embodiments, each R ¹¹ is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkenyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, C3.10 cycloalkyl-C1.3 alkylene, 4-10 membered heterocycloalkylC1.3 alkenylene, C6.10 aryl-C1.3 alkylene, 5-10 membered heteroaryl-C1.3 alkenylene, halogen, CN, OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 and NR ^c3 C(O)OR ^a3 ; wherein each said C1. ₆ αalkyl, C _{2. 6} alkenyl, C _{2. 6} alkynyl, C _{3. 10} cycloalkyl, 4-10-membered heterocycloalkyl, C _{6. 10} aryl, 5-10

- 6 048980 membered heteroaryl, C _3-10 cycloalkyl-C _1-3 alkylene, 4-10 membered heterocycloalkyl-C _1-3 alkylene, C _6-10 aryl-C _1-3 alkylene and 5-10 membered heteroaryl-C _1-3 alkylene are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² .

In some embodiments, each R ¹¹ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , and NR ^c3 C(O)R ^b3 ; wherein each said C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, C3-10 cycloalkyl, _4-10 membered heterocycloalkyl, _C6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R12 .

In some embodiments of the invention, each R ¹¹ is independently selected from C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a3 , C(O)OR ^a3 ; wherein each said C1-6 alkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ¹² .

In some embodiments, each R ¹⁰ is independently selected from methyl, bromine, fluoro, CN, ethyl, methoxy, 4-morpholinyl, 3-oxopiperazin-1-yl, 4-methylpiperazin-1-yl, 4methyl-3-oxopiperazin-1-yl, 4-ethylpiperazin-1-yl, 3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, piperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-cyclopropyl-3-oxopiperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, 4-bromophenyl, 4-cyanophenyl, 4-pyridyl, methylaminocarbonyl, isopropylaminocarbonyl, 3-hydroxypyrrolidin-1-yl, 3-methoxypiperidin-1-yl, 1-methylpiperidin-4-yl, ethylmethylamino, cyclopropyl, ethyl, 2-cyanophenyl, tetrahydro-2H-pyran-4yl, azetidin-3-yl, hydroxyethyl, 4-methoxypiperidin-1-yl, 3-fluoropyrrolidin-1-yl, 4-methylcarbonylpiperazin-1-yl and 4-hydroxypiperidin-1-yl, 4-methoxycarbonylpiperazin-1-yl, amino, 2-hydroxypropylamino, (1-methyl-1H-pyrazol-5-yl)methylamino and 3-cyanocyclopentylamino.

In some embodiments, each R ¹⁰ is independently selected from methyl, bromine, fluoro, CN, ethyl, methoxy, 4-morpholinyl, 3-oxopiperazin-1-yl, 4-methylpiperazin-1-yl, 4methyl-3-oxopiperazin-1-yl, 4-ethylpiperazin-1-yl, 3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl, 4(methylsulfonyl)piperazin-1-yl, piperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-cyclopropyl-3oxopiperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, 4-bromophenyl, 4-cyanophenyl, and 4-pyridyl.

In some embodiments of the invention, the compound of formula I has formula IV: 0^ l tM-V ιΰ O 14 n (IV) where n is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the compound of formula I has the formula Val:

(Vai) where n is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, n is 3.

In some embodiments of the invention, n is 2.

In some embodiments, each R ²⁰ is independently fluoro, methyl, trifluoromethyl, CH2NHCH3, CH ₂ NH(isopropyl), CH ₂ -azetidinyl, CH ₂ NH(CH ₂ )CH ₃ , or CH(CH3)(NHCH3).

In some embodiments of the invention

R ¹ is Cy ¹ ;

Cy ¹ is selected from C _3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C _6-10 aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one cyclic ring-forming carbon atom and 1, 2, 3 or 4 cyclic ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein the cyclic ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein each C _3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C _6-10 aryl and 5-10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents,

- 7 048980 independently selected from R ¹⁰ ;

Cy ^A is _C6.10aryl optionally substituted _with 1, 2, 3 or 4 substituents independently selected from ^R20 ;

R ² is H;

each R ¹⁰ is independently selected from C1-6 alkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3_10cycloalkyl-C1-3alkylene, 6-10 membered heterocycloalkyl-C1-3αalkylene, C6.10aryl-C1.3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halogen, CN, NO2, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , C(=NR ^e1 )R ^b1 , C(=NOR ^a1 )R ^b1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O)2R ^b1 , NR ^c1 S(O)2NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O)2R ^b1 and S(O)2NR ^c1 R ^d1 ; wherein each said C2.6 _αalkenyl , _C2 . ₆ alkynyl, _{C3_10} cycloalkyl, 4- to ₁₀ -membered heterocycloalkyl, _C6.10 aryl, _5- to 10- _membered heteroaryl, _{C3.10 -} cycloalkyl- _C1.3 alkylene, 6- to 10-membered heterocycloalkyl- _C1.3 alkylene, _C6.10 aryl- _{C1.3 alkylene} and _5- to ₁₀ -membered heteroaryl- _C1.3 alkylene are optionally substituted with 1, 2, 3 or ₄ substituents independently selected from ^R11 ;

or two R ¹⁰ substituents, together with the carbon atoms to which they are attached, form a 3- to ₇ -membered heterocycloalkyl spiro ring or a C _{3_6} cycloalkyl spiro ring; wherein each 3- to 7-membered heterocycloalkyl spiro 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 the ring-forming carbon atom of each 3- to 7-membered heterocycloalkyl spiro ring is optionally substituted with oxo to form a carbonyl group; and wherein each 3- to 7-membered heterocycloalkyl ring and the _{C 3_6} cycloalkyl spiro ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;

each R ¹¹ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10-membered heterocycloalkyl, C6.10aryl, 5-10-membered heteroaryl, C3_10cycloalkyl-C1.3alkylene, 4-10-membered heterocycloalkyl-C1.3αalkylene, C6.10aryl-C1.3alkylene, 5-10-membered heteroaryl-C1_3alkylene, halogen, CN, OR ^a 3, SR ^a 3, C(O)R ^b 3, C(O)NR ^c3 R ^d3 , C(O)OR ^a 3, NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O)2R ^b3 , NR ^c3 S(O)2NR ^c3 R ^d3 , S(O)R ^b 3, S(O)NR ^c3 R ^d3 , S(O)2R ^b 3 and S(O)2NR ^c3 R ^d3 ; wherein each said C1_ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ . ₁₀ cycloalkyl-C ₁ . ₃ alkylene, 4- to 10-membered heterocycloalkyl-C ₁ . ₃ αalkylene, C ₆ _ ₁₀ aryl-C ₁ . ₃ alkylene and 5- to 10-membered heteroaryl-C ₁ . ₃ alkylene optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ;

each R ¹² is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.6cycloalkyl, C6.10aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halogen, CN, OR ^a5 , SR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , NR ^c5 C(O)OR ^a5 , NR ^c5 S(O)R ^b5 , NR ^c5 S(O)2R ^b5 , NR ^c5 S(O)2NR ^c5 R ^d5 , S(O)R ^b5 , S(O)NR ^c5 R ^d5 , S(O)2R ^b5 and S(O)2NR ^c5 R ^d5 ; wherein each said _C1.6 alkyl, _{C2.6 αalkenyl} , _C2.6 alkynyl, _C3.6 cycloalkyl, _C6.10 aryl, _5-10 - _membered heteroaryl and _4-7 -membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ²⁰ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10-membered heterocycloalkyl, C6.10aryl, 5-10-membered heteroaryl, C3_10cycloalkyl-C1.3alkylene, 4-10-membered heterocycloalkyl-C1.3αalkylene, C6.10aryl-C1.3alkylene, 5-10-membered heteroaryl-C1_3alkylene, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , C(=NR ^e2 )R ^b2 , C(=NOR ^a2 ) R ^b2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C (=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; and each specified C1. ₆ αlkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, _C3.10 cycloalkyl, _4- to 10-membered heterocycloalkyl, _C6.10 aryl, _5- to 10- _membered heteroaryl, _{C3.10 cycloalkylC1.3} alkylene, 4- to 10-membered heterocycloalkyl- _C1.3 alkylene, _{C6.10 aryl} - _{C1.3 alkylene} and _5- to ₁₀ -membered heteroaryl- _C1.3 alkylene are optionally substituted with 1, 2, 3 or ₄ substituents independently selected from ^R21 ;

or two adjacent R ²⁰ substituents on the CyA ring, together with the atoms to which they are attached, form a C _{3_7} cycloalkyl fused ring; wherein the ring-forming carbon atom _{of the C 3_7 cycloalkyl fused} ring is optionally substituted with oxo to form a carbonyl group; and wherein the _{C 3_7 cycloalkyl} fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

each R ²¹ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4- to 10-membered heterocycloalkyl, C6.10aryl, 5- to 10-membered heteroaryl, C3.10cycloalkyl-C1.3alkylene, 4- to 10-membered heterocycloalkyl-C1.3αalkylene, C6.10aryl-C1.3αalkylene, 5- to 10-membered heteroaryl-C1_3alkylene, halogen, CN, OR ^a4 , SR ^a4 , C(O) ^RM , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 , NR ^c4 C(O)OR ^a4 , NR ^c4 S(O)R ^b4 , NR ^c4 S(O)2R ^b4 , NR ^c4 S(O)2NR ^c4 R ^d4 , S(O)RM ^M , S(O)NR ^c4 R ^d4 , S(O)2R ^b4 and S(O)2NR ^c4 R ^d4 ; and each specified C1. ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5-10 membered heteroaryl, C ₃ . ₁₀ cycloalkyl-C ₁ . ₃ alkylene, 4-10 membered heterocycloalkyl-C ₁ . ₃ αalkylene, C ₆ _ ₁₀ aryl-C ₁ . ₃ alkylene and 5- to 10-membered heteroaryl-C ₁ . ₃ alkylene optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ;

- 8 048980 or two R ²¹ substituents together with the carbon atom to which they are attached form a C ₃ . ₇ cycloalkyl spiro ring; wherein the ring-forming carbon atom of the C ₃ . ₇ cycloalkyl spiro ring is optionally substituted with oxo to form a carbonyl group; and wherein the C ₃ _ ₇ cycloalkyl spiro ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ;

each R ²² is independently selected from C1-6αalkyl, C2.6αalkenyl, C2-6alkynyl, C1-6haloalkyl, C3.6cycloalkyl, phenyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, halogen, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)OR ^a6 , NR ^c6 S(O)R ^b6 , NR ^c6 S(O)2R ^b6 , NR ^c6 S(O)2NR ^c6 R ^d6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O)2R ^b6 and S(O)2NR ^c6 R ^d6 ; wherein each said _C1.6 αalkyl, _{C2.6 alkenyl} , _C2.6 αalkynyl, _O3.6 cycloalkyl, phenyl, _{5- to} 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁ o cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁ o aryl and 5- to 10-membered heteroaryl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ;

or any R ^c1 and R ^d1 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ;

each R ^b1 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ;

each R ^e1 is independently selected from H, CN, _C1.6 alkyl, _{C1.6 haloalkyl} , _C1.6 αalkylthio, _C1.6 alkylsulfonyl, _C1.6 alkylcarbonyl, _C1.6 alkylαiminosulfonylα, carbamyl, _{C1.6 alkylcarbamyl} , _di ( _{C1_6} alkyl ₎ carbamyl, aminosulfonyl, _{C1.6 αalkylαiminosulfonylα and di ( C1_6 alkyl} )aminosulfonyl _;

each R ^a2 , R ^c2 and R ^d2 is independently selected from H, C _{1 _ 6} alkyl, C 2 . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- _to 10-membered heteroaryl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ;

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

each R ^b2 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ;

each R ^e2 is independently selected from H, CN, C _{1_6} alkyl, C _1.6 haloalkyl, _{C 1.6 αalkylthio} , C _1.6 alkylsulfonyl, C _{1.6 alkylcarbonyl} , C _1.6 alkylaminosulfonyl, carbamyl, _{C 1.6 alkylcarbamyl ,} di(C _{1.6 alkyl} )carbamyl, aminosulfonyl, C _1.6 αalkylaminosulfonyl, and _{di(C 1.6 αalkyl ) aminosulfonyl ;}

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

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

each R ^b3 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, ^-cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;

each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C 1 _{_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 1 . 6 haloalkyl , C 3-6 cycloalkyl , phenyl} , 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C _3-6 cycloalkyl, phenyl, 5- to ₆ -membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents, independently

- 9 048980 simo selected from R ²² ;

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

each R ^b4 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ;

each R ^a5 , R ^c5 and R ^d5 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^b5 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ αalkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^a6 , R ^c6 and R ^d6 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^b6 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ αalkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ^g is independently selected from OH, NO ₂ , CN, halogen, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkyl-C ₁ . ₂ alkylene, C ₁ . ₆ alkoxy, C ₁ . ₆ haloalkoxy, C ₁ . ₃ αlkoxy-C ₁ . ₃ alkyl, Cl.alkoxy-Cl.alkoxy, HO-C ₁ . ₃ αalkoxy, HO-C ₁ . ₃ alkyl, cyano-C ₁ . ₃ alkyl, H2NC ₁ . ₃ αalkyl, amino, C ₁ . ₆ αalkylamino, di(C ₁ . ₆ alkyl)amino, thio, C ₁ . ₆ alkylthio, C ₁ . ₆ alkylsulfinyl, C ₁ . ₆ αalkylsulfonyl, carbamyl, C ₁ . ₆ αalkylcarbamyl, di(C ₁ . ₆ alkyl)carbamyl, carboxy, C ₁ . ₆ alkylcarbonyl, C ₁ . ₆ alkoxycarbonyl, C ₁ . ₆ αalkylcarbonylamino, C ₁ . ₆ alkylsulfonylamino, aminosulfonyl, C ₁ . ₆ αalkylaminosulfonyl, di(C ₁ . ₆ alkyl)aminosulfonyl, aminosulfonylamino, C ₁ . ₆ α-alkylaminosulfonylamino, di(C ₁ . ₆ alkyl)aminosulfonylamino, aminocarbonylamino, C ₁ . ₆ α-alkylaminocarbonylamino and di(C ₁ . ₆ alkyl)aminocarbonylamino.

In some embodiments of the invention

R ¹ is Cy ¹ ;

Cy ¹ is selected from C ₃ . ₁ ocycloalkyl, 4-10-membered heterocycloalkyl, C ₆ . ₁ oaryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one cyclic ring-forming carbon atom and 1, 2, 3 or 4 cyclic ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein a cyclic ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein each C ₃ . ₁₀ cycloalkyl, 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ ;

Cy ^A is _C6.10aryl optionally substituted _with 1, 2, 3 or 4 substituents independently selected from ^R20 ;

R ² is H;

each R ¹⁰ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10 membered heterocycloalkyl, C6.10aryl, 5-10 membered heteroaryl, halogen, CN, NO2, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 and NR ^c1 C(O)OR ^a1 ; wherein each said _C2.6 alkenyl, C _{2.6 alkynyl} , C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ;

each R ¹¹ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4- to 10-membered heterocycloalkyl, C6.10aryl, 5- to 10-membered heteroaryl, halogen, CN, OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O)2R ^b3 and S(O)2NR ^c3 R ^d3 ; wherein each said C1. ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ;

each R ¹² is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, halogen, CN, OR ^a5 , SR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , NR ^c5 C(O)OR ^a5 , NR ^c5 S(O)R ^b5 , NR ^c5 S(O)2R ^b5 , NR ^c5 S(O)2NR ^c5 R ^d5 , S(O)R ^b5 , S(O)NR ^c5 R ^d5 , S(O)2R ^b5 and S(O)2NR ^c5 R ^d5 ; wherein each said _C1.6 alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ;

each R ²⁰ is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5-10 membered heteroaryl, 4-10

- 10 048980 membered heterocycloalkyl- _C1-3 alkylene, halogen, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 and NR ^c2 C(O)OR ^a2 ; wherein each said C1_ ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C _{6_ 10} aryl, 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl-C ₁ . ₃ alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ;

or two adjacent R ²⁰ substituents on the Cy ^A ring, together with the atoms to which they are attached, form a C ₃ . ₇ cycloalkyl fused ring; wherein the ring-forming carbon atom of the C ₃ . ₇ cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein the C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

each R ²¹ is independently selected from C1-6 alkyl, C2.6αalkenyl, C2.6alkynyl, C1-6haloalkyl, C3.10cycloalkyl, 4-10 membered heterocycloalkyl, C6.10aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a4 , SR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 and NR ^c4 C(O)OR ^a4 ; wherein each said C1-6 alkyl, C _2.6αalkenyl , C _2.6alkynyl , C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, _{C 6_10 aryl} and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ;

each R ²² is independently selected from C1_6alkyl, C2-6alkenyl, C2-6alkynyl, C1_6haloalkyl, phenyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, halogen, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 and NR ^c6 C(O)OR ^a6 ; wherein each said C^alkyl, _C2.6alkenyl , _C2-6alkynyl and 5-6-membered heteroaryl is optionally substituted with 1 substituent independently selected from R ^g ;

each R ^a1 _, R ^c1 and R ^d1 is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl and C _3-10 cycloalkyl; wherein each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-10 cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from R ¹¹ ;

each R ^b1 is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _{3_10} cycloalkyl, _4-10 membered heterocycloalkyl, C _{6_10} aryl and 5-10 membered heteroaryl; wherein each said C _{1_6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3_10} cycloalkyl, _4-10 membered heterocycloalkyl, _{C 6_10 aryl} and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ _;

each R ^a2 , R ^c2 and R ^d2 is independently selected from H, _{C1_6} alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _{C1_6} haloalkyl and 4-10 membered heterocycloalkyl; each said _{C1_6} alkyl and 4-10 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²¹ ;

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

each R ^b2 is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl; wherein each said C 1_ ₆ alkyl, C _{3_ 10} cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²¹ ;

each R ^a3 , R ^c3 and R ^d3 is independently selected from H, _{C1_6} alkyl, _C2-6 alkenyl, _C2-6 alkynyl and _{C1_6} haloalkyl;

each R ^b3 is independently selected from _{C1_6} alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _{C1_6} haloalkyl, and phenyl;

each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, phenyl, C _3-6 cycloalkyl, 5-6-membered heteroaryl and 4-7-membered heterocycloalkyl; wherein each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl, C _3-6 cycloalkyl, 5-6-membered heteroaryl and 4-7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²² ;

or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

each R ^b4 is independently selected from _{C1_6} alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _{C1_6} haloalkyl, _{C3_6 cycloalkyl} , and phenyl;

each R ^a5 , R ^c5 and R ^d5 is independently selected from H, _{C1_6} alkyl, _C2-6 alkenyl, _C2-6 alkynyl and _{C1_6} haloalkyl;

each R ^b5 is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _1-6 haloalkyl;

each R ^a6 , R ^c6 and R ^d6 is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _1-6 haloalkyl;

each R ^b6 is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _1-6 haloalkyl; and each R ^g is independently selected from OH, NO ₂ , CN, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _{3_6} cycloalkyl- _{C 1_2} alkylene, C _1-6 alkoxy, C _1-6 haloalkoxy, _{C 1_3 alkoxy} - _{C 1_3} alkyl, _{C 1_3 alkoxy} - _{C 1_3} alkoxy, HO-C _{1. 3} αalkoxy, HO- _{C 1 . 3} alkyl, cyano-C1_ ₃ alkyl, H ₂ NC1_ ₃ alkyl, amino, C1_ ₆ alkylamino, di(C1_ ₆ alkyl) amino, thio, C1_ ₆ alkylthio, C1_ ₆ alkylsulfinyl, C1_

- 11 048980 balkylsulfonyl, carbamyl, C _1-6 alkylcarbamyl, di(C _1-6 alkyl) carbamyl, carboxy, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamino, aminosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl) aminosulfonyl, aminosulfonylamino, C ₁ . ₆ alkylaminosulfonylamino, di(C _1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C ₁ - ₆ alkylaminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino.

In some embodiments of the invention

R ¹ is Cy ¹ ;

Cy ¹ is selected from 4-10-membered heterocycloalkyl, C _6-10 aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein the ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein the 4-10-membered heterocycloalkyl, C _6-10 aryl and 5-10-membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ ;

Cy ^A is C _6-10 aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²⁰ ;

R ² is H;

each R ¹⁰ is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a1 , C(O)NR ^c1 R ^d1 and NR ^c1 R ^d1 ; wherein each said C2_ ₆ alkenyl, C _{2.6 alkynyl, C3.10 cycloalkyl} , _4-10 membered heterocycloalkyl, _{C6.10 aryl} and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ;

each R ¹¹ is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a3 , C(O)OR ^a3 , C(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , S(O)2R ^b3 and S(O)2NR ^c3 R ^d3 ; wherein each said C1_ ₆ alkyl, C _{2.6 alkenyl} , C _2.6 alkynyl, _{C 3.10 cycloalkyl} , _4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ;

each R ¹² is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, halogen, and CN;

each R ²⁰ is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C1.3 alkylene, halogen, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR c2 R ^d2 , NR ^{c2 C} (O)R ^b2 , NR ^c2 C(O)OR ^a2 and NR ^c2 C(O)NR ^c2 R ^d2 ; wherein each said C1_6 alkyl, C2-6 alkenyl, C2. ₆ alkynyl, _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl, _C6.10 aryl, _5-10 membered heteroaryl and 4-10 membered heterocycloalkyl- _{C1.3 alkylene} is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R21 ;

or two adjacent R ²⁰ substituents on the CyA ring, together with the atoms to which they are attached, form a C _{3_7} cycloalkyl fused ring; wherein the ring-forming carbon atom _{of the C 3_7 cycloalkyl fused} ring is optionally substituted with oxo to form a carbonyl group; and wherein the _{C 3_7 cycloalkyl} fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

each R ²¹ is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5- to 10-membered heteroaryl, halogen, CN, OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O) ^RM and NR ^c4 C(O)OR ^a4 ; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ;

each R ²² is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halogen, CN, OR ^a6 , NR ^c6 R ^d6 and NR ^c6 C(O) R ^b6 ; wherein each said C1_ ₆ alkyl, C _{2.6 alkenyl} , C _{2.6 alkynyl} and 5-6 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ^g ;

each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C ₁ .6 _alkyl and C ₃ _ ₁₀ cycloalkyl; wherein each said C ₁ _ ₆ alkyl and C ₃ _ ₁₀ cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ¹¹ ;

each R ^a2 , R ^c2 and R ^d2 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl and 4- to 10-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and 4- to 10-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ;

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

- 12 048980 each R ^b2 is independently selected from _C1-6 alkyl, _C3-10 cycloalkyl, 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl; wherein each said _C1-6 alkyl, _C3-10 cycloalkyl, 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ;

each R ^a3 _, R ^c3 and R ^d3 is independently selected from H, _{C 1_6 alkyl} , C _2-6 alkenyl, C _2-6 alkynyl and C _{1_6} haloalkyl;

each R ^b3 is independently selected from C _{1_6} alkyl, _{C 2-6} alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, and phenyl;

each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 6-haloalkyl, C _3-6 cycloalkyl, 5-6-membered heteroaryl and 4-7-membered heterocycloalkyl; wherein each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, 5-6-membered heteroaryl and 4-7-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ²² ;

or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

each Rb ⁴ is independently selected from C _1-6 alkyl;

each R ^a6 is independently selected from H and C _1-6 alkyl;

each R ^c6 and R ^d6 is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and _C1-6 haloalkyl;

each R ^b6 is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _1-6 haloalkyl; and each R ^g is independently selected from C _1-6 alkyl.

In some embodiments of the invention:

R ¹ is Cy ¹ ;

Cy ¹ is selected from 4-10-membered heterocycloalkyl, C _6-10 aryl and 5-10 _- membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein the ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein the 4-10-membered heterocycloalkyl, C _6-10 aryl and 5-10-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ¹⁰ ;

Cy ^A is C _6-10 aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²⁰ ;

R ² is H;

each R ¹⁰ is independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a1 , C(O)NR ^c1 R ^d1 and NR ^c1 R ^d1 ; wherein each said _C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ¹¹ ;

each R ¹¹ is independently selected from C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halogen, CN, OR ^a3 , C(O)OR ^a3 and S(O)2R ^b3 ; wherein each said C _1-6 alkyl, C _6-10 aryl, _5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ¹² ;

each R ¹² is C _1-6 alkyl, halogen or CN;

each R ²⁰ is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1-3 alkylene, halogen, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 and NR ^c2 C(O)NR ^c2 R ^d2 ; wherein each said C1-6alkyl, _{C3-10cycloalkyl} , _4-10 -membered heterocycloalkyl and 4-10-membered heterocycloalkyl- _C1-3alkylene is optionally substituted with 1 or 2 substituents independently selected from ^R21 ;

or two adjacent R ²⁰ substituents on the CyA ring, together with the atoms to which they are attached, form a C _3-7 cycloalkyl fused ring; and wherein the C _3-7 cycloalkyl fused ring is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ;

each R ²¹ is C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 and NR ^c4 C(O)OR ^a4 ; wherein each said C1-6 alkyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ²² ;

each R ²² is independently selected from C1-6 alkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, OR ^a6 and NR ^c6 R ^d6 ; wherein each said C1-6 alkyl and 5-6 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ^g ;

each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C _1-6 alkyl and C _3-10 cycloalkyl; wherein each said C _1-6 alkyl and C _3-10 cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ¹¹ ;

each R ^a2 , R ^c2 and R ^d2 is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl and 4-10 membered heterocycloalkyl; wherein each said C _1-6 alkyl and 4-10 membered heterocycloalkyl is optionally

- 13 048980 but substituted with 1 or 2 substituents independently selected from R ²¹ ;

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

each R ^b2 is independently selected from C _1-6 alkyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl; wherein each said C _1-6 alkyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ;

each R ^a3 is independently selected from H and C _1-6 alkyl;

each R ^b3 is C _1-6 alkyl;

each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein each said C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ²² ;

or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

each R ^b4 is independently selected from C _1- 6 alkyl;

each R ^a6 is independently selected from H and C _1-6 alkyl;

each R ^c6 and R ^d6 is H; and each R ^g is independently selected from C _1-6 alkyl.

In some embodiments of the invention, the compound is selected from

4-(5-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)thiazol-2-yl)morpholine;

5-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3methylisoxazole;

5-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2methylthiazole;

1-(4-bromophenyl)-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4- 14 048980

c]pyridin-3-yl)piperazin-2-one;

2-(5-(2-fluoro-6-methoxymethyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)1,2,3,4-tetrahydroisoquinoline-7-carbonitrile;

4-(4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)piperazin-1-yl)benzonitrile;

5-(2-fluoro-6-methoxyphenyl)-3-(4-(pyridin-4-yl)piperazin-1-yl)1H-pyrazolo[3,4-c]pyridine;

1-[1-(3-fluoro-5-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1Hpyrazolo[3,4-c]pyridin-5-yl}phenyl)cyclopropyl]methanamine;

5-(2-fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)1H-pyrazolo[3,4-c]pyridine;

5-(2,6-difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridine;

5-(2,6-dimethylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridine;

3-(4-(4-methylpiperazin-1-yl)phenyl)-5-(2,4,6-trifluorophenyl)-1Hpyrazolo[3,4-c]pyridine;

5-(2-chloro-6-trifluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)1H-pyrazolo[3,4-c]pyridine;

3,5-difluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenol;

5-(2-fluoro-6-methylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridine;

5-(2-chloro-6-(trifluoromethyl)phenyl)-3-(4-(4-methylpiperazin-1yl)phenyl)-1H-pyrazolo[3,4-c]pyridine;

5-(2-ethoxy-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridine;

5-(2-chloro-6-methoxyphenyl)-3-(4-(4a-methylpiperazin-1-yl)phenyl)1H-pyrazolo[3,4-c]pyridine; And

5-(2-fluoro-6-(trifluoromethyl)phenyl)-3-(4-(4-methylpiperazin-1yl)phenyl)-1H-pyrazolo[3,4-c]pyridine;

or a pharmaceutically acceptable salt thereof.

Connection selected from

3,5-difluoro-N-(2-methoxyethyl)-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzamide;

- 15 048980 (3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)(3-methoxyazetidin-1-yl)methanone;

N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)cyclobutanecarboxamide;

N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-2-phenylacetamide;

2,4-difluoro-N-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)aniline;

2,4-difluoro-N,N-dimethyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)aniline;

3,5-difluoro-N,N-dimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyrilin-5-yl)aniline;

N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide;

N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide;

2-cyclopentyl-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide;

N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide;

2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(3,5-difluoro-4-(3 - (1-methyl 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-2-(7-oxa-2-azaspiro[3.5]nonan-2yl)acetamide;

N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)propanamide;

1-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-3-(2-methoxyethyl)urea;

2-(azetidin-1-yl)-N-(3-(difluoromethoxy)-5-fluoro-4-(3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide;

N-(3-chloro-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide N-(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

- 16 048980

2-(3,3-dimethylazetidin-1-yl)-N-(3-fluoro-5-methoxy-4-(3-(1-methyl 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide 1-methylpiperidin-4-yl-3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenylcarbamate;

2-(azetidin-1-yl)-N-(2,3,5-trifluoro-4-(3-(1-methyl-1H-pyrazol-4yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide;

N-(3-chloro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(dimethylamino)acetamide;

2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(3-methyl-4-(3-(1methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)acetamide;

N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide 2-(dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide;

2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(3-fluoro-5-methyl-4-(3-(1methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)acetamide;

2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(3-fluoro-5-methyl-4(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)acetamide;

3-(dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)propanamide;

2-cyano-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide;

N-methyl-1-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine;

N-methyl-1-(4-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine;

N-methyl-1-(3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-2-(trifluoromethyl)phenyl)methanamine;

5-(3-(azetidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

N-(3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-4-amine;

- 17 048980

N-(3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-2-(trifluoromethyl)benzyl)propan-2-amine;

1-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

N-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine;

5-(3-(azetidin-1-ylmethyl)-6-fluoro-2-methylphenyl)-3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

3-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-N-isopropylcyclobutanamine;

2-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-N-methylethanamine;

2-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-N-methylethanamine;

N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenethyl)tetrahydro-2H-pyran-4-amine;

N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenethyl)-1-isopropylazetidin-3-amine;

2-fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin3-yl)-N-methylbenzamide;

5-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-Nmethylpicolinamide;

4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2methoxy-N-methylbenzamide;

4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)N,2-dimethylbenzamide;

1-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-isopropyl-II-imidazole-4-carboxamide;

1-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-Nmethyl-1H-imidazole-4-carboxamide;

5-(4-(azetidin-2-ylmethoxy)-2,6-difluorophenyl)-3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

5-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-3-(1methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

5-(2,6-difluoro-4-(pyridin-4-ylmethoxy)phenyl)-3-(1-methyl-1H- 18 048980 pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyldimethylcarbamate;

3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenylmorpholine-4-carboxylate;

N-methyl-1-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine;

N-methyl-1-(4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-3-(trifluoromethyl)phenyl)methanamine;

1-(5-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ol;

1-(3-fluoro-4-(3-(6-(3-methoxypiperidin-1-yl)pyridin-3-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-5-methylphenyl)-N-methylmethanamine;

5-(2-fluoro-6-methoxyphenyl)-3-(6-(1-methylpiperidin-4-yl)pyridin2-yl)-1H-pyrazolo[3,4-c]pyridine;

1-(3-fluoro-5-methyl-4-(3-(6-morpholinopyridin-2-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

N-ethyl-6-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)-N-methylpyridin-2-amine;

1-(3-fluoro-4-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine;

1-(4-(3-(6-cyclopropylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethanamine;

1-(3-fluoro-4-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine;

1-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-N-methylmethanamine;

N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)benzyl)propan-2-amine;

N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)benzyl)pyridin-2-amine;

N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)benzyl)-1-methyl-1H-pyrazol-3-amine;

2-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- 19 048980

c]pyridin-5-yl)benzylamino)ethanol;

1-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-N-methylmethanamine;

N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)benzyl)propan-2-amine;

N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)benzyl)cyclopropanamine;

5-(2,6-difluoro-3-((3-methoxypiperidin-1-yl)methyl)phenyl)-3-(1methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

1-(3-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine;

1-(3-fluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-Nmethylmethanamine;

1-(4-(3-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-3-fluoro-5-methylphenyl)-N-methylmethanamine;

1-(4-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-3-fluoro-5-methylphenyl)-N-methylmethanamine;

2-(4-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)benzonitrile;

1-(3-fluoro-5-methyl-4-(3-(1-(tetrahydro-2H-pyran-4-yl)-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

1-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-N-methylcyclopropanamine;

1-(4-Fluoro-2-methoxy-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

N-(4-fluoro-2-methoxy-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine;

2-(4-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)benzonitrile;

1-(4-(3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-3,5-difluorophenyl)-N-methylmethanamine;

1-(3,5-difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

- 20 048980

2-(4-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)ethanol;

1-(3,5-difluoro-4-(3-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin5-yl)phenyl)-N-methylmethanamine;

1-(5-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol;

1-(3,5-difluoro-4-(3-(5-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

4-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide;

4-(5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-1H-pyrazolo[3,4 c]pyridin-3-yl)-N-methylbenzamide;

5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

5-(2-fluoro-6-methyl-4-(1-methylpyrrolidin-2-yl)phenyl)-3-(1-methyl1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (enantiomer 1);

5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (enantiomer 2);

N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine;

N-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)cyclopropanamine;

N-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine;

2,2,2-τρπφτορ-Ν-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl) 1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine;

2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzylamino)ethanol;

3-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzylamino)cyclobutanol;

5-(4-(azetidin-1-ylmethyl)-2-fluoro-6-methylphenyl)-3-(1-methyl-1H- 21 048980 pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzylamino)-2-methylpropan-2-ol;

5-(2-fluoro-4-((3-methoxyazetidin-1-yl)methyl)-6-methylphenyl)-3-(1methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-(1-methyl-1H-imidazol-4yl)methanamine;

N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-(oxazol-4-yl)methanamine;

2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzylamino)acetonitrile;

1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine;

1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine;

N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)acetamide;

Methyl 3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzylcarbamate;

1-(4-(6-(5-(2-(difluoromethoxy)-6-fluoro-4((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)pyridin-3-yl)piperazin-1-yl)ethanone;

2-(3-fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile;

(3-fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)methanamine;

(3-fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)methanol;

4,6-difluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine;

4,6-difluoro-N-methyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine;

6,8-difluoro-N-methyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine

- 22 048980

6,8-difluoro-N-methyl-7-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine 4-(5-(1,3-difluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-2yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide;

5,7-difluoro-N-methyl-6-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine 5,7-difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine 4-(5-(4,6-difluoro-3-(methylamino)-2,3-dihydro-1H-inden-5-yl)-1Hpyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide;

5,7-difluoro-N-methyl-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine;

5-fluoro-7-methoxy-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine;

5-fluoro-7-methoxy-6-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine;

5-(5-(2-fluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-1-yl)1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpicolinamide;

6-fluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine 6-fluoro-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;

2-(3,5-difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile;

5,7-difluoro-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol;

5,7-difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol;

1-(3,5-difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

1-(5-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)pyrimidin-2-yl)piperidin-4-ol;

1-(3,5-difluoro-4-(3-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

4-φτορ-Ν,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H- 23 048980 pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine;

5-(3-((3,3,Dimethylazetidin-1-yl)methyl)-6-fluoro-2-methylphenyl)-3(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

Trans-N-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)-3-methoxycyclobutanamine;

N-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)-3,3-dimethylcyclobutanamine;

N-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-(1methylcyclopropyl)methanamine;

1-(4-fluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-2-(trifluoromethyl)phenyl)-N-methylmethanamine;

5-(2-fluoro-4-(pyrrolidin-2-yl)-6-(trifluoromethyl)phenyl)-3-(1methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine;

1-(4-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-3-fluoro-5-methylphenyl)-N-methylethanamine;

3-(1-ethyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-(piperidin-2yl)phenyl)-1H-pyrazolo[3,4-c]pyridine;

3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4(piperidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine;

3-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)morpholine;

1-(3-(difluoromethyl)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine;

N-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine;

N-(3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-2-(trifluoromethyl)benzyl)ethanamine;

6-fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine and

6-fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine, or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the compound is 5-(3-(azetidin-1-ylmethyl)-6-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the compound is U-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the compound is 5-(4-(azetidin-1-ylmethyl)-2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the compound is N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to a pharmaceutical composition for inhibiting hematopoietic progenitor kinase 1 (HPK1) activity, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable

- 24 048980 carrier or excipient.

Another embodiment of the invention relates to a method of inhibiting hematopoietic progenitor kinase 1 (HPK1) activity, said method comprising administering to a patient a compound of the invention, or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to a method of treating a disease or disorder associated with inhibition of hematopoietic progenitor kinase 1 (HPK1) interaction, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to a method of treating cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer, or pancreatic cancer.

It is further understood that certain features of the invention which, for clarity, are described in the context of separate embodiments of the invention, are also provided in combination in a single embodiment of the invention (although it is intended that the embodiments of the invention are combined as if in multiple dependent form). Conversely, various features of the invention which, for brevity, are described in the context of a single embodiment of the invention, are also provided separately or in suitable subcombination. Accordingly, it is intended that features described as embodiments of the invention of compounds of formula (I) are combined in any suitable combination.

Certain features of the compounds are disclosed by groups or ranges at various places in this specification. Such disclosure is expressly intended to include any and all distinct subcombinations of members of such groups and ranges. For example, the term _{C1_6} alkyl is expressly intended to separately disclose (without limitation) methyl, ethyl, _C3 alkyl, _C4 alkyl, _C5 alkyl, and _C6 alkyl.

The term n-membered, where n is an integer, generally describes the number of ring-forming atoms in a molecular 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, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

Variables defining divalent linkers are described at various places in this description. Each linker substituent is specifically intended to include both left-to-right and right-to-left writing of the linker substituent. For example, -NR(CR'R)n- includes both -NR(CR'R)n- and -(CR'R'')nNR-, and is intended to be disclosed separately. When a linker is required in a structure, the linkers are intended to be the Markush variables listed for those linkers. For example, if a linker is required in a structure and the Markush group definition for a given variable lists alkyl or aryl, the alkyl or aryl is intended to be an alkylene linker or an arylene linker, respectively.

The term substituted implies that an atom or group of atoms formally replaces a hydrogen as a substituent attached to another group. The term substituted, unless otherwise specified, refers to any level of substitution, i.e. mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently chosen and the substitution occurs at any chemically accessible position. Substitution at a given atom is intended to be limited by valence. Substitution at a given atom is intended to result in a chemically stable molecule. The phrase optionally substituted implies unsubstituted or substituted. The term substituted means that a hydrogen atom is removed and replaced by a substituent. One divalent substituent, such as oxo, replaces two hydrogen atoms.

The term C _n _m indicates a range that includes extreme values, where n and m are integers and indicate the number of carbon atoms. Examples include Cm, C1_ ₆ , and the like.

The term alkyl, used alone or in combination with other terms, refers to a saturated hydrocarbon group that is straight or branched. _{The term C n_t alkyl} refers to any alkyl group having from n to m carbon atoms. An alkyl group formally corresponds to an alkane with one CH bond replaced by an alkyl group at the bond point to the remainder of the compound. In some embodiments, an alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 dicarbon atoms. Examples of alkyl moieties of a molecule include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; higher homologues, namely 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

The term alkenyl, used alone or in combination with other terms, refers to

- 25 048980 a straight or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene with one C H bond replaced by an alkenyl group at the bond point with the remainder of the compound. The term C _nm alkenyl refers to any alkenyl group having from n to m carbon atoms. In some embodiments of the invention, the alkenyl portion of the molecule contains from 2 to 6, from 2 to 4, or from 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

The term alkynyl, used alone or in combination with other terms, refers to a straight or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne with one C H bond replaced by an alkyl group at the bond point to the remainder of the compound. The term C _nm alkynyl refers to an alkynyl group having from n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl portion of the molecule contains from 2 to 6, from 2 to 4, or from 2 to 3 carbon atoms.

The term alkylene, used alone or in combination with other terms, refers to a divalent alkyl linker. An alkylene group formally corresponds to an alkane with two C H bonds replaced by an alkylene group at the bond point to the remainder of the compound. The term C _nm alkylene refers to an alkylene group having from n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methylpropane-1,3-diyl, and the like.

The term alkosky, used alone or in combination with other terms, refers to a group of the formula -O-alkyl, wherein the alkyl group is defined above. The term C _nm alkosky refers to an alkoxy group, the alkyl group of which contains from n to m carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkynyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

The term amino refers to a group of formula -NH2.

The term carbonyl, used alone or in combination with other terms, refers to the C(=O) group, which can also be written as C(O).

The term cyano or nitrile refers to a group with the formula -C=N, which can also be written as -CN.

The term halogen, used alone or in combination with other terms, refers to fluorine, chlorine, bromine, or iodine. In some embodiments, halogen refers to atoms selected from F, Cl, or Br. In some embodiments, halogen is F.

The term "haloalkyl" as used herein refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen atom. The term "C _nm haloalkyl" REFERS to a C _nm alkyl group having from n to m carbon atoms and at least 1 and up to {2(n to m)+1} halogen atoms, which are the same or different. In some embodiments, the halogen atoms are fluorine atoms. In some embodiments, the haloalkyl group has from 1 to 6 or from 1 to 4 carbon atoms. Examples of haloalkyl groups include CF ₃ , C ₂ F ₅ , CHF2, CH2F, CCl ₃ , CHCl ₂ , C ₂ Cl ₅ and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

The term haloalkoxy, used alone or in combination with other terms, refers to a group of the formula -O-haloalkyl, wherein the haloalkyl group is defined above. The term C _nm haloalkoxy refers to a haloalkoxy group, the haloalkyl group of which contains from n to m carbon atoms. Examples of haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkynyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

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

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 with aromatic character (i.e., having (4n+2) delocalized (pi) electrons, where n is an integer).

The term aryl, used alone or in combination with other terms, refers to an aromatic hydrocarbon group that is monocyclic or polycyclic (e.g.

- 26 048980 mers having 2 conjugated rings). The term C _n . _m aryl refers to an aryl group having from n to m carbon atoms in the ring. Aryl groups include, for example, phenyl, naphthyl, and the like. In some embodiments, aryl groups contain from 6 to about 10 carbon atoms. In some embodiments, aryl groups contain 6 carbon atoms. In some embodiments, aryl groups contain 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

The term heteroaryl or heteroaromatic, used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatomic ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring comprises 1, 2, 3, or 4 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety of the molecule is an N-oxide. In some embodiments, the heteroaryl comprises 5 to 14 ring atoms, including carbon atoms, and 1, 2, 3, or 4 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl comprises 5 to 10 ring atoms, including carbon atoms, and 1, 2, 3, or 4 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl comprises 5 to 6 ring atoms and 1 or 2 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-membered or 6-membered heteroaryl ring. In other embodiments, the heteroaryl is an 8-membered, 9-membered, or 10-membered conjugated bicyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolyl, isoquinolyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridinyl), 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 5-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, or 3) of the ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryl rings 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 6-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. Typical 6-membered heteroaryl rings include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

The term cycloalkyl, used alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic) including cyclized alkyl and alkenyl groups. The term C _{n_m cycloalkyl} refers to a cycloalkyl that contains from n to m carbon atoms in the ring. Cycloalkyl groups include mono- or polycyclic (e.g., having 2, 3, or 4 conjugated rings) groups or spiro rings. A cycloalkyl group contains 3, 4, 5, 6, or 7 ring-forming carbon atoms (C ₃ . ₇ ). In some embodiments, a cycloalkyl group contains from 3 to 6 ring members, from 3 to 5 ring members, or from 3 to 4 ring members. In some embodiments, a cycloalkyl group is monocyclic. In some embodiments, a cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a _{C 3_6 monocyclic} cycloalkyl group, the ring-forming carbon atoms in the cycloalkyl group are optionally oxylened to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Also included within the definition of cycloalkyl are moieties that have one or more aromatic rings conjugated with (i.e., having a bond along with) the cycloalkyl ring, for example, benzo- or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a conjugated aromatic ring is attached through any ring-forming atom, including a ring-forming atom of a conjugated 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.

- 27 048980

The term heterocycloalkyl, used alone or in combination with other terms, refers to a non-aromatic ring or ring system that optionally contains one or more alkenylene groups as part of the ring structure that contains at least one heteroatomic ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and that contains from 4 to 10 ring members, from 4 to 7 ring members, or from 4 to 6 ring members. Included within the term heterocycloalkyl are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups include mono- or bicyclic (e.g., having two conjugated rings or bridged rings) and spiro-cyclic ring systems. In some embodiments, a heterocycloalkyl group is a monocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. the ring-forming carbon atoms and heteroatoms in the heterocycloalkyl group are optionally oxidized to form an oxo or sulfido group, or other oxidized linkers (e.g., C(O), S(O), C(S) or S(O) ₂ , N-oxide, and the like), or the nitrogen atom is quaternary.

A heterocycloalkyl group is attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains from 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are moieties that have one or more aromatic rings conjugated with (i.e., having a bond along with) a heterocycloalkyl ring, for example, benzo- or thienyl derivatives of piperidine, morpholine, azepine, and the like. A heterocycloalkyl group containing a conjugated aromatic ring is attached via any ring-forming atom, including a ring-forming atom of a conjugated aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxo-piperazin-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-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, tropanyl, benzodioxole and thiomorpholino.

In certain places, definitions and embodiments of the invention refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings are attached to any member of the ring, provided that the valency of the atom is not exceeded. For example, the azetidine ring is attached to any position of the ring, with azetidin3-yl being attached at position 3.

The compounds described herein are asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, namely enantiomers and diastereomers, are intended. The compounds of this invention that contain asymmetrically substituted carbon atoms are isolated in optically active or racemic forms. Methods of preparing optically active forms from optically inactive starting materials are known in the art as methods of resolving racemic mixtures or stereoselective synthesis. The compounds described herein also contain many geometric isomers of olefins, C=N double bonds, and the like, and all such stable isomers are contemplated by this invention. Geometric cis and trans isomers of the compounds of this invention are described and can be isolated as mixtures of isomers or individual isomeric forms.

The separation of racemic mixtures of compounds is carried out by any of a number of methods known in the art. One method involves fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, namely the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, namely beta-camphorsulfonic acid. Other resolving agents for fractional recrystallization methods include stereoisomerically pure forms of alpha-methylbenzenamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Separation of racemic mixtures is also carried out by elution through a column filled with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine). A person skilled in the art can determine a suitable composition of the elution solvent.

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

The compounds of the invention also include tautomeric forms. The tautomeric forms form

- 28 048980 by exchange between a single bond and an adjacent double bond and the attendant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and net charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidoacid pairs, lactam-lactim pairs, enamine-imine pairs, and ring forms in which a proton occupies two or more positions in the heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms are in equilibrium or sterically locked into a single form by suitable substitution.

The compounds of the invention also include all isotopes of atoms appearing in the intermediate or final compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms in the compounds of the invention are replaced or substituted with isotopes of atoms that are abundant or uncommon in nature. In some embodiments, the compound comprises at least one deuterium atom. For example, one or more hydrogen atoms in a compound of this invention are replaced or substituted with deuterium. In some embodiments, the compound comprises one or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Methods for the synthesis of isotope introduction into organic compounds are known to those skilled in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765). Isotope indicators are used in various studies, namely NMR spectroscopy, metabolic studies and/or analysis.

Substitution with heavier isotopes, namely deuterium, provides certain therapeutic advantages as a result of greater metabolic stability, such as increased half-life in vivo, or reduced dosages, and is therefore preferred in certain 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 intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The term is also intended to refer to the compounds of the invention, regardless of how they are prepared, such as synthetically, by a biological process (e.g. metabolic or enzymatic saccharification), or a combination thereof.

All compounds and their pharmaceutically acceptable salts are in combination with other substances, namely water and solvents (e.g. hydrates and solvates), or isolated in pure form. The compounds and their salts in the solid state described herein are in various forms and include, for example, the form of solvates, including hydrates. The compounds are in any solid state, namely polymorphic or solvate, unless otherwise indicated, and it is intended that reference in the description to the compounds and their salts covers any solid state of the compound.

In some embodiments of the invention, the compounds of the invention or salts thereof are isolated in substantially pure form. Isolated in substantially pure form means that the compound is at least partially or substantially separated from the medium in which it was formed or found. Partial separation includes, for example, a composition enriched in the compounds of the invention. Partial separation includes 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 compound of the invention or a salt thereof.

As used herein, the phrase pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are medically suitable for contact with the tissues of human beings and animals without causing undue toxicity, irritation, allergic reaction or other problems or complications and that are commensurate with a reasonable balance of benefits and risks.

The expressions ambient temperature and room temperature as used in this text are understood in the art and generally refer to a temperature, for example a reaction temperature, which is approximately the temperature of the room in which the reaction occurs, for example 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 into a salt thereof. 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. Pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compounds formed, for example, from non-toxic inorganic or organic acids. Far

- 29 048980 The medically acceptable salts of this invention are synthesized from the parent compound, which contains a basic or acidic moiety of the molecule, by chemical methods. Generally, such salts are prepared by reacting the free acids or bases 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; in general, a non-aqueous medium is preferred, namely, ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN). A list of suitable salts is found in Remington's Pharmaceutical Sciences, 17th Ed., (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 illustrations, the compounds described herein include the N-oxide forms.

Synthesis.

The compounds of the invention, including their salts, are prepared by known organic synthesis techniques and according to any of the numerous possible synthetic routes, namely those described below in the schemes.

The reactions for obtaining the compounds of the invention are carried out in suitable solvents, which can be easily selected by a person skilled in the art of organic synthesis. Suitable solvents are generally inactive with respect to the starting materials (reagents), intermediates or products at the temperatures at which the reactions are carried out, for example, temperatures that are in the range from the freezing point of the solvent to the boiling point of the solvent. A given reaction is carried out in a solvent or in a mixture of more than one solvent. Depending on the specific reaction step, a person skilled in the art can select suitable solvents for a specific reaction step.

The preparation of the compounds of the invention involves the protection and deprotection of various chemical groups. One skilled in the art will readily recognize the need for protection and deprotection and the selection of suitable protecting groups. Protecting group chemistry is described, for example, 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, 6th Ed. (Wiley, 2007); Peturssion et al., Protecting Groups in Carbohydrate Chemistry, J. Chem. Educ, 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

The reactions are monitored by any suitable method known in the art. For example, product formation is monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or ^13C ), infrared spectroscopy, spectrophotometry (e.g., in the UV region), mass spectrometry, or chromatographic methods, such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC).

The schemes below provide general guidance for the preparation of compounds of the invention. One skilled in the art will appreciate that the preparation methods depicted in the schemes can be modified or optimized to prepare various compounds of the invention using general knowledge of organic chemistry.

Compounds of formula (I) are prepared using, for example, the methods shown in the diagrams below.

Compounds of formula (I) with various substituents at R ¹ described herein are prepared using the methods depicted in Scheme 1. In the method depicted in Scheme 1, compounds of formula 1-2 are formed after protection of the NH group of compounds of formula 1-1 with a suitable protecting group (e.g., SEM or BOC). The chloro substituent in compounds of formula 1-2 is converted to Cy ^A via various 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)) reactions, and others, to provide compounds of formula 1-3. Removal of the protecting group (e.g., under acidic conditions, such as by treatment with HCl or TFA) leads to the formation of compounds of formula 1-4. These compounds are further halogenated with one of the halogenating agents (e.g. NIS or iodine) to form compounds of formula 1-5. The NH group in the pyrazole ring of compounds of formula 1-5 is protected with a suitable protecting group, namely BOC or SEM, to form compounds of formula 1-6. The halogen substituent in compounds of formula 1-6 is converted to R ¹ via several cross-coupling reactions, including the Stille (ACS Catalysis 2015, 5, 3040-3053), Suzuki (Tetrahedron 2002, 58, 9633-9695), Sonogashira (Chem. Soc. Rev. 2011, 40, 5084-5121), Negishi (ACS Catalysis 2016, 6, 1540-1552), Buchwald-Hartwig amination (Chem. Sci. 2011, 2, 27-50), Cu-catalyzed amination (Org. React. 2014, 85, 1-688), and others, to produce compounds of formula 1-7. Finally, removal of the protecting group under acidic conditions (e.g., treatment with HCl or TFA) leads to the formation of the target compounds of formula (I).

- 30 048980

Scheme 1

Alternatively, to study the substitution at the Cy ^A position, compounds of formula (I) are prepared using the method depicted in Scheme 2. Iodination of compounds of formula 1-1 with one of the iodination agents, namely iodine or NIS, gives compounds of formula 2-2. The NH group on the pyrazole ring of compounds of formula 2-2 is protected with a suitable protecting group (e.g., BOC or SEM) to form compounds of formula 2-3. The iodine substituent in compounds of formula 2-3 is converted to R ¹ via several different cross-coupling reactions, including Suzuki, Sonogashira, Negishi, Buchwald-Hartwig amination, Cu-catalyzed amination, and others, to give compounds of formula 2-4. The chloro substituent in compounds of formula 2-4 is further converted to Cy ^A via several different cross-coupling reactions, including Suzuki, Stille, and others, to give compounds of formula 2-5. Finally, removal of the protecting group, for example under acidic conditions, namely by treatment with HCl or TFA, leads to the formation of the target compounds of formula (I).

Scheme 2

Compounds of formula (Ia) (compounds of formula I wherein R ¹ is NR ^c C(O)R ^b ) are prepared by the process depicted in Scheme 3. In the process depicted in Scheme 3, compounds of formula 3-1 are reacted with hydroxylamine hydrochloride to form intermediate oximes, which are further converted to compounds of formula 3-2 under standard conditions (e.g., treatment with cyanuric chloride). Cyclization upon treatment of compounds of formula 3-2 with hydrazine hydrate affords compounds of formula 3-3. The NH group on the pyrazole ring of compounds of formula 3-3 is protected with a suitable protecting group (e.g., BOC) to afford compounds of formula 34. The halogen substituent in compounds of formula 3-4 is further converted to Cy ^A via several different cross-coupling reactions, including Suzuki, Stille, and other reactions, to afford compounds of formula 3-5. Compounds of formula 3-5 react with various acid chlorides in the presence of a base, namely triethylamine or DIPEA, to form compounds of formula 36. Finally, removal of the protecting group, for example under acidic conditions, namely by treatment with HCl or TFA, leads to the formation of the target compounds of formula (Ia). Alternatively, compounds

- 31 048980 formulas 3-6 are alkylated or arylated and then deprotected to give amides where R ^c is not hydrogen.

Scheme 3

Compounds of formula (Ib) (compounds of formula I wherein R ¹ is C(O)NR ^c R ^d ) are prepared by the process depicted in Scheme 4. In the process depicted in Scheme 4, compounds of formula 1-6 are converted to compounds of formula 4-2 under Pd-catalyzed carbonylation conditions, namely, in the presence of a Pd catalyst (e.g., Pd(dppf)Cl ₂ *DCM) and a base (e.g., triethylamine) under carbon monoxide atmosphere. Hydrolysis of the ester group under basic conditions, namely, LiOH or NaOH, leads to the formation of a compound of formula 4-3. Compounds of formula 4-3 are conjugated with an amine, HNR ^c R ^{d ,} using standard amide coupling agents (e.g., HBTU, HATU, or EDC) to provide compounds of formula 4-4. Finally, removal of the protecting group, for example under acidic conditions, namely by treatment with HCl or TFA, leads to the formation of target compounds of formula (Ib).

Scheme 4

Compounds of formula (Ic) (compounds of formula I wherein R ² is F) are prepared by the method depicted in Scheme 5. As depicted in Scheme 5, cross-coupling reactions (e.g., Suzuki and Stille) with 2-bromo-3,5-difluoropyridine afford compounds of formula 5-2. Treatment of 5-2 with LDA at -78 °C followed by quenching with methyl formate affords 5-3, which is further converted to 5-4 by treatment with hydrazine. Upon treatment with NIS, 5-4 is converted to 5-5. The NH group on the pyrazole ring in 5-5 is protected with a suitable protecting group (e.g., BOC) to afford compounds of formula 5-6. The iodine substituent in 5-6 is further converted to R ¹ via several cross-coupling reactions (e.g., Suzuki, Stille, Buchwald-Hartwig, and others) to yield compounds of formula 5-7. Finally, deprotection yields the target compounds of formula (Ic).

- 32 048980

Scheme 5

Alternatively, compounds of formula (Ic) (compounds of formula I wherein R ² is F) are prepared using the method depicted in Scheme 6. As depicted in Scheme 6, treatment of 2-bromo-3,5-difluoropyridine with LDA at -78 °C followed by quenching with methyl formate provides 2-bromo-3,5-difluoroisonicotinaldehyde, which is further reduced to (2-bromo-3,5-difluoropyridinyl-4-yl)methanol by treatment with NaBH ₄ . (2-bromo-3,5-difluoropyridinyl-4-yl)methanol is then converted to compounds of formula 6-3 via cross-coupling reactions (e.g., Suzuki or Stille reactions). Upon oxidation (e.g., with Dess-Matrin periodinane), 6-3 is converted to 5-3, which is further converted to 5-4 by treatment with hydrazine. Treatment of 5-4 with NIS affords 5-5. The NH group on the pyrazole ring in 5-5 is protected with a suitable protecting group (e.g., BOC) to afford compounds of formula 5-6. The iodine substituent in 5-6 is further converted to R ¹ via several cross-coupling reactions (e.g., Suzuki, Stille, Buchwald-Hartwig, and others) to afford compounds of formula 5-7. Finally, deprotection affords the target compounds of formula (Ic).

Scheme 6

- 33 048980

Compounds of formula (I) with various substituents at the R ² position (rings, alkyl and alkenyl chains, and various functional groups) are prepared using the methods depicted in Scheme 7. In the method depicted in Scheme 7, bromination of 5-chloro-4-methylpyridin-3-amine 7-1 with bromination agents (e.g., bromine or BSI) leads to the formation of compounds of formula 7-2. Acylation of the KIU group in compounds of formula 7-2 with acylation agents (e.g., Ac ₂ O or AcCl) followed by treatment with amyl nitrite leads to the formation of compounds of formula 7-3. These compounds are further iodinated with one of the iodination agents (e.g., NIS or iodine) to form compounds of formula 7-4. The NH group on the pyrazole ring of compounds of formula 7-4 is protected with a suitable protecting group, namely BOC or SEM, to form compounds of formula 7-5. The iodo substituent in compounds of formula 7-5 is converted to R ¹ via several different cross-coupling reactions, including Suzuki, Stille, Negishi, Cu-catalyzed amination, and others, to provide compounds of formula 7-6. The bromo substituent in compounds of formula 7-6 is further converted to Cy ^A via several different cross-coupling reactions, including Suzuki, Stille, Negishi, and others, to provide compounds of formula 7-7. The chloro substituent in compounds of formula 7-7 is further converted to R ² via several different cross-coupling reactions, including Suzuki, Stille, Negishi, and others, to provide compounds of formula 7-8. Finally, removal of the protecting group, for example under acidic conditions, namely by treatment with HCl or TFA, leads to the formation of the target compounds of formula (I).

Scheme 7

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). T cells from HPK1-deficient mice showed greatly increased activation of proximal TKP signaling, increased IL-2 production, and hyperproliferation in vitro when stimulated with anti-CD3 (Shui, J.W., et al., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPK1 knockout B cells produced significantly higher amounts of IgM and IgG isoforms following KLH immunization and exhibited hyperproliferation, likely 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 phosphorylation of Tyr379 and its subsequent binding to the 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 at Ser376 or BLNK at Thr152, leading to accumulation of 14-3-3 signaling molecules and ultimately ubiquitin-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). Because SLP-76 and BLNK are essential for TCR/BCR-mediated activation of signaling pathways (e.g., ERK, phospholipase Cy1, calcium influx, and NFAT activation), HPK1-mediated downregulation of these adaptor proteins triggers a negative feedback mechanism to regulate signal intensity during T cell or B cell activation (Wang, X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

Bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout mice exhibit greater expression of costimulatory molecules (e.g., CD80/CD86) and increased production of proinflammatory cytokines (IL-12, TNF-α, etc.), and show superior ability to stimulate T cell proliferation in vitro and in vivo, compared with wild-type DCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). These data suggest that HPK1 also represents

- 34 048980 is an important negative regulator of dendritic cell activation (Alzabin, S., et al., J. Immunol., 2009. 182(10): p. 6187-94). However, the signal transduction mechanism underlying HPK1-mediated negative regulation of DC activation still requires clarification.

In contrast, HPK1 appears to be a positive regulator of regulatory T cell suppressor functions (Sawasdikosol, S. et al., The journal of immunology, 2012. 188 (supplement 1): p. 163). Foxp3+ Tregs mice lacking HPK1 were defective in suppressing TCR-induced effector T cell proliferation and, paradoxically, acquired the ability to produce IL-2 with subsequent TCR establishment (Sawasdikosol, S. et al., The Journal of Immunology, 2012. 188 (supplement 1): p. 163). These data suggest that HPK1 is an important regulator of regulatory T cell functions and peripheral self-tolerance.

HPK1 is also involved in PEG2-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 indicate that HPK1 kinase activity is increased by physiological concentrations of PEG2 in CD4+ T cells, and this effect is mediated by PEG2-induced activation of PKA. Proliferation of HPK1-deficient T cells is not suppressed by PEG2 (see US 2007/0087988). Therefore, PEG2-mediated activation of HPK1 represents a novel regulatory pathway for modulating the immune response.

Application of connections.

The present invention provides methods for regulating (e.g., inhibiting) HPK1 activity, said method comprising administering to a patient a compound of the disclosure or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the disclosure or pharmaceutically acceptable salts thereof are suitable for therapeutic administration to improve, stimulate, and/or enhance immunity in cancer. For example, a method of treating a disease or disorder associated with inhibition of HPK1 action comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof. The compounds of the disclosure are used alone, in combination with other agents or regimens, or as adjuvant or non-adjuvant treatment of diseases or disorders, including cancer. Any of the compounds of the disclosure, including any embodiments thereof, are useful for the uses described herein.

Examples of cancers treatable with the compounds of this disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or intraocular malignant myeloma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, fallopian tube carcinoma, endometrial mucosal carcinoma, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic and acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, bladder cancer, renal and urethral cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasia, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, squamous cell carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including asbestos induced cancers, and combinations of these cancers.

In some embodiments, cancer treatable with the compounds of this disclosure includes melanoma (e.g., metastatic malignant melanoma), kidney cancer (e.g., renal 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 can be inhibited using the compounds of the disclosure.

In some embodiments, cancers treatable using the compounds of this disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastrointestinal cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, and the like), hematological malignancies (e.g., lymphoma, leukemia, namely, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed and refractory NHL and recurrent follicular lymphoma), Hodgkin's lymphoma and multiple myeloma) and combinations of these cancer types.

In some embodiments of the invention, diseases and symptoms treatable with

- 35 048980 uses of the compounds of this disclosure include, but are not limited to, hematological malignancies, sarcoma, lung cancer, gastrointestinal cancer, urogenital tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

Typical hematological malignancies include lymphoma and leukemia, namely 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's lymphoma (including relapsed and refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorder (eg, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplastic syndrome (MDS), acute T-cell lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, and Burkitt's lymphoma.

Typical sarcoma includes chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hamartoma, and teratoma.

Typical 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 (alveolar cell) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

Common gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

Typical cancers of the urethogenital tract include cancer of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, hilus carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

Typical liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

Common bone cancers include, for example, osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor (chordoma), osteochronophoroma (osseous cartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.

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

Common gynecologic cancers include cancer of the uterus (carcinoma of the uterine mucosa), cervix (cervical carcinoma, precancerous cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenoarcinoma, unclassified carcinoma), granulosa 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, borthroid sarcoma (embryonic rhabdomyosarcoma) and fallopian tube (carcinoma).

Typical skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, skin cancer and Merkel cell carcinoma, nevus (atypical nevus), lipoma, angioma, dermatofibroma and keloid. In some embodiments, diseases and symptoms treatable with the compounds of this disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer and urothelial carcinoma.

Common head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell sarcoma, adenocarcinoma, oral cavity cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, thyroid and parathyroid cancer.

In some embodiments of the invention, HPK1 inhibitors are used to treat cancer.

- 36,048,980 tumors that produce PEG2 (e.g. tumors overexpressing Cox-2) and/or adenosine (tumors overexpressing CD73 and CD39). Cox-2 overexpression has been detected in several tumors, namely colorectal, breast, pancreatic and lung cancers, where it correlates with poor prognosis. Cox-2 overexpression has been reported in hematological cancer models, namely Raji (Burkitt lymphoma) and U937 (acute promonocytic leukemia), and in patient-derived blast cells. CD73 is overexpressed in a variety of human carcinomas, including colorectal, lung, pancreatic and ovarian carcinomas. Importantly, higher levels of CD73 expression are associated with tumor neovascularization, invasiveness and metastasis, and shorter patient survival in breast cancer.

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

The phrase therapeutically effective amount refers to the amount of an active compound or pharmaceutical agent that produces the biological or clinical response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician.

As used herein, the term "treatment" refers to one or more of (1) inhibiting a disease, such as a disease, condition, or disorder, in an individual who experiences or exhibits the pathology or symptomology of the disease, condition, or disorder (e.g., stopping the further progression of the pathology and/or symptomology); and (2) alleviating a disease, such as alleviating a disease, condition, or disorder in an individual who experiences or exhibits the pathology or symptomology of the disease, condition, or disorder (e.g., changing the pathology and/or symptomology), namely, reducing the severity of the disease.

In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases referred to herein; for example, preventing or reducing the risk of developing a disease, condition, or disorder in an individual predisposed to the disease, condition, or disorder, but who does not yet experience or exhibit the pathology and symptomology of the disease.

Combination therapy.

Cancer cell growth and survival are influenced by multiple signaling pathways. Therefore, it is useful to combine different enzyme/protein/receptor inhibitors that exhibit different specificities for the target whose activity they regulate for the treatment of such conditions. Examples of agents that can be combined with the compounds of the invention include PI3K-AKT-mTOR signaling pathway inhibitors, Raf-MAPK signaling pathway inhibitors, JAK-STAT signaling pathway inhibitors, beta-catenin signaling pathway inhibitors, notch signaling pathway inhibitors, hedgehog signaling pathway inhibitors, Pim kinase inhibitors, and heat shock protein and cell cycle progression inhibitors. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) reduces the likelihood of drug resistance in a cell population and/or reduces the toxicity of the treatment.

For the treatment of diseases, namely cancer, the compounds of this disclosure are used in combination with another one or more enzyme/protein/receptor inhibitors. Examples of cancer include solid tumors and soft tissue tumors, namely hematological malignancies. For the treatment of cancer, the compounds of this disclosure are used in combination with one or more inhibitors of the following kinases: Akt1, Akt2, Akt3, TGF-eR, PKA, PKG, PKC, CaM kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR, PDGFeR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some embodiments, for treating cancer, the compounds of this disclosure are used in combination with one or more of the following inhibitors. Non-limiting examples of inhibitors that can be combined with the compounds of this disclosure to treat cancer include an FGFR inhibitor (FGFR1, FGFR2, FGFR3, or FGFR4, such as AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JNJ42756493, Debio1347, INCB54828, INCB62079, and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, such as ruxolitinib, baricitinib, or INCB39110), an IDO inhibitor (such as epacadostat and NLG919), an LSD1 inhibitor (such as GSK2979552, INCB59872, and INCB60003), a TDO inhibitor, a PI3K delta inhibitor (e.g., INCB50797 and INCB50465), a PI3K gamma inhibitor, namely a selective PI3K gamma inhibitor, a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAM receptor tyrosine kinase (Tyro-3, Axl, and Mer), an angiogenesis inhibitor, an interleukin receptor inhibitor, inhibitors of bromo or extraterminal family members (e.g., bromodomain inhibitors or BET inhibitors, namely, OTX015, CPI-0610, INCB54329, and INCB57643), and an adenosine receptor antagonist, or

- 37 048980 a combination thereof. HDAC inhibitors, namely panobinostat and vorinostat. C-MET inhibitors, namely onartumzumab, tivantnib and INC-280. BTK inhibitors, namely ibrutinib. mTOR inhibitors, namely paramycin, sirolimus, temsirolimus and everolimus. Raf inhibitors, namely vemurafenib and dabrafenib. MEK inhibitors, namely trametinib, selumetinib and GDC-0973. Inhibitors of Hsp90 (eg, tanespimycin), cyclin dependent kinases (eg, palbocycline), PARP (eg, olaparib) and Pim kinases (LGH447, INCB053914 and SGI-1776) can also be combined with the compounds of this invention.

The compounds of the present invention are used in combination with one or more other immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors of immune checkpoint molecules, namely CD20, 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 molecules are stimulatory checkpoint molecules selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecules are inhibitory checkpoint molecules 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 are 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 immune checkpoint molecule inhibitor is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

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

In some embodiments, the immune checkpoint molecule inhibitor is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS935559, 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 immune checkpoint molecule inhibitor is a CTLA-4 inhibitor, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the immune checkpoint molecule inhibitor is a CSF1R inhibitor, such as an anti-CSF1R antibody. In some embodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.

In some embodiments, the immune checkpoint molecule inhibitor is a LAG3 inhibitor, such as an anti-LAGS antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, IMP321, or GSK2831781.

In some embodiments, the immune checkpoint molecule inhibitor is a GITR inhibitor, such as 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 immune checkpoint molecule inhibitor is an OX40 inhibitor, such as an anti-OX40 antibody or an 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 immune checkpoint molecule inhibitor is a TIM3 inhibitor, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is MBG-453.

In some embodiments, the immune checkpoint molecule inhibitor is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments of the invention, the compounds of this disclosure are used in

- 38 048980 combinations with one or more metabolic enzyme inhibitors. In some embodiments of the invention, the metabolic enzyme inhibitor is an IDO1, TDO or arginase inhibitor. Examples of IDO1 inhibitors are epacadostat and NGL919. An example of an arginase inhibitor is CB-1158.

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

For treating diseases, namely cancer, the compounds of this disclosure are used in combination with one or more agents. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include bendamustine, nitrogen mustards, an ethyleneimine derivative, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, domustine, struptozocin, dacarbazine, and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments of the invention, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (ROM).

The compounds of this disclosure are further used in combination with other cancer treatments, such as chemotherapy, radiation therapy, targeted tumor cell delivery, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy are cytokine therapy (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibodies, adoptive T-cell transfer, oncolytic virotherapy, and small molecule immunomodulators, including thalidomide or a JAK1/2 inhibitor, and the like. The compounds are administered in combination with one or more anticancer drugs, namely chemotherapeutic drugs. Examples of chemotherapy drugs are any of: abarilix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, axitidine, azacitidine, bevacizumab, bexarotene, baricidine, bicalutamib, bleomycin, botezomib, brivanib, buparlisib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, decarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubimycin, decitabine, degarelix, denileukin, denileukin-deftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamib, epidophyllotoxin, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitanib, gemtuzumab ozogamicin, goseriline acetate, acetate histrelina, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alpha 2a, irinocetan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, lakelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastin, pemetrexed disodium, pentostatin, pilaralisib, pipobromane, plicamycin, ponatinib, prednisone, procarbazine, quinacrine, rasburicase, regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib, struptozocin, 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.

Another anticancer agent(s) is an antibody therapeutic agent, namely trastuzumab (Herceptin), antibodies to costimulatory molecules, namely CTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL10, TGF-β, etc.). Examples of antibodies to PD-1 and/or PD-L1 that can be combined with the compounds of this disclosure for the treatment of cancer or infections, namely, viral, bacterial, fungal, or parasitic infections, include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736, and SHR-1210.

Other anticancer agents include inhibitors of kinase-associated cell proliferative disorder. These kinases include, but are 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, PDK1, PKA, PKC, Rsk, and SGK.

Other anticancer agents include agents that block the migration of immune cells

- 39,048,980 cells, namely antagonists to chemokine receptors, including CCR2 and CCR4.

The compounds of this disclosure are used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants, or therapeutic antibodies.

The compounds of formula (I) or any formula described herein, a compound of any claim and described herein, or salts thereof can be combined with other immunogenic agents, namely cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that may find use include melanoma antigen peptides, namely gp100 peptides, MAGE, Trp-2, MARTI and/or tyrosinase antigens, or tumor cells transfected to express the cytokine GM-CSF.

For the treatment of cancer, the compounds of formula (I) or any formula described herein, a compound of any claim and described herein, or salts thereof, can be combined with a vaccination schedule. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, the tumor vaccines comprise proteins from viruses implicated in human cancer, namely human papillomavirus (HPV), hepatitis virus (HBV and HCV), and Kaposi's sarcoma-associated herpes virus (KHSV). In some embodiments, the compounds of this disclosure are used in combination with a prostate-specific antigen, namely heat shock proteins isolated from the tumor tissue itself. In some embodiments of the invention, compounds of formula (I) or any formula described herein, a compound of any claim and described herein, or salts thereof, can be combined with dendritic cell vaccination to activate a potential anti-tumor response.

The compounds of this disclosure are used in combination with bispecific macrocyclic peptides that target effector cells expressing Fe-alpha or Fe-gamma receptors to tumor cells. The compounds of this disclosure can also be combined with macrocyclic peptides to activate host immunological reactivity.

For the treatment of various tumors of hematopoietic origin, the compounds of this disclosure are used in combination with a bone marrow transplant.

Suitable antiviral agents that are contemplated for use in combination with the compounds of this disclosure include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents.

Examples of suitable NNRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(ROM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emtricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and called beta-L-2',3'-dichlorooxy-5-fluorocytidine); DAPD, ((-)-beta-D-2,6,-diaminourine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (VNAR, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Representative 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 antivirals include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

If more than one pharmaceutical agent is administered to a patient, they are administered simultaneously, separately, sequentially, or in combination (e.g. for more than two agents).

Compositions, dosage forms and administration.

When used as a pharmaceutical, the compounds of this disclosure are administered in the form of a pharmaceutical composition. Accordingly, the invention provides a composition comprising a compound of formula (I) or any formula described herein, a compound recited in any claim and described herein, or a pharmaceutically acceptable salt thereof, or any embodiment thereof, and at least one pharmaceutically acceptable carrier or excipient. These compositions are prepared by any method well known in the pharmaceutical art and are administered by a variety of routes depending on whether local or systemic treatment is indicated and the area to be treated. Administration is local (including transdermal, cutaneous, ocular and through mucosal routes, including intranasal, vaginal or rectal delivery), inhalational (e.g. by inhalation or insufflation of powders or aerosols, including an inhaler; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, such as intrathecal or intraventricular administration.

- 40 048980 administration. Parenteral administration is a single bolus dose or, for example, a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional carriers (powders, water or oil based), thickeners, etc. may be required.

The present invention also includes pharmaceutical compositions that contain, as an active ingredient, a compound of this disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments of the invention, the composition is suitable for topical administration. In preparing the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or sealed in such a carrier, which has the form of, for example, a capsule, sachet, paper bag, and other containers. If the excipient is used as a diluent, it is a solid, semi-liquid, or liquid material that acts as a filler, carrier, or medium for the active ingredient. The compositions are therefore in the form of tablets, pills, powders, lozenges, sachets, cachets, nostokes, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid medium), ointments containing, for example, up to 10% by weight of the active ingredient, soft or hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders.

In preparing the composition, before mixing the active compound with the other ingredients, it is milled to obtain a suitable particle size. If the active compound is substantially insoluble, it is milled to pass through a 200 mesh sieve. If the active compound is substantially water-soluble, the particle size may be adjusted by milling to obtain a substantially uniform distribution in the composition, for example, about 40 mesh.

The compounds of the invention are milled using known milling techniques, namely wet milling, to obtain particle sizes suitable for tablet or other types of moulding. Finely divided (nanoparticulate) formulations of the compounds of the invention are prepared using methods known in the art (see, for example, WO 2002/000196).

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulations further include: lubricants, namely talc, magnesium stearate and mineral oil; wetting agents; emulsifying and dispersing agents; preservatives, namely methyl and propyl hydroxybenzoates; sweetening and flavouring agents.

The compositions of the invention are formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient, using techniques 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% by weight microcrystalline cellulose and about 2% by weight silicon dioxide.

In some embodiments, the composition is a delayed 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, or 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 Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4M Premier™) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).

In some embodiments of the invention, a process is used to obtain the composition.

- 41 048980 wet granulation. In some embodiments of the invention, a dry granulation process is used to obtain the composition.

The compositions are formulated in unit dosage form, each dose containing from about 5 to about 1000 mg (1 g), typically from about 100 mg to about 500 mg of the active ingredient. In some embodiments, each dose contains about 10 mg of the antivenin ingredient. In some embodiments, each dose contains about 50 mg of the antivenin ingredient. In some embodiments, each dose contains about 25 mg of the active ingredient. The term unit dosages refers to physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined quantity of the active ingredient calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.

Compounds used to formulate pharmaceutical compositions are of high purity and are substantially free of potentially harmful impurities (e.g., at least National Food Grade; generally at least analytical grade; and generally at least pharmaceutical grade). For human consumption, the compositions are preferably manufactured or formulated in accordance with Good Manufacturing Practice standards as defined in applicable U.S. Food and Drug Administration regulations. For example, suitable formulations are sterile and/or substantially isotonic and/or fully comply with Good Manufacturing Practice as defined in applicable U.S. Food and Drug Administration regulations.

The active compound is effective over a wide dosage range and is typically administered in a therapeutically effective amount. However, it is understood that the amount of compound actually administered is typically determined by the physician according to the relevant circumstances, including the condition being treated, the chosen administration schedule, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

A therapeutic dose of a compound of the invention varies according to, for example, the particular application being treated, the route of administration of the compound, the health status and condition of the patient, and the judgment of the treating physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition varies depending on a number of factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and the administration schedule. For example, the compounds of the invention are in an aqueous buffered saline solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage, in most cases, depends on variables such as the type and degree of progression of the disease or disorder, the general health of the particular patient, the relative biological activity of the selected compound, the composition of the excipient, and the administration schedule. Effective doses can be obtained by extrapolating dose/response curves obtained in vitro or in animal model test systems.

For the preparation of solid compositions, namely tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a preformulation containing a homogeneous mixture of the compound of this invention. When these preformulations are referred to as homogeneous, the active ingredient is generally dispersed uniformly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, namely tablets, pills and capsules. These solid preformulations are then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of this invention.

The tablets and pills of the present invention are coated or otherwise formulated to provide the advantages of prolonged action to the dosage forms. For example, a tablet or pill comprises an inner dosage form component and an outer dosage form component, the latter being in the form of a shell compared to the former. The two components are separated from each other by an enteric layer that helps prevent disintegration in the stomach and allows the inner component to enter the duodenum intact or delays its release. Various materials are used for such enteric layers or coatings, namely materials containing a number of polymeric acids and mixtures of polymeric acids, namely shellac, cetyl alcohol or cellulose acetate.

Liquid dosage forms in which the compounds and compositions of the present invention are incorporated for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils, namely cottonseed oil, sesame oil, coconut oil or peanut oil, as well as tinctures and similar pharmaceutical excipients.

Compositions for inhalation and insufflation include solutions and suspensions in pharmaceutical administration

- 42 048980 lem in an aqueous or organic solvent, or a mixture thereof, and powders. Liquid and solid compositions contain suitable pharmaceutically acceptable excipients described above. In some embodiments of the invention, the compositions are administered by an oral or nasal respiratory regimen to obtain a local or systemic effect. The compositions are nebulized using inert gases. Inhalation solutions are inhaled directly from a nebulizer or the nebulizer is attached to a face mask, a breathing mask or an intermittent positive pressure breathing apparatus. Compositions in the form of solutions, suspensions or powders are administered orally or nasally using a device that delivers the composition in a suitable manner.

The topical formulations contain one or more conventional carriers. In some embodiments of the invention, ointments contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier compositions in creams are based on water in combination with glycerol and one or more other components, for example, glycerol monostearate, PEG-glycerol monostearate, and cetyl stearyl alcohol. Gels are formulated using isopropyl alcohol and water, optionally in combination with other components, namely, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments of the invention, the topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of a compound of the invention. Topical formulations are suitably packaged in cylindrical tablets weighing, for example, 100 g, which are optionally accompanied by instructions for the treatment of a selected symptom, for example, psoriasis or another skin disease.

The amount of the compound or composition administered to the patient varies depending on what is administered, the purpose of administration, namely prevention or treatment, the patient's condition, the route of administration, and the like. When used for therapeutic purposes, the compositions are administered to a patient already suffering from a disease in an amount sufficient to eliminate or partially stop the symptoms of the disease and its complications. Effective doses depend on the state of the disease being treated, as well as on the assessment of the treating clinician, which depends on factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

The compositions that are administered to the patient are in the form of pharmaceutical compositions as described above. These compositions are sterilized by conventional sterilization techniques or by sterilizing filtration. Aqueous solutions are packaged for use as is or lyophilized, with the lyophilized preparations being combined with a sterile aqueous vehicle before administration. The pH of the preparations with the compound is generally in the range of 3 to 11, preferably 5 to 9, and most preferably 7 to 8. It should be understood that the use of the above excipients, carriers or stabilizers leads to the formation of pharmaceutical salts.

A therapeutic dose of a compound of the invention varies according to, for example, the particular application being treated, the route of administration of the compound, the health status and condition of the patient, and the judgment of the treating physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition varies depending on a number of factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and the administration schedule. For example, the compounds of the invention are in an aqueous buffered saline solution containing from about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage, in most cases, depends on variables such as the type and degree of progression of the disease or disorder, the general health of the particular patient, the relative biological activity of the compound selected, the composition of the excipient, and the administration schedule. Effective doses can be obtained by extrapolating dose/response curves obtained in vitro or in animal model test systems.

Labeled compounds and methods for determining quantitative composition.

The compounds of the present invention may find additional use in the study of biological processes in normal and pathological tissues. Accordingly, another aspect of the invention relates to fluorescent dyes, spin labels, heavy metal compounds and radioisotope-labeled compounds provided herein and useful not only for imaging methods but also for quantitative determination, in vitro and in vivo, for the purpose of localizing and quantifying HPK1 protein in tissue samples, including human ones, and for the determination of HPK1 ligands by inhibiting the binding of labeled compounds. Accordingly, the present invention includes an HPK1 binding assay that includes such labeled compounds.

The present invention further includes isotopically substituted compounds of the disclosure. An isotopically substituted compound is a compound of the invention in which one

- 43,048,980 or more atoms are replaced or substituted by an atom having the same atomic number but a different atomic weight and mass number. The compounds of the invention contain isotopes that are common and occur in nature. The compounds of the invention also contain isotopes in quantities exceeding those occurring in nature, for example by synthetically incorporating isotopes that are rare in nature into the compounds of the invention, so that they are enriched in a particularly useful isotope (for example, 2H and ^13C ). It should be understood that radioisotopically labeled compounds are compounds in which at least one radioactive isotope (e.g., a radionuclide) is incorporated, such as ³ H and ¹⁴ C. Suitable radionuclides to be incorporated into the compounds of the present invention include, but are not limited to, ³ H (also written as T for tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹³ N ^{, 15} N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, 75 Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ¹³¹ I. The radionuclides to be incorporated into contemporary radioisotopically labeled compounds depend on the particular application of the radioisotopically labeled compound. In some embodiments of the invention, the radionuclides are selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S, and ⁸² Br. For in vitro labeling of HPK1 and competitive assays, compounds in which ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I, or ³⁵ S are incorporated are generally most useful. For radioimaging applications, 11 C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, 75 Br, ⁷⁶ Br, or ⁷⁷ Br are generally ^most useful. Synthetic methods for incorporating radioisotopes into organic compounds are known in the art.

In particular, the labeled compounds of the invention are used in a screening assay to identify and/or quantify compounds. For example, a newly synthesized or identified labeled compound (e.g., a test compound) can be quantified by its ability to bind the aHPK1 protein by monitoring the change in its concentrations upon contact with HPK1 and tracking the label. For example, a test (labeled) compound can be quantified by its ability to reduce the binding of another compound known to bind to the aHPK1 protein (i.e., a standard compound). Accordingly, the ability of the test compound to compete with the standard compound for binding to the aHPK1 protein directly correlates with its binding ability. In contrast, in some other screening assays, the standard compound is labeled and the test compound is unlabeled. Accordingly, the concentration of the labeled standard compound is monitored to assess the competition between the standard compound and the test compound, and thus the relative binding ability of the test compound is assessed.

Sets.

The invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of diseases or disorders associated with HPK1 activity, namely cancer or infections, and which contain one or more containers containing a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or any embodiment thereof of the invention. Such kits additionally contain one or more conventional components of a pharmaceutical kit, namely, for example, containers with one or more pharmaceutically acceptable carriers, additional containers and the like, and are also obvious to those skilled in the art. The kit also contains instructions, either in the form of inserts or in the form of labels, indicating the recommended amounts of the compounds to be administered, instructions for administration and/or instructions for mixing the components.

The invention will be described in more detail with reference to specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize many non-critical parameters that can be changed or modified to obtain substantially the same results. The compounds of the examples were found to inhibit HPK1 activity according to at least one assay described herein.

EXAMPLES

Experimental procedures for the compounds of the invention are given below. Purification of some of the obtained compounds by preparative LC-MS was performed on Waters mass-directed fractionation systems. The basic equipment set, protocols and control software for operating these systems are described in detail in the literature. See, for example, 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 subjected to analytical liquid chromatography/mass spectrometry (LC-MS) to check purity under the following conditions: Instrument: Agilent 1100 series, LC-MS; Column: Waters Sunfire™ C ₁₈ , 5 μm particle size, 2.1 x 5.0 mm; Buffers: 0.025% TFA in water and mobile phase B: acetonitrile; Gradient B from 2 to 80% in 3 minutes at a flow rate of 2.0 mL/minute.

- 44 048980

Some of the prepared compounds are separated by preparative reversed-phase high-performance liquid chromatography (RP-HPLC) with MS detection or flash chromatography (silica gel), as indicated in the examples. Typical column conditions for preparative reversed-phase high-performance liquid chromatography (RP-HPLC) are as follows:

pH=2 for purification: Waters Sunfire™ C ₁₈ , 5 µm particle size, 19x100 mm column; elution with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; flow rate 30 ml/min, the separation gradient was selected for each compound using the Compound Specific Method Optimization protocol 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 in a 30x100 mm column is 60 ml/min.

pH=10 for purification: Waters XBridge C ₁₈ , 5 µm particle size, 19x100 mm column; elution with mobile phase A: 0.15% NH ₄ OH in water and mobile phase B: acetonitrile; flow rate 30 ml/min, the gradient for separation was selected for each compound using the Compound Specific Method Optimization protocol 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 in a 30x100 mm column is 60 ml/min.

Degassed water refers to water in which dissolved oxygen has been replaced with nitrogen by bubbling nitrogen through a layer of water for 15 minutes.

Example 1. N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

Step 1. 2-Bromo-5-fluoroisonicotinonitrile t t

N,A _f

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 heated under reflux for 2 h and then the solvent was removed in vacuo. The residue was redissolved in ethyl acetate. The organic phase was washed with saturated NaHCO ₃ solution and brine and dried over sodium sulfate. The solvent was evaporated in vacuo to obtain 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 at 0 °C, the resulting oxime was slowly added to the solution and the reaction mixture was stirred at rt for 1 h. The reaction mixture 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 solvent was evaporated under reduced pressure. The resulting 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

NHz

An aqueous 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 under reflux for 2 h, the solvent was evaporated and the resulting crude product was used in the next step without further purification. LC/MS calculated for C ₆ H ₆ BrN4 (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

Tue

NX

Vos

Di-tert-butyl dicarbonate (1.127 g, 5.16 mmol) was added to a solution of 5-bromo-1H-pyrazolo[3,4c]pyridin-3-amine (1.0 g, 4.69 mmol) and triethylamine (0.785 mL, 5.63 mmol) in _CH2Cl2 (15 mL). After stirring for 1 h, water was added and the mixture was extracted with DCM. The organic phase was washed _with

- 45 048980 was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the resulting crude product was purified using Biotage Isolera™ (1.4 g, 87%). LC/MS calculated for CnH ₁₄ BrN ₄ O ₂ (M+H) ⁺ : m/z=313.0; found 313.0.

Step 4. tert-Butyl 3-amino-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

tert-Butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.0 g, 3.19 mmol), (2-fluoro6-methoxyphenyl)boric acid (0.814 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, which was evacuated three times and refilled with nitrogen. Dioxane (20 mL) and degassed water (2 mL) were then added and the reaction mixture was stirred at 90 °C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated under reduced pressure and the resulting crude product was purified using Biotage Isolera™ (1.05 g, 92%). LC/MS calculated for C ₁₈ H ₂₀ FN ₄ O ₃ (M+H) ⁺ : m/z = 359.2; found 359.2.

Step 5. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide.

Benzoyl chloride (6.47 mg, 0.046 mmol) was added to a solution of tert-butyl 3-amino-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 mg, 0.042 mmol) and DIPEA (10.97 μL, 0.063 mmol) in THF (1 mL). After stirring at 60 °C for 2 h, the reaction mixture was quenched with methanol and the solvents were evaporated in vacuo. DCM (1 mL) and trifluoroacetic acid (1 mL) were added to the resulting residue and the reaction mixture was stirred at rt. for 1 h. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₀ H ₁₆ FN ₄ O ₂ (M+H) ⁺ : m/z = 3 63.1; found 3 63.2.

Example 2. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-methylbenzamide

This compound was prepared according to the procedure described in Example 1 using 4-methylbenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₁ H ₁₈ FN ₄ O ₂ (M+H) ⁺ : m/z=377.1; found 377.2.

Example 3. 4-Bromo-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedure described in Example 1 using 4-bromobenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₀ H ₁₅ BrFN ₄ O ₂ (M+H) ⁺ : m/z=441.0; found 441.1.

Example 4. 3-Bromo-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared using the methods described in Example 1, using 3-bromobenzoyl chloride instead of benzoyl chloride as starting material. LC/MS calculated for

C2oHi5BrFN4O2 (M+H)+: m/z=441.0; 441.1 found.

- 46 048980

Example 5. 4-Fluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described in Example 1 using 4-fluorobenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₀ H ₁₅ F ₂ N ₄ O ₂ (M+H) ⁺ : m/z=381.1; found 381.2.

Example 6. 3 -Φτορ-Ν-(5 -(2-fluoro-6-methoxyphenyl)-1 H-pyrazolo[3,4-c]pyridin-3 -yl)benzamide

This compound was prepared according to the procedures described in Example 1 using 3-fluorobenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₀ H ₁₅ F ₂ N ₄ O ₂ (M+H) ⁺ : m/z=381.1; found 381.2.

Example 7. 3-Cyano-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described in Example 1 using 3-cyanobenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₁ H ₁₅ FN ₅ O ₂ (M+H)+: m/z=388.1; found 388.2.

Example 8. 4-Ethyl-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described in Example 1 using 4-ethylbenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C22H20FN4O2 (M+H) ⁺ : m/z=391.2; found 391.3.

Example 9. N-(5-(2-fluoro-6-methoxyphenyl)-III-pyrazolo[3,4-c]pyridin-3-yl)-3-methoxybenzamide

This compound was prepared according to the procedures described in Example 1 using 3-methoxybenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₁ H ₁₈ FN ₄ O ₃ (M+H) ⁺ : m/z=393.1; found 393.2.

Example 10. 4-Fluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methylbenzamide

This compound was prepared according to the procedures described in Example 1 using 4-fluoro-3-methylbenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated

- 47 048980 for C ₂₁ H ₁₇ F2N ₄ O2 (M+H)+: m/z=395.1; 395.2 found.

Example 11. 3,5-Difluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described in Example 1 using 3,5-difluorobenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₀ H ₁₄ F ₃ N ₄ O ₂ (M+H) ⁺ : m/z=399.1; found 399.2.

Example 12. 3,4-Difluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described in Example 1 using 3,4-difluorobenzoyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₀ H ₁₄ F ₃ N ₄ O ₂ (M+H) ⁺ : m/z=399.1; found 399.2.

Example 13. N-(5-(2-Fluoro-6-methoxyphenyl)-1 H-pyrazolo[3,4-c]pyridin-3-yl)benzo[d][1,3]dioxol5-carboxamide

This compound was prepared according to the procedures described in Example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₂₁ H ₁₆ FN ₄ O ₄ (M+H) ⁺ : m/z = 407.1; found 407.2.

Example 14. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

This compound was prepared according to the procedures described in Example 1 using 1-methyl-1Hpyrazole-4-carbonyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₁₈ H ₁₆ FN ₆ O ₂ (M+H) ⁺ : m/z = 367.1; found 367.2.

Example 15. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide

This compound was prepared according to the procedures described in Example 1 using 1-methyl-1Hpyrazole-3-carbonyl chloride instead of benzoyl chloride as the starting material. LC/MS calculated for C ₁₈ H ₁₆ FN ₆ O ₂ (M+H) ⁺ : m/z = 3,67.1; found 3,67.2.

Example 16 N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-morpholinobenzamide

- 48 048980

Step 1. tert-Butyl 3-(3-bromobenzamido)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1carboxylate

3-Bromobenzoyl chloride (206 mg, 0.939 mmol) was added to a solution of tert-butyl 3-amino-5-(2-fluoro-6 methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (Example 1, step 4, 306 mg, 0.854 mmol) and DIPEA (224 µL, 1.281 mmol) in THF (6 mL). The reaction mixture was heated at 60 °C for 2 h. Methanol (1 mL) was then added and the solvents were evaporated in vacuo. The resulting crude product was purified using Biotage Isolera™ (360 mg, 87%). LC/MS calculated for C ₂₅ H ₂₃ BrFN ₄ O ₄ (M+H) ⁺ : m/z = 541.1; 541.2 found.

Step 2. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-morpholinobenzamide.

tert-Butyl 3-(3-bromobenzamido)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 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'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G2, 2.2 mg, 2.77 μmol) were placed in an ampoule, which was evacuated three times and refilled with nitrogen. Dioxane (2 ml) was then added and the reaction mixture was stirred at 100°C for 2 h. The mixture was cooled to rt and the solids were isolated by filtration. The filtrate was concentrated in vacuo.

To the resulting residue were added DCM (1 mL) and trifluoroacetic acid (1 mL) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₄ H ₂₃ FN ₅ O ₃ (M+H) ⁺ : m/z = 4 4 8.2; found 4 4 8.3.

Example 17. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(3-oxopiperazin-1yl)benzamide

This compound was prepared according to the procedures described in Example 16, using piperazin-2-one instead of morpholine as the starting material. LC/MS calculated for C ₂₄ H ₂₂ FN ₆ O ₃ (M+H)+: m/z=4 61.2; found 4 61.2.

Example 18. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-methylpiperazin1-yl)benzamide

This compound was prepared according to the procedures described in Example 16 using 1-methylpiperazine instead of morpholine as the starting material. LC/MS calculated for C ₂₅ H ₂₆ FN ₆ O ₂ (M+H) ⁺ : m/z = 4,61.2; found 4,61.2.

Example 19. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-methyl-3-oxo- 49 048980 piperazin-1-yl)benzamide

This compound was prepared according to the procedures described in Example 16 using 1-methylpiperazin-2-one instead of morpholine as the starting material. LC/MS calculated for C25H24FN6O3 (M+H)+: m/z=475.2; found 475.3.

Example 20. 3-(4-Ethylpiperazin-1-yl)-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)benzamide

This compound was prepared according to the procedures described in Example 16 using 1-ethylpiperazine instead of morpholine as the starting material. LC/MS calculated for C ₂₆ H ₂₈ FN ₆ O ₂ (M+H) ⁺ : m/z=475.2; found 475.2.

Example 21

This compound was prepared according to the procedures described in Example 16 using 1-(2,2,2-trifluoroethyl)piperazin-2-one instead of morpholine as starting material. LC/MS calculated for C ₂₆ H ₂₃ F ₄ N ₆ O ₃ (M+H) ⁺ : m/z=543.2; found 543.3.

Example 22. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)benzamide

This compound was prepared according to the procedures described in Example 16 using 1(methylsulfonyl)piperazine instead of morpholine as the starting material. LC/MS calculated for C ₂₅ H ₂₆ FN ₆ O ₄ S (M+H) ⁺ : m/z=525.2; found 525.1.

Example 23. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(piperazin-1yl)benzamide

- 50 048980

This compound was prepared according to the procedures described in Example 16 using tert-butylpiperazine-1-carboxylate instead of morpholine as the starting material. LC/MS calculated for C ₂₄ H ₂₄ FN ₆ O2 (M+H)+: m/z=447.2; found 447.2.

Example 24 N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide

A f ^a o· f— ^s n ΜΑ° Huni hn-n

Step 1. tert-Butyl 3-(4-bromobenzamido)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1carboxylate

This compound was prepared according to the procedures described in Example 16, Step 1, using 4-bromobenzoyl chloride instead of 3-bromobenzoyl chloride as the starting material. LC/MS calculated for C ₂₅ H ₂₃ BrFN ₄ O ₄ (M+H)+: m/z=541.1; found 541.2.

Step 2. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide.

tert-Butyl 3-(4-bromobenzamido)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 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'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G2, 2.2 mg, 2.77 μmol) were placed in an ampoule, which was evacuated three times and refilled with nitrogen. Dioxane (2 ml) was then added and the reaction mixture was stirred at 100°C for 2 h. The mixture was cooled to rt and the solids were isolated by filtration. The filtrate was concentrated in vacuo.

To the resulting residue were added DCM (1 mL) and trifluoroacetic acid (1 mL) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₄ H ₂₃ FN ₅ O ₃ (M+H)+: m/z = 4 4 8.2; found 4 4 8.2.

Example 25. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(3-oxopiperazin-1-yl)benzamide

IF^O^O^

Λ vCT ⁰

Win

This compound was prepared according to the procedures described in Example 24 using piperazin-2-one instead of morpholine as the starting material. LC/MS calculated for C ₂₄ H ₂₂ FN ₆ O ₃ (M+H)+: m/z=461.2; found 461.3.

Example 26. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin1-yl)benzamide η νΟ·' hn-n

This compound was prepared according to the procedures described in Example 24 using 1-methylpiperazine instead of morpholine as the starting material. LC/MS calculated for C25H26FN6O2 (M+H)+: m/z=461.2; found 461.3.

Example 27. N-(5-(2-fluoro-6-methoxyphenyl)-1H-nirazolo[3,4-c]pyridin-3-yl)-4-(4-methyl-3-oxopiperazin-1-yl)benzamide

- 51 048980

This compound was prepared according to the procedures described in Example 24 using 1-methylpiperazin-2-one instead of morpholine as starting material. LC/MS calculated for C25H24FN6O3 (M+H)+: m/z=475.2; found 475.3.

Example 28. 4-(4-Ethylpiperazin-1-yl)-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrαzolo[3,4-c]pyridin-3yl)benzamide

This compound was prepared according to the procedures described in Example 24 using 1-ethylpiperazine instead of morpholine as the starting material. LC/MS calculated for C ₂₆ H ₂₈ FN ₆ O ₂ (M+H) ⁺ : m/z=475.2; found 475.3.

Example 29. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl)benzamide

This compound was prepared according to the procedures described in Example 24 using 1-(2,2,2-trifluoroethyl)piperazin-2-one instead of morpholine as the starting material. LC/MS calculated for C ₂₆ H ₂₃ F ₄ N ₆ O ₃ (M+H) ⁺ : m/z=543.2; found 543.2.

Example 30

This compound was prepared according to the procedures described in Example 24 using 1-isopropylpiperazine instead of morpholine as the starting material. LC/MS calculated for C ₂₇ H ₃₀ FN ₆ O ₂ (M+H) ⁺ : m/z=489.2; found 489.3.

Example 31. 4-(4-Cyclopropyl-3-oxopiperazin-1-yl)-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide o

m-N

This compound was prepared according to the procedures described in Example 24 using 1-cyclopropylpiperazin-2-one instead of morpholine as starting material. LC/MS calculated for C ₂₇ H ₂₆ FN ₆ O ₃ (M+H) ⁺ : m/z=501.2; found 501.3.

Example 32. N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamide

- 52 048980

F

About ς-Ο

This compound was prepared according to the procedures described in Example 24 using _1- (methylsulfonyl)piperazine instead of morpholine as the starting material. LC/MS calculated for C25H26FN6O4S(M+H) ⁺ : m/z=525.2; found 525.2.

Example 33. X-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(piperazin-1yl)benzamide

F

N

This compound was prepared according to the procedures described in Example 24 using tert-butylpiperazine-1-carboxylate instead of morpholine as the starting material. LC/MS calculated for C ₂₄ H24FN ₆ O2 (M+H) ⁺ : m/z=447.2; found 447.1.

Example 34. 4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)thiazol-2-yl)morpholine

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

Tue

“S*

NaH in mineral oil (510 mg, 13 mmol) at 0 °C was slowly added to a solution of 5-bromo-1Hpyrazolo[3,4-c]pyridine (Astatech, 2.1 g, 11 mmol) and [3-(trimethylsilyl)ethoxy]methyl chloride (2.30 mL, 13 mmol) in tetrahydrofuran (25 mL). After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure and the resulting crude product was purified using Biotage Isolera™ (2.5 g, 70%). LC/MS calculated for Ci ₂ H ₁₉ BrN ₃ 0si (M+H) ⁺ : m/z = 32 8.1; 328.1 found.

Step 2. 5-(2-Fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

N.N.

O \ ) aSi \

5-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine (1.36 g, 4.16 mmol), (2-fluoro-6-methoxyphenyl)boric acid (0.85 g, 5.0 mmol), chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,D-biphenyl) [2-(2'-amino-1,D-biphenyl)]palladium(II) (Pd XPhos G2) (400 mg, 0.5 mmol),

-53048980 Potassium phosphate (3.6 g, 17 mmol) and a magnetic anchor were placed in a flask. The flask was sealed with a rubber stopper, evacuated and refilled with nitrogen (this process was repeated three times in total). Dioxane (20 mL) and degassed water (2 mL) were then added and the reaction mixture was heated to 90 °C for 1 h. The reaction mixture was then diluted with ethyl acetate, washed with brine and the separated organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (0.7 g, 45%). LC/MS calculated for C ₁₉ H ₂₅ FN ₃ O ₂ Si (M+H)+: m/z = 374.2; found 374.1.

Step 3. 5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine

A solution of 5-(2-fluoro-6-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine (0.70 g, 1.9 mmol) in a mixture of 1.0 M hydrogen chloride in water (8 mL, 8 mmol) and 4.0 M hydrogen chloride in dioxane (8 mL, 33.6 mmol) was stirred at 80 °C for 1 h. After cooling to rt, the reaction mixture was neutralized to pH 7. The mixture was then extracted with ethyl acetate and the organic phase was washed with brine. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting crude product was used in the next step without further purification. LC/MS calculated for C ₁₃ H ₁₁ FN ₃ O (M+H) ⁺ : m/z=244.1; found 244.0.

Step 4. 5 -(2-Fluoro-6-methoxyphenyl)-3-iodo-1 H-pyrazolo[3,4-c]pyridine

Potassium hydroxide (0.39 g, 6.9 mmol) and iodine (0.88 g, 3.4 mmol) were added to a solution of 5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine (from the previous step) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 50 °C for 2 h. After cooling to rt, water was added and the reaction mixture was neutralized to pH 7. The mixture was then extracted with ethyl acetate and the organic phase was washed with saturated sodium thiosulfate solution and brine. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting crude product was used in the next step without further purification. LC/MS calculated for C ₁₃ H ₁₀ FIN ₃ O (M+H) ⁺ : m/z = 370.0; 370.0 found.

Step 5. 5 -(2-Fluoro-6-methoxyphenyl)-3 -iodo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazolo[3,4c]pyridine

NaH in mineral oil (95 mg, 2.4 mmol) at 0 °C was slowly added to a solution of 5-(2-fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine (0.80 g, 2.2 mmol) and [p-(trimethylsilyl)ethoxy]methyl chloride (0.42 mL, 2.4 mmol) in tetrahydrofuran (10 mL). After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. The solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (650 mg, 59%). LC/MS calculated for C19H24FIN3O2Si (M+H) ⁺ : m/z=500.1; found 500.0.

Step 6. 4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)thiazol-2-yl)morpholine.

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (15 mg, 0.030 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)morpholine (13.3 mg, 0.045 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II) (Pd XPhos G2) (2.4 mg, 0.0030 mmol), potassium phosphate (13 mg, 0.062 mmol) and mag

- 54 048980 The filament anchor was placed in a septum-fitted vial, which was then evacuated three times and refilled with nitrogen. 1,4-Dioxane (1.5 mL) and degassed water (0.2 mL) were then added and the reaction mixture was stirred at 80 °C for 1 h. 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were then added and the reaction mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was then added and the reaction mixture was further stirred at 80 °C for 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₀ H ₁₉ FN ₅ O ₂ S (M+H)+: m/z=412.1; found 412.1.

Example 35 5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methylisoxazole

This compound was prepared according to the procedures described in Example 34 using 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole instead of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)morpholine as the starting material. LC/MS calculated for C17H14FN4O2 (M+H) ⁺ : m/z=325.1; found 325.1.

Example 36 5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-methylthiazole

This compound was prepared according to the procedures described in Example 34 using 2-methyl-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole instead of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)morpholine as the starting material. LC/MS calculated for C17H14FN4OS (M+H) ⁺ : m/z=341.1; found 341.2.

Example 37. 1-(4-Bromophenyl)-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)piperazin-2-one

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (Example 34, step 5, 15 mg, 0.030 mmol), 1-(4-bromophenyl)piperazin-2-one (11 mg, 0.042 mmol), cesium carbonate (18.1 mg, 0.055 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G2, 2.2 mg, 2.77 μmol) were placed in an ampoule, which was evacuated three times and refilled with nitrogen. Dioxane (2 ml) was then added and the reaction mixture was stirred at 100°C for 2 h. The mixture was cooled to rt, the solids were separated by filtration and the solvent from the filtrate was evaporated in vacuo.

Then, 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was added and the resulting reaction mixture was further stirred at 80 °C for 30 min. Then, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₃ H ₂₀ BrFN ₅ O ₂ (M+H) ⁺ : m/z = 496.1; found 496.2.

Example 38. 2-(5-(2-Fluoro-6-methoxymethyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile

- 55 048980

This compound was prepared according to the procedures described in Example 37 using 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile instead of 1-(4-bromophenyl)piperazin-2-one as the starting material. LC/MS calculated for C ₂₃ H ₁₉ FN5O (M+H)+: m/z=400.2; found 400.1.

Example 39. 4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)piperazin-1-yl)benzonitrile

This compound was prepared according to the procedures described in Example 37 using 4-piperazin-1-ylbenzonitrile instead of 1-(4-bromophenyl)piperazin-2-one as the starting material. LC/MS calculated for C ₂₄ H ₂₂ FN ₆ O (M+H)+: m/z=429.2; found 429.2.

Example 40. 5-(2-Fluoro-6-methoxyphenyl)-3-(4-(pyridin-4-yl)piperazin-1-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 37 using 1-(pyridin-4-yl)piperazine instead of 1-(4-bromophenyl)piperazin-2-one as the starting material. LC/MS calculated for C ₂₂ H ₂₂ FN ₆ O (M+H)+: m/z=405.2; found 405.2.

Example 41

This compound was prepared according to the procedures described in Example 37 using (4-(4-methylpiperazin-1-yl)phenyl)methanamine instead of 1-(4-bromophenyl)piperazin-2-one as the starting material. LC/MS calculated for C ₂₅ H ₂₈ FN ₆ O (M+H)+: m/z=447.2; found 447.2.

Example 42. 1-[1-(3-Fluoro-5-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-c]pyridin-5-yl}phenyl)cyclopropyl]methanamine

To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridine (2.012 g, 13.10 mmol) in DMF (40.0 mL) was added N-iodosuccinimide (4.47 g, 19.9 mmol). The mixture was then heated to 80 °C for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo. The resulting residue was purified on silica gel (120 g, 0-100% ethyl acetate in hexanes) to afford the title product as a white solid (3.16 g, 86%). LC/MS calculated for C ₆ H ₄ ClIN ₃ (M+H)+: m/z = 279.9; found 279.9.

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

- 56 048980

To a suspension of NaH (60% in mineral oil, 348.2 mg, 8.706 mmol) in DMF (10.0 mL) at 0 °C was added dropwise a solution of 5-chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine (1.488 g, 5.324 mmol) in DMF (10.0 mL) over 10 min. The mixture was then allowed to warm to room temperature and stirred for 20 min. After cooling the reaction mixture to 0 °C, a solution of [β(trimethylsilyl)ethoxy]methyl chloride (1184 mg, 7.102 mmol) in DMF (5.0 mL) was added dropwise over 10 min. The mixture was then allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (120 g, 0-50% ethyl acetate in hexane) to give the title product as a pale yellow solid (1.429 g, 66%). LC/MS calculated for C ₁₂ H ₁₈ ClIN ₃ OSi (M+H)+: m/z = 410.0; found 410.0.

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

A screw-cap ampoule equipped with a magnetic stirrer is charged with 5-chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine (1.429 g, 3.488 mmol), [4-(4-methylpiperazin-1-yl)phenyl]boric acid (1.147 g, 5.212 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (310.2 mg, 0.3798 mmol), and K3PO4 (2.424 g, 11.42 mmol). The ampoule is hermetically sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). 1,4-Dioxane (15.0 mL) was added followed by degassed water (5.00 mL). The reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes then 10% MeOH in CH ₂ Cl ₂ ) to give the desired product as a dark solid (1.379 g, 86%). LC/MS calculated for C23H3 ₃ ClN5OSi (M+H)+: m/z = 458.2; found 458.3.

Step 4. 1-[1-(3-Bromo-5-fluorophenyl)cyclopropyl]methanamine

To 1-(3-bromo-5-fluorophenyl)cyclopropanecarbonitrile (1.005 g, 4.186 mmol) was added 1.0 M borohydride in THF (13.0 mL, 13.0 mmol). The mixture was heated to 70 °C for 2 h. After cooling to room temperature, the mixture was treated with 6.0 M aqueous HCl (14.0 mL, 84.0 mmol). The mixture was stirred at 60 °C for 5 h. The mixture was diluted with ethyl acetate and adjusted to pH 12 with 4 N aqueous NaOH. The separated aqueous layer was extracted with ethyl acetate (three times). The organic mixture was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product as a yellow oil, which was used directly in the next step without further purification (2.11 g). LC/MS calculated for C ₁₀ H ₁₂ BrFN (M+H)+: m/z=244.0; found 2 4 4.0.

Step 5. tert-Butyl {[1-(3-bromo-5-fluorophenyl)cyclopropyl]methyl} carbamate

To a solution of 1-[1-(3-bromo-5-fluorophenyl)cyclopropyl]methanamine (1.022 g, 4.187 mmol) in CH ₂ Cl ₂ (10.0 mL) was added di-tert-butyl dicarbonate (1.531 g, 7.015 mmol). The mixture was stirred at room temperature for 10 min and then concentrated. The mixture was purified on silica gel (120 g, 0-100% ethyl acetate in hexanes) to give the title product as a white solid (1.252 g, 87%). LC/MS calculated for C ₁₅ H ₂₀ BrFNO ₂ (M+H)+: m/z = 344.1; found 344.0.

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Step 6. tert-Butyl ({1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl} methyl)carbamate

In a screw-cap ampoule equipped with a magnetic stirrer, tert-butyl {[1-(3-bromo-5-fluorophenyl)cyclopropyl]methyl}carbamate (589.7 mg, 1.713 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (672.2 mg, 2.647 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (389.8 mg, 0.4773 mmol) and KOAc (509.0 mg, 5.186 mmol) are loaded. The ampoule was sealed with a PTFE-lined septum, evacuated, and refilled with nitrogen (this process was repeated three times in total). 1,4-Dioxane (10.0 mL) was added. The reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ and filtered. The filtrate was concentrated. The resulting residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the desired product as a light yellow oil (571.4 mg, 85%). LC/MS calculated for C ₂₁ H ₃₁ BFNNaO ₄ (M+Na) ⁺ : m/z = 414.2; found 414.3.

Step 7. 1-[1-(3-Fluoro-5-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-c]pyridin-5-yl}phenyl)cyclopropyl]methanamine.

In a screw cap ampoule equipped with a magnetic stirrer, 5-chloro-3-[4(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine (30.0 mg, 0.0655 mmol), tert-butyl ({1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}methyl)carbamate (49.5 mg, 0.126 mmol), dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (XPhos Pd G2, 5.0 mg, 0.0063 mmol) and K ₃ PO ₄ (54.2 mg, 0.255 mmol). The ampoule was sealed with a Teflon-lined septum, evacuated, and refilled with nitrogen (this process was repeated three times in total). 1,4-dioxane (1.50 mL) was added, followed by degassed water (150.0 mL). The reaction mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ , filtered, and concentrated. The residue was dissolved in MeOH (3.00 mL) and treated with 4.0 M HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirred at 65°C for 2 h. After cooling to room temperature, the reaction mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product as a yellow solid (17.9 mg). LC/MS calculated for C ₂₇ H ₃₀ FN ₆ (M+H)+: m/z = 457.3; found 457.3.

Example 43 5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

In a screw cap ampoule equipped with a magnetic stirrer are charged 5-chloro-3-(4(4-methylpiperazin-1-yl)phenyl]-1-((2-(trimethylsilyl)ethoxy)methyl}-1H-pyrazolo[3,4-c]pyridine (Example 42, step 3, 30.1 mg, 0.066 mmol), (2-fluoro-6-methoxyphenyl)boric acid (22.9 mg, 0.135 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 5.0 mg, 0.0063 mmol) and K ₃ PO ₄ (51.4 mg, 0.242 mmol). The ampoule was sealed with a PTFE-lined septum, evacuated, and refilled with nitrogen (this process was repeated three times in total). 1,4-Dioxane (1.50 mL) was added, followed by degassed water (150.0 mL). The reaction mixture was stirred at 65 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ , filtered, and concentrated. The residue was dissolved in MeOH (3.00 mL) and treated with 4.0 M HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirred at 65 °C for 2 h. After cooling to room temperature, the reaction mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 ml/min) to obtain the desired product as a yellow solid (19.4 mg). LC/MS calculated for C ₂₄ H ₂₅ FN ₅ O (M+H)+: m/z=418.2; found 418.3.

Example 44 5-(2,6-Difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

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This compound was prepared according to the procedures described in Example 43 using (2,6-difluorophenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₃ H ₂₂ F ₂ N5 (M+H)+: m/z=406.2; found 406.2.

Example 45. 5 -(2,6-Dimethylphenyl)-3 -(4-(4-methylpiperazin-1 -yl)phenyl)-1 H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 43 using (2,6-dimethylphenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₅ H ₂₈ N ₅ (M+H)+: m/z=398.2; found 398.1.

Example 46 3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(2,4,6-trifluorophenyl)-1H-pyrazolo[3,4-c]pyridine

F

This compound was prepared according to the procedures described in Example 43 using (2,4,6-trifluorophenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₃ H ₂₁ F ₃ N ₅ (M+H)+: m/z=424.2; found 424.2.

Example 47 5-(2-Chloro-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 43 using (2-chloro-6-fluorophenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₃ H ₂₂ ClFN ₅ (M+H)+: m/z=422.2; found 422.2.

Example 48 3,5-Difluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenol

HE

This compound was prepared according to the procedures described in Example 43 using (2,6-difluoro-4-hydroxyphenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₃ H ₂₂ F ₂ N ₅ O (M+H)+: m/z=422.2; found 422.2.

Example 49 5-(2-Fluoro-6-methylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

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This compound was prepared according to the procedures described in Example 43 using (2-fluoro-6-methylphenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₄ H ₂₅ FN5 (M+H)+: m/z=402.2; found 402.2.

Example 50 5-(2-Chloro-6-(trifluoromethyl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 43 using (2-chloro-6(trifluoromethyl)phenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₄ H ₂₂ ClF ₃ N ₅ (M+H)+: m/z=472.2; found 472.2.

Example 51. 5-(2-Ethoxy-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 43 using (2-ethoxy-6-fluorophenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₅ H ₂₇ FN ₅ O (M+H)+: m/z=432.2; found 432.2.

Example 52 5-(2-Chloro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 43 using (2-chloro-6-methoxyphenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₄ H ₂₅ ClN ₅ O (M+H)+: m/z=434.2; found 434.2.

Example 53 5-(2-Fluoro-6-(trifluoromethyl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 43 using (2-fluoro-6(trifluoromethyl)phenyl)boronic acid instead of 2-fluoro-6-methoxyphenylboronic acid as the starting material. LC/MS calculated for C ₂₄ H ₂₂ F ₄ N ₅ (M+H)+: m/z=456.2; found 456.2.

Example 54

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Step 1. Methyl 5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridine-3-carboxylate

SEM

A mixture of 5-(2-fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridine (Example 34, step 5, 1.0 g, 2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (170 mg, 0.2 mmol, Combi-Blocks) was placed in a flask with a baffle. The flask was evacuated three times and backfilled with nitrogen. After the addition of methanol (20 mL) and triethylamine (0.57 mL, 4 mmol), the flask was evacuated three times and backfilled with carbon monoxide gas. A balloon of carbon monoxide gas was attached to the reaction flask and the reaction mixture was heated to 85°C overnight. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude material was purified using Biotage Isolera to afford the desired product (440 mg, 51%). LC/MS calculated for C ₂₁ H ₂₇ FN ₃ O ₄ Si (M+H)+: m/z = 432.2; found 432.2.

Step 2. 5-(2-Fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridine-3-carboxylic acid

Gu oo-soon N N

SEM

1 M sodium hydroxide in water (5 mL, 5 mmol) was added to a solution of methyl 5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (450 mg, 1 mmol) in tetrahydrofuran (5 mL) and methanol (3 mL). After stirring at rt for 2 h, the pH was adjusted to 5 with 1 M HCl. The mixture was then extracted with ethyl acetate and the separated organic phase was washed with brine. The organic phase was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The resulting solid was used in the next step without further purification (396 mg, 95%). LC/MS calculated for C ₂₀ H ₂₅ FN ₃ O ₄ Si (M+H) ⁺ : m/z=418.2; found 418.3.

Step 3. 5-(2-Fluoro-6-methoxyphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.

To a solution of 5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (15 mg, 0.035 mmol) and 4-(4-methylpiperazin-1-yl)aniline (10 mg, 0.05 mmol) in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine (13 μL, 0.07 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (15 mg, 0.04 mmol). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate, and the solvents were evaporated in vacuo. Then 1 M HCl in water (1 ml) and 4 M HCl in dioxane (1 ml) were added to the crude residue, and the reaction mixture was stirred at 80 °C for 1 h.

Methanol (1 mL) was added and the reaction mixture was stirred at 80 °C for an additional 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₅ H ₂₆ FN ₆ O ₂ (M+H) ⁺ : m/z = 461.2; found 461.3.

Example 55. 5-(2-Fluoro-6-methoxyphenyl)-N-(4-morpholinophenyl)-1H-pyrαzolo[3,4-c]pyridine-3-carboxamide

This compound was prepared according to the procedures described in Example 54 using 4-morpholinoaniline instead of 4-(4-methylpiperazin-1-yl)aniline as the starting material. LC/MS calculated for C ₂₄ H ₂₃ FN ₅ O ₃ (M+H) ⁺ : m/z = 448.2; found 448.3.

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Example 56

This compound was prepared according to the procedures described in Example 54 using 4-(4-ethylpiperazin-1-yl)aniline instead of 4-(4-methylpiperazin-1-yl)aniline as the starting material. LC/MS calculated for C ₂₆ H ₂₈ FN ₆ O ₂ (M+H) ⁺ : m/z = 475.2; found 475.2.

Intermediate 1. tert-Butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridine-1-carboxylate

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

To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridine (7.07 g, 46.0 mmol) in DMF (115 mL) was added NIS (10.57 g, 47.0 mmol). After stirring at 70 °C for 2 h, the reaction mixture was cooled to rt and triethylamine (9.63 mL, 69.1 mmol) was added, followed by boc-anhydride (15.07 g, 69.1 mmol). After additional stirring at rt for 2 h, water was added and the precipitated product was _{collected by} filtration, dried and used in the next step without further purification (17 g, 97%). LC/MS calculated for _{C11H12ClIN3O2} (M+H)+: m/z=380.0; found 380.0.

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

Tert-Butyl 5-chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (6.64 g, 17.49 mmol), _PdCl2 (dppf) _-CH2Cl2 adduct (1.429 g, 1.749 mmol), ₁ -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole (3.64 g, 17.49 mmol), and potassium phosphate (7.43 g, 35.0 mmol) were placed in a flask, which was evacuated three times and backfilled with nitrogen. Dioxane (100 mL) and degassed water (10.0 mL) were then added, and the reaction mixture was stirred at 80°C for 1 h. After cooling to rt. Water was added and the mixture was extracted with ethyl acetate. The organic phase mixture was washed with brine, dried over sodium sulfate and the solvent was evaporated. The crude product was purified using Biotage Isolera™ (4.7 g, 81%). LC/MS calculated for C ₁₅ H ₁₇ ClN ₅ O ₂ (M+H) ⁺ : m/z=334.1; found 334.2.

Intermediate 2. 5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 42 (steps 1-3), using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of [4-(4-methylpiperazin-1yl)phenyl]boronic acid as the starting material. LC/MS calculated for C ₁₆ H ₂₃ ClN ₅ OSi (M+H) ⁺ : m/z=364.1; found 364.1.

Example 5 7. 3,5-difluoro-N-(2-methoxyethyl)-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzamide

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Step 1. Methyl 3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzoate

5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (348 mg, 0.956 mmol, intermediate 2), methyl 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (342 mg, 1.148 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096 mmol) and potassium phosphate (406 mg, 1.91 mmol) were placed in flask, which was evacuated three times and refilled with nitrogen. Dioxane (20 mL) and degassed water (2 mL) were then added and the reaction mixture was stirred at 90 °C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified using Biotage Isolera™ (440 mg, 92%). LC/MS calculated for C ₂₄ H ₂₈ F ₂ N ₅ O ₃ Si (M+H)+: m/z = 500.2; found 500.2.

Step 2. 3,5-Difluoro-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyra-

1 M sodium hydroxide in water (5 mL, 5 mmol) was added to a solution of methyl 3,5-difluoro-4-(3(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzoate (440 mg, 0.881 mmol) in tetrahydrofuran (5 mL) and methanol (3 mL). After stirring at rt for 2 h, the pH was adjusted to 5 with 1 M HCl. The resulting mixture was then 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 in vacuo. The resulting solid product was used in the next step without further purification (403 mg, 94%). LC/MS calculated for C ₂₃ H ₂₆ F ₂ N ₅ O ₃ Si (M+H) ⁺ : m/z=486.2; found 486.3.

Step 3. 3,5-Difluoro-N-(2-methoxyethyl)-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin5-yl)benzamide.

To a solution of 3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzoic acid (15 mg, 0.031 mmol) and 2-methoxyethan-1-amine (4.64 mg, 0.062 mmol) in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine (13 μL, 0.07 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (15 mg, 0.04 mmol). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The mixture was extracted with ethyl acetate and the separated organic phase was washed with brine and dried over sodium sulfate. The solvents were evaporated in vacuo. Then 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was added and the reaction mixture was further stirred at 80 °C for 30 min. Then the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₀ H ₁₉ F ₂ N ₆ O2 (M+H) ⁺ : m/z = 413.2; found 413.3.

Example 5 8. (3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)(3 methoxyazetidin-1-yl)methanone

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This compound was prepared according to the procedures described in Example 57 using 3-methoxyazetidine instead of 2-methoxyethane-1-amine as the starting material. LC/MS calculated for C ₂₁ H ₁₉ F ₂ N ₆ O ₂ (M+H)+: m/z=425.2; found 425.2.

Example 5 9. N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutanecarboxamide

Step 1. 2,4-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1.831 g, 7.21 mmol), potassium acetate (1.415 g, 14.42 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.785 g, 0.962 mmol) under nitrogen atmosphere was added a solution of 3-bromo-2,4-difluoroaniline (1.0 g, 4.81 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was diluted with DCM and filtered through celite. The filtrate was concentrated in vacuo. The residue was purified using Biotage Isolera™ (740 mg, 60%). LC/MS calculated for C ₁₂ H ₁₇ BF ₂ NO ₂ (M+H)+: m/z=2 5 6.1; found 256.1.

Step 2. 2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)aniline

-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (348 mg, 0.956 mmol, intermediate 2), 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (293 mg, 1.148 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2 ) (75 mg, 0.096 mmol), and potassium phosphate (406 mg, 1.91 mmol) were placed in a flask which The mixture was evacuated three times and backfilled with nitrogen. Dioxane (20 mL) and degassed water (2 mL) were then added and the reaction mixture was stirred at 90 °C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (380 mg, 87%). LC/MS calculated for C ₂₂ H ₂₇ F ₂ N ₆ OSi (M+H)+: m/z = 457.2; found 457.2.

Step 3. N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutanecarboxamide

N,N-Diisopropylethylamine (13 μl, 0.07 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (15 mg, 0.04 mmol) were added to a solution of 2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline (15 mg, 0.033 mmol) and cyclobutanecarboxylic acid (3.29 mg, 0.033 mmol) in N,N-dimethylformamide (1.5 ml).

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After stirring the reaction mixture at rt for 2 h, it was quenched with water. The mixture was extracted with ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. Then 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Then methanol (1 mL) was added and the reaction mixture was stirred at 80 °C for an additional 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₁ H ₁₉ F ₂ N ₆ O (M+H) ⁺ : m/z=409.2; found 409.1.

Example 60

This compound was prepared according to the procedures described in Example 59 using 2-phenylacetic acid instead of cyclobutanecarboxylic acid as the starting material. LC/MS calculated for C ₂₄ H ₁₉ F ₂ N ₆ O (M+H)+: m/z=445.2; found 445.3.

Example: il)aniline

Example 5-yl)aniline

61. 2,4-Difluoro-N-methyl-3 -(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5-

62. 2,4-Difluoro-N,N-dimethyl-3-(3-(1-methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-

Sodium hydroxide (2 mg, 0.049 mmol, 60% in mineral oil) was added to a solution of 2,4-difluoro-3-(3(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline (15 mg, 0.033 mmol, Example 59, step 2) and iodomethane (13.99 mg, 0.099 mmol) in THF (2.0 mL). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The mixture was extracted with ethyl acetate. The organic phases were washed with brine, dried over sodium sulfate, and the solvents were evaporated in vacuo. Then, 1 M HCl in water (1 ml) and 4 M HCl in dioxane (1 ml) were added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Then, methanol (1 ml) was added and the reaction mixture was stirred at 80 °C for an additional 30 min. Then, to obtain the products of both Examples 61 and 62, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 ml/min).

Example 61. LC/MS calculated for C ₁₇ H ₁₅ F ₂ N ₆ (M+H) ⁺ : m/z=341.1; found 341.2.

Example 62. LC/MS calculated for C ₁₈ H ₁₇ F ₂ N ₆ (M+H) ⁺ : m/z=355.2; found 355.2.

Example 63. 3,5-Difluoro-N,N-dimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin5-yl)aniline

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Step 1. 3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.75 g, 10.8 mmol), potassium acetate (2.1 g, 21.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.785 g, 0.962 mmol) under nitrogen atmosphere was added a solution of 4-bromo-3,5-difluoroaniline (1.5 g, 7.21 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was diluted with DCM and filtered through celite. The filtrate was concentrated in vacuo. The crude product was purified using Biotage Isolera™ (1.4 g, 76%). LC/MS calculated for C ₁₂ H ₁₇ BF ₂ NO ₂ (M+H)+: m/z=256.1; found 256.2.

Step 2. 3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridin-3-yl)aniline

-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (348 mg, 0.956 mmol, intermediate 2), 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (293 mg, 1.148 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2 ) (75 mg, 0.096 mmol) and potassium phosphate (406 mg, 1.91 mmol) were placed in a flask, which was evacuated three times and backfilled with nitrogen. Dioxane (20 mL) and degassed water (2 mL) were then added and the reaction mixture was stirred at 90 °C for 2 h. After cooling to rt, the reaction mixture was extracted with ethyl acetate. The separated organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure and the resulting crude product was purified using Biotage Isolera™ (354 mg, 81%). LC/MS calculated for C ₂₂ H ₂₇ F ₂ N ₆ OSi (M+H)+: m/z = 457.2; found 457.2.

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

Sodium hydride (2 mg, 0.049 mmol, 60% in mineral oil) was added to a solution of 3,5-difluoro-4-(3-(1methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline (15 mg, 0.033 mmol) and iodomethane (13.99 mg, 0.099 mmol) in THF (2.0 mL). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The mixture was extracted with ethyl acetate. The separated organic phase was washed with brine, dried over sodium sulfate, and the solvents were evaporated in vacuo. Then, 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the resulting mixture was stirred at 80 °C for 1 h. Then, methanol (1 mL) was added and the reaction mixture was further stirred at 80 °C for 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₁₈ H ₁₇ F ₂ N ₆ (M+H)+: m/z = 355.2; found 355.3.

Example 64. N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

To a solution of 3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline (15 mg, 0.033 mmol, Example 63, step 2) and 2-(pyrrolidin-1yl)acetic acid (4.24 mg, 0.033 mmol) in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine (13 μL, 0.07 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphate

- 66 048980 uronium (15 mg, 0.04 mmol). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The mixture was extracted with ethyl acetate. The separated organic phases were washed with brine, dried over sodium sulfate, and the solvents were evaporated in vacuo. Then 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the resulting mixture was stirred at 80 °C for 1 h. Then methanol (1 mL) was added and the reaction mixture was stirred additionally at 80 °C for 30 min. Then the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₂ H ₂₂ F ₂ N ₇ O (M+H) ⁺ : m/z = 438.2; found 438.2. ¹ H-HM (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.15 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 7.47 (d, J = 9.2 Hz, 2H), 4.34 (s, 2H), 3.93 (s, 3H), 3.66 (s, 2H), 3.17 (s, 2H), 1.99 (d, J = 50.3 Hz, 4H) ppm.

Example 65. N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide

This compound was prepared according to the procedures described in Example 64 using 1-methyl-1H-pyrazole-4-carboxylic acid instead of 2-(pyrrolidin-1-yl)acetic acid as the starting material. LC/MS calculated for C ₂₁ H ₁₇ F ₂ N ₈ O (M+H)+: m/z=435.2; found 435.1.

Example 66. 2-Cyclopentyl-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyrudin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described in Example 64 using 2-cyclopentylacetic acid instead of 2-(pyrrolidin-1-yl)acetic acid as the starting material. LC/MS calculated for C ₂ 3H ₂₃ F ₂ N ₆ O (M+H) ⁺ : m/z = 437.2; found 437.2.

Example 67. N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide

This compound was prepared according to the procedures described in Example 64 using 2-(pyridin-3-yl)acetic acid instead of 2-(pyrrolidin-1-yl)acetic acid as the starting material. LC/MS calculated for C ₂₃ H ₁₈ F ₂ N ₇ O (M+H) ⁺ : m/z = 446.2; found 446.2.

Example 68. 2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

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Step 1. tert-Butyl 5-(4-amino-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridine-1-carboxylate

This compound was prepared according to the procedures described in Example 63 (steps 1-2), using Intermediate 1 instead of Intermediate 2 as starting material. LC/MS calculated for C ₂₁ H ₂₁ F ₂ N ₆ O ₂ (M+H)+: m/z=427.2; found 42 7.2.

Step 2. tert-Butyl 5-(4-(2-floroacetamido)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of 5-(4-amino-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (385 mg, 0.903 mmol) and 2-chloroacetic acid (85 mg, 0.903 mmol) in N,N-dimethylformamide (4 mL) were added N,N-diisopropylethylamine (315 μL, 1.8 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (515 mg, 1.35 mmol). After stirring at rt. Water was added over 2 h and the precipitated product was collected by filtration, dried and used in the next step without further purification (427 mg, 94%). LC/MS calculated for C ₂₃ H ₂₂ ClF ₂ N ₆ O ₃ (M+H)+: m/z=503.1; found 503.1.

Step 3. 2-(7-Azabicyclo[2.2.1]heptan-7-yl)-X-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide.

7-Azabicyclo[2.2.1]heptane (4.4 mg, 0.045 mmol) was added to a solution of tert-butyl 5-(4-(2-chloroacetamido)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate (15 mg, 0.030 mmol) and DIPEA (0.01 mL, 0.06 mmol) in THF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₄ H ₂₄ F ₂ N ₇ O (M+H)+: m/z=464.2; found 464.3. ¹ H-NMR (500 MHz, DMSO-b ₆ ) δ 11.12 (s, 1H), 9.14 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 8.12-8.00 (m, 1H), 7.48 (d, J=9.3 Hz, 2H), 4.26 (s, 2H), 4.15 (d, J=4.9 Hz, 2H), 3.93 (s, 3H), 2.05 (d, J=7.5 Hz, 4H), 1.76 (dd, J=19.6, 8.2 Hz, 4H) ppm.

Example 69

This compound was prepared according to the procedures described in Example 68 using 7-oxa-2-azaspiro[3.5]nonane instead of 7-azabicyclo[2.2.1]heptane as the starting material. LC/MS calculated for C ₂₅ H ₂₆ F ₂ N ₇ O ₂ (M+H)+: m/z=4,94.2; found 4,94.3.

Example 70. N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)propanamide

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Step 1. tert-Butyl 5-(4-(2-fluoropropanamido)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of 5-(4-amino-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (385 mg, 0.903 mmol, Example 68, step 1) and 2-chloropropionic acid (98 mg, 0.903 mmol) in N,N-dimethylformamide (4 mL) were added N,N-diisopropylethylamine (315 µL, 1.8 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (515 mg, 1.35 mmol). After stirring at rt. Water was added over 2 h and the precipitated product was collected by filtration, dried and used in the next step without further purification (427 mg, 88%). LC/MS calculated for C ₂₄ H ₂₄ ClF ₂ N ₆ O ₃ (M+H)+: m/z=517.2; found 517.2.

Step 3. N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2(pyrrolidin-1-yl)propanamide.

Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert-butyl 5-(4-(2-chloropropanamido)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₃ H ₂₄ F ₂ N ₇ O (M+H)+: m/z=452.2; found 452.3.

Example 71. 1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)3-(2-methoxyethyl)urea

Bis(trichloromethyl)carbonate (14.62 mg, 0.049 mmol) was added to a solution of 3,5-difluoro-4-(3-(1-methyl-1Hpyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline (15 mg, 0.033 mmol, Example 63, step 2) and triethylamine (0.018 mL, 0.131 mmol) in tetrahydrofuran (1.5 mL). After stirring at rt for 1 h, 2-methoxyethane-1-amine (5 mg, 0.06 mmol) was added and the resulting mixture was stirred for an additional 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic phases were washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. Then 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the resulting mixture was stirred at 80 °C for 1 h. Then methanol (1 mL) was added and the reaction mixture was stirred additionally at 80 °C for 30 min. Then the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂ qH ₂ qF ₂ N ₇ O ₂ (M+H)+: m/z = 428.2; found 42 8.1.

Example 72

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Step 1. 1-(Difluoromethoxy)-3-fluoro-5-nitrobenzene

To a mixture of sodium chlorodifluoroacetate (5.82 g, 38.2 mmol) and potassium carbonate (2.64 g, 19.10 mmol) in DMF (17 mL) and water (2 mL) was added 3-fluoro-5-nitrophenol (1.5 g, 9.55 mmol) and the mixture was stirred at 100 °C for 6 h (caution! a large amount of CO ₂ is evolved). After cooling, the mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified using Biotage Isolera™ (1.3 g, 66%).

Step 2. 3-(Difluoromethoxy)-5-fluoroaniline

A mixture of 1-(difluoromethoxy)-3-fluoro-5-nitrobenzene (1.3 g, 6.28 mmol), iron (2.454 g, 43.9 mmol) and ammonium chloride (2.02 g, 37.7 mmol) in tetrahydrofuran (5 mL), water (7 mL) and methanol (5 mL) was heated under reflux for 3 h. After cooling to rt, the solids were isolated by filtration and the solvents were evaporated in vacuo. The crude product concentrate was purified using Biotage Isolera™ (1.27 g, 99%). LC/MS calculated for C7H7F3NO (M+H)+: m/z=178.1; found 178.1.

Step 3. 4-Bromo-3-(difluoromethoxy)-5-fluoroaniline

BSI (1.3 g, 7.3 mmol) was added to a solution of 3-(difluoromethoxy)-5-fluoroaniline (1.27 g, 7.17 mmol) in DMF (15 mL) at 0 °C. After stirring at rt for 1 h, water was added and the reaction mixture was extracted with ethyl acetate. The separated organic layer was washed with brine and purified using Biotage Isolera™ (0.91g, 50%). LC/MS calculated for C7H ₆ BrF ₃ NO (M+H)+: m/z = 256.0; found 256.0.

Step 4. 3-(Difluoromethoxy)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1.35 g, 5.33 mmol), potassium acetate (1.05 g, 10.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.29 g, 0.36 mmol) under nitrogen atmosphere was added a solution of 4-bromo-3-(difluoromethoxy)5-fluoroaniline (0.909 g, 3.55 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was diluted with DCM and filtered through celite. The filtrate was concentrated in vacuo. The residue was purified using Biotage Isolera™ (540 mg, 50%). LC/MS calculated for C ₁₃ H ₁₈ BF ₃ NO ₃ (M+H)+: m/z=304.1; found 304.2.

Step 5. tert-Butyl 5-(4-amino-2-(difluoromethoxy)-6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)1H-pyrazolo[3,4-c]pyridine-1-carboxylate

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tert-Butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (330 mg, 0.989 mmol, intermediate 1), 3-(difluoromethoxy)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (360 mg, 1.186 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096 mmol) and potassium phosphate (406 mg, 1.91 mmol) were placed in flask, evacuated three times and refilled with nitrogen. Dioxane (20 mL) and degassed water (2 mL) were then added and the reaction mixture was stirred at 90 °C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (291 mg, 62%). LC/MS calculated for C ₂₂ H ₂₂ F ₃ N ₆ O ₃ (M+H)+: m/z=475.2; found 475.2.

Step 6. tert-Butyl 5-(4-(2-chloroacetamido)-2-(difluoromethoxy)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of 5-(4-amino-2-(difluoromethoxy)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (188 mg, 0.396 mmol) and 2-chloroacetic acid (37 mg, 0.39 mmol) in N,N-dimethylformamide (3 mL) were added N,N-diisopropylethylamine (138 μL, 0.79 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (226 mg, 0.59 mmol). After stirring at rt. Water was added over 2 h and the precipitated product was collected by filtration, dried and used in the next step without further purification (209 mg, 96%). LC/MS calculated for C ₂₄ H ₂₃ ClF ₃ N ₆ O ₄ (M+H)+: m/z=551.1; found 551.2.

Step 7. 2-(azetidin-1 -ul)-N-(3-(difluoromethoxy)-5-fluoro-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide.

Azetidine (3 mg, 0.05 mmol) was added to a solution of tert-butyl 5-(4-(2-chloroacetamido)-2-(difluoromethoxy)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 mg, 0.027 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₂ H ₂₁ F ₃ N ₇ O ₂ (M+H)+: m/z=472.2; found 472.2.

Example 7 3. N-(3-χλορ-5-fluoro-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1 -yl)acetamide

Step 1. tert-Butyl 5-(2-chloro-4-(2-chloroacetamido)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine-1-carboxylate

- 71 048980

This compound was prepared according to the procedures described in Example 72 (steps 3-6), using 3-chloro-5-fluoroaniline instead of 3-(difluoromethoxy)-5-fluoroaniline as the starting material. LC/MS calculated for C ₂₃ H ₂₂ Cl ₂ FN ₆ O ₃ (M+H)+: m/z=519.1; found 519.1.

Step 2. N-(3-chloro-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)2-(pyrrolidin-1-yl)acetamide.

Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert-butyl 5-(2-chloro-4-(2-chloroacetamido)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₂ H ₂₂ ClFN ₇ O (M+H) ⁺ : m/z=454.2; found 454.2.

Example 74. N-(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

[I 1 nA /

HN H

Step 1. tert-Butyl 5-(4-(2-chloroacetamido)-2-fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described in Example 72 (steps 3-6), using 3fluoro-5-methoxyaniline instead of 3-(difluoromethoxy)-5-fluoroaniline as the starting material. LC/MS calculated for C ₂₄ H ₂₅ ClFN ₆ O ₄ (M+H) ⁺ : m/z = 515.2; found 515.2.

Step 2. N-(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide.

Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert-butyl 5-(4-(2-chloroacetamido)-2-fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₃ H ₂₅ FN ₇ O ₂ (M+H) ⁺ : m/z=450.2; found 450.3.

Example 75. 2-(3,3-Dimethylazetidin-1-yl)-N-(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

- 72 048980

This compound was prepared according to the procedures described in Example 74 using 3,3-dimethylazetidine instead of pyrrolidine as the starting material. LC/MS calculated for C24H27FN7O2(M+H) ⁺ : m/z=464.2; found 464.3.

Example 76. 1-Methylpiperidin-4-yl-3-fluoro-5-methoxy-4-(3-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-6-yl)phenylcarbamate o X 1 j HN iS

E t C^

HN-N

Step 1. tert-Butyl 5-(4-amino-2-fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate yn ₂

F^T'OMe ί ίΓ Ν-Η Vos

This compound was prepared according to the procedures described in Example 72 (steps 3-5), using 3fluoro-5-methoxyaniline instead of 3-(difluoromethoxy)-5-fluoroaniline as the starting material. LC/MS calculated for C ₂₂ H ₂₄ FN ₆ O ₃ (M+H) ⁺ : m/z=439.2; found 439.2.

Step 2. 1-Methylpiperidin-4-yl-3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenylcarbamate.

Bis(trichloromethyl) carbonate (15.23 mg, 0.051 mmol) was added to a solution of tert-butyl 5-(4-amino-2-fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 mg, 0.034 mmol) and triethylamine (0.019 mL, 0.137 mmol) in tetrahydrofuran (1.0 mL). After stirring at rt for 30 min, 1-methylpiperidin-4-ol (3.94 mg, 0.034 mmol) was added and the reaction mixture was stirred for another 1 h. After quenching with methanol, the solvents were evaporated and TFA (1 mL) was added. After stirring at rt. The reaction mixture was diluted with acetonitrile for 30 min and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C24H27FN7O3 (M+H) ⁺ : m/z=480.2; found 480.1.

Example 77. 2-(Azetidin-1-yl)-N-(2,3,5-trifluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)acetamide

Step 1. tert-Butyl 5-(4-(2-chloroacetamido)-2,3,6-trifluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine-1-carboxylate

- 73 048980

This compound was prepared according to the procedures described in Example 72 (steps 3-6), using 2,3,5-trifluoroaniline instead of 3-(difluoromethoxy)-5-fluoroaniline as the starting material. LC/MS calculated for C ₂₃ H ₂₁ ClF ₃ N ₆ O ₃ (M+H)+: m/z=521.2; found 521.2.

Step 2. 2-(Azetidin-1-yl)-N-(2 _r 3,5-trifluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide.

Azetidine (2.2 mg, 0.04 mmol) was added to a solution of tert-butyl 5-(4-(2-chloroacetamido)-2,3,6-trifluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (10 mg, 0.019 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₁ H ₁₉ F ₃ N ₇ O (M+H) ⁺ : m/z=442.2; found 442.1.

Example 78. N-(3-chloro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(dimethylamino)acetamide

Step 1. tert-Butyl 5-(2-chloro-4-(2-chloroacetamido)-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described in Example 72 (steps 3-6), using 3-chloro-5-methylaniline instead of 3-(difluoromethoxy)-5-fluoroaniline as the starting material. LC/MS calculated for C ₂₄ H ₂₅ Cl ₂ N ₆ O ₃ (M+H) ⁺ : m/z = 515.1; found 515.2.

Step 2. N-(3-chloro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(dimethylamino)acetamide.

Dimethylamine hydrochloride (2 mg, 0.04 mmol) was added to a solution of tert-butyl 5-(2-chloro-4-(2-chloroacetamido)-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (10 mg, 0.019 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₁ H ₂₃ ClN ₇ O (M+H) ⁺ : m/z=424.2; found 424.2.

Example 79. 2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

- 74 048980

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

This compound was prepared according to the procedures described in Example 72 (steps 4-6), using 4-bromo-3-methylaniline instead of 4-bromo-3-(difluoromethoxy)-5-fluoroaniline as the starting material. LC/MS calculated for C ₂₄ H ₂₆ ClN ₆ O ₃ (M+H) ⁺ : m/z = 481.2; found 481.2.

Step 2. (1R,4S)-2-azabicyclo[2.2.1]heptan-3-one

Pd/C (0.583 g, 5 wt %) was added to a solution of (1S,4R)-2-azabicyclo[2.2.1]hept-5-en-3-one (2.39 g, 21.90 mmol) in MeOH (15.0 mL). After stirring under hydrogen at rt for 2 h, the catalyst was filtered off and the solvent was evaporated in vacuo. The resulting crude product was used in the next step without further purification. LC/MS calculated for _C6H10NO (M+H)+: m/z=112.1; found 112.1.

Step 3. (1R,4S)-2-azabicyclo[2.2.1]heptane, chloride

A solution (1.0 M in THF) of LAH (25.4 mL, 25.4 mmol) was added to a solution of (1R,4S)-2azabicyclo[2.2.1]heptan-3-one (2.35 g, 21.14 mmol) in THF (15.0 mL). The reaction mixture was heated under reflux for 3 h. The reaction mixture was carefully quenched with water and NaOH solution. The solids were filtered off and 4 M HCl in dioxane was added to the resulting solution. After evaporation of the solvent in vacuo, the resulting crude chloride of the desired product was used in the next step without further purification. LC/MS calculated for C ₆ H ₁₂ N (M+H) ⁺ : m/z = 98.1; found 98.1.

Step 4. 2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide.

(1R,4S)-2-azabicyclo[2.2.1]heptane (4 mg, 0.04 mmol) was added to a solution of tert-butyl 5-(4-(2-chloroacetamido)-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-o]pyridine-1-carboxylate (10 mg, 0.021 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₅ H ₂₈ N ₇ O (M+H) ⁺ : m/z=442.2; found 442.2. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 10.69-10.58 (m, 1H), 9.55 (s, 1H), 9.22 (s, 1H), 8.53 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.63-7.53 (m, 2H), 7.54-7.45 (m, 1H), 4.36-4.04 (m, 3H), 3.93 (s, 3H), 3.63-2.58 (m, 3H), 2.35 (s, 3H), 2.091.36 (m, 6H) ppm.

Example 80. N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-nirazolo[3,4-c]pyridin-5yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

- 75 048980

Step 1. tert-Butyl 5-(4-(2-chloroacetamido)-2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described in Example 72 (steps 3-6), using 3fluoro-5-methylaniline instead of 3-(difluoromethoxy)-5-fluoroaniline as the starting material. LC/MS calculated for C ₂₄ H ₂₅ ClFN ₆ O ₃ (M+H) ⁺ : m/z = 499.2; found 499.2.

Step 2. N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide.

Pyrrolidine (5 μl, 0.06 mmol) was added to a solution of tert-butyl 5-(4-(2-chloroacetamido)-2-fluoro-6methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (15 mg, 0.03 mmol) and DIPEA (0.01 ml, 0.06 mmol) in DMF (1 ml). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 ml/min). LC/MS calculated for C ₂₃ H ₂₅ FN ₇ O (M+H) ⁺ : m/z=434.2; found 434.2. ¹ H-NMR (600 MHz, DMSO-06) δ 10.78 (s, 1H), 9.15 (s, 1H), 8.49 (s, 1H), 8.08 (s, 1H), 8.07-8.01 (m, 1H), 7.54 (dd, J=11.4, 1.6 Hz, 1H), 7.27 (s, 1H), 4.30 (d, J=3.8 Hz, 2H), 3.92 (s, 3H), 3.66 (br, 2H), 3.17 (br, 2H), 2.17 (s, 3H), 2.04 (br, 2H), 1.94 (br, 2H) ppm.

Example 81. 2-(Dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described in Example 80 using dimethylamine instead of pyrrolidine as the starting material. LC/MS calculated for C ₂₁ H ₂₃ FN ₇ O (M+H)+: m/z = 408.2; found 408.2. ¹ H NMR (500 MHz, DMSO-D) δ 10.84 (s, 1H), 9.20 (s, 1H), 8.51 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.61-7.49 (m, 1H), 7.28 (s, 1H), 4.20 (s, 2H), 3.92 (s, 3H), 2.92 (s, 6H), 2.18 (s, 3H) ppm.

Example 82. 2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

- 76 048980

This compound was prepared according to the procedures described in Example 80 using 7azabicyclo[2.2.1]heptane instead of pyrrolidine as starting material. LC/MS calculated for C25H27FN7O (M+H)+: m/z=460.2; found 460.2. ¹ H-NMR (500 MHz, DMSO^) δ 10.90 (s, 1H), 9.23 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.57 (d, J=11.3 Hz, 1H), 7.31 (s, 1H), 4.25 (s, 2H), 4.13 (d, J=4.3 Hz, 2H), 3.92 (s, 3H), 2.18 (s, 3H), 2.05 (s, 4H), 1.76 (dd, J=20.9, 8.2 Hz, 4H) ppm.

Example 83. 2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described in Example 80 using 7-(1R,4S)-2azabicyclo[2.2.1]heptane (Example 79, step 3) instead of pyrrolidine as starting material. LC/MS calculated for C ₂₅ H ₂₇ FN ₇ O (M+H)+: m/z=460.2; found 460.2. ¹ H-NMR (500 MHz, DMSOd6) δ 10.84-10.71 (m, 1H), 9.15 (s, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.53 (d, J=11.5 Hz, 1H), 7.28 (s, 1H), 4.40-4.04 (m, 3H), 3.92 (s, 3H), 3.65-2.84 (m, 2H), 2.70-2.59 (m, 1H), 2.17 (s, 3H), 2.06-1.37 (m, 6H) ppm.

Example 84. 3-(Dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)propanamide

Step 1. tert-Butyl 5-(4-amino-2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described in Example 72 (steps 3-5), using 3fluoro-5-methylaniline instead of 3-(difluoromethoxy)-5-fluoroaniline as the starting material. LC/MS calculated for C ₂₂ H ₂₄ FN ₆ O ₂ (M+H)+: m/z=423.2; found 423.2.

Step 2. 3-(Dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)propanamide.

To a solution of 5-(4-amino-2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (10 mg, 0.024 mmol) and 3-(dimethylamino)propionic acid (2.77 mg, 0.024 mmol) in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine (13 μL, 0.07 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (15 mg, 0.04 mmol). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The resulting mixture was extracted with ethyl acetate. The separated organic phases were washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. TFA (1 mL) was then added and the mixture was stirred at rt for 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₂ H ₂₅ FN ₇ O (M+H)+: m/z = 422.2; found 422.3.

Example 8 5. 2-cyano-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

- 77 048980

This compound was prepared according to the procedures described in Example 84 using 2-cyanoacetic acid instead of 3-(dimethylamino)propionic acid as the starting material. LC/MS calculated for C ₂₀ H ₁₇ FN ₇ O (M+H) ⁺ : m/z = 390.2; found 3 90.3.

Example 86. N-methyl-1-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

Step 1. (2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.05 g, 8.1 mmol), potassium acetate (1.05 g, 10.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.44 g, 0.54 mmol) under nitrogen atmosphere was added a solution of (3-bromo-2-methylphenyl)methanol (1.08 g, 5.37 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was diluted with DCM and filtered through celite. The filtrate was concentrated in vacuo. The residue was purified using Biotage Isolera™ (446 mg, 36%). LC/MS calculated for C ₁₄ H ₂₀ BO ₂ (M+H-H ₂ O) ⁺ : m/z=231.2; found 231.2.

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

tert-Butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (500 mg, 1.498 mmol, intermediate 1), (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)methanol (446 mg, 1.798 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (118 mg, 0.15 mmol), and potassium phosphate (636 mg, 3 mmol) were placed in a flask, which was evacuated three times and again The reaction mixture was filled with nitrogen. Dioxane (15 mL) and degassed water (1.5 mL) were then added. The reaction mixture was stirred at 90°C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (190 mg, 30%). LC/MS calculated for C ₂₃ H ₂₆ N ₅ O ₃ (M+H)+: m/z = 420.2; found 420.3.

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

- 78 048980

Dess-Martin periodinane (231 mg, 0.544 mmol) was added to a solution of tert-butyl 5-(3-(hydroxymethyl)-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (190 mg, 0.453 mmol) and pyridine (44.0 µL, 0.544 mmol) in DCM (5 mL). After stirring at rt for 1 h, the solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (170 mg, 90%). LC/MS calculated for C ₂₃ H ₂₄ N ₅ O ₃ (M+H) ⁺ : m/z = 418.2; found 418.2.

Step 4. N-methyl-1-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

Sodium triacetoxyborohydride (10.15 mg, 0.048 mmol) was added to a solution of methanamine (2 M in THF, 12 µL, 0.024 mmol), acetic acid (2.74 µL, 0.048 mmol) and tert-butyl 5-(3-formyl-2-methylphenyl)3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (10 mg, 0.024 mmol) in DCE (1 mL). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The mixture was extracted with ethyl acetate. The separated organic phases were washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. TFA (1 mL) was then added and the reaction mixture was stirred at rt. for 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₁₉ H ₂₁ N ₆ (M+H) ⁺ : m/z=333.2; found 333.2.

Example 87. N-methyl-1-(4-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)methanamine

This compound was prepared according to the procedures described in Example 86 using (3-bromo-4 methylphenyl)methanol instead of (3-bromo-2-methylphenyl)methanol as the starting material. LC/MS calculated for C ₁₉ H ₂₁ N ₆ (M+H)+: m/z=333.2; found 333.2.

Intermediate 3. (3-bromo-2-(trifluoromethyl)phenyl)methanol

To a mixture of 3-bromo-2-(trifluoromethyl)benzoic acid (0.97 g, 3.61 mmol) and triethanolamine (0.528 mL, 3.79 mmol) in tetrahydrofuran (20 mL) was added isobutyl chloroformate (0.491 mL, 3.79 mmol). After stirring at rt for 30 min, the solids were separated by filtration and a solution of sodium tetrahydroborate (0.273 g, 7.21 mmol) in water (1.300 mL) was slowly added to the filtrate. After stirring at rt for 30 min, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated under vacuum and the resulting crude product was purified using Biotage Isolera™ (550 mg, 64%).

Example 88. N-methyl-1-(3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)phenyl)methanamine

This compound was prepared according to the procedures described in Example 86, using (3-bromo-2-(trifluoromethyl)phenyl)methanol (Intermediate 3) instead of (3-bromo-2-methylphenyl)methanol as starting material. LC/MS calculated for C ₁₉ H ₁₈ F ₃ N ₆ (M+H) ⁺ : m/z = 387.2; found 387.1.

¹ H-NMR (600 MHz, DMSO-D6) δ 9.10-9.00 (m, 2H), 8.48 (s, 1H), 8.10 (d, J=1.2 Hz, 1H), 8.06 (d, J=0.6 Hz, 1H), 7.86 (t, J=7.7 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 4.41 (s, 2H), 3.92 (s, 3H), 2.75 (t, J=5.2 Hz, 3H) ppm.

Example 89

- 79 048980

This compound was prepared according to the procedures described in Example 86 and 88, using azetidine instead of methanamine as the starting material. LC/MS calculated for C ₂₁ H ₂₀ F ₃ N ₆ (M+H)+: m/z=413.2; found 413.2.

Example 90

This compound was prepared according to the procedures described in Example 86 and 88, using tetrahydro2H-pyran-4-amine instead of methanamine as the starting material. LC/MS calculated for C ₂₃ H ₂₄ F ₃ N ₆ O (M+H)+: m/z=457.2; found 457.1.

Example 91

This compound was prepared according to the procedures described in Example 86 and 88, using propan-2-amine instead of methaneamine as the starting material. LC/MS calculated for C ₂₁ H ₂₂ F ₃ N ₆ (M+H)+: m/z=415.2; found 415.3. ¹ H-NMR (500 MHz, DMSO-4) δ 9.06 (d, J=1.0 Hz, 1H), 8.91 (br, 1H), 8.46 (s, 1H), 8.14-8.04 (m, 2H), 7.92-7.81 (m, 2H), 7.68 (t, J=4.4 Hz, 1H), 4.39 (br, 2H), 3.93 (s, 3H), 3.52 (dq, J=11.9, 5.9 Hz, 1H), 1.35 (d, J=6.5 Hz, 6H) ppm.

Intermediate 4. (3-Bromo-4-fluoro-2-methylphenyl)methanol

A solution of LAH (5.75 mL, 5.75 mmol, 1.0 M in THF) was added to a solution of ethyl 3-bromo-4-fluoro-2-methylbenzoate (Enamine, 1.25 g, 4.79 mmol) in THF (15.0 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was then carefully quenched with water and NaOH solution. After the solids were separated by filtration, the solvent from the filtrate was evaporated in vacuo. The resulting crude product was used in the next step without further purification. LC/MS calculated for C ₈ H ₇ BrF (M+H-H ₂ O) ⁺ : m/z = 201.0; found 201.0.

Example 92. 1-(4-Fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5 yl)phenyl)-X-methylmethanamine

This compound was prepared according to the procedures described in Example 86, using (3-bromo-4-fluoro-2-methylphenyl)methanol (Intermediate 4) instead of (3-bromo-2-methylphenyl)methanol as starting material. LC/MS calculated for C ₁₉ H ₂₀ FN ₆ (M+H)+: m/z=351.2; found 351.2.

Example 93

- 80 048980

This compound was prepared according to the procedures described in Example 86 and 92, using propan-2amine instead of methaneamine as the starting material. LC/MS calculated for C ₂₁ H ₂₄ FN ₆ (M+H)+: m/z=379.2; found 379.3. ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 8.67 (br, 1H), 8.48 (s, 1H), 8.04 (s, 2H), 7.58 (dd, J=8.5, 5.7 Hz, 1H), 7.30 (t, J=8.7 Hz, 1H), 4.30-4.16 (m, 2H), 3.92 (s, 3H), 3.48 (dp, J=12.4, 6.3 Hz, 1H), 2.15 (s, 3H), 1.34 (d, J=6.5 Hz, 6H) ppm.

Example 94. 5-(3-(Azetidin-1-ylmethyl)-6-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 86 and 92, using azetidine instead of methanamine as the starting material. LC/MS calculated for C ₂₁ H ₂₂ FN ₆ (M+H)+: m/z=377.2; found 377.3.

Example 95

Step 1. tert-Butyl 3-(3,5-difluorophenyl)cyclobutylcarbamate

Di-tert-Butyl dicarbonate (4.77 g, 21.83 mmol) was added to a solution of 3-(3,5-difluorophenyl)cyclobutan-1amine (2.5 g, 13.65 mmol) and triethylmine (4.14 g, 40.9 mmol) in THF (25 mL). After stirring at rt for 1 h, the solvents were evaporated in vacuo and the resulting crude product was purified using _Biotage Isolera™ ( _{3.2 g, 90%). LC/MS calculated for C11H12F2NO2 (} M+H- _C4H8 ) ⁺ : _m /z=228.1; found 228.1.

Step 2. tert-Butyl 3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate

In a solution of tert-butyl 3-(3,5-difluorophenyl)cyclobutylcarbamate (3.2 g, 11.29 mmol) in THF (35 ml)

- 81 048980 at -78°C was added to a solution of n-butyl lithium, 2.5 M in hexane (13.55 mL, 33.9 mmol). The reaction mixture was stirred at -78°C for 1 h, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.3 g, 33.9 mmol) was added dropwise. The resulting solution was stirred at -78°C for another 1 h, then warmed to rt and quenched with a saturated solution of NH4Cl in water (50 mL). The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (2.7 g, 65%). LC/MS calculated for C ₁₇ H ₂₃ BF ₂ NO ₄ (M+HC ₄ H ₈ ) ⁺ : m/z=354.2; found 354.2.

Step 3. tert-Butyl 5-(4-(3-(tert-butoxycarbonyl mino)cyclobutyl)-2,6-difluorophenyl)-3-(1methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (600 mg, 1.8 mmol, intermediate 1), (3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (1.177 g, 2.88 mmol), chloro(2-dicyclohexylphosphino2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (280 mg, 0.36 mmol), and potassium phosphate (626 mg, 2.9 mmol) was placed in a flask, evacuated three times and refilled with nitrogen. Dioxane (20 mL) and degassed water (2 mL) were then added. The reaction mixture was stirred at 90 °C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated under reduced pressure and the resulting crude product was purified using Biotage Isolera™ (753 mg, 72%). LC/MS calculated for C ₃₀ H ₃₅ F ₂ N ₆ O ₄ (M+H) ⁺ : m/z = 581.3; found 581.3.

Step 4. 3-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutanamine

4 M HCl in dioxane (2 mL, 8 mmol) was added to tert-butyl 5-(4-(3-((tert-butoxycarbonyl)amino)cyclobutyl)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (550 mg, 0.9 mmol) and the reaction mixture was stirred at rt for 1 h. The solvent was then evaporated in vacuo and the resulting crude product was dried and used in the next step without further purification. LC/MS calculated for C ₂₀ H ₁₉ F ₂ N ₆ (M+H)+: m/z = 381.2; found 381.1.

Step 5. 3-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-isopropylcyclobutanamine.

Sodium triacetoxyborohydride (16.7 mg, 0.08 mmol) was added to a solution of propan-2-one (2.290 mg, 0.039 mmol), acetic acid (2.74 μL, 0.048 mmol) and 3-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutan-1-amine (15.0 mg, 0.039 mmol) in DCE (1 mL). After stirring the reaction mixture at rt for 2 h, it was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₃ H ₂₅ F ₂ N ₆ (M+H) ⁺ : m/z=423.2; found 423.3.

Example 96. 2-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)N-methylethanamine

- 82 048980

This compound was prepared according to the procedures described in Example 95 (steps 2-3), using 2(3,5-difluorophenyl)ethanol instead of tert-butyl 3-(3,5-difluorophenyl)cyclobutylcarbamate as the starting material. LC/MS calculated for C ₂₃ H ₂₄ F ₂ N ₅ O ₃ (M+H)+: m/z=456.2; found 456.2.

Step 2. tert-Butyl 5-(2,6-difluoro-4-(2-oxoethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

Dess-Martin periodinane (870 mg, 2.05 mmol) was added to a solution of tert-butyl 5-(2,6-difluoro-3-(2hydroxyethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (0.78 g, 1.713 mmol) and pyridine (166.0 µL, 2.05 mmol) in DCM (15 mL). After stirring at rt for 1 h, the solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (653 mg, 84%). LC/MS calculated for C ₂₃ H ₂₂ F ₂ N ₅ O ₃ (M+H) ⁺ : m/z=454.2; 454.2 found.

Step 3. 2-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine

Sodium triacetoxyborohydride (10.15 mg, 0.048 mmol) was added to a solution of methanamine (2 M in THF, 12 µl, 0.024 mmol), acetic acid (2.74 µl, 0.048 mmol) and tert-butyl 5-(2,6-difluoro-4-(2oxoethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (11.0 mg, 0.024 mmol) in DCE (1 ml). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The reaction mixture was extracted with ethyl acetate. The separated organic phases were washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. TFA (1 mL) was then added and the mixture was stirred at rt for 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₁₉ H ₁₉ F ₂ N ₆ (M+H) ⁺ : m/z = 369.2; found 369.2.

Example 97. 2-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)N-methylethanamine

This compound was prepared according to the procedures described in Example 96 using 2-(2,4-difluorophenyl)ethanol instead of 2-(3,5-difluorophenyl)ethanol as the starting material. LC/MS, sol.

- 83 048980 read for C ₁₉ H ₁₉ F ₂ N6 (M+H)+: m/z=369.2; found 369.1.

Example 98. N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenethyl)tetrahydro-2H-pyran-4-amine

HN N

This compound was prepared according to the procedures described in Example 97 using tetrahydro-2Hpyran-4-amine instead of methanamine as the starting material. LC/MS calculated for C ₂₃ H ₂₅ F ₂ N ₆ O (M+H)+: m/z=439.2; found 439.2.

Example 99

This compound was prepared according to the procedures described in Example 96 using 1-isopropylazetidin-3-amine instead of methanamine as the starting material. LC/MS calculated for C ₂₄ H ₂₈ F ₂ N7 (M+H)+: m/z=452.2; found 452.2.

Intermediate 5. tert-Butyl 5-(2-fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[3,4c]pyridine-1-carboxylate

This compound was prepared according to the procedures described in Example 34 (steps 1-5), using Boc ₂ O instead of SEM-Cl as a reagent. LC/MS calculated for C ₁₈ H ₁₈ FIN ₃ O ₃ (M+H)+: m/z=470.0; found 470.0.

Example 100. 2-Fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-nirazolo[3,4-c]niridin-3-yl)-N-methylbenzamide

tert-Butyl 5-(2-fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.00 g, 2.131 mmol, intermediate 5), (3-fluoro-4-(methoxycarbonyl)phenyl)boric acid (0.506 g, 2.56 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II) (Pd XPhos G2) (280 mg, 0.36 mmol), and potassium phosphate (626 mg, 2.9 mmol) were placed in a flask, which was evacuated three times and refilled with nitrogen. Dioxane (20

- 84 048980 mL) and degassed water (2 mL) were added and the reaction mixture was stirred at 90 °C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the resulting crude product was purified using Biotage Isolera™ (835 mg, 79%). LC/MS calculated for C ₂₆ H ₂₄ F ₂ N ₃ O ₅ (M+H) ⁺ : m/z = 496.2; found 496.1.

Step 2. 2-Fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-nirazolo[3,4-c]pyridin-3-yl)benzoic acid

Lithium hydroxide (0.149 g, 6.23 mmol) was added to a solution of tert-butyl 3-(3-fluoro-4-(methoxycarbonyl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (618 mg, 1.246 mmol) in methanol (4 mL), THF (6.0 mL), and water (2.0 mL). After stirring at 45 °C for 3 h, the reaction mixture was neutralized with HCl solution and the solvents were evaporated in vacuo. The resulting crude product was dried and used in the next step without further purification. LC/MS calculated for C ₂₀ H ₁₄ F ₂ N ₃ O ₃ (M+H)+: m/z = 382.1; found 382.1.

Step 3. 2-Fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide.

To a solution of 2-fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzoic acid (10 mg, 0.026 mmol) and methanamine (2 M in THF, 24 µl, 0.048 mmol) in N,N-dimethylformamide (1.5 ml) were added N,N-diisopropylethylamine (13 µl, 0.07 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (15 mg, 0.04 mmol). After stirring the reaction mixture at rt. for 2 h it was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 ml/min). LC/MS calculated for C ₂₁ H ₁₇ F ₂ N ₄ O ₂ (M+H) ⁺ : m/z = 395.1; found 395.2.

Example 101 5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpicolinamide

This compound was prepared according to the procedures described in Example 100 using methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate instead of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid as the starting material. LC/MS calculated for C ₂₀ H ₁₇ FN ₅ O ₂ (M+H) ⁺ : m/z = 378.1; found 378.1.

Example 102 4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-methoxy-N-methylbenzamide

This compound was prepared according to the procedures described in Example 100 using 3-methoxy-4(methoxycarbonyl)phenylboronic acid instead of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid as the starting material. LC/MS calculated for C22H20FN4O3 (M+H) ⁺ : m/z=4,07.2; found 4,07.2.

Example 103. 4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N,2-dimethylbenzamide

This compound was prepared according to the procedures described in Example 100 using 4-(methoxycarbonyl)-3-methylphenylboronic acid instead of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid as the starting material. LC/MS calculated for C ₂₂ H ₂₀ FN ₄ O ₂ (M+H) ⁺ : m/z = 391.2; found 391.2.

- 85 048980

Example 104

Step 1. Methyl 1-(5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridin-3-yl)-1H-imidazol-4-carboxylate

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (200 mg, 0.400 mmol, Example 34, step 5), 8-hydroxyquinoline (11.63 mg, 0.080 mmol), potassium carbonate (111 mg, 0.801 mmol), and copper(I) iodide (15.2 mg, 0.080 mmol) were placed in a septum vial. The vial was evacuated three times and refilled with nitrogen. After addition of a solution of methyl 1H-imidazole 4-carboxylate (76 mg, 0.601 mmol) in DMSO (2 mL), the reaction mixture was stirred at 100 °C overnight. After cooling to rt. Water was added and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over sodium sulfate and the solvent was evaporated. The crude product was purified using Biotage Isolera™. LC/MS calculated for C24H29FNsO4Si (M+H)+: m/z=498.2; found 498.3.

Step 2. 1-(5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-imidazole-4-carboxylic acid

1 M sodium hydroxide in water (1 mL, 1 mmol) was added to a solution of methyl 1-(5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-imidazole-4-carboxylate (25 mg, 0.049 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL). After stirring at rt for 2 h, the pH was adjusted to 5 with 1 M HCl. The resulting mixture was then extracted with ethyl acetate and the organic phase was washed with brine. The organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The resulting solid product was used in the next step without further purification. LC/MS calculated for C ₂₃ H ₂₇ FN ₅ O ₄ Si (M+H)+: m/z=484.2; found 484.1.

Step 3. 1-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrαzolo[3,4-c]pyridin-3-yl)-N-isopropyl-1H-imidazole-4-carboxamide

To a solution of 1-(5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridin-3-yl)-1H-imidazole-4-carboxylic acid (0.01 g, 0.02 mmol) and isopropylamine (4.43 μL, 0.052 mmol) in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine (13 μL, 0.07 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriαzol-1-yl)uronium hexafluorophosphate (15 mg, 0.04 mmol). After stirring the reaction mixture at rt for 2 h, it was quenched with water. The mixture was extracted with ethyl acetate. The separated organic phases were washed with brine, dried over sodium sulfate and the solvents were evaporated in vacuo. Then 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Then methanol (1 mL) was added and the reaction mixture was stirred further at 80 °C for 30 min. Then the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₀ H ₂₀ FN ₆ O ₂ (M+H)+: m/z = 395.2; found 395.2.

Example 105. 1-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methyl-1H-imidazole-4-carboxamide

- 86 048980

This compound was prepared according to the procedures described in Example 104 using methaneamine instead of isopropylamine as the starting material. LC/MS calculated for C ₁₈ H ₁₆ FN6O ₂ (M+H)+: m/z=367.1; found 367.1.

Example 106

Step 1. 3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)phenol

This compound was prepared according to the procedures described in Example 57, Step 1, using (2,6-difluoro-4-hydroxyphenyl)boronic acid instead of 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)benzoate as the starting material. LC/MS calculated for C ₂₂ H ₂₆ F ₂ N ₅ O ₂ Si (M+H) ⁺ : m/z = 458.2; found 458.2.

Step 2. 5-(4-(Azetidin-2-ylmethoxy)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

To a solution of 3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenol (30 mg, 0.066 mmol) in DMF (1 mL) were added tert-butyl 2-(bromomethyl)azetidine-1-carboxylate (24.60 mg, 0.098 mmol) and cesium carbonate (32.0 mg, 0.098 mmol). After stirring the reaction mixture at 90 °C overnight, it was quenched with water. The mixture was extracted with ethyl acetate. The separated organic phases were washed with brine and dried over sodium sulfate.

The solvents were evaporated in vacuo. Then 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was added and the reaction mixture was further stirred at 80 °C for 30 min. Then the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₀ H ₁₉ F ₂ N6O (M+H) ⁺ : m/z = 397.2; found 397.2.

Example 107. 5-(2,6-Difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)1H-pyrazolo[3,4-c]pyridine

This compound is prepared according to the methods described in Example 106, using 4-chlorotetrahydro-2H-pyran instead of tert-butyl 2-(bromomethyl)azetidine-1-carboxylate as the starting material.

- 87 048980 of material. LC/MS calculated for C ₂₁ H ₂₀ F ₂ N ₅ O2 (M+H)+: m/z=412.2; found 412.2.

Example 108 5-(2,6-Difluoro-4-(pyridin-4-ylmethoxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 106, using 4(bromomethyl)pyridine instead of tert-butyl 2-(bromomethyl)azetidine-1-carboxylate as the starting material. LC/MS calculated for C ₂₂ H ₁₇ F ₂ N ₆ O (M+H) ⁺ : m/z = 419.1; found 419.1.

Example 109. 3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl dimethylcarbamate

To a solution of 3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenol (30 mg, 0.066 mmol, Example 106, step 1) in THF (1 mL) were added dimethylcarbamic acid chloride (10.58 mg, 0.098 mmol) and triethylamine (0.018 mL, 0.131 mmol). After stirring at rt for 30 min, 1-methylpiperidin-4-ol (3.94 mg, 0.034 mmol) was added and the reaction mixture was stirred for 1 h. After stirring the reaction mixture at rt for 1 h, it was quenched with water. The mixture was extracted with ethyl acetate. The separated organic phases were washed with brine and dried over sodium sulfate. The solvents were evaporated in vacuo. Then 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was added and the reaction mixture was further stirred at 80 °C for 30 min. Then the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₁₉ H ₁₇ F ₂ N ₆ O ₂ (M+H) ⁺ : m/z = 399.1; found 399.1.

Example 110 3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenylmorpholine-4-carboxylate

This compound was prepared according to the procedures described in Example 109 using morpholine-4-carbonyl chloride instead of dimethylcarbamic acid chloride as the starting material. LC/MS calculated for C ₂₁ H ₁₉ F ₂ N ₆ O ₃ (M+H) ⁺ : m/z = 441.2; found 441.1.

Example 111. N-methyl-1-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)methanamine

- 88 048980

This compound was prepared according to the procedures described in Example 86 using (4-bromo-3-methylphenyl)methanol instead of (3-bromo-2-methylphenyl)methanol as the starting material. LC/MS calculated for C ₁₉ H ₂₁ N ₆ (M+H)+: m/z=333.2; found 333.1.

Example 112. N-methyl-1-(4-(3-(1-methyl-1H-nirazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-(trifluoromethyl)phenyl)methanamine

This compound was prepared according to the procedures described in Example 86 using (4-bromo-3(trifluoromethyl)phenyl)methanol instead of (3-bromo-2-methylphenyl)methanol as the starting material. LC/MS calculated for C ₁₉ H ₁₈ F ₃ N ₆ (M+H)+: m/z=387.2; found 387.1.

Example 113. 1-(5-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)pyridin-2-yl)pyrrolidin-3-ol

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

N-Bromosuccinimide (15.8 g, 89 mmol) was added to a solution of 3-fluoro-5-methylaniline (Combi-Blocks, 11 g, 8 8 mmol) in DMF (80 mL) cooled to 0 °C in an ice bath. The reaction mixture was stirred at 0 °C for 30 min. After warming to rt, the reaction mixture was stirred for an additional 1 h. Water and ethyl acetate were added and the organic phase was washed with saturated aqueous NaHCO ₃ and brine. The organic phase was then dried over magnesium sulfate and the solvents were evaporated under reduced pressure. The crude product was purified using Biotage Isolera™ (17.2 g, 96%). LC/MS calculated for C ₇ H ₈ BrFN (M+H)+: m/z = 203.9; 204.0 found.

Step 2. 2-Bromo-1-fluoro-5-iodo-3-methylbenzene

To a solution of 4-bromo-3-fluoro-5-methylaniline (7.28 g, 36 mmol) in acetonitrile (190 mL) cooled to 0 °C in an ice bath was added sulfuric acid (4.75 mL, 89 mmol) dissolved in H ₂ O (10 mL). After stirring for 5 min, a solution of sodium nitrite (4.92 g, 71.4 mmol) in water (10 mL) was added dropwise and the reaction mixture was stirred at 0 °C for an additional 15 min. Sodium iodide (23.7 g, 143 mmol) in water (20 mL) was then added and the ice bath was removed. After stirring at rt, the reaction mixture was stirred for an additional 20 min, then the reaction mixture was quenched by adding aqueous Na ₂ S ₂ O ₃ . The mixture was then extracted with ethyl acetate and the organic phase mixture was washed with brine, dried over magnesium sulfate and the solvents were evaporated under reduced pressure. The crude product was purified using Biotage Isolera™ (10.3 g, 94%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.39 (br s, 1H), 7.29 (m, 1H), 2.38 (s, 3H) ppm.

Step 3. 2-Bromo-1-fluoro-3-methyl-5-vinylbenzene

- 89 048980

Br

To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (10.3 g, 32.8 mmol) in 1,4-dioxane (80 mL) and water (13.3 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich, 6.16 mL, 34.5 mmol), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl ₂ ) (2.40 g, 3.3 mmol), and tripotassium phosphate (13.9 g, 65.7 mmol). The reaction mixture was degassed, backfilled with nitrogen, and heated to 70 °C for 1 h. After cooling to rt, the reaction mixture was filtered through a pad of celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic phase mixture was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified using Biotage Isolera™ (5.46 g, 77%). 1H NMR (400 MHz, _CDCl3 ) δ 7.05 (br s, 1H), 7.01 (dd, J=2.0, 9.4 Hz, 1H), 6.60 (dd, J=10.9, 17.5 Hz, 1H), 5.75 (d, J=17.5 Hz, 1H), 5.31 (d, J=10.9 Hz, 1H), 2.42 (s, 3H) ppm.

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

H O jl!

Br

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

Step 5. 1-(4-Bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine

I

NH

F'^^Wo

Br

In a 20 mL scintillation vial with a magnetic anchor, 4-bromo-3-fluoro-5-methylbenzaldehyde (1.46 g, 6.70 mmol) was dissolved in MeOH (6.70 mL) and the reaction mixture was placed under nitrogen atmosphere. Then, a 33% solution of methaneamine (3.15 g, 33.5 mmol) in ethanol and titanium(IV) isopropoxide (0.982 mL, 3.35 mmol) was added and the reaction mixture was stirred at rt for 3 h. Then, sodium borohydride (1.01 g, 26.8 mmol) was added portionwise to the reaction mixture and stirring was continued at rt for an additional 1.5 h. NH4OH (30% aqueous solution) was added to the reaction mixture and stirring was continued for another 15 min. The reaction mixture was then acidified with 1 N HCl and extracted with ethyl acetate. The aqueous layer was then made basic and extracted with ethyl acetate. The organic phase mixture was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g, 85%) as a light yellow oil. The crude product was used in the next step without further purification. LC/MS calculated for C ₉ H ₁₂ BrFN (M+H)+: m/z = 232.0; found 231.9.

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

Vos

X

A

F'^^Me

Vg

To a solution of 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g, 5.67 mmol) and triethylamine (1.58 mL, 11.34 mmol) in THF (18.9 mL) was added di-tert-butyl dicarbonate (1.58 mL, 6.80 mmol). The reaction mixture was then stirred at ambient temperature for 1 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic mixture was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by

- 90 048980 by Biotage Isolera™ (1.42 g, 78%). LC/MS calculated for C ₁₀ H ₁₂ BrFNO ₂ (M+HC ₄ H ₈ )+: m/z=276.0; found 276.0.

Step 7. tert-Butyl-3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

Vos I

Ha

F^Vwe

R O o

In a 20 ml muffle-dried scintillation vial with a magnetic anchor, tert-butyl (4-bromo-3-fluoro-5-methylbenzyl)(methyl)carbamate (573 mg, 1.73 mmol) is dissolved in THF (11.5 ml).

The reaction mixture was cooled to -78 °C in a dry ice/acetone bath and BuLi (1.6 M solution in hexane, 1.19 mL, 1.90 mmol) was added dropwise. The reaction mixture was then stirred for 3 min after which 2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (427 μL, 2.25 mmol) was added dropwise. The mixture was warmed to rt and stirred for an additional 5 h. The reaction mixture was then quenched by adding water, acidified to pH 5-6 with 1 N HCl and extracted with ethyl acetate. The organic layer mixture was then washed with brine, dried over magnesium sulfate and concentrated to give tert-butyl 3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzyl(methyl)carbamate (679 mg, quantitative yield). The crude product was used in the next step without further purification. LC/MS calculated for C ₁₆ H ₂₄ BrFNO ₄ (M+HC ₄ H ₈ ) ⁺ : m/z = 324.2; found 324.1.

Step 8. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-1Hpyrazolo[3,4-c]pyridine-1-carboxylate

In a 20-mL scintillation vial with a magnetic stirrer, tert-butyl 5-chloro-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (0.649 g, 2.56 mmol) and tert-butyl (3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (970 mg, 2.56 mmol) are dissolved in 1,4-dioxane (8.0 mL) and water (2.0 mL). To this mixture were added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (400 mg, 0.51 mmol) and tripotassium phosphate (1.6 g, 7.67 mmol). The reaction mixture was degassed (by bubbling with nitrogen), sealed and heated to 75 °C for 1 h. After cooling to rt, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer mixture was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified using Biotage Isolera™ (300 mg, 25%). LC/MS calculated for C ₂₅ H ₃₂ FN ₄ O ₄ (M+H) ⁺ : m/z=471.2; found 471.2.

Step 9. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-iodo1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

In a 20-ml scintillation vial with a magnetic stirrer, tert-butyl 5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-1H-pyr is dissolved in 1,4-dioxane (5 ml) and water (5 ml).

- 91 048980 gold[3,4-c]pyridine-1-carboxylate (0.30 g, 0.638 mmol) and potassium carbonate (0.441 g, 3.19 mmol). The reaction mixture was heated to 80°C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase mixture was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude intermediate was dissolved in DMF (10 mL) and N-iodosuccinimide (0.15 g, 0.7 mmol) was added and the reaction mixture was heated to 60 °C for 1 h. Triethylamine (0.15 mL, 1 mmol) and di-tert-butyl carbonate (0.168 mL, 0.72 mmol) were added to the reaction mixture and it was stirred at rt for an additional 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product was purified using Biotage Isolera™. LC/MS calculated for C ₂₅ H ₃₁ FIN ₄ O ₄ (M+H)+: m/z = 597.1; found 597.1.

Step 10. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-(6chloropyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

tert-Butyl 5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (0.3 g, 0.503 mmol), _PdCl2 (dppf) _-CH2Cl2 adduct (0.082 g, 0.101 mmol), (6-chloropyridin- ₃ -yl)boric acid (0.103 g, 0.654 mmol) and potassium phosphate (320 mg, 1.51 mmol) were placed in a flask, which was evacuated three times and backfilled with nitrogen. Dioxane (5 mL) and degassed water (0.5 mL) were added and the reaction mixture was stirred at 80°C for 1 h. After cooling to rt. Water was added and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified using Biotage Isolera™. LC/MS calculated for C ₃₀ H ₃₄ ClFN ₅ O ₄ (M+H)+: m/z=582.2; found 582.2.

Step 11. 1-(5-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)pyridin-2-yl)pyrrolidin-3-ol.

Pyrrolidin-3-ol (8.98 mg, 0.103 mmol) was added to a solution of tert-butyl 5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-(6-chloropyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (0.020 g, 0.034 mmol) in 2-methoxyethane-1-ol (0.5 mL). After stirring at 120 °C overnight, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₄ H ₂₆ FN ₆ O (M+H)+: m/z=4 33.2; found 433.2.

Example 114. 1-(3-Fluoro-4-(3-(6-(3-methoxypiperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-methylphenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 113, using 3-methoxypiperidine instead of pyrrolidin-3-ol as the starting material. LC/MS calculated for C ₂₆ H ₃₀ FN ₆ O (M+H)+: m/z=461.2; found 461.2.

Example 115. 5-(2-Fluoro-6-methoxyphenyl)-3-(6-(1-methylpiperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridine

Step 1. 3-(6-Bromopyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-pyrazolo[3,4-c]pyridine

- 92 048980

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (0.3 g, 0.6 mmol, Example 34, step 5), trimethylphosphine palladium chloride (50 mg, 0.07 mmol) and 2-bromo-6(tributylstannyl)pyridine (0.6 g, 1.34 mmol) were placed in a flask, which was evacuated three times and refilled with nitrogen. DMF (4 mL) was added and the reaction mixture was stirred at 110 °C for 5 h. After cooling to rt, water was added and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated. The crude product was purified using Biotage Isolera™. LC/MS calculated for C ₂₄ H ₂₇ BrFN ₄ O ₂ Si (M+H)+: m/z=529.1; found 529.1.

Step 2. 5 -(2-Fluoro-6-methoxyphenyl)-3 -(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-yl)-1 ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

SEM

3-(6-Bromopyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (50 mg, 0.09 mmol), (1-methyl-1,2,3,6-tetrahydropyridin-4-yl)boric acid (20 mg, 0.14 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (5 mg, 0.006 mmol) and potassium phosphate (40 mg, 0.18 mmol) were placed in a flask, which was evacuated three times and refilled with nitrogen. Dioxane (1 mL) and degassed water (0.1 mL) were added and the reaction mixture was stirred at 90 °C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated under reduced pressure and the resulting crude product was purified using Biotage Isolera™. LC/MS calculated for C ₃₀ H ₃₇ FN ₅ O ₂ Si (M+H) ⁺ : m/z = 546.3; found 546.2.

Step 3. 5-(2-Fluoro-6-methoxyphenyl)-3-(6-(1-methylpiperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4c]pyridine.

Pd/C (20 mg, 5% wt) was added to a solution of 5-(2-fluoro-6-methoxyphenyl)-3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (16 mg, 0.03 mmol) in MeOH (2 mL). After stirring under hydrogen atmosphere at rt for 2 h, the catalyst was filtered off. The solvent was evaporated from the filtrate in vacuo. Then, 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were added to the obtained crude product and the reaction mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was added and the reaction mixture was further stirred at 80 °C for 30 min. Then, the reaction mixture was diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C24H25FN5O (M+H) ⁺ : m/z = 418.2; found 418.2.

Example 116. 3-(4-Bromostyrene)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (50 mg, 0.1 mmol), 1-bromo-4-vinylbenzene (55 mg, 0.3 mmol), chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (5 mg, 0.006 mmol) and potassium phosphate (20 mg, 0.1 mmol) were placed in a flask, which was evacuated three times and refilled with nitrogen. Dioxane (1 mL) and degassed water (0.1 mL) were then added and the reaction mixture was stirred at 80 °C overnight. After cooling to rt, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with brine. The separated organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo. 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were then added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was added and the reaction mixture was further stirred at 80 °C for

- 93 048980 for 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₁ H ₁₆ BrFN ₃ O (M+H) ⁺ : m/z = 424.1; found 424.1.

Example 117. 1-(3-Fluoro-5-methyl-4-(3-(6-morpholinopyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl-4-(3-(6-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylbenzyl(methyl)carbamate

This compound was prepared according to the procedures described in Example 115, Step 1, using tert-butyl 3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate in place of (2-fluoro-6-methoxyphenyl)boric acid and 2-chloro-6-(tributylstannyl)pyridine in place of 2-bromo-6(tributylstannyl)pyridine as starting material. LC/MS calculated for C ₃₁ H ₄₀ ClFN ₅ O ₃ Si (M+H) ⁺ : m/z = 612.2; found 612.2.

Step 2. 1-(3-fluoro-5-methyl-4-(3-(6-morpholinopyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine.

tert-Butyl (4-(3-(6-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylbenzyl)(methyl)carbamate (10 mg, 0.016 mmol), morpholine (14 mg, 0.163 mmol), cesium carbonate (5.3 mg, 0.016 mmol) and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G2, 5 mg, 6.3 μmol) were placed in an ampoule, which was evacuated three times and refilled with nitrogen. Dioxane (2 mL) was then added and the reaction mixture was stirred at 100 °C overnight. After cooling to rt, the solids were collected by filtration and the solvent from the filtrate was evaporated in vacuo. 1 M HCl in water (1 mL) and 4 M HCl in dioxane (1 mL) were then added to the crude residue and the reaction mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was added and the reaction mixture was stirred at 80 °C for an additional 30 min. The reaction mixture was then diluted with acetonitrile and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min). LC/MS calculated for C ₂₄ H ₂₆ FN ₆ O (M+H) ⁺ : m/z=433.2; found 433.3.

Example 118. N-Ethyl-6-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpyridin-2-amine

This compound was prepared according to the procedures described in Example 117 using N-methyl ethanamine instead of morpholine as the starting material. LC/MS calculated for C ₂₃ H ₂₆ FN6 (M+H)+: m/z=405.2; found 405.3.

Example 119. 1-(3-Fluoro-4-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin5-yl)-5-(trifluoromethyl)phenyl)-^methylmethanamine

- 94 048980

To a solution of 3-fluoro-5-(trifluoromethyl)benzaldehyde (20.0 g, 104 mmol) in MeOH (500 mL) was added a solution of methylamine (104 mL, 208 mmol, 2 M in THF) and the reaction mixture was stirred at rt for 1 h. After this time, sodium borohydride (7.88 g, 208 mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction mixture was concentrated to dryness and 300 mL of DCM was added. Aqueous sodium bicarbonate solution was added and the reaction mixture was stirred at rt for an additional 1 h. The organic layer was separated, dried over MgSO ₄ , filtered and concentrated to dryness. To a solution of the resulting residue in DCM (521 mL) was added triethylamine (14.5 mL, 104 mmol) and di-tert-butyl dicarbonate (22.7 g, 104 mmol). The resulting solution was stirred at rt for 1 h. The solution was concentrated to dryness and the residue was purified by silica gel chromatography with 0-70% acetate in hexane to give the title product as a colorless oil (15.1 g, 47.0%). LC/MS calculated for C ₁₀ H ₁₀ F ₄ NO ₂ (M+H-C ₄ H ₈ ) ⁺ : 252.1; found 252.2.

Step 2. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of tert-butyl (3-fluoro-5-(trifluoromethyl)benzyl)(methyl)carbamate (2.3 g, 7.5 mmol) in THF (33.3 mL) at -78 °C was added p-butyllithium (8.98 mL, 22.5 mmol) dropwise and the reaction mixture was stirred at -78 °C for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.57 g, 29.9 mmol) was added and the mixture was allowed to warm to rt over 1 h. The resulting solution was quenched with water, neutralized to pH = 6 and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ , filtered and then concentrated to dryness. Potassium phosphate (1.30 g, 7.48 mmol) and tert-butyl 5-chloro-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.0 g, 3.94 mmol) were added to a solution of the resulting residue in dioxane (33.3 mL) and water (8.32 mL). The mixture was degassed with N ₂ , chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2yl)palladium(II) (0.118 g, 0.150 mmol) was added and the reaction mixture was stirred at 60°C for 1 h. The mixture was concentrated to dryness. The residue was purified by silica gel chromatography with 0-100% ethyl acetate in hexane to afford the title product as a yellowish oil. LC/MS calculated for C ₂₅ H ₂₉ F ₄ N ₄ O ₄ (M+H)+: m/z=525.2; found 525.2.

Step 3. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-3-iodo-1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

- 95 048980

To a solution of tert-butyl 5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (0.30 g, 0.572 mmol) in dioxane (5 mL) and water (5 mL) was added potassium carbonate (0.395 g, 2.86 mmol) and the mixture was stirred at 80 °C for 2 h. The mixture was cooled to rt, diluted with DCM and washed with water, sodium bicarbonate and brine. The organic layer was dried over MgSO ₄ , filtered and then concentrated to dryness.

To a solution of the obtained residue in DMF (6 mL) was added NIS (0.143 g, 0.636 mmol). After stirring at 70 °C for 2 h, the reaction mixture was cooled to rt and triethylamine (0.089 mL, 0.636 mmol) was added, followed by di-tert-butyl dicarbonate (0.148 mL, 0.636 mmol). After stirring at rt for an additional 2 h, water was added. The mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over sodium sulfate and the solvent was evaporated. The crude product was purified using Biotage Isolera™. LC/MS calculated for C ₂₅ H ₂₈ F ₄ IN ₄ O ₄ (M+H)+: m/z = 651.1; found 651.1.

Step 4. 1-(3-Fluoro-4-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)5-(trifluoromethyl)phenyl)-N-methylmethanamine.

In a screw cap ampoule equipped with a magnetic stirrer, 5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (38.4 mg, 0.059 mmol), 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridin-2-yl)piperazine (18 mg, 0.059 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,G-biphenyl)]palladium(II) (XPhos Pd G2, 7.0 mg, 8.90 μmol) and cesium carbonate (59.7 mg, 0.183 mmol). The vial was sealed with a septum with a Teflon liner, evacuated and refilled with nitrogen (this process was repeated three times in total). Then 1,4-dioxane (2.00 mL) was added via syringe, followed by water (200.0 μL). The reaction mixture was heated to 60 °C for 16 h. The reaction mixture was concentrated. To the residue was added CH ₂ Cl ₂ (2.0 mL) followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₅ H ₂₆ F ₄ N ₇ (M+H) ⁺ : m/z=500.2; found 500.2. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.17 (d, J = 1.2 Hz, 1H), 9.05 (br, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 8.9, 2.4 Hz, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 4.50 (d, J = 13.0 Hz, 2H), 4.35 (t, J = 5.6 Hz, 2H), 3.54 (d, J = 11.8 Hz, 2H), 3.27-3.15 (m, 2H), 3.12 (s, 2H), 2.87 (s, 3H), 2.66 (t, J=5.2 Hz, 3H) ppm.

Example 120. 1-(4-(3-(6-Cyclopropylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 119 using 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine as the starting material. LC/MS calculated for C ₂₃ H ₂₀ F ₄ N ₅ (M+H) ⁺ : m/z = 442.2; found 442.2.

Example 121. 1-(3-Fluoro-4-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(tri-

This compound was prepared according to the procedures described in Example 119 using 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine instead of 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine as the starting material. LC/MS calculated for C ₂₄ H ₂₃ F ₄ N ₆ O (M+H) ⁺ : m/z = 487.2; found 487.2. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 9.16 (d, J=1.2 Hz, 1H), 8.98 (br, 1H), 8.77 (d, J=2.1 Hz, 1H), 8.24-8.15 (m, 2H), 7.92 (s, 1H), 7.82 (d, J=9.5 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 4.35 (t, J=5.8 Hz, 2H), 3.77-3.69 (m, 4H), 3.58-3.50 (m, 4H), 2.66 (t, J=5.3 Hz, 3H) ppm.

- 96 048980

Example 122. 1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1. (3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

Sodium borohydride (0.677 g, 17.91 mmol) was added to a solution of 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)banzaldehyde (4.0 g, 14.92 mmol) in tetrahydrofuran (149 mL). After 2 h, the reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over sodium sulfate, and concentrated. The crude product was used in the next step without further purification.

Step 2. 1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo-^,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine.

This compound was prepared according to the procedures described in Example 86 (steps 2-4), using (3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol instead of (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol as the starting material. LC/MS calculated for C18H17F2N6 (M+H) ⁺ : m/z=355.2; found 355.2. ¹ H-NMR (600 MHz, DMSO-4) δ 9.16 (d, J=1.2 Hz, 1H), 9.09 (br, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.07 (d, J=0.6 Hz, 1H), 7.43-7.35 (m, 2H), 4.27 (t, J=5.5 Hz, 2H), 3.93 (s, 3H), 2.64 (t, J=5.1 Hz, 3H) ppm.

Example 123

This compound was prepared according to the procedures described in Example 86 (steps 2-4) and 122, using propan-2-amine instead of methaneamine as the starting material. LC/MS calculated for C ₂₀ H ₂₁ F ₂ N ₆ (M+H) ⁺ : m/z=383.2; found 383.3. ¹ H-NMR (600 MHz, DMSO-4) δ 9.17 (d, J=1.2 Hz, 1H), 9.02 (br, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 8.07 (d, J=0.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 2H), 4.38-4.19 (m, 2H), 3.93 (s, 3H), 3.37 (dt, J=12.3, 6.0 Hz, 1H), 1.33 (d, J=6.5 Hz, 6H) ppm.

Example 124

This compound was prepared according to the procedures described in Example 86 (steps 2-4) and 122, using pyridin-2-amine instead of methanamine as the starting material. LC/MS calculated for C ₂₂ H ₁₈ F ₂ N ₇ (M+H)+: m/z=418.2; found 418.2.

- 97 048980

Example 125

This compound was prepared according to the procedures described in Example 86 (steps 2-4) and 122, using 1-methyl-1H-pyrazol-3-amine instead of methanamine as the starting material. LC/MS calculated for C ₂₁ H ₁₉ F ₂ N ₈ (M+H)+: m/z=421.2; found 421.2.

Example 126

This compound was prepared according to the procedures described in Example 86 (steps 2-4) and 122, using 2-aminoethanol instead of methanamine as the starting material. LC/MS calculated for C ₁₉ H ₁₉ F ₂ N ₆ O (M+H) ⁺ : m/z=385.2; found 385.2.

Example 127. 1-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-X-methylmethanamine

Step 1. (2,4-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

This compound is prepared according to the procedures described in Example 122 (step 1), using 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde instead of 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde.

Step 2. 1-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 86 (steps 2-4), using (2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol instead of (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol as the starting material. LC/MS calculated for C ₁₈ H ₁₇ F ₂ N ₆ (M+H) ⁺ : m/z = 355.2; found 355.1.

Example 128

This compound is obtained according to the methods described in Example 86 (steps 2-4) and 127, with the help of

- 98 048980 using propan-2-amine instead of methanamine as starting material. LC/MS calculated for C20H21F2N6 (M+H)+: m/z=383.2; found 383.2.

Example 129

This compound was prepared according to the procedures described in Example 86 (steps 2-4) and 127, using cyclopropanamine instead of methanamine as the starting material. LC/MS calculated for C ₂₀ H ₁₉ F ₂ N ₆ (M+H) ⁺ : m/z=381.2; found 381.2.

Example 130

This compound was prepared according to the procedures described in Example 86 (steps 2-4) and 127, using 3-methoxypiperidine instead of methanamine as the starting material. LC/MS calculated for C ₂₃ H ₂₅ F ₂ N ₆ O (M+H) ⁺ : m/z=439.2; found 439.2.

Example 131. 1-(3-Fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 119 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine as the starting material. LC/MS calculated for C ₁₉ H ₁₇ F ₄ N ₆ (M+H) ⁺ : m/z = 405.2; found 405.2. ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 9.22-9.03 (m, 2H), 8.46 (s, 1H), 8.21-8.14 (m, 1H), 8.04 (d, J=0.7 Hz, 1H), 7.93 (s, 1H), 7.83 (d, J=9.5 Hz, 1H), 4.36 (t, J=5.5 Hz, 2H), 3.92 (s, 3H), 2.66 (t, J=5.0 Hz, 3H) ppm.

Example 132. 1-(3-Fluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5(trifluoromethyl)phenyl)-X-methylmethanamine

This compound was prepared according to the procedures described in Example 119 using 4-(4-methylpiperazin-1-yl)phenylboronic acid instead of 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine as the starting material. LC/MS calculated for C ₂₆ H ₂₇ F ₄ N ₆ (M+H) ⁺ : m/z = 499.2; found 499.2. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 9.20 (br, 1H), 9.16 (s, 1H), 8.14 (s, 1H), 8.02-7.91 (m, 3H), 7.83 (d, J=9.1 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 4.36 (s, 2H), 4.01-3.87 (m, 2H), 3.66-3.45 (m, 2H), 3.28-3.14 (m, 2H), 3.12-2.98 (m, 2H), 2.88 (s, 3H), 2.66 (s, 3H) ppm.

Example 133. 1-(4-(3-(1-Ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylphenyl)-N-methylmethanamine

- 99 048980

In a screw cap ampoule equipped with a magnetic stirrer, tert-butyl 5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-(methylphenyl)-3-iodo-1H-pyrazolo[3,4c]pyridine-1-carboxylate (300.0 mg, 0.503 mmol, Example 113, step 9), (1-ethyl-1H-pyrazol-4-yl)boric acid (106 mg, 0.754 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 40 mg, 50 μmol) and potassium phosphate (213 mg, 1.006 mmol). The ampoule is sealed with a septum with a Teflon liner, evacuated and refilled with nitrogen (this process is repeated three times in total). Then 1,4-dioxane (5.00 mL) is added via syringe, followed by water (500.0 μL). The reaction mixture is heated to 80 °C for 2 h. The reaction mixture is concentrated. To the residue is added CH ₂ Cl ₂ (2.0 mL) followed by TFA (2.0 mL). The mixture is stirred at room temperature for 15 min and then concentrated. The residue is purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C20H22FN6 (M+H) ⁺ : m/z=365.2; found 365.3. ^1H NMR (500 MHz, DMSO-D) δ 9.17 (s, 1H), 8.99 (br, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 8.07 (d, J=0.6 Hz, 1H), 7.38-7.17 (m, 2H), 4.28-4.08 (m, 4H), 2.63 (t, J=5.3 Hz, 3H), 2.18 (s, 3H), 1.44 (t, J=7.3 Hz, 3H) ppm.

Example 134. 1-(4-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylphenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 133 using 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of (1-ethyl-1H-pyrazol-4-yl)boronic acid as the starting material. LC/MS calculated for C ₂₁ H ₂₂ FN6 (M+H)+: m/z=377.2; found 377.2. 1H-NMR (500 MHz, DMSO^) δ 9.17 (s, 1H), 9.02 (br, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.36-7.14 (m, 2H), 4.21 (t, J=5.6 Hz, 2H), 3.80 (tt, J=7.5, 3.8 Hz, 1H), 2.63 (t, J=5.2 Hz, 3H), 2.18 (s, 3H), 1.19-1.12 (m, 2H), 1.06-0.94 (m, 2H) ppm.

Example 135

This compound was prepared according to the procedures described in Example 133 using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile instead of (1-ethyl-1H-pyrazol-4-yl)boric acid as the starting material. LC/MS calculated for C ₂₅ H ₂₁ FN ₇ (M+H) ⁺ : m/z = 438.2; found 438.1.

Example 136. 1-(3-Fluoro-5-methyl-4-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

- 100 048980

This compound was prepared according to the procedures described in Example 133 using 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of (1-ethyl-1Hpyrazol-4-yl)boric acid as the starting material. LC/MS calculated for C ₂₃ H ₂₆ FN ₆ O (M+H)+: m/z=421.2; found 421.2.

Example 137. 1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylcyclopropanamine

This compound was prepared according to the procedures described in Example 95 using 1-(3,5-difluorophenyl)cyclopropanamine instead of 3-(3,5-difluorophenyl)cyclobutan-1-amine and formaldehyde instead of propan-2-one as starting material. LC/MS calculated for C ₂₀ H ₁₉ F ₂ N6 (M+H)+: m/z=381.2; found 381.2.

Example 138. 1-(4-Fluoro-2-methoxy-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5 yl)phenyl)-N-methylmethaneαamine

Step 1. tert-Butyl-(4-fluoro-2-methoxybenzyloxy)dimethylsilane

To a solution of (4-fluoro-2-methoxyphenyl)methanol (1.21 g, 7.75 mmol) in DCM (38.7 mL) was added imidazole (0.791 g, 11.62 mmol) and TBS-Cl (9.30 mL, 9.30 mmol). After 1 h at rt, the reaction mixture was quenched with water and the layers were separated. The aqueous layer was extracted with DCM and the organic layer mixture was washed with brine, dried over sodium sulfate and concentrated. The residue was purified using a Biotage Isolera™ (0 to 20% ethyl acetate/hexane evaporation system) to afford the desired product as a brown solid. LC/MS calculated for C ₁₄ H ₂₄ FO ₂ Si (M+H)+: m/z = 271.2; found 271.2.

Step 2. 1-(4-Fluoro-2-methoxy-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine.

This compound was prepared according to the procedures described in Example 96 using tert-butyl (4-fluoro-2-methoxybenzyloxy) dimethylsilane instead of 2-(3,5-difluorophenyl)ethanol as the starting material. LC/MS calculated for C ₁₉ H ₂₀ FN ₆ O (M+H)+: m/z=367.2; found 367.2.

Example 139. N(4-fluoro-2-methoxy-3 -(3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5 yl)benzyl)ethanamine

This compound is obtained by methods similar to those in Example 138, with the replacement of

- 101 048980 methylamine with ethylamine. LC/MS calculated for C ₂₀ H ₂₂ FN ₆ O (M+H)+: m/z=381.1; found: 381.2.

Example 140

To a suspension of 4-(4-methylpiperazin-1-yl)benzoic acid (528 mg, 2.395 mmol) in DCM (8 mL) were added DMF (12.36 μL, 0.160 mmol) and oxalyl chloride (419 μL, 4.79 mmol) and the reaction mixture was stirred until the initial orange suspension turned into a white homogeneous suspension (~2 h). The mixture was then concentrated and dried in vacuo to remove excess oxalyl chloride. THF (8 mL) was added followed by Hunig's base (837 μL, 4.79 mmol). After stirring for 5 min, solid tert-butyl 3-amino-5-bromo-1H-pyrazolo[3,4c]pyridine-1-carboxylate (500 mg, 1.597 mmol) was added in one portion and the reaction mixture was heated to 85 °C for 3 h. After cooling to rt, the mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate and concentrated. The residue was purified using a Biotage Isolera™ (0 to 10% methanol/dichloromethane evaporative purification system) to afford the title product as a brown solid (342 mg, 46%). LC/MS calculated for C ₁₈ H ₂₀ BrN ₆ O (M+H) ⁺ : m/z=415.2/417.2; found 415.2/417.2.

Step 2. tert-Butyl-3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(isopropyl)carbamate

To a solution of 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.5 g, 9.33 mmol) and DCE (46.6 mL) were added propan-2-amine (1.621 mL, 18.65 mmol) and acetic acid (1.602 mL, 28.0 mmol). After stirring at rt for 30 min, sodium triacetoxyborohydride (3.95 g, 18.65 mmol) was added and the reaction mixture was stirred at rt for an additional 1 h. The reaction mixture was then concentrated and redissolved in DCM (37 mL), washed with saturated sodium bicarbonate, dried over sodium sulfate and filtered. Triethylamine (2.60 mL, 18.65 mmol) and BOC anhydride (3.25 mL, 13.99 mmol) were added to the filtrate and the resulting mixture was stirred at rt for 2 h. The mixture was quenched with water and extracted with DCM. The organic layer was washed, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification.

Step 3. tert-Butyl-5-(4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(4(4-methylpiperazin-1 -yl)benzamido)-1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

In a mixture of tert-butyl-5-bromo-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1

- 102 048980 carboxylate (239 mg, 0.464 mmol), tert-butyl (3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzyl)(isopropyl)carbamate (763 mg, 1.855 mmol), XPhos Pd G2 (36.5 mg, 0.046 mmol) and potassium phosphate (246 mg, 1.159 mmol) were added 1,4-dioxane (2 mL) and water (500 μL) and the flask with the reaction mixture was evacuated, refilled with nitrogen and then stirred at 80 °C for 1 h. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified using a Biotage Isolera™ (2 to 10% methanol/dichloromethane evaporative purification system) to afford the desired product as a brown solid. LC/MS calculated for C ₃₈ H ₄₈ F ₂ N ₇ O ₅ (M+H)+: m/z=720.3; found 720.3.

Step 4. N-(5-(2,6-difluoro-4-((isopropylαmino)methyl)phenyl)-1H-pyαzolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide.

A solution of tert-butyl 5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(4(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (253 mg, 0.351 mmol) in DCM (900 µL) and TFA (900 µL) was stirred at rt for 30 min, then concentrated and immediately purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA and a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₈ H ₃₂ F ₂ N ₇ O (M+H)+: m/z=520.2, found 520.2. ¹ H-NMR (500 MHz, DMSO-d6) δ 13.57 (s, 1H), 10.94 (s, 1H), 10.10 (s, 1H), 9.12 (d, J=1.2 Hz, 1H), 8.94 (s, 2H), 8.03 (d, J=9.0 Hz, 2H), 7.97 (s, 1H), 7.44 (d, J=8.2 Hz, 2H), 7.12 (d, J=9.1 Hz, 2H), 4.32-4.23 (m, 2H), 4.08 (d, J=11.4 Hz, 2H), 3.54 (s, 2H), 3.37 (dt, J=12.2, 5.9 Hz, 1H), 3.12 (m, 2H), 2.88 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H).

Example 141. N-(5-(2,6-difluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)4-(4-methylpiperazin-1-yl)benzamide

HN H

Step 1. tert-Butyl 5-(2,6-difluoro-4-formylphenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

Vos

To a mixture of tert-butyl 5-bromo-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (319 mg, 0.619 mmol, Example 140, step 1), (3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)methanol (585 mg, 2.166 mmol, Example 122, step 1), XPhosPd G2 (48.7 mg, 0.062 mmol), and tripotassium phosphate (263 mg, 1.238 mmol) were added 1,4-dioxane (5 mL) and water (1 mL), and the reaction flask was evacuated and backfilled with nitrogen. The reaction mixture was stirred at 80 °C for 1 h. The mixture was then cooled to rt, diluted with DCM and filtered through a pad of celite. The filtrate was concentrated and redissolved in DCM (4 mL). Manganese dioxide (538 mg, 6.19 mmol) was added and the reaction mixture was heated to 60 °C overnight. The mixture was then filtered through a pad of celite and the solids were washed with more DCM. The filtrate was concentrated and the residue was purified using Biotage Isolera™ (evaporative purification system with ethyl acetate/hexane 20 to 100% then methanol/dichloromethane 0 to 10%) to afford the title product as a brown solid. LC/MS calculated for C ₃₀ H ₃₁ F ₂ N ₆ O ₄ (M+H)+: m/z=577.2; found 577.2.

Step 2. N-(5-(2,6-difluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4methylpiperazin-1-yl)benzamide

To a solution of tert-butyl 5-(2,6-difluoro-4-formylphenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1Hpyrazolo[3,4-c]pyridine-1-carboxylate (53 mg, 0.092 mmol) and pyrrolidine (13.07 mg, 0.184 mmol) in DCE (919 µL) were added acetic acid (15.79 µL, 0.276 mmol) and sodium triacetoxyborohydride (48.7 mg, 0.230 mmol). After stirring at rt for 2 h, the mixture was quenched with saturated sodium bicarbonate and extracted with DCM. The organic layer was washed, dried over sodium sulfate and conc.

- 103 048980 centered. The residue was dissolved in 1:1 TFA/DCM (1 mL) and stirred at rt for 30 min, then diluted with methanol and immediately purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₉ H ₃₂ F ₂ N ₇ O (M+H)+: m/z=532.2, found 532.2. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.59 (s, 1H), 10.95 (s, 1H), 10.32 (s, 1H), 10.17 (s, 1H), 9.12 (d, J=1.2 Hz, 1H), 8.04 (d, J=9.0 Hz, 2H), 7.98 (s, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.12 (d, J=9.1 Hz, 2H), 4.45 (d, J=4.3 Hz, 2H), 4.08 (d, J=10.6 Hz, 2H), 3.54 (s, 2H), 3.48 (s, 2H), 3.14 (s, 4H), 2.88 (s, 3H), 2.07 (s, 2H), 1.90 (d, J=5.8 Hz, 2H).

Example 142. N-(5-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4(4-methylpiperazin-1-yl)benzamide

This compound was prepared by procedures similar to those in Example 141, replacing pyrrolidine with azetidine hydrochloride. LC/MS calculated for C ₂₈ H ₃₀ F ₂ N ₇ O (M+H) ⁺ : m/z=518.2; found: 518.2.

Example 143

This compound was prepared by procedures similar to those in Example 141, replacing pyrrolidine with 4-methoxyazetidine. LC/MS calculated for C29H32F2N7O2 (M+H) ⁺ : m/z=548.2; found: 548.2.

Example 144. N-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1 methyl-1H-pyrazole-4-carboxamide

Step 1. tert-Butyl 3,5-difluorobenzyl (methyl)carbamate

To a solution of 3,5-difluorobanzaldehyde (5.0 g, 35.2 mmol) in MeOH (176 mL) was added methaneamine (21.11 mL, 42.2 mmol, 2 M solution in THF) and the reaction mixture was stirred for 30 min, then sodium borohydride (1.730 g, 45.7 mmol) was added. Stirring was continued until bubbling ceased (~15 min). The mixture was then concentrated, redissolved in DCM and washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and filtered. Triethylamine (7.36 mL, 52.8 mmol) and BOC anhydride (9.80 mL, 42.2 mmol) were added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was then quenched with water and extracted with DCM. The organic layer was washed, dried over sodium sulfate and concentrated. The residue was purified using Biotage Isolera™ (0 to 10% ethyl acetate/hexane evaporation system).

- 104 048980

40%) to give the desired product as a solid (9.0 g, 99%). LC/MS calculated for C ₁₃ H ₁₈ F ₂ NO ₂ (M+H)+: m/z=258.2; found 258.2.

Step 2. tert-Butyl-3-amino-5-(4-((tert-butoxycarbonyl (methyl)amino)methyl)-2,6-difluorophenyl)1 I-pyrazolo[3,4-c]pyridine-1-carboxylate

n-BuLi (5.75 mL, 14.37 mmol, 2.5 M in hexane) was added dropwise to a solution of tert-butyl (3,5-difluorobenzyl)(methyl)carbamate (1849 mg, 7.18 mmol) in THF (16 mL) at -78°C.

The reaction mixture was stirred at -78 °C for 45 min and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.204 mL, 10.78 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 30 min, then warmed to rt. The mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. To the residue was added 1,4-dioxane (10 mL) followed by a solid mixture of tert-butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (750 mg, 2.395 mmol, Example 1, step 3), potassium phosphate (1271 mg, 5.99 mmol), and XPhosPd G2 (188 mg, 0.239 mmol). Water (2.0 mL) was added and the reaction flask was evacuated and backfilled with nitrogen. The mixture was stirred at 80 °C for 1 h. After cooling, the mixture was diluted with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the organic layer mixture was dried over sodium sulfate and concentrated. The residue was purified using Biotage Isolera™ (0 to 100% ethyl acetate/hexane evaporative purification system) to afford the title product as a solid (280 mg, 24%). LC/MS calculated for C ₂₄ H ₃₀ F ₂ N ₅ O ₄ (M+H)+: m/z=490.2; found 490.2.

Step 3. N-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyrudin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide.

To a suspension of 1-methyl-1H-pyrazole-4-carboxylic acid (19.36 mg, 0.154 mmol) in DCM (0.5 mL) were added DMF (0.396 µL, 5.12 µmol) and oxalyl chloride (0.013 mL, 0.154 mmol). The reaction mixture was stirred at rt for 1 h. A solution of tert-butyl 3-amino-5-(4-(((tertbutoxycarbonyl)(methyl)amino)methyl)-2,6-difluorophenyl)-1H-indazole-1-carboxylate (25 mg, 0.051 mmol) and Hunig's base (0.045 mL, 0.256 mmol) in THF (0.500 mL) were added. The reaction mixture was heated to 80 °C for 3 h. The mixture was then cooled and concentrated. The residue was dissolved in 1:1 TFA/DCM. The resulting mixture was stirred at rt for 30 min, diluted with methanol and immediately purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₁₉ H ₁₈ F ₂ N ₇ O (M+H)+: m/z = 398.2; found 398.2.

Example 145. N-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-nirazolo[3,4-c]niridin-3-yl)-3(4-methylpiperazin-1-yl)benzamide

This compound is prepared by methods similar to those in Example 144, replacing 1-methyl-1H-pyrazole-4-carboxylic acid with 3-(4-methylpiperazin-1-yl)benzoic acid.

The reaction was carried out at 90°C. LC/MS calculated for C ₂₆ H ₂₈ F ₂ N ₇ O (M+H)+: m/z=492.2; found: 492.2.

Example 146

- 105 048980

Step 1. tert-Butyl-3-amino-5-(4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-2,6-difluorophenyl)-1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared by procedures similar to those in Example 144, steps 1-2, replacing methylamine with isopropylamine. LC/MS calculated for C ₂₆ H ₃₄ F ₂ N ₅ O ₄ (M+H)+: m/z=518.2; found 518.2.

Step 2. N-(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3methoxybenzamide

To a solution of tert-butyl 3-amino-5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (25 mg, 0.048 mmol) and Hunig's base (42.2 μL, 0.242 mmol) in THF (966 μL) was added 3-methoxybenzoyl chloride (24.72 mg, 0.145 mmol). The resulting mixture was stirred at 60 °C for 2 h and then concentrated. The residue was dissolved in a 1:1 mixture of TFA/DCM. The resulting solution was stirred at rt. for 1 h, diluted with methanol and immediately purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₄ H ₂₄ F ₂ N ₅ O ₂ (M+H)+: m/z=452.2; found 452.2.

Example 147 Methyl 4-(4-(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate

To a mixture of methyl 4-bromobenzoate (1.0 g, 4.65 mmol), benzylpiperazine-1-carboxylate (1.348 mL, 6.98 mmol), Ruphos Pd G2 (0.181 g, 0.233 mmol), and cesium carbonate (4.55 g, 13.95 mmol) was added 1,4-dioxane (15 mL), and the reaction flask was evacuated and refilled with nitrogen. The reaction mixture was stirred at 80 °C overnight. The mixture was then diluted with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the organic layer mixture was dried over sodium sulfate and concentrated. The residue is purified using Biotage Isolera™ (an evaporative purification system with ethyl acetate/hexane at a ratio of 0 to 100%) to obtain the desired product.

The resulting product was dissolved in a 1:1 mixture of THF/water (20 mL) and lithium hydroxide (0.334 g, 13.95 mmol) was added. The resulting mixture was stirred at 60 °C overnight. The mixture was diluted with ethyl acetate and washed with 1 N HCl and brine, and the organic phase was dried over sodium sulfate.

- 106 048980 and concentrated. The crude product was used in the next step without further purification. LC/MS calculated for C ₁₉ H ₂₁ N2O ₄ (M+H)+: m/z=341.2; found 341.2.

Step 2. tert-Butyl-5-(4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(4(piperazin-1 -yl)benzamido)-1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

Vos

Vos

To a solution of 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)benzoic acid (165 mg, 0.484 mmol) in DCM (968 μL) was added DMF (1.5 μL, 0.019 mmol) and oxalyl chloride (85 μL, 0.968 mmol). The reaction mixture was stirred for 15 min and then concentrated. Toluene was added and the resulting mixture was concentrated. The resulting foam was dried under high vacuum for 2 h. The resulting solid was then dissolved in THF (968 μL) and Hunig's base (169 μL, 0.968 mmol) was added. A solution of tert-butyl 3-amino-5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-1H-indazole-1-carboxylate (100 mg, 0.194 mmol, Example 122, step 1) in THF was added and the resulting mixture was stirred at 85 °C overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified using a Biotage Isolera™ (0 to 100% ethyl acetate/hexane evaporative purification system) to afford the desired product as a solid.

The resulting solid was dissolved in methanol (2 mL) and palladium on carbon (41.2 mg, 0.039 mmol) was added. The reaction flask was evacuated and refilled with nitrogen gas from a balloon. After stirring at rt for 1 h, the mixture was filtered through a pad of celite and the filtrate was concentrated. The crude product (71 mg, 52%) was used in the next step without further purification. LC/MS calculated for C ₃₇ H ₄₆ F ₂ N ₇ O ₅ (M+H)+: m/z = 706.3; found 706.3.

Step 3. Methyl 4-(4-(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin3-ylcarbamoyl)phenyl)piperazine-1-carboxylate.

To a solution of tert-butyl 5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-3(4-(piperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (14 mg, 0.020 mmol) and Hunig's base (17.32 μL, 0.099 mmol) in DCM (400 μL) was added methyl chloroformate (4.61 μL, 0.060 mmol). The reaction mixture was stirred at rt for 30 min, TFA was added and stirring was continued for an additional 30 min. The mixture was then diluted with methanol and immediately purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₉ H ₃₂ F ₂ N ₇ O ₃ (M+H)+: m/z=564.2; found 564.2.

Example 148 Methyl 4-(4-(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)-3-fluorophenyl)piperazine-1-carboxylate

This compound is obtained analogously to Example 147 by replacing methyl 4-bromobenzoate with methyl 4-bromo-2-fluorobenzoate in Step 1. LC/MS calculated for C ₂₉ H ₃₁ F ₃ N ₇ O ₃ (M+H)+: m/z=582.2; found 582.2.

Example 149

- 107 048980

Step 1. tert-Butyl-5-(4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(2methoxy-4-(piperazin-1 -yl)benzamido)-1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described in Example 147, steps 1-2, replacing methyl 4-bromobenzoate with methyl 4-bromo-2-methoxybenzoate. LC/MS calculated for C ₃₈ H ₄₈ F ₂ N ₇ O ₆ (M+H) ⁺ : m/z=736.3; found 736.3.

Step 2. N-(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2methoxy-4-(4-methylpiperazin-1-yl)benzamide

To a solution of tert-butyl 5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-3(2-methoxy-4-(piperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (17 mg, 0.023 mmol), paraformaldehyde (10.51 μL, 0.116 mmol) and acetic acid (3.97 μL, 0.069 mmol) was added sodium triacetoxyborohydride (14.69 mg, 0.069 mmol). The reaction mixture was stirred at rt for 1 h. TFA (0.5 mL) was added and stirring was continued at rt for 30 min. The mixture was diluted with methanol and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA, flow rate 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₉ H ₃₄ F ₂ N ₇ O ₂ (M+H) ⁺ : m/z=550.2; found 550.2.

Example 150

This compound is obtained analogously to Example 149 by replacing methyl 4-bromobenzoate with methyl 3-bromo-2-fluorobenzoate in Step 1. LC/MS calculated for C ₂₈ H ₃₁ F ₃ N ₇ O (M+H) ⁺ : m/z=538.2; found 538.2.

Example 151. N(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)-4-fluoro-3-(4-methylpiperazin-1-yl)benzamide

This compound is obtained analogously to Example 149 by replacing methyl 4-bromobenzoate with methyl 3-bromo-4-fluorobenzoate in Step 1. LC/MS calculated for C ₂₈ H ₃₁ F ₃ N ₇ O (M+H)+: m/z=538.2; found 538.2.

Example 152. N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1yl)benzamide

- 108 048980

To a mixture of tert-butyl 5-bromo-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (20 mg, 0.039 mmol, Example 140, step 1), (2-fluoro-6-methylphenyl)boric acid (9 mg, 0.058 mmol), XPhosPd G2 (3.05 mg, 3.88 μmol) and potassium phosphate (16.47 mg, 0.078 mmol) were added 1,4-dioxane (323 μL) and water (64 μL). The reaction flask was evacuated and backfilled with nitrogen. The reaction mixture was stirred at 80 °C for 1 h. The mixture was cooled to rt and quenched with water. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in 1:1 DCM/TFA. The resulting mixture was stirred at rt for 30 min, diluted with methanol and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₅ H ₂₆ FN ₆ O (M+H)+: m/z=445.2, found 445.2. 1H NMR (600 MHz, DMSO-d ₆ ) δ 13.50 (s, 1H), 10.89 (s, 1H), 9.87 (s, 1H), 9.12 (d, J=1.1 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H), 7.81 (s, 1H), 7.36 (td, J=8.0, 6.0 Hz, 1H), 7.15 (dd, J=24.4, 8.3 Hz, 2H), 7.11 (d, J=9.0 Hz, 2H), 4.08 (d, J=12.6 Hz, 2H), 3.54 (d, J=11.1 Hz, 2H), 3.12 (dt, J=24.9, 10.5 Hz, 4H), 2.87 (s, 3H), 2.15 (s, 3H).

Example 153. N-(5-(2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound is obtained analogously to Example 152 by replacing (2-fluoro-6-methylphenyl)boric acid with (2-fluoro-6-(trifluoromethyl)phenyl)boric acid. LC/MS calculated for C ₂₅ H ₂₃ F ₄ N ₆ O (M+H)+: m/z=499.2; found 499.2.

Example 154. N-(5-(4-((ethylamino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

Step 1. tert-Butyl ethyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl)carbamate

This compound is obtained analogously to Example 144 (at stages 1-2) by replacing 3,5-difluorobenzaldehyde with 3-fluoro-5-(trifluoromethyl)benzaldehyde and methanamine with ethanamine. LC/MS calculated for C ₂₁ H ₃₁ BF ₄ NO ₄ (M+H)+: m/z=448.2; found 448.2.

Step 2. N-(5-(4-((ethylamino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound is obtained analogously to Example 152 by replacing (2-fluoro-6-methylphenyl)boric acid with tert-butyl ethyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl)carbamate. LC/MS calculated for C ₂₈ H ₃₀ F ₄ N ₇ O (M+H)+: m/z=556.2; found 556.2.

- 109 048980

Example 155

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

5-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (3.157 g, 7.71 mmol, Example 42, step 2) was dissolved in DMF (11.56 mL) and ethanol (7.71 mL). Triethylamine (3.22 mL, 23.12 mmol) was added, followed by dppf-PdCl ₂ (0.629 g, 0.771 mmol). The reaction flask was evacuated and refilled with CO gas from a balloon. The resulting solution was stirred at 80 °C overnight. The reaction mixture was 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 using Biotage Isolera™ (0 to 75% ethyl acetate/hexane evaporative purification system) to afford the desired product. LC/MS calculated for C ₁₅ H ₂₃ ClN ₃ O ₃ Si (M+H)+: m/z=356.2; found 356.2.

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

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 (1152 µL) was added potassium tert-butoxide (922 µL, 0.922 mmol) and the reaction mixture was stirred at rt for 30 min. 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 using Biotage Isolera™ (2 to 10% methanol/dichloromethane evaporative purification system) to afford the desired product. LC/MS calculated for C ₂₄ H ₃₄ ClN ₆ O ₂ Si (M+H)+: m/z=501.2; found 501.2.

Step 3. 5-(2,6-Difluoro-4-formylphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide

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 (250 mg, 0.499 mmol), (3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)methanol (202 mg, 0.748 mmol), XPhos Pd G2 (39.3 mg, 0.050 mmol) and potassium phosphate (212 mg, 0.998 mmol) were added 1,4-dioxane (2079 μL) and water (416 μL) and the flask with the reaction mixture was evacuated and refilled with nitrogen. The reaction mixture was stirred at 80 °C for 1 h. The mixture was cooled to rt, quenched with water and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in DCM (4 mL) and manganese oxide (434 mg, 4.99 mmol) was added. The reaction mixture was heated to 60 °C for 1 h and then filtered through a pad of celite. The filtrate was concentrated and the residue was purified using Biotage Isolera™ (2 to 10% methanol/dichloromethane evaporative purification system) to afford the desired product. LC/MS calculated for C ₃₁ H ₃ 7F2N ₆ O ₃ Si (M+H)+: m/z = 607.2; found 607.2.

Step 4. 5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[3,4-c]pyridine-3-carboxamide

To a solution of 5-(2,6-difluoro-4-formylphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (50 mg, 0.082 mmol) and propan-2-one (13.49 μL, 0.165 mmol) in toluene (824 μL) was added acetic acid (14 μL, 0.247 mmol) and the reaction mixture was heated to 80 °C. After 1 h, it was cooled to rt and methanol (1 mL) was added. Sodium borohydride (6.24 mg, 0.165 mmol) was then added at rt. After 5 min, 4 N HCl in dioxane (1 mL) was added and the reaction mixture was heated to 80 °C for 1 h. The mixture was then cooled to rt, diluted with methanol and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₈ H ₃₂ F ₂ N ₇ O (M+H) ⁺ : m/z = 520.2; found 520.2.

Example 156. N-(5-(2,6-difluoro-4-(2-(pyrrolidin-1-yl)acetamido)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

Step 1. tert-Butyl 5-(4-amino-2,6-difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1 H-pyrazolo[3,4-c]pyridine-1-carboxylate

Vos

To a mixture of tert-butyl 5-bromo-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (200 mg, 0.388 mmol, Example 140, step 1), 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (198 mg, 0.776 mmol, Example 63, step 1), XPhosPd G2 (28.0 mg, 0.039 mmol) and potassium phosphate (206 mg, 0.970 mmol) were added 1,4-dioxane (3234 μL) and water (647 μL) and the flask with the reaction mixture was evacuated and backfilled with nitrogen. The reaction mixture was stirred at 80°C for 2 h. The mixture was cooled to rt, diluted with DCM and filtered through a pad of celite. The filtrate was concentrated and used in the next step without further purification. LC/MS calculated for C ₂₉ H ₃₂ F ₂ N ₇ O ₃ (M+H) ⁺ : m/z = 564.2; found 564.2.

Step 2. N-(5-(2,6-difluoro-4-(2-(pyrrolidin-1-yl)acetamide)phenyl)-1H-nirazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide.

To a solution of tert-butyl 5-(4-amino-2,6-difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1Hpyrazolo[3,4-c]pyridine-1-carboxylate (21 mg, 0.037 mmol) and Hunig's base (19.52 μL, 0.112 mmol) in DCM (745 μL) at 0 °C was added 2-chloroacetyl chloride (4.45 μL, 0.056 mmol) and the reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was then quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated.

The residue was dissolved in DCM (745 µL) and pyrrolidine (15.41 µL, 0.186 mmol) was added. The mixture was stirred at 50 °C for 1 h, then cooled to rt, 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 dissolved in 1:1 DCM:TFA and stirred at rt for 1 h. The mixture was diluted with methanol and purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA and a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₃₀ H ₃₃ F ₂ N ₈ O ₂ (M+H) ⁺ : m/z=575.2; found 575.2.

Example 157. 2-Amino-N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

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To a mixture of tert-butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.79 g, 5.72 mmol), (2-fluoro-6-methylphenyl)boric acid (1.320 g, 8.57 mmol), XPhosPd G2 (0.225 g, 0.286 mmol) and potassium phosphate (2.427 g, 11.43 mmol) were added 1,4-dioxane (15, 24 mL) and water (3.81 mL), and the flask with the reaction mixture was evacuated and refilled with nitrogen. The reaction mixture was stirred at 80 °C for 1 h. The mixture was then diluted with water and ethyl acetate and the layers were separated. The organic layer was dried over sodium sulfate and concentrated. The residue was purified using Biotage Isolera™ (0 to 100% ethyl acetate/hexane evaporative purification system) to afford the title product as a brown powder (1.7 g, 87%). LC/MS calculated for C ₁₈ H ₂₀ FN ₄ O ₂ (M+H)+: m/z=343.2; found 343.2.

Step 2. tert-Butyl 3-(4-fluoro-2-nitrobenzamido)-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a suspension of 4-fluoro-2-nitrobenzoic acid (595 mg, 3.21 mmol) in DCM (7 mL) were added DMF (11.31 µL, 0.146 mmol) and oxalyl chloride (281 µL, 3.21 mmol) and the reaction mixture was stirred at rt until it became homogeneous (~1 h). To the mixture was added a solution of tert-butyl 3-amino-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (500 mg, 1.460 mmol) and Hunig's base (765 µL, 4.38 mmol) in THF (7 mL). The mixture was stirred at rt overnight. 1-Methylpiperazine (488 µL, 4.38 mmol) was added and the reaction mixture was stirred at rt for an additional 1 h. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified using a Biotage Isolera™ (0 to 100% ethyl acetate/hexane evaporative purification system) to afford the desired product as a pale yellow solid (524 mg, 70%). LC/MS calculated for C ₂ 5H ₂₂ F ₂ N ₅ O ₅ (M+H)+: m/z = 510.2; found 510.2.

Step 3. 2-Amino-N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

To a solution of tert-butyl 3-(4-fluoro-2-nitrobenzamido)-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4c]pyridine-1-carboxylate (524 mg, 1.029 mmol) and Hunig's base (539 µL, 3.09 mmol) in DMSO (10 mL) was added 1-methylpiperazine (229 µL, 2.057 mmol) and the reaction mixture was heated to 90 °C for 3 h. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to afford the desired product. The crude product was dissolved in methanol (10 mL) and palladium on carbon (386 mg, 0.363 mmol) was added. The reaction flask was evacuated and refilled with hydrogen gas from a balloon. The reaction mixture was stirred at 55 °C for 1 h. The mixture was filtered through a pad of celite and the filtrate was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₅ H ₂₇ FN ₇ O (M+H)+: m/z = 460.2; found 460.2.

Example 158. N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-(2-hydroxypropylamino)-4-(4-methylpiperazin-1-yl)benzamide

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To a solution of 2-amino-N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (15 mg, 0.033 mmol, Example 157), tetramethylammonium triacetoxyborohydride (42.9 mg, 0.163 mmol) and TFA (12.57 μL, 0.163 mmol) in DCE (653 μL) was added 2-((tert-butyldimethylsilyl)oxy)propanal (18.4 mg, 0.098 mmol). The reaction mixture was stirred at rt for 5 min, quenched with TFA (0.5 mL) and stirred overnight. The reaction mixture was diluted with methanol and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA, flow rate 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₈ H ₃₃ FN ₇ O ₂ (M+H)+: m/z=518.2; found 518.2.

Example 159. N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-((1-methyl-1H-pyrazol-5-yl)methylamino)-4-(4-methylpiperazin-1-yl)benzamide

This compound is obtained analogously to Example 158 by replacing 2-((tert-butyldimethylsilyl)oxy)propanal with 1-methyl-1H-pyrazole-4-carbaldehyde. LC/MS calculated for C ₃₀ H ₃₃ FN9O (M+H) ⁺ : m/z=554.2; found 554.2.

Example 160. 2-(3-Cyanocyclopentylamino)-N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound is obtained analogously to Example 158 by replacing 2-((tert-butyldimethylsilyl)oxy)propanal with 3-oxocyclopentane-1-carbonitrile. LC/MS calculated for C ₃₁ H ₃₄ FN ₈ O (M+H) ⁺ : m/z=553.2; found 553.2.

Example 161. 2-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)1H-pyrazol-1-yl)benzonitrile

Step 1. tert-Butyl 5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2,6-difluorophenyl)-3-iodo-1Hpyrazolo[3,4-c]pyridine-1-carboxylate

This compound is prepared according to the methods described in Example 119, steps 1-3, using 3.5

- 113 048980 difluorobenzaldehyde instead of 3-fluoro-5-(trifluoromethyl)benzaldehyde as starting material. LC/MS calculated for C ₂₄ H ₂₈ F ₂ IN ₄ O ₄ (M+H) ⁺ : m/z=601.1; found 601.0.

Step 2. 2-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1Hpyrazol-1-yl)benzonitrile.

A mixture of tert-butyl 5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2,6-difluorophenyl-3-iodo-1Hpyrazolo[3,4-c]pyridine-1-carboxylate (20 mg, 0.033 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile (29.5 mg, 0.100 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) in complex with dichloromethane (1:1) (2.72 mg, 3.33 μmol) and potassium carbonate (13.81 mg, 0.100 mmol) in dioxane (2 ml) and water (0.4 ml) was stirred at 70 °C for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo. The crude mixture was then dissolved in DCM (2.0 ml) and TFA (2.0 ml) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 ml) and 10% aqueous NH4OH (1.5 ml). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 ml/min) to afford the desired product. LC/MS calculated for C ₂₄ H ₁₈ F ₂ N ₇ (M+H) ⁺ : m/z = 442.2; found 442.2.

Example 162. 1-(4-(3-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorophenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 161, Step 7, using tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile as the starting material. LC/MS calculated for C ₂₀ H ₂₀ F ₂ N ₇ (M+H) ⁺ : m/z = 396.2; found 396.2.

Example 163. 1-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 161, Step 7, using 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile as the starting material. LC/MS calculated for C ₂₄ H ₂₆ F ₂ N ₇ (M+H)+: m/z=450.2; found 450.2.

Example 164. 2-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)1H-pyrazol-1-yl)ethanol

This compound was prepared according to the procedures described in Example 161, Step 7, using 2-(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile as the starting material. LC/MS calculated for C ₁₉ H ₁₉ F ₂ N ₆ O (M+H) ⁺ : m/z = 385.2; found 385.2.

Example 165 1-(3,5-Difluoro-4-(3-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

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This compound was prepared according to the procedures described in Example 161, Step 7, using (4methoxyphenyl)boronic acid instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)benzonitrile as the starting material. LC/MS calculated for C ₂₁ H ₁₉ F ₂ N ₄ O (M+H)+: m/z=381.2; found 381.1.

Example 166. 1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)pyridin-2-yl)piperidin-4-ol

Step 1. tert-Butyl-3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzyl(methyl)carbamate

To a solution of tert-butyl (3,5-difluoro-4-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)(methyl)carbamate (3.80 g, 7.60 mmol, Example 161, step 5) in THF (38 mL) at rt were added N,N-diisopropylethylamine (1.99 mL, 11.4 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.42 mL, 7.98 mmol). After stirring for 18 h, the mixture was quenched with water (60 mL) and extracted with ethyl acetate. To obtain the crude product, the solvents from the separated organic layers were evaporated under reduced pressure. To obtain the desired product, the resulting crude product was purified using Biotage Isolera™. LC/MS calculated for C ₂₅ H ₃₄ F ₂ IN ₄ O ₃ Si (M+H)+: m/z=631.1; found 631.2.

Step 2. tert-Butyl-4-(3-(6-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorobenzyl(methyl)carbamate

A mixture of tert-butyl-(3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4

c]pyridin-5-yl)benzyl) (methyl)carbamate (176 mg, 0.279 mmol), (6-chloropyridin-3-yl)boric acid (48.3 mg, 0.307 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complexed with dichloromethane (1:1) (22.80 mg, 0.028 mmol) and potassium carbonate (77 mg, 0.558 mmol) in dioxane (20 mL) and water (4 mL) were stirred at 70 °C for 2 h. After cooling to rt, the mixture was concentrated in vacuo. The resulting crude product was purified using Biotage Isolera™ to obtain the desired product. LC/MS calculated for C ₃₀ H ₃₇ ClF ₂ N ₅ O ₃ Si (M+H)+: m/z=616.2; found 616.3.

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Step 3. 1-(5-(5-(2,6-Difluoro-4-((methylαamino)methyl)phenyl)-1H-nurazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol.

A mixture of tert-butyl (4-(3-(6-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorobenzyl)(methyl)carbamate (15 mg, 0.024 mmol), piperidin-4-ol (4.92 mg, 0.049 mmol), RuPhos Pd G3 (2.0 mg, 2.43 μmol) and cesium carbonate (23.8 mg, 0.073 mmol) in dioxane (1 mL) was stirred at 90 °C for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo. The crude mixture was dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The resulting mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₄ H ₂₅ F ₂ N ₆ O (M+H)+: m/z = 451.2; found 451.2.

Example 167. 1-(3,5-Difluoro-4-(3-(5-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl-4-(3-(5-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorobenzyl (methyl)carbamate

A mixture of tert-butyl (3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)(methyl)carbamate (874 mg, 1.39 mmol, Example 166, Step 1), 5-chloro-2-(tributylstannyl)pyridine (614 mg, 1.53 mmol), tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.139 mmol) and CuI (52.8 mg, 0.277 mmol) in dioxane (30 mL) was stirred at 100°C for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo. To obtain the desired product, the resulting crude product was purified using Biotage Isolera™. LC/MS calculated for _{C30H37ClF2N5O3Si} (M+H) ⁺ : m/z=616.2; found 616.1.

Step 2. 1-(3,5-Difluoro-4-(3-(5-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin5 -yl)phenyl)-N-methylmethanamine.

A mixture of tert-butyl (4-(3-(5-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorobenzyl)(methyl)carbamate (22 mg, 0.036 mmol), 3-fluoropyrrolidine (6.36 mg, 0.071 mmol), RuPhos Pd G3 (2.98 mg, 3.57 μmol) and cesium carbonate (34.9 mg, 0.107 mmol) in dioxane (1 mL) was stirred at 90 °C for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo. The crude mixture was then dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with _an acetonitrile/water _gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for _C23H22F3N6 (M+H) ⁺ : m/ _z =439.2; found 439.2.

Example 168. 1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)-N-methylmethanamine

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A mixture of tert-butyl (4-bromo-3-fluoro-5-methylbenzyl)(methyl)carbamate (60 mg, 0.181 mmol, Example 113, steps 1-6), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (68.8 mg, 0.271 mmol), potassium acetate (53.2 mg, 0.542 mmol) (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complexed with dichloromethane (1:1) (29.5 mg, 0.036 mmol) in dioxane (10 mL) was stirred at 110°C for 24 h. After cooling to room temperature, the mixture was concentrated in vacuo. A mixture of this crude material, 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridine (21.8 mg, 0.060 mmol, intermediate 2), XPhosPd G2 (4.42 mg, 6.00 μmol), and cesium carbonate (58.6 mg, 0.180 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 70 °C for 18 h. The crude mixture was then dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₁₉ H ₂₀ FN ₆ (M+H) ⁺ : m/z = 351.2; found 351.1. ¹ H-NMR (TFA salt, 600 MHz, (CD ₃ ) ₂ SO) δ 9.16 (d, J=1.3 Hz, 1H), 9.01 (br s, 2H), 8.49 (d, J=0.8 Hz, 1H), 8.10 (t, J=1.1 Hz, 1H), 8.05 (d, J=0.8 Hz, 1H), 7.34-7.27 (m, 2H), 4.19 (t, J=5.7 Hz, 2H), 3.91 (s, 3H), 2.62 (t, J=5.2 Hz, 3H), 2.17 (s, 3H).

Example 169. 4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)N-methylbenzamide

A solution of 5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (215 mg, 0.525 mmol, Example 42, step 2), (4-(methylcarbamoyl)phenyl)boric acid (94 mg, 0.525 mmol), (1,1'bis(diphenylphosphino)ferrocene)dichloropalladium(II) complexed with dichloromethane (1:1) (42.9 mg, 0.052 mmol) and potassium carbonate (145 mg, 1.05 mmol) in dioxane (3.0 mL) and water (0.5 mL) was stirred at 70°C for 5 h. After cooling to room temperature, the mixture was concentrated in vacuo. To obtain the target product, the resulting crude product was purified using Biotage Isolera™. LC/MS calculated for C ₂₀ H ₂₆ ClN ₄ O ₂ Si (M+H)+: m/z=417.2; found 417.2.

Step 2. 4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-III-pyrazolo[3,4-c]pyridin-3-yl)-X-methylbenzamide.

This compound was prepared according to the procedures described in Example 168 using 4-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide instead of 5-chloro-3-(1methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine as the starting material. LC/MS calculated for C ₂₃ H ₂₃ FN ₅ O (M+H) ⁺ : m/z = 404.2; found 404.1.

Example 170. 4-(5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-Nmethylbenzamide

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Step 1. tert-Butyl 4-(4-bromo-3-fluoro-5-methylphenyl)-4-oxobutylcarbamate

To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (1.34 g, 4.25 mmol, Example 168, step 2) in THF (30 mL) was added dropwise at -40 °C a solution of isopropylmagnesium chloride in THF (2.13 mL, 4.25 mmol, 2 M). After stirring at -40 °C for 1 h, the mixture was cooled to -78 °C and tert-butyl 2-oxopyrrolidine-1-carboxylate (0.726 mL, 4.25 mmol) was added. The resulting mixture was slowly warmed to rt over 1.5 h. The mixture was quenched with 1 M HCl and extracted with ethyl acetate. The separated organic layers were concentrated in vacuo. The resulting crude product was purified using Biotage Isolera™ to obtain the desired product. LC/MS calculated for C11H ₁₄ BrFNO (M-C ₅ H ₈ O ₂ +H) ⁺ : m/z=274.0; found 274.0.

Step 2. tert-Butyl 2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl 4-(4-bromo-3-fluoro-5-methylphenyl)-4-oxobutylcarbamate (1.30 g, 3.47 mmol) in DCM (15 mL) was added 15 mL TFA and the reaction mixture was stirred at rt for 30 min. The mixture was concentrated by vacuum and dissolved in 30 mL THF. To this solution were added triethylamine (0.593 mL, 4.25 mmol) and sodium triacetoxyborohydride (1.80 g, 8.51 mmol). The mixture was stirred at rt for 18 h and then quenched with 1 M NaOH. The mixture was extracted with ethyl acetate. The separated organic layers were concentrated in vacuo. The resulting crude product was dissolved in THF (20 mL). To this solution at rt was added 1 M NaOH. di-tert-butyl dicarbonate (1.86 g, 8.51 mmol) and triethylamine (0.513 mL, 3.68 mmol) were added. After stirring for 1 h, the solvents were evaporated under reduced pressure and the resulting crude product was purified using Biotage Isolera™ to obtain the desired product. LC/MS calculated for C ₁₂ H ₁₄ BrFNO ₂ (M-C ₄ H ₈ +H) ⁺ : m/z = 302.0; found 302.0.

Step 3. 4-(5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-Nmethylbenzamide.

A mixture of tert-butyl 2-(4-bromo-3-fluoro-5-methylbenzyl)pyrrolidine-1-carboxylate (65 mg, 0.181 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (69.1 mg, 0.272 mmol), potassium acetate (53.4 mg, 0.544 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complexed with dichloromethane (1:1) (29.6 mg, 0.036 mmol) in dioxane (10 ml) was stirred at 110°C for 24 h. After cooling to room temperature, the mixture was concentrated in vacuo. A mixture of this crude material, 4-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide (23.41 mg, 0.056 mmol, Example 169, step 1), XPhosPd G2 (4.14 mg, 5.61 μmol), and cesium carbonate (54.9 mg, 0.168 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 70 °C for 18 h. The crude mixture was then dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with _an acetonitrile/water gradient containing 0.1% TFA at a flow rate of ₆₀ mL/min) to afford the desired product. LC/MS calculated for _C25H25FN5O (M+H) ⁺ : m/z=430.2; found 430.2.

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Example 171. 5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine

Step 1. tert-Butyl 2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl 2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate (850 mg, 2.37 mmol, Example 170, step 2) in THF (10 mL) at -78 °C was added nBuLi (1.56 mL, 2.491 mmol, 1.6 M). After stirring for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (629 μL, 3.08 mmol) was added dropwise and the mixture was slowly warmed to rt over 6 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate. To obtain the crude material, the solvents from the separated organic layers were evaporated under reduced pressure. A mixture of the crude material, 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (691 mg, 1.90 mmol, intermediate 2), XPhos Pd G2 (93 mg, 0.119 mmol) and cesium carbonate (1.55 g, 4.75 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 60 °C for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo. The resulting crude product was purified using Biotage Isolera™ to obtain the desired product. The two enantiomers were separated by chiral preparative HPLC (Phenomenex Lux Amylose-1 21.2 x 250 mm, 5 micron, eluting with 15% ethyl acetate in hexane at a flow rate of 18 mL/min, t _R , peak 1 = 8.67 min, t _R , peak ₂ = 12.75 min). Peak 1: LC/MS calculated for C ₃₂ H ₄₄ FN ₆ O ₃ Si (M+H)+: m/z = 607.3; found 607.3. Peak 2: LC/MS calculated for C ₃₂ H ₄₄ FN ₆ O ₃ Si (M+H)+: m/z = 607.3; found 607.3. Step 2. 5-(2-Fluoro-6methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine.

tert-Butyl 2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)pyrrolidine-1-carboxylate (peak 1, 200 mg) was dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₁ H ₂₂ FN ₆ (M+H)+: m/z=377.2; found 377.3. 1H-NMR (TFA salt, 500 MHz, (CD3) ₂ SO) δ 9.50 (br s, 1H), 9.14 (d, J=1.3 Hz, 1H), 8.79 (br s, 1H), 8.48 (s, 1H), 8.118.01 (m, 2H), 7.37-7.29 (m, 2H), 4.63 (m, 1H), 3.92 (s, 3H), 3.44 (m, 1H), 3.36 (m, 1H), 2.44 (m, 1H), 2.20 (s, 3H), 2.20-1.98 (m, 3H).

Example 172. 5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine

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This compound was prepared according to the procedures described in Example 171 using tert-butyl 2-(3fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)pyrrolidine-1-carboxylate (peak 2, Example 171, step 1) instead of tert-butyl 2-(3fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)pyrrolidine-1-carboxylate (peak 1) as the starting material. LC/MS calculated for C ₂₁ H ₂₂ FN ₆ (M+H)+: m/z=377.2; found 377.3. ¹ H-NMR (TFA salt, 500 MHz, (CD ₃ )2SO) δ 9.50 (br s, 1H), 9.14 (d, J=1.3 Hz, 1H), 8.79 (br s, 1H), 8.48 (s, 1H), 8.11-8.01 (m, 2H), 7.37-7.29 (m, 2H), 4.63 (m, 1H), 3.92 (s, 3H), 3.44 (m, 1H), 3.36 (m, 1H), 2.44 (m, 1H), 2.20 (s, 3H), 2.20-1.98 (m, 3H).

Example 173. 5-(2-Fluoro-6-methyl-4-(1-methylpyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)1H-pyrazolo[3,4-c]pyridine

To a solution of 5-(2-fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (10 mg, 0.027 mmol, peak 1, Example 171, step 2) in THF at rt was added a solution of formaldehyde (37% in water, 20 μL) and sodium triacetoxyborohydride (22.5 mg, 0.106 mmol). After stirring for 1 h, the solvents were evaporated under reduced pressure and the resulting crude product was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₂ H ₂₄ FN ₆ (M+H) ⁺ : m/z=391.2; found 391.3.

Example 174. 5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

Step 1. tert-Butyl 6-(4-bromo-3-fluoro-5-methylphenyl)-3,4-dihydropyridine-1(2H)-carboxylate

A solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (526 mg, 1.67 mmol, Example 168, step 2), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (516 mg, 1.67 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complexed with dichloromethane (1:1) (136 mg, 0.167 mmol) and potassium carbonate (461 mg, 3.34 mmol) in dioxane (10 ml) and water (2 ml) was stirred at 65°C for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo. To obtain the target product, the resulting crude product was purified using Biotage Isolera™. LC/MS calculated for C ₁₃ H ₁₄ BrFNO ₂ (MS ₄ H ₈ +H) ⁺ : m/z=314.0; found 313.9.

Step 2. tert-Butyl 2-(4-bromo-3-fluoro-5-methylphenyl)piperidine-1-carboxylate

In a solution of tert-butyl 6-(4-bromo-3-fluoro-5-methylphenyl)-3,4-dihydropyridine-1(2H)-carboxylate

- 120 048980 (530 mg, 1.42 mmol) in DCM (10 mL) was added 10 mL TFA and the mixture was stirred at rt for 30 min. The mixture was concentrated in vacuo and dissolved in 20 mL THF. To this solution were added triethylamine (0.233 mL, 1.67 mmol) and sodium triacetoxyborohydride (707 mg, 3.34 mmol). The mixture was stirred at rt for 18 h and then quenched with 1 M NaOH. The mixture was extracted with ethyl acetate. The separated organic layers were concentrated in vacuo. The resulting crude product was dissolved in THF (20 mL). To this solution at rt was added di-tert-butyl dicarbonate (364 mg, 1.67 mmol). After stirring for 3 h, the solvents were evaporated under reduced pressure and the resulting crude product was purified using Biotage Isolera™ to obtain the desired product. LC/MS calculated for C ₁₃ H ₁₆ BrFNO ₂ (MS ₄ H ₈ +H)+: m/z=316.0; found 315.9.

Step 3. tert-Butyl 2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)piperidine-1-carboxylate

To a solution of tert-butyl 2-(4-bromo-3-fluoro-5-methylphenyl)piperidine-1-carboxylate (258 mg, 0.693 mmol) in THF (10 mL) at -78 °C was added nBuLi (0.48 mL, 0.762 mmol, 1.6 M). After stirring for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (184 μL, 0.901 mmol) was added dropwise and the resulting mixture was slowly warmed to rt over 6 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate. To obtain the crude material, the separated organic layers were evaporated under reduced pressure. A mixture of the crude material, 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (202 mg, 0.554 mmol, intermediate 2), XPhos Pd G2 (27.3 mg, 0.035 mmol) and cesium carbonate (452 mg, 1.39 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 60 °C for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo. The resulting crude product was purified using Biotage Isolera™ to obtain the desired product. The two enantiomers were separated by chiral preparative HPLC (Phenomenex Lux Amylose-2 21.1 x 250 mm, 5 microns, eluting with 45% ethyl acetate in hexane at a flow rate of 18 ml/min, t _R , peak 1 = 6.33 min, t _R , peak ₂ = 9.98 min). Peak 1: LC/MS calculated for C ₃₃ H ₄₆ FN ₆ O ₃ Si (M+H)+: m/z = 621.3; found 621.3. Peak 2: LC/MS calculated for C ₃₃ H ₄₆ FN ₆ O ₃ Si (M+H)+: m/z = 621.3; found 621.3.

Step 4. 5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine tert-Butyl 2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)piperidine-1-carboxylate (peak 1, 100 mg) was dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₂ H ₂₄ FN ₆ (M+H)+: m/z=391.2; found 391.2. 1H-NMR (TFA salt, 500 MHz, (CD3) ₂ SO) δ 9.14 (d, J=1.3 Hz, 1H), 9.05 (m, 1H), 8.76 (m, 1H), 8.49 (s, 1H), 8.14-8.01 (m, 2H), 7.37-7.26 (m, 2H), 4.31 (t, J=11.4 Hz, 1H), 3.92 (s, 3H), 3.42 (m, 1H), 3.09 (m, 1H), 2.53 (m, 1H), 2.19 (s, 3H), 2.02 (m, 1H), 1.96-1.80 (m, 2H), 1.80-1.58 (m, 2H).

Example 175. 5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared using the methods described in Example 174 using tert-butyl 2-(3fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4

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c]pyridin-5-yl)phenyl)piperidine-1-carboxylate (peak 2, example 174, step 3) in place of tert-butyl 2-(3fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)piperidine-1-carboxylate (peak 1) as starting material. LC/MS calculated for C ₂₂ H ₂₄ FN ₆ (M+H)+: m/z=391.2; found 391.2.

Example 176

Step 1. 5-(2-Fluoro-6-methyl-4-vinylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

To a solution of 2-bromo-1-fluoro-3-methyl-5-vinylbenzene (1.03 g, 4.79 mmol, Example 168, step 3) in THF (40 mL) at -78 °C was added nBuLi (3.14 mL, 5.03 mmol, 1.6 M). After stirring for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.27 mL, 6.23 mmol) was added dropwise and the resulting mixture was slowly warmed to rt over 6 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate. The separated organic layers were concentrated under reduced pressure to obtain the crude material. A mixture of the crude material, 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (1.39 g, 3.83 mmol, intermediate 2), XPhos Pd G2 (188 mg, 0.239 mmol), cesium carbonate (3.12 g, 9.58 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 60 °C for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo. To obtain the desired product, the resulting crude product was purified using Biotage Isolera™. LC/MS calculated for C ₂₅ H ₃₁ FN ₅ OSi (M+H) ⁺ : m/z = 464.2; 464.2 found.

Step 2. 3 -Fluoro-5-methyl-4-(3-( 1 -methyl-1H-pyrazol-4-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzaldehyde

To a mixture of 5-(2-fluoro-6-methyl-4-vinylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (1.82 g, 3.93 mmol), sodium periodate (3.36 g, 15.7 mmol) in acetone (20 mL) and water (2 mL) was added a solution of osmium tetroxide (4% in water, 2.49 g, 0.393 mmol). After stirring at rt for 5 h, the mixture was quenched with water (10 mL) and extracted with ethyl acetate. The separated organic layers were concentrated under reduced pressure and the resulting crude product was purified using Biotage Isolera™ to obtain the desired product. LC/MS calculated for C ₂₄ H ₂₉ FN ₅ O ₂ Si (M+H) ⁺ : m/z=466.2; found 466.3.

Step 3. N-(3-fluoro-5 -methyl-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5 -yl)benzyl)ethanamine.

To a solution of 3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzaldehyde (80 mg, 0.172 mmol), a solution of ethylamine (2 M in THF, 0.258 mL, 0.515 mmol) and acetic acid (0.030 mL, 0.515 mmol) in THF (10 mL) was added sodium triacetoxyborohydride (109 mg, 0.515 mmol). After stirring for 18 h, the mixture was concentrated in vacuo. The crude mixture was then dissolved in DCM (2.0 mL) and added dropwise at room temperature

- 122 048980 TFA (2.0 mL) was added. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH ₄ OH (1.5 mL). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₀ H ₂₂ FN ₆ (M+H) ⁺ : m/z = 365.2; found 365.3. ^-NMR (TFA salt, 600 MHz, (CD ₃ ) ₂ SO) δ 13.64 (br s, 1H), 9.13 (d, J=l.4 Hz, 1H), 8.82 (br s, 2H), 8.47 (s, 1H), 8.14-7.94 (m, 2H), 7.38-7.24 (m, 2H), 4.21 (m, 2H), 3.91 (s, 3H), 3.02 (m, 2H), 2.18 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).

Examples 177-178 were prepared by the methods described in Example 176, using the indicated starting material instead of ethylamine.____________________________________________________

Example Structure Name Source material Analysis data 177 Y HN A ην-ν N-(3-fluoro-5-methyl-4-(3-(1methyl-1Hpyrazol-4-yl)1H-pyrazolo[3,4c]pyridin-5yl)benzyl)cyclopropaneamine cyclopro panamine LC/MS detected 377.1. 178 ηνΓ Ha TUA ΗΝ-Ν N-(3-fluoro-5methyl-4-(3-(1methyl-1Hpyrazol-4-yl)1H-pyrazolo[3,4c]pyridin-5yl)benzyl)propane-2-amine propan2-amine LC/MS found 379.1. SH-NMR (TFA salt, 500 MHz, (CD ₃ ) ₂ SO) δ 9.15 (d, J=l,3 Hz, 1H), 8.82 (br s, 2H), 8.47 (s, 1H), 8.09-8.02 (m, 2H), 7.38-7.32 (m, 2H), 4.22 (t, J=6.3 Hz, 2H), 3.94 (s, 3H), 3.36 (m, 1H), 2.19 (s, 3H), 1.32 (d, J=6.5 Hz, 6H).

- 123 048980

179 l = JF l / \ ^Ζ Ά —\x #—\ / \=/ _ΖΙ \ ^g < A z z- ^z _x 2,2,2-τρπφτορ-Ν(3-fluoro-5-methyl4-(3-(1-methyl1H-pyrazol-4yl)-1Hpyrazolo[3,4c]pyridin-5yl)benzyl)ethanamine 2,2,2trifluoroe tanamine LC/MS detected 419.1. 180 L Z \= Z // _x \___/ \__ ' I ζ 1 o ζ- ^ζ _χ ³ 2-(3-fluoro-5methyl-4-(3-(1methyl-1Hpyrazol-4-yl)1H-pyrazolo[3,4c]pyridin-5yl)benzylamino)e tanol 2- aminoeth NOL LC/MS found 381.2. ^X H-NMR (TFA salt, 500 MHz, (CD ₃ ) ₂ SO) δ 9.14 (d, J=l,3 Hz, 1H), 8.96 (br s, 2H), 8.48 (s, 1H), 8.11-8.01 (m, 2H), 7.397.29 (m, 2H), 4.24 (t, J=5.5 Hz, 2H), 3.92 (s, 3H), 3.71 (m, 2H), 3.03 (m, 2H), 2.19 (s, 3H). 181 T| Ζ \= Ζ // _x x__/ \__ ^Ζ Ά /—\X /U x 2=^ ²³ 1 2 g 3-(3-fluoro-5methyl-4-(3-(1methyl-1Hpyrazol-4-yl)1H-pyrazolo[3,4c]pyridin-5yl)benzylamino)ts iclobutanol 3- aminocycline lobutano LC/MS detected 407.2 . 182 See Ssu YVvN hn-n 5-(4-(azetidin1-ylmethyl)-2fluoro-6methylphenyl)-3- (1-methyl-1Hpyrazol-4-yl)1H-pyrazolo[3,4c]pyridine azetidine LC/MS found 377.2. SH-NMR (TFA salt, 400 MHz, (CD ₃ ) ₂ SO) δ 10.10 (br s, 2H), 9.13 (d, J=l.3 Hz, 1H), 8.49 (s,

- 124 048980

- 125 048980

N- (3-φτορ-5- 186 F iS V 1 methyl-4-(3-(1methyl-1Hpyrazol-4-yl) 1H-pyrazolo[3,4c]pyridin-5- (1- methyl- 1H- imidazole 4 LC/MS 431.2. discovered HN-N / yl)benzyl)-1-(1methyl-1Nimidazol-4yl)methanamine yl)methane amine 187 F N -N. A N-N N A N— (3-fluoro-5methyl-4-(3-(1methyl-1Hpyrazol-4-yl)1H-pyrazolo[3,4c]pyridin-5yl)benzyl)— 1— (oxazol-4- yl)methanamine oxazole- 4- ilmethane min LC/MS 418.2. discovered N > ^M 2-(3-fluoro-5methyl-4-(3-(1- 188 F A A I U methyl-1Hpyrazol-4-yl)1H-pyrazolo[3,4c]pyridin-5yl)benzylamino)a 2- aminoacetonitrile LC/MS 376.2. discovered ην-ν cetonitrile

Example 189. 1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5 yl)phenyl)-N-methylethanamine

Step 1. 1-(3 -Fluoro-5 -methyl-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)ethanone

This compound was prepared according to the procedures for tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane described in Example 176, using 4,4,5,5 instead of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane as the starting material. LC/MS calculated for C ₂₅ H ₃₁ FN ₅ O ₂ Si (M+H)+: m/z=480.2; found 480.3.

Step 2. tert-Butyl-1-(3-fluoro-5-methyl-4-(3-(1 -methyl-1H-pyrazol-4-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethyl (methyl)carbamate

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To a solution of 1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethan-1-one (1.06 g, 2.21 mmol), methylamine hydrochloride (0.448 g, 6.63 mmol) and titanium(IV) isopropoxide (1.94 mL, 6.63 mmol) in MeOH (20 mL) at rt was added sodium borohydride (0.167 g, 4.42 mmol). After stirring for 1 h, the mixture was quenched with 1 M NaOH, extracted with ethyl acetate and concentrated in vacuo. The crude product was then dissolved in THF (20 mL) and di-tert-butyl dicarbonate (965 mg, 4.42 mmol) was added. After stirring for 2 h, the mixture was concentrated in vacuo. To obtain the desired product, the resulting crude product was purified using Biotage Isolera™. The two enantiomers were then separated by chiral preparative HPLC (Phenomenex Lux Cellulose-1 21.2 x 250 mm, 5 micron, eluting with 3% ethyl acetate in hexane at a flow rate of 18 mL/min, tR peak 1 = 22.02 min, _tR peak 2 = 24.22 min). Peak 1: LC/MS calculated for C ₃₁ H ₄₄ FN ₆ O ₃ Si (M+H)+: m/z = 595.3; found 595.4. Peak 2: LC/MS calculated for C ₃₁ H ₄₄ FN ₆ O ₃ Si (M+H) ⁺ : m/z=595.3; found 595.4.

Step 3. 1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine.

tert-Butyl 1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethyl(methyl)carbamate (peak 2, 100 mg) was dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₀ H ₂₂ FN ₆ (M+H) ⁺ : m/z = 365.2; found 365.1. ¹ H-NMR (TFA salt, 500 MHz, (CD3)2SO) δ 9.20-9.04 (m, 2H), 8.92 (br s, 1H), 8.50 (s, 1H), 8.09 (d, J=1.5 Hz, 1H), 8.05 (s, 1H), 7.38-7.25 (m, 2H), 4.38 (m, 1H), 3.92 (s, 3H), 2.52 (m, 3H), 2.19 (s, 3H), 1.59 (d, J=6.8 Hz, 3H).

Example 190. 1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)-N-methylethanamine

HN- _h

Peki

This compound was prepared according to the procedures described in Example 189 using tert-butyl 1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)ethyl(methyl)carbamate (peak 1, Example 189, step 2) instead of tert-butyl 1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethyl(methyl)carbamate (peak 2) as the starting material. LC/MS calculated for C ₂₂ H ₂₄ FN ₆ (M+H) ⁺ : m/z=391.2; found 391.2.

Example 191

Step 1. (3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- 127 048980 pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

To a solution of 3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzaldehyde (100 mg, 0.215 mmol, Example 176, step 2), ammonium acetate (331 mg, 4.30 mmol) in MeOH (10 mL) was added sodium cyanoborohydride (27.0 mg, 0.430 mmol). After stirring for 18 h, the mixture was concentrated in vacuo. The crude mixture was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C24H ₃ 2FN6OSi (M+H) ⁺ : m/z=467.2; found 467.2.

Step 2. N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)acetamide

To a solution of (3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine (10 mg, 0.021 mmol) in THF (2 mL) at rt were added pyridine (0.017 mL, 0.214 mmol) and acetic anhydride (10.9 mg, 0.107 mmol). After stirring for 18 h, the mixture was concentrated in vacuo. The crude product was dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at rt. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The mixture was purified by preparative LC/MS (XBridge C18 column, eluting with _an acetonitrile/water gradient containing 0.1% TFA at a flow rate of ₆₀ mL/min) to afford the desired product. LC/MS calculated for _C20H20FN6O (M+H) ⁺ : m/z=379.2; found 379.2.

Example 192 Methyl 3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)benzylcarbamate

This compound was prepared according to the procedures described in Example 191 using methyl chloroformate instead of acetic anhydride as the starting material. LC/MS calculated for C20H20FN6O2 (M+H) ⁺ : m/z=395.2; found 395.2.

Example 193. 1-(4-(6-(5-(2-(Difluoromethoxy)-6-fluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4c]pyridin-3-yl)pyridin-3-yl)piperazin-1-yl)ethanone

Step 1. tert-Butyl 4-bromo-3-(difluoromethoxy)-5-fluorobenzyl)methyl)carbamate

This compound was prepared according to the procedures described in Example 168 using 3-(difluoromethoxy)-5-fluoroaniline (Example 72, step 3) instead of 3-fluoro-5-methylaniline as the starting material. LC/MS calculated for C ₁₀ H ₁₀ BrF ₃ NO ₃ (MS ₄ H ₈ +H)+: m/z=328.0; found 327.9.

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Step 2. tert-Butyl-4-(3-(5-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-(difluoromethoxy)-5-fluorobenzyl (methyl)carbamate

This compound was prepared according to the procedures described in Example 167, using tert-butyl 4-bromo-3-(difluoromethoxy)-5-fluorobenzyl(methyl)carbamate instead of tert-butyl 3,5-difluorobenzyl(methyl)carbamate as the starting material. LC/MS calculated for C ₃₁ H ₃₈ ClF ₃ N ₅ O ₄ Si (M+H) ⁺ : m/z = 664.2; found 664.3.

Step 3. 1-(4-(6-(5-(2-(Difluoromethoxy)-6-fluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperazin-1-yl)ethanone.

This compound was prepared according to the procedures described in Example 167 using 1-(piperazin-1-yl)ethan-1-one instead of 3-fluoropyrrolidine as the starting material. LC/MS calculated for C ₂₆ H ₂₇ F ₃ N ₇ O ₂ (M+H) ⁺ : m/z=526.2; found 526.0.

Example 194

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

This compound was prepared according to the procedures described for Intermediate 1, using (4-(4-methylpiperazin-1-yl)phenyl)boronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole as starting material. LC/MS calculated for C ₂₂ H ₂₇ ClN ₅ O ₂ (M+H)+: m/z = 428.2; found 428.2.

Step 2. 2-(2-Bromo-3-fluorophenyl)acetonitrile

To a mixture of 2-bromo-1-(bromomethyl)-3-fluorobenzene (1.755 g, 6.55 mmol) and KCN (674.5 mg, 10.36 mmol) was added ethyl acetate (100.0 mL) followed by water (30.00 mL). The resulting homogeneous solution was stirred at 70 °C for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO ₃ . The separated organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (40 g, 0-50% ethyl acetate in hexanes) to give the title product as a white solid (726.8 mg, 52%).

Step 3. 2-(3-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

A screw-capped ampoule equipped with a magnetic stirrer is charged with 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (997.2 mg, 3.93 mmol), potassium acetate (1138 mg, 11.60 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (416.3 mg, 0.510 mmol). The ampoule is sealed with a septum with a Teflon liner, evacuated and refilled with nitrogen (this process is repeated three times in total).

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A solution of 2-(2-bromo-3-fluorophenyl)acetonitrile (726.9 mg, 3.40 mmol) in 1,4-dioxane (15.0 mL) was added. The reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and washed with brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the desired product (622.9 mg, 70%). LC/MS calculated for Ci ₄ H ₁₈ BFNO ₂ (M+H) ⁺ : m/z = 262.1; found 262.2.

Step 4. 2-(3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile.

A screw-capped ampoule equipped with a magnetic stirrer was charged with tert-butyl 5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (34.4 mg, 0.080 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,Gbiphenyl)]palladium(II) (XPhos Pd G2, 9.5 mg, 0.012 mmol), and cesium carbonate (88.2 mg, 0.271 mmol). The ampoule was sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process was repeated three times in total). A solution of 2-(3-fluoro-2(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (35.5 mg, 0.136 mmol) in 1,4-dioxane (2.00 mL) was added, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture _was concentrated. _CH2Cl2 (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₅ H ₂₄ FN ₆ (M+H) ⁺ : m/z=427.2; found 427.2.

Example 195. (3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)methanamine

HN-W

Step 1. tert-Butyl-2-bromo-3-fluorobenzylcarbamate

To a solution of 2-bromo-3-fluorobenzonitrile (2.460 g, 12.30 mmol) in THF (50.0 mL) at room temperature was added 1.0 M solution of borane-THF complex in THF (52.0 mL, 52.0 mmol). The mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with 4.0 OM HCl in water (50.0 mL, 200 mmol). The mixture was stirred at 50 °C for 3 h and then cooled to 0 °C. The mixture was treated with 2 M aqueous K ₂ CO ₃ until the pH reached 10. The mixture was extracted with diethyl ether. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was dissolved in CH ₂ Cl ₂ (100 mL). Di-tert-butyl dicarbonate (4.07 g, 18.65 mmol) was added. The mixture was stirred at room temperature for 10 min and then concentrated. The residue was purified on silica gel (120 g, 0-50% ethyl acetate in hexanes) to _give the title product as _{a white solid (2.497 g, 67%). LC/MS calculated for C8H8BrFNO2 (} M+H- _C4H8 ) ⁺ : _m /z=248.0; found 248.0.

Step 2. (3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine.

This compound was prepared according to the procedures described in Example 194 using tert-butyl 2-bromo-3-fluorobenzylcarbamate instead of 2-(2-bromo-3-fluorophenyl)acetonitrile as the starting material. LC/MS calculated for C ₂₄ H ₂₆ FN ₆ (M+H) ⁺ : m/z = 417.2; found 417.2.

Example 196. (3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanol

This compound was prepared according to the procedures described in Example 195 using 2-fluoro-6(hydroxymethyl)phenylboronic acid instead of tert-butyl (3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate as the starting material. LC/MS calculated for C ₂₄ H ₂₅ FN ₅ O (M+H) ⁺ : m/z = 418.2; found 418.2.

Example 197. 4,6-difluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyri- 130048980 din-5-yl)-2,3-dihydro-1H-inden-1-amine

Step 1. tert-Butyl 4,6-difluoro-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a solution of 4,6-difluoro-2,3-dihydro-1H-inden-1-one (Ark Pharm, 4.015 g, 23.88 mmol) in 2-propanol (90.0 mL) was added methylamine (2.0 M in methanol) (60.0 mL, 120 mmol) followed by titanium(IV) isopropoxide (15.31 mL, 51.7 mmol). The mixture was stirred at 35 °C for 16 h and then cooled to room temperature. Sodium borohydride (1.312 g, 34.7 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and quenched with HCl (6.0 N in water) (60.0 mL, 360 mmol). The reaction mixture was stirred at room temperature for 2 h and treated with NaOH (4.0 N in water) until the pH reached 10. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in CH ₂ Cl ₂ (100 mL) and treated with BOC anhydride (5.21 g, 23.88 mmol). After stirring at room temperature for 30 min, the reaction mixture was concentrated. The residue was purified on silica gel (120 g, 0-100% ethyl acetate in hexane) to give the title product as an oil (5.27 g, 78%). LC/MS calculated for C11H ₁₂ F ₂ NO ₂ (MS ₄ H ₈ +H)+: m/z = 228.1; found 228.1.

Step 2. tert-Butyl-4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1Ninden-1-yl(methyl)carbamate

To a solution of tert-butyl (4,6-difluoro-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (5.27 g, 18.60 mmol) in THF (100.0 mL) at -78 °C under N ₂ was added a solution of n-BuLi (2.5 M in hexane) (15.00 mL, 37.5 mmol) slowly over 20 min. The reaction mixture was allowed to warm to -60 °C and stirred for 90 min. The reaction mixture was then cooled again to -78 °C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.79 g, 58.0 mmol) was added slowly over 20 min.

After stirring at -78 °C for an additional 10 min, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NaHCO ₃ and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (120 g, 0-100% ethyl acetate in hexanes) to give the title product as an oil (1.74 g, 23%). LC/MS calculated for C ₁₇ H ₂₃ BF ₂ NO ₄ (MS ₄ H ₈ +H)+: m/z = 354.2; found 354.1.

Step 3. 4,6-difluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5yl)-2,3-dihydro-1H-inden-1-amine.

In a screw-cap ampoule equipped with a magnetic stirrer, tert-butyl 5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (31.4 mg, 0.073 mmol, Example 194, step 1), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.3 mg, 10.55 μmol) and cesium carbonate (76.3 mg, 0.234 mmol) are charged. The ampoule was sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process was repeated three times in total). A solution of tert-butyl (4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (28.8 mg, 0.070 mmol) in 1,4-dioxane (2.00 mL) was added, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h and concentrated. CH ₂ Cl ₂ (2.0 mL) was added to the residue, followed by

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TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₇ H ₂₉ F ₂ N ₆ (M+H) ⁺ : m/z = 475.2; found 475.3.

Example 198. 4,6-Difluoro-N-methyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedures described in Example 197, using tert-butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (Intermediate 1) instead of tert-butyl 5-chloro-3-(4-(4-methylpiperizin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate as the starting material. LC/MS calculated for C ₂₀ H ₁₉ F ₂ N ₆ (M+H) ⁺ : m/z = 381.2; found 381.2. ¹ H-NMR (TFA salt, 500 MHz, DMSO) δ 9.14 (d, J=1.2 Hz, 1H), 9.09 (br, 2H), 8.46 (s, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 4.88 (m, 1H), 3.91 (s, 3H), 3.13 (m, 1H), 3.05-2.90 (m, 1H), 2.66 (t, J=5.3 Hz, 3H), 2.62-2.52 (m, 1H), 2.27 (m, 1H).

Example 199. 6,8-Difluoro-N-methyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine

This compound was prepared according to the procedures described in Example 197 using 6,8-difluoro-3,4-dihydronaphthalen-2(1H)-one (Ark Pharm) instead of 4,6-difluoro-2,3-dihydro-1H-inden-1-one as the starting material. LC/MS calculated for C ₂₈ H ₃₁ F ₂ N ₆ (M+H) ⁺ : m/z = 489.3; found 489.3.

Example 200. 6,8-Difluoro-N-methyl-7-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-1,2,3,4-tetrahydronaphthalen-2-amine

This compound was prepared according to the procedures described in Example 199 using tert-butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate instead of tert-butyl 5-chloro-3-(4-(4-methylpiperizin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate as the starting material. LC/MS calculated for C ₂₁ H ₂₁ F2N ₆ (M+H)+: m/z=395.2; found 395.2.

Example 201. 4-(5-(1,3-Difluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazolo[3,4c]pyridin-3-yl)-N-methylbenzamide

Step 1. tert-Butyl 5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4 tetrahydronaphthalen-1-yl(methyl)carbamate

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This compound was prepared according to the procedures described in Example 197 using 5,7-difluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm) instead of 4,6-difluoro-2,3-dihydro-1H-inden-1-one as the starting material. LC/MS calculated for C ₂₂ H ₃₂ BrF ₂ NNaO ₄ (M+Na)+: m/z=446.2; found 446.2.

Step 2. tert-Butyl 5-chloro-3-(4-methylcarbamoyl)phenyl)-III-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described for Intermediate 1, using N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting material. LC/MS calculated for C ₁₉ H ₂₀ ClN ₄ O ₃ (M+H) ⁺ : m/z = 387.1; found 387.1.

Step 3. 4-(5-(1,3-difluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazolo[3,4c]pyridin-3-yl)-N-methylbenzamide.

Tert-butyl 5-chloro-3-(4-methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (30.3 mg, 0.078 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) are loaded into a screw-cap ampoule equipped with a magnetic stirrer.

[2-(2'-amino-1,1'biphenyl)]palladium(II) (XPhos Pd G2, 8.5 mg, 10.80 mgmol) and cesium carbonate (77.7 mg, 0.238 mmol). The ampoule is sealed with a septum with a Teflon lining, evacuated and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl (5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1yl)(methyl)carbamate (29.7 mg, 0.070 mmol) in 1,4-dioxane (2.00 mL) is added, followed by water (200.0 µL). The reaction mixture was heated to 50 °C for 16 h and then concentrated. The residue was treated with CH ₂ Cl ₂ (2.0 mL) followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, eluting with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₅ H ₂₄ F ₂ N ₅ O (M+H) ⁺ : m/z = 448.2; found 448.3.

Example 202. 5,7-Difluoro-N-methyl-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-1,2,3,4-tetrahydronaphthalen-1-amine

This compound was prepared according to the procedures described in Example 201 using tert-butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate instead of tert-butyl 5-chloro-3-(4-methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate as the starting material. LC/MS calculated for C ₂₁ H ₂₁ F ₂ N ₆ (M+H) ⁺ : m/z = 395.2; found 395.2.

Example 203. 5,7-Difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

- 133 048980

Step 1. tert-Butyl-5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalene-1-ylcarbamate

This compound was prepared according to the procedures described in Example 2 01 using ammonium acetate instead of methylamine as the starting material. LC/MS calculated for C ₂₁ H ₃₀ BF ₂ NNaO ₄ (M+Na)+: m/z=4 32.2; found 432.2.

Step 2. tert-Butyl-5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine1-carboxylate

This compound was prepared according to the procedures described for Intermediate 1, using 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine instead of 1methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting material. LC/MS calculated for C ₂₁ H ₂₆ ClN ₆ O ₂ (M+H)+: m/z = 429.2; found 429.1.

Step 3. 5,7-Difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine.

A screw-cap ampoule equipped with a magnetic stirrer is charged with tert-butyl 5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (28.9 mg, 0.067 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II) (XPhos Pd G2, 7.5 mg, 9.53 μmol), and cesium carbonate (72.7 mg, 0.223 mmol). The ampoule is sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl (5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (26.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 mL) was added, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h and then concentrated. To the residue was added CH ₂ Cl ₂ (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₆ H ₂₈ F ₂ N ₇ (M+H)+: m/z=476.2; found 476.3.

Example 204. 4-(5-(4,6-Difluoro-3-(methylamino)-2,3-dihydro-1H-inden-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

This compound was prepared according to the procedures described in Example 201 using 5,7-difluoro-2,3-dihydro-1H-indene-1-amine, HCl salt (AstaTech), instead of 5,7-difluoro-3,4-dihydronaphthalen-1(2H)-one as the starting material. LC/MS calculated for C ₂₄ H ₂₂ F ₂ N ₅ O (M+H)+: m/z=434.2; found 434.3.

Example 205. 5,7-Difluoro-N-methyl-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

- 134 048980

This compound was prepared according to the procedures described in Example 204, using tert-butyl 5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate instead of tert-butyl 5-chloro-3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate as the starting material. LC/MS calculated for C ₂₇ H ₂₉ F ₂ N ₆ (M+H)+: m/z = 475.2; found 475.3.

Example 206. 5-Fluoro-7-methoxy-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin5-yl)-2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedures described in Example 197 using 5-fluoro-7methoxy-2,3-dihydro-1H-inden-1-one (NetChem) instead of 4,6-difluoro-2,3-dihydro-1H-inden-1-one as the starting material. LC/MS calculated for C ₂₇ H ₃₀ FN ₆ O (M+H)+: m/z=473.2; found 473.3.

Example 207. 5-Fluoro-7-methoxy-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedures described in Example 206, using tert-butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate instead of tert-butyl 5-chloro-3-(4-(4-methylpiperizin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate as the starting material. LC/MS calculated for C ₂₀ H ₂₀ FN ₆ O (M+H)+: m/z = 379.2; found 379.2.

Example 208. 5-(5-(2-Fluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-1-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpicolinamide

Step 1. tert-Butyl 5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

To a solution of 5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm, 352.6 mg, 1.451 mmol) in 2-propanol (10.0 mL) was added methylamine (2.0 M in methanol) (2.50 mL, 5.00 mmol) followed by titanium(IV) isopropoxide (596.0 mg, 2.097 mmol). The mixture was stirred at 35 °C for 16 h and then cooled to room temperature. Sodium borohydride (53.4 mg, 1.412 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and quenched with HCl (1.0 N in water) (30.0 mL, 30 mmol). The mixture was stirred at room temperature for 2 h and treated with NaOH (4.0 N in water) until the pH reached 10. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in CH ₂ Cl ₂ (10 mL) and treated with BOC

- 135 048980 anhydride (426.4 mg, 1.954 mmol). After stirring at room temperature for 30 min, the reaction mixture was concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the desired product (461.0 mg, 89%). LC/MS calculated for C ₁₂ H ₁₄ BrFNO ₂ (M+HC ₄ H ₈ ) ⁺ : m/z = 302.0; found 302.1.

Step 2. tert-Butyl 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl (methyl)carbamate

A screw-capped ampoule equipped with a magnetic stirrer is charged with 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (517.4 mg, 2.037 mmol), potassium acetate (416.8 mg, 4.2 5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (210.2 mg, 0.257 mmol). The ampoule is hermetically sealed with a septum with a Teflon liner, evacuated and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl (5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate (461.0 mg, 1.287 mmol) in 1,4-dioxane (6.0 mL) was added via syringe. The reaction mixture was heated to 100 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ and filtered. The filtrate was concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the desired product (337.4 mg, 65%). LC/MS calculated for C ₂₂ H ₃₃ BFNNaO ₄ (M+Na) ⁺ : m/z = 428.2; found 428.2.

Step 3. tert-Butyl 5-chloro-3-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1carboxylate

This compound was prepared according to the procedures described for Intermediate 1, using N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide instead of 1-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting material. LC/MS calculated for C ₁₈ H ₁₉ ClN ₅ O ₃ (M+H) ⁺ : m/z = 388.1; found 388.1.

Step 4. 5-(5-(2-fluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-1-yl)-1H-pyrazolo[3,4-c]pyridin3-yl)-N-methylpicolinamide.

A screw-cap ampoule equipped with a magnetic stirrer is charged with tert-butyl 5-chloro-3-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (30.3 mg, 0.078 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.5 mg, 10.80 μmol), and cesium carbonate (77.2 mg, 0.237 mmol). The ampoule is sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl (6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate (28.1 mg, 0.069 mmol) in 1,4-dioxane (2.00 mL) was added, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h and then concentrated. To the residue was added CH ₂ Cl ₂ (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₄ H ₂₄ FN ₆ O (M+H) ⁺ : m/z = 431.2; found 431.3.

Example 209. 6-Fluoro-N-methyl-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

- 136 048980

ΉΗ

ην-ν

This compound was prepared according to the procedures described in Example 208, using tert-butyl 5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate instead of tert-butyl 5-chloro-3-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate as the starting material. LC/MS calculated for C ₂₈ H ₃₂ FN ₆ (M+H)+: m/z = 471.3; found 471.3.

Example 210. 6-Fluoro-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalene- 1-amine

Step 1. tert-Butyl-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalene-1-ylcarbamate

This compound was prepared according to the procedures described in Example 208 using ammonium acetate instead of methylamine as the starting material. LC/MS calculated for C ₁₇ H ₂₄ BFNO ₄ (M+HC ₄ H ₈ ) ⁺ : m/z = 336.2; found 336.3.

Step 2. 6-Fluoro-5-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalene-1-amine.

A screw-cap ampoule equipped with a magnetic stirrer was charged with tert-butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (24.9 mg, 0.075 mmol, intermediate 1), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 7.5 mg, 9.53 μmol), and cesium carbonate (72.4 mg, 0.222 mmol). The ampoule was sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process was repeated three times in total). A solution of tert-butyl 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1yl)carbamate (25.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 mL) was added via syringe, followed by water (200.0 μL). The reaction mixture was heated to 60 °C for 16 h. The reaction mixture was concentrated. To the residue was added CH ₂ Cl ₂ (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₇ H ₃₀ FN ₆ (M+H) ⁺ : m/z = 457.2; found 457.2.

Example 211. 2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4c]pyridin-6-yl)phenyl)acetonitrile, N

HN-N

Step 1. 4-(4-Bromo-3,5-difluorophenyl)isoxazole

- 137 048980

A screw-cap ampoule equipped with a magnetic stirrer is charged with 2-bromo-1,3-difluoro-5-iodobenzene (1360.8 mg, 4.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (828.0 mg, 4.25 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (727.0 mg, 0.890 mmol), and cesium carbonate (2843 mg, 8.73 mmol). The ampoule is hermetically sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). 1,4-Dioxane (12.0 mL) was then added via syringe, followed by water (2.0 mL). The reaction mixture was heated to 50°C for 16 h. After cooling to room temperature, the organic layer was separated and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the title product as a pale yellow solid (502.9 mg, 46%).

Step 2. 2-(4-Bromo-3,5-difluorophenyl)acetonitrile

To a mixture of 4-(4-bromo-3,5-difluorophenyl)isoxazole (489.4 mg, 1.882 mmol) and potassium fluoride (584.8 mg, 10.07 mmol) was added DMF (5.0 mL) followed by water (5.0 mL). The reaction mixture was heated to 90 °C for 3 h. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and washed with brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to afford the title product as a white metallic solid (363.4 mg, 83%).

Step 3. 2-(3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

This compound was prepared according to the procedures described in Example 194 using 2-(4-bromo-3,5-difluorophenyl)acetonitrile instead of 2-(2-bromo-3-fluorophenyl)acetonitrile as the starting material. LC/MS calculated for C ₁₄ H ₁₇ BF ₂ NO ₂ (M+H)+: m/z=280.1; found 280.0.

Step 4. tert-Butyl 5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described for Intermediate 1, using 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting material. LC/MS calculated for C ₂₀ H ₂₅ ClN ₇ O ₂ (M+H) ⁺ : m/z = 430.2; found 430.2.

Step 5. 2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile.

Tert-butyl 5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (40.9 mg, 0.095 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II) (XPhos Pd G2, 11.2 mg, 0.014 mmol) and cesium carbonate (95.2 mg, 0.292 mmol) are added to a screw-cap ampoule equipped with a magnetic stirrer. The ampoule is hermetically sealed with a partition with a Teflon gasket, evacuated and refilled with nitrogen (this process is repeated three times in total). A solution of 2-(3.5

- 138 048980 difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (66.8 mg, 0.239 mmol) in 1,4-dioxane (2.0 mL) followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was concentrated. The residue was treated with CH ₂ Cl ₂ (2.0 mL) followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₃ H ₂₁ F ₂ N ₈ (M+H)+: m/z=447.2; found 447.2.

Example 212. 5,7-Difluoro-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1 H-inden-1-ol

To a solution of 5,7-difluoro-2,3-dihydro-1H-inden-1-one (1.134 g, 6.74 mmol) in MeOH (24.0 mL) was added NaBH ₄ (773.2 mg, 20.44 mmol). After stirring at room temperature for 10 min, the mixture was diluted with CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ . The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexane) to afford the title product as a colorless oil (981.4 mg, 86%).

Step 2. 5,7-Difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol

To a solution of 5,7-difluoro-2,3-dihydro-1H-inden-1-ol (981.4 mg, 5.77 mmol) in THF (40.0 mL) at -78 °C under N ₂ was added a solution of n-BuLi (2.5 M in hexane) (7.00 mL, 17.50 mmol) slowly over 20 min via syringe. The reaction mixture was allowed to warm to -60 °C and stirred for 60 min. The reaction mixture was then cooled again to -78 °C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.64 mL, 22.73 mmol) was added slowly over 20 min via syringe. After stirring for 20 min at -78°C, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated _NaHCO3 and extracted with ethyl acetate. The organic layer was dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexane) to give the title product as a colorless oil (1.085 g, 64%).

Step 3. 5,7-Difluoro-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro1H-inden-1-ol.

A screw-cap ampoule equipped with a magnetic stirrer was charged with tert-butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (26.4 mg, 0.079 mmol, intermediate 1), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 10.0 mg, 0.013 mmol), and cesium carbonate (86.3 mg, 0.265 mmol). The ampoule was sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process was repeated three times in total). A solution of 5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol (25.0 mg, 0.084 mmol) in 1,4-dioxane (2.00 mL) was added, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was concentrated. CH2Cl2 (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₁₉ H ₁₆ F ₂ N ₅ O (M+H) ⁺ : m/z=368.1; found 368.2.

Example 213

- 139 048980

This compound was prepared according to the procedures described in Example 212, using tert-butyl 5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate instead of tert-butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate as the starting material. LC/MS calculated for C ₂₅ H ₂₅ F ₂ N ₆ O (M+H)+: m/z = 463.2; found 463.2.

Example 214. 6,8 - Difluoro-7-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine

Step 1. tert-Butyl 6-chloro-5-methoxypyridin-3-ylcarbamate

To a solution of 6-chloro-5-methoxypyridin-3-amine (1.992 g, 12.56 mmol) in THF (100.0 mL) at 0 °C was added a solution of KHMDS (1.0 M in THF) (28.0 mL, 28.0 mmol) slowly over 10 min via syringe. The reaction mixture was stirred at 0 °C for 30 min. A solution of BOC anhydride (3.28 g, 15.03 mmol) in THF (10.0 mL) was added slowly over 20 min via syringe. The mixture was allowed to warm to room temperature. After stirring for 2 h, the reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified on silica gel (120 g, 0-100% ethyl acetate in hexanes) to give the title product as a yellow foamed solid (2.162 g, 67%). LC/MS calculated for C ₁₁ H ₁₆ ClN ₂ O ₃ (M+H)+: m/z = 259.1; found 259.1.

Step 2. tert-Butyl 6-chloro-5-methoxy-4-methylpyridin-3-ylcarbamate

To a solution of tert-butyl (6-chloro-5-methoxypyridin-3-yl)carbamate (2.102 g, 8.13 mmol) in THF (80.0 mL) at -78 °C under N ₂ was added TEMED (3.81 mL, 25.3 mmol). A solution of n-BuLi (2.5 M in hexane) (9.00 mL, 22.50 mmol) was added slowly via syringe over 30 min. The mixture was allowed to warm to -30 °C and stirred for 2 h. The reaction mixture was cooled again to -78 °C. MeI (2.0 M in MTBE) (7.00 mL, 14.00 mmol) was added dropwise via syringe over 30 min. After stirring at 78°C for 1 h, the white suspension was allowed to warm to -20°C and stirred for 2 h. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate. The organic layer was dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified on silica gel (120 g, 0-100% ethyl acetate _in hexane) to afford the _desired product as _a white solid (2.055 g, 93%). LC/MS calculated for _C12H18ClN2O3 (M+H)+: m/z=273.1; found 273.1.

Step 3. 6-Chloro-5-methoxy-4-methylpyridin-3-amine

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To a solution of tert-butyl (6-chloro-5-methoxy-4-methylpyridin-3-yl)carbamate (2.055 g, 7.53 mmol) in CH ₂ Cl ₂ (20.0 mL) was added TFA (20.0 mL). The mixture was stirred at room temperature for 50 min and then concentrated. The residue was dissolved in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ . The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to afford the title product as a white solid (1.110 g, 85%). LC/MS calculated for C ₇ H ₁₀ ClN ₂ O (M+H)+: m/z = 173.0; 173.1 found.

Step 4. 5-Chloro-4-methoxy-1H-pyrazolo[3,4-c]pyridine

To a solution of 6-chloro-5-methoxy-4-methylpyridin-3-amine (1.104 g, 6.40 mmol) and acetic acid (22.0 mL) was added amyl nitrite (1.096 mL, 8.16 mmol). After stirring at room temperature for 5 min, the mixture was heated to 80 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was used directly in the next step without further purification. LC/MS calculated for C ₇ H ₇ ClN ₃ O (M+H) ⁺ : m/z = 184.0; found 184.1.

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

This compound was prepared according to the procedures described for intermediate 1, using 5-chloro-4-methoxy-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-1H-pyrazolo[3,4-c]pyridine as starting material. LC/MS calculated for C ₁₆ H ₁₉ ClN ₅ O ₃ (M+H) ⁺ : m/z = 364.1; found 364.1.

Step 6. 6,8-difluoro-7-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine

A screw-cap ampoule equipped with a magnetic stirrer is charged with tert-butyl 5-chloro-4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (31.5 mg, 0.087 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 9.6 mg, 0.012 mmol), and cesium carbonate (99.2 mg, 0.304 mmol). The ampoule is sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl (6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)carbamate (34.4 mg, 0.081 mmol, Example 199, step 2) in 1,4-dioxane (2.00 mL) was added, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was concentrated. To the residue was added CH ₂ Cl ₂ (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₂ H ₂₃ F ₂ N ₆ O (M+H) ⁺ : m/z = 425.2; found 425.2.

Example 215. 1-(3,5-Difluoro-4-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 214 using tert-butyl 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate instead of tert-butyl (6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)carbamate as the starting material. LC/MS calculated for C ₁₉ H ₁₉ F ₂ N ₆ O (M+H) ⁺ : m/z = 385.2; found 385.2.

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Example 216. 5,7-Difluoro-6-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)2,3-dihydro-1H-inden-1-amine

Step 1. tert-Butyl-6-chloro-5-fluoropyridin-3-ylcarbamate

A flask equipped with a magnetic stirrer is charged with 5-bromo-2-chloro-3-fluoropyridine (5.237 g, 24.89 mmol), chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (XantPhos Pd G2, 2.254 g, 2.54 mmol), tert-butyl carbamate (3.191 g, 27.2 mmol), and cesium carbonate (20.06 g, 61.6 mmol). The flask is sealed with a septum, evacuated, and backfilled with nitrogen (this process is repeated three times in total). 1,4-dioxane (90.0 mL) is added. The reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ and filtered. The filtrate was concentrated. The residue was purified on silica gel (120 g, 0-50% ethyl acetate in hexanes) to give the desired product as a pale yellow solid (2.745 g, 45%). LC/MS calculated for C ₁₀ H ₁₃ ClFN ₂ O ₂ (M+H)+: m/z = 247.1; found 247.1.

Step 2. tert-Butyl-6-chloro-5-fluoro-4-methylpyridin-3-ylcarbamate

To a solution of tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate (2.745 g, 11.13 mmol) in THF (30.0 mL) at -78 °C under N ₂ was added a solution of n-BuLi (2.5 M in hexane) (12.0 mL, 30.0 mmol) slowly over 30 min via syringe. The reaction mixture was allowed to warm to -30 °C and stirred for 2 min. The reaction mixture was cooled again to -78 °C. MeI (2.0 M in MTBE) (9.00 mL, 18.00 mmol) was added dropwise over 30 min via syringe. After stirring at -78 °C for 1 h, the white suspension was allowed to warm to -20 °C and stirred for 2 h. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (120 g, 0-50% ethyl acetate in hexanes) to give the title product as a pale yellow solid (2.512 g, 87%). LC/MS calculated for C _n H ₁₅ ClFN ₂ O ₂ (M+H) ⁺ : m/z = 261.1; found 261.1.

Step 3. 6-Chloro-5-fluoro-4-methylpyridin-3-amine

To a solution of tert-butyl (6-chloro-5-fluoro-4-methylpyridin-3-yl)carbamate (2.512 g, 9.64 mmol) in CH ₂ Cl ₂ (30.0 mL) was added TFA (30.0 mL). The mixture was stirred at room temperature for 50 min and then concentrated. The residue was dissolved in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ . The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to afford the title product as a white solid (1.420 g, 92%). LC/MS calculated for C ₆ H ₇ ClFN ₂ (M+H) ⁺ : m/z = 161.0; 161.1 found.

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

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This compound was prepared according to the procedures described in Example 214 using 6-chloro-5-fluoro-4-methylpyridin-3-amine instead of 6-chloro-5-methoxy-4-methylpyridin-3-amine as the starting material. LC/MS calculated for C ₁₅ H ₁₆ ClFN ₅ O ₂ (M+H)+: m/z=352.1; found 352.2.

Step 5. 5,7-Difluoro-6-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1 H-inden-1-amine.

A screw-cap ampoule equipped with a magnetic stirrer is charged with tert-butyl 5-chloro-4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (28.2 mg, 0.080 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.5 mg, 10.80 μmol), and cesium carbonate (72.4 mg, 0.222 mmol). The ampoule is sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl (5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (27.6 mg, 0.070 mmol, Example 204, step 2) in 1,4-dioxane (2.00 mL) was added, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was concentrated. To the residue was added CH ₂ Cl ₂ (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₁₉ H ₁₆ F ₃ N ₆ (M+H) ⁺ : m/z = 385.1; found 385.2.

Example 217. 1-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 161 using 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile as starting material. LC/MS calculated for C ₂₃ H ₂₅ F ₂ N ₈ (M+H)+: m/z = 451.2; found 451.3. ¹ H-NMR (TFA salt, 600 MHz, DMSO-d ₆ ) δ 10.18 (br, 1H), 9.21 (d, J=1.1 Hz, 1H), 9.10 (br, 2H), 9.07 (s, 2H), 8.32 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 4.79 (m, 2H), 4.24 (t, J=4.5 Hz, 2H), 3.54 (m, 2H), 3.34 (m, 2H), 3.10 (m, 2H), 2.85 (s, 3H), 2.62 (t, J=4.5 Hz, 3H).

Example 218. 1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)pyrimidin-2-yl)piperidin-4-ol

HNN

This compound was prepared according to the procedures described in Example 161 using 1-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidin-4-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile as the starting material. LC/MS calculated for C ₂₃ H ₂₄ F ₂ N ₇ O (M+H)+: m/z = 452.2; found 452.2.

Example 219. 1-(3,5-difluoro-4-(3-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

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This compound was prepared according to the procedures described in Example 161 using 5-(4-methylpiperazin-1-yl)pyridin-3-ylboronic acid instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile as the starting material. LC/MS calculated for C ₂₄ H ₂₆ F ₂ N ₇ (M+H)+: m/z=450.2; found 450.3.

Example 220. 4-Fluoro-N,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)-2,3-dihydro-1H-inden-1-amine

Step 1. 5-(Benzyloxy)-4-fluoro-6-iodo-2,3-dihydro-1H-inden-1-one

To a mixture of 4-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one (2.017 g, 12.14 mmol) and NIS (2.742 g, 12.19 mmol) was added DMF (30.0 mL). The mixture was stirred at room temperature for 24 h. Benzyl bromide (2.820 g, 16.49 mmol) was added followed by K ₂ CO ₃ (5.088 g, 36.8 mmol). The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (120 g, 0-100% ethyl acetate in hexanes) to give the title product as a yellow solid (2.36 g, 51%). LC/MS calculated for Ci ₆ Hi ₃ FIO ₂ (M+H)+: m/z=383.0; found 383.0.

Step 2. tert-Butyl-5-(benzyloxy)-4-fluoro-6-iodo-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a solution of 5-(benzyloxy)-4-fluoro-6-iodo-2,3-dihydro-1H-inden-1-one (2.36 g, 6.18 mmol) in 2-propanol (40.0 mL) was added methylamine (2.0 M in methanol) (16.0 mL, 32.0 mmol) followed by titanium(IV) isopropoxide (3.962 g, 13.94 mmol). The mixture was stirred at 35 °C for 16 h and then cooled to rt. Sodium borohydride (351.3 mg, 9.29 mmol) was added. After stirring at room temperature for 30 h, the reaction mixture was quenched with HCl (6.0 N in water) (20.0 mL, 120 mmol). The resulting mixture was stirred at 40 °C for 2 h and cooled to room temperature. The mixture was treated with 4 N NaOH until the pH reached 10 and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in CH ₂ Cl ₂ . BOC anhydride (1.505 g, 6.90 mmol) was added. After stirring at room temperature for 30 min, the reaction mixture was quenched with MeOH and concentrated. The residue was purified on silica gel (120 g, 0-100% ethyl acetate in hexanes) to give the title product as a solid (2.60 g, 85%).

Step 3. tert-Butyl-5-(benzyloxy)-4-fluoro-6-methyl-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

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A screw-cap ampoule equipped with a magnetic stirrer is charged with tert-butyl (5-(benzyloxy)-4-fluoro-6-iodo-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (1001.4 mg, 2.013 mmol), dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (XPhos Pd G2, 317.1 mg, 0.403 mmol), and potassium phosphate (1783 mg, 8.40 mmol). The ampoule is sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). A solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (830.6 mg, 6.62 mmol) in 1,4-dioxane (10.0 mL) was added, followed by water (2.00 mL). The reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and washed with brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to afford the desired product. LC/MS calculated for C ₂₃ H ₂₈ FNNaO ₃ (M+Na) ⁺ : m/z = 408.2; found 408.2.

Step 4. tert-Butyl 4-fluoro-5-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To tert-butyl 5-(benzyloxy)-4-fluoro-6-methyl-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (776.0 mg, 2.013 mmol) was added MeOH (25.0 mL) followed by THF (5.00 mL). Palladium hydroxide on carbon (20 wt%) (566.2 mg, 0.806 mmol) was added. The mixture was bubbled with _H2 and stirred under _H2 (1 atm) for 16 h. The mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the title product as a yellow foamy solid (234.1 mg, 39%).

Step 5. 1-(tert-Butoxycarbonyl(methyl)amino)-4-fluoro-6-methyl-2,3-dihydro-1H-inden-5-yl trifluoromethanesulfonate

To a solution of tert-butyl (4-fluoro-5-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (234.1 mg, 0.793 mmol) in CH ₂ Cl ₂ (5.0 mL) at 0 °C was added pyridine (1001.7 mg, 12.66 mmol). A solution of trifluoromethanesulfonic anhydride (671.2 mg, 2.379 mmol) in CH ₂ Cl ₂ (5.0 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. The reaction mixture was quenched with aqueous 2 M K ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the desired product (284.9 mg, 84%). LC/MS calculated for C ₁₃ H ₁₄ F ₄ NO ₅ S (M+HC ₄ H ₈ )+: m/z=372.1; found 372.1.

Step 6. tert-Butyl-4-fluoro-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro1 H-inden-1-yl(methyl)carbamate

In a screw-cap ampoule equipped with a magnetic stirrer, 4,4,4',4',5,5,5',5'-octamethyl-[2,2']bis(1,3,2-dioxaborolane) (231.6 mg, 0.912 mmol), potassium acetate (227.4 mg,

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2.317 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a complex with dichloromethane (1:1) (109.8 mg, 0.134 mmol). The ampoule is hermetically sealed with a septum with a Teflon lining, evacuated and refilled with nitrogen (this process is repeated three times in total). A solution of 1-((tert-butoxycarbonyl)(methyl)amino)-4-fluoro-6-methyl-2,3-dihydro-1-ninden-5-yl trifluoromethanesulfonate (284.9 mg, 0.667 mmol) in 1,4-dioxane (5.0 mL) is injected via syringe. The mixture is stirred at 100 °C for 16 h. After cooling to room temperature, the mixture is filtered. The filtrate is used immediately in the next step.

Step 7. 4-Fluoro-N,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine.

This compound was prepared according to the procedures described in Example 198 using tert-butyl 4-fluoro-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate instead of tert-butyl 4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate as the starting material. LC/MS calculated for C ₂₁ H ₂₂ FN ₆ (M+H)+: m/z = 377.2; found 377.2. 1H NMR (TFA salt, 600 MHz, DMSO-d ₆ ) δ 9.13 (d, J = 1.0 Hz, 1H), 9.05-8.87 (m, 2H), 8.47 (s, 1H), 8.03 (s, 1H), 8.03 (d, J = 0.6 Hz, 1H), 7.38 (s, 1H), 4.80 (m, 1H), 3.90 (s, 3H), 3.10 (m, 1H), 2.99-2.89 (m, 1H), 2.65 (t, J = 5.4 Hz, 3H), 2.57-2.50 (m, 1H), 2.24 (m, 1H), 2.14 (s, 3H).

Example 221

GTHk /

Ol t

This compound was prepared according to the procedures described in Example 86 and 92 using 3,3-dimethylazetidine instead of methanamine as the starting material. LC/MS calculated for C ₂₃ H ₂₆ FN ₆ (M+H) ⁺ : m/z=405.2; found 405.3. ¹ H-NMR (500 MHz, DMSO-de) δ 9.21 (s, 1H), 8.49 (s, 1H), 8.11 (s, 1H), 8.08-8.03 (m, 1H), 7.60 (dd, J=8.6, 5.7 Hz, 1H), 7.29 (t, J=8.7 Hz, 1H), 4.52 (d, J=5.7 Hz, 2H), 4.09-3.94 (m, 4H), 3.92 (s, 3H), 2.14 (s, 3H), 1.35 (s, 3H), 1.30 (s, 3H) ppm.

Example 222. trans-N-(4-Fluoro-2-methyl-3 -(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin5 -yl)benzyl)-3-methoxycyclobutanamine

This compound was prepared according to the procedures described in Example 86 and 92, using trans-3-methoxycyclobutanamine instead of methanamine as the starting material. LC/MS calculated for C ₂₃ H ₂₆ FN ₆ O (M+H) ⁺ : m/z = 421.2; found 421.2.

Example 223

This compound was prepared according to the procedures described in Example 86 and 92 using 3,3-dimethylcyclobutanamine instead of methanamine as the starting material. LC/MS calculated for C ₂₄ H ₂₈ FN ₆ (M+H) ⁺ : m/z=419.2; found 419.2.

Example 224

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This compound was prepared according to the procedures described in Example 86 and 92 using (1 methylcyclopropyl)methanamine instead of methanamine as the starting material. LC/MS calculated for C ₂₃ H ₂₆ FN ₆ (M+H)+: m/z=405.2; found 405.2.

Example 225. 1-(4-Fluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described in Example 131 using 4-fluoro-2-(trifluoromethyl)benzaldehyde instead of 3-fluoro-5-(trifluoromethyl)benzaldehyde as the starting material. LC/MS calculated for C ₁₉ H ₁₇ F ₄ N ₆ (M+H)+: m/z=405.2; found 405.2. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 9.14 (br, 1H), 9.10 (s, 1H), 8.46 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.97-7.82 (m, 2H), 4.39 (br, 2H), 3.91 (s, 3H), 2.73 (s, 3H) ppm.

Example 226 and 227. 5-(2-Fluoro-4-(pyrrolidin-2-yl)-6-(trifluoromethyl)phenyl)-3-(1-methyl-1H-pyrazol4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 171 using 1-bromo-3-fluoro-5-(trifluoromethyl)benzene instead of 2-bromo-1-fluoro-5-iodo-3-methylbenzene as the starting material. Peak 1: LC/MS calculated for C ₂₁ H ₁₉ F ₄ N ₆ (M+H)+: m/z=431.2; found 431.2. ¹ H-NMR (TFA salt, 500 MHz, (CD ₃ ) ₂ SO) δ 13.70 (br s, 1H), 9.52 (br s, 1H), 9.11 (d, J=1.3 Hz, 1H), 8.95 (br s, 1H), 8.45 (s, 1H), 8.16 (d, J=1.3 Hz, 1H), 8.04 (d, J=0.8 Hz, 1H), 7.92-7.86 (m, 2H), 4.79 (m, 1H), 3.91 (s, 3H), 3.48 (m, 1H), 3.38 (m, 1H), 2.23-2.03 (m, 4H). Peak 2: LC/MS calculated for C ₂₁ H ₁₉ F ₄ N ₆ (M+H)+: m/z=431.2; found 431.2.

Example 228 and 229. 1-(4-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3fluoro-5-methylphenyl)-N-methylethanamine

This compound was prepared according to the procedures described in Example 189 using 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as the starting material. Peak 1: LC/MS calculated for C ₂₂ H ₂₄ FN ₆ (M+H)+: m/z=391.2; found 391.2. Peak 2: LC/MS calculated for C ₂₂ H ₂₄ FN ₆ (M+H)+: m/z=391.2; found 391.2.

Example 230 and 231

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This compound is obtained using the following methods:

described in Example 174, using 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting material. Peak 1: LC/MS calculated for C ₂₃ H ₂₆ FN ₆ (M+H)+: m/z=405.2; found 405.2. Peak 2: LC/MS calculated for C ₂₃ H ₂₆ FN ₆ (M+H)+: m/z=405.2; found 405.2.

Example 232 and 233. 3-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described in Example 174 using 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as the starting material. Peak 1: LC/MS calculated for C ₂₄ H ₂₆ FN ₆ (M+H)+: m/z=417.2; found 417.2. Peak 2: LC/MS calculated for C ₂₄ H ₂₆ FN ₆ (M+H)+: m/z=417.2; found 417.2.

Example 234 3-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)morpholine

A solution of 3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)benzaldehyde (40 mg, 0.086 mmol, Example 176, step 2), SnAPM reagent (31.3 mg, 0.086 mmol) in toluene (1 mL) was heated under reflux at 120 °C for 1 h. The mixture was concentrated under reduced pressure to afford the intermediate imine. A solution of Cu(OTf) ₂ (31.1 mg, 0.086 mmol) in hexafluoroisopropynol (0.7 mL) was separately treated at rt with 2,6-lutidine (10.01 µL, 0.086 mmol). After stirring for 1 h, a solution of the intermediate imine in DCM (1 mL) was added and the resulting mixture was stirred at rt for 16 h. The mixture was then treated with aqueous NH ₄ OH and extracted with ethyl acetate. To obtain the crude product, the organic phase mixture was concentrated under reduced pressure. The crude product was dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH ₄ OH (1.5 mL) and purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₁ H ₂₂ FN ₆ O (M+H)+: m/z=393.2; found 393.2.

Example 235. 1-(3-(Difluoromethyl)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

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This compound was prepared according to the procedures described in Example 113 (steps 3-6), using 1-bromo-3-(difluoromethyl)-5-fluorobenzene instead of 2-bromo-1-fluoro-5-iodo-3-methylbenzene as the starting material. LC/MS calculated for C10H11F3NO2 (M+HC ₄ H ₈ )+: m/z=234.2; found 234.1.

Step 2. tert-Butyl-3-(difluoromethyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

To a solution of tert-butyl (3-(difluoromethyl)-5-fluorobenzyl)(methyl)carbamate (256.5 mg, 0.887 mmol) in THF (8.0 mL) at -78 °C was added dropwise lithium diisopropylamide (2.0 M in THF) (600.0 μL, 1.200 mmol). The mixture was stirred at -78 °C for 30 min. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (336.0 mg, 1.806 mmol) in THF (5.0 mL) was added dropwise. The mixture was stirred at -78 °C for 15 min and then allowed to warm to room temperature. After stirring at room temperature for 20 min, the reaction mixture was treated with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic phase mixture was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on silica gel (20 g, 0-100% ethyl acetate in hexanes) to give the title product (62.6 mg, 17%). LC/MS calculated for C ₁₆ H ₂₂ BF ₃ NO ₄ (M+H-C ₄ H ₈ ) ⁺ : m/z = 360.2; found 360.2.

Step 3. 1-(3-(Difluoromethyl)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)-N-methylmethanamine.

A screw-capped ampoule equipped with a magnetic stirrer was charged with tert-butyl 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (50.5 mg, 0.151 mmol, intermediate 1), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 11.9 mg, 0.015 mmol), and cesium carbonate (156.2 mg, 0.479 mmol). The ampoule was sealed, evacuated, and refilled with nitrogen (this process was repeated three times in total). A solution of tert-butyl (3-(difluoromethyl)-5-fluoro4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (62.6 mg, 0.151 mmol) in 1,4-dioxane (3.0 mL) was added via syringe, followed by water (300.0 μL). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was cooled and concentrated. The residue was dissolved in CH ₂ Cl ₂ (5.0 mL) and treated with TFA (5.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The crude reaction residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₁₉ H ₁₈ F ₃ N ₆ (M+H)+: m/z=387.2; found 387.1. ¹ H-NMR (TFA salt, 500 MHz, DMSO) δ 13.72 (br, 1H), 9.14 (d, J=1.2 Hz, 1H), 8.96 (br, 2H), 8.46 (s, 1H), 8.22 (s, 1H), 8.04 (d, J=0.6 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J=10.2 Hz, 1H), 7.01 (t, J=54.7 Hz, 1H), 4.31 (t, J=5.8 Hz, 2H), 3.91 (s, 3H), 2.63 (t, J=5.2 Hz, 3H).

Example 236

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This compound was prepared according to the procedures described in Example 86 and 92, using ethanamine instead of methaneamine as the starting material. LC/MS calculated for C ₂₀ H ₂₂ FN ₆ (M+H)+: m/z=365.2; found 365.2.

Example 237

This compound was prepared according to the procedures described in Example 86 and 88, using ethanamine instead of methaneamine as the starting material. LC/MS calculated for C ₂₀ H ₂₀ F ₃ N ₆ (M+H)+: m/z=401.2; found 401.2.

Example 238. 4-Fluoro-N,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-5-

Peak 1.

The two enantiomers of Example 220 were separated by chiral preparative HPLC (Phenomenex Lux Cellulose-4 21.1 x 250 mm, 5 microns, eluting with 45% ethyl acetate in hexane at a flow rate of 18 ml/min, tR, peak 1 = 9.5 min, t _R , peak 2 = 12.8 min). Peak 1: LC/MS calculated for C ₂₁ H ₂₂ FN ₆ (M+H)+: m/z = 377.2; found 377.2.

Example 239. 4-Fluoro-N,6-dimethyl-5-(3-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridine-5 -

Peak 2.

The two enantiomers of Example 220 were separated using chiral preparative HPLC (Phenomenex Lux Cellulose-4 21.1x250 mm, 5 microns, eluting with 45% ethyl acetate in hexane at a flow rate of 18 ml/min, t _R , peak 1 = 9.5 min, t _R , peak 2 = 12.8 min).

Peak 2. LC/MS calculated for C ₂₁ H ₂₂ FN ₆ (M+H)+: m/z=377.2; found 377.2.

Example 240. 6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyrudin-3-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl 5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl (methyl)carbamate

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Tue

To a solution of 5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm, 312.6 mg, 1.286 mmol) in 2-propanol (10.0 mL) was added methylamine (2.0 M in methanol) (2.50 mL, 5.00 mmol) followed by titanium(IV) isopropoxide (596.0 mg, 2.097 mmol). The mixture was stirred at 35 °C for 16 h and then cooled to room temperature. Sodium borohydride (53.4 mg, 1.412 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and quenched with HCl (1.0 N in water) (30.0 mL, 30 mmol). The mixture was stirred at room temperature for 2 h and treated with NaOH (4.0 N in water) until the pH reached 10. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in CH ₂ Cl ₂ (10 mL) and treated with BOC anhydride (426.4 mg, 1.954 mmol). After stirring at room temperature for 30 min, the reaction mixture was concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexane) to give the title product (461.0 mg, 89%). LC/MS calculated for C ₁₂ H ₁₄ BrFNO ₂ (M+HC ₄ H ₈ ) ⁺ : m/z = 302.0; found 302.1.

Step 2. tert-Butyl 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

A screw-capped ampoule equipped with a magnetic stirrer is charged with 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (517.4 mg, 2.037 mmol), potassium acetate (416.8 mg, 4.25 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (210.2 mg, 0.257 mmol). The ampoule is hermetically sealed with a septum with a Teflon liner, evacuated and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl (5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate (461.0 mg, 1.287 mmol) in 1,4-dioxane (6.0 mL) was added via syringe. The mixture was heated to 100 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ and filtered. The filtrate was concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the title product (337.4 mg, 65%). LC/MS calculated for C ₂₂ H ₃₃ BFNNaO ₄ (M+Na) ⁺ : m/z = 428.2; found 428.2.

Step 3. 6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyrudin-3-yl)-1H-pyrazolo[3,4-c]pyrudin-5-yl)-1,2,3,4-tetrahydronaphthalene-1-amine.

Tert-butyl 5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (34.0 mg, 0.079 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17 μmol) and cesium carbonate (81.4 mg, 0.250 mmol) are added to a screw-cap ampoule equipped with a magnetic stirrer. The ampoule was sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process was repeated three times in total). A solution of tert-butyl (6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate (28.1 mg, 0.069 mmol) in 1,4-dioxane (2.0 mL) was added via syringe, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was concentrated. CH ₂ Cl ₂ (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₇ H ₃₁ FN ₇ (M+H) ⁺ : m/z = 472.3; found 472.3.

Example 241. 6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)1,2,3,4-tetrahydronaphthalen-1-amine

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Step 1. tert-Butyl-5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

To a mixture of 5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm, 309.5 mg, 1.273 mmol), sodium cyanoborohydride (824.0 mg, 13.11 mmol) and ammonium acetate (2.184 g, 28.3 mmol) was added 2-propanol (10.0 mL). The reaction mixture was stirred at 70 °C for 16 h. After cooling to room temperature, the mixture was diluted with aqueous 2 M K ₂ CO ₃ and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in CH ₂ Cl ₂ (20 mL) and treated with BOC anhydride (425.9 mg, 1.951 mmol). After stirring at room temperature for 30 min, the reaction mixture was concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the desired product as a white solid (316.3 mg, 72%). LC/MS calculated for C11H ₁₂ BrFNO ₂ (M+HC ₄ H ₈ ) ⁺ : m/z = 288.0; found 288.0.

Step 2. tert-Butyl-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalene-1-ylcarbamate

A screw-capped ampoule equipped with a magnetic stirrer is charged with 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (319.0 mg, 1.256 mmol), potassium acetate (272.1 mg, 2.77 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (150.1 mg, 0.184 mmol). The ampoule is hermetically sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl 5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (316.3 mg, 0.919 mmol) in 1,4-dioxane (6.0 mL) was added via syringe. The mixture was heated to 100 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ and filtered. The filtrate was concentrated. The residue was purified on silica gel (40 g, 0-100% ethyl acetate in hexanes) to give the desired product (200.0 mg, 56%). LC/MS calculated for C ₁₇ H ₂₄ BFNO ₄ (M+HC ₄ H ₈ )+: m/z = 336.2; found 336.3.

Step 3. 6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine.

A screw-cap ampoule equipped with a magnetic stirrer is charged with tert-butyl 5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (30.0 mg, 0.070 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17 μmol), and cesium carbonate (72.8 mg, 0.223 mmol). The ampoule is sealed with a septum with a Teflon liner, evacuated, and refilled with nitrogen (this process is repeated three times in total). A solution of tert-butyl (6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (25.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 mL) was added via syringe, followed by water (200.0 μL). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was concentrated. CH2Cl2 (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min and then concentrated. The residue was purified by preparative LC/MS (XBridge C18 column, elution with an acetonitrile/water gradient containing 0.1% TFA at a flow rate of 60 mL/min) to afford the desired product. LC/MS calculated for C ₂₇ H ₃₀ FN ₆ (M+H) ⁺ : m/z = 457.3; found 457.3.

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Example A. HPK1 kinase binding assay.

A stock solution of 1 mM of the test compound is prepared in DMSO. The compound in the Petri dish is prepared by 3-fold and 11-point serial dilutions. 0.1 µl of the compound in DMSO is transferred from the compound in the Petri dish to a white 384-well polystyrene plate. The assay buffer contains 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 is added to the Petri dish. The target enzyme concentration is calculated based on the target concentration of the stock solution specified by the supplier. 5 µl of 18 nM 222 label (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody (ThermoFisher PV5595) are added. After one hour of incubation at 25°C, the plate is read using a PHERAstar FS plate reader (BMG Labtech). Ki values are determined.

The compounds of the present invention given in the examples have Ki values in the following ranges: +=Ki<100 nM; ++=100 nM <Ki<500 nM; +++=500 nM <Ki<2000 nM.

Table 1

Example NRK1 K1, nM Example NRK1 K1, nM 1 + 121 + 2 + 122 + 3 + 123 + 4 + 124 + 5 + 125 + 6 + 126 + 7 + 127 + 8 + 128 + 9 + 129 + 10 + 130 + 11 + 131 + 12 + 132 + 13 + 133 + 14 + 134 + 15 + 135 + 16 + 136 + 17 + 137 + 18 + 138 + 19 + 139 + 20 + 140 + 21 + 141 + 22 + 142 + 23 + 143 + 24 + 144 + 25 + 145 + 26 + 146 +

- 153 048980

- 154 048980

61 + 62 + 63 + 64 + 65 + 66 + 67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 + 80 + 81 + 82 + 83 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 + 93 + 94 +

181 + 182 + 183 + 184 + 185 + 186 + 187 + 188 + 189 + 190 + 191 + 192 + 193 + 194 + 195 + 196 + 197 + 198 + 199 + 200 + 201 + 202 + 203 + 204 + 205 + 206 + 207 + 208 + 209 + 210 + 211 + 212 + 213 + 214 +

- 155 048980

95 + 215 + 96 + 216 + 97 + 217 + 98 + 218 + 99 + 219 + 100 + 220 + 101 + 221 + 102 + 222 + 103 + 223 + 104 + 224 + 105 + 225 + 106 + 226 + 107 + 227 + 108 + 228 + 109 + 229 + 110 + 230 + 111 + 231 + 112 + 232 + 113 + 233 + 114 + 234 + 115 + 235 + 116 + 236 + 117 + 237 + 118 + 238 + 119 + 239 + 120 + 240 + 241 +

Example B. Analysis of p-SLP76S376 HTRF.

One or more compounds of the invention can be tested using the p-SLP76S376 HTRF assay described below. Jurkat cells (cultured in RPMI1640 medium with 10% FBS) are collected and centrifuged, and then redispersed in the appropriate medium at 3x106 cells/mL. Jurkat cells (35 μL) are dispensed into each well of a 384-well plate. Test compounds are diluted in growth medium to achieve a 40-fold dilution (39 μL growth medium is injected into 1 μL of compound). Jurkat cells in a well plate are treated with the test compounds at different concentrations (5 μl of the diluted compound is added to 35 μl of Jurkat cells, starting with 3 μl at a 1:3 dilution) for 1 h at 37°C, 5% CO2), followed by treatment with anti-CD3 (5 μl/ml, clone OKT3) for 30 min. A 1:25 dilution of 100x blocking reagent (from the p-SLP76 ser376HTRF kit) with 4x lysis buffer (LB) is prepared, 15 μl of 4x LB buffer with blocking reagent are added to each well and incubated at room temperature for 45 min with gentle shaking. Cell lysate (16 µl) was added to a white Grenier plate treated with pSLP76 ser376HTRF reagents (2 µl donor, 2 µl acceptor) and incubated at 4°C overnight. Homogeneous time-resolved fluorescence (HTRF) was measured the following day using a PHERAstar plate reader. IC ₅₀ was determined by fitting a curve of percent inhibition to the logarithm of inhibitor concentration using GraphPad Prism 5.0 software.

Example C: Isolation of CD4+ or CD8+ T cells and cytokine measurement.

Blood samples are collected from healthy donors. CD4+ or CD8+ T cells are isolated using negative selection and CD4+ or CD8+ enrichment kits (lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells is determined by flow cytometry and is typically >80%. Cells are cultured in RPMI 1640 supplemented with 10% FBS, glutamine and antibiotics (Invitrogen Life Technologies, USA). For cytokine measurement, Jurkat cells or primary CD4+ or CD8+ T cells are plated at 200,000 cells/well and stimulated for 24 h with anti-CD3/anti-CD28 beads in the presence or absence of the test compounds at various concentrations. Then 16 μl of the supernatants are transferred to a white assay plate and analyzed using kits

- 156 048980 for human IL-2 or IFNy assay (Cisbio).

Example G. Analysis of regulatory T cells.

One or more compounds of the invention can be tested using the regulatory T cell proliferation assay described below. Primary CD4+/CD25- T cells or CD4+/CD25+ regulatory T cells are isolated from human peripheral blood mononuclear cells using Thermo Fisher Scientific isolation kits (11363D). CD4+/CD25- T cells are labeled with CFSE (Thermo Fisher Scientific, C34554) following the protocol provided by the supplier. T cells and CD4+/CD25+ regulatory T cells labeled with CFSE are redispersed at a concentration of 1X106 cells/mL in RPMI-1640 medium. 100 μl of CFSE-labeled T cells were mixed or not mixed with 50 μl of CD4+/CD25+ regulatory T cells treated with 5 μl of anti-CD3/CD28 beads (Thermo Fisher Scientific, 11132D) and various concentrations of compounds diluted in 50 μl of RPMI-1640 medium. Mixed cell populations were cultured for 5 days (37°C, 5% _CO2 ) and CFSE-labeled T cell proliferation was analyzed on day 5 using a BD LSRFortessa X-20 using the FITC channel.

From the foregoing description, various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are also intended to be within the scope of the appended claims. Each reference, including, without limitation, all patents, patent applications, and publications cited in this disclosure, are incorporated herein by reference in their entirety.

Claims (44)

1. Compound of formula I: or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is Cy ¹ ; Cy ¹ is selected from C ₃ . ₁₀ cycloalkyl, 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one cyclic ring-forming carbon atom and 1, 2, 3 or 4 cyclic ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein a cyclic ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein each C ₃ . ₁₀ cycloalkyl, 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ ; Cy ^A is _C6.10aryl optionally substituted _with 1, 2, 3 or 4 substituents independently selected from ^R20 ; R ² is H; each R ¹⁰ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10-membered heterocycloalkyl, C6.10aryl, 5-10-membered heteroaryl, C3_10cycloalkyl-C1.3alkylene, 4-10-membered heterocycloalkyl-C1.3alkylene, C6.10aryl-C1.3alkylene, 5-10-membered heteroaryl-C1.3αalkylene, halogen, CN, NO2, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , C(=NR ^e1 )R ^b1 , C(=NOR ^a1 )R ^b1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O)2R ^b1 , NR ^c1 S(O)2NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O)2R ^b1 and S(O)2NR ^c1 R ^d1 ; wherein each said _C1.6 alkyl, _{C2.6 alkenyl} , _C2 . ₆ alkynyl, _C3.10 cycloalkyl, _4- to 10-membered heterocycloalkyl, _C6.10 aryl, _5- to 10- _membered heteroaryl, _{C3_10} cycloalkyl- _C1.3 alkylene, _4- to 10-membered heterocycloalkyl- _C1.3 alkylene, _{C6.10 aryl} - _{C1.3 alkylene} and 5- to 10 _- membered heteroaryl- _C1.3 alkylene are optionally substituted with 1, 2, 3 or ₄ substituents independently selected from ^R11 ; or two R ¹⁰ substituents, together with the carbon atoms to which they are attached, form a 3- to 7-membered heterocycloalkyl spiro ring or a C ₃ . ₆ cycloalkyl spiro ring; wherein each 3- to 7-membered heterocycloalkyl spiro 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 the ring-forming carbon atom of each 3- to 7-membered heterocycloalkyl spiro ring is optionally substituted with oxo to form a carbonyl group; and wherein each 3- to 7-membered heterocycloalkyl ring and the C ₃ . ₆ cycloalkyl spiro ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ; each R ¹¹ is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ _ ₁₀ cyclo - 157 048980 alkyl-C ₁ . ₃ alkylene, 4-10-membered heterocycloalkyl-C _1-3 alkylene, C ₆ . ₁₀ aryl-C ₁ . ₃ alkylene, 5-10 membered heteroaryl-C1.3 alkylene, halogen, CN, OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O)2R ^b3 , NR ^c3 S(O)2NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O)2R ^b3 and S(O)2NR ^c3 R ^d3 ; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . _10- cycloalkyl, _4-10 -membered heterocycloalkyl, _C6.10aryl , 5-10-membered heteroaryl, _C3.10 - _cycloalkyl - _C1.3alkylene , _4-10 -membered heterocycloalkyl- _C1.3alkylene , _C6.10aryl - _C1.3alkylene and _5-10 -membered heteroaryl- _C1.3alkylene are optionally substituted with 1, 2, ₃ or ₄ substituents independently selected from ^R12 _; each R ¹² is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.6cycloalkyl, C6.10aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halogen, CN, OR ^a5 , SR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , NR ^c5 C(O)OR ^a5 , NR ^c5 S(O)R ^b5 , NR ^c5 S(O)2R ^b5 , NR ^c5 S(O)2NR ^c5 R ^d5 , S(O)R ^b5 , S(O)NR ^c5 R ^d5 , S(O)2R ^b5 and S(O)2NR ^c5 R ^d5 ; wherein each said _C1.6 alkyl, _{C2.6αalkenyl} , _C2.6alkynyl , _{C3.6cycloalkyl} , _C6-10 aryl, 5-10-membered heteroaryl and 4-7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ²⁰ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10-membered heterocycloalkyl, C6.10aryl, 5-10-membered heteroaryl, C3_10cycloalkyl-C1.3alkylene, 4-10-membered heterocycloalkyl-C1.3alkylene, C6.10aryl-C1.3alkylene, 5-10-membered heteroaryl-C1.3αalkylene, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , C(=NR ^e2 )R ^b2 , C(=NOR ^a2 )R ^b2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; and each specified C1. ₆ αlkyl, C ₂ . ₆ alkenyl, C ₂ .6αalkenyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C _{6- 10} aryl, 5- to 10-membered heteroaryl, C ₃ . ₁₀ cycloalkyl-C ₁ . ₃ alkylene, 4- to 10-membered heterocycloalkyl-C ₁ . ₃ alkylene, C ₆ . ₁₀ aryl-C ₁ . ₃ alkylene and 5- to 10-membered heteroaryl-C ₁ . ₃ alkylene are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on the Cy ^A ring, together with the atoms to which they are attached, form a C ₃ . ₇ cycloalkyl fused ring; wherein the ring-forming carbon atom of the C ₃ . ₇ cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein the C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ; each R ²¹ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10-membered heterocycloalkyl, C6.10aryl, 5-10-membered heteroaryl, C3_10cycloalkyl-C1.3alkylene, 4-10-membered heterocycloalkyl-C1.3alkylene, C6.10aryl-C1.3alkylene, 5-10-membered heteroaryl-C1.3αalkylene, halogen, CN, OR ^a4 , SR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 , NR ^c4 C(O)OR ^a4 , NR ^c4 S(O)R ^b4 , NR ^c4 S(O)2R ^b4 , NR ^c4 S(O)2NR ^c4 R ^d4 , S(O) ^RM , S(O)NR ^c4 R ^d4 , S(O)2R ^b4 and S(O)2NR ^c4 R ^d4 ; wherein each said _C1.6 alkyl, _C2.6 alkenyl, _C2.6 alkynyl, _C3.10 cycloalkyl, _4- to 10-membered heterocycloalkyl, _C6-10 aryl, _5- to 10-membered heteroaryl, _C3.10 cycloalkyl- _C1.3 alkylene, _4- to 10-membered heterocycloalkyl- _{C1.3 αalkylene, C6.10 aryl - C1} . ₃ alkylene and 5-10 membered heteroaryl-C ₁ . ₃ alkylene optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ; or two R ²¹ substituents together with the carbon atom to which they are attached form a C ₃ . ₇ cycloalkyl spiro ring; wherein the ring-forming carbon atom of the C ₃ . ₇ cycloalkyl spiro ring is optionally substituted with oxo to form a carbonyl group; and wherein the C ₃ _ ₇ cycloalkyl spiro ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ; each R ²² is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.6cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halogen, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)OR ^a6 , NR ^c6 S(O)R ^b6 , NR ^c6 S(O)2R ^b6 , NR ^c6 S(O)2NR ^c6 R ^d6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O)2R ^b6 and S(O)2NR ^c6 R ^d6 ; wherein each said _C1.6 αalkyl, _{C2.6 alkenyl} , _C2.6 αalkylyl, _C3.6 cycloalkyl, phenyl, _{5- to} 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; or any R ^c1 and R ^d1 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; each R ^b1 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl, and 5- to 10-membered heteroaryl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl, and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents, independently - 158 048980 mo selected from R ¹¹ ; each R ^e1 is independently selected from H, CN, _{C1.6 alkyl} , _C1.6 haloalkyl, _C1.6 αalkylthio, _C1.6 alkylsulfonyl, _C1.6 alkylcarbonyl, _C1.6 alkylaminosulfonyl, carbamyl, _{C1.6 alkylcarbamyl , di} ( _{C1_6} alkyl) _carbamyl , aminosulfonyl, _C1.6 alkylaminosulfonyl, _and di _{( C1_6 alkyl )} aminosulfonyl _; each R ^a 2, R ^c 2 and R ^d 2 is independently _selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ^ralogenalkyl, C _3-10 cycloalkyl, _4-10 membered _{heterocycloalkyl} , C _{6-10 aryl} and 5-10 membered heteroaryl; _wherein each said C _1-6 alkyl, C _2-6 alkenyl, C _{2-6 alkynyl} , C _3-10 cycloalkyl, _4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, ₃ or 4 substituents independently selected from R ²¹ ; or any R ^c2 and R ^d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; each R ^b2 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; each R ^e2 is independently selected from H, CN, C _{1_6} alkyl, C _{1_6} haloalkyl, _{C 1_6 alkylthio} , C _{1_6} alkylsulfonyl, C _{1_6} alkylcarbonyl, C _{1_6} alkylaminosulfonyl, carbamyl, _{C 1_6 alkylcarbamyl} , di(C _{1_6 alkyl} )carbamyl, aminosulfonyl, C _{1_6 alkylaminosulfonyl} , and _{di(C 1_6 alkyl ) aminosulfonyl ;} each R ^a3 , R ^c3 and R ^d3 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, O ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; or any R ^c3 and R ^d3 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ¹² ; each R ^b3 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ _ ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ; each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ; or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ²² ; each R ^b4 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C _3-6 cycloalkyl, phenyl, 5-6-membered heteroaryl and 4-7-membered heterocycloalkyl; wherein each said C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, O ₃ . ₆ cycloalkyl, phenyl, 5-6-membered heteroaryl and 4-7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ; each R ^a5 , R ^c5 and R ^d5 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^b5 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl and C ₁ _ ₆ haloalkyl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ _ ₆ αalkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^a6 , R ^c6 and R ^d6 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ _ ₆ alkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^b6 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ αalkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^g is independently selected from OH, NO2, CN, halogen, _C1.6 alkyl, _C2.6 alkenyl, _C2.6 alkynyl, _C1.6 haloalkyl, _C3.6 cycloalkyl, _C3.6 cycloalkyl- _{C1.2 alkylene} , _C1.6 alkoxy, _C1.6 haloalkoxy, _{C1.3 α- alkoxy} - _{C1_3 alkyl, C1.3 alkoxy-C1_3 alkoxy , HO - C1_3 α - alkoxy ,} HO _{- C1_3 alkyl} , _{cyano - C1.3 alkyl} , _{H2NC1 . 3} αalkyl, amino, C ₁ . ₆ αalkylamino, di(C ₁ _ ₆ αalkyl)amino, thio, C ₁ . ₆ alkylthio, C ₁ . ₆ alkylsulfinyl, C ₁ . ₆ αl - 159 048980 alkylsulfonyl, carbamyl, _C1-6 alkylcarbamyl, di(C _1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C _1-6 alkyloxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamino, aminosulfonyl, _C1-6 alkylaminosulfonyl, di(C _1-6 alkyl)aminosulfonyl, aminosulfonylamino, _C1-6 alkylaminosulfonylamino, di(C _1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino, wherein said heteroaryl groups contain carbon atoms and 1 to 4 heteroatoms, independently selected from N, O and S, and said heterocycloalkyl groups contain carbon atoms and 1-4 heteroatoms independently selected from N, O and S; and wherein the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group may be oxidized to form carbonyl, N-oxide or sulfonyl groups. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that Cy ^A is phenyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²⁰ . 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R ²⁰ is independently selected from C1-6 alkyl, C2-6 α alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl, 5-10 membered heteroaryl, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; wherein each said C1-6αalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkyl- _{C1-3αalkylene} , _{C6.10 aryl} and 5-10-membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from ^R21 ; or two adjacent R ²⁰ substituents on the Cy ^A ring, together with the atoms to which they are attached, form a C _3-7 cycloalkyl fused ring; wherein the ring-forming carbon atom of each C _3-7 cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein each C _3-7 cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ . 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R ²⁰ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; wherein each said C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, _4-10 membered heterocycloalkyl, _C6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on the ^C3A ring, together with the atoms to which they are attached, form a _C3-7 cycloalkyl fused ring; wherein the ring-forming carbon atom of each _{C3-7cycloalkyl} fused ring is optionally substituted with oxo to form a carbonyl group; and wherein each _{C3-7cycloalkyl} fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from _{R21 .} 5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R ²⁰ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl, 5-10 membered heteroaryl, halogen, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 and NR ^c2 C(O)NR ^c2 R ^d2 ; wherein each said C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, _4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl- _C1-3 alkylene, _C6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on the Cy ^A ring, together with the atoms to which they are attached, form a _C3-7 cycloalkyl fused ring; wherein the ring-forming carbon atom of each _C3-7 cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein each _{C3-7cycloalkyl} fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from ^R21 . 6. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that each R ²⁰ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halogen, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 and NR ^c2 C(O)OR ^a2 ; wherein each said C1-6alkyl, _C2-6alkenyl , _C2-6alkynyl , _{C3-10cycloalkyl} , _4-10membered heterocycloalkyl, _C6-10aryl and 5-10membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from ^R21 ; or two adjacent ^R20 substituents on the ^CyA ring, together with the atoms to which they are attached, form a _{C3-7cycloalkyl} fused ring; wherein the ring-forming carbon atom of each _{C3-7cycloalkyl} fused ring is optionally substituted with oxo to form a carbonyl group; and wherein each _{C3-7cycloalkyl} fused ring is optionally substituted with - 160 048980 but with 1, 2, 3 or 4 substituents independently selected from R ²¹ . 7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R ²⁰ is independently selected from C1.6αalkyl, C1.6haloalkyl, C3.10cycloalkyl, halogen, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkyl-C1.3alkylene, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 and NR ^c2 C(O)NR ^c2 R ^d2 ; wherein each said O^alkyl, C3. ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl and 4- to 10-membered heterocycloalkylC ₁ . ₃ αalkylene are optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on the Cy ^A ring, together with the atoms to which they are attached, form a C ₃ _ ₇ cycloalkyl fused ring; and wherein each C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ . 8. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R ²⁰ is independently selected from C alkyl, C 1.6 haloalkyl, C 3.10 cycloalkyl, halogen and OR ^a2 ; wherein each said C alkyl and C 3_ ₁₀ cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents in a C _{3_ 7} cycloalkyl ring, together with the atoms to which they are attached, form a C 3_ 7 cycloalkyl fused ring; and wherein each C _{3_ 7} cycloalkyl fused ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ . 9. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that each R ²⁰ is independently selected from methyl, trifluoromethyl, cyclopropyl substituted with methanamine, fluorine, chlorine, hydroxy, methoxy, ethoxy, C(O)NH(CH ₂ ) ₂ OCH ₃ , CO-(3-methoxyazetidin-1-yl), NHC(O)cyclobutyl, NHC(O)-benzyl, methylamino, dimethylamino, NHC(O)CH ₂ -(pyrrolidin-1-yl), NHC(O)-(1methyl-1H-pyrazol-4-yl), NH(CO)CH ₂ -(cyclopentyl), NHC(O)CH ₂ -(pyridin-3-yl), NHC(O)CH ₂ -(7-azabicyclo[2.2.1]heptan-7-yl), NHC(O)-(7-oxa-2-azaspiro[3.5]nonan-2-yl), NHC(O)CH (CH ₃ )(pyrrolidin-1-yl), NHC(O)NH(CH ₂ ) ₂ OCH ₃ , NHC(O)CH ₂ -(azetidin-1-yl), NHC(O)Ch ₂ -(3,3-dimethylazetidin-1-yl), NHC(O)O-(1-methylpiperidin-4-yl), NHC(O)CH ₂ -(dimethylamino), NHC(O)CH ₂ ((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl), NHc(O)(CH ₂ ) ₂ -(dimethylamino), NHC(O)CH ₂ CN, (methylamino)methyl, azetidin-1-ylmethyl, CH ₂ NH-(tetrahydro-2H-pyran-4-yl), (isopropylamino)methyl, cyclobutyl-NHCH(CH ₃ ) ₂ , (methylamino)ethyl, (CH ₂ ) ₂ NH-(tetrahydro-2H-pyran-4-yl), (CH ₂ ) ₂ NH-(1-isopropylazetidin-3-yl), OCH ₂ -(azetidin-2-yl), tetrahydro-2H-pyran-4-yloxy, OCH ₂ -(pyridin-4-yl), OC(O)N (CH ₃ ) ₂ , OC(O)-(morpholin-4-yl), CH ₂ NH-(pyridin-5-yl), CH ₂ NH-(1-methyl-1H-pyrazol-3-yl), CH ₂ NH(CH ₂ ) ₂ OH, CH ₂ NH-cyclopropyl, (3-methoxypiperidin-1-yl)methyl, (ethylamino)methyl, pyrrolidin-1-ylmethyl, 3-methoxyazetidin-1-ylmethyl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl, CH ₂ NHCH ₂ CF ₃ , CH ₂ NH-(3-cyclobutan-1-ol), (1-pyrrolidin-3-ol)methyl, CH ₂ NHCH ₂ C(CH ₃ ) ₂ OH, CH ₂ NHCH ₂ -( 1 -methyl-1 H-imidazol-4-yl), CH ₂ NHCH ₂ -(oxazol-4-yl), CH2NHCH2CN, CH(CH3)NH(CH3), CH2NHC(O)CH3, CHNHC(O)O(CH3), difluoromethoxy, cyanomethyl, aminomethyl, (hydroxyl)methyl, amino, _CH2 (3,3-dimethylazetidin-1-yl), _CH2NH- (3methoxycyclobutyl), _CH2NHCH2- ( ₁ -methylcyclopropyl) and morpholinyl. 10. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that each R ²⁰ is independently selected from methyl, trifluoromethyl, cyclopropyl substituted with methanamine, fluorine, chlorine, hydroxy, methoxy and ethoxy. 11. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that each R ²⁰ is independently selected from methoxy or fluorine. 12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, characterized in that Cy ^A is selected from 2-fluoro-6-methoxyphenyl, 1-[1-(3-fluoro-5-phenyl)cyclopropyl]methanamine, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2,4,6-trifluorophenyl, 2-chloro-6-fluorophenyl, 1-hydroxy-3,5-difluorophen-4-yl, 2-fluoro-6-methylphenyl, 2-ethoxy-6-fluorophenyl, 2-chloro-6-methoxyphenyl and 2-fluoro-6-(trifluoromethyl)phenyl. 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Cy ¹ is selected from 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein a ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein each 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ . 14. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Cy ¹ is thiazolyl, isoxazolyl, piperazinonyl, 1,2,3,4-tetrahydroisoquinolyl, piperazinyl, phenyl, pyrazolyl, pyridinyl, imidazolyl or pyrimidinyl; each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ . 15. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, characterized in that Cy ¹ is thiazolyl, isoxazolyl, piperazinonyl, 1,2,3,4-tetrahydroiso - 161 048980 quinolyl, piperazinyl or phenyl; each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ . 16. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, characterized in that R ¹⁰ is independently selected from C1.6αalkyl, C2.6alkenyl, C2.6alkynyl, C1. 6haloalkyl, C3.10cycloalkyl, 4-10-membered heterocycloalkyl, C6.10aryl, 5-10-membered heteroaryl, halogen, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O)2R ^b1 , NR ^c1 S(O)2NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O)2R ^b1 and S(O)2NR ^c1 R ^d1 ; wherein each said _C1.6 alkyl, _C2.6 alkenyl, _C2.6 alkynyl, _{C3.10 cycloalkyl} , _4-10 membered heterocycloalkyl, _{C6.10 aryl} and 5-10 membered heteroaryl is optionally substituted _with 1, 2, 3 or 4 substituents independently selected from ^R11 . 17. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C 1 ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5- to 10-membered heteroaryl, halogen, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , NR ^c1 R ^d1 and NR ^c1 C(O)R ^b1 ; wherein each of the said C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ . 18. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁰ is independently selected from C1.6 alkylα, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a1 , C(O)NR ^c1 R ^d1 and NR ^c1 R ^d1 ; wherein each said _C1.6 alkyl, _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl, _{C6.10 aryl} and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ¹¹ . 19. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁰ is independently selected from C1.6 alkylα, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN and OR ^a1 ; wherein each said _C1.6 alkyl, _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl, _{C6.10 aryl} and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ¹¹ . 20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein each R ¹¹ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10-membered heterocycloalkyl, C6.10aryl, 5-10-membered heteroaryl, C3.10cycloalkyl-C1.3αalkylene, 4-10-membered heterocycloalkyl-C1.3alkylene, C6.10aryl-C1.3alkylene, 5-10-membered heteroaryl-C1.3alkylene, halogen, CN, OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 and NR ^c3 C(O)OR ^a3 ; wherein each said _C1.6 alkyl, _{C2.6 αalkenyl} , _C2.6 alkynyl, _C3.10 cycloalkyl, _4- to ₁₀ -membered heterocycloalkyl, C6.10 aryl, _5- to 10-membered _{heteroaryl, C3.10 cycloalkyl} - _C1.3 alkylene, _4- to 10-membered heterocycloalkyl- _{C1.3 alkylene} , _C6.10 aryl- _{C1.3 alkylene} and _5- to ₁₀ -membered heteroaryl- _C1 . ₃ alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² . 21. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein each R ¹¹ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10-membered heterocycloalkyl, C6.10aryl, _5-10 -membered heteroaryl, halogen, CN, OR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 and NR ^c3 C(O)R ^b3 ; _wherein each said _C1.6αalkyl , _C2.6alkenyl , _C2.6alkynyl , _C3 . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² . 22. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein each R ¹¹ is independently selected from C1.6αalkyl, C6.10aryl, 5-10-membered heteroaryl, halogen, CN, OR ^a3 , C(O)OR ^a3 ; wherein each said _C1.6 alkyl, _{C6.10 aryl} and 5-10-membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ¹² . 23. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁰ is independently selected from methyl, bromine, fluorine, CN, ethyl, methoxy, 4-morpholinyl, 3-oxopiperazin-1-yl, 4-methylpiperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl, 4-ethylpiperazin-1-yl, 3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, piperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-cyclopropyl-3-oxopiperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, 4-bromophenyl, 4-cyanophenyl, 4-pyridyl, methylaminocarbonyl, isopropylaminocarbonyl, 3-hydroxypyrrolidin-1-yl, 3-methoxypiperidin-1-yl, 1-methylpiperidin-4-yl, ethylmethylamino, cyclopropyl, ethyl, 2-cyanophenyl, tetrahydro-2H-pyran-4-yl, azetidin-3-yl, hydroxyethyl, 4-methoxypiperidin-1-yl, 3-fluoropyrrolidin-1-yl, 4-methylcarbonylpiperazin-1-yl and 4-hydroxypiperidin-1-yl, 4-methoxycarbonylpiperazin-1-yl, amino, 2-hydroxypropylamino, (1-methyl-1H-pyrazol-5-yl)methylamino and 3-cyanocyclopentylamino. 24. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, characterized in that each R ¹⁰ is independently selected from methyl, bromine, fluorine, CN, ethyl, methoxy, 4 - 162 048980 morpholinyl, 3-oxopiperazin-1-yl, 4-methylpiperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl, 4-ethylpiperazin-1-yl, 3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, piperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-cyclopropyl-3-oxopiperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, 4-bromophenyl, 4-cyanophenyl and 4-pyridyl. 25. A compound according to claim 1, having formula IV: (IV) , where n is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 26. The compound according to claim 1, having the formula Va1: (Val) , where n is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 25 or 26 or a pharmaceutically acceptable salt thereof, characterized in that n is 3. 28. The compound according to claim 25 or 26 or a pharmaceutically acceptable salt thereof, characterized in that n is 2. 29. The compound according to claim 25 or 26 or a pharmaceutically acceptable salt thereof, characterized in that each R ²⁰ , independently, is fluorine, methyl, trifluoromethyl, CH ₂ NHCH ₃ , CH ₂ NH(isopropyl), CH ₂ -azetidinyl, CH ₂ NH(CH ₂ )CH ₃ or CH(CH ₃ )(NHCH ₃ ). 30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is Cy ¹ ; Cy ¹ is selected from C _3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C _6-10 aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein the ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein each _C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, _C6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R10 ; Cy ^A is C _6-10 aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²⁰ ; R ² is H; each R ¹⁰ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 6-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halogen, CN, NO2, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , C(=NR ^e1 )R ^b1 , C(=NOR ^a1 )R ^b1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O)2R ^b1 , NR ^c1 S(O)2NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O)2R ^b1 and S(O)2NR ^c1 R ^d1 ; wherein each said C2-6alkenyl, _C2-6alkynyl , _{C3-10cycloalkyl} , 4-10-membered heterocycloalkyl, _C6-10aryl , 5-10-membered heteroaryl, _{C3-10cycloalkylC1-3alkylene} , 6-10-membered heterocycloalkyl- _C1-3alkylene , _C6-10aryl - _C1-3alkylene and 5-10-membered heteroaryl- _C1-3alkylene is optionally substituted with 1, ₂ , 3 or 4 substituents independently selected from ^R11 ; or two R ¹⁰ substituents, together with the carbon atoms to which they are attached, form a 3-7 membered heterocycloalkyl spiro ring or a C _3-6 cycloalkyl spiro ring; wherein each 3-7 membered heterocycloalkyl spiro 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 the ring-forming carbon atom of each 3-7 membered heterocycloalkyl spiro ring is optionally substituted with oxo to form a carbonyl group; and wherein each 3-7 membered heterocycloalkyl ring and C _3-6 cycloalkyl spiro ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ; each R ¹¹ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl ... - 163 048980 cycloalkyl-C1-3 alkylene, 4- to 10-membered heterocycloalkyl- _C1-3 alkylene, C6-10-aryl- _C1-3 alkylene, 5- to 10-membered heteroaryl- _C1-3 alkylene, halogen, CN, OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O)2R ^b3 , NR ^c3 S(O)2NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O)2R ^b3 and S(O)2NR ^c3 R ^d3 ; wherein each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl-C _1-3 alkylene, 4-10 membered heterocycloalkyl-C _1-3 alkylene, _{C 6_10} aryl-C _{1_3} alkylene and 5-10 membered heteroaryl-C _1-3 alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² _; each R ¹² is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halogen, CN, OR ^a5 , SR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , NR ^c5 C(O)OR ^a5 , NR ^c5 S(O)R ^b5 , NR ^c5 S(O)2R ^b5 , NR ^c5 S(O)2NR ^c5 R ^d5 , S(O)R ^b5 , S(O)NR ^c5 R ^d5 , S(O)2R ^b5 and S(O)2NR ^c5 R ^d5 ; wherein each said C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, _C6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ²⁰ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3_10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3_10 cycloalkyl-C1_3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6_10 aryl-C1_3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , C(=NR ^e2 )R ^b2 , C(=NOR ^a2 ) R ^b2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; wherein each said C1-6alkyl, _C2-6alkenyl , _C2-6alkynyl , C3-10cycloalkyl, _4-10 -membered heterocycloalkyl, _C6-10aryl , 5-10-membered heteroaryl, _{C3.10cycloalkyl} - _C1.3alkylene , _4-10 -membered heterocycloalkyl- _C1-3alkylene , _{C6_10aryl} - _{C1_3alkylene} and _{5-10 -} membered heteroaryl- _C1-3alkylene is optionally substituted with ₁ , 2, ₃ or 4 substituents independently selected from ^R21 ; or two adjacent R ²⁰ substituents on the Cy ^A ring, together with the atoms to which they are attached, form a C _3-7 cycloalkyl fused ring; wherein the ring-forming carbon atom of the C _3-7 cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein the C _3-7 cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ; each R ²¹ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, 5-10 membered heteroaryl-C2-alkylene, halogen, CN, OR ^a4 , SR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 , NR ^c4 C(O)OR ^a4 , NR ^c4 S(O)R ^b4 , NR ^c4 S(O)2R ^b4 , NR ^c4 S(O)2NR ^c4 R ^d4 , S(O)RM ^M , S(O)NR ^c4 R ^d4 , S(O)2R ^b4 and S(O)2NR ^c4 R ^d4 ; wherein each said C1-6alkyl, _C2-6alkenyl , _C2-6alkynyl , C3-10cycloalkyl, _4-10 -membered heterocycloalkyl, C6-10aryl, 5-10-membered heteroaryl, _{C3_10cycloalkyl} - _{C1_3alkylene} , _{4-10 -} membered heterocycloalkyl- _C1-3alkylene , _{C6_10aryl} - _{C1_3alkylene} and 5-10 _- membered heteroaryl- _C1-3alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected ^from _{R22 ;} or two R ²¹ substituents together with the carbon atom to which they are attached form a C _3-7 cycloalkyl spiro ring; wherein the ring-forming carbon atom of the C _3-7 cycloalkyl spiro ring is optionally substituted with oxo to form a carbonyl group; and wherein the C _3-7 cycloalkyl spiro ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ; each R ²² is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halogen, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 , NR ^c6 C(O)OR ^a6 , NR ^c6 S(O)R ^b6 , NR ^c6 S(O)2R ^b6 , NR ^c6 S(O)2NR ^c6 R ^d6 , S(O)R ^b6 , S(O)NR ^c6 R ^d6 , S(O)2R ^b6 and S(O)2NR ^c6 R ^d6 ; wherein each said C1-6alkyl, _C2-6alkenyl , _C2-6alkynyl , _{C3-6cycloalkyl} , phenyl, 5-6-membered heteroaryl and 4-7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1_ ₆ haloalkyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl; wherein each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3_ 10} cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; or any R ^c1 and R ^d1 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; each R ^b1 is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, _4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl; wherein each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents, independently - 164 048980 mo selected from R ¹¹ ; each R ^e1 is independently selected _from H, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, C _1-6 alkylaminosulfonyl, carbamyl, C _1-6 alkylcarbamyl, _{di(C 1-6 alkyl} )carbamyl, aminosulfonyl, C _1-6 alkylaminosulfonyl, and di(C _1-6 alkyl)aminosulfonyl _; each R ^a 2, R ^c 2 and R ^d 2 is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1.6 haloalkyl} , C _3.10 cycloalkyl, _4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl; wherein each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; or any R ^c2 and R ^d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; each R ^b2 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; each R ^e2 is independently selected from H, CN, C _{1_6} alkyl, C _{1_6} haloalkyl, _{C 1_6 alkylthio} , C _{1_6} alkylsulfonyl, C _{1_6} alkylcarbonyl, C _{1_6} alkylaminosulfonyl, carbamyl, _{C 1_6 alkylcarbamyl} , di(C _{1_6 alkyl} )carbamyl, aminosulfonyl, C _{1_6 alkylaminosulfonyl} , and _{di(C 1_6 alkyl ) aminosulfonyl ;} each R ^a3 , R ^c3 and R ^d3 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; or any R ^c3 and R ^d3 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ¹² ; each R ^b3 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ _ ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ; each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, O ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ; or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ²² ; each R ^b4 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, O ₃ . ₆ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ; each R ^a5 , R ^c5 and R ^d5 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ αalkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl and C ₂ . ₆ alkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^b5 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl and C ₁ _ ₆ haloalkyl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ _ ₆ αalkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^a6 , R ^c6 and R ^d6 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ _ ₆ alkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^b6 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ αalkynyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^g is independently selected from OH, NO2, CN, halogen, _C1.6 alkyl, _C2.6 alkenyl, _C2.6 alkynyl, _C1.6 haloalkyl, _C3.6 cycloalkyl _{, C3.6 cycloalkyl} - _C1.2 alkylene, _C1.6 alkoxy, _C1.6 haloalkoxy, _{C1.3 αalkoxy} - _{C1_3} alkyl, _{C1.3 alkoxy - C1_3} alkoxy, _{HO - C1_3 αalkoxy} , _{HO - C1_3 alkyl} , _{cyano - C1.3 alkyl , H2NC1 . 3} αalkyl,amino, C ₁ . ₆ αalkylamino, di(C ₁ _ ₆ alkyl)amino, thio, C ₁ . ₆ alkylthio, C ₁ . ₆ alkylsulfinyl, C ₁ . ₆ al - 165 048980 alkylsulfonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di(C ₁ . ₆ alkyl)carbamyl, carboxy, C1-alkylcarbonyl, C1-balkoxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamino, aminosulfonyl, C ₁ . ₆ alkylaminosulfonyl, di(C _1-6 alkyl)aminosulfonyl, aminosulfonylamino, C ₁ . ₆ alkylaminosulfonylamino, di(C _1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino. 31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is Cy ¹ ; Cy ¹ is selected from C _{3_10} cycloalkyl, 4-10- _membered heterocycloalkyl, C _6-10 aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein the ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein each C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ ; Cy ^A is C _6-10 aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²⁰ ; R ² is H; each R ¹⁰ is independently selected from C1-6αalkyl, C2-6αalkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, CN, NO2, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 Rd1, NR ^c1 C(O)R ^b1 and NR ^c1 C(O)OR ^a1 ; wherein each said C2-6alkenyl, _C2-6alkynyl , _{C3-10cycloalkyl} , 4-10-membered heterocycloalkyl, _C6-10aryl and 5-10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R11 ; each R ¹¹ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4- to 10-membered heterocycloalkyl, C6.10aryl, 5- to 10-membered heteroaryl, halogen, CN, OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O)2R ^b3 and S(O)2NR ^c3 R ^d3 ; wherein each said C _{1_6 αalkyl} , C _{2.6 alkenyl} , C _2.6 alkynyl, C _3.10 cycloalkyl, _4-10 membered heterocycloalkyl, C _{6.10 aryl} and 5-10 membered heteroaryl is optionally substituted _with 1, 2, 3 or 4 substituents independently selected from R ¹² ; each R ¹² is independently selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, halogen, CN, OR ^a5 , SR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , NR ^c5 C(O)OR ^a5 , NR ^c5 S(O)R ^b5 , NR ^c5 S(O)2R ^b5 , NR ^c5 S(O)2NR ^c5 R ^d5 , S(O)R ^b5 , S(O)NR ^c5 R ^d5 , S(O)2R ^b5 and S(O)2NR ^c5 R ^d5 ; wherein each said _C1.6 alkyl, C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ²⁰ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10 membered heterocycloalkyl, C6.10aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C1.3alkylene, halogen, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 and NR ^c2 C(O)OR ^a2 ; wherein each said C1. ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl-C ₁ . ₃ αalkylene are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on a CyA ring, together with the atoms to which they are attached, form a C ₃ . ₇ cycloalkyl fused ring; wherein the ring-forming carbon atom of the C ₃ . ₇ cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein the C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ; each R ²¹ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10 membered heterocycloalkyl, C6.10aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a4 , SR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 and NR ^c4 C(O)OR ^a4 ; _wherein each said _{C1_ 6} alkyl, C _2.6αalkenyl , C _2.6alkynyl , C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ; each R ²² is independently selected from C1.6 alkyl, C2 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halogen, CN, OR ^a6 , SR ^a6 , C(O)R ^b6 , C(O)NR ^c6 R ^d6 , C(O)OR ^a6 , NR ^c6 R ^d6 , NR ^c6 C(O)R ^b6 and NR ^c6 C(O)OR ^a6 ; wherein each said C1_6αalkyl, _C2.6 alkenyl, _C2.6 alkynyl and _5-6 membered heteroaryl is optionally substituted with 1 substituent independently selected from R ^g ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl and C ₃ . ₁₀ cycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₃ . ₁₀ cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from R ¹¹ ; each R ^b1 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, - 166 048980 _{C3-10 cycloalkyl} , 4-10-membered heterocycloalkyl, C6-10 aryl and 5-10-membered heteroaryl; wherein each said _C1-6 alkyl, _{C2-6 alkenyl} , _C2-6 alkynyl, _C3-10 cycloalkyl, _4-10 -membered heterocycloalkyl, _{C6-10 aryl} and 5-10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R11 ; each R ^a2 , R ^c2 and R ^d2 is independently selected from H, C _{1_6} alkyl, _{C 2_6 αalkenyl} , C _{2_6} alkynyl, C _{1_6} haloalkyl and _4-10 membered heterocycloalkyl; each said _{C 1_6 alkyl} and 4-10 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²¹ _; or any R ^c2 and R ^d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; each R ^b2 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl; wherein each said C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²¹ ; each R ^a3 , R ^c3 and R ^d3 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl and C ₁ . ₆ haloalkyl; each R ^b3 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, and phenyl; each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, phenyl, C ₃ . ₆ cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, phenyl, C ₃ . ₆ cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from R ²² ; or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; each R ^b4 is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, and phenyl; each R ^a5 , R ^c5 and R ^d5 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ αalkenyl and C ₁ _ ₆ haloalkyl; each R ^b5 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, and C ₁ _ ₆ haloalkyl; each R ^a6 , R ^c6 and R ^d6 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ αalkenyl and C ₁ _ ₆ haloalkyl; each R ^b6 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, and C ₁ . ₆ haloalkyl; and each R ^g is independently selected from OH, NO2, CN, halogen, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkyl-C ₁ . ₂ alkylene, C ₁ . ₆ alkoxy, C ₁ . ₆ haloalkoxy, C ₁ . ₃ αlkoxy-C ₁ . ₃ alkyl, C ₁ . ₃ alkoxy-C ₁ . ₃ alkoxy, HO-C ₁ . ₃ αalkoxy, HO-C ₁ . ₃ alkyl, cyano-C ₁ . ₃ alkyl, H2NC ₁ . ₃ αalkyl, amino, C ₁ . ₆ αalkylamino, di(C ₁ . ₆ αalkyl)amino, thio, C ₁ . ₆ alkylthio, C ₁ . ₆ alkylsulfinyl, C ₁ . ₆ alkylsulfonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di(C ₁ _ ₆ alkyl)carbamyl, carboxy, C ₁ _ ₆ αalkylcarbonyl, C ₁ . ₆ αlkoxycarbonyl, C ₁ . ₆ alkylcarbonylamino, C ₁ . ₆ alkylsulfonylamino, aminosulfonyl, _C1-6 alkylaminosulfonyl, di(C ₁ _ ₆ alkyl)aminosulfonyl, aminosulfonylamino, C ₁ . ₆ alkylaminosulfonylamino, di(C ₁ _ ₆ alkyl)aminosulfonylamino, aminocarbonylamino, C ₁ . ₆ alkylaminocarbonylamino and di(C ₁ _ ₆ alkyl)aminocarbonylamino. 32. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is Cy ¹ ; Cy ¹ is selected from 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one cyclic ring-forming carbon atom and 1, 2, 3 or 4 cyclic ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxylenes; wherein a cyclic ring-forming carbon atom in the 5-10-membered heteroaryl or 4-10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein the 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ ; Cy ^A is C ₆ _ ₁₀ aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²⁰ ; R ² is H; each R ¹⁰ is independently selected from C1.6αalkyl, C2.6αalkenyl, C2.6alkynyl, C1.6haloalkyl, C3.10cycloalkyl, 4-10 membered heterocycloalkyl, C6.10aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a1 , C(O)NR ^c1 R ^d1 and NR ^c1 R ^d1 ; wherein each _{said C2.6αalkenyl} , _C2.6alkynyl , _{C3.10cycloalkyl} , _4-10 membered heterocycloalkyl, _C6.10aryl and _5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; each R ¹¹ is independently selected from C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5- to 10-membered heteroaryl, halogen, CN, OR ^a3 , C(O)OR ^a3 , C(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , S(O)2R ^b3 and S(O)2NR ^c3 R ^d3 ; wherein each specified - 167 048980 the defined C _1-6 alkyl, C ₂ .6 alkynyl, C 2 .6 cycloalkyl, _4-10 -membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; each R ¹² is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, halogen, and CN; each R ²⁰ is independently selected from C1-alkyl, C2-alkenyl, C2-alkylynyl, C1-haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C1-3alkylene, halogen, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 and NR ^c2 C(O)NR ^c2 R ^d2 ; wherein each said _C1.6 alkyl, C ₂ . _b alkenyl, C ₂ . _b alkynyl, C ₃ . ₁₀ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ₆ . ₁₀ aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl-C ₁ . ₃ αalkylene are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on the Cy ^A ring, together with the atoms to which they are attached, form a C ₃ . ₇ cycloalkyl fused ring; wherein the ring-forming carbon atom of the C ₃ . ₇ cycloalkyl fused ring is optionally substituted with oxo to form a carbonyl group; and wherein the C ₃ _ ₇ cycloalkyl fused ring is optionally substituted with 1,2,3, or 4 substituents independently selected from R ²¹ ; each R ²¹ is independently selected from C1_alkyl, C2_alkenyl, C2_alkynyl, C1_haloalkyl, C3_cycloalkyl, 4- to 10-membered heterocycloalkyl, C6_aryl, 5- to 10-membered heteroaryl, halogen, CN, OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 and NR ^c4 C(O)OR ^a4 ; wherein each said C1_ _αalkyl , _{C2_alkenyl} , _{C2_alkynyl} and _{C3_cycloalkyl , 4- to} 10-membered heterocycloalkyl, _{C6_aryl} . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²² ; each R ²² is independently selected from C1.alkyl, C2.alkenyl, C2.balkynyl, C1.6haloalkyl, phenyl, 5-6-membered heteroaryl, 4-7 _- membered heterocycloalkyl, halogen, CN, OR ^a6 , NR ^c6 R ^d6 and NR ^c6 C(O)R ^b6 ; wherein each said _C1.6alkyl , _C2.6alkenyl , _C2.6alkynyl and 5-6-membered heteroaryl is optionally substituted with 1 or 2 _substituents independently selected from R ^g ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C ₁ .6 _alkyl and C ₃ _ ₁₀ cycloalkyl; wherein each said C ₁ _ ₆ alkyl and C ₃ _ ₁₀ cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ¹¹ ; each R ^a2 , R ^c2 and R ^d2 is independently selected from H, C _{1 _ 6} alkyl, C ₂ . ₆ α alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl and 4- to 10-membered heterocycloalkyl; wherein each said C ₁ _ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ α alkynyl and 4- to 10-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; or any R ^c2 and R ^d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ²¹ ; each R ^b2 is independently selected from C ₁ _ ₆ alkyl, C ₃ _ ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl; wherein each said C ₁ _ ₆ alkyl, C ₃ _ ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; each R ^a3 , R ^c3 and R ^d3 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ αalkenyl and C ₁ _ ₆ haloalkyl; each R ^b3 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, and phenyl; each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C ₁ . ₆ αalkyl, C ₂ . ₆ αalkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ αalkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ²² ; or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; each Rb ⁴ is independently selected from C ₁ . ₆ alkyl; each R ^a6 is independently selected from H and _{C 1_6 alkyl} ; each R ^c6 and R ^d6 is independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, and C ₁ _ ₆ haloalkyl; each R ^b6 is independently selected from C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, and C ₁ . ₆ haloalkyl; and each R ^g is independently selected from C ₁ . ₆ alkyl. 33. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is Cy ¹ ; Su ¹ is selected from 4-10-membered heterocycloalkyl, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, wherein each 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from - 168 048980 N, O and S; wherein N and S are optionally oxylenes; wherein the ring-forming carbon atom in the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; and wherein the 4- to 10-membered heterocycloalkyl, _C6 . _10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 or 2 substituents independently selected from ^R10 ; Cy A is _C6.10aryl optionally substituted _with 1, 2, 3 or 4 substituents independently selected from ^R20 ; R ² is H; each R ¹⁰ is independently selected from C1.6 alkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a1 , C(O)NR ^c1 R ^d1 and NR ^c1 R ^d1 ; wherein each said _C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, _C6.10 aryl and 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ¹¹ ; each R ¹¹ is independently selected from C1.6αalkyl, C1.6haloalkyl, C6.10aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halogen, CN, OR ^a3 , C(O)OR ^a3 and S(O)2R ^b3 ; wherein each said _{C 1.6 alkyl} , _C6.10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ¹² ; each R ¹² is C ₁ . ₆ alkyl, halogen, or CN; each R ²⁰ is independently selected from C1.6 alkyl, C1.6 haloalkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1.3 alkylene, halogen, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 and NR ^c2 C(O)NR ^c2 R ^d2 ; wherein each said _C1.6 alkyl, _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl and 4-10 membered heterocycloalkyl-C ₁ . ₃ αalkylene is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; or two adjacent R ²⁰ substituents on the Cy A ring, together with the atoms to which they are attached, form a C ₃ . ₇ cycloalkyl fused ring; and wherein the C ₃ . ₇ cycloalkyl fused ring is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; each R ²¹ is C1.6 alkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, C6.10 aryl, 5-10 membered heteroaryl, halogen, CN, OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 and NR ^c4 C(O)OR ^a4 ; wherein each said _C1.6 alkyl, _C3.10 cycloalkyl, _4-10 membered heterocycloalkyl, _{C6.10 aryl} and 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ²² ; each R ²² is independently selected from C1.6 alkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, OR ^a6 and NR ^c6 R ^d6 ; wherein each said _C1.6 alkyl and 5-6 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ^g ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H, C ₁ . ₆ alkyl and C ₃ . ₁₀ cycloalkyl; wherein each said C ₁ . ₆ alkyl and C ₃ . ₁₀ cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ¹¹ ; each R ^a2 , R ^c2 and R ^d2 is independently selected from H, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl and 4- to 10-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl and 4- to 10-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; or any R ^c2 and R ^d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; each R ^b2 is independently selected from C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl; wherein each said C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R ²¹ ; each R ^a3 is independently selected from H and C ₁ . ₆ alkyl; each R ^b3 is C ₁ . ₆ alkyl; each R ^a4 , R ^c4 and R ^d4 is independently selected from H, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl; wherein each said C ₁ . ₆ alkyl, C ₃ . ₆ cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R ²² ; or any R ^c4 and R ^d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; each Rb ⁴ is independently selected from C ₁ . ₆ alkyl; each R ^a6 is independently selected from H and C ₁ . ₆ alkyl; each R ^c6 and R ^d6 is H; and each R ^g is independently selected from C ₁ . ₆ alkyl. 34. The compound according to claim 1, selected from 4-(5-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)thiazol-2-yl)morpholine; 5-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methylisoxazole; 5-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-methylthiazole; 1-(4-bromophenyl)-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)piperazin-2-one; 2-(5-(2-fluoro-6-methoxymethyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7 - 169 048980 carbonitrile; 4-(4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)piperazin-1-yl)benzonitrile; 5-(2-fluoro-6-methoxyphenyl)-3-(4-(pyridin-4-yl)piperazin-1-yl)-1H-pyrazolo[3,4-c]pyridine; 1-[1-(3-fluoro-5-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-c]pyridin-5-yl}phenyl)cyclopropyl]methanamine; 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4c]pyridine; 5-(2,6-difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 5-(2,6-dimethylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-(4-(4-methylpiperazin-1-yl)phenyl)-5-(2,4,6-trifluorophenyl)-1H-pyrazolo[3,4-c]pyridine; 5-(2-chloro-6-trifluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3,5-difluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenol; 5-(2-fluoro-6-methylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 5-(2-chloro-6-(trifluoromethyl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 5-(2-ethoxy-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 5-(2-chloro-6-methoxyphenyl)-3-(4-(4a-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; And 5-(2-fluoro-6-(trifluoromethyl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; or a pharmaceutically acceptable salt thereof. 35. The compound according to claim 1, selected from 3,5-difluoro-N-(2-methoxyethyl)-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)benzamide; (3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)(3-methoxyazetidin-1-yl)methanone; K-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutanecarboxamide; K-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-phenylacetamide; 2,4-difluoro-N-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline; 2,4-difluoro-K,K-dimethyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline; 3,5-difluoro-K,K-dimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyrilin-5-yl)aniline; K-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide; K-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide; 2-cyclopentyl-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide; H-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide; 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)acetamide; K-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(7-oxa-2azaspiro[3.5] nonan-2-yl)acetamide; K-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)propanamide; 1-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-3-(2-methoxyethyl)urea; 2-(azetidin-1-yl)-N-(3-(difluoromethoxy)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridin-5-yl)phenyl)acetamide; K-(3-chloro-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide; K-(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2(pyrrolidin-1-yl)acetamide; 2-(3,3-dimethylazetidin-1-yl)-H-(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide; 1-methylpiperidin-4-yl-3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenylcarbamate; 2-(azetidin-1-yl)-N-(2,3,5-trifluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)acetamide; K-(3-chloro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(dimethylamino)acetamide; 2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyra - 170 048980 zolo[3,4-c]pyridin-5-yl)phenyl)acetamide; N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-nyrazol-4-yl)-1H-nyrazolo[3,4-c]niridin-5-yl)phenyl)-2-(nirrolidin-1-yl)acetamide; 2-(dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-N-pyrazolo[3,4-c]pyridin5-yl)phenyl)acetamide; 2-(7-azabicyclo[2.2.1]hentan-7-yl)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-nirazol-4-yl)-1H-nirazolo[3,4-c]pyridin-5-yl)phenyl)acetamide; 2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide; 3-(dimethylamino)-M-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-III-pyrazolo[3,4-c]pyridin5-yl)phenyl)propanamide; 2-cyano-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-N-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide; Nmethyl-1-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine; Nmethyl-1-(4-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine; N-methyl-1-(3-(3-(1-methyl-1H-pyrazol-4-yl)-III-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)phenyl)methanamine; 5-(3-(azetidin-1 -ylmethyl)-2-(trifluoromethyl)phenyl)-3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4c]pyridine; N-(3-(3-(1 -methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-4-amine; N-(3-(3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)benzyl)propan-2-amine; 1-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine; N-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine; 5-(3-(azetidin-1-ylmethyl)-6-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4c]pyridine; 3-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-isopropylcyclobutanamine; 2-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine; 2-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine; N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenethyl)tetrahydro-2H-pyran-4-amine; N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenethyl)-1-isopropylazetidin-3-amine; 2-fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide; 5-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpicolinamide; 4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-methoxy-N-methylbenzamide; 4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N,2-dimethylbenzamide; 1 -(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-isopropyl-1H-imidazole-4-carboxamide; 1-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methyl-1H-imidazole-4-carboxamide; 5-(4-(azetidin-2-ylmethoxy)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine; 5-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine; 5-(2,6-difluoro-4-(pyridin-4-ylmethoxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine; 3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl dimethylcarbamate; 3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenylmorpholine-4carboxylate; N-methyl-1-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine; N-methyl-1-(4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-(trifluoromethyl)phe - 171 048980 nil)methanamine; 1-(5-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2yl)pyrrolidin-3-ol; 1-(3-fluoro-4-(3-(6-(3-methoxypiperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5 methylphenyl)-N-methylmethanamine; 5-(2-fluoro-6-methoxyphenyl)-3-(6-(1-methylpiperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridine; 1-(3-fluoro-5-methyl-4-(3-(6-morpholinopyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine; N-ethyl-6-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpyridin-2-amine; 1-(3-fluoro-4-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine; 1-(4-(3-(6-cyclopropylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethanamine; 1-(3-fluoro-4-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methyl ethylamine; 1-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine; N(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2amine; N(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)pyridin-2amine; N(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-methyl1H-pyrazol-3-amine; 2-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzylamino)ethanol; 1-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine; N-(2,4-difluoro-3 -(3 -(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2amine; N-(2,4-difluoro-3 -(3 -(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)cyclopropanamine; 5-(2,6-difluoro-3-((3-methoxypiperidin-1-yl)methyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine; 1-(3-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methyl ethylamine; 1-(3-fluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methyl ethylmethanamine; 1-(4-(3-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylphenyl)-N-methylmethanamine; 1-(4-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylphenyl)N-methylmethanamine; 2-(4-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)benzonitrile; 1-(3-fluoro-5-methyl-4-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine; 1-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylcyclopropanamine; 1-(4-fluoro-2-methoxy-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine; N-(4-fluoro-2-methoxy-3-(3 -(1 -methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine; 2-(4-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1yl)benzonitrile; 1-(4-(3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorophenyl)-N-methylmethanamine; 1-(3,5-difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethylamine; 2-(4-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1yl)ethanol; 1-(3,5-difluoro-4-(3-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine; - 172 048980 1-(5-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2yl)piperidin-4-ol; 1-(3,5-difluoro-4-(3-(5-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-N-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethaneamine; 1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-N-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine; 4-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide; 4-(5-(2-fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide; 5-(2-fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine; 5-(2-fluoro-6-methyl-4-(1-methylpyrrolidin-2-yl)phenyl)-3-(1-methyl-III-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine; 5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (enantiomer 1); 5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (enantiomer 2); K-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine; K-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)cyclopropanamine; K-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine; 2,2,2-trifluoro-N-(3-fluoro-5-methyl-4-(3-(1-methyl-N-pyrazol-4-yl)-N-pyrazolo[3,4-c]pyridin-5yl)benzyl)ethanamine; 2-(3-fluoro-5-methyl-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5 -yl)benzylamino)ethanol; 3 -(3-fluoro-5-methyl-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5 -yl)benzylamino)cyclobutanol; 5-(4-(azetidin-1 -ylmethyl)-2-fluoro-6-methylphenyl)-3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4c]pyridine; 1 -(3-fluoro-5-methyl-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5 -yl)benzylamino)2-methylpropan-2-ol; 5-(2-fluoro-4-((3 -methoxyazetidin-1 -yl)methyl)-6-methylphenyl)-3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridine; K-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-III-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-(1methyl-1H-imidazol-4-yl)methanamine; K-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-(oxazol-4-yl)methanamine; 2-(3-fluoro-5-methyl-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5 -yl)benzylamino)acetonitrile; 1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-III-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-Nmethylethanamine; 1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-III-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-Nmethylethanamine; K-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)acetamide; methyl-3-fluoro-5-methyl-4-(3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5 -yl)benzylcarbamate; 1-(4-(6-(5-(2-(difluoromethoxy)-6-fluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3yl)pyridin-3-yl)piperazin-1-yl)ethanone; 2-(3-fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile; (3-fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine; (3-fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanol; 4,6-difluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine; 4,6-difluoro-N-methyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-N-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine; 6,8-difluoro-N-methyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)1,2,3,4-tetrahydronaphthalen-2-amine; - 173 048980 6,8-difluoro-N-methyl-7-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine; 4-(5-(1,3-difluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridin-3yl)-N-methylbenzamide; 5,7-difluoro-N-methyl-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine; 5,7-difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)- 1,2,3,4-tetrahydronaphthalene-1-amine; 4-(5-(4,6-difluoro-3-(methylamino)-2,3-dihydro-1H-inden-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide; 5,7-difluoro-N-methyl-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3dihydro-1H-inden-1-amine; 5-fluoro-7-methoxy-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine; 5-fluoro-7-methoxy-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine; 5-(5-(2-fluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-1-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)N-methyl ethylpicolinamide; 6-fluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine; 6-fluoro-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine; 2-(3,5-difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)acetonitrile; 5,7-difluoro-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1Ninden-1-ol; 5,7-difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol; 1-(3,5-difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-5yl)phenyl)-N-methylmethanamine; 1-(5-(5-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-2yl)piperidin-4-ol; 1-(3,5-difluoro-4-(3-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethylamine; 4-fluoro-N,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro1H-inden-1-amine; 5-(3-((3,3-dimethylazetidin-1 -yl)methyl)-6-fluoro-2-methylphenyl)-3 -(1 -methyl-1 H-pyrazol-4-yl)-1Hpyrazolo[3,4-c]pyridine; trans-N-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)3-methoxycyclobutanamine; N-(4-fluoro-2-methyl-3 -(3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-3,3dimethylcyclobutanamine; N-(4-fluoro-2-methyl-3 -(3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-(1methylcyclopropyl)methanamine; 1-(4-fluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)phenyl)-N-methylethylamine; 5-(2-fluoro-4-(pyrrolidin-2-yl)-6-(trifluoromethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine; 1-(4-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylphenyl)N-methylethanamine; 3-(1-ethyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-1H-pyrazolo[3,4c]pyridine; 3 -(3-fluoro-5-methyl-4-(3 -(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5 -yl)phenyl)morpholine; 1-(3-(difluoromethyl)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethylamine; N-(4-fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine; N-(3-(3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)benzyl)ethanamine; - 174 048980 6-fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)1,2,3,4-tetrahydronaphthalen-1-amine and 6-fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine, or a pharmaceutically acceptable salt thereof. 36. The compound of claim 1, wherein the compound is 5-(3-(azetidin-1-ylmethyl)-6-fluoro-2methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine or a pharmaceutically acceptable salt thereof. 37. The compound of claim 1, wherein the compound is N-(4-fluoro-2-methyl-3-(3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine or a pharmaceutically acceptable salt thereof. 38. The compound of claim 1, wherein the compound is 5-(4-(azetidin-1-ylmethyl)-2-fluoro-6methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine or a pharmaceutically acceptable salt thereof. 39. The compound of claim 1, wherein the compound is N-(3-fluoro-5-methyl-4-(3-(1-methyl-1Hpyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine or a pharmaceutically acceptable salt thereof. 40. A pharmaceutical composition for inhibiting the activity of hematopoietic progenitor kinase 1 (HPK1), comprising a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 41. A method for inhibiting the activity of hematopoietic progenitor kinase 1 (HPK1), said method comprising administering to a patient a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt thereof. 42. A method for treating a disease or disorder associated with inhibition of hematopoietic progenitor kinase 1 (HPK1) interaction, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof. 43. A method of treating cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof. 44. The method according to claim 43, characterized in that the cancer is selected from breast cancer, colon and rectal cancer, lung cancer, ovarian cancer, or pancreatic cancer.