RU2788000C2 - Mkk4 protein kinase inhibitors for stimulation of liver regeneration or reduction or prevention of hepatocyte death - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to pyrazolo-pyridine compounds, namely to a compound of the formula (Ic) or its pharmaceutically acceptable salt or optical isomer. In the formula (Ic), R¹ is H; R^W is -NR¹⁰SO₂R¹²; R^x is F; R^y is F; R⁴ is H; R⁵ is phenyl substituted with 1, 2, or 3 groups independently selected from C₁-C₆ alkyl, hydroxy, halogen, C₁-C₆ halogen alkyl, C₁-C₆ alkyl sulfonyl, C₁-C₆ alkyl-SO(=NR¹⁰)-, C₁-C₆ alkyl sulfonyl-NR¹⁰-, -NR¹⁰R¹⁰, R¹⁰R¹⁰NSO₂-, R¹⁰R¹¹N(C=O)-, C₁-C₆ alkoxy, -OCH₂CH₂O- (ethylenedioxy attached in neighboring positions to a phenyl ring), -NO₂, -COOR¹⁰, R¹⁰R¹⁰N(C=O)-, and tetrazolyl, or R⁵ is pyridyl, pyridyl substituted with -COOR¹⁰, or pyrimidinyl substituted with CF₃; R⁶ is H; R¹⁰, in each case, is independently H or C₁-C₆ alkyl; R¹¹ is alkyl, which is substituted with 1 or 2 hydroxy groups; and R¹² is C₁-C₆ alkyl, phenylC₁-C₆ alkyl, or -NR¹⁰R¹⁰. A compound selected from a group of individual compounds, a pharmaceutical composition, the use of a compound, and a method for selective inhibition of MKK4 protein kinase compared to JNK1 and MKK7 protein kinases or stimulation of liver regeneration or prevention of hepatocyte death are also proposed.

EFFECT: proposed compounds inhibit mitogen-activated protein kinase-kinase 4 (hereinafter – MKK4) and, in particular, selectively inhibit MKK4 compared to JNK1 and MKK7 protein kinases; compounds are useful for stimulation of liver regeneration or reduction or prevention of hepatocyte death.

(Ic)

10 cl, 8 tbl, 97 ex

Description

The present invention relates to pyrazolo-pyridine protein kinase inhibitors which inhibit mitogen-activated protein kinase kinase 4 (MKK4) and in particular selectively inhibit MKK4 over the protein kinases JNK1 and MKK7.

BACKGROUND OF THE INVENTION

Liver disease can be caused by infection, trauma, exposure to toxic compounds such as alcohol or drugs, autoimmune processes, genetic defects, and other factors. The liver has a remarkable regenerative capacity, which, however, may be impaired in a disease state and therefore may not be sufficient to compensate for the loss of hepatocytes and organ function.

WO 2007/002433 describes compounds that are protein kinase inhibitors useful in the treatment of diseases and conditions associated with aberrant activity of protein kinases. These compounds are inhibitors of the Raf protein kinase, in particular B-Raf and c-Raf and their mutations, and are therefore useful in the treatment of malignancies. In addition, they are said to inhibit a wide variety of other protein kinases, among which are the N-terminal c-Jun kinases (JNK) and, in particular, JNK1. WO 2007/002325 contains a similar disclosure, and WO 2012/109075 and WO 2014/194127 disclose modified compounds having Raf protein kinase inhibitory activity. H. Vin et al. refers to two compounds of WO 2007/002433 as B-Raf inhibitors that suppress apoptosis by off-target inhibition of JNK signaling. WO 2010/111527 describes pyrazolo[3,4-b]pyridine compounds which are protein kinase inhibitors useful in the treatment of a Raf protein kinase mediated disease or condition such as cancer. In addition, they are said to inhibit a wide variety of other protein kinases, among which are the N-terminal c-Jun kinases (JNK) and, in particular, JNK1. WO 2012/136859 discloses certain compounds which are described as inhibitors of mitogen-activated protein kinase 4 (MKK4) and which are useful in treating liver failure, in protecting hepatocytes from apoptosis, and in regenerating hepatocytes. Wuestefeld et al. (Cell 153: 389-401, 2013) describe a functional genetic approach to identify target genes that can be used to increase the regenerative capacity of hepatocytes. In particular, Wuestefeld et al. identified the protein kinase MKK4 as a key regulator of liver regeneration and reported that suppression of MKK4 enhances hepatocyte regeneration through compensatory activation of MKK7 and JNK1-dependent activation of ATF2 and ELK1. Based on prior art results, it has been concluded that MKK4 and JNK1 inhibitors may be useful in the treatment of JNK1 mediated diseases. However, despite the recognition that JNK1 inhibition may be beneficial in the treatment of liver disease, no clinical studies have been conducted. WO 2018/134254 discloses pyrrolo-pyridine compounds which are protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death.

SUMMARY OF THE INVENTION

The object underlying the invention was to provide compounds that are useful MKK4 inhibitors, in particular MKK4 inhibitors that selectively inhibit MKK4 over MKK7 and JNK1. Another challenge has been to provide compounds that are MKK4 inhibitors that selectively inhibit MKK4 over MKK7 and JNK1 that are useful in treating liver diseases and especially in promoting liver regeneration or reducing or preventing hepatocyte death.

This problem has been solved by providing a compound of formula (I).

Thus, the invention relates to the following embodiments:

1. Compound having formula (I)

(I)

(I)

and its pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates and stereoisomers,

where the variables in formula (I) have the following meanings:

R ¹ is H, alkyl, or heterocycloalkyl having 4 to 5 ring carbon atoms and 1 or 2 heteroatoms independently selected from O, NH, or N-alkyl;

A is a bond or linking group selected from

CO-,

-S-,

-SO-,

_-SO2- ,

-O-,

-C (=N-NHR ¹⁰ )-,

-CH<,

-NR ¹⁰ -,

alkylene which is optionally substituted with OH or alkoxy,

alkylene-NR ¹⁰ -alkylene,

alkylene-NR ¹⁰ SO ₂ -alkylene,

alkylene-NR ¹⁰ SO ₂ -alkylene,

alkylene-NR ¹⁰ SO ₂ -alkylene,

-CONR ¹⁰ -,

-NR ¹⁰ CO-,

-NR ¹⁰ -SO ₂ -,

-O ₂ S-NR ¹⁰ -,

-CO-alkylene,

alkylene-CO-,

alkylene-NR ¹⁰ CO-,

-OCNR ¹⁰ -alkylene,

alkylene-NR ¹⁰ ,

NR ¹⁰ -alkylene,

alkylene-NR ¹⁰ SO ₂ -,

-SO ₂ NR ¹⁰ -alkylene,

alkylene-CONR ¹⁰ -alkylene,

alkylene-NR ¹⁰ CO-alkylene,

alkylene-NR ¹⁰ CONR ¹⁰ -,

-NR ¹⁰ CONR ¹⁰ -alkylene,

alkylene-NR ¹⁰ CSNR ¹⁰ -,

-NR ¹⁰ CSNR ¹⁰ -alkylene,

alkylene-NR ¹⁰ -alkylene-NR ¹⁰ -,

-NR ¹⁰ -alkylene-NR ¹⁰ -alkylene,

-CO-alkylene-O- and

-O-alkylene-CO-;

Q is an aromatic or heteroaromatic 5- or 6-membered monocyclic or aromatic or heteroaromatic 9- or 10-membered bicyclic group, wherein the heteroaromatic groups have 1, 2, or 3 heteroatoms independently selected from O, N, and S,

where Q is substituted with -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ ;

and optionally substituted with 1, 2 or 3 groups independently selected from

alkyl which is optionally substituted with 1 or 2 substituents independently selected from phenyl, halogenated phenyl, halogen, OH, CN, -NR ¹⁰ R ¹⁰ , cycloalkyl and a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms, independently selected from O, N and S;

halogen;

hydroxy;

alkoxy;

haloalkoxy;

phenyl which is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxyalkyl, alkoxy, halogen, alkylthio and NR ¹⁰ R ¹⁰ ;

-NR ¹⁰ R ¹⁰ ;

-NR ¹⁰ SO ₂ R ¹² ;

-NR ¹⁰ SO ₂ R ¹³ ;

-NR ¹⁰ SO ₂ NHR ¹⁰ ;

-NR ¹⁰ CONR ¹⁰ R ¹⁷ ;

-NR ¹⁰ COR ¹⁸ ;

-NR ¹⁰ COOR ¹⁰ ;

-CO-NR ¹⁰ R ¹⁹ ;

-alkylene-NR ¹⁰ SO ₂ R20;

-SO ₂ R ²¹ ; and

-alkylene-NR ¹⁰ COR ²³ ;

R ⁴ is

h,

halogen,

CN,

_NO2 ,

alkyl,

phenyl which is optionally substituted with 1, 2 or 3 groups independently selected from alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkylsulfonyl, CN and NO ₂ , or

a heteroaromatic or non-aromatic heterocyclic 5- or 6-membered monocyclic or heteroaromatic 9- or 10-membered bicyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is optionally substituted with 1 or 2 groups, independently selected from alkyl, alkoxy, halogen, cycloalkyl and NR ¹⁰ R ¹⁰ ;

R ⁵ is

halogen,

alkyl which is optionally substituted with 1 or 2 groups independently selected from alkoxy, NR ¹⁰ R ¹⁰ , -COOR ¹⁰ and oxadiazolyl,

alkoxy,

alkenyl,

alkynyl,

phenyl or naphthyl which is optionally substituted with 1, 2 or 3 groups independently selected from alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-SO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ -, R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C(=O)-NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N(C=O)-, alkoxy, benzyloxy, haloalkoxy, -OCH ₂ O- (methylenedioxy attached at adjacent positions to the phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring), NO ₂ , -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)-, CN, alkylcarbonyl-NR ¹⁰ -, tetrazolyl, alkenyl, -CONR ¹⁰ -O-alkylene-OH, -CONR ¹⁰ -O-alkylene-O-alkyl and carboxyl-substituted alkenyl, phenylalkenyl, where the phenyl group is optionally substituted with 1, 2 or 3 groups independently selected from OH, alkoxy and -CONR ¹⁰ R ¹⁹ , or

a heteroaromatic or non-aromatic heterocyclic 5- or 6-membered monocyclic or heteroaromatic 9- or 10-membered bicyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is optionally substituted with 1 or 2 groups, independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ , alkylSO(=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH, -CONR ¹⁰ -O-alkylene-O-alkyl, -COOR ¹⁰ , morpholinyl, piperazinyl, oxadiazolyl and phenylcarbonyl;

R ⁶ is H, alkoxy, NR ¹⁰ R ¹⁰ or -NR ¹⁰ -phenyl, where the phenyl group is optionally substituted with NR ¹⁰ R ¹⁰ , alkoxy, morpholinyl, halogen or -SO ₂ morpholinyl;

R ¹⁰ is independently at each occurrence H, alkyl, phenyl which is optionally substituted with hydroxyl or alkoxy, or is phenylalkyl where the phenyl group is optionally substituted with halogen;

R ¹¹ is alkyl which is substituted with 1, 2 or 3 hydroxy groups;

R ¹² is H, alkyl, phenylalkyl, phenyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , heteroalkyl having 1, 2 or 3 heteroatoms independently selected from O, N and S, or is phenyl which is optionally substituted with 1 , 2 or 3 groups independently selected from alkyl, alkoxy, alkoxycarbonyl, haloalkoxy, halogen, haloalkyl, CN, NO ₂ , alkylcarbonylamino, oxazolyl, -OCH ₂ O-(methylenedioxy attached at adjacent positions to the phenyl ring) and -OCH ₂ CH ₂ O- (ethylenedioxy attached in adjacent positions to the phenyl ring),

R ¹³ is a heteroaromatic or non-aromatic heterocyclic 5- or 6-membered group having 1, 2 or 3 heteroatoms independently selected from O, N and S, this group being optionally substituted with 1 or 2 groups independently selected from alkyl, pyridyl, alkoxycarbonyl, oxazolyl and oxazolyl which is substituted by alkyl or alkoxycarbonyl;

R ¹⁴ is alkyl which is substituted with 1 or 2 groups independently selected from

-NR ¹⁰ R ¹⁰ hydroxy or alkoxy;

R ¹⁷ is H,

alkyl,

haloalkyl,

alkoxyalkyl,

cycloalkyl,

a heteroaromatic 5- or 6-membered group having 1, 2 or 3 heteroatoms independently selected from O, N and S, this group being optionally substituted with alkyl or alkoxy,

morpholinoalkyl,

cycloalkylalkyl,

N-benzylpyrrolidinyl,

phenyl which is optionally substituted with alkyl, alkoxy, haloalkyl, -NR ¹⁰ R ¹⁰ or halogen, or

phenylalkyl, where the phenyl group is optionally substituted with alkyl, haloalkyl, or halogen, or

R ¹⁷ and R ¹⁰ together form a cycloalkyl ring which is optionally substituted with an acetylamino group,

R ¹⁸ is alkyl, haloalkyl, phenyl,

morpholinyl or pyrrolidinyl which is optionally substituted with -NR ¹⁰ R ¹⁰ ;

R ¹⁹ is H, alkyl, phenylalkyl, phenyl, phenyl which is substituted with alkoxy, or is alkylene-SO ₂ -alkyl or;

R ²⁰ is phenyl which is optionally substituted with alkyl, phenyl or phenyl which is substituted with alkyl or hydroxyalkyl;

R ²¹ is NR ¹⁰ R ¹⁰ , alkyl or phenyl which is optionally substituted with halogen;

R ²³ is phenyl or phenyl substituted with alkyl which is optionally substituted with piperazinyl or alkyl-substituted piperazinyl;

2. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 1, characterized in that

R ¹ is H, alkyl, or heterocycloalkyl having 4 to 5 ring carbon atoms and 1 or 2 heteroatoms independently selected from O, NH, or N-alkyl;

A is a bond or linking group selected from

CO-,

-CO-CO-,

-S-,

-SO-,

_-SO2- ,

-O-,

-NR ¹⁰ -,

alkylene which is optionally substituted with 1 or 2 groups independently selected from OH and alkoxy,

-CONR ¹⁰ -,

-NR ¹⁰ CO-,

-NR ¹⁰ -SO ₂ - and

-O ₂ S-NR ¹⁰ -;

Q is an aromatic or heteroaromatic 5- or 6-membered monocyclic or 9- or 10-membered bicyclic group,

where Q is substituted with -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ and is optionally substituted with 1, 2 or 3 groups independently selected from

alkyl which is optionally substituted with 1 or 2 substituents independently selected from phenyl, halogenated phenyl and halogen; and

halogen;

R ⁴ is H, halo, or alkyl;

R ⁵ is

halogen,

alkyl which is optionally substituted with 1 or 2 groups independently selected from

alkoxy, NR ¹⁰ R ¹⁰ , -COOR ¹⁰ and oxadiazolyl,

alkenyl,

alkynyl,

phenyl or naphthyl which is optionally substituted with 1, 2 or 3 groups independently selected from

alkyl,

halogen,

haloalkyl,

hydroxy;

hydroxyalkyl,

alkylthio,

alkylsulfonyl,

alkylsulfonyl-NR ¹⁰ -,

alkyl-SO(=NR ¹⁰ )-,

alkylsulfonyl-NR ¹⁰ -,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ NSO ₂ -,

R ¹⁰ R ¹¹ NSO ₂ -,

alkyl-C(=O)-NR ¹⁰ SO ₂ -,

R ¹⁰ R ¹¹ N(C=O)-,

alkoxy,

benzyloxy,

haloalkoxy,

-OCH ₂ O- (methylenedioxy attached in adjacent positions to the phenyl ring),

-OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring),

_NO2 ,

-COOR ¹⁰ ,

-COOR ¹⁴ ,

R ¹⁰ R ¹⁰ N(C=O)-,

CN,

alkylcarbonyl-NR ¹⁰ -,

tetrazolyl,

alkenyl,

-CONR ¹⁰ -O-alkylene-OH,

-CONR ¹⁰ -O-alkylene-O-alkyl, and

carboxyl-substituted alkenyl,

phenylalkenyl, where the phenyl group is optionally substituted with 1, 2 or 3 groups independently selected from OH, alkoxy and -CONR ¹⁰ R ¹⁹ , or

a heteroaromatic or non-aromatic heterocyclic 5- or 6-membered monocyclic or heteroaromatic 9- or 10-membered bicyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is optionally substituted with 1 or 2 groups, independently selected from

alkyl,

haloalkyl,

alkoxy,

-NR ¹⁰ R ¹⁰ ,

halogen,

-NR ¹⁰ -cycloalkyl,

tetrazolyl,

-O-alkylene-NR ¹⁰ R ¹⁰ ,

-NR ¹⁰ -alkylene-O-alkyl,

-CN,

-CONR ¹⁰ R ¹⁰ ,

-COOR ¹⁰ ,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH,

-CONR ¹⁰ -O-alkylene-O-alkyl, and

morpholinyl,

piperazinil,

oxadiazolyl and

phenylcarbonyl;

R ⁶ is H or alkyl;

R ¹⁰ is independently at each occurrence H, alkyl, phenyl which is optionally substituted with hydroxyl or alkoxy, or is phenylalkyl where the phenyl group is optionally substituted with halogen;

R ¹¹ is alkyl which is substituted with 1, 2 or 3 hydroxy groups;

R ¹² is H, alkyl, phenylalkyl or —NR ¹⁰ R ¹⁰ ;

R ¹⁴ is alkyl which is substituted with 1 or 2 groups independently selected from

-NR ¹⁰ R ¹⁰ hydroxy or alkoxy;

R ¹⁹ is H, alkyl, phenylalkyl, phenyl, phenyl which is substituted with alkoxy, or is

alkylene-SO ₂ -alkyl or

3. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers according to embodiment 1 or 2, characterized in that R ¹ is H or heterocycloalkyl having 4 to 5 ring carbon atoms and 1 oxygen heteroatom.

4. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 1 or 2, characterized in that R ¹ is H.

5. A compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 1 or 2, wherein R ¹ is a heterocycloalkyl having 4 to 5 ring carbon atoms and 1 oxygen heteroatom.

6. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers according to any of the preceding embodiments, characterized in that A is a linking group selected from

CO-,

-S-,

-SO-,

_-SO2- ,

alkylene which is optionally substituted with 1 or 2 groups independently selected from OH and alkoxy,

-CONR ¹⁰ - and

-NR ¹⁰ CO-.

7. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to any of the preceding embodiments, wherein Q is phenyl or naphthyl and is substituted and optionally substituted as defined in paragraph 2.

8. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 7, wherein Q is phenyl and is substituted and optionally substituted as defined in paragraph 2.

9. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers according to embodiments 7 or 8, characterized in that Q is phenyl substituted with -NR ¹⁰ SO ₂ R ¹² and further substituted with 1, 2 or 3 groups, independently selected from halogen and alkyl which is optionally substituted with 1 or 2 substituents independently selected from phenyl and halogenated phenyl.

10. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 9, wherein Q is phenyl substituted with -NR ¹⁰ SO ₂ R ¹² and further substituted with 1, 2 or 3 halogen atoms.

11. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 10, characterized in that phenyl is substituted with -NR ¹⁰ SO ₂ R ¹² and is further substituted with 2 or 3 halogen atoms.

12. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 9, 10 or 11, wherein the halogen atom or halogen atoms are F or Cl, in particular F.

13. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any of the preceding embodiments, wherein R ⁴ and R ⁶ are H or alkyl.

14. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 1-13, wherein [3-(5-bromo-1H-pyrazolo[3,4-b])pyridine- Propan-1-sulfonic acid 3-carbonyl)-2,4-difluorophenyl]amide is excluded.

15. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 2-13, wherein R ⁵ is

alkyl which is optionally substituted with 1 or 2 groups independently selected from

alkoxy, NR ¹⁰ R ¹⁰ , -COOR ¹⁰ and oxadiazolyl,

alkenyl,

alkynyl,

phenyl or naphthyl which is optionally substituted with 1, 2 or 3 groups independently selected from

alkyl,

halogen,

haloalkyl,

hydroxy;

hydroxyalkyl,

alkylthio,

alkylsulfonyl,

alkylsulfonyl-NR ¹⁰ -,

alkyl-SO(=NR ¹⁰ )-,

alkylsulfonyl-NR ¹⁰ -,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ NSO ₂ -,

R ¹⁰ R ¹¹ NSO ₂ -,

alkyl-C(=O)-NR ¹⁰ SO ₂ -,

R ¹⁰ R ¹¹ N(C=O)-,

alkoxy,

benzyloxy,

haloalkoxy,

-OCH ₂ O- (methylenedioxy attached in adjacent positions to the phenyl ring),

-OCH ₂ CH ₂ O- (ethylenedioxy attached in adjacent positions to the phenyl ring), NO ₂ ,

-COOR ¹⁰ ,

-COOR ¹⁴ ,

R ¹⁰ R ¹⁰ N(C=O)-,

CN,

alkylcarbonyl-NR ¹⁰ -,

tetrazolyl,

alkenyl,

-CONR ¹⁰ -O-alkylene-OH,

-CONR ¹⁰ -O-alkylene-O-alkyl and

carboxyl-substituted alkenyl,

phenylalkenyl, where the phenyl group is optionally substituted with 1, 2 or 3 groups independently selected from OH, alkoxy and -CONR ¹⁰ R ¹⁹ , or

a heteroaromatic or non-aromatic heterocyclic 5- or 6-membered monocyclic or heteroaromatic 9- or 10-membered bicyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is optionally substituted with 1 or 2 groups, independently selected from

alkyl,

haloalkyl,

alkoxy,

-NR ¹⁰ R ¹⁰ ,

halogen,

-NR ¹⁰ -cycloalkyl,

tetrazolyl,

-O-alkylene-NR ¹⁰ R ¹⁰ ,

-NR ¹⁰ -alkylene-O-alkyl,

-CN,

-CONR ¹⁰ R ¹⁰ ,

-COOR ¹⁰ ,

morpholinyl,

piperazinil,

oxadiazolyl and

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-O-alkyl and

phenylcarbonyl;

16. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers according to any of the previous embodiments, characterized in that R ⁵ is

phenyl or naphthyl which is optionally substituted with 1, 2 or 3 groups independently selected from

alkyl,

halogen,

haloalkyl,

hydroxy;

hydroxyalkyl,

alkylthio,

alkylsulfonyl,

alkylsulfonyl-NR ¹⁰ -,

alkyl-SO(=NR ¹⁰ )-,

alkylsulfonyl-NR ¹⁰ -,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ NSO ₂ -,

R ¹⁰ R ¹¹ NSO ₂ -,

alkyl-C(=O)-NR ¹⁰ SO ₂ -,

R ¹⁰ R ¹¹ N(C=O)-,

alkoxy,

benzyloxy,

haloalkoxy,

-OCH ₂ O- (methylenedioxy attached in adjacent positions to the phenyl ring),

-OCH ₂ CH ₂ O- (ethylenedioxy attached in adjacent positions to the phenyl ring), NO ₂ ,

-COOR ¹⁰ ,

-COOR ¹⁴ ,

R ¹⁰ R ¹⁰ N(C=O)-,

CN,

alkylcarbonyl-NR ¹⁰ -,

tetrazolyl,

alkenyl,

-CONR ¹⁰ -O-alkylene-OH,

-CONR ¹⁰ -O-alkylene-O-alkyl and

carboxyl-substituted alkenyl or

a heteroaromatic or non-aromatic heterocyclic 5- or 6-membered monocyclic or heteroaromatic 9- or 10-membered bicyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is optionally substituted with 1 or 2 groups, independently selected from

alkyl,

haloalkyl,

alkoxy,

-NR ¹⁰ R ¹⁰ ,

halogen,

-NR ¹⁰ -cycloalkyl,

tetrazolyl,

-O-alkylene-NR ¹⁰ R ¹⁰ ,

-NR ¹⁰ -alkylene-O-alkyl,

-CN,

-CONR ¹⁰ R ¹⁰ ,

-COOR ¹⁰ ,

morpholinyl,

piperazinil,

oxadiazolyl and

alkyl-SO(=NR ¹⁰ )-,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH,

-CONR ¹⁰ -O-alkylene-O-alkyl and

phenylcarbonyl;

17. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 16, characterized in that R ⁵ is phenyl or naphthyl, where phenyl or naphthyl is substituted with 1, 2 or 3 groups independently selected from alkyl , hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylSO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ -, R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -OCH ₂ O- (methylenedioxy attached at adjacent positions to the phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy, attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)-, tetrazolyl, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O -alkylene-O-alkyl.

18. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 2-16, characterized in that R ⁵ is a heteroaromatic 5- or 6-membered monocyclic or heteroaromatic 9- or 10-membered bicyclic a group having 1, 2 or 3 heteroatoms independently selected from O, N and S, this group optionally substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ - cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ , -COOR ¹⁰ , alkylSO(=NR ¹⁰ )-, -CONR ¹⁰ -O -alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl.

19. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 18, characterized in that R ⁵ is a heteroaromatic 5- or 6-membered monocyclic group having 1, 2, or 3 heteroatoms, independently selected from the group O, N and S, this group being optionally substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ , -COOR ¹⁰ , alkylSO(=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O- alkylene-O-alkyl.

20. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 19, characterized in that R ⁵ is a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms, independently selected from the group O, N and S, this group being unsubstituted or substituted by 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ and -COOR ¹⁰ .

21. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to Embodiment 20, wherein the heteroaromatic group is unsubstituted or substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, or —COOR ¹⁰ .

22. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 20, characterized in that the heteroaromatic group is pyridyl, pyridyl substituted with -COOR ¹⁰ , pyrimidinyl, or pyrimidinyl substituted with a group selected from CF ₃ , haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN and -CONR ¹⁰ R ¹⁰ .

23. A compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to Embodiment 22, wherein the heteroaromatic group is pyrimidinyl or pyrimidinyl substituted in the 2-position.

24. A compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to Embodiment 22, characterized in that the heteroaromatic group is pyridyl or pyridyl substituted with -COOR ¹⁰ .

25. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any of the preceding embodiments, wherein R ¹⁰ is H or alkyl.

26. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any of the preceding embodiments, wherein R ¹² is alkyl or phenylalkyl.

27. A compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 26, wherein R ¹² is C ₁ -C ₃ alkyl or benzyl.

28. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 2-24 having formula (Ia)

(Ia)

(Ia)

characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ ;

R ^x is H, halogen or alkyl;

R ^y is H, halo or alkyl;

R ^z is H, halo or alkyl;

where one or two of R ^x , R ^y or R ^z are halogen and the other(s) of R ^x , R ^y and R ^z is H, halogen or alkyl;

R ¹ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and R ¹² are as defined in any one of Embodiments 2-27.

29. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 28, characterized in that

R ¹ is H or alkyl;

R ⁴ is H or alkyl;

R ⁶ is H or alkyl;

R ¹⁰ is H, alkyl or phenylalkyl;

R ¹² is H, alkyl or phenylalkyl;

R ^w is -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ ;

R ^x is H, halogen or alkyl;

R ^y is H, halo or alkyl;

R ^z is H, halo or alkyl;

where one or two of R ^x , R ^y or R ^z are halogen and the other(s) of R ^x , R ^y and R ^z is H, halogen or alkyl;

R ⁵ is

phenyl substituted with 1, 2 or 3 groups independently selected from

alkyl,

hydroxy;

halogen,

haloalkyl,

alkylsulfonyl-NR ¹⁰ -,

alkyl-SO(=NR ¹⁰ )-,

alkylsulfonyl-NR ¹⁰ -,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ NSO ₂ -,

R ¹⁰ R ¹¹ NSO ₂ -,

alkyl-C(=O)-NR ¹⁰ SO ₂ -,

R ¹⁰ R ¹¹ N(C=O)-,

alkoxy,

-OCH ₂ O- (methylenedioxy attached in adjacent positions to the phenyl ring),

-OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring),

-NO ₂ ,

-COOR ¹⁰ ,

-COOR ¹⁴ ,

R ¹⁰ R ¹⁰ N(C=O)-,

tetrazolyl,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from

alkyl,

haloalkyl,

alkoxy,

-NR ¹⁰ R ¹⁰ ,

halogen,

-NR ¹⁰ -cycloalkyl,

tetrazolyl,

-O-alkylene-NR ¹⁰ R ¹⁰ ,

-NR ¹⁰ -alkylene-O-alkyl,

-CN,

-CONR ¹⁰ R ¹⁰ ,

-COOR ¹⁰ ,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl;

R ¹¹ is alkyl which is substituted with 1, 2 or 3 hydroxy groups; and

R ¹⁴ is alkyl which is substituted with 1 or 2 groups independently selected from

-NR ¹⁰ R ¹⁰ hydroxy or alkoxy.

30. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 29, characterized in that

R ⁵ is

phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylSO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ - , R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -OCH ₂ O - (methylenedioxy attached in adjacent positions to phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)-, tetrazolyl, - CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from alkyl, haloalkyl and —COOR ¹⁰ .

31. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 28-30 having the formula (Iaa)

(Iaa)

(Iaa)

32. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of Embodiments 2-27 having formula (Ib)

мм (Ib)

mm (Ib)

characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ ;

R ^x is halogen;

R ^y is a halogen and

R ¹ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and R ¹² are as defined in any one of Embodiments 2-30.

33. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 32, characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² ;

R ^x is halogen;

R ^y is a halogen and

R ⁵ is

phenyl substituted with 1, 2 or 3 groups independently selected from

alkyl,

hydroxy;

halogen,

haloalkyl,

alkylsulfonyl-NR ¹⁰ -,

alkyl-SO(=NR ¹⁰ )-,

alkylsulfonyl-NR ¹⁰ -,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ NSO ₂ -,

R ¹⁰ R ¹¹ NSO ₂ -,

alkyl-C(=O)-NR ¹⁰ SO ₂ -,

R ¹⁰ R ¹¹ N(C=O)-,

alkoxy,

-OCH ₂ O- (methylenedioxy attached in adjacent positions to the phenyl ring),

-OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring),

-NO ₂ ,

-COOR ¹⁰ ,

-COOR ¹⁴ ,

R ¹⁰ R ¹⁰ N(C=O)-,

tetrazolyl,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl or

A heteroaromatic 5- or 6-membered monocyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from

alkyl,

haloalkyl,

-COOR ¹⁰ ,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl;

R ¹¹ is alkyl which is substituted with 1, 2 or 3 hydroxy groups; and

R ¹⁴ is alkyl which is substituted with 1 or 2 groups independently selected from

-NR ¹⁰ R ¹⁰ hydroxy or alkoxy.

34. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 33, characterized in that

R ⁵ is phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ -, R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -NO ₂ , -COOR ¹⁰ , R ¹⁰ R ¹⁰ N (C \u003d O )- and tetrazolyl.

35. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 33, characterized in that

R ⁵ is a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, this group being unsubstituted or substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, - COOR ¹⁰ .

36. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of Embodiments 2-31 having formula (Ic)

(Ic)

(ic)

characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ ;

R ^x is halogen;

R ^y is halogen; and

R ¹ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and R ¹² are as defined in any one of embodiments 2-30.

37. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 36, characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² ;

R ^x is halogen;

R ^y is a halogen and

R ⁵ is

halogen,

phenyl substituted with 1, 2 or 3 groups independently selected from

alkyl,

hydroxy;

halogen,

haloalkyl,

alkylsulfonyl-NR ¹⁰ -,

alkyl-SO(=NR ¹⁰ )-,

alkylsulfonyl-NR ¹⁰ -,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ NSO ₂ -,

R ¹⁰ R ¹¹ NSO ₂ -,

alkyl-C(=O)-NR ¹⁰ SO ₂ -,

R ¹⁰ R ¹¹ N(C=O)-,

alkoxy,

-OCH ₂ O- (methylenedioxy attached in adjacent positions to the phenyl ring),

-OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring),

-NO ₂ ,

-COOR ¹⁰ ,

-COOR ¹⁴ ,

R ¹⁰ R ¹⁰ N(C=O)-,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH,

-CONR ¹⁰ -O-alkylene-O-alkyl and

tetrazolyl, or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from

alkyl,

haloalkyl,

alkoxy,

-NR ¹⁰ R ¹⁰ ,

halogen,

-NR ¹⁰ -cycloalkyl,

tetrazolyl,

-O-alkylene-NR ¹⁰ R ¹⁰ ,

-NR ¹⁰ -alkylene-O-alkyl,

-CN,

-CONR ¹⁰ R ¹⁰ ,

-COOR ¹⁰ ,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl;

R ¹¹ is alkyl which is substituted with 1, 2 or 3 hydroxy groups; and

R ¹⁴ is alkyl which is substituted with 1 or 2 groups independently selected from

-NR ¹⁰ R ¹⁰ hydroxy or alkoxy.

38. The compound and its pharmaceutically acceptable salts, prodrugs, solvates, and optical isomers, according to embodiment 37, wherein R ⁵ is

phenyl substituted with 1, 2 or 3 groups independently selected from

alkyl,

hydroxy;

halogen,

haloalkyl,

alkylsulfonyl-NR ¹⁰ -,

alkyl-SO(=NR ¹⁰ )-,

alkylsulfonyl-NR ¹⁰ -,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ NSO ₂ -,

R ¹⁰ R ¹¹ NSO ₂ -,

alkyl-C(=O)-NR ¹⁰ SO ₂ -,

R ¹⁰ R ¹¹ N(C=O)-,

alkoxy,

-OCH ₂ O- (methylenedioxy attached in adjacent positions to the phenyl ring),

-OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring),

-NO ₂ ,

-COOR ¹⁰ ,

-COOR ¹⁴ ,

R ¹⁰ R ¹⁰ N(C=O)-,

tetrazolyl,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from

alkyl,

haloalkyl,

alkoxy,

-NR ¹⁰ R ¹⁰ ,

halogen,

-NR ¹⁰ -cycloalkyl,

tetrazolyl,

-O-alkylene-NR ¹⁰ R ¹⁰ ,

-NR ¹⁰ -alkylene-O-alkyl,

-CN,

-CONR ¹⁰ R ¹⁰ ,

-COOR ¹⁰ ,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl.

39. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 37, characterized in that

R ⁵ is phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halo, alkylSO(=NR ¹⁰ )-, R ¹⁰ R ¹⁰ NSO ₂ -, -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)- and tetrazolyl.

40. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 37, wherein R ⁵ is pyridyl, pyridyl substituted with -COOR ¹⁰ , pyrimidinyl or pyrimidinyl substituted with CF ₃ .

41. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of Embodiments 2-31 having the formula (Id)

(Id)

(Id)

characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ ;

R ^x is halogen; and

R ¹ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and R ¹² are as defined in any one of embodiments 2-30.

42. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 41, characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² ;

R ^x is halogen;

R ⁵ is

halogen,

phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylSO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ - , R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -OCH ₂ O - (methylenedioxy attached in adjacent positions to phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)- and tetrazolyl, or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ and -COOR ¹⁰ ;

R ¹¹ is alkyl which is substituted with 1, 2 or 3 hydroxy groups; and

R ¹⁴ is alkyl which is substituted with 1 or 2 groups independently selected from

-NR ¹⁰ R ¹⁰ hydroxy or alkoxy.

43. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 42, characterized in that R ⁵ is

phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylSO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ - , R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -OCH ₂ O - (methylenedioxy attached in adjacent positions to phenyl ring), -OCH ₂ CH ₂ O-(ethylenedioxy attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , and -COOR ¹⁴ , or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, this group being unsubstituted or substituted by 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, halogen, - NR ¹⁰ -cycloalkyl and -COOR ¹⁰ .

44. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 42, characterized in that

R ⁵ is phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, halogen, alkoxy, -OCH ₂ O- (methylenedioxy attached at adjacent positions to the phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy, attached at adjacent positions to the phenyl ring).

45. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 42, wherein R ⁵ is pyridyl, pyridyl substituted with -COOR ¹⁰ , pyrimidinyl or pyrimidinyl substituted with CF ₃ .

46. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of Embodiments 2-31 having formula (Ie)

(Ie)

(Ie)

characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ ;

R ^x is halogen;

R ^y is a halogen and

R ^z is halogen; and

R ¹ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and R ¹² are as defined in any one of embodiments 2-30.

47. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 46, characterized in that

R ^w is -NR ¹⁰ SO ₂ R ¹² ;

R ^x is halogen;

R ^y is a halogen and

R ⁵ is halogen,

phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylSO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ - , R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -OCH ₂ O - (methylenedioxy attached in adjacent positions to phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)-, tetrazolyl, alkylSO (=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ , -COOR ¹⁰ , alkylSO (=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl;

R ¹¹ is alkyl which is substituted with 1, 2 or 3 hydroxy groups; and

R ¹⁴ is alkyl which is substituted with 1 or 2 groups independently selected from

-NR ¹⁰ R ¹⁰ hydroxy or alkoxy.

48. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 47, characterized in that R ⁵ is

phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylSO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ - , R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -OCH ₂ O - (methylenedioxy attached in adjacent positions to phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)-, tetrazolyl, alkylSO (=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ , -COOR ¹⁰ , alkylSO(=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl.

49. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 43, characterized in that

R ⁵ is phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halo, alkylSO(=NR ¹⁰ )-, R ¹⁰ R ¹⁰ NSO ₂ -, -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)- and tetrazolyl.

50. A compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 47 or 48, characterized in that R ⁵ is pyridyl, pyridyl substituted with -COOR ¹⁰ , pyrimidinyl or pyrimidinyl substituted with CF ₃ .

51. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments from 28 to 25-41, characterized in that R ^x , R ^y and R ^z are F or Cl, in particular F .

52. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers having the formula (Ic)

(Ic)

(ic)

R ¹ is H or alkyl;

R ⁴ is H or alkyl;

R ⁵ is halogen,

phenyl substituted with 1, 2 or 3 groups independently selected from

alkyl,

hydroxy;

halogen,

haloalkyl,

alkylsulfonyl-NR ¹⁰ -,

alkyl-SO(=NR ¹⁰ )-,

alkylsulfonyl-NR ¹⁰ -,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ NSO ₂ -,

R ¹⁰ R ¹¹ NSO ₂ -,

alkyl-C(=O)-NR ¹⁰ SO ₂ -,

R ¹⁰ R ¹¹ N(C=O)-,

alkoxy,

-OCH ₂ O- (methylenedioxy attached in adjacent positions to the phenyl ring),

-OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring),

-NO ₂ ,

-COOR ¹⁰ ,

-COOR ¹⁴ ,

R ¹⁰ R ¹⁰ N(C=O)-,

tetrazolyl,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2, or 3 heteroatoms independently selected from O, N, and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from

alkyl,

haloalkyl,

alkoxy,

-NR ¹⁰ R ¹⁰ ,

halogen,

-NR ¹⁰ -cycloalkyl,

tetrazolyl,

-O-alkylene-NR ¹⁰ R ¹⁰ ,

-NR ¹⁰ -alkylene-O-alkyl,

-CN,

-CONR ¹⁰ R ¹⁰ ,

-COOR ¹⁰ ,

alkyl-SO(=NR ¹⁰ )-,

-CONR ¹⁰ -O-alkylene-OH and

-CONR ¹⁰ -O-alkylene-O-alkyl;

R ⁶ is H or alkyl;

R ¹⁰ is H, alkyl or phenylalkyl;

R ¹¹ is alkyl which is substituted with 1, 2 or 3 hydroxy groups;

R ¹² is H, alkyl or phenylalkyl;

R ¹⁴ is alkyl which is substituted with 1 or 2 groups independently selected from

-NR ¹⁰ R ¹⁰ hydroxy or alkoxy.

R ^w is -NR ¹⁰ SO ₂ R ¹² or -N=S(=O)R ¹⁰ NR ¹⁰ R ¹⁰ ;

R ^x is halogen; and

R ^y is halogen.

53. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 52, wherein R ¹ , R ⁴ and R ⁶ are H.

54. A compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 52 or 53, wherein R ^w is —NR ¹⁰ SO ₂ R ¹² .

55. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 52-54, characterized in that R ¹² is C ₁ -C ₄ -alkyl, in particular C ₁ -C ₃ - alkyl or benzyl.

56. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 52-55, wherein R ⁵ is

phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylSO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ - , R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -OCH ₂ O - (methylenedioxy attached in adjacent positions to phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)-, tetrazolyl, alkylSO (=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl, or

a heteroaromatic 5- or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ , -COOR ¹⁰ , alkylSO (=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl.

57. The compound and its pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, according to embodiment 56, characterized in that R ⁵ is

phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halogen, haloalkyl, alkylsulfonyl, alkylSO(=NR ¹⁰ )-, alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ - , R ¹⁰ R ¹¹ NSO ₂ -, alkyl-C (= O) -NR ¹⁰ SO ₂ -, R ¹⁰ R ¹¹ N (C \u003d O) -, alkoxy, -OCH ₂ O - (methylenedioxy attached in adjacent positions to phenyl ring), -OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)-, tetrazolyl, alkylSO (=NR ¹⁰ )-, -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl, or

a heteroaromatic 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, which group is unsubstituted or substituted with 1 or 2 groups independently selected from alkyl, haloalkyl, alkoxy, -NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ , -COOR ¹⁰ , alkylSO(=NR ¹⁰ )- , -CONR ¹⁰ -O-alkylene-OH and -CONR ¹⁰ -O-alkylene-O-alkyl.

58. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 52-57, characterized in that

R ⁵ is phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, halo, alkylSO(=NR ¹⁰ )-, R ¹⁰ R ¹⁰ NSO ₂ -, -COOR ¹⁰ , -COOR ¹⁴ , R ¹⁰ R ¹⁰ N(C=O)- and tetrazolyl.

59. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 52-58, characterized in that R ⁵ is pyridyl, pyridyl substituted with -COOR ¹⁰ , pyrimidinyl or pyrimidinyl substituted with haloalkyl, alkoxy ,

-NR ¹⁰ R ¹⁰ , halogen, -NR ¹⁰ -cycloalkyl, tetrazolyl, -O-alkylene-NR ¹⁰ R ¹⁰ , -NR ¹⁰ -alkylene-O-alkyl, -CN, -CONR ¹⁰ R ¹⁰ and -COOR ¹⁰ .

60. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 59, characterized in that R ⁵ is pyridyl, pyridyl substituted with -COOR ¹⁰ , pyrimidinyl or pyrimidinyl substituted with haloalkyl, in particular CF ₃ .

61. A compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof, according to embodiment 59 or 60, characterized in that R ⁵ is pyrimidinyl substituted in the 2-position (i.e., at the carbon atom between two nitrogen atoms ).

62. The compound and pharmaceutically acceptable salts, prodrugs, solvates and optical isomers thereof according to any one of embodiments 52-61, wherein R ^x and R ^y are F or Cl, in particular F.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, R ⁵ is not halo. In a further embodiment, R 1 , R ⁴ and R 6 are independently H or alkyl, and in particular are H.

In yet another embodiment, R ¹⁰ is H, alkyl or phenylalkyl, where the phenyl group is optionally substituted with halogen, and in particular R ¹⁰ is H or alkyl.

In yet another embodiment, A is -CO-.

In yet another embodiment, Q is phenyl which is substituted as defined above.

In another embodiment, the invention relates to a compound of formula I and its pharmaceutically acceptable salts, prodrugs, esters, solvates and optical isomers, where R ¹ , R ⁴ -R ⁶ , R ¹⁰ , A and Q are as defined above for any combination.

In another further embodiment, the invention relates to a compound of formula (Ia), (Ib), (Ic) and (Id) and its pharmaceutically acceptable salts, prodrugs, esters, solvates and optical isomers, where the variables are as defined in embodiments above.

In a further embodiment, at least one or at least two of R ^x , R ^y or R ^z are halogen and the others of R ^x , R ^y and R ^z are H, halogen or alkyl, in in particular alkyl or halogen. Halogen is preferably F or Cl.

In a further embodiment, R ¹ , R ⁴ and R ⁶ are H.

In a further embodiment, R ¹² is methyl, ethyl, or propyl.

In one embodiment, the invention relates to MKK4 inhibitors of formulas (I) and (Ia)-(Id) and their pharmaceutically acceptable salts, prodrugs, solvates and optical isomers, in particular MKK4 inhibitors, which selectively inhibit MKK4 protein kinase compared to protein kinases JNK1 and MKK7.

In addition, the invention also relates to compounds of the invention for use in inhibition of MKK4 protein kinase and in particular for use in selective inhibition of MKK4 protein kinase over JNK1 and MKK7 protein kinases.

In addition, the invention also relates to said compounds for use in accelerating liver regeneration or reducing or preventing hepatocyte death and at the same time for use in enhancing hepatocyte proliferation.

The invention also includes pharmaceutically acceptable salts of the above compounds. The pharmaceutically acceptable salts are especially acid addition salts or base addition salts with pharmaceutically acceptable acids or bases. Examples of suitable pharmaceutically acceptable organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfamic acid, C ₁ -C ₄ -alkyl sulfonic acids such as methanesulfonic acid, cycloaliphatic sulfonic acids such as S-(+)- 10-camphorsulfonic acid, aromatic sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having from 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid , tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid. Other useful acids are described, for example, in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basel and Stuttgart, 1966. Examples of suitable pharmaceutically acceptable organic and inorganic bases are alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as calcium or magnesium hydroxide, ammonium hydroxide, organic nitrogenous bases such as dimethylamine, trimethylamine, ethanolamine, diethanolamine, triethanolamine choline, 2-amino-2-hydroxymethylpropane-1,3-diol , meglumine, procaine, etc. L-arginine, L-lysine, ethylenediamine, or hydroxyethylpyrrolidine.

The invention also includes any tautomeric, crystalline and polymorphic forms of the compounds and salts of the present invention and mixtures thereof.

The invention also includes solvates such as hydrates.

The compounds of the invention may contain one or more chiral centers and exist in various optically active forms such as enantiomers and diastereomers.

As used herein, the term "prodrug" refers to an agent that is converted in vivo to the parent drug by some physiological chemical process. An example, without limitation, of a prodrug may be a compound of the present invention in ester form.

Prodrugs have many beneficial properties. For example, the prodrug may be more water soluble than the final drug, making it easier to administer the drug intravenously. The prodrug may also have a higher level of oral bioavailability than the final drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the final drug to the blood or tissue. Exemplary prodrugs include, but are not limited to, compounds with carboxylic acid substituents wherein the free hydrogen is replaced by (C ₁ -C ₄ )alkyl, (C ₁ -C ₁₂ )alkanoyloxymethyl, (C ₄ -C ₉ )1-(alkanoyloxy )ethyl, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl -1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonylamino)ethyl having 4 to 10 carbon atoms, 3 -phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-(C ₁ -C ₂ )alkylamino(C ₂ -C ₃ )alkyl (such as β-dimethylaminoethyl), carbamoyl-(C ₁ -C ₂ )alkyl, N, N-di (C ₁ -C ₂ )-alkylcarbamoyl-(C ₁ -C ₂ )alkyl and piperidino-, pyrrolidino- or morpholino(C ₂ -C ₃ )-alkyl Other prodrugs release formula alcohol (I), where the free hydrogen of the hydroxyl substituent (e.g., the R group contains hydroxyl) is substituted with (C ₁ -C ₆ )alkanoyloxymethyl, 1-((C ₁ -C ₆ )alkanoyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ )alkanoyloxy)ethyl, (C ₁ -C ₁₂ )alkoxycarbonyloxymethyl, N-(C ₁ -C ₆ )alkoxycarbonylaminomethyl, succinoyl, (C ₁ -C ₆ )alkanoyl, α-amino(C ₁ -C ₄ ) alkanoyl, aryllactyl and α-aminoacyl or α-aminoacyl-α-minoacyl, wherein said α-aminoacyl moieties are independently any of the naturally occurring L-amino acids present in proteins, P(O)(OH) ₂ , -P( O)(O(C ₁ -C ₆ ) alkyl) ₂ or glycosyl (a radical resulting from the elimination of the hydroxyl of the carbohydrate hemiacetal).

Expression of an MKK4 inhibitor means that MKK4 kinase activity is inhibited at an IC _{50 of} <10 µmol/L, preferably <1 µmol/L and in particular <0.5 µmol/L. The expression "selectively inhibits MKK4 protein kinase over JNK1 and MKK7 protein kinases" in the context of the present description means that the ratio of MKK7 inhibitory activity to MKK4 inhibitory activity, or the ratio of JNK1 inhibitory activity to MKK4 inhibitory activity, expressed as a percentage of control or Kd is ≥10 as measured by KINOMEscan™.

As used herein, "promoting liver regeneration or reducing or preventing hepatocyte death" means an increase in the relative number of proliferating hepatocytes of at least 30%, preferably at least 50%, compared to the number of proliferating cells at the start of therapy. In particular, the expression means an increase of ≥100% compared to the number of proliferating cells at the beginning of therapy. In this context, experimental determination and quantification will be performed using standard methods, such as quantification of the Ki67 protein, which is strictly associated with cell proliferation. To quantify proliferating hepatocytes on a slide, several immunohistochemical standard methods are available that use a primary anti-Ki67 antibody followed by visualization of anti-Ki67 antibody binding using, for example, a secondary antibody conjugated to horseradish peroxidase. The amount of peroxidase activity, which is visualized by enzymatic conversion of chromogenic substrates, correlates with the amount of Ki67 protein and the number of proliferating cells.

In the experiments described below, hepatocyte proliferation was quantified by Ki67 staining using Abcam's primary anti-Ki67 rabbit polyclonal antibody (Part No. ab15580, Abcam, Cambridge, USA) and Invitrogen's fluorophore-tetramethylrhodamine-containing secondary goat polyclonal antibody from Invitrogen (Part No. 16101, Invitrogen/ThermoFisher).

Based on data obtained from several preclinical mouse models, shRNA (short hairpin RNA) mediated MKK4 suppression in a CCl4 (carbon tetrachloride) chronic liver injury model was found to increase hepatocyte proliferation from 13% to 27%. (vs. shRNA control) and is associated with reduced liver damage (transaminase) and reduced liver fibrosis. As defined in the previous chapter, the relative increase in proliferating cells was 108%. In an alcohol-induced steatohepatitis (ASH) model, shRNA-mediated MKK4 silencing resulted in a hepatocyte proliferation rate of 4% compared to 2% with control shRNA (relative increase: 100%). A doubling of hepatocyte proliferation was associated with reduced steatosis (fat deposition) and reduced liver damage as measured by transaminases. Similarly, shRNA-mediated MKK4 silencing increased hepatocyte proliferation from 16% (shRNA control) to 33% (relative increase: 106%) in a partial hepatectomy model (48 hours after surgical removal of two-thirds of the liver). Again, increased hepatocyte proliferation has been associated with improved liver regeneration and faster recovery of liver mass. In conclusion, these studies confirm that MKK4 is a therapeutic target for the treatment of acute and chronic liver diseases. In addition, WO 2018/134254 discloses novel compounds that selectively inhibit MKK4 over MKK7 and JNK1. In experimental models of liver regeneration in vitro and in vivo, these compounds were effective in preventing acute liver failure caused by administration of the Jo2 antibody and induced the proliferation of isolated primary mouse hepatocytes.

The novel compounds disclosed in this application are potent inhibitors of MKK4 with selectivity for MKK7 and JNK1 and therefore, in analogy to the compounds disclosed in WO 2018/134254, can be used to treat liver diseases and to promote liver regeneration or reduce or prevent death of hepatocytes.

The organic moieties mentioned in the variable definitions above are - like the term halogen - collective terms for separate listings of individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.

The term halogen means in each case fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine, and preferably fluorine.

Alkyl is a straight or branched alkyl group, which is preferably a C ₁ -C ₆ alkyl group, i. e. an alkyl group having 1 to 6 carbon atoms, and more preferably a C ₁ -C ₄ alkyl group, and in particular a C ₁ -C ₃ alkyl group. Examples of the alkyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1- ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

The definition of alkyl also applies to any group that includes an alkyl group.

Haloalkyl is a halogenated alkyl group as defined above, wherein at least one, for example 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or the appropriate number of the same or different halogen atoms, such as trifluoromethyl, chloromethyl, bromomethyl, difluoromethyl, fluoromethyl, difluoroethyl, etc. Specific examples include fluorinated C ₁ -C ₄ alkyl groups as defined, such as trifluoromethyl, difluoromethyl, fluoromethyl, or difluoroethyl.

Cycloalkyl is a cycloaliphatic radical, which is preferably a C ₃ -C ₈ -cycloalkyl, ie a cycloalkyl group having 3 to 8 carbon atoms. In particular, 3 to 6 carbon atoms form a cyclic structure such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The ring structure may be unsubstituted or may carry 1, 2, 3 or 4 C ₁ -C ₄ alkyl radicals, preferably one or more methyl radicals.

Carbonyl is >C=O.

Aminocarbonyl is NH ₂ C(O)-.

Alkenyl is a monounsaturated hydrocarbon radical, which is preferably a C ₂ -C ₆ -alkenyl group, that is, an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms, for example, vinyl, allyl (2-propene-1- yl), 1-propen-1-yl, 2-propen-2-yl, metallyl (2-methylprop-2-en-1-yl) and the like. C ₃ -C ₅ -alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3-buten-1-yl, metallyl, 2-penten-1 -yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl, 2-hexen-1-yl .

Alkynyl is a monounsaturated hydrocarbon radical which is preferably a C ₂ -C ₆ alkynyl group, i.e. an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms, for example ethynyl, 2-propyn-1-yl, 1-propyn-1-yl, 2-propyn-2-yl and the like. C3-C5 alkynyl is in particular 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl , 4-pentyn-1-yl.

Alkylene is a straight or branched alkylene group, which is preferably a C ₁ -C ₅ alkylene group, ie an alkylene group having 1 to 5 carbon atoms. Alkylene groups having 2 to 4 and in particular 2 to 3 carbon atoms are particularly preferred. Examples include methylene, ethylene and 1-methylethylene. Another example is propylene. Another additional example is butylene. The definition of alkylene also applies to any group that includes an alkylene group.

A heteroalkylene is a straight or branched chain alkyl group having 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of heteroalkylene are alkyloxyalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkylthioalkyl. Any alkyl or alkylene group is as defined above. Alkoxyalkyl is preferred.

Alkenylene is a straight or branched chain alkenylene group, which is preferably a C ₂ -C ₄ alkenylene group, that is, an alkenylene group having 2 to 4 carbon atoms. Examples include vinyl and propenyl.

Alkynylene is a straight or branched alkynylene group, which is preferably a C ₂ -C ₄ alkynylene group, that is, an alkynylene group having 2 to 4 carbon atoms. Examples include propynylene.

An aryl (or aromatic group) is a 6-12 membered, in particular 6-10 membered, aromatic cyclic radical, which may be a monocyclic aromatic ring such as phenyl, etc., or a fused polycyclic aromatic ring containing the first a monocyclic aromatic ring; and one or more carbocycles which are saturated, partially unsaturated or aromatic, eg naphthyl, indenyl, tetrahydronaphthyl, indanyl.

A heteroaromatic (or heteroaryl) group is a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic aromatic group having 1, 2, or 3 heteroatoms selected from O, N, or S. The heteroaryl or heteroaromatic group may be linked to adjacent group through a carbon atom (C-bonded) or through a nitrogen heteroatom (N-bonded). Heterocyclic radicals can be linked through a carbon atom (C-linked) or a nitrogen atom (N-linked). Preferred heteroaromatic radicals contain 1 nitrogen atom as a ring member and optionally 1 or 2 additional heteroatoms as ring members, which are independently selected from O, S and N. Examples are:

C-linked 5-membered heteroaromatic rings:

2-furyl, 3-furyl, 5-furyl, 2-thienyl, 3-thienyl, 5-thienyl, pyrrol-2-yl, pyrrol-3-yl, pyrrol-5-yl, pyrazol-3-yl, pyrazol- 4-yl, pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2- yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2,3-oxadiazol-imidazol-4-yl, 4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol - 5-yl, 1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl , 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl tetrazol- 5-yl;

C-linked 6-membered heteroaromatic rings:

pyridin-2-yl, pyridin-3-yl (3-pyridyl), pyridin-4-yl (4-pyridyl), pyridin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-6- yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-5-yl, 1,3,5-triazin-2-yl, 1,2,4- triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl;

N-linked 5-membered heteroaromatic rings:

pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl.

Bicyclic heteroaromatic groups include one of the described 5- or 6-membered heteroaromatic rings and an additional fused, saturated or unsaturated or aromatic carbocycle such as a benzene, cyclohexane, cyclohexene or cyclohexadiene ring. Examples are quinolinyl, isoquinolinyl, indolyl, indolizinyl, isoindolyl, 4-, 5-, 6- or 7-azaindole, indazolyl, benzofuryl, benzthienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, imidazo[b]thiazolyl, thieno [b]pyridyl, imidazo[a]pyridyl, pyrazo[a]pyridyl and pyrrole[d]pyrimidyl. Examples of 5- or 6-membered heteroaromatic compounds comprising an annelated cycloalkenyl ring include dihydroindolyl, dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrobenzofuryl, chromenyl, chromanyl, dihydropyrol[a]imidazolyl, and tetrahydrobenzothiazolyl.

A non-aromatic 5- or 6-membered group (heterocyclic group) may be saturated or partially unsaturated and includes 1, 2, or 3 heteroatoms selected from O, N, and S. Heterocyclic radicals may be bonded via a carbon atom (C-linked) or a nitrogen (N-linked). Preferred heterocyclic groups contain 1 nitrogen atom as a ring member and optionally 1 or 2 additional heteroatoms as ring members independently selected from O, S and N. Examples are:

C-linked 5-membered saturated rings such as

tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, tetrahydropyrazol-3-yl, tetrahydropyrazol-4-yl tetrahydroisoxazol-3 -yl, tetrahydroisoxazol-4-yl, tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl, 1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl , tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl, 1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl, tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl , tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl , 1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl, 1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl , 1,3,2-dioxathiolan-4-yl;

C-linked 6-membered saturated rings such as

tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran- 3-yl, tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxatian-2-yl, 1,3-oxatian-4-yl, 1,3-oxatian-5-yl, 1,3-oxatian-6-yl, 1,4-oxatian-2-yl, 1,4-oxatian-3-yl, 1,2-dithian-3-yl, 1,2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl, tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl, tetrahydro-1,3-oxazin- 6-yl, tetrahydro-1,3-thiazin-2-yl, tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl, tetrahydro-1,3-thiazin-6- yl, tetrahydro-1,4-thiazin-2-yl, tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl, tetrahydro-1,4-oxazin-3-yl,tetrahydro-1,2-oxazin-3-yl, tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl, tetrahydro-1,2-oxazin-6-yl;

N-linked 5-membered saturated rings such as

tetrahydropyrrol-1-yl (pyrrolidin-1-yl), tetrahydropyrazol-1-yl, tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl, tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrooxazol-3-yl;

N-linked 6-membered saturated rings such as

piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl (piperazin-1-yl), hexahydropyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl, tetrahydro-1,3-thiazine -3-yl, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yl (morpholin-1-yl), tetrahydro-1,2-oxazin-2-yl;

C-linked, 5-membered, partially unsaturated rings such as

2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl, 2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2, 5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol- 3-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl, 3,4-dihydro-5H-pyrrol-2-yl, 3,4- dihydro-5H-pyrrol-3-yl, 4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl, 4,5-dihydro-1H-pyrazol-5- yl, 2,5-dihydro-1H-pyrazol-3-yl, 2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl, 4,5-dihydroisoxazol- 3-yl, 4,5-dihydroisoxazol-4-yl, 4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl, 2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol- 5-yl, 2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl, 2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl, 4,5- dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl, 2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl, 2,5-dihydroisothiazol-5-yl, 2,3 -dihydroisothiazol-3-yl, 2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl, 4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazole - 4-yl, 4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl, 2,5-dihydro-1H-imidazol-4-yl, 2.5 -dihydro-1H-imidazol-5-yl, 2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl, 4,5-dihydro-oxazol-2-yl , 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl, 2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl , 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl , 4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl, 2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl, 2,3-dihydrothiazol-2-yl , 2,3-dihydrothiazol-4-yl, 2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1,3-dioxol-4-yl, 1,3-dithiol-2-yl , 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl, 1,3-oxathiol-4- yl, 1,3-oxathiol-5-yl;

C-linked 6-membered partially unsaturated rings such as

2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl, 2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl, 2H- 3,4-dihydrothiopyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl, 2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl, 2H-3, 4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1, 2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2- yl, 2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl, 2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl, 2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl, 2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl, 2H- 5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl, 1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4- yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3, 4, 5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, 2 ,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl-, 4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran- 3-yl, 4H-thiopyran-4-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H- thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4- yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4- yl, 3,4-dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4- yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4- yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2H-5,6-dihydro-1,2-oxazin-3 yl, 2H-5,6-dihydro-1,2 -oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5-yl, 2H-5,6-dihydro-1,2-oxazin- 6-yl, 2H-5,6-dihydro-1,2-thiazin-3-yl, 2H-5,6-dihydro-1,2-thiazin-4-yl, 2H-5,6-dihydro-1, 2-thiazin-5-yl, 2H-5,6-dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro-1,2-oxazin-3-yl, 4H-5,6- dihydro-1,2-oxazin-4-yl, 4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro-1,2-oxazin-6-yl, 4H- 5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thiazin-4-yl, 4H-5,6-dihydro-1,2-thiazin-5- yl, 4H-5,6-dihydro-1,2-thiazin-6-yl, 2H-3,6-dihydro-1,2-oxazin-3-yl, 2H-3,6-dihydro-1,2- oxazin-4-yl, 2H-3,6-dihydro-1,2-oxazin-5-yl, 2H-3,6-dihydro-1,2-oxazin-6-yl, 2H-3,6-dihydro- 1,2-thiazin-3-yl, 2H-3,6-dihydro-1,2-thiazin-4-yl, 2H-3,6-dihydro-1,2-thiazin-5-yl, 2H-3, 6-dihydro-1,2-thiazin-6-yl, 2H-3,4-dihydro-1,2-oxazin-3-yl, 2H-3,4-dihydro-1, 2-oxazin-4-yl, 2H-3,4-dihydro-1,2-oxazin-5-yl, 2H-3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin- 3-yl, 2H-3,4-dihydro-1,2-thiazin-4-yl, 2H-3,4-dihydro-1,2-thiazin-5-yl, 2H-3,4-dihydro-1, 2-thiazin-6-yl, 2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl, 2,3,4,5-tetrag idropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6-tetrahydropyridazin-4-yl, 1, 2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin- 6-yl, 1,2,3,6-tetrahydropyridazin-3-yl, 1,2,3,6-tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin- 6-yl, 4H-5,6-dihydro-1,3-thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4-yl, 4H-5,6-dihydro-1, 3-thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl, 3,4,5-6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin- 4-yl, 3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl, 1,2,3, 4-tetrahydropyrazin-2-yl, 1,2, 3,4-tetrahydropyrazin-5-yl, 1,2,3,4-tetrahydropyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl, 1,2,3,4-tetrahydropyrimidin-5- yl, 1,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1,4-thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl, 2, 3-dihydro-1 ,4-thiazin-5-yl, 2,3-dihydro-1,4-thiazin-6-yl, 2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2Н -1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1 ,3-thiazin-5-yl, 2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl, 4H-1,3 -oxazin-5-yl, 4H-1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazine -5-yl, 4H-1,3-thiazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1, 3-oxazin-5 -yl, 6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl , 6H-1,3-thiazin-6-yl, 2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H -1,4-oxazin-6-yl, 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H-1,4-thiazin-5-yl, 2H-1 ,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl, 4H-1,4-thiazin-2-yl, 4H-1,4 -thiazin-3-yl, 1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl, 1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl, 1,4 -dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl, 1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl, 1,2- dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl, 1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl, 3,4- dihydropyrimidin-2-yl, 3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or 3,4-dihydropyrimidin-6-yl;

N-linked, 5-membered, partially unsaturated rings such as

2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H- pyrazol-1-yl, 2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl, 2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl, 2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl, 2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1- yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl;

N-linked, 6-membered, partially unsaturated rings such as

1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl, 1,4-dihydropyridin-1-yl, 1,2-dihydropyridin-1-yl, 2H- 5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl, 2H-3,6-dihydro-1,2-oxazin-2- yl, 2H-3,6-dihydro-1,2-thiazin-2-yl, 2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1, 2- thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6-tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-2-yl, 1, 2,3,6-tetrahydropyridazin-1-yl, 3,4,5,6-tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyrazin-1-yl, 1,2,3,4-tetrahydropyrimidin- 1-yl, 1,2,3,4-tetrahydropyrimidin-3-yl, 2,3-dihydro-1,4-thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1, 2-thiazin-2-yl, 4H-1,4-oxazin-4-yl, 4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl, 1,4-dihydropyrazin-1- yl, 1,2-dihydropyrazin-1-yl, 1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl.

Any group containing heteroatoms may contain 1, 2 or 3 heteroatoms, which may be the same or different.

Compounds of the invention can be prepared as described in WO 2010/111527, which is incorporated herein by reference in its entirety, or in accordance with similar procedures. Acid or base addition salts are prepared in the usual manner by mixing the free base with the appropriate acid, or by mixing the free acid with the desired base. Optionally, the reaction is carried out in solution in an organic solvent, for example a lower alcohol such as MeOH, ethanol or propanol, an ether such as methyl t-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone, or in an ester such as EtOAc.

The compounds of the invention are useful for promoting liver regeneration or reducing or preventing hepatocytes while increasing hepatocyte proliferation. Therefore, these compounds are useful in the treatment, modulation, amelioration, or prevention of diseases that involve acute or chronic liver injury, which may be caused by infection, trauma, exposure to toxic compounds, abnormal accumulation of normal substances in the blood, an autoimmune process, a genetic defect, or unknown causes. .

Such liver diseases include all diseases in which enhancement of liver regeneration and reduction or prevention of hepatocyte death may be beneficial to achieve a potential therapeutic effect, ie partial or complete recovery of liver function. Such diseases include

acute and chronic or exacerbation of chronic liver diseases such as acute and chronic viral hepatitis such as hepatitis B, C, E, hepatitis caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus and other viruses, all types of autoimmune hepatitis, primary sclerosing hepatitis, alcoholic hepatitis;

metabolic liver diseases such as metabolic syndrome, non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), Morbus Wilson, hemochromatosis, alpha-1 antitrypsin deficiency, glycogen storage disease;

all types of cirrhosis of the liver, such as primary biliary cirrhosis of the liver, ethyltoxic cirrhosis of the liver, cryptogenic cirrhosis of the liver;

acute (fulminant) or chronic liver failure, such as toxic liver failure, such as acetaminophen (paracetamol)-induced liver failure, alpha-amanitin-induced liver failure, drug-induced hepatotoxicity, liver failure caused, for example, by antibiotics, non-steroidal anti-inflammatory drugs, and anticonvulsants, acute liver failure caused by herbal supplements (kava, ephedra, skullcap, pennyroyal, etc.), liver disease and failure due to vascular diseases such as Budd-Chiari syndrome, acute liver failure of unknown origin, chronic liver disease due to right-sided heart failure;

galactosemia, cystic fibrosis, porphyria, hepatic ischemia, perfusion injury, small liver lobe syndrome after liver transplantation, primary sclerosing cholangitis, or hepatic encephalopathy.

To promote liver regeneration or reduce or prevent hepatocyte death, the compounds of the invention are administered to a patient in need thereof in a therapeutically effective amount. There are various diagnostic methods for detecting liver diseases. Blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above clinically acceptable normal levels are known to indicate ongoing liver damage. Blood levels of bilirubin or other liver enzymes may be used as criteria for detection or diagnosis. Routine monitoring of patients with liver disease for blood levels of ALT and AST is used to measure the progress of liver disease during treatment. A reduction in elevated ALT and AST levels within the accepted normal range is accepted as clinical evidence reflecting a reduction in the severity of liver injury in patients. Commercial assays such as FibroTest/FibroSURE, HepaScore®, FibroMeter or Cirrhometer evaluate the combined results of five or more biochemical parameters to detect hepatic steatosis, fibrosis and cirrhosis. In addition, non-invasive, innovative physical imaging techniques such as magnetic resonance imaging, sonography, and in particular elastography techniques are available to detect and monitor the status and progression of liver disease.

In addition, shRNA-mediated MKK4 suppression has been found to attenuate TNF-α-induced cartilage matrix degradation in osteoarthritis (Cell Death and Disease (2017) 8, e3140). Therefore, inhibition of MKK4 activity using the compounds of the invention is further useful in the treatment of osteoarthritis and rheumatoid arthritis.

In addition, MKK4 inhibitors may also be useful in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Grueninger et al. found that in human neuroblastoma cells, MKK4 plays a key role in the phosphorylation of the Tau protein at serine 422, which promotes Tau aggregation (Mol Cell Biochem (2011) 357: 199-207). Tau phosphorylation inhibitors that prevent Tau aggregation are considered useful in the prevention or treatment of Alzheimer's disease.

Recently, an MKK4 inhibitor with potent neuroprotective effects in vitro and in vivo has been described. In hippocampal cultures, incubation with an MKK4 inhibitor prevented glutamate-induced cell death and caspase-3 activation, and also inhibited N-methyl-4-phenylpyridinium iodide and amyloid β1-42-induced cell death in SH-SY5Y cells. The same compound alleviates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopaminergic neurons in mice (Biochemical Pharmacology (2018), doi: https://doi.org/10.1016/). j.bcp.2018.10.008).

The compounds of the invention are usually administered in the form of pharmaceutical compositions which contain at least one compound of the invention, optionally together with an inert carrier (eg, a pharmaceutically acceptable excipient) and, if necessary, other drugs. These compositions can be administered, for example, orally, rectally, transdermally, subcutaneously, intraperitoneally, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical compositions are solid dosage forms such as powders, granules, tablets, in particular film-coated tablets, lozenges, sachets, porridge, sugar-coated tablets, capsules such as hard gelatin capsules and soft gelatin capsules, or suppositories. , semi-solid dosage forms such as ointments, creams, hydrogels, pastes or patches, as well as liquid dosage forms such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, such as lotions, injectables and infusion preparations . In addition, liposomes or microspheres can also be used.

When preparing compositions, the compounds of the invention are optionally mixed or diluted with one or more carriers (auxiliaries). Carriers (auxiliaries) may be solid, semi-solid or liquid materials which serve as carriers or vehicles for the active compound.

Suitable carriers (excipients) are listed in specialized medical monographs. In addition, the formulations may contain pharmaceutically acceptable excipients such as wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; auxiliary coatings; emulsion stabilizers; film formers; gelling agents; odor masking agents; taste modifiers; resins; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; lyophilizing additives; stabilizers; sterilizers; bases for suppositories; tablet excipients such as binders, fillers, glidants, disintegrants or coatings; propellant; drying agents; matting agents; thickeners; waxes; plasticizers and white mineral oils. The composition in this respect is based on specialist knowledge, as described, for example, in Fiedler, HP, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliaR ^y substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV -Editio-Cantor-Verlag, 1996.

The compounds of the invention may also be suitable for combination with other therapeutic agents. Therefore, the invention further relates to a combination comprising a compound of the invention with one or more additional therapeutic agents, in particular for use promoting liver regeneration or reducing or preventing hepatocyte death. The combination therapy of the invention may be administered additionally. By additional administration is meant the co-administration or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regimen for therapeutic administration of two or more therapeutic agents is commonly referred to by those skilled in the art and herein as an additional therapeutic administration; this is also known as supplemental therapeutic administration. Any and all regimens in which a patient receives separate but similarly distributed or overlapping therapeutic administration of the compounds of the invention and at least one additional therapeutic agent are within the scope of the present invention. In one embodiment of an additional therapeutic administration as described herein, the patient is typically stabilized on therapeutic administration of one or more components for a period of time and then receives administration of the other component.

The combination therapy of the invention can also be administered simultaneously. By simultaneous administration is meant a treatment regimen in which the individual components are administered together, either in the form of a single pharmaceutical composition or device containing both components, or as separate compositions or devices each containing one of the components administered simultaneously. Such combinations of separate individual components for simultaneous combination can be provided in the form of a set of parts.

Suitable agents for use in combination with the compounds of the invention include, for example:

ACC inhibitors such as TOFA (5-(tetradecyloxy)-2-furanoic acid), PF-05221304,

GS 0976 and ACC inhibitors disclosed in WO 2016/112305,

angiotensin II receptor antagonists,

angiotensin-converting enzyme (ACE) inhibitors such as enalapril

caspase inhibitors such as emrikasan,

cathepsin B inhibitors such as the mixed cathepsin B/HCV NS3 protease inhibitor type VBY-376,

CCR2 chemokine antagonists such as a mixed CCR2/CCR5 chemokine antagonist such as cenicriviroc,

CCR5 chemokine antagonists,

chloride channel stimulants such as cobiprostone,

cholesterol solubilizers,

diacylglycerol-O-acyltransferase 1 (DGAT1) inhibitors such as LCQ908,

a diacylglycerol-O-acyltransferase 2 (DGAT2) inhibitor such as PF-06865571, a ketohexokinase (KHK) inhibitor such as PF-06835919,

dipeptidyl peptidase IV (DPPIV) inhibitors such as linagliptin,

farnesoid X receptor (FXR) agonists such as INT-747 (obeticholic acid), LJN452 (tropifexor) and analogs disclosed in Tully et al. (J. Med. Chem., 2017, 60 (24), 9960-9973) or GS-9674 (PX-102),

Dual FXR/TGR5 agonists such as INT-767

galectin-3 inhibitors such as GR-MD-02,

glucagon-like peptide 1 (GLP1) agonists such as liraglutide or exenatide,

glutathione precursors,

HCV NS3 protease inhibitors such as a mixed HBV/HCV NS3 protease inhibitor such as VBY-376,

HMG CoA reductase inhibitors such as a statin such as atorvastatin,

11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitors such as R05093151,

IL-1β antagonists,

IL-6 antagonists such as a mixed IL-6/IL-1β/TNFα ligand inhibitor such as BLX-1002,

IL-10 agonists such as peg-ilodecakin,

IL-17 antagonists such as KD-025

ileal sodium bile acid cotransporter inhibitors such as SHP-626,

leptin analogues such as metreleptin,

5-lipoxygenase inhibitors such as a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor such as tipelukast,

LPL gene stimulators such as alipogen tiparvovec,

lysyl oxidase 2 (LOXL2) homologue inhibitors such as an anti-LOXL2 antibody such as GS-6624,

PDE3 inhibitors such as a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor such as tipelukast,

PDE4 inhibitors such as ASP-9831 or a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor such as tipelukast

phospholipase C (PLC) inhibitors such as a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor such as tipelukast,

PPARα agonists such as a mixed PPARα/δ agonist such as GFT505,

PPARγ agonists such as pioglitazone

PPARδ agonists,

Rho-associated protein kinase 2 (ROCK2) inhibitors such as KD-025,

sodium glucose transporter type 2 (SGLT2) inhibitors such as remogliflozin etabonate,

stearoyl-CoA desaturase-1 inhibitors such as aramchol or CVT-12805,

thyroid hormone β receptor agonists such as MGL-3196,

tumor necrosis factor α (TNFα) ligand inhibitors,

transglutaminase inhibitors and precursors of transglutaminase inhibitors such as mercaptamine,

PTPlb inhibitors such as A119505, A220435, A321842, CPT633, ISIS-404173, JTT-551, MX-7014, MX-7091, MX-7102, NNC-521246, OTX-001, OTX-002 or TTP814 and

ASK1 inhibitors such as GS4977.

In some embodiments, one or more additional therapeutic agents are selected from acetylsalicylic acid, alipogen, tiparvovec, aramchol, atorvastatin, BLX-1002, cenicriviroc, cobiprostone, colesevelam, emnasan, enalapril, GFT-505, GR-MD-02, hydrochlorothiazide, ethyl icosapent ester (ethyl-eicosapentaenoic acid), IMM-124E, KD-025, linagliptin, liraglutide, mercaptamine, MGL-3196, obeticholic acid, olesoxime, peg-ilodecakin, pioglitazone, GS-9674, remogliflozin etabonate, SHP-626, solitromycin , tipelukast, TRx-318, ursodeoxycholic acid, and VBY-376.

In some embodiments, one of the one or more additional therapeutic agents is selected from acetylsalicylic acid, alipogen, tiparvovec, aramchol, atorvastatin, BLX-1002, and cenicriviroc.

In one embodiment, the invention provides a method for inhibiting MKK4 protein kinase, selectively inhibiting MKK4 protein kinase over JNK1 and MKK7 protein kinases, promoting liver regeneration or preventing hepatocyte death, treating acute, exacerbation of chronic or chronic liver diseases, treating acute and chronic or exacerbations of chronic liver diseases such as acute and chronic viral hepatitis such as hepatitis B, C, E, hepatitis caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus and other viruses, all types of autoimmune hepatitis, primary sclerosing hepatitis, alcoholic hepatitis;

treatment of metabolic liver diseases such as metabolic syndrome, non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), Morbus Wilson, hemochromatosis, alpha-1 antitrypsin deficiency, glycogen storage disease;

treatment of all types of cirrhosis of the liver, such as primary biliary cirrhosis of the liver, ethyltoxic cirrhosis of the liver, cryptogenic cirrhosis of the liver;

treatment of acute (fulminant) or chronic liver failure such as toxic liver failure such as acetaminophen (paracetamol)-induced liver failure, alpha-amanitin-induced liver failure, drug-induced hepatotoxicity, and liver failure caused by, for example, antibiotics, non-steroidal anti-inflammatory drugs , anticonvulsants, acute liver failure caused by herbal supplements (kava, ephedra, skullcap, pennyroyal, etc.), liver disease and failure due to vascular diseases such as Budd-Chiari syndrome, acute liver failure of unknown origin, chronic disease liver due to right-sided heart failure;

treatment of galactosemia, cystic fibrosis, porphyria, hepatic ischemia, perfusion injury, small lobe syndrome after liver transplantation, primary sclerosing cholangitis or hepatic encephalopathy,

treatment of osteoarthritis, rheumatoid arthritis or diseases associated with the central nervous system, such as Alzheimer's disease and Parkinson's disease,

which comprises administering an effective amount of a compound or composition as defined above to a patient in need thereof.

In one embodiment, the compounds of the invention are administered at a dose of 0.2 to 15 mg/kg or 0.5 to 12 mg/kg to the patient being treated. The compounds can be administered one or more times a day. Compounds are administered over 4-12 weeks.

The following examples illustrate the invention without limiting it.

EXAMPLES

ABBREVIATIONS:

Boc2O-di-tert-butyloxycarbonate

CPME cyclopentyl methyl ether

DCM dichloromethane

4-DMAP 4-dimethylaminopyridine

DME dimethyl ether

DMF dimethylformamide

DMSO: dimethyl sulfoxide

EtOAc ethyl acetate

HPLC high performance liquid chromatography

LDA lithium diisopropylamide

MeCN acetonitrile

MeOH methanol

NaHCO ₃ Sodium bicarbonate

NH ₄ Cl ammonium chloride

Na ₂ SO ₄ sodium sulfate

Pd2 (dba3) tris(dibenzylideneacetone) dipalladium (0)

PE petroleum ether

RT room temperature

Solv. Solution

THF tetrahydrofupan

TLC Thin Layer Chromatography

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Example 1 Synthesis of N-(3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (VI)

Step 1: Synthesis of 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (II)

To a stirred mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine ((I), 6.81 g, 34.4 mmol) and KOH (6.75 g, 120.4 mmol) in DMF (45 ml) iodine (45 ml) was added. 9.60 g, 37.8 mmol) in one serving at room temperature. After a short induction period, an exothermic reaction began. After 1 hour, another 1 g portion of iodine was added and the mixture was stirred at 45° C. for 1 hour. The mixture was poured into 300 ml dilute Na ₂ SO ₃ solution and the mixture was acidified with 2N HCl. The solids were collected by vacuum filtration, washed with water and dried in an oven at 110°C. Yield: 10.92 g, HPLC purity: 95%, ¹ H NMR (200 MHz, DMSO) δ 14.29 (s, 1H), 8.62 (s, 1H), 8.17 (s, 1H) ; ¹³ C NMR (50 MHz, DMSO) δ 150.53, 150.17, 131.86, 120.58, 112.43, 91.95; [M-N] - = 322.0 / 324.0.

Stage 2. Synthesis of 5-bromo-1Н-pyrazolo[3,4-b]pyridine-3-carboxylic acid (III)

5-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine ((II), 10.44 g, 32.2 mmol) was combined with DMF, MeOH and triethylamine (75 ml each). The vessel was evacuated and purged with argon (4 times). XantPhos (1.12 g, 1.93 mmol) and Pd(OAc) 2 (217 mg, 0.97 mmol) were added and carbon monoxide (formed from formic and sulfuric acids) was bubbled through the solution while heating to 60°C. The mixture was stirred under carbon monoxide atmosphere (balloon) for 8 hours. Every 1.5 hours carbon monoxide was bubbled through the solution for 5 minutes. The mixture was concentrated under reduced pressure and the residue was triturated with 2N HCl. The solids were heated at 95°C in about 100 ml of 1N NaOH overnight. After cooling to room temperature, the mixture was acidified with conc. HCl and precipitate were collected by vacuum filtration and washed with water. The solids were dried in an oven at 110°C to constant weight. The solids were sonicated in 100 ml toluene for 5 minutes and stirred for 30 minutes. The product was filtered off, washed with an additional 20 ml of toluene and dried at 110°C. Yield: 7.92 g, HPLC purity: >99%, ¹ H NMR (200 MHz, DMSO) δ 8.64 (d, J=7.9 Hz, 2H), 5.69 (br.s., 1H); ¹³ C NMR (50 MHz, DMSO) δ 163.27, 150.97, 149.67, 136.69, 132.65, 115.73, 113.6; [M-N] - = 239.9 / 241.9.

Stage 3: Synthesis of 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (IV)

5-Bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid ((III), 7.91 g, 32.7 mmol) and 1,1'-carbonyldiimidazole (5.83 g, 35, 9 mmol) were stirred in 200 ml. DMF at 60°C for 45 minutes. To the resulting suspension was added N,O-dimethylhydroxylamine hydrochloride (3.51 g, 35.9 mmol) and the mixture was stirred for 4 hours at 65°C. Most of the solvent was removed in vacuo and the residue half saturated. Added a solution of NaHCO ₃ . The solids were collected by vacuum filtration, washed with water and dried at 110°C. Yield: 7.94 g, HPLC purity: 96%, ¹ H NMR (200 MHz, DMSO) δ 14.46 (s, 1H), 8.62 (d, J=20.4 Hz, 2H), 3 .76 (s, 3H), 3.44 (s, 3H), [MH]- = 283.0/285.0.

Step 4. Synthesis of (3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (V)

2,4-Difluoroaniline (6.25 g, 48.4 mmol) was dissolved in 50 ml dry THF and cooled to -78° C. under argon. 2.5 M n-butyl lithium in hexane (19.4 mL, 48.4 mmol) was added dropwise. After 15 minutes, 1,2-bis(chlorodimethylsilyl)ethane (10.9 g, 49.5 mmol) in 15 ml dry THF was added dropwise and the mixture was stirred for 30 minutes. 2.5 M n-butyl lithium in hexane (19.4 mL, 48.4 mmol) was added dropwise and the mixture was allowed to reach room temperature over 1 hour. After cooling to -78°C, 2.5 M n-butyllithium in hexane (19.4 ml, 48.4 mmol) was added dropwise and stirred for 1 hour at 78°C. (This is considered solution A).

5-Bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide ((IV), 6.00 g, 21.1 mmol) was suspended in 50 ml of dry THF and cooled to 0 °C in an argon atmosphere. NaH (60% in mineral oil, 0.88 g, 22.1 mmol) was added in portions and the solution was stirred at room temperature for 1 hour. (This is considered solution B).

Solution B was added dropwise to solution A at -78°C. After the addition was complete, the mixture was warmed to room temperature over 30 minutes. 12 ml conc. HCl was added carefully and the mixture was stirred for 30 minutes. Solid NaHCO ₃ was added to neutralize the solution, the solids were filtered off and washed with THF. The filtrate was evaporated and the residue triturated with MeOH and water and dried at 110°C. Yield: 4.03 g; Purity HPLC: 97%, ¹ H NMR (200 MHz, DMSO) δ 14.91 (s, 1H), 8.77 (dd, J=5.4, 2.1 Hz, 2H), 7.18-6 .59 (m, 2H), 5.25 (s, 2H); ¹³ C NMR (50 MHz, DMSO) δ 183.95, 151.04, 150.79, 150.27 (dd, J=161.0, 6.8 Hz), 145.50 (dd, J=167, 3, 6.8 Hz), 141.34, 133.35 (dd, J=12.8, 2.6 Hz), 132.28, 117.45 (dd, J=8.4, 6.5 Hz ), 116.24 (dd, J=22.7, 19.1 Hz), 115.55, 114.81, 111.26 (dd, J=21.7, 3.5 Hz); [M-N] ^- = 351.1 / 353.1.

Step 5. Synthesis of N-(3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (VI)

(3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone ((V), 2.00 g, 5.66 mmol) and 4 -DMAP (35 mg (0.28 mmol) was heated in 9 ml of pyridine to 65°C and 1-propanesulfonyl chloride (1.21 g, 0.96 ml, 8.50 mmol) was added. After 2 hours another 0.19 ml 1-propanesulfonyl chloride The warm solution was added to about 80 ml 2N HCl, the solid was collected and washed with water The solid was dissolved in EtOAc, washed with 2N HCl and brine and dried over Na ₂ SO ₄ The solvent was evaporated and the product was purified by flash chromatography (SiO2, DCM/EtOAc gradient, 0% to 20% EtOAc) and triturated with n-hexane Yield: 1.68 g, HPLC purity: 97%, ¹ H NMR (200 MHz, DMSO) δ 9.86 (s, 1H), 8.79 (dd, J=5.3, 2.0 Hz, 3H), 7.64 (td, J=9.0, 6.0. Hz, 1H), 7.30 (t, J=8.9 Hz, 1H), 3.17-2.96 (m, 3H), 1.87-1.62 (m, 2H), 0.96 (t, J=7.4 Hz, ^4H ); .3 Hz), 151.56, 151.34, 141.39, 132.59, 130.78-130.05 (m), 122.20 (dd, J=13.5, 3.6 Hz), 117.19 (dd, J=23.0, 20.9 Hz), 116.14, 115.18, 112.59 (dd, J=22.2, 3.8 Hz), 54.14, 17.22 12.97; [M-N] ^- = 457.1 / 459.1.

Example 2 Synthesis of [3,4-b] fluoro-3-(5-phenyl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide

A magnetic stirrer, N-(3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide ((VI), 50 mg, 0.11 mmol), phenylboronic acid (15 mg, 0.12 mmol), Pd (PPh3) 4 (6 mg, 5 mol%) and purged with argon. Degassed 1,4-dioxane (0.3 ml) and a degassed aqueous solution of 1.5 M K ₂ CO ₃ (0.25 ml, 0.38 mmol) were added and the mixture was heated to 120°C under microwave irradiation for 30 minutes. After cooling, the mixture was diluted with EtOAc and neutralized with saturated NH ₄ Cl solution. The solvents were removed and the product was isolated by flash chromatography and dried at 100° C. in a vacuum oven. Yield: 27 mg, HPLC purity: ^97.1 H NMR (200 MHz, DMSO), δ 7.84 (d, J=7.2 Hz, 2H), 7.71-7.40 (m, 4H) , 7.31 (t, J=8.7 Hz, 1H.), 3.18-3.04 (m, 2H), 1.87-1.63 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). [MH] ^- = 455.1.

General Suzuki Reaction Procedure: Microwave chamber loaded with magnetic stirrer, N-(3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide , the corresponding boronic acid or pinacol ester of boronic acid (1.1 eq.) and Pd (PPh3) 4 [(tBu) 3P Pd G4 and/or XPhos Pd G4 (G4: 4th generation; commercially available) for nitrophenylboronic acid , 4-hydroxyphenylboronic acid and 4-dimethylaminophenylboronic acid pinacol ester] (0.05 eq.) and purged with argon, degassed 1,4-dioxane (0.4 M) and degassed aqueous 1.5 M K ₂ CO ₃ ( 3.5 eq.) and the mixture is heated to 120°C under microwave irradiation until complete conversion (typically 30 minutes). After cooling, the mixture was diluted with EtOAc and neutralized with sat. NH ₄ Cl solution. The solvents are removed and the product is isolated by flash chromatography and dried at 100° C. in a vacuum oven.

By analogy, the compounds shown in the following Table 1 were obtained.

Example 44 Synthesis of N-(5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide

Synthesis of 2,6-difluoro-3-(propylsulfonamido)benzoic acid (Intermediate E)

Synthesis of N-(5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide:

Example 45: Synthesis of 5-(4-chlorophenyl)-N-(2,6-difluoro-3-(propylsulfonamido)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

Synthesis of N-(3-amino-2,4-difluorophenyl)propane-1-sulfonamide (Intermediate F)

Synthesis of 5-(4-chlorophenyl)-N-(2,6-difluoro-3-(propylsulfonamido)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide:

Example 46 Synthesis of N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)thio)-2,4-difluorophenyl)propane-1-sulfonamide

Synthesis of N-(2,4-difluoro-3-mercaptophenyl)propane-1-sulfonamide (intermediate C)

Synthesis of N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)thio)-2,4-difluorophenyl)propane-1-sulfonamide:

Example 47 and 48: Synthesis of N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)sulfinyl)-2,4-difluorophenyl)propane-1- sulfonamide (Note 47) and N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)sulfonyl)-2,4-difluorophenyl)propan-1 -sulfonamide (Note 48)

Example 49: Synthesis of N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)(hydroxy)methyl)-2,4-difluorophenyl)propan-1 -sulfonamide

Synthesis of N-(2,4-difluoro-3-formylphenyl)propane-1-sulfonamide (Intermediate A):

Synthesis of N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)(hydroxy)methyl)-2,4-difluorophenyl)propane-1-sulfonamide:

Example 50 Synthesis of N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)-2,4-difluorophenyl)propane-1-sulfonamide

Пример 51:

Example 51:

Compounds of Example 51a-51m were prepared according to the procedure shown in Scheme 1.

Scheme 1:

(3-Amino-2,6-difluorophenyl)(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (1) was prepared as described in Example 1 (Steps 1-4).

The subsequent conversion to sulfonyl chloride leading to intermediate 2 was carried out in analogy to Example 1, Step 5.

Suzuki coupling reactions with end products 51a-51m were carried out as follows (general procedure): a magnetic stirrer, 5-bromo-1H-pyrazolopyridine derivatives, the corresponding boronic acid or pinacol boronic acid ester (1.1 eq.) and XPhos Pd G3 or Pd G4 (0.05 eq) and purged with argon. Degassed 1,4-dioxane (0.4 M) and degassed aqueous 1.5 M K ₂ CO ₃ (3.5 eq., +1 eq. for each acid functional group) and the mixture was heated to 120°C (100° C for amides) under microwave irradiation until complete conversion (30 to 60 minutes). After cooling, the mixture was diluted with EtOAc and neutralized with sat. NH ₄ Cl solution (or acidified 2N HCl for acid functional groups). The solvents were removed and the product was isolated by flash chromatography (using mixtures of DCM, EtOAc and/or MeOH), triturated if necessary and dried at 100° C. in a vacuum oven.

Example 51a: 4-(3-(2,6-difluoro-3-((phenylmethyl)sulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

Stage 1: N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-1-phenylmethanesulfonamide:

(3-amino-2,6-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone (350 mg, 0.991 mmol) and N, N-dimethylpyridin-4- amine (6.05 mg, 0.0496 mmol) was dissolved in pyridine (1.98 ml) and heated to 65°C. Phenylmethanesulfonyl chloride (283 mg, 1.49 mmol) was added and the mixture was stirred for 2 hours. The mixture was poured into aqueous 2N HCl and extracted with EtOAc. The organic phase was washed with 2N HCl and brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (n-hexane+EtOAc) from 0 to 50% and triturated with n-hexane. N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-1-phenylmethanesulfonamide (315 mg, 0.6210 mmol, 63% yield) ,

¹ H NMR (200 MHz, CDCl ₃ ) δ 14.22 (s, 1H), 8.96 (s, 1H), 8.79 (d, J=2.2 Hz, 1H), 8.59 (d , J=2.1 Hz, 1H), 7.52-7.25 (m, 6H), 6.87 (td, J=9.1, 1.6 Hz, 1H), 4.32 (s, 2H);

¹³ C NMR (101 MHz, CDCl ₃ ) δ 182.7, 156.6 (dd, J=251, 6.8 Hz), 153.03 (d, J=7.7 Hz), 151.2, 150 .6, 150.5, 141.6, 132.9, 130.8, 127.75 (dd, J=151.3, 7.9 Hz), 126.9, 121.87 (dd, J=13 .1, 3.9 Hz), 117.12 (dd, J=22.8, 20.7 Hz), 115.7, 115.5, 111.61 (dd, J=22.5, 3.8 Hz), 58.8

MS: [M-1] ^- = 504.7

Stage 2: Suzuki combination according to the general procedure (see example 2 above)

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 15.01 (s, 1H), 9.89 (s, 1H), 9.11 (d, J=1.7 Hz, 1H), 8.87 (d, J=1.7 Hz, 1H), 8.17-7.81 (m, 4H), 7.70-7.14 (m, 9H), 4.54 (s, 2H);

¹³ C NMR (101 MHz, DMSO) δ 182.6, 155.95 (dd, J=248.0, 6.2 Hz), 152.4, 152.14 (dd, J=251.0, 7, 4Hz), 149.8, 143.5, 142.0, 140.4, 132.0, 131.9, 131.5, 131.5, 131.4, 130.9, 129.2, 128, 7, 128.6, 128.3, 128.3, 127.9, 127.5, 126.4, 126.3, 122.10 (dd, J=13.1, 3.5 Hz), 117, 2, 117.0, 113.4, 111.90 (dd, J=22.0 3.9 Hz) 58.5;

MS: [M-1] ^- = 581.8.

Example 51b: 4-(3-(2,6-difluoro-3-(methylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

Stage 1: N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl]methanesulfonamide:

(3-amino-2,6-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone (350 mg, 0.991 mmol) and N, N-dimethylpyridin-4- amine (6.05 mg, 0.0496 mmol) was dissolved in pyridine (1.98 ml) and heated to 65°C. Methansulfonyl chloride (0.357 ml, 1.49 mmol) was added and the mixture was stirred for 2 hours. The mixture was poured into aqueous 2N HCl and extracted with EtOAc. The organic phase was washed with 2N HCl and brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (DCM+EtOAc) from 0 to 30% and triturated with n-hexane. N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl]methanesulfonamide (164 mg, 0.3800 mmol, 38% yield)

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 15.07 (s, 1H), 9.82 (s, 1H), 8.80 (dd, J=4.8, 2.1 Hz, 2H), 7, 65 (td, J=9.0, 5.9 Hz, 1H) 7.32 (td, J=8.9, 1.5 Hz, 1H), 3.07 (s, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.3, 156.4 (dd, J=248.8, 6.6 Hz), 152.92 (dd, J=251.8, 8.1 Hz), 151.0, 150.9, 141.0, 132.2, 130.1, 130.0, 121.80 (dd, J=13.2, 3.7 Hz), 116.84 (dd, J= 23.0, 20.9 Hz), 115.7, 114.7, 112.16 (dd, J=22.4, 3.7 Hz), 40.4;

MS: [M-1] ^- = 428.7.

Stage 2: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.99 (s, 1H), 9.85 (s, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.86 (d, J=2.1Hz, 1H), 8.03 (dd, J=20.8, 8.4Hz, 4H), 7.65 (td, J=9.1, 6.1Hz, 1H), 7.48 (s, 2H), 7.33 (t, J=8.8 Hz, 1H), 3.08 (s, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 156.40 (dd, J=248.5, 6.7 Hz), 153.0 (dd, J=251.5, 8.0 Hz), 152.4, 149.8, 143.5, 142.0, 140.3, 131.5, 130.0, 129.9 128.2, 127.9, 126.4, 121.8 (dd, J =13.3, 3.5 Hz), 117.13 (dd, J=23.0, 21.5 Hz), 113.4, 112.15 (dd, J=22.1, 3.1 Hz) .40.4;

MS: [M-1] ^- = 505.9.

Example 51c: 4-(3-(3-(Butylsulfonamido)-2,6-difluorobenzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

Stage 1: N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl] butane-1-sulfonamide:

(3-amino-2,6-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone (350 mg, 0.991 mmol) and N, N-dimethylpyridin-4- amine (6.05 mg, 0.0496 mmol) was dissolved in pyridine (1.98 ml) and heated to 65°C. Butane-1-sulfonyl chloride (0.357 mL, 1.49 mmol) was added and the mixture was stirred overnight. 0.25 eq. butane-1-sulfonyl chloride was added and stirring was continued for 2 h at 65°C. The mixture was poured into aqueous 2N HCl and extracted with EtOAc. The organic phase was washed with 2N HCl and brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexane+EtOAc) from 10% to 50% and triturated with n-hexane. N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl]butane-1-sulfonamide (180 mg, 0.3800 mmol, 38% yield )

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 15.03 (s, 1H), 9.83 (s, 1H), 9.02-8.62 (m, 2H), 3.21-3.03 (m , 2H), 1.70 (dt, J=15.0, 7.5). Hz, 2H), 1.37 (dc, J=14.5, 7.3 Hz, 2H), 0.84 (t, J=7.2 Hz, 3H);

¹³ C NMR (50 MHz, DMSO) δ 182.4, 151.1, 151.0, 141.1, 132.3, 115.8, 114.8, 51.8, 25.1, 20.7, 13.4;

MS: [M-1] ^- = 470.8.

Stage 2: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 15.00 (s, 1H), 9.82 (s, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.86 (d, J=2.0Hz, 1H), 8.13-7.93(m, 4H), 7.64(td, J=9.0, 6.2Hz, 1H), 7.48(s, 2H ), 7.32 (td, J=8.9, 1.2 Hz, 1H), 3.21-3.07 (m, 2H), 1.82-1.61 (m, 2H), 1, 50-1.27 (m, 2H), 0.85 (t, J=7.2 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 156.3 (dd, J=248.2, 6.3 Hz), 152.7 (dd, J=251.1, 8.8 Hz), 152.4, 149.8, 143.5, 142.0, 140.3, 131.5, 129.9, 129.8, 128.2, 127.9, 127.5, 126.4, 126, 3, 121.8 (dd, J=13.0, 3.7 Hz), 117.08 (dd, J=23.1, 21.2 Hz), 113.4, 112.2, 112.2, 112.0, 51.8, 25.1, 20.7, 13.4;

MS: [M-1] ^- = 547.9.

Example 51d: 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid

Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.99 (s, 1H), 13.14 (br.s. 1H), 9.83 (s, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.04 (dd, J=22.3, 8.5 Hz, 4H), 7.64 (td, J=9 .0, 5.9 Hz, 1H), 7.31 (td, J=8.9, 1.5 Hz, 1H), 3.21-3.03 (m, 2H), 1.86-1, 61 (m, 2H), 0.97 (t, J=7.4 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 167.0, 152.4, 149.8, 142.0, 141.3, 131.8, 130.2, 130.1, 128.1, 127.6, 113.5, 53.8, 16.8, 12.5;

MS: [M-1] ^- = 499.6.

Example 51e: N-[2,4-difluoro-3-[5-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl] propane-1-sulfonamide

Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.99 (s, 1H), 9.83 (s, 1H), 9.14 (d, J=2.1 Hz, 1H), 8.88 (d, J=2.2Hz, 1H), 8.17(dd, J=19.9, 8.4Hz, 4H), 7.65(td, J=9.0, 6.1Hz, 1H), 7.32 (td, J=9.0, 1.4 Hz, 1H), 3.20-3.05 (m, 2H), 1.90-1.59 (m, 2H), 0.97 ( t, J=7.4 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 156.29 (dd, J=248.3, 6.4 Hz), 152.8 (dd, J=251.2, 8.2 Hz), 152.4, 149.8, 142.0, 139.7, 131.7, 129.9, 129.8, 128.3, 127.9, 127.7, 127.6, 123.8, 121, 79 (dd, J=13.4, 3.4 Hz), 117.1, 113.5, 112.12 (dd, J=22.6, 4.3 Hz), 53.8, 16.8, 12.5;

MS: [M-1] ^- = 522.9.

Example 51f: 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide

Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 14.97 (s, 1H), 9.83 (s, 1H), 9.10 (d, J=1.3 Hz, 1H), 8.83 (d, J=1.3 Hz, 1H), 8.13-7.92. (m, 5H), 7.64 (td, J=8.9, 6.2 Hz, 1H), 7.46 (s, 1H), 7.32 (t, J=8.7 Hz, 1H) , 3.18-3.06 (m, 2H), 1.83-1.68 (m, 2H), 0.97 (t, J=7.5 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.6, 167.4, 152.4, 149.8, 142.0, 139.8, 133.7, 132.0, 128.4, 127.9, 127.2, 113.5, 53.8, 16.8, 12.6;

MS: [M-1] ^- = 498.0.

Example 51g: N-(2,4-difluoro-3-(5-(4-(methylsulfonamido)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide

Step 1: N-(4-bromophenyl)methanesulfonamide (2)

4-Bromaniline (1, 2.08 g, 12.1 mmol) and 4-dimethylaminopyridine (0.0739 g, 0.605 mmol) were dissolved in pyridine (12.1 ml) and methanesulfonyl chloride (1.03 ml, 13.3 mmol) at room temperature, resulting in an exothermic reaction. After reaching room temperature again (30 min), the mixture was poured into 2N HCl. The product was extracted with EtOAc, the extract was washed with 2N HCl and brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure, and the residue was triturated with n-hexane to give N-(4-bromophenyl)methanesulfonamide (2.40 g, 9.6 mmol, 79% yield.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.91 (s, 1H), 7.60-7.42 (m, 2H), 7.22-7.09 (m, 2H), 3.00 (s , 3Н);

¹³ C NMR (50 MHz, DMSO) δ 137.9, 132.2, 121.5, 115.9, 39.3; [M-1] ^- = 247.7.

Stage 2: N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide (3)

The vessel was charged with N-(4-bromophenyl)methanesulfonamide (2.252 mg, 1.01 mmol), bis(pinacolato)diborone (281 mg, 1.11 mmol), potassium acetate (297 mg, 3.02 mmol) and degassed dry 1,4-dioxane (5.04 ml). The vessel was evacuated and refilled with argon (3x), XPhos Pd G4 (8.67 mg, 0.0101 mmol) was added and the mixture was stirred at 85° C. for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc and acetic acid (0.173 ml, 3.02 mmol), stirred for 30 minutes and filtered through celite. The solvent was removed under reduced pressure. The residue was dissolved in a minimum amount of EtOAc, precipitated with n-heptane and the solids were collected by suction filtration to give N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] methanesulfonamide (281 mg, 0.9460 mmol, 94% yield), which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.60 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 2.99 (s, 3H) , 1.27 (s, 12H);

¹³ C NMR (50 MHz, DMSO) δ 142.4, 135.8, 117.9, 83.5, 24.7.

Stage 3: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.93 (s, 1H), 9.98 (s, 1H), 9.83 (s, 1H), 9.02 (d, J=2.2 Hz, 1H), 8.73 (d, J=2.1 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.64 (td, J=9.0, 6.1 Hz, 1H), 7.43-7.26 (m, 3H), 3.19-3.03 (m, 5H), 1.86-1.63 (m, 2H), 0.97 (t, J=7.4 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 152.1, 149.6, 141.8, 138.5, 132.4, 128.3, 127.0, 120.0, 113.5, 53.8, 16.8, 12.5;

[M-1] ^- = 547.8.

Example 51h: 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-methylbenzenesulfonamide

Stage 1: 4-bromo-N-methylbenzenesulfonamide (2)

To a solution of 4-bromobenzenesulfonyl chloride (1.2.52 g, 9.86 mmol) in tetrahydrofuran (49.3 ml) was added methylamine (14.8 ml, 29.6 mmol) 2M in THF. The reaction mixture was stirred at room temperature for 15 minutes, poured into a solution of NH ₄ Cl and was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , concentrated and triturated with n-hexane to give 4-bromo-N-methylbenzenesulfonamide (2.15 g, 8.6 mmol, 87% yield)

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.77-7.59 (m, 1H), 5.03 (dd, J=10.0, 4.9 Hz, 1H), 2.62 (d, J=5.2 Hz, 1H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 137.8, 132.5, 128.9, 127.8, 29.3; [M-1] ^- = 247.8.

Step 2: [4-(methylsulfamoyl)phenyl]boronic acid (3)

To a solution of 4-bromo-N-methylbenzenesulfonamide (2, 1.05 g, 4.20 mmol) and triisopropylborate (1.45 ml, 6.30 mmol) in tetrahydrofuran (8.40 ml) was added n-butyllithium (4. 20 ml, 10.5 mmol) at -70°C. The mixture was slowly heated to 0°C, then a 10% HCl solution was added to pH 3-4. The resulting mixture was extracted with EtOAc. The organic layer was extracted with NaOH (2 M) and the aqueous phase was washed with diethyl ether. The aqueous phase was acidified to pH 3, extracted with EtOAc (impurities and unused reagent were still present), dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was triturated with diethyl ether to give [4-(methylsulfamoyl)phenyl]boronic acid (187 mg, 0.8700 mmol, 21% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.96 (d, J=8.1 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.42 (q, J= 4.9 Hz, 1H), 2.39 (d, J=5.0 Hz, 3H);

¹³ C NMR (50 MHz, DMSO) δ 140.6, 134.8, 125.7, 28.8.

Stage 3: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 15.01 (s, 1H), 9.83 (s, 1H), 9.11 (d, J=2.1 Hz, 1H), 8.87 (d, J=2.0Hz, 1H), 8.11(d, J=8.3Hz, 2H), 7.93(d, J=8.3Hz, 2H), 7.64(td, J= 9.0, 5.9Hz, 1H), 7.58(kv, J=5.0Hz, 1H), 7.32(t, J=8.7Hz, 1H), 3.19-3, 02 (m, 2H), 1.80-1.70 (m, 2H), 0.97 (t, J=7.5 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.6, 152.5, 149.9, 142.0, 141.0, 138.8, 131.4, 128.4, 128.2, 127.5, 113.4, 53.8, 28.6, 16.8, 12.5;

MS: [M-1] ^- = 547.9.

Example 51i: 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-ethylbenzenesulfonamide

Stage 1: 4-bromo-N-ethylbenzenesulfonamide (2)

4-Bromobenzenesulfonyl chloride (1, 2.57 g, 10.1 mmol) was dissolved in DCM (25.1 ml). Triethylamine (3.50 ml, 25.1 mmol) and ethylamine hydrochloride (1.07 g, 13.1 mmol) were added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted half-saturated. NH ₄ Cl solution and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was triturated with n-hexane to give 4-bromo-N-ethylbenzenesulfonamide (2.40 g, 9.09 mmol, 90% yield).

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.92-7.47 (m, 4H), 5.17 (s, 1H), 3.08-2.81 (m, 2H), 1.08 ( t, J=7.2 Hz, 3H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 139.1, 132.4, 128.7, 127.6, 38.3, 15.1; [M-1] ^- = 261.7.

Step 2: [4-(ethylsulfamoyl)phenyl]boronic acid (3)

To a solution of 4-bromo-N-ethylbenzenesulfonamide (2, 1.06 g, 4.01 mmol) and triisopropyl borate (1.39 ml, 6.02 mmol) in tetrahydrofuran (20.1 ml) was added n-butyl lithium (4. 01 ml, 10.0 mmol) at -70°C. The mixture was slowly heated to 0°C, then a 10% HCl solution was added to pH 3-4. The resulting mixture was extracted with EtOAc and the extract was washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give [4-(ethylsulfamoyl)phenyl]boronic acid (368 mg, 1.61 mmol, 40% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 8.41 (s, 2H), 7.94 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H) , 7.52 (t, J=5.7 Hz, 1H), 2.87-2.67 (m, 2H), 0.93 (t, J=7.2 Hz, 3H);

¹³ C NMR (50 MHz, DMSO) δ 142.1, 135.0, 125.7, 37.9, 15.0.

Stage 3: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 14.97 (s, 1H), 9.82 (s, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.86 (d, J=2.1 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 7.73-7.58 ( m, 2H), 7.31 (t, J=8.7 Hz, 1H), 3.16-3.06 (m, 2H) 2.89-2.80 (m, 2H), 1.81- 1.69 (m, 2H), 1.05-0.94 (m, 6H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 152.5, 149.8, 142.0, 140.8, 140.0, 131.4, 128.3, 128.2, 127.3, 113.4, 53.8, 37.6, 16.8, 14.8, 12.5;

MS: [M-1] ^- = 561.9.

Example 51j: 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2,3-dihydroxypropyl)benzenesulfonamide

Step 1: 4-bromo-N-(2,3-dihydroxypropyl)benzenesulfonamide (2)

4-Bromobenzenesulfonyl chloride (1, 2.10 g, 8.22 mmol) and triethylamine (2.29 ml, 16.4 mmol) were combined in DCM (41.1 ml). 3-Aminopropane-1,2-diol (0.952 ml, 12.3 mmol) was added and the mixture was stirred for 1 hour at room temperature. After evaporation of the solvent, the residue was dissolved in EtOAc, washed with 1 N HCl, water and brine. The extract was dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The product was washed with water and diethyl ether and dried to give 4-bromo-N-(2,3-dihydroxypropyl)benzenesulfonamide (0.980 g, 3.16 mmol, 38% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.77 (dd, J=17.1, 8.5 Hz, 5H), 4.79 (s, 1H), 4.56 (s, 1H), 3, 46 (s, 1H) under water peak, 3.27 (s, 2H), 2.89 (dd, J=12.6, 4.2 Hz, 1H), 2.61 (dd, J=12 .5, 7.1 Hz, 1H);

¹³ C NMR (50 MHz, DMSO) δ 139.9, 132.3, 128.7, 126.1, 70.3, 63.5, 46.3; [M-1] ^- = 307.8.

Step 2: N-(2,3-dihydroxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (3)

The vessel was charged with 4-bromo-N-(2,3-dihydroxypropyl)benzenesulfonamide (2.205 mg, 0.661 mmol), potassium acetate (195 mg, 1.98 mmol), bis(pinacolato)diborone (185 mg, 0.727 mmol ) and degassed dry 1,4-dioxane (6.61 ml). The vessel was evacuated and filled with argon (3x), XPhos Pd G4 (5.69 mg, 0.00661 mmol) was added and the mixture was stirred at 85°C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and stirred for 30 minutes, filtered through celite and the solvent was removed under reduced pressure. The residue was dissolved in a minimum of EtOAc, precipitated with n-heptane and the solids were collected by suction filtration to give N-(2,3-dihydroxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)benzenesulfonamide (202 mg, 0.5650 mmol, 86% yield), which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.80 (q, J=8.0 Hz, 3H), 7.44 (s, 2H), 3.52-2.56 (m, 5H), 1, 35-1.22 (m, 7H), 1.15 (s, 5H), 1.07 (s, 2H).

Stage 3: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 15.00 (s, 1H), 9.82 (s, 1H), 9.11 (d, J=2.1 Hz, 1H), 8.87 (d, J=2.1 Hz, 1H), 8.09 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.68-7.60 ( m, 2H), 7.32 (t, J=8.3 Hz, 1H), 4.82 (d, J=5.2 Hz, 1H), 4.58 (t, J=5.7 Hz, 1H), 3.50 (dc, J=10.6, 5.3 Hz, 1H), 3.32-3.22 (m, 2H), 3.14-3.08 (m, 2H), 2 .94 (ddd, J=11.7, 6.6, 4.9 Hz, 1H), 2.66 (ddd, J=12.8, 7.0, 5.8 Hz, 1H), 1.83 -1.69 (m, 2H), 0.97 (t, J=7.5 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 152.5, 149.8, 142.0, 140.8, 140.0, 131.4, 128.3, 128.1, 127.3, 113.4, 70.3, 63.5, 53.8, 46.1, 16.8, 12.5;

MS: [M-1] ^- = 607.8.

Example 51k: N-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)acetamide

Stage 1: N-(4-bromophenyl)sulfonylacetamide (2)

4-Bromobenzenesulfonyl chloride (1.22 g, 9.08 mmol) and acetamide (1.34 g, 22.7 mmol) (washed with diethyl ether before use) were dissolved in tetrahydrofuran (30.3 ml). Sodium hydride (0.908 g, 22.7 mmol) (60%) was added portionwise at 0° C. and the mixture was stirred for 2 hours. The mixture was acidified with conc. HCl and water were added until the phases separated. The phases were separated and the aqueous layer was extracted with EtOAc. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was triturated with water and dried in vacuo to give N-(4-bromophenyl)sulfonylacetamide (1.33 g, 4.78 mmol, 53% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 12.22 (s, 1H), 7.84 (s, 4H), 1.93 (s, 3H);

¹³ C NMR (50 MHz, DMSO) δ 169.0, 138.6, 132.3, 129.6, 127.7, 23.3; [M-1] ^- = 275.8.

Stage 2: N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylacetamide (3)

The vessel was charged with N-(4-bromophenyl)sulfonylacetamide (2.206 mg, 0.741 mmol), potassium acetate (218 mg, 2.22 mmol), bis(pinacolato)diborone (207 mg, 0.815 mmol), and degassed dry 1. 4-dioxane (7.41 ml). The vessel was evacuated and refilled with argon (3x), XPhos Pd G4 (6.37 mg, 0.00741 mmol) was added and the mixture was stirred at 85° C. overnight. Added more XPhos Pd G4 and bis(pinacolato)diborone and the mixture was stirred for another 2 hours. After cooling to room temperature, the mixture was diluted with EtOAc and stirred for 30 minutes and filtered through celite. The filtrate was removed and the filter was washed with 2N HCl and EtOAc. The solvent was removed under reduced pressure and the residue was triturated with n-heptane to give N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylacetamide (163 mg, 0 .5010 mmol, 68% yield, which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 12.14 (s, 1H), 8.02-7.81 (m, 4H), 1.92 (s, 3H), 1.30 (s, 12H);

¹³ C NMR (50 MHz, DMSO) δ 168.8, 141.8, 134.9, 126.8, 84.3, 24.6, 23.2.

Stage 3: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 15.01 (s, 1H), 12.21 (s, 1H), 9.83 (s, 1H), 9.11 (d, J=2.1 Hz, 1H), 8.87 (d, J=2.1 Hz, 1H), 8.12 (d, J=8.5 Hz, 2H), 8.05 (d, J=8.5 Hz, 2H) , 7.64 (td, J=9.0, 5.9 Hz, 1H), 7.32 (t, J=8.5 Hz, 1H), 3.11 (dd, J=5.7, 3 .8 Hz, 2H), 1.96 (s, 3H), 1.83-1.69 (m, 2H), 0.97 (t, J=7.5 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.6, 152.5, 149.9, 142.0, 141.0, 138.8, 131.4, 128.4, 128.2, 127.5, 113.4, 53.8, 28.6, 16.8, 12.5;

MS: [M-1] ^- = 575.7.

Example 51I: 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2,3-dihydroxypropyl)benzamide

Step 1: 4-bromo-N-(2,3-dihydroxypropyl)benzamide (2)

Methyl 4-bromobenzoate (2.41 g, 11.2 mmol) and 3-aminopropane-1,2-diol (1.12 g, 12.3 mmol) were heated to 125° C. for 4 hours. The mixture was diluted with MeOH, evaporated over celite and purified on a short column. (DCM+MeOH+formic acid (99+0+1 to 90+9+1). After evaporation of the solvents, the oily residue was dried at 0.05 mbar to crystallize. It was then triturated with diethyl ether to give 4-bromo-N- (2,3-dihydroxypropyl)benzamide (1.90 g, 6.93 mmol, 62% yield) as white solid ¹ H NMR (200 MHz, DMSO) δ 8.49 (s, 1H), 7, 73 (d, J=22.1 Hz, 4H), 4.72 (d, J=48.1 Hz, 2H), 3.83-2.99 (m, 5H), ¹³ C NMR (50 MHz, DMSO) δ 165.8, 133.7, 131.3, 129.5, 124.9, 70.4, 64.0, 43.2; [M-1] ^- = 271.7.

Step 2: N-(2,3-dihydroxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (3)

The vessel was charged with 4-bromo-N-(2,3-dihydroxypropyl)benzamide (656 mg, 2.39 mmol), bis(pinacolato)diborone (669 mg, 2.63 mmol), potassium acetate (705 mg, 7. 18 mmol) and degassed dry 1,4-dioxane (12.0 ml). The vessel was evacuated and refilled with argon (3x), XPhos Pd G3 (10.3 mg, 0.0120 mmol) was added and the mixture was stirred at 85°C for 2 hours. After cooling to room temperature, the mixture was diluted with EtOAc, stirred for 30 minutes and filtered through celite. The solvent was removed under reduced pressure. The residue was dissolved in a minimum amount of EtOAc, added dropwise to n-heptane with stirring, and the solids were collected by vacuum filtration to give N-(2,3-dihydroxypropyl)-4-(4,4,5,5-tetramethyl)-1 ,3,2-dioxaborolan-2-yl)benzamide (410 mg, 1.28 mmol, 53% yield), which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.91-7.65 (m, 4H), 1.30 (s, 12H), 1.15 (s, 4H), 1.07 (s, 2H);

¹³ C NMR (101 MHz, DMSO) δ 134.2, 126.5, 83.8, 81.3, 73.5, 70.3, 64.0, 39.5, 24.9, 24.6, 24.4.

Stage 3: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.10 (d, J=2.1 Hz, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.54 (t, J= 5.7Hz, 1H), 8.00(kv, J=8.5Hz, 4H), 7.64(td, J=9.0, 5.8Hz, 1H), 7.32(td, J=9.1, 1.3 Hz, 1H), 4.87 (d, J=5.1 Hz, 1H), 4.62 (t, J=5.7 Hz, 1H), 3.80- 3.58 (m, 1H), 3.26-3.02 (m, 3H), 1.75 (dc, J=14.9, 7.4 Hz, 2H), 0.97 (t, J= 7.4 Hz, 3H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 182.6, 166.1, 152.5, 142.0, 139.7, 133.9, 132.0, 128.2, 127.3, 113.6 , 70.4, 64.0, 53.8, 43.1, 16.9, 12.6;

MS: [M-1] ^- = 571.7.

Example 51m: 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-fluorobenzenesulfonamide

Stage 1: 4-bromo-3-fluorobenzenesulfonamide (2)

To an ice-cold solution of 4-bromo-3-fluorobenzenesulfonyl chloride (1, 1.03 g, 3.77 mmol) in acetonitrile (1.88 ml) was added dropwise 25% ammonia solution (1.46 ml, 9.41 mmol ). The mixture was stirred for 10 minutes at room temperature, diluted with water and extracted with diethyl ether. The extract was washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to give 4-bromo-3-fluorobenzenesulfonamide (0.780 g, 3.07 mmol, 82% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.95 (dd, J=8.2, 6.9 Hz, 1H), 7.75 (dd, J=8.4, 2.1 Hz, 1H), 7.64-7.57 (m, 3H);

¹³ C NMR (50 MHz, DMSO) δ 157.9 (d, J=249.0 Hz), 145.5 (d, J=6.1 Hz), 134.6, 123.2 (d, J= 3.8 Hz), 114.1 (d, J=25.3 Hz) 112.3 (d, J=20.8 Hz).

Step 2: 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (3)

The vessel was charged with 4-bromo-3-fluorobenzenesulfonamide (2.255 mg, 1.00 mmol), bis(pinacolato)diborone (280 mg, 1.10 mmol), potassium acetate (295 mg, 3.01 mmol) and degassed dry 1,4-dioxane (5.02 ml). The vessel was evacuated and refilled with argon (3x), XPhos Pd G4 (4.32 mg, 0.00502 mmol) was added and the mixture was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc and acetic acid (0.172 ml, 3.01 mmol), stirred for 30 minutes and filtered through celite. The solvent was removed under reduced pressure. The residue was dissolved in a minimum amount of EtOAc, precipitated with n-heptane and the solids were collected by suction filtration to give 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (220 mg, 0.7310 mmol, 73% yield), which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.91-7.09 (m, 5H), 1.42-0.95 (m, 12H);

¹³ C NMR (50 MHz, DMSO) δ 148.6 (d, J=8.2 Hz), 137.5 (d, J=8.3 Hz), 121.05 (d, J=2.1 Hz ), 112.48 (d, J=27.6 Hz), 83.9 73.6, 25.0, 24.7.

Stage 3: Suzuki combination according to the general procedure

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 15.06 (s, 1H), 9.83 (s, 1H), 8.95 (s, 1H), 8.81 (s, 1H), 7.99 ( t, J=8.0 Hz, 1H), 7.88 7.74 (m, 2H), 7.73-7.55 (m, 3H), 7.40-7.23 (m, 1H), 3.22-2.98 (m, 2H), 1.88-1.59 (m, 2H), 0.97 (t, J=). 7.4 Hz, 3H).

MS: [M-1] ^- = 551.7.

EXAMPLE 52

Compounds of Examples 52a-52c were prepared according to the procedure shown in Scheme 2.

Scheme 2

Stage 1: N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (2 )

To a suspension of N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (1, 0.333 g, 0.725 mmol)) dihydropyran (0.132 ml, 1.45 mmol) and p-toluenesulfonic acid monohydrate (0.0276 g, 0.145 mmol) were added to DCM (2.90 ml) and the mixture heated to reflux for 45 minutes. After cooling, the mixture was washed with sat. NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was dissolved in a minimum amount of DCM and added dropwise to n-hexane with stirring. After 5 minutes, the solids were collected by vacuum filtration and dried to give N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4 -difluorophenyl]propane-1-sulfonamide (0.297 g, 0.5470 mmol, 75% yield), which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.83 (s, 1H), 8.65 (s, 1H), 7.70 (dd, J=13.6, 8.1 Hz, 1H), 7 .02 (d, J=9.6 Hz, 2H), 6.14 (d, J=9.2 Hz, 1H), 4.14-3.64 (m, 2H), 3.22-2, 90 (m, 2H), 2.61-2.31 (m, 1H), 2.15-1.16 (m, 10H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 182.4, 151.0, 149.7, 140.7, 133.7, 127.33 (d, J=8.6 Hz), 121.36 (dd , J=13.1, 3.8 Hz), 116.8, 116.6, 112.44 (dd, J=22.6, 3.7 Hz), 83.3, 77.2, 68.2 , 54.1, 28.9, 24.8, 22.4, 17.3, 12.9;

MS: [M-1] ^- = 540.7.

Step 2: N-[2,4-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (3)

N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (2 , 271 mg, 0.499 mmol), bis(pinacolato)diborone (139 mg, 0.549 mmol) and anhydrous potassium acetate (147 mg, 1.50 mmol). Degassed dry 1,4-dioxane (4.99 ml) was added and the vessel was evacuated and refilled with argon (3x). 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium (1:1) (9.12mg, 0.0125mmol) was added and the mixture was stirred at 85°C overnight. After cooling to room temperature, the mixture was diluted with EtOAc, filtered through celite and the solvent was removed. The residue was dissolved in DCM, petroleum ether (60/90) was added and the DCM was removed under reduced pressure. After cooling for 1 hour at 4°C, the solids were collected by vacuum filtration and dried to give N-[2,4-difluoro-3-[1-(oxan-2-yl)-5-(4.4.5 G.). 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (267 mg, 0.4520 mmol, 91% yield) which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 9.11 (s, 1H), 8.94 (s, 1H), 7.68 (d, J=5.9 Hz, 1H), 7.12-6 .83 (m, 2H), 6.22 (d, J=9.0 Hz, 1H), 4.19-3.60 (m, 2H), 3.07 (s, 2H), 2.57- 1.11 (m, 23H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 182.5, 155.5, 152.4, 141.9, 139.3, 127.3 (d, J=9.0 Hz), 121.23 (dd , J=13.1, 4.0 Hz), 114.9, 112.33 (dd, J=23.2, 2.9 Hz), 84.4, 82.8, 77.2, 68.1 , 54.1, 29.0, 24.9, 22.5, 17.2, 12.9;

MS: [M-1] ^- = 588.9.

Example 52a 3-chloro-4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide

Stage 1: 4-bromo-3-chlorobenzenesulfonamide (2)

To an ice-cold solution of 4-bromo-3-chlorobenzenesulfonyl chloride (1, 0.450 g, 1.55 mmol) in acetonitrile (7.76 ml) was added 25% ammonia solution (0.602 ml, 3.88 mmol) dropwise. The mixture was stirred for 10 minutes at room temperature, diluted with water and extracted with EtOAc. The extract was washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to give 4-bromo-3-chlorobenzenesulfonamide (0.370 g, 1.37 mmol, 88% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 8.01 (d, J=8.1 Hz, 2H), 7.89-7.47 (m, 3H);

¹³ C NMR (50 MHz, DMSO) δ 144.9, 134.8, 133.8, 127.3, 125.8, 125.5;

MS: [M-1] ^- = 267.7.

Stage 2: 3-chloro-4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide (3)

The vessel was loaded with N-[2,4-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (71.0 mg, 0.120 mmol), tetrakis Pd (6.95 mg, 0.00601 mmol) and 4-bromo-3 -chlorobenzenesulfonamide (2 (39.0 mg, 0.144 mmol) and purged with argon. Degassed 1,4-dioxane (0.401 ml) and degassed aqueous 1.5 M potassium carbonate (0.240 ml, 0.361 mmol) were added and the vessel was evacuated and filled argon (3x) The mixture was heated to 55°C for 1 h, the Mixture was cooled to room temperature, diluted with iPrOH, conc HCl was added until the mixture became strongly acidic, and stirring was continued at 70°C overnight. After cooling to room temperature, solid NaHCO ₃ was added to neutralize the mixture, the solvents were removed and the residue was purified by flash chromatography (DCM+EtOAc 20% to 60%) to give 3-chloro-4-[3-[2,6-difluoro- 3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide (23.0 mg, 0.0378 mm ol, yield 31%).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 8.82 (d, J=2.0 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H), 7.96-7.81 ( m, 2H), 7.74-7.55 (m, 3H) 7.31 (t, J=8.7 Hz, 1H), 3.19-3.05 (m, 3H), 1.87- 1.62 (m, 2H), 0.97 (t, J=7.5 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 183.1, 152.7, 151.3, 145.9, 142.5, 140.2, 133.4, 132.9, 131.2, 130.6, 127.3, 125.2, 122.4, 113.3, 54.4, 17.3, 13.1;

MS: [M-1] ^- = 567.9.

Example 52b: 4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-fluorobenzenesulfonamide

Stage 1: 4-bromo-2-fluorobenzenesulfonamide (2)

To an ice-cold solution of 4-bromo-2-fluorobenzenesulfonyl chloride (1, 0.450 g, 1.55 mmol) in acetonitrile (10.6 ml) was added 25% ammonia solution (0.823 ml, 5.30 mmol) dropwise. The mixture was stirred for 10 minutes at room temperature, diluted with water and extracted with EtOAc. The extract was washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to give 4-bromo-2-fluorobenzenesulfonamide (0.520 g, 2.05 mmol, 97% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.87-7.67 (m, 4H), 7.60 (dd, J=8.6, 1.5 Hz, 1H);

¹³ C NMR (50 MHz, DMSO) δ 158 (d, J=258 Hz), 131.1 (d, J=15 Hz), 129.9, 127.9 (d, J=4 Hz), 126, 4 (d, J=9 Hz) 120.5 (d, J=25 Hz);

MS: [M-1] ^- = 251.8.

Step 2: 4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-fluorobenzenesulfonamide (3)

The vessel was loaded with N-[2,4-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (74.0 mg, 0.125 mmol), 4-bromo-2-fluorobenzenesulfonamide (35.0 mg, 0.138 mmol) and XPhos Pd G3 (1.06 mg, 0.00125 mmol) and purged with argon. Degassed 1,4-dioxane (0.401 ml) and degassed aqueous 1.5 M potassium carbonate (0.240 ml, 0.361 mmol) were added and the vessel was evacuated and filled with argon (3x). The mixture was heated to 55°C for 2 hours. The mixture was cooled to room temperature, diluted with iPrOH (3 ml), conc. HCl was added until the mixture became strongly acidic and stirring was continued at 70° C. overnight. After cooling to room temperature, solid NaHCO ₃ was added to neutralize the mixture, the solvents were removed and the residue was purified by flash chromatography (DCM+EtOAc 20% to 60%) to give 4-[3-[2,6-difluoro-3-(propylsulfonylamino )benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-fluorobenzenesulfonamide (26.0 mg, 0.0460 mmol, 37% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 15.01 (s, 1H), 9.81 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H), 8.14- 7.53 (m, 6H), 7.43-7.21 (m, 1H), 3.21-3.06 (m, 2H), 1.90-1.63 (m, 2H), 0. 97 (t, J=7.5 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 159.6, 157.1, 155.0, 155.0, 154.0, 153.9, 152.5, 149.8, 143.2, 143.2, 142.0, 130.8, 130.7, 130.3, 130.2, 129.9, 129.8, 129.0, 128.6, 123.3 123.3, 121.8 , 121.8, 121.7, 121.7, 116.0, 115.7, 113.3, 112.2, 112.2, 112.0, 53.8, 16.7, 12.5, all registered peaks;

MS: [M-1] ^- = 551.9.

Example 52c: 4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methylbenzenesulfonamide

Stage 1: 4-bromo-3-methylbenzenesulfonamide (2):

To an ice-cold solution of 4-bromo-3-methylbenzenesulfonyl chloride (1, 0.690 g, 2.76 mmol) in acetonitrile (1.48 ml) was added 25% ammonia solution (1.15 ml, 7.42 mmol) dropwise. The mixture was stirred for 10 minutes at room temperature, diluted with water and extracted with diethyl ether. The extract was washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to give 4-bromo-3-methylbenzenesulfonamide (0.690 g, 2.76 mmol, 93% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.86-7.72 (m, 2H), 7.56 (ddd, J=8.4, 2.3, 0.5 Hz, 1H), 7.43 (s, 2H), 2.41 (s, 3H);

¹³ C NMR (50 MHz, DMSO) δ 143.5, 138.5, 132.8, 127.9, 125.0, 22.6;

MS: [M-1] ^- = 247.7.

Step 2: 4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methylbenzenesulfonamide (3)

The vessel was loaded with N-[2,4-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (75.0 mg, 0.127 mmol), 4-bromo-3-methylbenzenesulfonamide (34.9 mg, 0.140 mmol) and XPhos Pd G3 (2.69 mg, 0.00318 mmol) and purged with argon. Degassed 1,4-dioxane (0.401 ml) and degassed aqueous 1.5 M potassium carbonate (0.240 ml, 0.361 mmol) were added and the vessel was evacuated and filled with argon (3x). The mixture was heated to 55°C for 1.5 hours. The solvent was removed under reduced pressure, the residue was dissolved in 2 ml of THF and 1.25 M HCl in iPrOH and stirred at 70°C overnight. The solvent was removed, the residue was neutralized with NaHCO ₃ and was extracted with EtOAc. The solvent was removed and the residue was purified by flash chromatography (DCM+EtOAc 10 to 50%) and triturated with DCM to give 4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3, 4-b]pyridin-5-yl]-3-methylbenzenesulfonamide (41.0 mg, 0.0739 mmol, 58% yield).

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 15.00 (s, 1H), 9.82 (s, 1H), 8.76 (d, J=2.0 Hz, 1H), 8.55 (d, J=1.9Hz, 1H), 7.84(s, 1H), 7.78(dd, J=8.0, 1.3Hz, 1H), 7.67-7.56(m, 2H ), 7.44 (s, 2H), 7.31 (t, J=8.7 Hz, 1H), 3.16-3.07 (m, 2H), 1.80-1.69 (m, 2H), 0.97 (t, J=7.4 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.5, 152.0, 150.7, 143.7, 141.8, 141.0, 136.6, 132.4, 130.9, 129.9, 127.3, 123.3, 113.0, 53.8, 20.1, 16.8, 12.5;

MS: [M-1] ^- = 547.9.

EXAMPLE 53

Compounds of Example 53a-53c were prepared according to the procedure shown in Scheme 3.

Scheme 3

Stage 1: 5-bromo-N-methoxy-N-methyl-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carboxamide

To a suspension of 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (4.43 g, 15.5 mmol) in DCM (62.2 ml) was added dihydropyran (2.84 ml, 31.1 mmol) and p-toluenesulfonic acid monohydrate (0.591 g, 3.11 mmol) and the mixture heated to reflux for 30 minutes. After cooling, the mixture was washed with sat. NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexane+EtOAc 10% to 50%) to give 5-bromo-N-methoxy-N-methyl-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3- carboxamide (5.05 g, 13.7 mmol, 88% yield) as an oil which solidified after high vacuum drying and standing.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.69 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.2 Hz, 1H), 6.12 (dd, J =10.0, 2.4 Hz, 1H), 4.15-4.01 (m, 1H), 3.93-3.71 (m, 4H), 3.54 (s, 3H), 2, 71-2.48 (m, 1H), 2.22-1.65 (m, 5H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 150.5, 149.0, 136.5, 134.2, 118.3, 115.1, 83.0, 68.2, 61.9, 29.2 , 25.0, 22.8;

MS: [M+H] ⁺ =390.8.

Step 2a: (3-amino-2,6-difluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]methanone:

2M lithium diisopropylamide ( 6.32 ml, 12.6 mmol) in THF/heptane/ethylbenzene dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. 5-Bromo-N-methoxy-N-methyl-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carboxamide (1.06 g, 2.87 mmol) was added and the mixture was cooled to -30°C. Lithium diisopropylamide (3.16 mL, 6.32 mmol) in THF/heptane/ethylbenzene was added dropwise and the mixture was stirred at -15° C. for 10 minutes. 2N HCl (20 ml) was added and stirring was continued at room temperature for 20 minutes. The pH of the mixture was adjusted to ~9 with 2N NaOH and extracted with EtOAc. The extract was washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed. The residue was purified by flash chromatography (hexane+EtOAc, 10 to 40%) to give (3-amino-2,6-difluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4- b]pyridin-3-yl]methanone (0.732 g, 1.67 mmol, 58% yield) as a yellow solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 8.86 (d, J=2.2 Hz, 1H), 8.79 (d, J=2.2 Hz, 1H), 7.31-6.69 ( m, 2H), 6.14 (dd, J=9.8, 2.0 Hz, 1H), 5.28 (s, 2H), 4.02-3.85 (m, 1H), 3.81 -3.62 (m, 1H), 2.42-2.14 (m, 1H), 2.04-1.46 (m, 5H);

¹³ C NMR (50 MHz, DMSO) δ 183.7, 151.0, 149.1, 140.3, 132.8, 116.3, 115.5, 82.9, 67.1, 28.4, 24.4, 21.6;

MS: [M+Na] ⁺ =458.9.

Step 2b: (3-amino-2,4,6-trifluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]methanone:

2M diisopropylamide lithium (5.36 ml, 10.7 mmol) in THF/heptane/ethylbenzene dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. 5-Bromo-N-methoxy-N-methyl-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carboxamide (1.06 g, 2.87 mmol) was added and the mixture was cooled to -30°C. Lithium diisopropylamide (2.68 ml, 5.36 mmol) in THF/heptane/ethylbenzene was added dropwise and the mixture was stirred at -15° C. for 20 minutes. 2N HCl (20 ml) was added and stirring was continued at room temperature for 10 minutes. The pH of the mixture was adjusted to pH 9 using 2N NaOH and extracted with EtOAc. The extracts were washed with saline, dried over Na ₂ SO ₄ and the solvent was removed. TLC-MS showed almost no deprotection of the TMS groups. The residue was dissolved in 10 ml THF, 1 ml conc. HCl was added. The unprotection was completed immediately. After dilution with EtOAc, solid K ₂ CO ₃ was added, the suspension was filtered and the solvent was removed. The residue was purified by flash chromatography (hexane+EtOAc 5 to 25%). Yield: 715 mg, 64%.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 8.85 (d, J=2.1 Hz, 1H), 8.79 (d, J=2.2 Hz, 1H), 7.34-7.16 ( m, 1H), 6.14 (d, J=8.4 Hz), 1H), 5.36 (s, 2H), 4.03-3.82 (m, 1H), 3.84-3, 58 (m, 1H), 2.44-2.17 (m, 1H), 2.05-1.51 (m, 5H);

¹³ C NMR (50 MHz, DMSO) δ 183.7, 151.0, 149.1, 140.3, 132.8, 116.3, 115.5, 82.9, 67.1, 28.4, 24.4, 21.6;

MS: [M+Na] ⁺ =476.9.

Example 53a 4-[3-[2,6-difluoro-3-(phenylsulfamoylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide

Step 1: Preparation of sodium N-phenylsulfamate (2)

Aniline (1, 3.95 g, 42.4 mmol) and triethylamine (59.1 ml, 424 mmol) were dissolved in DCM (106 ml). Chlorosulfuric acid (2.82 ml, 42.4 mmol) was added dropwise at -5°C and the mixture was stirred for 10 minutes. The mixture was concentrated in vacuo and the solid was dissolved in 1 N sodium hydroxide (84.8 ml, 84.8 mmol). The mixture was concentrated to dryness in vacuo. The product was suspended in about 500 ml of boiling EtOH, filtered while hot and reduced to about 150 ml. After cooling to 7° C. overnight, the product was collected by filtration and dried in vacuo to give sodium N-phenylsulfamate (3.94 g, 20.2 mmol, 48% yield) as a white solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.90 (s, 1H), 7.15-7.01 (m, 4H), 6.74-6.63 (m, 1H);

¹³ C NMR (50 MHz, DMSO) δ 143.7, 128.2, 118.5, 116.3.

Stage 2: obtaining phenylsulfamoyl chloride (3)

Sodium N-phenylsulfamate (2.12 g, 5.74 mmol) and phosphorus pentachloride (1.20 g, 5.74 mmol) were heated in toluene (19.1 ml) at 80° C. in an oil bath for 6 hours. The reaction mixture was filtered and concentrated in vacuo to give N-phenylsulfamoyl chloride (0.990 g, 5.17 mmol, 90% yield) as an oil which solidifies on standing. The product was used without further purification and characterization.

Step 3: [5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]-[2,6-difluoro-3-(phenylsulfamoylamino)phenyl]methanone (4)

To a solution of (3-amino-2,6-difluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]methanone (0.127 g, 0.290 mmol) and triethylamine (0.0607 ml, 0.436 mmol) in DCM (1.45 ml) was added N-phenylsulfamoyl chloride (0.0724 g, 0.378 mmol) in DCM (1.45 ml) at 0°C. After stirring for 10 minutes at room temperature, the mixture was diluted with DCM, washed with water and NH ₄ Cl solution, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to give [5-bromo-1-(oxan-2-yl )) pyrazolo[3,4-b]pyridin-3-yl]-[2,6-difluoro-3-(phenylsulfamoylamino)phenyl]methanone (0.170 g, 0.2870 mmol, 99% yield), which was used without additional cleaning. 2 ml of Et2O was added to the sticky oil and the solvent was quickly removed in vacuo to give the product as a foamy solid.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.89 (d, J=2.1 Hz, 1H), 8.71 (d, J=2.1 Hz, 1H), 7.73 (td, J =8.9, 5.4Hz, 1H), 7.47-6.97(m, 8H), 6.21(dd, J=9.7, 2.1Hz, 1H), 3.97( dd, J=46.6, 10.1 Hz, 2H), 2.66-2.39 (m, 1H), 2.22-1.56 (m, 5H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 182.4, 151.0, 149.6, 140.7, 136.0, 133.7, 129.5, 125.8, 121.6, 116.8 , 116.6, 83.4, 68.2, 29.0, 24.8, 22.4;

MS: [M-1] ^- = 589.8.

Step 4: 4-[3-[2,6-difluoro-3-(phenylsulfamoylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide (5)

[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]-[2,6-difluoro-3-(phenylsulfamoylamino)phenyl]methanone (4, 0.0880 g, 0.149 mmol), (4-sulfamoylphenyl)boronic acid (32.8 mg, 0.163 mmol) and XPhos Pd G3 (3.77 mg, 0.00446 mmol) and purged with argon. Degassed 1,4-dioxane (0.495 ml) and degassed 1.5 M aqueous potassium carbonate (0.297 ml, 0.446 mmol) were added and the mixture was stirred at 65°C for 1.5 hours. Sat. a solution of NH ₄ Cl and EtOAc was added and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and evaporated. The residue was dissolved in THF (3 ml) and TFA (300 μl) was added at room temperature. After stirring overnight, another 300 μl TFA was added and stirring was continued for 2 hours (10-12 hours). (Still no conversion) The mixture was concentrated and taken up in DCM (3 ml) and sonicated. An additional 300 μl of TFA was added and stirring was continued at room temperature. After 3 h, 3 ml of TFA was added at room temperature and the mixture was stirred overnight and quenched in NaHCO ₃ solution. The aqueous layer was extracted with EtOAc, the extract was dried over Na ₂ SO ₄ and the solvent was removed. The product was purified by flash chromatography (DCM+MeOH 3% to 13%) to give 4-[3-[2,6-difluoro-3-(phenylsulfamoylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridine- 5-yl]benzenesulfonamide (34.0 mg, 0.0547 mmol, 37% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.96 (s, 1H), 10.20 (s, 1H), 10.09 (s, 1H), 9.09 (d, J=1.9 Hz, 1H), 8.84 (d, J=1.9 Hz), 1H), 8.14-7.89 (m, 4H), 7.60-7.41 (m, 3H), 7.37- 7.15 (m, 5H), 7.02 (t, J=6.9 Hz, 1H);

MS: [M-1] ^- = 583.0.

Example 53b: 4-[3-[2,6-difluoro-3-(sulfamoylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide

Stage 1: Obtaining tert-butyl N-chlorosulfonylcarbamate (2)

To a solution of chlorosulfonyl isocyanate (1, 1.78 ml, 20.4 mmol) in toluene (8.17 ml) was slowly added a solution of 2-methylpropan-2-ol (1.66 g, 22.5 mmol) in toluene (1. 16 ml). The mixture was stirred at room temperature for 1 hour. Hexane (23.1 ml) was added and the solution was stirred for 30 minutes. The resulting precipitate was filtered off and washed with hexane to give tert-butyl-N-chlorosulfonylcarbamate (3.33 g, 15.4 mmol, 76% yield) as a white solid which was stored under nitrogen at -20°C.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 1.56 (s, 9H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 148.0, 87.3, 27.9.

Step 2: tert-Butyl N-[[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4-difluorophenyl]sulfamoyl]carbamate ( 3)

To a solution of (3-amino-2,6-difluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]methanone (3, 0.126 g). , 0.288 mmol) and triethylamine (0.0602 ml, 0.432 mmol) in DCM (1.15 ml) was added tert-butyl-N-chlorosulfonylcarbamate (0.0808 g, 0.375 mmol) in DCM (1 ml) at 0°C . After stirring for 10 minutes at room temperature, the mixture was diluted with DCM, washed with water and NH ₄ Cl solution, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to give tert-butyl N-[[3-[5-bromo -1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4-difluorophenyl]sulfamoyl]carbamate (0.176 g, 0.2860 mmol, 99% yield) as yellow foam which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.89 (d, J=1.8 Hz, 1H), 8.70 (d, J=1.8 Hz, 1H), 7.74 (td, J =8.9, 5.8 Hz, 1H), 7.06 (t, J=8.4 Hz, 1H), 6.19 (d, J=7.6 Hz, 1H), 4.08 (d , J=11.1 Hz, 1H), 3.91-3.72 (m, 1H), 2.66-2.39 (m, 1H) 2.22-1.90 (m, 2H), 1 .88-1.57 (m, 3H), 1.45 (s, 9H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 182.4, 151.0, 150.4, 149.7, 140.7, 133.7, 116.8, 116.6, 84.2, 83.5 , 77.2, 68.2, 46.0, 27.9, 24.8, 22.4.

MS: [M-1] ^- = 613.9.

Step 3: 4-[3-[2,6-difluoro-3-(sulfamoylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide (4)

The vessel was loaded with tert-butyl N-[[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4-difluorophenyl]sulfamoyl]carbamate (3, 129 mg, 0.209 mmol), (4-sulfamoylphenyl)boronic acid (46.3 mg, 0.230 mmol) and XPhos Pd G3 (5.31 mg, 0.00628 mmol) and purged with argon. Degassed 1,4-dioxane (0.698 ml) and degassed 1.5 M aqueous potassium carbonate (0.419 ml, 0.628 mmol) were added and the mixture was stirred at 65°C for 1.5 hours. Sat. a solution of NH ₄ Cl and EtOAc was added and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and evaporated. The residue was dissolved in DCM (3 ml) and TFA (300 μl) was added at room temperature. After stirring overnight, the mixture was quenched in NaHCO ₃ solution and extracted with EtOAc. The extract was dried over Na ₂ SO ₄ and the solvent was removed. The product was purified by flash chromatography (DCM+MeOH 1% to 11%) to give 4-[3-[2,6-difluoro-3-(sulfamoylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridine- 5-yl]benzenesulfonamide (37.0 mg, 0.0728 mmol, 35% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.96 (s, 1H), 9.32 (s, 1H), 9.10 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.0Hz, 1H), 8.02 (dd, J=20.7, 8.4Hz, 4H), 7.68 (td, J=8.9, 5.9Hz, 1H), 7.47 (s, 2H), 7.36-7.13 (m, 3H);

MS: [M-1] ^- = 507.0.

Example 53c: 4-[3-[2,4,6-trifluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide

Step 1: N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4,6-trifluorophenyl]-N-propylsulfonylpropan- 1-sulfonamide (2)

To (3-amino-2,4,6-trifluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]methanone (1, 0.289 g, 0.635 mmol) and triethylamine (0.133 ml, 0.952 mmol) in DCM (2.54 ml) were added slowly 1-propanesulfonyl chloride (0.0715 ml, 0.635 mmol) at 0°C. After stirring at room temperature for 15 minutes, the mixture was diluted with DCM, washed with NH ₄ Cl solution, dried over Na ₂ SO ₄ and the solvents were removed. The residue was purified by flash chromatography (hexane+EtOAc, 0 to 25%) to give N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl ]-2,4,6-trifluorophenyl]-N-propylsulfonylpropane-1-sulfonamide (0.233 g, 0.3490 mmol, 55% yield). The resulting oil was dissolved in DCM, hexane was added and the solvents were removed. Yellowish solid.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.81 (d, J=2.0 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H), 6.97 (td, J =9.1, 1.8 Hz, 1H), 6.15 (dd, J=9.9, 2.2 Hz, 1H), 4.03 (d, J=11.1 Hz, 1H), 3 .88-3.48 (m, 5H), 2.53 (dd, J=20.4, 11.9 Hz, 1H), 2.15-1.51 (m, 9H), 1.07 (td , J=7.4, 3.9 Hz, 6H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 182.4, 151.0, 150.4, 149.7, 140.7, 133.7, 116.8, 116.6, 84.2, 83.5 , 77.2, 68.2, 46.0, 27.9, 24.8, 22.4.

MS: [M+Na] ⁺ =688.8.

Stage 2: N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4,6-trifluorophenyl]propane-1-sulfonamide (3)

To a solution of N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4,6-trifluorophenyl]-N-propylsulfonylpropan-1 -sulfonamide (2, 0.227 g, 0.340 mmol) in tetrahydrofuran (1.2 ml) and MeOH (0.40 ml) was added 1 M aqueous NaOH solution (1.02 ml, 1.02 mmol). After stirring for 1 hour, water (3 ml) was added and the organic solvents were evaporated. 2N HCl was added to neutralize the mixture. The solids were collected by vacuum filtration and dried to give N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4,6- trifluorophenyl]propane-1-sulfonamide (0.159 g, 0.2830 mmol, 83% yield) as a yellowish solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.70 (s, 1H), 8.84 (d, J=10.9 Hz, 2H), 7.62 (t, J=9.3 Hz, 1H) , 6.15 (d, J=8.6 Hz, 1H), 4.08-3.59 (m, 2H), 3.25-3.06 (m, 2H), 2.40-2.16 (m, 1H), 2.08-0.76 (m, 10H);

¹³ C NMR (50 MHz, DMSO) δ 151.2, 149.2, 139.8, 132.7, 116.6, 115.5, 82.9, 67.1, 54.8, 28.4, 24.4, 21.7, 16.9, 12.6;

MS: [M-1] ^- =559.0.

Step 3: 4-[3-[2,4,6-trifluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide (4)

N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,4,6-trifluorophenyl]propane-1 was loaded into the vessel. -sulfonamide (3, 0.113 g, 0.201 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (62.7 mg, 0.221 mmol) and XPhos Pd G3 (4.26 mg, 0.00503 mmol) and purged with argon. Degassed 1,4-dioxane (0.671 ml) and degassed 1.5 M potassium carbonate (0.403 ml, 0.604 mmol) were added and the mixture heated to 65°C for 1 hour. NH ₄ Cl solution was added and the mixture was extracted with EtOAc. The extracts were washed with saline, dried over Na ₂ SO ₄ and the solvent was removed. The residue was dissolved in DCM (3 ml) and TFA (300 μl) was added and the mixture was stirred at room temperature overnight. Added 3 ml of TFA and stirring was continued for 1 hour. The reaction mixture was quenched with NaHCO ₃ solution, extracted with EtOAc, dried over Na ₂ SO ₄ and the solvent was removed. The residue was purified by flash chromatography (DCM+MeOH 1% to 11%) to give 4-[3-[2,4,6-trifluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b] pyridin-5-yl]benzenesulfonamide (60.0 mg, 0.1070 mmol, 53% yield).

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 15.02 (s, 1H), 9.66 (s, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.1Hz, 1H), 8.02(dd, J=37.6, 8.5Hz, 4H), 7.59(t, J=9.4Hz, 1H), 7.47( s, 2H), 3.14 (dd, J=8.7, 6.6 Hz, 2H), 1.88-1.73 (m, 2H), 0.99 (t, J=7.4 Hz , 3H);

¹³ C NMR (101 MHz, DMSO) δ 181.5, 152.4, 149.9, 143.5, 141.8, 140.3, 131.5, 128.2, 127.9, 126.4, 113.4, 54.7, 16.8, 12.5;

MS: [M-1] ^- = 552.0.

Example 53d: 4-[3-[3-(ethylsulfamoylamino)-2,6-difluorobenzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide (5)

Stage 1: N-ethylsulfamoyl chloride (2)

By analogy with the procedure described in the literature: a mixture of ethylamine hydrochloride (2.00 g, 24.5 mmol) and sulfuryl chloride (7.93 ml, 98.1 mmol) in acetonitrile (4.91 ml) was heated to 75 ° C in during the night. The mixture was evaporated, treated with diethyl ether and filtered. The solvent was removed to give N-ethylsulfamoyl chloride (3.28 g, 22.8 mmol, 93% yield), which was used without further characterization.

Step 2: [5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]-[3-(ethylsulfamoylamino)-2,6-difluorophenyl]methanone (4)

To a solution of (3-amino-2,6-difluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]methanone (90.0 mg, 0.206 mmol) and triethylamine (0.0373 ml, 0.268 mmol) in DCM (0.823 ml) was added N-ethylsulfamoyl chloride (35.5 mg, 0.247 mmol) in DCM (0.823 ml) at 0°C. After stirring for 10 minutes at room temperature, the mixture was diluted with DCM, washed with water and NH ₄ Cl solution, dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to give [5-bromo-1-(oxan-2-yl )pyrazolo[3,4-b]pyridin-3-yl]-[3-(ethylsulfamoylamino)-2,6-difluorophenyl]methanone (4, 0.110 g, 0.202 mmol, 98% yield) as a yellow foam which was used without further purification.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.85 (s, 1H), 8.67 (s, 1H), 7.69 (td, J=8.9, 5.6 Hz, 1H), 7 .01 (t, J=8.9 Hz, 1H), 6.73 (s, 1H), 6.15 (d, J=7.5 Hz, 1H), 4.75 (t, J=5, 9 Hz, 1H), 4.13-3.97 (m, 1H), 3.90-3.67 (m, 1H), 3.24-3.04 (m, 2H), 2.63-2 .31 (m, 1H), 2.21-1.51 (m, 5H), 1.16 (t, J=7.2 Hz, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 182.6, 156.8 (dd, J=252.0, 6.7 Hz), 151.5 (dd, J=250.7, 7.5 Hz) , 151.1, 149.7, 140.8, 133.8, 125.8 (dd, J=9.8, 2.0 Hz), 122.0 (dd, J=12.7, 3.5 Hz), 116.8, 116.6, 112.29 (dd, J=22.2, 3.8 Hz), 83.4, 68.3, 38.6, 29.0, 24.8, 22 .5, 15.1.

Step 3: 4-[3-[3-(ethylsulfamoylamino)-2,6-difluorobenzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide (5)

[5-Bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]-[3-(ethylsulfamoylamino)-2,6-difluorophenyl]methanone (4) was loaded into the vessel. 94.0 mg, 0.173 mmol), (4-sulfamoylphenyl)boronic acid (38.2 mg, 0.190 mmol) and XPhos Pd G3 (4.38 mg, 0.00518 mmol) and purged with argon. Degassed 1,4-dioxane (0.576 ml) and degassed 1.5 M aqueous potassium carbonate (0.345 ml, 0.518 mmol) were added and the mixture was stirred at 65°C for 1.5 hours. Sat. a solution of NH ₄ Cl and EtOAc was added and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and evaporated. The residue was dissolved in DCM (3 ml) and TFA (300 μl) was added at room temperature. After 4 hours the mixture was quenched with NaHCO ₃ solution and extracted with EtOAc. The extract was dried over Na ₂ SO ₄ and the solvent was removed. The product was purified by flash chromatography (DCM+MeOH 1% to 11%) to give 4-[3-[3-(ethylsulfamoylamino)-2,6-difluorobenzoyl]-1H-pyrazolo[3,4-b]pyridine-5 -yl]benzenesulfonamide (5, 35.0 mg, 0.0652 mmol, 38% yield).

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 14.97 (s, 1H), 9.54 (s, 1H), 9.10 (d, J=2.0 Hz, 1H), 8.86 (d, J=1.9Hz, 1H), 8.02 (dd, J=38.5, 8.3Hz, 4H), 7.64 (td, J=9.0, 5.9Hz, 1H), 7.51-7.41 (m, 3H), 7.30 (t, J=8.7 Hz, 1H), 3.04-2.88 (m, 2H), 1.04 (t, J= 7.2 Hz, 3H);

¹³ C NMR (101 MHz, DMSO) δ 182.8, 162.8, 152.4, 149.8, 143.5, 142.0, 140.3, 131.4, 128.2, 127.9, 126.4, 113.4, 37.2, 14.6;

MS: [M-1] ^- = 535.0.

Example 54: Synthesis of N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]methanesulfonamide (6)

Step 1: N-(2,6-difluorophenyl)acetamide

2,6-difluoroaniline (1.33 g, 25.9 mmol) and acetic anhydride (2.56 ml, 27.2 mmol) were combined in DCM (34.5 ml) and stirred overnight at room temperature. The reaction mixture was diluted with DCM (50 ml), washed with water and saturated sodium bicarbonate, dried over Na ₂ SO ₄ and evaporated to give N-(2,6-difluorophenyl)acetamide (2, 3.88 g, 22.7 mmol, yield 88%) as a white solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.69 (s, 1H), 7.43-7.23 (m, 1H), 7.13 (t, J=7.9 Hz, 2H), 2, 08 (s, 3H);

¹³ C NMR (50 MHz, DMSO) δ 168.5, 160.4, 160.3, 155.5, 155.4, 128.0, 127.8, 127.6, 115.1, 114.7, 114.4, 112.1, 112.0, 111.9, 111.8, 111.6, 111.6, 22.4, all peaks recorded;

MS: [M+H] ⁺ =171.9.

Stage 2: 3-bromo-2,6-difluoroaniline (3)

N-(2,6-difluorophenyl)acetamide (2, 8.77 g, 51.2 mmol) was dissolved in sulfuric acid (41.0 ml, 769 mmol) and N-bromosuccinimide (9.12 g, 51.2 mmol ) was added in portions at room temperature. The reaction mixture was stirred overnight at room temperature and slowly quenched with stirring in ice water (400 ml). The solids were collected by vacuum filtration and washed again with water, hexane, hexane+EtOAc (8+2) and again with hexane. The solids were dissolved in ethanol (30.0 ml) and conc. HCl (30 ml) and refluxed for 3 hours. The mixture was poured onto ice (400 g), neutralized with solid NaOH and the solids collected by vacuum filtration, washed with water and dried under vacuum to give 3-bromo-2,6-difluoroaniline (3.7.83 g, 37.6 mmol, yield 73%).

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 6.95-6.59 (m, 2H), 3.84 (s, 2H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 152.2 (dd, J=133.8, 6.5 Hz), 147.5 (dd, J=132.7, 6.9 Hz), 125.4 (t, J=16.9 Hz), 122, 119.6 (d, J=8.4 Hz), 111.7 (dd, J=19.9, 3.1 Hz), 103.8 (dd , J=19.2, 3.8 Hz).

Step 3: (3-amino-2,4-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (5)

To 3-bromo-2,6-difluoroaniline (3, 12.9 g, 61.9 mmol) in tetrahydrofuran (76.9 ml) was added dropwise 2M isopropylmagnesium chloride in THF (30.9 ml, 61.9 mmol) at 0°C and stirred for 15 minutes at room temperature. After cooling to 0°C, chlorotrimethylsilane (7.85 ml, 61.9 mmol) was added and the mixture was heated to 25°C and stirred for 20 minutes. The suspension was cooled to 0° C. and 2M isopropylmagnesium chloride in THF (30.9 ml, 61.9 mmol) was added dropwise and stirred for 15 minutes at room temperature. After cooling to 0°C, chlorotrimethylsilane (7.85 ml, 61.9 mmol) was added, stirring was continued for 20 minutes at 25°C. The suspension was again cooled to 0°C and 2M isopropyl magnesium chloride in THF (30.9 ml, 61.9 mmol) was added dropwise and the mixture was stirred for 10 minutes at 0°C (solution A). Meanwhile, 2M isopropylmagnesium chloride in THF (13.5 mL, 26.9 mmol) was added dropwise to a suspension of 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (4, 7.67 g, 26.9 mmol) in tetrahydrofuran (76.9 ml) at 0°C. The resulting suspension was stirred for 5 minutes and transferred to solution A. The reaction mixture was stirred overnight at room temperature, conc. HCl (26.9 ml, 323 mmol) was added and stirred for 10 minutes. Water was added until the phases were clear. The mixture was neutralized with 2N NaOH, saturated with NaCl and extracted with THF. The extracts were washed with brine, dried over Na ₂ SO ₄ and filtered. After evaporation of the solvent, the solids were stirred in 100 ml of DCM, collected by vacuum filtration, and dried to give 6.35 g of the first precursor as a light yellow solid. The filtrate was evaporated, triturated with diethyl ether and DCM to give the second precursor (0.41 g). Total yield of (3-amino-2,4-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone (5, 6.76 g, 19.1 mmol, yield 71%).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.55 (s, 1H), 8.65 (dd, J=5.2, 2.1 Hz, 2H), 7.13-6.86 (m, 2H ), 5.44 (s, 2H);

¹³ C NMR (50 MHz, DMSO) δ 186.1, 153.5 (dd, J=188, 9 Hz), 150.8, 150.3, 148.6 (dd, J=191, 9 Hz), 141.1, 132.5, 126.1 (t, J=17). Hz), 122.8 (dd, J=12, 3 Hz), 116.2 (dd, J=9, 3 Hz), 115.4, 115, 110.6 (dd, J=19, 3 Hz) ;

MS: [M-1] ^- = 351.2.

Step 4: N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]methanesulfonamide (6)

To a suspension of (3-amino-2,4-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (5, 0.620 g, 1.76 mmol) in pyridine ( 2.83 ml, 35.1 mmol) was added methanesulfonyl chloride (0.544 ml, 7.02 mmol) at room temperature 50°C for 2 hours. The reaction mixture was concentrated and dissolved in 2 M sodium hydroxide solution (13.2 ml, 26.3 mmol) and stirred for 15 minutes. The solution was poured into chilled 3N HCl 20 ml, extracted with EtOAc and the extracts washed with 2N HCl, dried over Na ₂ SO ₄ and evaporated. The product was purified by flash chromatography (DCM+EtOAc 0 to 40%) to give N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl] methanesulfonamide (0.390 g, 0.9040 mmol, 52% yield) as a red solid.

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 14.87 (s, 1H), 9.75 (s, 1H), 8.71 (d, J=13.9 Hz, 2H), 7.85 (d, J=6.6 Hz, 1H), 7.39 (t J=8.5 Hz, 1H), 3.12 (s, 3H);

¹³ C NMR (101 MHz, DMSO) δ 184.7, 160.8 (dd, J=255, 3 Hz), 157.06 (dd, J=257.4, 4.2 Hz), 150.8, 150.5, 140.9, 132.4, 130.6 (dd, J=10, 3 Hz), 123.3 (dd, J=13, 3 Hz), 115.4, 115.1, 114, 3 (t, J=17 Hz), 111.9 (dd, J=21.3 Hz), 41.5;

MS: [M-1] ^- = 429.1.

Example 54a N-[2,6-difluoro-3-[5-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl] methanesulfonamide

The microwave chamber was loaded with N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]methanesulfonamide (60.0 mg, 0.139 mmol), XPhos Pd G3 (3.53 mg, 0.00417 mmol) and [4-(1H-tetrazol-5-yl)phenyl]boronic acid (31.7 mg, 0.167 mmol) and purged with argon. Degassed 1,4-dioxane (0.464 ml) and degassed aqueous 1.5 M potassium carbonate (0.325 ml, 0.487 mmol) were added and the mixture was heated to 110°C under microwave irradiation for 60 minutes. After cooling, the mixture was diluted with EtOAc and neutralized with saturated NH ₄ Cl solution. The organic phase was concentrated under reduced pressure and the product was isolated by flash chromatography (DCM + MeOH (+ 1% formic acid) from 5% to 15%), triturated with MeOH and dried at 100°C in a vacuum oven to give N-[ 2, 6-difluoro-3-[5-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (21.0 mg, 0 , 0423 mmol, 30% yield.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.85 (s, 1H), 9.75 (s, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.86 (d, J=2.2Hz, 1H), 8.25-8.00(m, 4H), 7.97-7.81(m, 1H), 7.41(td, J=8.9, 1, 3 Hz, 1H), 3.12 (s, 3H);

MS: [M-1] ^- = 495.2.

Example 54b: 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzamide

The microwave chamber was loaded with N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]methanesulfonamide (60.0 mg, 0.139 mmol), XPhos Pd G3 (5.89 mg, 0.00696 mmol) and (4-carbamoylphenyl)boronic acid (27.5 mg, 0.167 mmol) and purged with argon. Degassed 1,4-dioxane (0.464 ml) and degassed aqueous 1.5 M potassium carbonate (0.325 ml, 0.487 mmol) were added and the mixture was heated to 110°C under microwave irradiation for 60 minutes. After cooling, the mixture was diluted with EtOAc and neutralized with saturated NH ₄ Cl solution. The solvents were removed under reduced pressure and the product was isolated by flash chromatography (DCM+MeOH, 5% to 15%) and dried at 100° C. in a vacuum oven to give 4-[3-[2,4-difluoro-3-(methanesulfonamido )benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzamide (40.0 mg, 0.0789 mmol, 57% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.06 (d, J=1.9 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.14-7.80 ( m, 6H), 7.49-7.33 (m, 2H) 3.11 (s, 3H);

MS: [M-1] ^- = 470.3

Example 54c: 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide

The microwave chamber was loaded with N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]methanesulfonamide (60.0 mg, 0.139 mmol), XPhos Pd G3 (5.89 mg, 0.00696 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (47.3 mg, 0.167 mmol) and purged argon. Degassed 1,4-dioxane (0.464 ml) and degassed aqueous 1.5 M potassium carbonate (0.325 ml, 0.487 mmol) were added and the mixture was heated to 110°C under microwave irradiation for 60 minutes. After cooling, the mixture was diluted with EtOAc and neutralized with saturated NH ₄ Cl solution. The solvents were removed under reduced pressure and the product was isolated by flash chromatography (DCM+EtOAc, 50% to 100%) and dried at 100°C in a vacuum oven to give 4-[3-[2,4-difluoro-3-(methanesulfonamido )benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide (31.0 mg, 0.0574 mmol, 41% yield). ¹ H NMR (200 MHz, DMSO) δ 9.07 (d, J=2.1 Hz, 1H), 8.84 (d, J=2.1 Hz, 1H), 8.12-7.78 ( m, 4H), 7.50-7.32 (m, 2H) 3.11 (s, 3H); [M-1] ^- = 506.2.

Example 55: Synthesis of 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoic acid (4) and ethyl 4-[ 3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoate (5)

Step 1: N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]methanesulfonamide (2)

To a suspension of N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]methanesulfonamide (380 mg, 0.881 mmol) and p-toluenesulfonic acid monohydrate ( 33.5 mg, 0.176 mmol) in DCM (2.94 ml) was added dihydropyran (0.161 ml, 1.76 mmol) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was diluted with DCM, washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated. The residue was triturated with n-hexane to give N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]methanesulfonamide ( 370 mg, 0.7180 mmol, 81% yield as a beige solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.78 (s, 1H), 8.80 (dd, J=13.4, 1.6 Hz, 2H), 7.88 (dd, J=14.6 , 7.8 Hz, 1H), 7.43 (t, J=9.0 Hz, 1H), 6.14 (d, J=8.6 Hz, 1H), 3.94 (d, J=11 .6 Hz, 1H), 3.72 (dd, J=14.6, 9.1 Hz, 1H), 3.13 (s, 3H) 2.46-2.19 (m, 1H); 2.00-1.18 (m, 5H);

¹³ C NMR (50 MHz, DMSO) δ 184.4, 150.8, 149.0, 139.9, 133.0, 116.1, 116.0, 82.7, 67.2, 41.5, 28.5, 24.5, 21.8;

MS: [M-1] ^- = 513.2.

Step 2: 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]benzoic acid (3 )

N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]methanesulfonamide (355 mg, 0.689 mmol) and 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (188 mg, 0.758 mmol)d XPhos Pd G3 (17.5 mg, 0.0207 mmol) were combined into degassed 1,4-dioxane (2.30 ml) and 1.5 M potassium carbonate (2.07 ml, 3.10 mmol). The reaction mixture was evacuated and purged with argon (3 times). XPhos Pd G3 (17.5 mg, 0.0207 mmol) was added and the reaction mixture was stirred at an oil bath temperature of 60° C. for 3 hours. After cooling, the mixture was acidified with 2N HCl and extracted with EtOAc. The extract was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (DCM+MeOH 3% to 25%) and triturated with n-hexane to give 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxane-2 -yl)pyrazolo[3,4-b]pyridin-5-yl]benzoic acid (276 mg, 0.4960 mmol, 72% yield).

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.83 (d, J=2.1 Hz, 1H) , 8.09 (d, J=8.3 Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 7.90 (dd, J=14.8, 7.6 Hz, 1H), 7.44 (t, J=8.8 Hz, 1H), 6.21 (dd, J=9.9, 2.0 Hz), 1H), 4.01-3.91 (m, 1H), 3.80-3.68 (m, 1H), 3.59 (t, J=6.6 Hz, 2H), 3.13 (s, 3H), 2.46-2.33 (m , 1H), 2.06-1.93 (m, 2H), 1.84-1.68 (m, 2H);

MS: [M-1] ^- = 555.4.

Step 3: 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoic acid (4)

4-[3-[2,4-Difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]benzoic acid (203 mg, 0.365 mmol) suspended in 3N HCl and heated to 70°C with stirring overnight. The reaction mixture was concentrated, the solids were collected by vacuum filtration, washed with water and dried at 100°C to give 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b ]pyridin-5-yl]benzoic acid (133 mg, 0.2820 mmol, 77% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.06 (d, J=2.1 Hz, 1H), 8.83 (d, J=2.1 Hz, 1H), 8.10 (d, J= 8.3 Hz, 2H), 8.00-7.80 (m, 3H), 7.40 (td, J=9.0, 1.3 Hz, 1H), 3.12 (s, 3H);

MS: [M-1] ^- = 471.2.

Stage 4: ethyl 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoate (5)

4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]benzoic acid (50.0 mg , 0.0898 mmol) was stirred in 1.25 M HCl in ethanol (0.719 ml, 0.898 mmol) at 75°C in a sealed vessel. After 3 hours, 200 μl H ₂ SO ₄ was added and stirring was continued at 75° C. overnight. The reaction was quenched in NaHCO ₃ solution, the solids were collected by centrifugation, washed with water and diethyl ether and dried in vacuo to give ethyl 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3, 4-b]pyridin-5-yl]benzoate (22.0 mg, 0.0440 mmol, 49% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.86 (s, 1H), 9.74 (s, 1H), 9.06 (d, J=2.1 Hz, 1H), 8.83 (d, J=2.1Hz, 1H), 8.18-7.80(m, 5H), 7.41(t, J=8.9Hz, 1H), 4.36(kv, J=7.0 Hz, 2H), 3.12 (s, 3H), 1.35 (t, J=7.0 Hz, 3H);

MS: [M-1] ^- = 499.4.

Example 56: Synthesis of [(2S)-2-amino-3-methoxy-3-oxopropyl] 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b ]pyridin-5-yl]benzoate hydrochloride

Step 1: [(2S)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]4-bromobenzoate

4-Bromobenzoyl chloride (1.13 g, 5.15 mmol) was dissolved in 25.7 ml THF and cooled to 0°C. Triethylamine (0.861 ml, 6.18 mmol) was added and to the resulting suspension was added methyl (2S)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (1.35 g, 6.18 mmol ) and 4-DMAP (31.5 mg, 0.257 mmol). The mixture was stirred at room temperature for 60 minutes, then diluted with EtOAc and washed with water, sat. NaHCO ₃ and sat. NH ₄ Cl solution. After drying over Na ₂ SO ₄ the solvent was removed in vacuo. The residue was dissolved in a small amount of MeOH and added to water with stirring. The solids were collected by vacuum filtration and dried to give [(2S)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]4-bromobenzoate (1.70 g, 4.23 mmol, yield 82%).

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.89-7.78 (m, 2H), 7.61-7.50 (m, 2H), 5.38 (d, J=8.0 Hz, 1H), 4.70 (dd, J=8.2, 4.0 Hz, 1H), 4.59 (d, J=4.0 Hz, 2H), 3.76 (d, J=4.3 Hz, 3H), 1.42 (d, J=4.2 Hz, 9H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 170.4, 165.4, 155.2, 132.0, 131.3, 128.7, 128.5, 80.6, 65.3, 53.1 , 52.9, 28.4.

MS (ESI+): m/z 424.04 [M+1] ⁺ .

Step 2: N-(2,6-difluoro-3-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)methanesulfonamide

The vessel was loaded with N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]methanesulfonamide (0.630 g, 1. 22 mmol), bis(pinacolato)diborone (341 mg, 1.34 mmol), anhydrous potassium acetate (360 mg, 3.67 mmol) and dry 1,4-dioxane (4.08 ml). The vessel was evacuated and filled with argon (3x). 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium (1:1) (17.9mg, 0.0245mmol) was added and the reaction mixture was stirred at 80°C overnight. After cooling, EtOAc was added, the suspension was stirred for 30 minutes and filtered through celite. The solvent was concentrated, n-heptane was added and the solids were collected by vacuum filtration, washed with hexane and dried to give N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (0.690 g, 1.23 mmol, quant.).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 8.94-8.71 (m, 2H), 7.19-6.88 (m, 2H), 6.18 (d, J=9.1 Hz, 1H ), 4.05-3.61 (m, 2H), 2.64 (s, 3H), 2.44-1.10 (m, 18H).

Stage 3: [(2S)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl] -1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]benzoate

The vessel was loaded with N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (101 mg, 0.180 mmol), [(2S)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3 -oxopropyl]4-bromobenzoate (79.5 mg, 0.198 mmol), potassium fluoride (31.3 mg, 0.539 mmol), Pd(dppf)Cl ₂ DCM (7.33 mg, 0.00898 mmol) and degassed 1, 4-dioxane/water (4+1) (0.6 ml) followed by evacuation and filling with argon (3x). The reaction mixture was heated to 65°C overnight with stirring. The mixture was diluted with EtOAc, washed with brine and the solvents were removed. The product was isolated by flash chromatography (DCM/EtOAc gradient, 0% to 20% EtOAc) to give [(2S)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl ]4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]benzoate (68.0 mg .0 (0897 mmol, 50% yield) as a white solid.

Analytical data:

¹ H NMR (400 MHz, acetone) δ 9.00 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.1 Hz, 1H), 8.47 (s, 1H) , 8.17 (d, J=8.3 Hz, 2H), 7.97-7.89 (m, 3H), 7.33 (t, J=8.5 Hz, 1H), 6.65 ( d, J=7.6 Hz, 1H), 6.26 (dd, J=9.9, 2.3 Hz, 1H), 4.79 4.58 (m, 3H), 4.02 (d, J=11.4 Hz, 1H), 3.85-3.69 (m, 4H), 3.21 (s, 3H), 2.60-2.46 (m, 1H), 2.17-2 .06 (m, 1H), 2.04-1.96 (m, 1H), 1.92-1.78 (m, 1H), 1.74-1.57 (m, 2H), 1, 42 (s, 9H).

¹³ C NMR (101 MHz, acetone) δ 185.7, 171.1, 166.2, 162.2 (dd, J=256, 3 Hz), 158.7 (dd, J=258, 5 Hz), 156.4, 151.9, 150.3, 143.3, 142.2, 133.6, 131.6 (dd, J=11.4 Hz), 131.3, 130.3, 130.2, 128.6, 124.7 (dd, J=14.4 Hz), 116.2, 115.8 (t, J=17 Hz), 112.7 (dd, J=21.4 Hz), 83, 9, 79.8, 68.3, 65.4, 54.0, 52.8, 42.1, 29.8, 29.8, 28.6, 25.7, 23.1.

TLC-MS (ESI-): m/z 756.5 [M-1] ^- .

Step 4: [(2S)-2-amino-3-methoxy-3-oxopropyl]4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b] pyridin-5-yl]benzoate hydrochloride

[(2S)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1- (oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]benzoate (63.0 mg, 0.0831 mmol) was stirred in trifluoroacetic acid (1 ml) at room temperature for 3 hours. The mixture was heated to 50°C for 40 min. After cooling on ice, 4 N HCl (1.04 ml, 4.16 mmol) in 1,4-dioxane was added to the solution, stirring was continued for 5 minutes and diethyl ether (3 ml) was added. The product was collected by vacuum filtration, washed with diethyl ether and dried in vacuo to give [(2S)-2-amino-3-methoxy-3-oxopropyl]4-[3-[2,4-difluoro-3-(hydrochloridemethanesulfonamido)benzoyl ]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoate (44.0 mg, 0.0721 mmol, 87% yield) as a yellowish solid.

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 14.92 (s, 1H), 9.76 (s, 1H), 9.10 (d, J=2.0 Hz, 1H), 8.97 (s, 2H), 8.86 (d, J=2.1 Hz), 1H), 8.20 (d, J=8.5 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H ), 7.88 (dd, J=14.7, 7.6 Hz, 1H), 7.41 (t, J=8.7 Hz), 1H), 4.73 (d, J=3.3 Hz, 2H), 4.67 (s, 1H), 3.81 (s, 3H), 3.12 (s, 3H).

¹³ C NMR (101 MHz, DMSO) δ 185.1, 167.4, 164.8, 152.2, 149.5, 142.3, 141.8, 131.1, 130.5, 128.5, 128.0, 127.5, 114.0, 62.2, 53.1, 51.3, 41.5, 40.1.

TLC-MS (ESI-): m/z 572.4 [M-1].

Example 57 Synthesis of (2S)-2-amino-3-[4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridine-5- hydrochloride yl]benzoyl]hydroxypropanoic acid

Stage 1: benzyl(2S)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate

A solution of di-tert-butyl dicarbonate (7.06 ml, 30.7 mmol) in 1,4-dioxane (14.5 ml) was added to a solution of (2S)-2-amino-3-hydroxypropanoic acid (2.69 g, 25.6 mmol) and potassium carbonate (3.54 g, 25.6 mmol) in water (14.5 ml). The solution was stirred for 16 hours at room temperature. 1,4-Dioxane was evaporated and the aqueous solution was washed 3× with diethyl ether (10 ml). The water was evaporated in vacuo and the remaining traces were azeotropically removed with EtOH. The resulting white powder was suspended in DMF (28.9 ml) and benzyl bromide (3.44 ml, 28.9 mmol) was added. The mixture was stirred at room temperature for 16 hours. DMF was evaporated in vacuo and the residue was stirred with toluene (28.9 ml) and filtered. The phase was washed twice with water and brine and dried over Na ₂ SO ₄ . After filtration, the solvent was evaporated at 90° C. under vacuum. Butyric benzyl (2S)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (4.77 g, 16.2 mmol, 63% yield) was used in the next step without further purification.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.34 (s, 5H), 5.56 (s, 1H), 5.20 (s, 2H), 4.40 (s, 1H), 3.92 (cd, J=11.2, 3.7 Hz, 2H) 2.46 (s, 1H), 1.43 (s, 9H).

Stage 2: [(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxo-3-phenylmethoxypropyl] 4-bromobenzoate

To a solution of 4-bromobenzoyl chloride (0.500 g, 2.28 mmol) in THF (11.4 ml) was added triethylamine (0.381 ml, 2.73 mmol) and 4-DMAP (0.0139 g, 0.114 mmol). Benzyl (2S)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (0.807 g, 2.73 mmol) in 2 ml THF was added to the resulting suspension, and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was diluted with EtOAc, washed with water, sat. NaHCO ₃ and sat. NH ₄ Cl solution. After drying over Na ₂ SO ₄ the solvent was removed in vacuo. The product was purified by flash chromatography (n-hexane/EtOAc gradient, 0% to 20% EtOAc) to give [(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxo-3-phenylmethoxypropyl ]4-bromobenzoate (0.501 g, 1.05 mmol, 46% yield) as a white solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.84 (d, J=8.5 Hz, 2H), 7.75-7.64 (m, 3H), 7.38-7.23 (m, 5H ), 5.26-5.03 (m, 2H), 4.55 (dd, J=16.6, 7.0 Hz, 3H), 1.38 (s, J=14.3 Hz, 9H) .

¹³ C NMR (50 MHz, DMSO) δ 169.6, 164.7, 155.4, 135.7, 131.7, 131.3, 128.5, 128.3, 128.0, 127.7, 127.5, 78.6, 66.3, 52.7, 28.1.

MS: [M+Na] ⁺ =500.3.

Step 3: [(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxo-3-phenylmethoxypropyl]4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl] -1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]benzoic acid

[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxo-3-phenylmethoxypropyl]4-bromobenzoate (124 mg, 0.260 mmol), N-[2,6difluoro-3 -[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl ]phenyl]methanesulfonamide (146 mg, 0.260 mmol), Pd(dppf)Cl ₂ DCM (10.6 mg, 0.0130 mmol), potassium fluoride (45.2 mg, 0.779 mmol) and degassed 1,4-dioxane/ water (4+1) (0.8 ml) and the vessel was evacuated and filled with argon (3x). The reaction mixture was heated to 50°C with stirring for 6 hours. The mixture was diluted with EtOAc, washed with brine and the solvents were removed. The product was isolated by flash chromatography (3x column hexane/EtOAc (80/20 v/v, then DCM/EtOAc 80/20 v/v to elute the product) to give [(2S)- 2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxo-3-phenylmethoxypropyl]4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2- yl)pyrazolo[3,4-b]pyridin-5-yl]benzoate (147 mg, 0.1760 mmol, 68% yield) as a white solid.

Analytical data:

¹ H NMR (200 MHz, acetone) δ 9.06 (s, 1H), 8.90 (s, 1H), 8.55 (s, 1H), 8.22-7.89 (m, 5H), 7.59-7.31 (m, 5H), 6.82 (d, J=7.6 Hz, 1H), 6.34 (d, J=9.2 Hz, 1H), 5.44-5 .23 (m, 2H), 4.99-4.72 (m, 3H), 4.20-3.76 (m, 2H), 3.30 (s, 3H), 2.62 (dd, J =20.1, 9.7 Hz, 1H), 2.25-1.61 (m, 5H), 1.60-1.32 (m, 10H).

¹³ C NMR (50 MHz, acetone) δ 185.7, 170.6, 166.1, 156.4, 151.7, 150.3, 143.1, 142.1, 136.8, 133.5, 131.3, 130.1, 129.3, 129.0, 128.9, 128.4, 116.1, 83.8, 79.8, 68.3, 67.6 65.4, 54.2 , 42.0, 29.7, 28.5, 25.7, 23.1.

TLC-MS (ESI-): m/z 833.0 [M-1] ^- .

Step 4: (2S)-2-amino-3-[4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl hydrochloride ]benzoyl]hydroxypropanoic acid

[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxo-3-phenylmethoxypropyl]4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1- (oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]benzoate (142 mg, 0.170 mmol) was dissolved in EtOAc (1.70 mL) and 14 mg of palladium on charcoal (10%) was added The reaction mixture was stirred under H2 (3 bar) overnight. The reaction mixture was degassed, 5 mg of palladium on activated carbon (10%) was added and the reaction mixture was stirred under H 5 atmosphere at 5 bar (for 6 hours). The reaction mixture was filtered through celite and the solvent was removed. The residue was dissolved in 2 ml TFA and stirred at room temperature for 2 hours. 4N HCl in dioxane (2 ml) was added under ice cooling. After 5 minutes, 5 ml THF was added and the solids were collected by vacuum filtration, washed with THF and dried in vacuo to give (2S)-2-amino-3-[4-[3-[2,4-difluoro-3-( methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]oxypropanoic acid (50.0 mg, 0.0814 mmol, 48% yield) as a yellowish solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.92 (s, 1H), 9.76 (s, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.86 (d, J=2.1Hz, 1H), 8.78(s, 3H), 8.22(d, J=8.5Hz, 2H), 8.03(d, J=8.5Hz, 2H) , 7.88 (dd, J=15.0, 7.6 Hz, 1H), 7.41 (td, J=8.9, 1.2 Hz, 1H), 4.71 (s, 2H), 4.53 (s, 1H), 3.12 (s, 3H).

¹³ C NMR (50 MHz, DMSO) δ 185.2, 168.4, 164.9, 152.3, 149.6, 142.4, 141.9, 131.1, 130.5, 128.6, 128.2, 127.6, 114.1, 66.3, 51.4, 41.5.

TLC-MS (ESI-): m/z 558.2 [M-1] ^- .

Example 58 Synthesis of 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]pyridine-2-carboxylic acid hydrochloride

Step 1. Methyl 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]pyridin-2- carboxylate

The vessel was loaded with N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (132 mg, 0.235 mmol), methyl 5-bromopyridine-2-carboxylate (55.8 mg, 0.258 mmol), potassium fluoride (40.9 mg , 0.704) mmol), Pd(dppf)Cl ₂ ·DCM (9.58 mg, 0.0117 mmol) and degassed 1,4-dioxane/water (4+1) (0.6 mL) and the vessel was evacuated and filled with argon (3x). The reaction mixture was heated to 50° C. overnight with stirring. The mixture was diluted with EtOAc, washed with brine and the solvents were removed. The product was isolated by flash chromatography (DCM/EtOAc gradient, 20% to 60% EtOAc) to give methyl 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2 -yl)pyrazolo[3,4-b]pyridin-5-yl]pyridine-2-carboxylate (97.0 mg, 0.1700 mmol, 72% yield) as a white solid.

Analytical data:

¹ H NMR (400 MHz, acetone) δ 9.14 (d, J=1.9 Hz, 1H), 9.06 (d, J=2.1 Hz, 1H), 8.91 (d, J= 2.1 Hz, 1H), 8.40 (dd, J=8.1, 2.3 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 7.95 (dd, J=14.9, 7.5Hz, 1H), 7.34(dd, J=8.8, 8.0Hz, 1H), 6.27(dd, J=9.9, 2.4Hz , 1H), 4.09-3.91 (m, 4H), 3.80 (td, J=11.2, 3.5 Hz, 1H), 3.21 (s, 3H), 2.54 ( ddd, J=16.4 13.3, 4.0 Hz, 1H), 2.19-2.06 (m, 1H), 2.05-1.97 (m, 1H), 1.94-1 .77 (m, 1H), 1.76-1.56 (m, 2H).

¹³ C NMR (101 MHz, acetone) δ 185.7, 166.1, 162.3 (dd, J=256, 3 Hz), 158.7 (dd, J=258, 5 Hz), 152.0, 150.3, 149.3, 148.5, 142.3, 137.3, 136.7, 131.63 (dd, J=10.9, 3.2 Hz), 130.7, 125.9, 124.7 (dd, J=14.4 Hz), 116.2, 115.8 (t, J=17 Hz), 112.8 (dd, J=21.4 Hz), 83.9, 68, 4, 52.8, 42.1, 29.8, 25.8, 23.1.

TLC-MS (ESI-): m/z 570.4 [M-1] ^- .

Step 2: Methyl 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]pyridine-2-carboxylate

To a solution of methyl 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]pyridin-2- carboxylate (60.0 mg, 0.105 mmol) in MeOH (0.525 ml) was added methanesulfonic acid (0.0273 ml, 0.420 mmol) and the mixture was stirred at 65°C for 1.5 hours. The mixture was cooled to room temperature and slowly added to 15 ml diethyl ether, the solid was collected by vacuum filtration, washed with diethyl ether and dried in vacuum to give methyl 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]- 1H-pyrazolo[3,4-b]pyridin-5-yl]pyridine-2-carboxylate (36.0 mg, 0.0739 mmol, 70% yield) as a white solid.

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 14.90 (s, 1H), 9.74 (s, 1H), 9.16 (dd, J=12.4, 1.9 Hz, 2H), 8 .93 (d, J=2.0 Hz, 1H), 8.47 (dd, J=8.2, 2.3 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H) , 7.88 (dd, J=14.8, 7.7 Hz, 1H), 7.41 (t, J=8.7 Hz, 1H) 3.93 (s, 3H), 3.12 (s , 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 185.1, 165.0, 152.4, 149.6, 148.3, 146.5, 141.9, 136.1, 136.0, 129.2 , 128.4, 125.0, 114.0, 52.5, 41.5.

MS: [M+Na] ⁺ =510.4.

Step 3: 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]pyridine-2-carboxylic acid hydrochloride

Methyl 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-5-yl]pyridine-2-carboxylate ( 46.0 mg, 0.0805 mmol) was stirred in 3 N HCl (2.68 ml, 8.05 mmol) at 70° C. overnight in an open vessel. The solvent was removed, the remaining water was azeotropically removed with toluene. The residue was dissolved in MeOH (1 ml) and added dropwise to diethyl ether. The solid was collected by vacuum filtration, washed with diethyl ether and dried in vacuo to give 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridine-5- hydrochloride yl]pyridine-2-carboxylic acid (33.0 mg, 0.0647 mmol, 80% yield).

Analytical data:

¹ H NMR (200 MHz, CDCl ₃ ) δ 14.96 (s, 1H), 9.77 (s, 1H), 9.18 (s, 1H), 9.13 (d, J=1.9 Hz , 1H), 8.93 (d, J=1.9 Hz), 1H), 8.48 (d, J=8.1 Hz, 1H), 8.19 (d, J=7.8 Hz, 1H), 7.88 (dd, J=14.7, 7.8 Hz, 1H), 7.41 (t, J=8.6 Hz), 1H), 3.12 (s, 3H).

¹³ C NMR (101 MHz, DMSO) δ 185.0, 152.3, 149.5, 141.9, 136.1, 114.2, 114.0, 48.5, 41.5, 15.1.

TLC-MS (ESI-): m/z 472.3 [M-1] ^- .

Example 59 Synthesis of N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]methanesulfonamide hydrochloride

Step 1: N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-pyridin-4-ylpyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide

The vessel was loaded with N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (86.0 mg, 0.153 mmol), 4-bromopyridine hydrochloride (29.7 mg, 0.153 mmol), Pd(dppf)Cl ₂ DCM ( 3.75 mg, 0.00459 mmol), degassed 1,4-dioxane (0.382 ml) and degassed 1.5 M aqueous potassium carbonate (0.408 ml, 0.612 mmol). The vessel was evacuated and filled with argon (3x) and heated to 60°C for 2 hours. After cooling, the reaction mixture was diluted with EtOAc, neutralized NH 4 Cl solution, the aqueous phase was discarded and the organics were concentrated. The product was isolated by flash chromatography (DCM/MeOH gradient, 2% to 12% MeOH). N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-pyridin-4-ylpyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (63.0 mg , 0 1230 mmol, 80% yield.

Analytical data:

¹ H NMR (200 MHz, acetone) δ 9.03 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.1 Hz, 1H), 8.72 (d, J= 5.9Hz, 3H), 7.94 (ddd, J=8.8, 7.5, 6.2Hz, 1H), 7.80 (dd, J=4.5, 1.6Hz, 2H ), 7.34 (td, J=9.0, 1.7 Hz, 1H), 6.25 (dd, J=9.9, 2.3 Hz, 1H), 4.12-3.95 ( m, 1H), 3.90-3.68 (m, 1H), 3.21 (s, 3H), 2.51 (dt, J=10.1, 7.1 Hz, 1H), 2.16 -1.57 (m, 5H),

¹³ C NMR (50 MHz, acetone) δ 185.7, 152.1, 151.4, 150.1, 145.8, 142.2, 131.9, 131.6 (dd, J=10, 4 Hz ), 130.3, 124.6 (dd, J=13.4 Hz), 122.8 116.1, 115.8, 112.8 (dd, J=21.4 Hz), 83.8, 68 .3, 42.0, 29.7, 25.7, 25.3, 23.1.

TLC-MS (ESI-): m/z 512.6 [M-1] ^- .

Step 2: N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]methanesulfonamide hydrochloride

N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-pyridin-4-ylpyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (60.0 mg , 0.117 mmol) was heated under reflux in MeOH (2 ml) and 4 N HCl in dioxane (0.5 ml) for 1 hour. The solvent was removed and the residue was triturated with THF to give N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]methanesulfonamide hydrochloride ( 37.0 mg, 0.0794 mmol, 68% yield as a white solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 15.09 (s, 1H), 9.77 (s, 1H), 9.28 (d, J=2.3 Hz, 1H), 9.13 (d, J=2.3 Hz, 1H), 8.99 (d, J=6.7 Hz, 2H), 8.52 (d, J=6.7 Hz, 2H), 7.90 (dd, J= 15.0, 7.6 Hz, 1H), 7.42 (td, J=8.9, 1.2 Hz, 1H), 3.12 (s, 3H).

¹³ C NMR (101 MHz, DMSO) δ 184.9, 160.7 (dd, J=255, 3 Hz), 157.1 (dd, J=257, 4 Hz), 153.0, 151.8, 149.7, 143.6, 142.3, 130.5, 127.3, 124.1, 123.4 (dd, J=13.4 Hz), 114.3 (t, J=17 Hz), 112.0 (dd, J=21.3 Hz), 41.5.

TLC-MS (ESI-): m/z 428.6 [M-1] ^- .

Example 60 Synthesis of N-[2,6-difluoro-3-[5-[4-(methylsulfonimidoyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide

Stage 1: (4-bromophenyl)-imino-methyl-oxo-λ^{6}-sulfan

1-Bromo-4-methylsulfanylbenzene (0.970 g, 4.78 mmol), ammonium acetate (1.47 g, 19.1 mmol) and (diacetoxyiodo)benzene (3.85 g, 11.9 mmol) were combined in 9, 55 ml MeOH at room temperature. The reaction mixture was stirred for 1 hour, diluted with water (20 ml) and extracted with EtOAc. The extracts were washed with water, dried over Na ₂ SO ₄ and the solvents were removed in vacuo. The product was isolated by flash chromatography (DCM/MeOH, 97/3% v/v) (4-bromophenyl) imino-methyl-oxo-λ^{6}-sulfane (0.570 g, 2.43 mmol, yield 51%).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 7.91-7.76 (m, 4H), 4.24 (s, 1H), 3.08 (s, 1H).

¹³ C NMR (50 MHz, DMSO) δ 143.5, 132.0, 129.4, 126.4, 45.6.

MS: [M+H] ⁺ =234.1.

Stage 2: N-[2,6-difluoro-3-[5-[4-(methylsulfonimidoyl)phenyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl ]methanesulfonamide

The vessel was loaded with N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (93.0 mg, 0.165 mmol), (4-bromophenyl) imino-methyl-oxo-λ^{6}-sulfan (38.7 mg , 0.165 mmol), Pd(dppf)Cl ₂ DCM (4.05 mg, 0.00496 mmol), potassium fluoride (28.8 mg, 0.496 mmol) and degassed 1,4-dioxane/water (4:1, 0.5 ml). The vessel was evacuated and filled with argon (3x) and heated to 50°C for 3 hours. After cooling, the reaction mixture was diluted with EtOAc, washed with brine and the solvents were removed. The product was isolated by flash chromatography (DCM/MeOH gradient, 1% to 8% MeOH). N-[2,6-difluoro-3-[5-[4-(methylsulfonimidoyl)phenyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide ( 63.0 mg, 0.1070 mmol, 65% yield.

Analytical data:

¹ H NMR (200 MHz, acetone) δ 8.97 (d, J=1.9 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.63 (s, 1H) , 8.13 (d, J=8.3 Hz, 2H), 8.03-7.87 (m, 3H), 7.33 (td, J=8.9, 1.3 Hz, 1H), 6.24 (dd, J=9.7, 1.9 Hz, 1H), 4.11-3.93 (m, 1H), 3.87-3.70 (m, 1H), 3.18 ( e, J=13.0 Hz, 7H), 2.66-2.37 (m, 1H), 2.18-1.52 (m, 5H).

¹³ C NMR (50 MHz, acetone) δ 151.8, 150.4, 142.7, 142.1, 130.3, 129.4, 129.0, 116.1, 83.8, 68.4, 46.6, 42.0, 35.2, 32.3, 29.8, 25.7, 23.1, 14.3.

TLC-MS (ESI-): m/z 588.4 [M-1] ^- .

Step 3: N-[2,6-difluoro-3-[5-[4-(methylsulfonimidoyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide

K N-[2,6-difluoro-3-[5-[4-(methylsulfonimidoyl)phenyl]-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (63.0 mg, 0.107 mmol) in 2 ml MeOH was added 4 N HCl in 1,4-dioxane (2 ml) and the reaction mixture was stirred at reflux temperature for 1 hour. After cooling, the mixture was concentrated, treated with dry THF/diethyl ether (1+1) and the solids were collected by vacuum filtration, washed with diethyl ether. The solids were dissolved in water and neutralized with NaHCO ₃ solution. The product was collected by vacuum filtration, washed with water and dried in vacuo to give N-[2,6-difluoro-3-[5-[4-(methylsulfonimidoyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3 -carbonyl]phenyl]methanesulfonamide (24.0 mg, 0.0451 mmol, 42% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.08 (s, 1H), 8.85 (s, 1H), 8.07 (s, 4H), 7.87 (dd, J=14.8, 8 .0 Hz, 1H), 7.41 (t, J=8.5 Hz, 1H), 4.31 (s, 1H), 3.13 (d, J=3.4 Hz, 6H).

¹³ C NMR (101 MHz, DMSO) δ 185.1, 152.3, 149.5, 143.5, 141.8, 141.1, 131.0, 128.6, 128.1, 127.9, 114.0, 45.8, 41.5.

MS: [M+H]+=506.4.

Example 61 Synthesis of N-[3-[5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide

Stage 1: N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]propane-1-sulfonamide

To a suspension of (3-amino-2,4-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (805 mg, 2.28 mmol) and triethylamine (3, 50 ml). 25.1 mmol) in DCM (11.4 ml) was slowly added 1-propanesulfonyl chloride (898 μl, 7.98 mmol) in DCM (11.4 ml) at -10°C and the reaction mixture was stirred at -10°C for within 15 minutes. The reaction mixture was diluted with DCM, washed with 2N HCl and brine, dried over Na ₂ SO ₄ and evaporated. The residue was dissolved in THF (2 ml) and 2 N KOH (2 ml) was added. After 10 minutes the reaction mixture was diluted with water and the THF was evaporated. The solution was added to 2N HCl (10 ml) with stirring, stirring was continued for 30 minutes and the solids were collected by vacuum filtration, washed with 2N HCl and water and dried at 100°C to give N-[3-(5-bromo-1H -pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]propane-1-sulfonamide (801 mg, 1.69 mmol, 74% yield).

Analytical data:

¹ H NMR (200 MHz, acetone) δ 13.77 (s, 1H), 8.72 (d, J=12.1 Hz, 2H), 8.38 (s, 1H), 7.91 (dd, J=14.8, 7.6Hz, 1H), 7.30(t, J=8.7Hz, 1H), 3.40-3.14(m, 2H), 2.03-1.81 (m, 2H), 1.07 (t, J=7.4 Hz, 3H).

¹³ C NMR (50 MHz, acetone) δ 185.7, 162.1 (dd, J=255, 4 Hz), 153.7 (dd, J=222, 4 Hz), 152.0, 151.6, 142.5, 133.7, 131.5 (dd, J=11.4 Hz), 124.5 (dd, J=14.4 Hz), 116.6, 116.2, 115.7 (t, J=17 Hz), 112.8, 112.7, 112.4, 112.3, 56.2, 18.1, 13.1.

MS: [M-1] ^- = 457.3.

Step 2: N-[3-[5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide

N-[3-(5-Bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]propane-1-sulfonamide (60.0 mg, 0.131 mmol ).), (4-chlorophenyl)boric acid (21.4 mg, 0.137 mmol) and Pd(dppf)Cl ₂ ·DCM (5.33 mg, 0.00653 mmol) and purged with argon. Degassed 1,4-dioxane (0.435 ml) and degassed aqueous 1.5 M K ₂ CO ₃ (0.261 ml, 0.392 mmol) were added and the mixture was stirred at 110° C. under microwave irradiation for 30 minutes. A spatula of Pd(dppf)Cl ₂ was added and heating was continued for 30 minutes. After cooling, the mixture was neutralized with sat. NH ₄ Cl solution and diluted with EtOAc. The aqueous phase was discarded and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (DCM/EtOAc gradient, 0 to 35% EtOAc) and triturated with DCM to give N-[3-[5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine- 3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide (30.0 mg, 0.0605 mmol, 46% yield) as a white solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.81 (s, 1H), 9.66 (s, 1H), 9.01 (d, J=2.1 Hz, 1H), 8.77 (d, J=2.1Hz, 1H), 7.98-7.78(m, 3H), 7.60(d, J=8.4Hz, 2H), 7.40(t, J=8.7 Hz, 1H), 3.22-3.09 (m, 2H), 1.92-1.70 (m, 2H), 1.00 (t, J=7.5 Hz, 3H).

¹³ C NMR (101 MHz, DMSO) δ 185.2, 152.1, 149.4, 141.8, 136.2, 133.1, 131.3, 129.2, 128.1, 114.1, 55.0, 39.5, 16.9, 12.7.

MS: [M-1] ^- = 489.5.

Example 68 Synthesis of N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]-1-phenylmethanesulfonamide

Stage 1: N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]-1-phenylmethanesulfonamide

To a solution of (3-amino-2,4-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (830 mg, 2.35 mmol) and 4-DMAP ( 0.574 g, 4.70 mmol) in pyridine (4.74 ml, 58.8 mmol) was added phenylmethanesulfonyl chloride (583 mg, 3.06 mmol) at -10°C and the mixture was stirred at -10°C for 10 minutes until formation of a homogeneous suspension. Stirring was continued at room temperature for 10 minutes and the reaction mixture was heated to 50°C for 30 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in 2N NaOH (3.53 ml, 7.05 mmol) and stirred at room temperature for 10 minutes. The mixture was diluted with water and slowly added to 25 ml of 2N HCl with stirring. After 10 minutes the solids were collected by vacuum filtration, washed with water and dried at 100°C to give N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6 -difluorophenyl]-1-phenylmethanesulfonamide (1.02 g, 2.01 mmol, 86% yield) as a yellowish solid.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.98 (s, 1H), 9.81 (s, 1H), 8.73 (dd, J=6.1, 2.2 Hz, 2H), 7, 88 (dd, J=14.9, 7.6 Hz, 1H) 7.50-7.30 (m, 6H), 4.53 (s, 2H).

¹³ C NMR (50 MHz, DMSO) δ 184.8, 150.9, 150.6, 140.9, 132.5, 131.0, 129.4, 128.4, 128.3, 115.5, 115.2, 59.4.

MS: [M-1] ^- = 505.2.

Stage 2: N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]-1-phenylmethanesulfonamide

The microwave chamber was loaded with N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]-1-phenylmethanesulfonamide (75.0 mg, 0.148 mmol) 4-pyridinylboronic acid (21.8 mg, 0.177 mmol) and Pd(dppf) Cl2 DCM (6.04 mg, 0.00739 mmol) and purged with argon. Degassed 1,4-dioxane (0.493 ml) and degassed aqueous 1.5 M K ₂ CO ₃ (0.345 ml, 0.517 mmol) were added and the mixture was heated to 110° C. under microwave irradiation for 60 minutes. After cooling, the reaction mixture was diluted with EtOAc and neutralized with NH ₄ Cl solution. The aqueous phase was cut open and the solvent was evaporated. The residue was purified by flash chromatography (DCM+MeOH 2% to 10%) and triturated with DCM to give N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4- b]pyridine-3-carbonyl)phenyl]-1-phenylmethanesulfonamide (40.0 mg, 0.0783 mmol, 53% yield).

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 14.91 (s, 1H), 9.77 (s, 1H), 9.13 (d, J=2.3 Hz, 1H), 8.92 (d, J=2.3Hz, 1H), 8.72(dd J=4.7, 1.4Hz, 2H), 8.07-7.68(m, 3H), 7.53-7.26( m, 6H), 4.53 (s, 2H). [M-1] ^- = 504.4.

Example 69: Synthesis of N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]ethanesulfonamide

Step 1: (3-amino-2,4-difluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]methanone

To 3-bromo-2,6-difluoroaniline (4.69 g, 22.6 mmol) in tetrahydrofuran (19.6 ml) was added 2M isopropylmagnesium chloride in THF (11.3 ml, 22.6 mmol) dropwise at 0° C and stirred for 15 minutes without additional cooling. After re-cooling to 0° C., chlorotrimethylsilane (2.86 ml, 22.6 mmol) was added and the mixture was heated to 25° C. and stirred for 20 minutes. The solution was cooled to 0°C and chlorotrimethylsilane (2.86 ml, 22.6 mmol) was added while continuing to stir for 20 minutes at 25°C. The solution was again cooled to 0°C and 2M isopropylmagnesium chloride in THF (11.3 ml, 22.6 mmol) was added dropwise and the mixture was stirred for 10 minutes at 0°C. 5-bromo-N-methoxy-N-methyl-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carboxamide (3.62 g, 9.80 mmol) was dissolved in 10 ml THF and added to the mixture and stirring was continued for 1 hour at room temperature. the reaction was quenched with sat. NH ₄ Cl solution, water was added until the aqueous phase became clear and the phases were separated. The aqueous layer was extracted with EtOAc, the extracts were washed with brine, dried over Na ₂ SO ₄ and the solvent was removed. The oily residue was dissolved in 25 ml of THF and 2 ml of conc. HCl was added with stirring. After 5 minutes the mixture was carefully neutralized with solid K ₂ CO ₃ , diluted with EtOAc and filtered. Solvents were removed and the residue was purified by flash chromatography (n-hexane/EtOAc gradient, 0% to 40% EtOAc) to give (3-amino-2,4-difluorophenyl)-[5-bromo-1-(oxane)-2 -yl)pyrazolo[3,4-b]pyridin-3-yl]methanone (2.35 g, 5.37 mmol, 55% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 8.76 (dd, J=13.9, 2.1 Hz, 2H), 7.15-6.89 (m, 2H), 6.12 (d, J = 7.8 Hz, 1H), 5.51 (s, 2H) 4.08-3.56 (m, 2H), 2.46-2.20 (m, 1H), 2.06-1.46 (m, 5H).

¹³ C NMR (50 MHz, DMSO) δ 185.6, 153.6 (dd, J=190, 9 Hz), 150.6, 149.0, 148.8 (d, J=9 Hz), 140, 2, 133.0, 126.3 (t, J=17 Hz) 122.3 (dd, J=11.3 Hz), 116.4 (d, J=3 Hz), 116.2, 116.2 , 115.7, 110.7 (dd, J=19.3 Hz), 82.7, 67.0, 28.5, 24.4, 21.8.

MS: [M+Na+MeOH] ⁺ =491.05.

Step 2: N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]ethanesulfonamide

To a solution of (3-amino-2,4-difluorophenyl)-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-3-yl]methanone (286 mg, 0.654 mmol) and triethylamine (0.547 ml, 3.92 mmol) in DCM (3.27 ml) was added ethanesulfonyl chloride (143 μl, 1.50 mmol) at 0°C. The reaction mixture was stirred at room temperature for 15 minutes and washed with 2N HCl and brine. The solvent was removed and dissolved in 2 ml of THF and 2 ml of 2 N aqueous KOH and stirred for 10 minutes. The reaction mixture was acidified with 2N HCl, diluted with water and extracted with EtOAc. The extract was washed with brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by flash chromatography (n-hexane/EtOAc gradient, 5% to 40% EtOAc) to give N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b] pyridine-3-carbonyl]-2,6-difluorophenyl]ethanesulfonamide (0.267 g, 0.5040 mmol, 77% yield).

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 9.70 (s, 1H), 8.80 (dd, J=14.1, 2.1 Hz, 2H), 7.87 (dd, J=14.8 , 7.7 Hz, 1H), 7.43 (td, J=8.9, 1.0 Hz, 1H), 6.14 (dd, J=9.6, 1.7 Hz, 1H), 4 .07-3.87(m, 1H), 3.83-3.62(m, 1H), 3.20(q, J=7.2Hz, 2H), 2.34(dd, J=22 .5, 11.3 Hz, 1H), 2.07-1.46 (m, 5H), 1.33 (t, J=7.3 Hz, 3H).

¹³ C NMR (50 MHz, DMSO) δ 184.4.161.8 (dd, J=191, 4 Hz), 156.7 (dd, J=193, 4 Hz), 150.8, 149.0, 139, 9, 133.0, 130.8 (dd, J=11.4 Hz), 122.9 (dd, J=13.4 Hz), 116.1, 116.0, 114.4 (t, J= 17 Hz), 112.2 (dd, J=21, 4 Hz), 82.7, 67.1, 47.7, 28.5 24.5, 21.8, 8.0.

MS: [M-1] ^- = 527.1.

Step 3: N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]ethanesulfonamide

N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]ethanesulfonamide (76.0 mg , 0.144 mmol), 4-pyridinylboronic acid (19.4 mg, 0.158 mmol) and tri(tert-butyl)phosphine Pd G3 (6.08 mg, 0.00718 mmol) and purged with argon. Degassed 1,4-dioxane (0.479 ml) and degassed 1.5 M aqueous potassium carbonate (0.287 ml, 0.431 mmol) were added and the reaction mixture was stirred at 70° C. for 45 minutes under microwave irradiation. The reaction mixture was acidified with 2 ml of 6N HCl diluted with 3 ml of MeOH and heated to 70° C. under microwave irradiation for 60 minutes. The mixture was diluted with water, neutralized with 2N NaOH and extracted with THF. The extract was washed with saline, dried over Na ₂ SO ₄ and the solvent was removed. The residue was purified by flash chromatography (DCM/MeOH gradient, 2% to 10% MeOH) to give N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4]- b]pyridine-3-carbonyl)phenyl]ethanesulfonamide (42.0 mg, 0.0947 mmol, 66% yield).

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 14.89 (s, 1H), 9.66 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.91 (d, J=2.3Hz, 1H), 8.72(d, J=5.9Hz, 2H), 7.91-7.83(m, 3H), 7.40(t, J=8.8 Hz, 1H), 3.18 (kv, J=7.3 Hz, 2H), 1.33 (t, J=7.3 Hz), 3H).

¹³ C NMR (101 MHz, DMSO) δ 185.0, 152.6, 150.3, 149.3, 144.4, 141.9, 129.5, 128.7, 121.8, 114.0, 47.7, 7.9.

MS: [M-1] ^- = 442.1.

Example 70 Synthesis of 4-(3-(2,4-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-methylbenzenesulfonamide

Stage 1: N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide

To a suspension of N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]propane-1-sulfonamide (778 mg, 1.64 mmol) in DCM (8.47 ml) was added p-toluenesulfonic acid monohydrate (31.3 mg, 0.164 mmol) and dihydropyran (0.165 ml, 1.81 mmol) and the reaction mixture was heated to 40°C for 1 hour. The reaction mixture was washed with NaHCO ₃ solution and the solvent was removed. The residue was purified by flash chromatography (n-hexane+EtOAc, 5% to 45%) to give N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine- 3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide (693 mg, 1.28 mmol, 78% yield).

Analytical data:

¹ H NMR (200 MHz, acetone) δ 8.73 (dt, J=8.0, 1.8 Hz, 2H), 8.39 (s, 1H), 7.92 (ddd, J=8.8 , 7.4, 6.2 Hz, 1H), 7.32 (td, J=8.9, 1.7 Hz, 1H), 6.18 (dd, J=9.8, 2.4 Hz, 1H), 4.03-3.67 (m, 2H), 3.33-3.20 (m, 2H), 2.61-2.38 (m, 1H) 2.01-1.54 (m , 5H), 1.07 (t, J=7.5 Hz, 3H).

¹³ C NMR (50 MHz, acetone) δ 361.8, 339.4 (dd, J=178, 4 Hz), 334.3 (dd, J=181, 4 Hz), 327.9, 326.8, 317.5, 310.4, 308.0 (dd, J=11.4 Hz), 300.7 (dd, J=13.4 Hz), 293.8, 293.2, 292.2 (t, J=17Hz), 289.0 (dd, J=22, 4Hz), 260.2, 244.7, 232.6, 206.3 206.0, 202.0, 199.4, 194.5 , 189.5.

TLC-MS (ESI-): m/z 541.0/543.0 [M-H] ^- .

Step 2: N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide

N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide (875 mg, 1.61 mmol), bis(pinacolato)diborone (429 mg, 1.69 mmol), bis(triphenylphosphine) palladium(II) dichloride (22.6 mg, 0.0322 mmol), anhydrous potassium acetate (474 mg , 4.83 mmol) and dry 1,4-dioxane (8.05 ml). The vessel was evacuated and filled with argon (3x), and the reaction mixture was heated to 80°C for 3 hours. After cooling, the reaction mixture was diluted with EtOAc, filtered through celite and evaporated. The residue was taken up in EtOAc (ca. 20 ml), activated charcoal was added and the mixture was refluxed for 10 minutes. After cooling, the mixture was filtered through celite, the solvent was evaporated and the residue was sonicated with n-hexane. The solids were collected by vacuum filtration and in vacuo to give N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3) 2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (765 mg, 1.3 mmol, 80% yield) as a colorless solid.

Stage 3:

The vessel was loaded with N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (100 mg, 0.169 mmol), potassium fluoride (29.5 mg, 0.508 mmol), 4-bromo-3-methylbenzenesulfonamide (46 .6 mg, 0.186 mmol), Pd(dppf)Cl ₂ ·DCM (6.92 mg, 0.00847 mmol) and 0.5 ml 1,4-dioxane/water (4+1). The vessel was evacuated and filled with argon (3x) and heated to 60°C for 2 hours. The reaction mixture was acidified with conc. HCl (0.3 ml), diluted with MeOH (0.2 ml) and heated to 60°C overnight. After cooling, the reaction mixture was diluted with EtOAc and water. The organic phase was evaporated and the product was purified by flash chromatography (DCM/EtOAc gradient, 10% to 50% EtOAc) 4-[3-[2,4-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4 -b]pyridin-5-yl]-3-methylbenzenesulfonamide (42.0 mg, 0.0764 mmol, 45% yield).

Analytical data:

TLC-MS (ESI-): m/z 528.2/548.1 [M-H] ^- .

Example 71 Synthesis of N-(2,6-difluoro-3-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane -1-sulfonamide

The vessel was loaded with N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (88.0 mg, 0.149 mmol), 5-bromo-2-(trifluoromethyl)pyrimidine (37.2 mg, 0.164 mmol) , potassium fluoride (26.0 mg, 0.447 mmol), bis(triphenylphosphine)palladium (II) dichloride (5.23 mg, 0.00745 mmol) and 0.5 ml 1,4-dioxane/water (4+1) . The vessel was evacuated and filled with argon (3x) and heated to 60°C for 2 hours. The reaction mixture was acidified with conc. HCl (0.3 ml), diluted with MeOH (0.2 ml) and heated to 60°C overnight. After cooling, the reaction mixture was diluted with EtOAc and water. The organic phase was evaporated and the product was purified by flash chromatography (DCM/EtOAc gradient, 5% to 35% EtOAc) N-[2,6-difluoro-3-[5-[2-(trifluoromethyl)pyrimidin-5yl]-1H -pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (42.0 mg, 0.0798 mmol, 54% yield).

Analytical data:

TLC-MS (ESI-): m/z=505.1, 525.1 [M-H] ^-

Example 72 Synthesis of N-(3-(5-(4-chloro-2-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide

The vessel was loaded with N-[2,6-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (80.0 mg, 0.135 mmol), 1-bromo-4-chloro-2-methylbenzene (18.0 µl, 0.135 mmol ), potassium fluoride (23.6 mg, 0.406 mmol), bis(triphenylphosphine)palladium(II) dichloride (4.76 mg, 0.00677 mmol) and 0.5 ml 1,4-dioxane/water (4+1 ). The vessel was evacuated and filled with argon (3 times) and heated to 60°C for 1 hour. The reaction mixture was acidified with conc. HCl (0.2 ml), diluted with MeOH (0.2 ml) and heated to 60°C overnight. After cooling, the reaction mixture was diluted with EtOAc and water. The organic phase was evaporated and the product was purified by flash chromatography (DCM/EtOAc gradient, 0%-40% EtOAc) to give N-[3-[5-(4-chloro-2-methylphenyl)-1H-pyrazolo[3,4- b]pyridine-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide (32.0 mg, 0.0608 mmol, 45% yield).

Analytical data:

TLC-MS (ESI-): m/z=483.3, 503.3 [M-H] ^-

Example 73 Synthesis of N-(3-(5-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl) ethanesulfonamide

Step 1: N-(3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl)ethanesulfonamide

To a suspension of (3-amino-2,4-difluorophenyl)-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (823 mg, 2.33 mmol) and triethylamine (3, 57 ml, 25.6 mmol) in DCM (11.7 ml) was slowly added ethanesulfonyl chloride (0.773 ml, 8.16 mmol) in DCM (11.7 ml) at -10°C and the reaction mixture was stirred at -10°C within 20 minutes. The reaction mixture was washed with 2N HCl and brine and the solvent was removed. The remaining resin was dissolved in 10 ml THF and 2N NaOH (6.99 ml, 14.0 mmol) was added. After stirring for 30 minutes, the solution was acidified with 2N HCl. Water was added, THF was removed in vacuo and the solids were collected by vacuum filtration, washed with water and dried at 100° C. to give N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl )-2,6-difluorophenyl]ethanesulfonamide (761 mg, 1.71 mmol, 73% yield).

Step 2: N-(3-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl) ethanesulfonamide

To a suspension of N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]ethanesulfonamide (529 mg, 1.19 mmol) and p-toluenesulfonic monohydrate acid (22.6 mg, 0.119 mmol) in DCM (5.94 ml) was added dihydropyran (0.130 ml, 1.43 mmol) and the reaction mixture was heated to 30°C for 1 hour. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO ₃ solution and brine, and the solvent was removed. The product was purified by flash chromatography (n-hexane/EtOAc gradient, 0%-40% EtOAc) to give N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine -3-carbonyl]-2,6-difluorophenyl]ethanesulfonamide (534 mg, 1.01 mmol, 85% yield).

Stage 3:

Analytical data:

TLC-MS (ESI-): m/z=509.3 [M-H] ^-

Example 74 Synthesis of N-(3-(5-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl) propane-1-sulfonamide

N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide (80 .0 mg, 0.147 mmol), [4-(1H-tetrazol-5-yl)phenyl]boric acid (33.6 mg, 0.177 mmol) and Pd(dppf)Cl ₂ DCM (6.01 mg, 0. 00736 mmol) and purged with argon, degassed 1,4-dioxane (0.491 ml) and degassed 1.5 M aqueous potassium carbonate (0.393 ml, 0.589 mmol) were added, the vessel was sealed and the reaction mixture was heated to 80°C for 2.5 . The reaction mixture was diluted with MeOH, acidified with conc. HCl and stirring continued at 60°C for 3 hours. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, the solvent was removed and the product was purified by flash chromatography (DCM+MeOH (+1% formic acid), 5% to 10%), triturated with DCM and dried at 100°C to give N-[2.6 -difluoro-3-[5-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (38.0 mg, 0.0724 mmol, 49% yield.

Analytical data:

¹ H NMR (200 MHz, DMSO) δ 14.99 (s, 1H), 9.83 (s, 1H), 9.14 (d, J=2.1 Hz, 1H), 8.88 (d, J=2.2Hz, 1H), 8.17(dd, J=19.9, 8.4Hz, 4H), 7.65(td, J=9.0, 6.1Hz, 1H), 7.32 (td, J=9.0, 1.4 Hz, 1H), 3.20-3.05 (m, 2H), 1.90-1.59 (m, 2H), 0.97 ( t, J=7.4 Hz, 3H).

¹³ C NMR (101 MHz, DMSO) δ 182.5, 156.29 (dd, J=248.3, 6.4 Hz), 152.8 (dd, J=251.2, 8.2 Hz), 152.4, 149.8, 142.0, 139.7, 131.7, 129.9, 129.8, 128.3, 127.9, 127.7, 127.6, 123.8, 121, 79 (dd, J=13.4, 3.4 Hz), 117.1, 113.5, 112.12 (dd, J=22.6, 4.3 Hz), 53.8, 16.8, 12.5.

TLC-MS (ESI-): m/z=522.9 [M-H] ^- .

Example 75: Synthesis of N-(3-(5-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl) )-1-phenylmethanesulfonamide

N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]-1-phenylmethanesulfonamide (76, 0 mg, 0.129 mmol), [4-(1H-tetrazol-5-yl)phenyl]boric acid (26.9 mg, 0.141 mmol) and Pd(dppf)Cl ₂ DCM (5.25 mg, 0.00643 mmol) and purged with argon. Degassed 1,4-dioxane (0.428 ml) and degassed 1.5 M aqueous potassium carbonate (0.343 ml, 0.514 mmol) were added, the vessel was sealed and the reaction mixture was heated to 80°C for 2.5 hours. The reaction mixture was diluted with MeOH (1 ml), acidified with conc. HCl (1 ml) and stirring was continued at 60°C for 3 hours. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, the solvent was removed and the product was purified by flash chromatography (DCM/MeOH gradient (+ 1% formic acid), 5% to 15% MeOH (1% formic acid)), triturated with DCM and dried at 100°C , giving N-[2,6-difluoro-3-[5-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]- 1-phenylmethanesulfonamide (40.0 mg, 0.0699 mmol, 54% yield).

TLC-MS (ESI-): m/z 571.0 [M-H] ^-

Example 76 Synthesis of N-(2,6-difluoro-3-(5-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide

N-[3-[5-bromo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide (72 .0 mg, 0.133 mmol), (4-hydroxyphenyl)boronic acid (20.1 mg, 0.146 mmol), potassium fluoride (23.1 mg, 0.398 mmol) and Pd(dppf)Cl ₂ DCM (5.41 mg , 0.00663 mmol) and purged with argon. Added degassed 1,4-dioxane/water (4+1) and the mixture was stirred at 80°C for 20 minutes. After cooling, the mixture was diluted with 1 ml of MeOH, acidified with 0.3 ml of conc. HCl and stirred at 60°C for 2 hours. The reaction mixture was dissolved in water and EtOAc, the organic phase was washed with saline, dried over Na ₂ SO ₄ and evaporated. The product was purified by flash chromatography (DCM 7EtOAc gradient, 20% to 60% EtOAc) and triturated with DCM to give N-[2,6-difluoro-3-[5-(4-hydroxyphenyl)-1H-pyrazolo[3, 4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide (39.0 mg, 0.0817 mmol, 62% yield).

Analytical data:

¹ H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 9.70 (s, 2H), 8.94 (d, J=1.9 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 7.85 (dd, J=14.5, 7.8 Hz, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.39 ( t, J=8.8 Hz, 1H), 6.93 (d, J=8.5 Hz, 2H), 3.20-3.06 (m, 2H), 1.87-1.75 (m , 2H), 1.00 (t, J=7.4 Hz, 3H).

¹³ C NMR (101 MHz, DMSO) δ 182.3, 156.4 (dd, J=248.8, 6.6 Hz), 152.92 (dd, J=251.8, 8.1 Hz), 151.0, 150.9, 141.0, 132.2, 130.1, 130.0, 121.80 (dd, J=13.2, 3.7 Hz), 116.84 (dd, J= 23.0, 20.9 Hz), 115.7, 114.7, 112.16 (dd, J=22.4, 3.7 Hz), 40.4;

TLC-MS (ESI-): m/z 450.9, 471.0 [M-H] ^- .

Example 77: Biological activity

Example 77-1 Binding Assays

The kinase activities of the compounds of the present invention were measured using the KINOMEscan™ Profiling Service at DiscoveR ^x Corporation, 42501 Albrae St. Fremont, CA 94538, USA, which is based on a competitive binding assay that quantifies the ability of a compound to compete with an immobilized ligand directed to the active site. The analysis was performed by combining three components: DNA-tagged kinase; immobilized ligand; and test compound. The ability of a test compound to compete with the immobilized ligand was measured using a quantitative PCR DNA tag. The technology is described in detail in Fabian, MA et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol., 23, 329-336 (2005) and in Karaman, MW et al. A quantitative analysis of kinase inhibitor selectivity, Nat. Biotechnol., 26, 127-132 (2008).

To study affinity for MKK4, MKK7 and JNK1, kinases were produced in HEK-293 cells and subsequently labeled with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to prepare affinity resins for kinase assay. The liganded beads were blocked with excess biotin and washed with blocking buffer (SEABLOCK™ (Pierce), 1% BSA, 0.05% TWEEN®20, 1 mM DTT) to remove unbound ligand and reduce non-specific binding. Binding reactions were collected by combining kinases, liganded affinity beads and test compounds in 1x binding buffer (20% SEABLOCK™, 0.17x PBS, 0.05% TWEEN®20, 6 mM DTT). All reactions were carried out in polystyrene 96-well plates in a final volume of 0.135 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% TWEEN®20). The beads were then resuspended in elution buffer (1xPBS, 0.05% TWEEN®20, 0.5 11M non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.

Mean Z' values and standard deviations were calculated for each kinase based on fourteen control wells per experiment in more than 135 independent experiments spanning a period of sixteen months. Average Z'= 0.71.

The effectiveness of the tested compounds:

Compounds were screened at the indicated concentrations and results for binding interactions are presented as [% of control], where lower numbers indicate stronger binding, ie higher activity.

Details on the kinases tested are shown in Table 2 below.

Test compounds were provided as 10 mM stock solutions. Test solutions at the indicated final concentrations were prepared in DiscoveR ^x . The results are shown in tables 3-6 below.

Table 2:

MKK4 MKK7 JNK1 Group STE STE CMCG Kinase construction Partial length full size full size Access number NP_003001.1 NP_660186.1 NP_002741.1 Kinds Person Person Person Kinase form wild type wild type wild type Expression system Mammals Mammals Mammals Amino Acid Start/Stop S84/D399 M1/R419 M1/Q384 Mean Z' panel 0.67 0.78 0.79

MKK4 Efficiency:

The potency of the compounds of Examples 2-43 against MKK4 protein kinase, expressed as percent residual control binding (PoC), was determined at a concentration of 100 nM. The results are shown in Table 3 below (N/D means not determined).

PoC<1="+++"; 1 ≤ PoC <10 = "++"; 10 ≤ PoC <30 = "+"; PoC ≥ 30 = "O".

Selectivity against JNK1:

The selectivity of Examples 2-67 against non-target JNK1, determined by calculating the ratio of residual percent control binding (PoC) to JNK1 and MKK4, was determined at a concentration of 100 nM. The results are shown in Table 4 below.

PoC (JNK1)/PoC (MKK4) ≥ 30 = "+++"; 30> PoC (JNK1)/PoC (MKK4) ≥ 10 = "++"; 10>PoC(JNK1)/PoC(MKK4) ≥ 3="+"; PoC (JNK1)/PoC (MKK4) <3 = "O".

MKK4 potency and selectivity against MKK7:

The selectivity of Examples 2-43 against non-target MKK7, determined by calculating the ratio of residual percent control binding (PoC) to MKK7 and MKK4, was determined at a concentration of 100 nM. The results are shown in Table 5 below.

PoC (MKK7)/PoC (MKK4) ≥ 30 = "+++"; 30> PoC (MKK7)/PoC (MKK4) ≥ 10 = "++"; 10>PoC(JNK1)/PoC(MKK4) ≥ 3="+"; PoC (JNK1)/PoC (MKK4) <3 = "O".

Efficacy and selectivity of MKK4 against BRaf:

The selectivity of Examples 2-43 for non-target BRaf, determined by calculating the ratio of residual percent control binding (PoC) to BRaf and MKK4, was determined at a concentration of 100 nM. The results are shown in Table 6 below.

PoC (BRaf)/PoC (MKK4) ≥ 30 = "+++"; 30> PoC (BRaf)/PoC (MKK4) ≥ 10 = "++"; 10> PoC (BRaf)/PoC (MKK4) ≥ 3 = "+"; PoC (BRaf)/PoC (MKK4) <3 = "O".

Example 77-2: Functional analysis of enzymes

(a) Material

Recombinant kinase proteins (commercially available)

MEKK2, recombinant, active: ProQinase product # 0583-0000-1

MEKK2, recombinant, activated: ProQinase product # 0583-0000-1

MKK4, recombinant, not activated: ProQinase product # 0948-0000-2

substrate proteins

Casein (Sigma C-4765)

JNK1 K55R/K56R Recombinant Inactive: Product ProQinase # 0524-0000-1

(b) Methods

(b-1) MEKK2-dependent MKK4 activation

MKK4 (not activated) is incubated with MEKK2 (active) at a ratio of 10:1 (w/w), corresponding to a molar ratio of 20:1, in the presence of compound or vehicle and 20 μM ATP for 30 minutes at 30°C. The activation step is carried out in 50 mM HEPES, pH 7.5, 50 mM NaCl, 3.8 mM MgCl ₂ , 2.5 mM DTT, 10% (v/v) glycerol. The final concentration of DMSO is 1%. The activating mixture is pipetted in the following order:

2.5 µl compound in 4% DMSO

2.5 µl ATP/MgCl ₂

5 µl MKK4:MEKK2 kinase premix solution 10:1 (w/w)

Protein concentrations in the activation mixture are 1 μM MKK4 and 50 nM MEKK2.

(b-2) Protein kinase assay

Radiometric protein kinase assay was used to measure the kinase activity of the respective protein kinases. All kinase assays were performed in 96-well polypropylene plates. After the reactions were stopped, the assay mixtures were transferred to 96-well MSFC filter plates (Millipore). The reaction mixture was passed through a filtering membrane by aspiration, the membrane was washed 3 times with 150 mm H ₃ PO ₄ , once with ethanol, dried and a liquid scintillation cocktail was added. Radioactivity was determined by counting the samples in a Microbeta multiwell scintillation counter (Wallac). The reactions were pipetted in the following order:

a) MEKK2-MKK4 activation mixture

20 µl standard assay buffer

10 µl MEKK2-MKK4 activation mix

5 µl radioactive solution ³³ P - ATP (usually 106 ppm/well)γ

10 µl substrate solution

b) Single kinases

20 µl standard assay buffer

5 µl compound in 10% DMSO

20 µl smsi enzyme-substrate

10 µl substrate solution

The assay contained 70 mM HEPES-NaOH, pH 7.5, 3 mM MgCl ₂ , 3 mM MnCl 2 , 3 M Na orthovanadate, 1.2 mM DTT, ATP (variable amounts corresponding to the apparent ATP-Km of the respective kinase, see Table 1). [ ³³ P-γ-ATP (approximately 8×10 ⁵ pulses per minute per well), protein kinase (variable amounts; see Table 1) and substrate (variable amounts; see Table 7 below). The results are shown in Table 8 below.

Table 7: Enzymes, substrates and assay conditions (amount/well)

# Kinase Conc. kinases Conc. kinases Conc. ATP substrate Name ng/50µl nM µM Name µg/50µl nM 1 MKK4-MEKK2 mix 25 10 0.2 JNK1 KRKR 1 430 2 MKK4 active 25 10 0.2 JNK1 KRKR 1 430 3 MEKK2 150 thirty 0.2 Casein 1 870

Table 8: Efficacy of test compounds

Note. Cascade MKK4 MEKK2 Note. Cascade MKK4 MEKK2 2 + +++ O 51k +++ +++ O 3 + +++ O 51l + ++ + four + + O 51m + +++ + five + +++ O 52a N/D +++ N/D 8 O + O 52b N/D ++ N/D nine + ++ + 52c N/D ++ N/D 13 + +++ + 53a N/D ++ N/D fourteen + ++ O 53b N/D ++ N/D 15 + +++ + 53c N/D +++ N/D 17 + + O 53d N/D ++ N/D eighteen ++ +++ + 54a N/D +++ N/D nineteen + +++ + 54b N/D +++ N/D 21 + ++ + 54c N/D +++ N/D 23 O O O 55 N/D +++ N/D 24 O ++ O 57 N/D +++ N/D 25 + ++ O 58 N/D +++ N/D 27 ++ +++ + 59 N/D +++ N/D 31 + +++ + 61 N/D +++ N/D 32 + ++ O 62 N/D +++ N/D 37 ++ +++ + 63 N/D +++ N/D 39 O + O 64 N/D +++ N/D 40 O + O 65 + ++ + 41 + + O 66 + +++ + 42 + + O 67 +++ +++ +++ 51a ++ ++ + 68 N/D +++ N/D 51b + ++ + 69 N/D +++ N/D 51c ++ +++ + 70 ++ +++ ++ 51d +++ +++ + 71 ++ +++ O 51e +++ +++ + 72 + ++ + 51f + +++ + 73 N/D +++ N/D 51g + ++ + 74 +++ +++ + 51j + +++ O 75 ++ +++ + 76 N/D +++ N/D

*: efficacy derived from IC50 (PoC) values according to the following classification rule:

IC50 ≥ _10µM 10 > IC ₅₀ ≥ 1 µM 1 > IC ₅₀ ≥ 0.5 µM IC ₅₀ < 0.5 µM O + ++ +++

Claims (142)

1. A compound of formula (Ic), or a pharmaceutically acceptable salt or optical isomer thereof

(ic) where R ¹ is H; R ^w is -NR ¹⁰ SO ₂ R ¹² ; ^Rx is F; R ^y is F; R ⁴ is H; R ⁵ is phenyl substituted with 1, 2 or 3 groups independently selected from C ₁ -C ₆ alkyl, hydroxy, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkyl-SO(=NR ¹⁰ )-, C ₁ -C ₆ alkylsulfonyl-NR ¹⁰ -, -NR ¹⁰ R ¹⁰ , R ¹⁰ R ¹⁰ NSO ₂ -, R ¹⁰ R ¹¹ N(C=O)-, C ₁ -C ₆ alkoxy, -OCH ₂ CH ₂ O- (ethylenedioxy attached at adjacent positions to the phenyl ring), -NO ₂ , -COOR ¹⁰ , R ¹⁰ R ¹⁰ N(C=O)-, and tetrazolyl, or R ⁵ is pyridyl, pyridyl substituted with -COOR ¹⁰ , or pyrimidinyl substituted with CF ₃ ; R ⁶ is H; R ¹⁰ at each occurrence is independently H or C ₁ -C ₆ alkyl; R ¹¹ is alkyl which is substituted with 1 or 2 hydroxy groups; and R ¹² is C ₁ -C ₆ alkyl, phenylC ₁ -C ₆ alkyl or -NR ¹⁰ R ¹⁰ . 2. A compound and a pharmaceutically acceptable salt or optical isomer thereof according to claim 1, wherein R ⁵ is pyridyl, pyridyl substituted with -COOR ¹⁰ , pyrimidinyl or pyrimidinyl substituted with CF ₃ . 3. The compound or its pharmaceutically acceptable salt or optical isomer according to claim 1, where R ⁵ is phenyl substituted with 1, 2 or 3 groups independently selected from C ₁ -C ₆ alkyl, hydroxy, halo, C ₁ -C ₆ alkyl-SO(=NR ¹⁰ )-, R ¹⁰ R ¹⁰ NSO ₂ - , -COOR ¹⁰ , R ¹⁰ R ¹⁰ N(C=O)- and tetrazolyl. 4. A compound selected from the group consisting of N-(2,4-difluoro-3-(5-phenyl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(2-chloro-4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(3-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-(5-(4-(dimethylamino)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-(5-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-(5-(4-tert-butylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(4-isopropylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(3,4-dimethylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-o-tolyl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide; N-(2,4-difluoro-3-(5-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(3-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(4-aminophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-p-tolyl-1H-pyrazole [3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(2-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(3,5-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(2-aminophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-(5-(3-aminophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-(5-(3-(dimethylamino)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-m-tolyl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(2-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(3-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(3,4-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(2,4-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-(5-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2,4-difluoro-3-(5-(3-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(3-(5-(2-chloro-4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2-fluorophenyl)methanesulfonamide; N-(2-fluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)methanesulfonamide; N-(3-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2-fluorophenyl) methanesulfonamide; N-(3-(5-(2-chloro-4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2-fluorophenyl)butane-1-sulfonamide; N-(2-fluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)butane-1-sulfonamide; N-(3-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2-fluorophenyl) butane-1-sulfonamide; N-(5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide; 5-(4-chlorophenyl)-N-(2,6-difluoro-3-(propylsulfonamido)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide; N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)thio)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)sulfinyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)sulfonyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)(hydroxy)methyl)-2,4-difluorophenyl)propane-1-sulfonamide; N-(3-((5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)-2,4-difluorophenyl)propane-1-sulfonamide; 4-(3-(2,6-difluoro-3-((phenylmethyl)sulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide; 4-(3-(2,6-difluoro-3-(methylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide; 4-(3-(3-(butylsulfonamido)-2,6-difluorobenzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide; 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid; N-[2,4-difluoro-3-[5-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1 -sulfonamide; 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide; N-(2,4-difluoro-3-(5-(4-(methylsulfonamido)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-methyl-benzenesulfonamide; 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-ethylbenzenesulfonamide; 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2,3-dihydroxypropyl)benzenesulfonamide; N-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)acetamide; 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2,3-dihydroxypropyl)benzamide; 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-fluorobenzenesulfonamide; 3-chloro-4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide; 4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-fluorobenzenesulfonamide; 4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methyl-benzenesulfonamide; 4-[3-[2,6-difluoro-3-(phenylsulfomoylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide; 4-[3-[2,6-difluoro-3-(sulfomoylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide; 4-[3-[2,4,6-trifluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide; 4-[3-[3-(ethylsulfamoylamino)-2,6-difluorobenzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide; N-[3-(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl]methanesulfonamide; N-[2,6-difluoro-3-[5-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide; 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzamide; 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzenesulfonamide; 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoic acid; ethyl 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoate; [(2S)-2-amino-3-methoxy-3-oxopropyl] 4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridine-5 yl]benzoate; (2S)-2-amino-3-[4-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]oxypropanoic acids; 5-[3-[2,4-difluoro-3-(methanesulfonamido)benzoyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]pyridine-2-carboxylic acid; N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]methanesulfonamide; N-[2,6-difluoro-3-[5-[4-(methylsulfonimidoyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]methanesulfonamide; N-[3-[5-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide; 4-(3-(2,4-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid; N-(3-(5-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide; N-(2,6-difluoro-3-(5-(4-isopropyl-phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; N-(2,6-difluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; 4-(3-(2,4-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide; N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]-1-phenylmethanesulfonamide; N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl]ethanesulfonamide; 4-(3-(2,4-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-methylbenzenesulfonamide; N-(2,6-difluoro-3-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide ; N-(3-(5-(4-chloro-2-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide; N-(3-(5-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl)ethanesulfonamide; N-(3-(5-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propan-1- sulfonamide; N-(3-(5-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,6-difluorophenyl)-1-phenidemethanesulfonamide ; N-(2,6-difluoro-3-(5-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide; or a pharmaceutically acceptable salt or optical isomer thereof. 5. N-(2,6-difluoro-3-(5-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide or pharmaceutically thereof acceptable salt or optical isomer. 6. Pharmaceutical composition for selective inhibition of protein kinase MKK4 compared to protein kinases JNK1 and MKK7, containing an effective amount of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or optical isomer thereof. 7. A pharmaceutical composition for promoting liver regeneration or reducing or preventing hepatocyte death, comprising an effective amount of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or optical isomer thereof. 8. The use of a compound or a pharmaceutically acceptable salt or optical isomer thereof according to any one of claims 1 to 5 for inhibition of protein kinase MKK4 and, in particular, for use in selective inhibition of protein kinase MKK4 compared to protein kinases JNK1 and MKK7; or promoting liver regeneration or reducing or preventing hepatocyte death. 9. Use according to claim 8, characterized in that the compound is administered at a dose of 0.2 to 15 mg/kg to the patient to be treated for 1 to 12 months. 10. Method selective inhibition of protein kinase MKK4 compared to protein kinases JNK1 and MKK7, or stimulating liver regeneration or preventing the death of hepatocytes, which comprises administering an effective amount of a compound according to any one of claims 1 to 5 or a composition according to claim 6 or 7 to a patient in need thereof.