RU2822216C2 - Protein kinase inhibitors for enhancing liver regeneration or reducing or preventing hepatocyte death - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to compounds which are inhibitors of MKK4 (mitogen-activated protein kinase 4), pharmaceutical compositions based thereon and use for enhancing liver regeneration and reducing or preventing hepatocyte death.

EFFECT: obtaining compounds which selectively inhibit protein kinase MKK4 relative to protein kinases JNK and MKK7 and can be used to enhance liver regeneration and reducing or preventing death of hepatocytes associated with selective inhibition of protein kinase MKK4 relative to protein kinase JNK and MKK7.

6 cl, 8 tbl, 243 ex

Description

The present invention relates to protein kinase inhibitors that inhibit mitogen-activated protein kinase kinase 4 (MKK4) and, in particular, selectively inhibit MKK4 relative to the protein kinases JNK1 and MKK7.

PREREQUISITES FOR CREATION OF THE INVENTION

Liver disease can be caused by infection, injury, exposure to toxic compounds such as alcohol or drugs, autoimmune processes, genetic defects and other factors. The liver has an amazing regenerative capacity, which, however, can be impaired in disease states 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 for the treatment of diseases and conditions associated with aberrant protein kinase activity. These compounds are inhibitors of Raf protein kinase, in particular B-Raf and c-Raf and their mutations, and are therefore useful for the treatment of malignant tumors. In addition, they are reported to inhibit a wide range of other protein kinases, including c-Jun N-terminal kinases (JNKs), and in particular JNK1. WO 2010/002325 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. cite two compounds from WO 2007/002433 as B-Raf inhibitors that suppress apoptosis through off-target inhibition of the JNK signaling pathway. WO 2010/111527 describes pyrazolo[3,4-b]pyridine compounds that are protein kinase inhibitors useful for treating a Raf protein kinase-mediated disease or condition, such as cancer. In addition, they are reported to inhibit a wide range of other protein kinases, including c-Jun N-terminal kinases (JNKs), and in particular JNK1. WO 2012/136859 discloses several compounds which are described as mitogen-activated protein kinase kinase 4 (MKK4) inhibitors and which are useful for the treatment of liver failure, for the protection of hepatocytes from apoptosis and for the regeneration of hepatocytes. The paper by Wuestefeld et al. (Cell 153:389-401, 2013) describes a functional genetic approach to identify target genes that can be used to enhance the regenerative potential of hepatocytes. In particular, protein kinase MKK4 is defined in Wuestefeld et al. as a key regulator of liver regeneration, and it was reported that MKK4 suppression enhanced hepatocyte regeneration through compensatory up-regulation of MKK7 and JNK1-dependent activation of ATF2 and ELK1. Based on prior art studies, it was concluded that MKK4 and JNK1 inhibitors may be useful for the treatment of JNK1-mediated diseases.

However, as it turned out from clinical practice, the treatment of liver diseases with such compounds was unsuccessful.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

The main object of the present invention is to provide compounds useful as MKK4 inhibitors, in particular MKK4 inhibitors that selectively inhibit MKK4 relative to MKK7 and JNK1. A further objective was to provide compounds that are MKK4 inhibitors, which selectively inhibit MKK4 relative to MKK7 and JNK1 and which are useful for the treatment of liver diseases and, in particular, for enhancing liver regeneration and reducing or preventing the death of hepatocytes.

This problem was solved by providing compounds of formula (I).

Thus, the present invention relates to the following embodiments:

1. The compound characterized by formula (I)

Where

R ¹ represents H or alkyl;

R ² represents H or alkyl;

R ⁴ represents H, halogen, CN or alkyl;

R ⁶ represents H, alkoxy or alkyl;

R ^w represents -NR ¹⁰ SO ₂ R ¹² ;

R ¹⁰ represents H, alkyl or phenylalkyl;

R ¹² selected from

H,

alkyl, where the alkyl group is optionally substituted with 1 or 2 hydroxy groups or an acetyl group,

haloalkyl or

phenylalkyl, wherein the phenyl group is optionally substituted with 1 or 2 groups independently selected from alkyl and halogen;

R ^x , R ^y , R ^z and R ^zz selected from:

a) R ^x and R ^y represent F, and R ^z and R ^zz represent H;

b) R ^x , R ^y and R ^zz are independently halogen, and R ^z is H;

c) R ^x , R ^z and R ^zz are independently halogen, and R ^y is H; And

d) R ^x , R ^y and R ^z are independently halogen, and R ^zz is H;

R ⁵ selected from

(a) phenyl which is substituted with 1, 2 or 3 groups independently selected from

halogen,

alkyl,

alkoxy,

alkoxy, where the alkyl group is replaced by 1, 2 or 3 hydroxy groups,

alkoxy, where the alkyl group is replaced by 1, 2 or 3 halogen atoms,

haloalkyl,

hydroxy

-SO ₂ NR ¹⁰ R ¹⁰ ,

-CO ₂ R ¹⁰ ,

-CN,

-SF ₅ ,

-(NR ¹⁰ =)S(=O)-alkyl (S-alkylsulfonimidoyl),

1H- or 2H-tetrazolyl,

-SO ₂ alkyl, where the alkyl group is optionally substituted with 1, 2 or 3 halogen atoms,

-SOalkyl,

alkylsulfanyl, where the alkyl group is optionally substituted with -NR ¹⁰ R ¹⁰ or 1, 2 or 3 halogen atoms,

-POdi(alkyl),

_-NO2 ,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ N-CO-,

-NR ¹⁰ COalkyl,

hydroxyalkyl-ONH-CO-,

cycloalkyl,

a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S, the group being optionally substituted by 1 or 2 groups independently selected from alkyl and C ₂ -C ₅ -alkanoyl, And

alkoxy, wherein the alkyl group is substituted with a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein the monocyclic group is optionally substituted with 1 or 2 groups independently selected from alkyl and halogen ;

(b) naphthyl;

(c) a heteroaromatic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the heteroaromatic group is optionally substituted with 1, 2 or 3 groups independently selected from

alkyl,

haloalkyl,

cycloalkyl,

-NR ¹⁰ R ¹⁰ ,

halogen,

hydroxy

alkoxy, which is optionally substituted with -NR ¹⁰ R ¹⁰ ,

-CN,

alkenyl,

alkynyl,

R ¹⁰ R ¹⁰ N-CO-,

-SO ₂ NR ¹⁰ R ¹⁰ ,

-SO ₂ alkyl,

-(NR ¹⁰ =)S(=O)-alkyl,

cycloalkyl-NR ¹⁰ -,

alkyl-NR ¹⁰ -, where the alkyl group is replaced by hydroxy or alkoxy,

alkylsulfanyl,

benzimidazolyl,

And

a non-aromatic heterocyclic 4-, 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O, N, S, SO and SO ₂ , wherein the heterocyclic group is optionally substituted with alkyl, hydroxyalkyl or hydroxy;,

(d) C ₂ -C ₅ -alkynyl;

(e) C ₂ -C ₅ alkenyl;

(f) halogen;

(g) cycloalkyl;

(h) phenyl which is fused to a heteroaromatic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S;

i) 1,3-dialkylyl-1-oxido-1H-benzo[e][1,2]thiazine;

j) a saturated or unsaturated non-aromatic heterocyclic 4-, 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N, S, SO and SO ₂ , wherein the heterocyclic group is optionally substituted with 1 or 2 groups , independently selected from alkyl, C ₂ -C ₅ -alkanoyl, benzoyl, hydroxy, -CO ₂ R ¹⁰ or carbonyl (one of the ring carbon atoms is a >C=O group);

k) oxetanamino;

and its pharmaceutically acceptable salts, solvates and optical isomers.

2. The connection according to embodiment 1, where

R ¹ represents H or alkyl;

R ² represents H or alkyl;

R ⁴ represents H or alkyl;

R ⁶ represents H or alkyl;

R ^w represents -NR ¹⁰ SO ₂ R ¹² ;

R ¹⁰ represents H, alkyl or phenylalkyl;

R ¹² represents H, alkyl, haloalkyl or phenylalkyl, wherein the phenyl group is optionally substituted with 1 or 2 groups independently selected from alkyl and halogen;

R ^x , R ^y , R ^z and R ^zz selected from:

a) R ^x and R ^y represent F, and R ^z and R ^zz represent H;

b) R ^x , R ^y and R ^zz are independently halogen, and R ^z is H;

c) R ^x , R ^z and R ^zz are independently halogen, and R ^y is H; And

d) R ^x , R ^y and R ^z are independently halogen, and R ^zz is H;

R ⁵ selected from

(a) phenyl which is substituted with 1, 2 or 3 groups independently selected from

halogen,

alkyl,

alkoxy,

alkoxy, where the alkyl group is replaced by 1, 2 or 3 hydroxy groups,

haloalkyl,

hydroxy

-SO ₂ NR ¹⁰ R ¹⁰ ,

-CO ₂ R ¹⁰ ,

-CN,

-(NR ¹⁰ =)S(=O)-alkyl (S-alkylsulfonimidoyl) and

1H- or 2H-tetrazolyl;

(b) naphthyl;

(c) a heteroaromatic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the heteroaromatic group is optionally substituted with 1, 2 or 3 groups independently selected from

alkyl,

haloalkyl,

cycloalkyl,

-NR ¹⁰ R ¹⁰ ,

halogen,

hydroxy

alkoxy, which is optionally substituted with -NR ¹⁰ R ¹⁰ ,

-CN,

alkenyl,

alkynyl,

R ¹⁰ R ¹⁰ N-CO-,

alkyl-S(=O)(=NR ¹⁰ )-,

cycloalkyl-NR ¹⁰ -,

alkyl-NR ¹⁰ -, where the alkyl group is replaced by hydroxy or alkoxy,

alkylsulfanyl,

benzimidazolyl,

And

a non-aromatic heterocyclic 4-, 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, wherein the heterocyclic group is optionally substituted with alkyl, hydroxyalkyl and hydroxy,

(d) C ₂ -C ₅ -alkynyl,

(e) C ₂ -C ₅ alkenyl,

(f) halogen and

(g) cycloalkyl,

and its pharmaceutically acceptable salts, solvates and optical isomers.

3. The connection according to embodiment 2, where R ⁵ is selected from

(a) phenyl which is substituted with 1, 2 or 3 groups independently selected from

halogen,

alkyl,

alkoxy,

alkoxy, where the alkyl group is replaced by 1 or 2 hydroxy groups,

hydroxy

-SO ₂ NR ¹⁰ R ¹⁰ ,

-CO ₂ R ¹⁰ ,

-CN,

-SF ₅ ,

-(NR ¹⁰ =)S(=O)-alkyl (S-alkylsulfonimidoyl) and

1H- or 2H-tetrazolyl;

(b) naphthyl;

(c) a heteroaromatic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the heteroaromatic group is optionally substituted with 1, 2 or 3 groups independently selected from

alkyl,

haloalkyl,

cycloalkyl,

-NR ¹⁰ R ¹⁰ ,

halogen,

alkoxy, which is optionally substituted with -NR ¹⁰ R ¹⁰ ,

-CN,

alkenyl,

alkynyl,

R ¹⁰ R ¹⁰ N-CO-,

alkyl-S(=O)(=NR ¹⁰ )-,

cycloalkyl-NR ¹⁰ -,

alkyl-NR ¹⁰ -, where the alkyl group is replaced by hydroxy or alkoxy,

alkylsulfanyl,

benzimidazolyl,

And

a non-aromatic heterocyclic 4-, 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, wherein the heterocyclic group is optionally substituted with alkyl, hydroxyalkyl and hydroxy,

(f) halogen and

(g) cycloalkyl,

and its pharmaceutically acceptable salts, solvates and optical isomers.

4. The compound according to any one of embodiments 1-3, wherein if R ⁵ is substituted with 1, 2 or 3 halogens, then the halogen is independently selected from F or Cl,

and its pharmaceutically acceptable salts, solvates and optical isomers,

5. The compound according to any one of embodiments 1-3, wherein R ⁵ is phenyl which is substituted with 1, 2 or 3 groups independently selected from

halogen,

alkyl,

alkoxy,

alkoxy, where the alkyl group is replaced by 1 or 2 hydroxy groups,

hydroxy

-SO ₂ NR ¹⁰ R ¹⁰ ,

-CO ₂ R ¹⁰ ,

-CN,

-SF ₅ ,

-(NR ¹⁰ =)S(=O)-alkyl (S-alkylsulfonimidoyl) and

1H- or 2H-tetrazolyl.

6. The compound according to any of embodiments 1-3, wherein R ⁵ is a heteroaromatic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, wherein the heteroaromatic group is optionally substituted with 1, 2 or 3 groups independently selected from

alkyl,

haloalkyl,

cycloalkyl,

-NR ¹⁰ R ¹⁰ ,

halogen,

alkoxy, which is optionally substituted with -NR ¹⁰ R ¹⁰ ,

-CN,

alkenyl,

alkynyl,

R ¹⁰ R ¹⁰ N-CO-,

alkyl-S(=O)(=NR ¹⁰ )-,

cycloalkyl-NR ¹⁰ -,

alkyl-NR ¹⁰ -, where the alkyl group is replaced by hydroxy or alkoxy,

alkylsulfanyl,

benzimidazolyl,

And

a non-aromatic heterocyclic 4-, 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, wherein the heterocyclic group is optionally substituted with alkyl, hydroxyalkyl or hydroxyl.

7. The compound of Embodiment 6, wherein the heteroaromatic 5- or 6-membered monocyclic group is selected from pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and the group is optionally substituted as defined in any of embodiments 1- 3 or 6, and in particular as defined in embodiment 6.

8. The compound of Embodiment 7, wherein the heteroaromatic 5- or 6-membered monocyclic group is selected from pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and the group is optionally substituted as defined in Embodiment 6.

9. The compound of Embodiment 8, wherein the heteroaromatic 5- or 6-membered monocyclic group is selected from pyridyl and pyrimidinyl, and the group is optionally substituted as defined in Embodiment 6.

10. The compound according to embodiment 9, wherein the heteroaromatic 5- or 6-membered monocyclic group is pyridyl, which is optionally substituted with 1, 2 or 3 groups independently selected from halogen, in particular F or Cl, alkyl, alkoxy, haloalkyl, in in particular CF ₃ , cycloalkyl, -NR ¹⁰ R ¹⁰ , cycloalkyl-NR ¹⁰ -, alkenyl, in particular vinyl, and alkyl-S(=O)(=NR ¹⁰ )-.

11. The compound of Embodiment 9, wherein the heteroaromatic 5- or 6-membered monocyclic group is pyrimidinyl which is optionally substituted with 1 or 2 groups independently selected from

alkyl,

alkoxy, which is optionally substituted with -NR ¹⁰ R ¹⁰ ,

halogen, in particular F or Cl,

alkyl-NR ¹⁰ -, where the alkyl group is replaced by hydroxy or alkoxy,

-NR ¹⁰ R ¹⁰ ,

haloalkyl, in particular CF ₃ ,

cycloalkyl,

alkenyl,

-CN,

alkylsulfanyl,

-NR ¹⁰ R ¹⁰ ,

R ¹⁰ R ¹⁰ N-CO-,

cycloalkyl-NR ¹⁰ -,

benzimidazolyl and

a non-aromatic heterocyclic 4-, 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, wherein the heterocyclic group is optionally substituted with alkyl, hydroxyalkyl or hydroxy.

12. The compound of embodiment 11, wherein the pyrimidinyl is substituted with a non-aromatic heterocyclic 4-, 5- or 6-membered monocyclic group selected from azetidinyl, which is optionally substituted with hydroxy, pyrrolidinyl, which is optionally substituted with hydroxy, piperidinyl, morpholidinyl, and piperazidinyl, which is optionally substituted alkyl, hydroxy or hydroxyalkyl.

13. The compound according to embodiment 11, wherein the pyrimidinyl is substituted with a cycloalkyl, in particular a C ₃ -C ₆ cycloalkyl.

14. The compound of embodiment 12 or 13, wherein the pyrimidinyl is linked at the 5-position to 1H-pyrrolo[2,3-b]pyridine and substituted at the 2-position.

15. The compound according to embodiment 3, wherein R ⁵ is selected from C ₃ -C ₆ -cycloalkyl.

16. A compound according to any of the preceding embodiments, wherein R ¹² represents C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, in particular -CH ₂ CH ₂ CF ₃ , or benzyl.

17. The compound of Embodiment 12, wherein R ¹² is C ₁ -C ₄ alkyl and preferably methyl, ethyl or propyl.

18. The compound according to any of the preceding embodiments, characterized by formula (Ia)

and its pharmaceutically acceptable salts, solvates and optical isomers.

19. The compound according to any one of embodiments 1 to 17, characterized by formula (Ib)

and its pharmaceutically acceptable salts, solvates and optical isomers.

20. The compound according to any one of embodiments 1 to 17, characterized by formula (Ic)

and its pharmaceutically acceptable salts, solvates and optical isomers.

21. The compound according to any one of embodiments 1 to 17, characterized by formula (Id)

and its pharmaceutically acceptable salts, solvates and optical isomers.

22. A compound according to any of the preceding embodiments, wherein ^R1 , ^R2 , ^R3 , ^R4 , and ^R6 are H or alkyl, in particular H.

23. A compound according to any of the preceding embodiments, wherein R ¹⁰ represents H or alkyl, in particular H.

Additional embodiments are:

24. The compound characterized by formula (I)

Where

R ¹ represents H or alkyl;

R ² represents H or alkyl;

R ⁴ represents H, halogen, CN or alkyl;

R ⁶ represents H, alkoxy or alkyl;

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

R ¹⁰ represents H, alkyl or phenylalkyl;

R ¹² represents H, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl or phenylalkyl, wherein the phenyl group is optionally substituted with 1 or 2 groups independently selected from alkyl, halogen;

R ^x represents H, halogen, CN or alkyl;

R ^y represents H, halogen, CN or alkyl;

R ^z is H, halogen, CN or alkyl;

R ⁵ selected from

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

alkyl,

alkoxy,

alkoxy, where the alkyl group is replaced by 1, 2 or 3 hydroxy groups,

alkoxy, wherein the alkyl group is substituted with a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein the monocyclic group is optionally substituted with 1 or 2 groups independently selected from alkyl and halogen ,

haloalkyl,

hydroxy

NR ¹⁰ R ¹⁰ ,

alkylsulfonyl-NR ¹⁰ -,

-SO ₂ NR ¹⁰ R ¹⁰ ,

alkylsulfanyl, where the alkyl group is optionally substituted with NR ¹⁰ R ¹⁰ or 1, 2 or 3 halogen atoms,

alkylsulfinyl,

alkylsulfonyl, where the alkyl group is optionally substituted with 1, 2 or 3 halogen atoms,

haloalkoxy,

cycloalkyl,

thioguanidino (H ₂ NC(=NH)-S-),

R ¹⁰ R ¹⁰ N-CO-,

R ¹⁰ R ¹¹ NSO ₂ -,

alkylcarbonyl-NR ¹⁰ -,

CN, and

a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S, which is optionally substituted with 1 or 2 groups independently selected from alkyl, C ₂ -C ₅ -alkanoyl and benzoyl ,

(b) phenyl which is fused to a heteroaromatic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S,

(c) a heteroaromatic 5- or 6-membered monocyclic or a heteroaromatic 9- or 10-membered bicyclic group, wherein the heteroaromatic groups contain 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein the heteroaromatic group is optionally substituted

alkyl,

haloalkyl,

cycloalkyl,

-NR ¹⁰ R ¹⁰ ,

halogen,

alkoxy,

-CO ₂ R ¹⁰ and

a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N, S, SO and SO ₂ , wherein the heterocyclic group is optionally substituted with an alkylsulfanyl or 1 or 2 hydroxy groups,

(d) a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N, S, SO and SO ₂ , wherein the heterocyclic group is optionally substituted with 1 or 2 groups independently selected from

alkyl,

C ₂ -C ₅ -alkanoyl,

benzoyl,

hydroxy

-CO ₂ R ¹⁰ and

carbonyl (one of the ring carbon atoms is a >C=O group),

(e) C ₂ -C ₅ -alkynyl,

(f) C ₂ -C ₅ alkenyl,

(g) halogen,

(h) cycloalkyl, and

its pharmaceutically acceptable salts, solvates and optical isomers.

25. The connection according to embodiment 24, where R ⁵ is selected from

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

alkyl,

alkoxy,

alkoxy, where the alkyl group is replaced by 1, 2 or 3 hydroxy groups,

alkoxy, where the alkyl group is substituted by a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, and the monocyclic is optionally substituted by 1 or 2 alkyl groups,

-SO ₂ NR ¹⁰ R ¹⁰ ,

alkylsulfanyl, where the alkyl group is optionally substituted with NR ¹⁰ R ¹⁰ or 1, 2 or 3 halogen atoms,

alkylsulfinyl,

alkylsulfonyl, where the alkyl group is optionally substituted with 1, 2 or 3 halogen atoms,

cycloalkyl,

thioguanidino,

NR ¹⁰ R ¹⁰ and

a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, which is optionally substituted by 1 or 2 groups independently selected from alkyl and C ₂ -C ₅ -alkanoyl,

(b) phenyl which is fused to a heteroaromatic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S,

(c) a heteroaromatic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein the heteroaromatic group is optionally substituted

alkyl,

cycloalkyl,

-NR ¹⁰ R ¹⁰ ,

-CO ₂ R ¹⁰ and

a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N, S, SO and SO ₂ , wherein the heterocyclic group is optionally substituted with an alkylsulfanyl or 1 or 2 hydroxy groups,

(d) a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O, N, S, SO and SO ₂ , wherein the heterocyclic group is optionally substituted with 1 or 2 groups independently selected from

alkyl,

C ₂ -C ₅ -alkanoyl,

hydroxy

-CO ₂ R ¹⁰ and

carbonyl,

(e) C ₂ -C ₅ -alkynyl,

(f) halogen and

(g) cycloalkyl.

26. The connection according to embodiment 24 or 25, where R ⁵ is selected from

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

alkyl,

alkoxy,

alkoxy, where the alkyl group is replaced by 1, 2 or 3 hydroxy groups,

alkoxy, where the alkyl group is substituted with a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1 or 2 oxygen heteroatoms, and the monocyclic group is optionally substituted with 1 or 2 alkyl groups,

-SO ₂ NR ¹⁰ R ¹⁰ ,

alkylsulfanyl, where the alkyl group is optionally substituted with NR ¹⁰ R ¹⁰ or 1, 2 or 3 halogen atoms,

alkylsulfinyl,

alkylsulfonyl, where the alkyl group is optionally substituted with 1, 2 or 3 halogen atoms,

cycloalkyl,

thioguanidino,

NR ¹⁰ R ¹⁰ and

a non-aromatic heterocyclic 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, which is optionally substituted by 1 or 2 groups independently selected from alkyl and C ₂ -C ₅ -alkanoyl,

(b) phenyl which is fused to a heteroaromatic 5-membered monocyclic group containing 1 or 2 heteroatoms independently selected from N, O and S,

(c) a heteroaromatic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S, which is optionally substituted

alkyl,

haloalkyl,

cycloalkyl,

-NR ¹⁰ R ¹⁰ ,

-CO ₂ R ¹⁰ or

a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N, S, SO and SO ₂ , wherein the heterocyclic group is optionally substituted with an alkylsulfanyl or 1 or 2 hydroxy groups,

(d) a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O, N, S, SO and SO ₂ , wherein the heterocyclic group is optionally substituted with 1 or 2 groups independently selected from alkyl, C ₂ -C ₅ -alkanoyl and hydroxy,

(e) C ₂ -C ₅ -alkynyl,

(f) halogen and

(g) cycloalkyl.

27. The connection according to any one of embodiments 24-26, where R ⁵ is selected from

phenyl substituted with 1, 2 or 3 groups independently selected from alkyl, alkoxy, C ₂ -C ₄ -alkoxy, where the alkyl group is substituted with 1, 2 or 3 hydroxy groups, C ₂ -C ₄ -alkoxy, where the alkyl group is substituted with a non-aromatic heterocyclic a 5- or 6-membered monocyclic group containing 1 or 2 oxygen heteroatoms, wherein the monocyclic group is optionally substituted with 1 or 2 alkyl groups, -SO ₂ NR ¹⁰ R ¹⁰ , alkylsulfonyl, NR ¹⁰ R ¹⁰ , a non-aromatic heterocyclic 6-membered monocyclic group, containing 1 or 2 heteroatoms independently selected from O and N, which is optionally substituted with 1 or 2 groups independently selected from alkyl and C ₂ -C ₅ -alkanoyl.

28. The compound according to any one of embodiments 24-26, wherein R ⁵ is selected from benzothiophene and benzofuran.

29. The compound according to any one of embodiments 24-26, wherein R ⁵ is selected from furanyl, thiazolyl, alkylsulfanyl-substituted thiazolyl, pyrazolyl, triazolyl, thiadiazolyl, alkylsulfanyl-substituted thiadiazolyl, pyrimidinyl, pyridinyl and pyridazinyl.

30. The compound according to any of embodiments 24-26, wherein R ⁵ is selected from morpholinyl, which is optionally substituted with 1 or 2 alkyl groups, piperazinyl, which is optionally substituted with 1 or 2 alkyl groups, oxacycloalkyl, azacycloalkyl, which is optionally substituted with 1 or 2 groups , independently selected from alkyl, hydroxy, -COOR ¹⁰ and oxoazacycloalkyl.

31. The compound of any one of embodiments 24-26, wherein R ⁵ is ethynyl or cycloalkyl.

32. The compound of any one of embodiments 24-31, wherein R ^w is -NR ¹⁰ SO ₂ R ¹² .

33. The compound of Embodiment 32, wherein R ¹² is alkyl, hydroxyalkyl, or phenylalkyl, wherein the phenyl group is optionally substituted with 1 or 2 groups independently selected from alkyl and halogen.

34. The compound of Embodiment 33, wherein R ¹² is alkyl.

35. The compound according to any one of embodiments 24-34, characterized by formula (Ia)

36. The compound according to any one of embodiments 24-34, characterized by formula (Ib)

37. The compound according to any one of embodiments 24-34, characterized by formula (Ic)

38. The compound according to any one of embodiments 24-34, characterized by formula (Id)

39. The compound according to any one of embodiments 24-34, characterized by formula (Ie)

40. The compound according to any one of embodiments 24-34, characterized by the formula (If)

41. The compound according to any one of embodiments 24-34, characterized by formula (Ig)

42. The compound according to any one of embodiments 24-34, characterized by formula (Ih)

43. The compound of Embodiment 35 wherein R ⁵ is phenyl which is substituted with halogen and R ^w is -NR ¹⁰ SO ₂ R ¹² wherein R ¹² is alkyl.

44. The compound of Embodiment 36 wherein R ⁵ is alkenyl, R ^x and R ^y are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² wherein R ¹² is alkyl.

45. The connection according to embodiment 36, where

R ⁵ represents phenyl which is substituted with a group selected from

a) a non-aromatic heterocyclic 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, which is optionally substituted by 1 or 2 groups independently selected from alkyl and C ₂ -C ₅ -alkanoyl,

b) C ₂ -C ₄ -alkoxy, where the alkyl group is substituted with a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1 or 2 oxygen heteroatoms, and the monocyclic group is optionally substituted with 1 or 2 alkyl groups,

c) alkoxy, where the alkyl group is substituted with 1, 2 or 3 hydroxy groups, and where R ⁵ is optionally substituted with halogen and/or alkyl,

d) alkylsulfonyl, which is optionally substituted with 1, 2 or 3 halogen atoms,

e) alkylsulfanyl, where the alkyl group is optionally substituted with NR ¹⁰ R ¹⁰ or 1, 2 or 3 halogen atoms,

f) thioguanidine and

g) cycloalkyl,

R ^x and R ^y are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² where R ¹² is alkyl or benzyl which is optionally substituted with 1 or 2 groups independently selected from alkyl and halogen.

46. The connection according to embodiment 36, where

R ⁵ is phenyl which is substituted with alkoxy, -SO ₂ NR ¹⁰ R ¹⁰ , halogen, alkoxy where the alkyl group is substituted with 1, 2 or 3 hydroxy groups, alkyl, a heteroaromatic 5 or 6 membered monocyclic group containing 1 or 2 heteroatoms , independently selected from N and S, which is optionally substituted with alkyl, cycloalkyl and -NR ¹⁰ R ¹⁰ ,

R ^x and R ^y are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² where R ¹² is benzyl which is optionally substituted with 1 or 2 groups independently selected from alkyl and halogen.

47. The compound of Embodiment 36, wherein R ⁵ is a heteroaromatic 5-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S, which is optionally substituted

a) alkylsulfanyl,

b) cycloalkyl,

c) oxacycloalkyl,

d) azacycloalkyl, which is optionally substituted with hydroxy,

e) -CO ₂ R ¹⁰ ,

f) oxodihydropyrazinyl,

g) oxopiperidinyl and

h) morpholinyl, which is optionally substituted with 1 or 2 alkyl groups,

R ^x and R ^y represent halogen, and R ^w represents -NR ¹⁰ SO ₂ R ¹² where R ¹² represents alkyl.

48. The connection according to embodiment 36, where R ⁵ is selected from

a) pyrimidine, which is optionally substituted with cycloalkyl,

b) pyridazine,

c) benzothiophene,

d) benzofuran,

e) pyridinyl, which is substituted with -SO ₂ NR ¹⁰ R ¹⁰ , morpholinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl, alkylsulfonyl,

f) furan,

g) thiazole,

h) pyrazole,

i) a triazole, in particular 1,2,4-triazole,

j) thiadiazole,

k) alkylthio-substituted thiadiazole and

l) alkylthio-substituted thiazole,

R ^x and R ^y are independently halogen or CN, and R ^w is -NR ¹⁰ SO ₂ R ¹² where R ¹² is alkyl or benzyl which is optionally substituted with 1, 2 or 3 groups independently selected from alkyl and halogen .

49. The compound of Embodiment 47, wherein R ⁵ is pyridinyl which is substituted with morpholinyl, thiomorpholinyl or 1,1-dioxidothiomorpholinyl, R ^x and R ^y are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² where R ¹² represents alkyl which is substituted with 1, 2 or 3 halogen atoms.

50. The compound of Embodiment 36, wherein R ⁵ is a non-aromatic heterocyclic 5- or 6-membered monocyclic group containing 1 or 2 heteroatoms independently selected from O and N, which is optionally substituted with 1 or 2 alkyl groups,

R ^x and R ^y represent halogen, and R ^w represents -NR ¹⁰ SO ₂ R ¹² where R ¹² represents alkyl.

51. The compound of Embodiment 37, wherein R ⁵ is a heteroaromatic 6-membered monocyclic group containing 1, 2 or 3 heteroatoms independently selected from O, N and S, which is optionally substituted

a) cycloalkyl,

b) alkyl,

c) haloalkyl,

d) -COOR ¹⁰ ,

e) an oxacycloalkane, which is optionally substituted with hydroxyl,

R ^x and R ^y are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² where R ¹² is alkyl, alkoxyalkyl or haloalkyl.

52. The compound of Embodiment 51, wherein the heteroaromatic 6-membered monocyclic group is pyridyl, pyrimidyl or pyridazyl.

53. The compound of Embodiment 38 wherein R ⁵ is phenyl which is substituted with 1 or 2 halogen atoms, R ^x and R ^y are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² wherein R ¹² is alkyl

54. The compound of Embodiment 39 wherein R ⁵ is phenyl which is substituted with 1 or 2 halogen atoms, R ^x , R ^y and R ^z are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² where R ¹² is alkyl.

55. The compound of Embodiment 40, wherein R ⁵ is phenyl which is substituted with 1 or 2 halogen atoms, R ^x , R ^y and R ^z are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² , where R ¹² is alkyl.

56. The compound of Embodiment 41 wherein R ⁵ is phenyl which is substituted with 1 or 2 halogen atoms, R ^x , R ^y and R ^z are halogen, and R ^w is -NR ¹⁰ SO ₂ R ¹² where R ¹² is alkyl.

57. The compound of Embodiment 42 wherein R ⁵ is phenyl which is substituted with 1 or 2 halogen atoms and R ^w is -NR ¹⁰ SO ₂ R ¹² wherein R ¹² is alkyl.

58. A compound according to any one of embodiments 24-57, wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁶ are H or alkyl, particularly H.

59. A compound according to any of the preceding embodiments, wherein R ¹⁰ represents H or alkyl, in particular H.

36. A compound according to any one of embodiments 24-59, wherein R ¹² is alkyl, in particular C ₁ -C ₄ alkyl, and most preferably methyl, ethyl or propyl.

DETAILED DESCRIPTION OF THE INVENTION

According to an embodiment, the present invention relates to compounds that selectively inhibit MKK4, and their pharmaceutically acceptable salts, solvates and optical isomers, where the compounds are represented by formula I, in which the values of R ¹ -R ⁶ , R ¹⁰ , A and Q are defined in the above embodiments in any combination.

In an embodiment, the compounds of the present invention and their pharmaceutically acceptable salts, solvates and optical isomers selectively inhibit the MKK4 protein kinase relative to the JNK1 and MKK7 protein kinases.

Moreover, the present invention also relates to the use of said compounds for enhancing liver regeneration or reducing or preventing the death of hepatocytes and, at the same time, enhancing the proliferation of hepatocytes.

The present invention also includes pharmaceutically acceptable salts of the above compounds. Pharmaceutically acceptable salts are primarily acid addition or base addition salts with pharmaceutically acceptable acids or bases. Examples of suitable pharmaceutically acceptable organic and inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfamic acid, C ₁ -C ₄ -alkylsulfonic 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 containing from 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid acid, tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid. Other possible acids are described, for example, in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ft., Birkhäuser Verlag, Basel and Stuttgart, 1966. Examples of suitable pharmaceutically acceptable organic and inorganic bases are alkali hydroxides metals such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as calcium or magnesium hydroxide, ammonium hydroxide, organic nitrogen 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 present invention also includes any tautomeric, crystalline and polymorphic forms of the compounds and salts of the present invention and mixtures thereof.

The present invention also includes solvates such as hydrates.

The compound of the present invention may contain one or more chiral centers and may exist in various optically active forms, such as enantiomers and diastereoisomers.

As used herein, the term “prodrug” refers to an agent that is converted in vivo to a final drug through some physiological chemical process. An example of a prodrug, without limitation, is potentially 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, thereby facilitating intravenous administration of the drug. The prodrug may also have a higher degree of bioavailability than the final drug. Once administered, the prodrug is cleaved enzymatically or chemically to release the final drug into the blood or tissue. Exemplary prodrugs include, but are not limited to, compounds with carboxyacid substituents in which the free hydrogen is replaced by (C ₁ -C ₄ )alkyl, (C ₁ -C ₁₂ )alkanoyloxymethyl, (C ₄ -C ₉ )-(alkanoyloxy)ethyl, 1- methyl-1-(alkanoyloxy)ethyl containing from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl containing from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl containing from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy) )ethyl containing from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl containing from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl containing from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-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 exemplary prodrugs release an alcohol of formula (I) in which the free hydrogen of the hydroxyl substituent (eg, the R group contains hydroxyl) is replaced by (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 )-alkoxycarbonyl-aminomethyl, succinoyl, (C ₁ -C ₆ )alkanoyl, α-amino(C ₁ -C ₄ )alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, wherein said α-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, P(O)(OH) ₂ , -P(O)(O(C ₁ -C ₆ )alkyl) ₂ or glycosyl (radical resulting from the abstraction of hydroxyl from the hemiacetal of a carbohydrate).

The expression "MKK4 inhibitor" means that after administration, the kinase activity of MKK4 is inhibited with an IC ₅₀ of <10 μmol/L, preferably <1 μmol/L, and in particular <0.5 μmol/L. As used herein, the expression “selectively inhibit MKK4 protein kinase relative to JNK1 and MKK7 protein kinases” means the ratio of MKK7 inhibitory activity to MKK4 inhibitory activity or the ratio of JNK1 inhibitory activity to MKK4 inhibitory activity, expressed either as a percentage of control, or as Kd, is ≥ 10 as measured by KINOMEscan™.

As used herein, the expression “enhancing liver regeneration or reducing or preventing hepatocyte death” means an increase in the relative number of proliferating hepatocytes by at least 30%, preferably by at least 50%, compared to the number of proliferating cells at the beginning of therapy. In particular, this expression means an increase of ≥100% compared to the number of proliferating cells at the beginning of therapy. In this context, experimental detection and quantification will be carried out using standard methods, for example, quantification of the Ki67 protein, which is strictly associated with cell proliferation. To quantify proliferating hepatocytes in a tissue preparation, several immunohistochemical standard methods are available that use primary anti-Ki67 antibodies followed by visualization of anti-Ki67 binding using, for example, horseradish peroxidase conjugated to secondary antibodies. The value 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 a primary polyclonal rabbit anti-Ki67 antibody from Abcam (product no. ab15580, Abcam, Cambridge, USA) and a secondary polyclonal goat antibody containing the fluorophore tetramethylrhodamine from Invitrogen (product no. 16101 , Invitrogen/ThermoFisher) Based on data obtained in several preclinical mouse models, shRNA (small hairpin RNA) was found to mediate MKK4 suppression in a mouse model of CCl ₄ (carbon tetrachloride)-mediated chronic liver injury, enhancing proliferation. hepatocytes by 13%-27% (compared to control shRNA), and is associated with a decrease in liver damage (transaminases) and a decrease in liver fibrosis. In accordance with the definition presented in the previous chapter, the relative increase in proliferating cells was 108%. alcohol steatohepatitis (ASH), shRNA mediated MKK4 silencing, resulting in an increase in hepatocyte proliferation rate of up to 4% compared to 2% with control shRNA (relative increase: 100%). A doubling of hepatocyte proliferation was associated with a decrease in steatosis (fat accumulation) and with a decrease in liver damage, assessed by transaminase levels. Similarly, shRNA mediated MKK4 silencing, increasing hepatocyte proliferation from 16% (control shRNA) to 33% (relative increase: 106%) in a partial hepatectomy model (48 hours after surgical removal of two-thirds of the liver). In addition, increased hepatocyte proliferation was associated with improved liver regeneration and faster liver mass recovery.

The organic fragments mentioned above in the variable definitions are, like the term halogen, collective terms for individual lists of representatives of a particular group. The prefix C _n -C _m indicates the possible number of carbon atoms in the group in each case.

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

Alkyl is a straight or branched alkyl group, which is preferably a C ₁ -C ₆ alkyl group, i.e. an alkyl group containing from 1 to 6 carbon atoms, and more preferably a C ₁ -C ₄ alkyl group. Examples of the alkyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert- 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 applies equally to any group that includes an alkyl group.

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

Cycloalkyl is a cycloaliphatic radical which is preferably C ₃ -C ₈ -cycloalkyl, i.e. a cycloalkyl group containing from 3 to 8 carbon atoms. In particular, 3 to 6 carbon atoms form a cyclic structure such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclic structure may be unsubstituted or may contain 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 singly unsaturated hydrocarbon radical which is preferably a C ₂ -C ₆ alkenyl group, i.e. an alkenyl group containing 2, 3, 4, 5 or 6 carbon atoms, for example vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, metallyl (2- methylprop-2-en-1-yl), etc. In particular, C ₃ -C ₅ -alkenyl is 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 singly unsaturated hydrocarbon radical which is preferably a C ₂ -C ₆ alkynyl group, i.e. an alkynyl group containing 2, 3, 4, 5 or 6 carbon atoms, for example ethynyl, 2-propyn-1-yl, 1-propyn-1-yl, 2-propyn-2-yl, etc. In particular, C ₃ -C ₅ -alkynyl is 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4 -pentin-1-yl.

A heteroaromatic (or heteroaryl) group is a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic aromatic group containing 1, 2, or 3 heteroatoms selected from O, N, and S. The heteroaryl or heteroaromatic group may be connected to neighboring group via a carbon atom (C-linked) or via a nitrogen heteroatom (N-linked). Heterocyclic radicals can be linked via a carbon atom (C-linked) or via 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, each 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, 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- silt;

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 annealed, 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 pyrrolo[d]pyrimidyl. Examples of 5- or 6-membered heteroaromatic compounds containing an annulated cycloalkenyl ring include dihydroindolyl, dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrobenzofuryl, chromenyl, chromanyl, dihydropyrrolo[a]imidazolyl, and tetrahydrobenzothiazolyl.

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

C-linked 4-membered saturated rings such as

azetidin-2-yl, azetidin-3-yl, oxetan-2-yl, oxetan-3-yl;

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, tetrahydroisothiazol-2-yl, tetrahydroisothiazol-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- 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-oxathian-2-yl, 1,3-oxathian- 4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl, 1,4-oxathian-2-yl, 1,4-oxathian-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 4-membered saturated rings such as

azetidin-1-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, tetrahydrothiazol-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-imidazol-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-dihydropyran-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-thiazine -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-tetrahydropyridazin-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, 2H-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-thiazin-5-yl, 4H-1,3-thiazin-6-yl, 6H-1,3-oxazine -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 -il;

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

The compounds of the present invention, including their pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates and stereoisomers, can be prepared as disclosed in WO 2007/002433, which is incorporated herein by reference in its entirety, or in accordance with similar techniques. Acid addition or base addition salts are prepared in a conventional manner by mixing the free base with the corresponding 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 methanol, ethanol or propanol, an ether such as methyl t- butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester, such as EtOAc.

The compounds of the present invention are useful for enhancing liver regeneration or reducing or preventing the death of hepatocytes and, at the same time, enhancing the proliferation of hepatocytes. Therefore, the compounds of the present invention are useful for the treatment, modulation, amelioration or prevention of diseases involving acute or chronic liver damage, which may be due to infection, injury, exposure to toxic compounds, abnormal formation of normal substances in the blood, autoimmune process, genetic defect or for unknown reasons.

Such liver diseases include all diseases in which enhancing liver regeneration and reducing or preventing hepatocyte death may be beneficial to achieve a potential therapeutic effect, i.e., partial or complete restoration of liver function. Such diseases include

acute and chronic diseases or exacerbations of chronic liver diseases, such as acute and chronic viral hepatitis, for example, hepatitis B, C, E, hepatitis caused by the 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, steatosis, eg non-alcoholic steatosis (NAFL), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), Wilson's disease, hemochromatosis, α1-antitrypsin deficiency, glycogen storage diseases;

all types of liver cirrhosis, such as primary biliary cirrhosis, liver cirrhosis caused by the toxic effects of ethyl alcohol, cryptogenic cirrhosis;

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

galactosemia, cystic fibrosis, porphyria, ischemic perfusion injury of the liver, undersize syndrome after liver transplantation, primary sclerosing cholangitis or hepatic encephalopathy.

To enhance liver regeneration or reduce or prevent the death of hepatocytes, the compounds of the present invention are administered to a patient in need thereof in a therapeutically effective amount. Various diagnostic methods are available to determine the presence of liver disease. Blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above clinically acceptable normal ranges are known to indicate ongoing liver damage. Levels of bilirubin or other liver enzymes in the blood can be used as a detection or diagnostic criterion. Routine monitoring of blood levels of ALT and AST in patients with liver disease is used to assess the progression of liver disease during medical treatment. A decrease in the initially elevated ALT and AST levels to an acceptable normal range is considered clinical confirmation, reflecting a decrease in the severity of the patient's liver injury. Commercial assays such as FibroTest/FibroSURE, HepaScore ^® , FibroMeter or Cirrhometer evaluate the combined results of five or more biochemical parameters to determine steatosis, fibrosis and cirrhosis. In addition, noninvasive, innovative physical imaging techniques such as magnetic resonance imaging, ultrasound, and particularly elastographic techniques are available to determine and monitor the status and progression of liver disease.

Additionally, shRNA-mediated suppression of MKK4 was found to reduce TNF-α-regulated cartilage matrix degradation in osteoarthritis (Cell Death and Disease (2017) 8, e3140). Therefore, inhibition of MKK4 activity using the compounds of the present invention is further useful for the treatment of osteoarthritis and rheumatoid arthritis.

The compounds of the present invention are typically administered in the form of pharmaceutical compositions that contain at least one compound of the present invention, optionally together with an inert carrier (eg, a pharmaceutically acceptable excipient) and, if necessary, with other drugs. Such compositions may 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, wafers, 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, and liquid dosage forms such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, e.g. lotions, injections drugs and infusions. In addition, it is also possible to use liposomes or microspheres.

During the preparation of the compositions, the compounds of the present invention are optionally mixed with or diluted with one or more carriers (excipients). Carriers (excipients) can be solid, semi-solid or liquid substances that serve as carrier media, carriers or media for the active compound.

Suitable carriers (excipients) are listed in medical monographs for specialists. In addition, the dosage forms may contain pharmaceutically acceptable excipients such as humectants; emulsifiers and suspending agents; preservatives; antioxidants; anti-irritants; chelating agents; integumentary aids; emulsion stabilizers; means for forming a film coating; gel forming agents; odor masking agents; taste modifiers; resins; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; fattening agents; raw materials for ointments, creams or oils; silicone derivatives; distributing aids; stabilizers; sterilants; bases for suppositories; tablet excipients such as binders, fillings, glidants, disintegrants or coating agents; propellants; drying agents; opacifying agents; thickeners; waxes; plasticizers and white mineral oils. In this sense, the composition is based on the knowledge of the specialist, as described, for example, in Fiedler, HP, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4 ^th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.

The compounds of the present invention may also be suitable for combination with other therapeutic agents. Therefore, the present invention further relates to a combination containing a compound according to the present invention and one or more additional therapeutic agents, in particular used to enhance liver regeneration or reduce or prevent the death of hepatocytes. The combination therapies of the present invention can be administered adjunctively. By adjunctive administration is meant the sequential or parallel administration of each of the components in the form of separate pharmaceutical compositions or devices. Such a regimen of therapeutic administration of two or more therapeutic agents is generally referred to by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as adjunctive therapeutic administration. Any and all treatment regimens in which a patient receives separate, but sequential or concurrent, therapeutic administration of compounds of the present invention and at least one additional therapeutic agent fall within the scope of the present invention. In one embodiment of adjunctive therapeutic administration described herein, a patient is typically stabilized on a regimen of therapeutic administration of one or more components for a specified period of time and then another component is administered.

The combination therapies of the present 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 or including both components, or in the form of simultaneously administered separate compositions or devices, each containing one of the components. Such combinations of separate individual components for simultaneous administration may be provided in the form of a composite kit.

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

ACC inhibitors such as TOFA (5-(tetradecyloxy)-2-furancarboxylic acid), 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 emricasan,

cathepsin B inhibitors, such as a mixed cathepsin B/hepatitis C virus NS3 protease inhibitor, for example 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,

dipeptidyl peptidase IV (DPPIV) inhibitors such as linagliptin,

farnesiod X receptor (FXR) agonists such as INT-747 (obeticholic acid) 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

hepatitis C virus NS3 protease inhibitors, such as a mixed cathepsin B/hepatitis C virus NS3 protease inhibitor, for example VBY-376,

HMG CoA reductase inhibitors such as a statin, e.g. atorvastatin,

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

IL-1ß antagonists,

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

IL-10 agonists such as pegilodecakin,

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 homologue 2 (LOXL2) inhibitors, such as anti-LOXL2 antibody, e.g. 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 (elafibranor),

PPARγ agonists such as pioglitazone,

PPARδ agonists,

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

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

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

thyroid hormone receptor β agonists such as MGL-3196,

tumor necrosis factor α (TNFα) ligand inhibitors,

transglutaminase inhibitors and transglutaminase inhibitor precursors such as mercaptamine,

PTPIb 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 (selonsertib).

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

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

According to an embodiment, the present invention relates to a method

inhibition of protein kinase MKK4,

selective inhibition of protein kinase MKK4 relative to protein kinases JNK1 and MKK7, enhancing liver regeneration or preventing the death of hepatocytes,

treatment of an acute disease, exacerbation of a chronic disease or chronic liver disease,

treatment of acute and chronic disease or exacerbation of chronic liver disease, such as acute and chronic viral hepatitis, for example, hepatitis B, C, E, hepatitis caused by the 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, steatosis, e.g. non-alcoholic steatosis of the liver (NAFL), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), Wilson's disease, hemochromatosis, α1-antitrypsin deficiency, glycogen storage diseases;

treatment of all types of liver cirrhosis, such as primary biliary cirrhosis, liver cirrhosis caused by the toxic effects of ethyl alcohol, cryptogenic cirrhosis;

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

treatment of galactosemia, cystic fibrosis, porphyria, ischemic perfusion injury of the liver, undersize syndrome after liver transplantation, primary sclerosing cholangitis or hepatic encephalopathy, or

treatment of osteoarthritis or rheumatoid arthritis,

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

In an embodiment, the compounds of the present invention are administered at a dose of 0.2 to 15 mg/kg or 0.5 to 12 mg/kg of the body weight of the subject to be treated. The compounds can be administered once or several times per day. The compounds are administered over a period of 4 to 12 weeks.

The following examples illustrate the present invention without limiting it.

EXAMPLES

Abbreviations:

AcOH acetic acid ATP adenosine triphosphate _BOC2O di -tert -butyloxycarbonate CDE 1,2-dimethylpropylamine CPME cyclopentyl methyl ether DCE dichloroethane DCM dichloromethane D.E.A. diethyl ether DIPEA diisopropylethylamine 4-DMAP (4-)dimethylaminopyridine DMA dimethylacetamide DME dimethyl ether DMF dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide DTT dithiothreitol EtOH ethanol EtOAc ethyl acetate HEPES 2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethanesulfonic acid HOBt hydroxybenzotriazole HPLC high performance liquid chromatography IPA (or iPrOH) isopropyl alcohol KOAc potassium acetate LAH lithium aluminum hydride LCMS liquid chromatography/mass spectrometry LDA lithium diisopropylamide LiHDMS lithium bis(trimethylsilyl)amide mCPBA meta- peroxychlorobenzoic acid MeCN acetonitrile MeOH methanol nhex n-hexane NIS N-iodosuccinimide NMP N-methylpyrrolidone Pd ₂ (dba ₃ ) tris(dibenzylideneacetone)dipalladium (0) Pd(dppf) _Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride P.E. petroleum ether pMBCl para- methoxybenzyl chloride k.t. room temperature Ruphos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl SFC supercritical liquid chromatography rr solution TEA triethylamine TfOH trifluoromethanesulfonic acid THE tetrahydrofuran TLC thin layer chromatography Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Examples

Example 1: Synthesis of sulfonamide derivatives of substituted benzoic acid (general procedure)

Example 1a

Stage 1a-1:

Oxalyl chloride (1.1 eq.) was added to the 1 eq. suspension. benzoic acid derivative (1) in anhydrous DCM (0.5 M). A few drops of DMF were added and the resulting mixture was stirred at room temperature (RT) until gas evolution was completed. Excess MeOH was added to the solution, and the solvent was evaporated under reduced pressure. The residue was dried under vacuum, and the product was used without further purification. (X represents H or a substituent as defined in the examples, description and claims).

Stage 1a-2:

Pd/C (0.1 eq) was added to a solution of methyl 3-nitrobenzoate derivative (2, 1.0 eq) in EtOH (0.2 M). The suspension was purged with H ₂ and stirred at room temperature. until the starting material is completely consumed. The mixture was then passed through a bed of Celite and the filtrate was concentrated under vacuum. The product was used without further purification.

Stage 1a-3:

A solution of methyl 3-aminobenzoate derivative (3, 1.0 eq.) and Et ₃ N (2.2 eq.) in anhydrous DCM (0.25 M) was cooled to 0°C and the corresponding sulfonyl chloride (1 ,1 eq., 2.2 eq. for disulfonamides, respectively). Once complete, the ice bath was removed and the solution was stirred at room temperature. for ~1 hour. The solution was then diluted with water, extracted with EtOAc, and the combined organic layers were dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the product was purified by flash chromatography (SiO ₂ , nHex/EtOAc 9/1).

The ester/mono-/disulfonamide was dissolved in THF/MeOH (1 M, 4:1), cooled to 0°C and treated with aq. NaOH (2 M, 2-3 eq.). After 10 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature. until complete hydrolysis. THF/MeOH was removed under vacuum, the residue was treated with aq. HCl (2 M) until the product precipitates. The precipitate was filtered, dried and used without any additional purification.

Example 1b

Step 1b-1: (substituted) 3-nitrobenzoic acid (2)

To a solution stirred and cooled in an ice bath, 1 eq. benzoic acid derivative (1) in conc. 1 eq. of sulfuric acid (20 ml) was added in portions over 15 min. potassium nitrate. The reaction mixture was stirred at 0°C for 1 hour, then poured into 50 ml ice water and extracted with EtOAc (15 ml × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the corresponding 3-nitrobenzoic acid derivative (2) in >80% yield.

Step 1b-2 and 1b-3: 2,6-dibromo-3-(N-(propylsulfonyl)propylsulfonamido)benzoic acid (4)

To the mixed solution 1 eq. 3-nitrobenzoic acid (2) in THF (20 ml) at room temperature. added 3 eq. tin chloride. The mixture was stirred at 80°C for 3 hours. The progress of the reaction was monitored by TLC (30% EtOAc in hexane). After completion of the reaction, the reaction mixture was quenched by adding aq. ammonia solution (10 ml), and the product was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the 3-aminobenzoic acid derivative (3) as a crude material, which was used in the next step without further purification.

To a stirred solution of 3-aminobenzoic acid (3) in dichloromethane (DCM, 20 ml) was added 4 eq. TEA, and cooled the mixture to 0°C. Added 2 eq. 1-alkylsulfonyl chloride, and the reaction was monitored by TLC. After completion of the reaction (~12 h), the reaction mixture was quenched by adding 2N HCl (10 ml), and the product was extracted with DCM (10 ml x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain crude 3-(N-(alkylsulfonyl)propyl-sulfonamido)benzoic acid derivative (4), which was used in the next step without further purification . (X represents H or a substituent as defined in the examples, description and claims).

Example 2

Example 2a: (general procedure)

The benzoic acid derivative (1) obtained in Example 1a (1.1 eq.) was suspended in anhydrous DCM (0.5 M), and oxalyl chloride (1.05 eq.) and a few drops of DMF were sequentially added. After gas formation was completed, the resulting solution was added dropwise to the suspension of 1 equiv. azaindole (2) and AlCl ₃ (5 eq.) in anhydrous DCM (0.5 M). The mixture was stirred at room temperature. for 0.5-3 hours. To quench the reaction mixture, a saturated aqueous solution of NH ₄ Cl was added. The aqueous phase was extracted with EtOAc (3×), the combined organic layers were dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. Product (3) was purified by flash chromatography (SiO ₂ , nHex/EtOAc 1:1 or DCM/MeOH 1-3%) to give the title compound.

The following compounds were prepared according to this procedure:

Example 13, stage 2; Example 14, stage 2; Example 15, stage 2; Example 16, stage 2; Example 17, stage 2.

Example 2b: Synthesis of N-(2,4-dibromo-3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide

To a stirred solution of 2,6-dibromo-3-(N-(propylsulfonyl)propylsulfonamido)benzoic acid (1) (1 eq., 900 mg, crude product) in DCM (10 ml) at 0°C was added oxalyl chloride (2 eq., 450.6 mg, 3.55 mmol), followed by a catalytic amount of DMF. The reaction mixture was stirred at room temperature. for 4 hours. After completion of the reaction (TLC), the solvent was removed under reduced pressure, and the resulting residue was dissolved in DCM (10 ml). Hereinafter in the text, this reagent is referred to as “solution A”.

AlCl ₃ (1.18 g, 8.87 mmol) was added to DCM (40 ml), the mixture was stirred for 10 min at RT and then cooled to 0°C. 5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine (2) (1 eq., 405.92 mg, 1.77 mmol) was added and the mixture was stirred for 30 min and then heated to k.t. for 3 hours. Solution A was slowly added to the suspension obtained above at 0°C, and the reaction mixture was stirred for 2 days at room temperature. After completion of the conversion, the reaction mixture was quenched by the addition of methanol (MeOH, 10 ml) and concentrated to obtain a dark brown residue. Cold water (50 ml) was added to the residue, and the solution was adjusted to neutral pH 7 by adding aq. ammonia. EtOAc (50 ml) was added and the mixture was stirred for 30 minutes. Then, the mixture was filtered through Celite, the filtrate was extracted with EtOAc (20 ml x 3), the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain crude N-(2,4-dibromo-3 -(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide (900 mg, crude product), which was used in the next step without further purification.

Crude N-(2,4-dibromo-3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide (900 mg) was dissolved in THF (5 ml), aq. was added to it. NaOH (2 eq., 238.9 mg, 7.09 mmol) in water (5 mL), and the reaction mixture was stirred at room temperature. for 4 hours. After completion of the reaction, adjusted to pH 6 with 5N HCl, and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give crude material, which was purified by FCC (flash chromatography) to obtain N-(2,4-dibromo-3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl) phenyl)propane-1-sulfonamide (5) (400 mg, 0.65 mmol, 36% yield).

According to Example 2b, the following compounds were prepared as shown in Table 1:

Table 1

Example Reagent Chemical structure Analytical data 2c ¹ H-NMR (400 MHz, DMSO) δ 12.93 (s, 1H), 9.66 (s, 1H), 8.69 (dd, J=8.2, 2.2 Hz, 2H), 8 .09 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.65 (d, J=6.1 Hz, 1H), 7.58 (d, J=8, 5 Hz, 2H), 7.35 (t, J=8.8 Hz, 1H), 3.20-3.03 (m, 2H), 1.81 (dd, J=15.2, 7.6 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H).
Calculated 489.92 for C ₂₃ H ₁₈ ClF ₂ N ₃ O ₃ S. Measured 490.05 for [M+H] ⁺ . 2d ¹ H-NMR (400 MHz, DMSO) δ 12.94 (s, 1H), 9.69 (s, 1H), 8.69 (dd, J=6.8, 2.1 Hz, 2H), 8 .08 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.66-7.51 (m, 4H), 3.24-3.13 (m, 2H), 1.90-1.76 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated 506.37 for C ₂₃ H ₁₈ Cl ₂ FN ₃ O ₃ S. Measured 507.05 for [M+H] ⁺ . 2e ¹ H-NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 9.63 (s, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.65 (s , 1H), 8.29 (s, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.55 (dd, J=20.8, 8.6 Hz, 3H), 3 .18-3.09 (m, 2H), 1.79 (d.kv, J=14.9, 7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H).
Calculated 507.91 for C ₂₃ H ₁₇ ClF ₃ N ₃ O ₃ S. Measured 508.1 for [M+H] ⁺ . 2f ¹ H-NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 10.09 (s, 1H), 8.68 (dt, J=11.5, 5.8 Hz, 2H), 8 .18 (s, 1H), 7.77 (t, J=10.0 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 7.43 (ddd, J=9, 3, 6.0, 3.1 Hz, 1H), 7.34-7.25 (m, 1H), 3.25-3.18 (m, 2H), 1.75 (d.kv, J= 14.9, 7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H).
Calculated 489.92 for C ₂₃ H ₁₈ ClF ₂ N ₃ O ₃ S. Measured 488.10 for [M+H] ^- . 2g ¹ H-NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 10.03 (s, 1H), 8.70 (d, J=18.1 Hz, 2H), 8.41 (s , 1H), 7.81 (d, J=8.1 Hz, 2H), 7.61 (dd, J=25.9, 8.9 Hz, 3H), 3.24-3.13 (m, 2H), 1.74 (d, J=7.3 Hz, 2H), 0.97 (t, J=7.2 Hz, 3H).
Calculated 507.91 for C ₂₃ H ₁₇ ClF ₃ N ₃ O ₃ S. Measured 508.1 for [M+H] ⁺ . 2h ¹ H-NMR (400 MHz, DMSO) δ 8.66 (d, J=2.0 Hz, 2H), 8.12 (s, 1H), 7.79-7.65 (m, 3H), 7 .60-7.51 (m, 2H), 3.20-3.10 (m, 2H), 1.84-1.69 (m, 2H), 0.96 (t, J=7.4 Hz , 3H).
Calculated 507.91 for C ₂₃ H ₁₇ ClF ₃ N ₃ O ₃ S. Measured 508.1 for [M+H] ⁺ .

Example 3: Synthesis of halogen-substituted (=X) N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)alkyl-1-sulfonamides (alkyl=R ₂ )

The 3-aminophenyl derivative (1.1 eq.) was dissolved in pyridine (1 M) and sulfonyl chloride (1.5 eq.) was added portionwise. The mixture was heated to 60°C and stirred for 1-6 hours. After complete consumption of the starting material, the crude material was diluted with 1N aqueous HCl and extracted three times with EtOAc. The organic layers were dried over sodium sulfate and the solvent was evaporated. The product was purified by flash chromatography using the following solvent gradient: DCM/EtOAc/MeOH (95/5/0-92/5/3).

Example 4: Synthesis of halogen-substituted (=X) N-(3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)alkyl-1-sulfonamides (alkyl=R ₂ )

Stage 4-1:

To a solution of 1 equiv. 1H-pyrrolo[2,3-b]pyridine derivative (1) prepared in accordance with Example 3, triethylamine (1.05 eq.) was added to THF (0.1 M). The resulting solution was cooled to 0°C, 2,6-dichlorobenzoyl chloride (1.01 eq.) was added dropwise, and then 0.1 eq. 4-DMAP. The ice bath was removed and the reaction mixture was stirred at room temperature. until complete consumption of the starting material is detected by TLC (approximately 30 min). The crude material was poured into water and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, the solvent was removed in vacuo, and the product was purified by flash chromatography (SiO ₂ , PE/EtOAc 15-25%).

Stage 4-2:

1 eq. was suspended in anhydrous 1,4-dioxane (0.5 M). intermediate 2, B ₂ Pin ₂ (bis(pinacolato)diboron) (1.05 eq.) and KOAc (3.0 eq.), and degassed with argon for 5 min. Pd(PPh ₃ ) ₂ Cl ₂ (0.05 eq.) was added and the mixture was stirred for 5 hours at 80°C. The crude material was passed through a layer of Celite, and the layer was washed with EtOAc. The organic phase was washed successively with brine and water. After drying the organic phase over sodium sulfate, the solvent was removed. Flash chromatography (SiO ₂ , PE/EtOAc 25%) gave the pure product.

Stage 4-3:

Pinacol ester (B ₂ Pin ₂ ) (1 eq.), aryl bromide (1.5 eq.) and potassium carbonate (2 eq.) were dissolved in 1,4-dioxane/water (2:1, 1 M), and degassed mixture with argon. Pd(dppf)Cl ₂ (0.06 eq) was added and the mixture was heated to 60°C for 2 hours. The crude mixture was passed through a bed of Celite, washed with MeOH and EtOAc, and the solvent was removed under vacuum. The residue was redissolved in MeOH, potassium carbonate (1 g) was added and the suspension was stirred for 3 hours at room temperature. Water was added and adjusted to pH 6-8 by adding 1 M aq. HCl, the aqueous phase was extracted with EtOAc, the layers were separated, the organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was prepurified by flash chromatography using DCM/EtOAc/acetone (70/25/5) as eluent. The pre-purified product was re-dissolved in DCM/iPrOH (9:1), precipitated with n-pentane, filtered and dried under vacuum.

According to Example 4, the compounds of Examples 20, 21, 22, 23, 24, 25, 29, 35, 36, 39, 45, 46, 47, 48, 49, 50 and 51 were prepared.

Example 5: Synthesis of 5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine

Method: 5-bromo-1H-pyrrolo[2,3-b]pyridine (1.2 g, 10.2 mmol, 1.0 eq.), K ₂ CO ₃ (2.8 g, 20.3 mmol, 2 eq.) and (4-chlorophenyl)boronic acid (1.8 g, 11.2 mmol, 1.1 eq.) were suspended in DME/H ₂ O (30 ml, 4:1) and degassed with argon. Pd(PPh ₃ ) ₄ (587 mg, 508 μmol, 0.05 eq.) was added and the reaction mixture was refluxed until the starting material was completely consumed. The resulting solution was passed through a layer of Celite, diluted with EtOAc and washed with water. The combined organic layers were dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO ₂ , nHex/EtOAc 6:4).

Yield: 2.23 g, 9.4 mmol, 92% (white solid).

TLC: PE/EtOAc 1:1

¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 11.76 (s, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.20 (d , J=1.9 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.57-7.43 (m, 3H), 6.50 (dd, J=3, 2, 1.7 Hz, 1H); ¹³ C-NMR (DMSO-d _6, 50 Hz, ppm): δ 148.2, 141.4, 138.0, 131.7, 128.9, 128.6, 127.1, 126, 9, 126.1, 119.7, 100.2.

Example 6

Starting material 1 was prepared in accordance with Example 5.

Step 6-1 and Step 6-2 were carried out similarly to the method described by Zhang et al. (Nature, 256, 583-586, Supplementary material; doi: 10.1038/nature14982).

Stage 6-3:

One equivalent (1 eq.) of 3-aminophenyl-1H-pyrrolo[2,3-b]pyridine derivative (3) was dissolved in pyridine (1 M) and sulfonyl chloride (1.5 eq.) was added portionwise. The mixture was heated to 60°C and stirred for 1-6 hours. After complete consumption of the starting material, the crude product was diluted with 1N aq. HCl and extracted three times with EtOAc. The organic layers were combined and dried over sodium sulfate. After evaporation of the solvent, the product was purified by flash chromatography using the following solvent gradient: DCM/EtOAc/MeOH (95/5/0-92/5/3).

Compounds of Examples 37, 38, 42, 43 and 44 were prepared according to Example 6.

Example 7:

1 eq. 5-Bromo-1H-pyrrolo[2,3-b]pyridine, K ₂ CO ₃ (2 eq.) and boronic acid/pinacol ester (1.5 eq.) were suspended in DME/H ₂ O (0.15 M, 4:1) or in a mixture of 1,4-dioxane/H ₂ O (0.15 M, 2:1) and degassed with argon for 10 min. Pd(PPh ₃ ) ₄ (0.1 eq) was added and the suspension was then irradiated in a microwave oven at 130°C for 30 min (µw). The resulting mixture was passed through a layer of Celite and the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography (SiO ₂ , DCM/EtOAc/MeOH 95/5/0-92/5/3) to give the title compound.

According to Example 7, compounds of Examples 21, 26, 27, 32, 33 and 34 were prepared.

Example 8: Synthesis of (3-amino)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone derivatives

Step 8-1: (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(3-nitrophenyl)methanone (2)

At k.t. in an argon atmosphere 5 equiv. AlCl ₃ was stirred in 300 ml of anhydrous DCM. After 1 hour, 1 eq. was added. 5-bromo-1H-pyrrolo[2,3-b]pyridine (1). The reaction mixture was further stirred at room temperature. for 1 hour and then cooled to 0°C. The freshly obtained 3-nitrobenzoyl chloride derivative was dissolved in 150 ml of DCM and added dropwise to the reaction mixture. Once completed, the mixture was stirred at room temperature. within 3 days. The progress of the reaction was monitored by TLC (40% EtOAc in hexane). The resulting mixture was then carefully quenched at 0°C by adding a mixture of acetonitrile:H ₂ O (1:1, 300 ml). The precipitated solid was filtered, washed with MeOH and dried to give (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(3-nitrophenyl)methanone derivative 2 (20.0 g, crude product ), which was used in the subsequent reaction without further purification.

Step 8-2: (3-aminophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone derivative (3)

To the mixed solution 1 eq. (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(3-nitrophenyl)methanone derivative (2) in 2-methyl-THF at room temperature. stannous chloride (3 eq., 29.77 g, 157.02 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The progress of the reaction was monitored by TLC (30% EtOAc in hexane). After completion of the reaction, the reaction mixture was quenched by adding 20% aq. K ₂ CO ₃ solution (100 ml), stirred for 10 min, filtered through a layer of Celite, and washed the layer with Celite THF (250 ml). The resulting organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude compound. MeOH was added to the crude compound to yield a solid, which was filtered and dried to yield (3-aminophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone derivative 3 as an off-white solid, which was used in the subsequent reaction without further purification.

Example 9: Synthesis of halogen-substituted (=X) N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)alkyl-1-sulfonamides (alkyl=R ₂ )

The (3-aminophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone derivative (1) obtained in accordance with Example 8 (1 eq.) was dissolved in pyridine (1 M), and the appropriate sulfonyl chloride (1.5 eq.) was added in portions. The mixture was heated to 60°C and stirred for 1-6 hours. After complete consumption of the starting material, the crude material was diluted with 1N aqueous HCl and extracted three times with EtOAc. The organic layers were dried over sodium sulfate and the solvent was evaporated. Compound (2) was purified by flash chromatography using the following solvent gradient: DCM/EtOAc/MeOH (95/5/0-92/5/3).

Example 10:

P- toluenesulfonic acid monohydrate (0.6 eq) was added to a solution of acetal (1 eq) in ethanol (EtOH, 0.05 M) and water (0.21 M). The mixture was heated to 50°C for 6 hours, then concentrated to dryness, the residue was taken up in EtOAc, and the organic phases were washed twice with aqueous sodium bicarbonate (5%). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was redissolved in EtOAc and precipitated with n-pentane, the solid was filtered and dried under vacuum from the expected product.

Compounds of Examples 30, 31, 40 and 41 were prepared according to Example 10.

Example 11:

A solution of the appropriate phenol (1.0 eq.) and K ₂ CO ₃ or Cs ₂ CO ₃ (1.5 eq.) in DMF (0.4 M) was stirred for 30 min at RT. The specified haloalkane (1.5 eq.) and KI (1.0 eq.) were added to the suspension, and the mixture was stirred for 2 hours at 80°C. The mixture was cooled to room temperature. and diluted with a saturated aqueous solution of NH ₄ Cl. The aqueous phase was extracted with Et ₂ O, the organic extracts were dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (SiO ₂ , PE/EtOAc 0-5%).

According to Example 11, the compounds of Examples 25 (step 1) and 29 (step 1) were prepared.

Example 12

The starting reagent (1) was prepared in accordance with Example 8.

Step 12-1: (3-(3-amino-2,4-difluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone (2 )

To a stirred solution of (3-amino-2,4-difluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (1.1 eq., 11.0 g, 31. 24 mmol) in 2-methyl-THF (200 ml) was added Et ₃ N (1.1 eq., 3.47 g, 34.36 mmol), then 4-DMAP (0.1 eq. , 0.38 g, 3.12 mmol), and the reaction mixture was stirred for 5 minutes. To this mixture at 0°C, 2,6-dichlorobenzoyl chloride (1 eq., 6.54 g, 31.24 mmol) was added dropwise over 2 hours. The reaction mixture was stirred at room temperature. for 1 hour. The development of the reaction was monitored by TLC (20% EtOAc in hexane). After completion of the reaction, the reaction mixture was quenched by adding water (100 ml) and extracted with EtOAc (500 ml x 2). The organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Trituration of the crude residue with MeOH followed by filtration gave (3-(3-amino-2,4-difluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6- dichlorophenyl)methanone (2, 14.0 g, 85%) as an off-white solid.

Analytical data: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (d, J=1.96 Hz, 1H), 8.53 (br s, 1H), 8.31 (br. s, 1H), 7.67 (m, 3H), 7.11 (t, J=9.29 Hz, 1H), 6.88-6.96 (m, 1H), 5.59 (s, 2H ).

Step 12-2: (3-(3-amino-2,4-difluorobenzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[ 2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone derivative (3)

To a stirred solution of (3-(3-aminobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone derivative (2.1 eq., 7. 0 g, 13.33 mmol) in anhydrous 1,4-dioxane (100 mL), add bis(pinacolato)diboron (1.20 eq., 4.06 g, 16.00 mmol) and then add potassium acetate (melt , 2.50 eq., 3.28 g, 33.33 mmol). PdCl ₂ (dppf)Cl ₂ (0.05 eq, 0.54 g, 0.67 mmol) was added and the reaction mixture was stirred at 80°C for 3 hours. Reaction progress was monitored by TLC (20% EtOAc in hexane ) and LCMS. After completion, the reaction mixture was cooled to room temperature. and filtered through a layer of Celite. The resulting organic layer was concentrated under reduced pressure. The resulting crude product was dissolved in Et ₂ O (200 ml), filtered, and the organic layer was concentrated under reduced pressure. Trituration of the crude residue with acetonitrile followed by filtration gave (3-(3-amino-2,4-difluorobenzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone (3, 7.0 g) as a light brown solid.

Analytical data: LCMS (ESI) m/z=572.20 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (d, J=1.47 Hz, 1H), 8.49 (br s, 1H), 8.29 (b s, 1H ), 7.66 (s, 3H), 7.11 (t, J=9.54 Hz, 1H), 6.95-6.88 (m, 1H), 5.58 (s, 2H), 1 .31 (s, 12 H).

Step 12-3: This reaction was carried out in the same way as described in Example 4, step 3.

Step 12-4: This reaction was carried out in the same way as described in Example 6, step 3.

Step 12-5: Removal of the 2,6-dichlorophenylmethanone protecting group was carried out by dissolving intermediate 5 in MeOH followed by the addition of potassium carbonate and stirring the mixture at room temperature. within 3 hours

By analogy with Example 12, compounds of Examples 75 and 76 were obtained.

Synthesis of individual compounds

Example 13: Synthesis of N-(3-bromo-5-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide

Step 13-1: Compound 1 was prepared according to Example 1a.

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 8.06 (d, J=2.3 Hz, 1H), 7.66 (dd, J=8.8 , 2.5 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 3.23-3.09 (m, 2H), 1.75-1.52 (m, 2H) , 0.91 (t, J=7.4 Hz, 3H).

¹³ C-NMR (DMSO-d _6, 50 MHz, ppm): δ 168.4, 140.5, 135.5, 133.6, 121.3, 119.4, 113.5, 52, 7, 16.8, 12.4.

TLC-MS: m/z calculated for C ₁₀ H ₁₂ BrNO ₄ S ([MH] ^- ): 320.0, found: 320.0.

Step 13-2: Synthesis of N-(3-bromo-5-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide (2)

The title compound was prepared according to Example 2a.

Yield: 71 mg, 133 µmol, 38% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.88 (s, 1H), 9.48 (s, 1H), 8.69 (d, J=2 ,2 Hz, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J=2.3 Hz, 1H), 7, 77 (d, J=8.5 Hz, 3H), 7.57 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.7 Hz, 1H), 3.13- 3.07 (m, 2H), 1.58 (d.kv, J=14.9, 7.4 Hz, 2H), 0.80 (t, J=7.4 Hz, 3H);

¹³ C-NMR (DMSO-d _6, 101 MHz, ppm): 188.5, 148.9, 143.5, 138.3, 137.1, 135.1, 134.2, 133.9 , 132.4, 132.2, 129.8, 129.1, 128.8, 127.4, 125.7, 118.5, 116.9, 114.6, 53.6, 16.8, 12 ,3. TLC-MS: m/z calculated for C ₂₃ H ₁₉ BrClN ₃ O ₃ S ([MH] ^- ): 530.0, found: 529.9.

Purity: 95%

Example 14: Synthesis of 3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-N-propylbenzenesulfonamide

Stage 14-1

Step 14-1: 3-(N-propylsulfamoyl)benzoic acid (I) was prepared according to Example 1 (Step 3) with the following exception: Sulfonyl chloride was dissolved in DCM, and then propylamine and trimethylamine were added. The mixture was stirred overnight at room temperature.

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 8.32 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 8, 01 (d, J=7.8 Hz, 1H), 7.82-7.64 (m, 1H), 2.69 (dd, J=13.0, 6.8 Hz, 1H), 1.48 -1.23 (m, 1H), 0.76 (t, J=7.3 Hz, 1H).

¹³ C-NMR (DMSO-d _6, 50 MHz, ppm): δ 166.3, 141.3, 133.0, 131.9, 130.7, 130.0, 127.2, 44, 5, 22.5, 11.2.

Step 14-2: 3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-N-propylbenzenesulfonamide

Method: The title compound was prepared according to Example 2a.

Yield: 317 mg, 750 µmol, 73% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.02 (s, 1H), 8.65 (d, J=2.3 Hz, 1H), 8, 48 (d, J=2.3 Hz, 1H), 8.22 (s, 1H), 8.16 (t, J=1.4 Hz, 1H), 8.07 (m, 2H), 7, 84-7.71 (m, 2H), 2.74 (dd, J=13.0, 6.7 Hz, 2H), 1.39 (h, J=7.0 Hz, 2H), 0.80 (t, J=7.3 Hz, 3H); ¹³ C-NMR (DMSO-d _6, 101 MHz, ppm): 188.2, 147.6, 145.0, 141.1, 139.8, 137.7, 132.3, 131.6 , 129.8, 129.4, 126.2, 120.3, 113.8, 112.8, 44.4, 22.5, 11.2.

TLC-MS: m/z calculated for C ₁₇ H ₁₆ BrN ₃ O ₃ S ([MH] ^- ): 420.0, found: 419.7.

Example 15: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide

Step 1: 3-(propylsulfonamido)benzoic acid

Step 15-1: 3-(propylsulfonamido)benzoic acid (1) was prepared according to Example 1a.

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 13.05 (s, 1H), 10.01 (s, 1H), 7.81 (s, 1H), 7.65 (t, J=4.1 Hz, 1H), 7.44 (d, J=4.8 Hz, 2H), 3.08 (dd, J=8.6, 6.7 Hz, 2H ), 1.79-1.55 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

¹³ C-NMR (DMSO-d _6, 50 MHz, ppm): δ 166.9, 138.8, 131.9, 129.7, 124.4, 123.4, 119.8, 52, 5, 16.8, 12.5.

TLC-MS: m/z calculated for C ₁₀ H ₁₃ NO ₄ S ([MH] ^- ): 242.1, found: 241.8.

Step 15-2: N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide (2) was prepared according to the general method 2a

Yield: 62 mg, 137 µmol, 52% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 11.40 (s, 1H), 8.73 (d, J=2.2 Hz, 1H), 8, 88 (d, J=2.2 Hz, 1H), 8.18 (s, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.88 (s, 1H), 7, 52 (m, 5H), 3.17-3.08 (m, 2H), 1.77-1.83 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); ¹³ C-NMR (DMSO-d _6, 101 MHz, ppm): 189.0, 148.7, 143.4, 140.4, 138.8, 137.3, 136.6, 132.3 , 129.6, 129.6, 129.0, 128.8, 127.6, 123.5, 122.2, 119.3, 118.7, 113.7, 52.7, 16.8, 12 ,5. TLC-MS: m/z calculated for C ₂₃ H ₂₀ ClN ₃ O ₃ S ([MH] ^- ): 452.1, found: 451.9.

Purity: 96%

Example 16: Synthesis of N-(3-chloro-5-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide

Step 16-1: 3-Chloro-5-(propylsulfonamido)benzoic acid (1) was prepared by analogy with Example 1a. The reduction of the nitro group was not carried out in accordance with Example 1a (step 2), but as follows: Methyl 3-chloro-5-nitrobenzoate (1.0 eq.) was suspended in EtOH/H ₂ O (4:1, 0.5 M ), finely ground Fe ⁰ (1.5 eq.) and solid NH ₄ Cl (3 eq.) were added. The mixture was heated to sublimation for 3 hours. The crude material was poured onto a layer of Celite, and the solvent was concentrated to a minimum. The residue was diluted with EtOAc and washed with brine, the combined organic extracts were dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was used in step 3 without any further purification.

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 10.86 (s, 1H), 7.94 (d, J=2.1 Hz, 1H), 7. 72-7.52 (m, 2H), 3.34-3.18 (m, 2H), 1.78-1.51 (m, 2H), 0.92 (t, J=7.4 Hz, 3H).

¹³ C-NMR (DMSO-d _6, 50 MHz, ppm): δ 168.7, 139.5, 134.1, 130.8, 126.4, 119.6, 118.3, 53, 0, 16.8, 12.4.

TLC-MS: m/z calculated for C ₁₀ H ₁₂ ClNO ₄ S ([MH] ^- ): 276.0, found: 275.9.

Step 16-2: N-(3-chloro-5-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide (2) was prepared similar to Example 2a.

Yield: 78 mg, 160 µmol, 61% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.89 (s, 1H), 9.49 (s, 1H), 8.68 (dd, J=5 ,4, 2.2 Hz, 2H), 8.12 (d, J=3.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.71 (d, J =2.5 Hz, 1H), 7.65 (dd, J=8.7, 2.5 Hz, 1H), 7.57 (dd, J=8.7, 3.0 Hz, 3H), 3 .14-3.06 (m, 2H), 1.64-1.52 (m, 2H), 0.80 (t, J=7.4 Hz, 3H);

¹³ C-NMR (DMSO-d _6, 101 MHz, ppm): 188.5, 148.8, 143.5, 138.3, 137.1, 134.5, 133.7, 132.4 , 131.2, 129.8, 129.4, 129.0, 128.9, 128.7, 127.4, 125.5, 118.5, 114.6, 53.6, 16.7, 12 ,3.

TLC-MS: % calculated for C ₂₃ H ₁₉ Cl ₂ N ₃ O ₃ S ([MH] ^- ): 486.1, found: 486.1.

Purity: >99%

Example 17: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-5-fluorophenyl)propane-1-sulfonamide

Step 17-1: 3-Fluoro-5-(propylsulfonamido)benzoic acid was prepared according to Example 1a.

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 13.47 (b s, 1H), 10.47 (s, 1H), 7.85-7.36 (m, 2H), 3.41-3.05 (m, 2H), 1.83-1.46 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

¹³ C-NMR (DMSO-d _6, 50 MHz, ppm): δ 168.72 (d, J=2.3 Hz), 157.12 (d, J=241.1 Hz), 136, 86 (d, J=2.5 Hz), 121.74 (d, J=22.8 Hz), 120.50 (d, J=7.7 Hz), 118.23 (d, J=6, 9 Hz), 117.42 (d, J=23.9 Hz), 53.0, 16.8, 12.4.

TLC-MS: m/z calculated for C ₁₀ H ₁₂ FNO ₄ S ([MH] ^- ): 260.1, found: 260.0.

Step 17-2: N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-5-fluorophenyl)propane-1-sulfonamide (2) was prepared in according to Example 2a.

Yield: 113 mg, 239 µmol, 55% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.88 (s, 1H), 9.33 (s, 1H), 8.69 (s, 2H), 8.10 (s, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.60-7.50 (m, 4H), 7.44 (td, J=8.5, 3.0 Hz, 1H), 3.08-2.98 (m, 2H), 1.62-1.49 (m, 2H), 0.76 (t, J=7.4 Hz, 3H);

¹³ C-NMR (DMSO-d _6, 101 MHz, ppm): 188.6, 158.8 (d, J=244.5 Hz), 148.9, 143.5, 138.4, 137 ,1, 135.1 (d, J=6.2 Hz), 132.4, 131.5 (d, J=2.4 Hz), 129.8, 129.1, 128.8, 127.4 , 127.2 (d, J=8.4 Hz), 118.4, 118.0 (d, J=22.5 Hz), 116.4 (d, J=24.0 Hz), 114.6 , 53.5, 16.7, 12.3.

TLC-MS: m/z calculated for C ₂₃ H ₁₉ ClFN ₃ O ₃ S ([MH] ^- ): 470.1, found: 470.1.

Purity: 91%

Example 18: Synthesis of N-(3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Method: N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (100 mg, 218 µmol, 1.0 eq.), CuI (8 mg, 44 μmol, 0.2 eq.) and Pd(PPh ₃ ) ₂ Cl ₂ (31 mg, 44 μmol, 0.2 eq.) were suspended in MeCN. Triethylamine (76 μL, 546 μmol, 2.5 eq.) and ethynylmethylsilane (93 μL, 655 μmol, 3.0 eq.) were added and the mixture was heated in the microwave for 2 h at 130°C. The crude material was poured onto a layer of Celite, which was washed with EtOAc, the organic phase was washed with brine and dried over sodium sulfate. After removing the solvent, the residues were dissolved in MeOH and 0.5 g K ₂ CO ₃ was added. The mixture was stirred at room temperature. until TMS was completely degraded, and the solvent was removed under reduced pressure. Subsequent flash chromatography (SiO ₂ , DCM/MeOH 0-2%) gave the desired product in sufficient purity.

Yield: 45 mg, 112 µmol, 51% (beige solid).

TLC: nHex/EE (1:1)

PKL440: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.15 (s, 1H), 9.79 (s, 1H), 8.52 (d, J=1, 6 Hz, 1H), 8.50 (s, 1H), 8.30 (d, J=2.2 Hz, 1H), 7.59 (td, J=9.0, 6.0 Hz, 1H) , 7.28 (t, J=8.4 Hz, 1H), 4.34 (s, 1H), 3.16-3.06 (m, 2H), 1.79-1.67 (m, 2H ), 0.96 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₁₉ H ₁₅ F ₂ N ₃ O ₃ S ([MH] ^- ): 402.1, found: 402.0.

Purity: 97%

Example 19: Synthesis of N-(2,4-difluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)butane-1- sulfonamide

Step 19-1: N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-fluorophenyl)propane-1-sulfonamide (2) was prepared according to Example 2a .

Yield: 1.4 g, 3 mmol, 84% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.99 (s, 1H), 9.80 (s, 1H), 8.59 (d, J=1 ,4 Hz, 1H), 8.47 (d, J=1.6 Hz, 1H), 8.08 (s, 1H), 7.60 (t, J=7.2 Hz, 1H), 7, 37 (m, 2H), 3.23-3.09 (m, 2H), 1.81-1.59 (m, 2H), 1.38 (d.kv, J=14.0, 7.0 Hz, 2H), 0.85 (t, J=7.1 Hz, 3H).

TLC-MS: m/z calculated for C ₁₈ H ₁₇ BrFN ₃ O ₃ S ([MH] ^- ): 452.0, found: 452.4.

Step 19-2: N-(2,4-difluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)butane-1 -sulfonamide (3) was prepared in accordance with Example 7.

Yield: 37 mg, 73 µmol, 49% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.02 (s, 1H), 9.78 (s, 1H), 8.37 (d, J=2 .0 Hz, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.58 (td, J=8.9, 6.0 Hz, 1H), 7.36 (dd , J=8.3, 6.1 Hz, 1H), 7.28 (t, J=8.7 Hz, 1H), 7.23 (dd, J=10.1, 2.5 Hz, 1H) , 7.14 (td, J=8.5, 2.6 Hz, 1H), 3.18-3.07 (m, 2H), 2.26 (s, 3H), 1.69 (dt, J =15.2, 7.6 Hz, 2H), 1.43-1.32 (m, 2H), 0.85 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₅ H ₂₂ F ₃ N ₃ O ₃ S ([MH] ^- ): 500.1, found: 500.0.

Purity: 97%

Example 20: Synthesis of N-(3-(5-(4-( tert- butoxy)-2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane -1-sulfonamide

Method: The title compound was prepared according to Example 4, Step 3.

Yield: 52 mg, 93 µmol, 63% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (d, J=1.7 Hz, 1H), 9.78 (s, 1H), 8, 47 (s, 1H), 8.45 (d, J=2.1 Hz, 1H), 8.27 (d, J=1.9 Hz, 1H), 7.59 (td, J=9.0 , 6.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.28 (t, J=8.3 Hz, 1H), 7.22 (d, J=2 ,3 Hz, 1H), 7.12 (dd, J=8.4, 2.4 Hz, 1H), 3.15-3.09 (m, 2H), 1.80-1.67 (m, 2H), 1.37 (s, 9H), 0.96 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₇ H ₂₆ ClF ₂ N ₃ O ₄ S ([MH] ^- ): 560.1, found: 559.9.

Purity: >99%

Example 21: Synthesis of N-(3-(5-(2-chloro-4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)butane-1-sulfonamide

Method: The title compound was prepared according to Example 7.

Yield: 37 mg, 69 µmol, 47% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (s, 1H), 9.78 (s, 1H), 8.44 (s, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.26 (d, J=0.7 Hz, 1H), 7.58 (td, J=9.0, 6.0 Hz, 1H ), 7.47 (d, J=8.5 Hz, 1H), 7.31-7.25 (m, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.07 (dd, J=8.6, 2.6 Hz, 1H), 3.85 (s, 3H), 3.18-3.08 (m, 2H), 1.69 (dt, J=15.2 , 7.6 Hz, 2H), 1.43-1.30 (m, 2H), 0.85 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₅ H ₂₂ ClF ₂ N ₃ O ₄ S ([MH] ^- ): 532.1, found: 531.9.

Purity: 97%

Example 22: Synthesis of N-(2,4-difluoro-3-(5-(4-morpholinophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide

Method: The title compound was prepared according to Example 4, Step 3.

Yield: 18 mg, 32 µmol, 22% (beige solid).

TLC: nHex/EE (1:1)

PKL503: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.91 (s, 1H), 9.77 (s, 1H), 8.66 (d, J=1, 8 Hz, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.66-7.54 (m, 3H), 7.28 (t, J=8.6 Hz, 1H), 7.09 (d, J=8.6 Hz, 2H), 3.82-3.72 (m, 4H), 3.21-3.15 (m, 4H), 3.14-3 .09 (m, 2H), 1.79-1.67 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). TLC-MS: m/z calculated for C ₂₇ H ₂₆ F ₂ N ₄ O ₄ S ([MH] ^- ): 539.2, found: 539.0.

Purity: 97%

Example 23: Synthesis of N-(2,4-difluoro-3-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl) phenyl)propane-1-sulfonamide

Method: The title compound was prepared according to Example 4, Step 3.

Yield: 38 mg, 68 µmol, 48% (beige solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.96 (s, 1H), 9.92 (s, 1H), 8.66 (d, J=18 Hz, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.86-7.53 (m, 3H), 7.28 (t, J=8.6 Hz, 1H ), 7.09 (d, J=8.6 Hz, 2H), 3.31 (s, 4H), 3.17-3.07 (m, 2H), 2.74 (s, 4H), 2 .42 (s, 3H), 1.74 (d.kv, J=14.8, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H). TLC-MS: m/z calculated for C ₂₈ H ₂₉ F ₂ N ₅ o ₃ S ([MH] ^- ):

552.2, found: 551.9.

Purity: 96%

Example 24: Synthesis of N-(3-(5-(4-(4-acetylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide

Step 1: N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1- sulfonamide

Step 24-1: N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane- 1-sulfonamide (2) was prepared in accordance with Example 4, step 1.

Yield: 5.1 g, 8.1 mmol, 74% (light beige solid).

TLC: nHex/EE 25%

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 9.84 (s, 1H), 8.90 (s, 1H), 8.72 (d, J=2 .0 Hz, 1H), 8.31 (s, 1H), 7.72-7.62 (m, 4H), 7.33 (t, J=8.9 Hz, 1H), 3.21-3 .10 (m, 2H), 1.83-1.68 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). TLC-MS: m/z calculated for C ₂₄ H ₁₆ BrCl ₂ F ₂ N ₃ O ₄ S ([MH] ^- ): 627.9, found: 628.0.

Step 24-2: N-(3-(1-(2,6-dichlorobenzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo [2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (3) was prepared according to Example 4, Step 2.

Yield: 2.8 g, 4.1 mmol, 88% (beige solid).

TLC: nHex/EE 25%

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 9.06 (d, J=1.6 Hz, 1H), 8.48 (s, 1H), 8, 37 (s, 1H), 7.77 (td, J=8.9, 5.6 Hz, 1H), 7.45-7.32 (m, 3H), 7.09 (t, J=8, 5 Hz, 1H), 6.74 (s, 1H), 3.18-3.05 (m, 2H), 1.90 (dp, J=10.3, 7.5 Hz, 2H), 1, 33 (s, 12H), 1.07 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₃₀ H ₂₈ BCl ₂ F ₂ N ₃ O ₆ S ([MH] ^- ): 676.1, found: 676.5.

Step 24-3: N-(3-(5-(4-(4-acetylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl )propane-1-sulfonamide (4) was prepared according to Example 4, Step 3. Yield: 29 mg, 49 µmol, 33% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data:

¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.73 (s, 1H), 9.52 (s, 1H), 8.66 (d, J=1.9 Hz , 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.68-7.53 (m, 3H), 7.28 (t, J=8.6 Hz, 1H) , 7.10 (d, J=8.6 Hz, 2H), 3.61 (s, 4H), 3.28-3.22 (m, 2H), 3.22-3.15 (m, 2H ), 3.15-3.08 (m, 2H), 2.06 (s, 3H), 1.80-1.67 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₉ H ₂₉ F ₂ N ₅ O ₄ S ([MH] ^- ): 580.2, found: 579.8.

Purity: >99%

Example 25: Synthesis of N-(3-(5-(2-chloro-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide:

Step 25-1: 4-((4-Bromo-3-chlorophenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (1) was prepared according to Example 11.

Yield: 447 mg, 1.4 µmol, 96% (white solid).

TLC: nHex/EE 25%

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 7.63 (d, J=8.9 Hz, 1H), 7.27 (d, J=2.9 Hz, 1H), 6.91 (dd, J=8.9, 2.9 Hz, 1H), 4.46-4.31 (m, 1H), 4.13-3.92 (m, 3H) , 3.73 (dd, J=8.3, 6.3 Hz, 1H), 1.34 (s, 3H), 1.29 (s, 3H).

¹³ C-NMR (DMSO-d _6, 50 MHz, ppm): δ 158.5, 134.1, 133.6, 116.4, 115.9, 112.0, 108.9, 73, 5, 69.4, 65.5, 26.5, 25.3.

Step 25-2: N-(3-(5-(2-chloro-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3 -b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (2) was prepared in accordance with Example 4, step 3.

Yield: 97 mg, 156 µmol, 70% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.99 (s, 1H), 9.76 (s, 1H), 8.44 (s, 1H), 8.41 (d, J=1.9 Hz, 1H), 8.26 (s, 1H), 7.58 (td, J=9.0, 6.0 Hz, 1H), 7.47 (d , J=8.5 Hz, 1H), 7.32-7.23 (m, J=14.0, 5.6 Hz, 2H), 7.09 (dd, J=8.6, 2.5 Hz, 1H), 4.50-4.38 (m, 1H), 4.19-4.03 (m, 3H), 3.78 (dd, J=8.3, 6.4 Hz, 1H) , 3.17-3.08 (m, 2H), 1.82-1.67 (m, 2H), 1.38 (s, 3H), 1.32 (s, 3H), 0.96 (t , J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₉ H ₂₈ ClF ₂ N ₃ O ₆ S ([MH]): 618.1, found: 617.8

Purity: 95%

Example 26: Synthesis of N-(2,4-difluoro-3-(5-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-1-phenylmethanesulfonamide

Method: The title compound was prepared according to Example 7.

Yield: 11 mg, 21 µmol, 15% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.97 (s, 1H), 9.83 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.51 (dd, J=14.7, 8.7 Hz , 1H), 7.43-7.30 (m, J=9.6 Hz, 5H), 7.24 (t, J=8.7 Hz, 1H), 7.09 (d, J=8, 4 Hz, 2H), 4.53 (s, 2H), 3.82 (s, 3H).

TLC-MS: m/z calculated for C ₂₈ H ₂₁ F ₂ N ₃ O ₄ S ([MH]): 532.1, found: 531.8.

Purity: 99%

Example 27: Synthesis of 4-(3-(2,6-difluoro-3-((phenylmethyl)sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide

Method: The title compound was prepared according to Example 7.

Yield: 75 mg, 129 µmol, 65% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.10 (s, 1H), 9.85 (s, 1H), 8.80 (s, 1H), 8.75 (s, 1H), 8.27 (d, J=1.8 Hz, 1H), 7.98 (kv, J=8.5 Hz, 4H), 7.52 (dd, J=14 ,9, 9.0 Hz, 1H), 7.46 (s, 2H), 7.43-7.32 (m, 5H), 7.25 (t, J=8.7 Hz, 1H), 4 .55 (s, 2H).

TLC-MS: % calculated for C ₂₇ H ₂₀ F ₂ N ₄ O ₅ S ₂ ([MH]): 581.1, found: 580.7.

Purity: 93%

Example 28: Synthesis of N-(2,4-difluoro-3-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-1-phenylmethanesulfonamide

Step 28-1: (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone (1) was prepared according to Example 6, Step 1 (ref: Zhang et al [doi: 10.1038/nature14982]).

Yield: 17.3 g, 45.3 mmol, 59% (beige solid).

TLC: PE/EtOAc 1:1

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 13.16 (s, 1H), 8.64 (d, J=2.3 Hz, 1H), 8, 51 (d, J=2.3 Hz, 1H), 8.49-8.37 (m, 2H), 7.54 (ddd, J=9.5, 8.3, 1.6 Hz, 1H) . ¹³ C-NMR (DMSO-d ₆ , 50 Hz, ppm): δ 178.9, 1615 (dd, J=257.6, 7.5 Hz), 152.8 (dd, J=264, 4, 9.3 Hz), 147.9, 145.5, 140.3, 134.4 (dd, J=7.9, 3.8 Hz), 131.2, 129.1 (dd, J= 11.4, 1.2 Hz), 119.2 (dd, J=25.1, 23.0 Hz), 119.0, 114.7, 114.5, 113.3 (dd, J=24, 0, 4.2 Hz).

TLC-MS: m/z calculated for C ₁₄ H ₆ BrF ₂ N ₃ O ₃ ([MH] ^- ): 380.0, found: 380.1.

Step 28-2: (3-Amino-2,6-difluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl) methanone (2) was prepared according to Example 6, Step 2 (ref: Zhang et al [doi:10.1038/nature14982]).

Yield: 16.8 g, 44.4 mmol, 98% (beige solid).

TLC: PE/EtOAc 1:1

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 13.04 (s, 1H), 8.56 (d, J=2.2 Hz, 1H), 8, 49 (d, J=2.3 Hz, 1H), 8.15 (s, 1H), 7.03-6.81 (m, 2H), 5.22 (s, 2H).

¹³ C-NMR (DMSO-d _6, 50 Hz, ppm): δ 182.27 (s), 150.0 (dd, J=157.3, 7.2 Hz), 147.7, 145 .2 (dd, J=163.6, 7.1 Hz), 145.1, 138.7, 133.48 (dd, J=13.1, 2.4 Hz), 131.1, 119.1 , 117.88 -116.41 (m), 115.2, 114.1, 111.44 (dd, J=22.0, 3.3 Hz).

TLC-MS: m/z calculated for C ₁₄ H ₈ BrF ₂ N ₃ O ([MH] ^- ): 350.0, found: 349.9.

Step 28-3: N-(3-(S-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-1-phenylmethanesulfonamide (3) was prepared according to Example 6, stage 3.

Yield: 1.7 g, 3.4 mmol, 79% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.15 (s, 1H), 9.86 (s, 1H), 8.61 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.51 (td, J=8.9, 6.3 Hz, 1H ), 7.43 -7.30 (m, 5H), 7.23 (t, J=8.7 Hz, 1H), 4.53 (s, 2H).

TLC-MS: m/z calculated for C ₂₁ H ₁₄ BrF ₂ N ₃ O ₃ S ([MH] ^- ): 504.0, found: 503.8.

Step 28-4: N-(2,4-difluoro-3-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-1-phenylmethanesulfonamide (4) prepared in accordance with Example 7.

Yield: 27 mg, 51 µmol, 37% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.02 (s, 1H), 9.84 (s, 1H), 8.70 (s, 1H), 8.64 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8.1, 5.6 Hz, 2H), 7.51 (dd , J=14.7, 8.9 Hz, 1H), 7.41-7.31 (m, 7H), 7.24 (t, J=8.7 Hz, 1H), 4.54 (s, 2H).

TLC-MS: m/z calculated for C ₂₇ H ₁₈ F ₃ N ₃ O ₃ S ([MH]): 520.1, found: 519.8

Purity: 93%

Example 29: Synthesis of N-(3-(5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin- 3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Step 29-1: 4-((4-Bromophenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (1) was prepared according to Example 11.

Yield: 474 mg, 1.7 µmol, 95% (colorless oil).

TLC: nHex/EE 25%

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 7.43 (d, J=9.1 Hz, 2H), 8.92 (d, J=9.1 Hz, 2H), 4.48-4.31 (m, 1H), 4.13-3.92 (m, 3H), 3.73 (dd, J=8.3, 8.3 Hz, 1H) , 1.34 (s, 3H), 1.29 (s, 3H).

¹³ C-NMR (DMSO-d _6, 50 MHz, ppm): δ 157.8, 132.2, 116.9, 112.3, 109.0, 73.7, 69.0, 65, 7, 28.7, 25.4.

Step 29-2: N-(3-(5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine -3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (2) was prepared in accordance with Example 4, step 3.

Yield: 67 mg, 114 µmol, 52% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.96 (s, 1H), 9.77 (s, 1H), 8.67 (d, J=2 .2 Hz, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.59 (td, J=9 ,0, 6.0 Hz, 1H), 7.28 (t, J=8.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 2H), 4.51-4.39 (m, 1H), 4.18-4.00 (m, 3H), 3.79 (dd, J=8.3, 8.4 Hz, 1H), 3.18-3.03 (m, 2H ), 1.80-1.88 (m, 2H), 1.38 (s, 3H), 1.32 (s, 3H), 0.98 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₉ H ₂₉ F ₂ N ₃ O ₆ S ([MH]): 584.2, found: 583.7.

Purity: 95%

Example 30: Synthesis of N-(3-(5-(2-chloro-4-(2,3-dihydroxypropoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluorophenyl)propane-1-sulfonamide

Method: The title compound was prepared according to Example 10.

Yield: 18 mg, 31 µmol, 38% (off-white solid).

TLC: DCM/MeOH 5%

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.03 (s, 1H), 9.78 (s, 1H), 8.44 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.28 (s, 1H), 7.58 (td, J=9.0, 6.0 Hz, 1H), 7.48 (d , J=8.5 Hz, 1H), 7.28 (t, J=8.7 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.07 (dd, J =8.6, 2.5 Hz, 1H), 5.03 (d, J=5.1 Hz, 1H), 4.72 (t, J=5.6 Hz, 1H), 4.11 (dd , J=10.1, 4.0 Hz, 1H), 3.97 (dd, J=10.0, 6.2 Hz, 1H), 3.87-3.79 (m, 1H), 3, 47 (t, J=5.6 Hz, 2H), 3.17-3.06 (m, 2H), 1.81-1.65 (m, 2H), 0.96 (t, J=7, 4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₆ H ₂₄ ClF ₂ N ₃ O ₆ S ([MH]): 578.1, found: 577.7.

Purity: >99%

Example 31: Synthesis of N-(3-(5-(4-(2,3-dihydroxypropoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane- 1-sulfonamide

Method: The title compound was prepared according to Example 10.

Yield: 25 mg, 45 µmol, 66% (off-white solid).

TLC: DCM/MeOH 5%

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.92 (s, 1H), 9.81 (s, 1H), 8.67 (d, J=2 ,1 Hz, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.58 (td, J=9 ,0, 6.1 Hz, 1H), 7.27 (t, J=8.4 Hz, 1H), 7.09 (d, J=8.7 Hz, 2H), 5.00 (d, J =4.5 Hz, 1H), 4.71 (s, 1H), 4.07 (dd, J=9.8, 4.1 Hz, 1H), 3.93 (dd, J=9.8, 6.2 Hz, 1H), 3.83 (td, 3= 10.7, 5.7 Hz, 1H), 3.48 (s, 2H), 3.17-3.06 (m, 2H), 1.74 (d.kv, 3= 14.9, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₆ H ₂₅ F ₂ N ₃ O ₆ S ([MH]): 544.1, found: 543.8.

Purity: 95%

Example 32: Synthesis of N-(3-(5-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Method: The title compound was prepared according to Example 7.

Yield: 50 mg, 102 µmol, 47% (beige solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (s, 1H), 9.78 (s, 1H), 8.74 (d, J=1 .9 Hz, 1H), 8.66 (s, 1H), 8.27 (s, 1H), 7.83 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.64-7.52 (m, 2H), 7.48 (d, 3= 7.9 Hz, 1H), 7.29 (t, J=8.6 Hz, 1H), 3.18-3 .07 (m, 2H), 1.74 (d.kv, J=14.8, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H). TLC-MS: m/z calculated for C ₂₃ H ₁₈ ClF ₂ N ₃ O ₃ S ([MH] ^- ): 488.1, found: 487.8.

Purity: 92%

Example 33: Synthesis of N-(3-(5-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Method: The title compound was prepared according to Example 7.

Yield: 50 mg, 101 µmol, 46% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.07 (s, 1H), 9.78 (s, 1H), 8.57 (s, 1H), 8.55 (s, 1H), 8.28 (d, 3= 1.6 Hz, 1H), 7.73 (dd, J=15.5, 8.7 Hz, 1H), 7.59 (td , J=8.9, 6.1 Hz, 1H), 7.48-7.39 (m, 1H), 7.32-7.21 (m, 2H), 3.17-3.06 (m , 2H), 1.80-1.67 (m, 2H), 0.96 (t, 3= 7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₃ H ₁₇ F ₄ N ₃ O ₃ S ([MH] ^- ): 490.1, found: 489.9.

Purity: 99%

Example 34: Synthesis of N-(2,4-difluoro-3-(5-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide

Method: The title compound was prepared according to Example 7.

Yield: 31 mg, 66 µmol, 30% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.06 (s, 1H), 9.78 (s, 1H), 8.59 (s, 2H), 8.27 (s, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.59 (dd, J=14.7, 8.8 Hz, 1H), 7.49 (dd , J=12.3, 6.3 Hz, 1H), 7.38 (dd, J=16.4, 8.7 Hz, 2H), 7.29 (t, J=8.5 Hz, 1H) , 3.18-3.07 (m, 2H), 1.74 (d.kv, J=14.1, 7.0 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H ).

TLC-MS: m/z calculated for C ₂₃ H ₁₈ F ₃ N ₃ O ₃ S ([MH] ^- ): 472.1, found: 471.9.

Purity: 99%

Example 35: Synthesis of N-(2,4-difluoro-3-(5-(4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide

Method: The title compound was prepared according to Example 4, Step 3.

Yield: 54 mg, 115 µmol, 52% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.93 (s, 1H), 9.77 (s, 1H), 9.63 (s, 1H), 8.63 (d, J=1.7 Hz, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 7.64-7.50 (m, 3H), 7.28 (t, J=8.7 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 3.19-3.05 (m, 2H), 1.81-1.65 ( m, 2H), 0.96 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₃ H ₁₉ F ₂ N ₃ O ₄ S ([MH] ^- ): 470.1, found: 469.9.

Purity: 97%

Example 36: Synthesis of N-(2,4-difluoro-3-(5-(2-fluoro-4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1- sulfonamide

Method: The title compound was prepared according to Example 4, Step 3.

Yield: 54 mg, 107 µmol, 48% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.02 (s, 1H), 9.78 (s, 1H), 8.53 (s, 2H), 8.25 (s, 1H), 7.64-7.54 (m, 2H), 7.28 (t, J=8.7 Hz, 1H), 7.02 (dd, J=12.8, 2.1 Hz, 1H), 6.95 (dd, J=8.6, 2.1 Hz, 1H), 3.84 (s, 3H), 3.19-3.06 (m, 2H), 1.74 (d.kv, J=14.9, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₄ H ₂₀ F ₃ N ₃ O ₄ S ([MH] ^- ): 502.1, found: 502.0.

Purity: >99%

Example 37: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-1-( metatolyl )-methanesulfonamide

Method: The title compound was prepared according to Example 6, Step 3.

Yield: 31 mg, 57 µmol, 27% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (s, 1H), 9.82 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 8.24 (s, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.61-7.50 (m, 3H), 7.28 -7.12 (m, 5H), 4.49 (s, 2H), 2.24 (s, 3H). TLC-MS: m/z calculated for C ₂₈ H ₂₀ ClF ₂ N ₃ O ₃ S ([MH] ^- ): 550.1, found: 549.6.

Purity: 93%

Example 38: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-1-( para -tolyl )methanesulfonamide

Method: The title compound was prepared according to Example 6, Step 3.

Yield: 31 mg, 58 µmol, 27% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (s, 1H), 9.78 (s, 1H), 8.72 (d, J=2 .2 Hz, 1H), 8.88 (s, 1H), 8.24 (s, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.57 (d, J=8 .5 Hz, 2H), 7.52 (td, J=9.0, 8.0 Hz, 1H), 7.29-7.21 (m, 3H), 7.18 (d, J=7, 9 Hz, 2H), 4.48 (s, 2H), 2.28 (s, 3H). TLC-MS: ^m 4 calculated for C ₂₈ H ₂₀ ClF ₂ N ₃ O ₃ S ([MH] ^- ): 550.1, found: 549.9.

Purity: 94%

Example 39: Synthesis of N-(2,4-difluoro-3-(5-(4-methoxy-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1- sulfonamide

Method: The title compound was prepared according to Example 4, Step 3.

Yield: 81 mg, 122 µmol, 55% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 200 MHz, ppm): δ 12.97 (s, 1H), 9.76 (s, 1H), 8.35 (d, J=1 .9 Hz, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.58 (td, J=9.0, 8.0 Hz, 1H), 7.27 (t , J=8.8 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 8.94 (d, J=2.4 Hz, 1H), 6.88 (dd, J =8.4, 2.5 Hz, 1H), 3.80 (s, 3H), 3.15-3.08 (m, 2H), 2.24 (s, 3H), 1.81-1, 87 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₅ H ₂₃ F ₂ N ₃ O ₄ S [MH] ^- : 498.1, found: 498.0.

Purity: >99%

Example 40: Synthesis of N-(3-(5-(4-(2,3-dihydroxypropoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-1 -phenylmethanesulfonamide

Method: The title compound was prepared according to Example 10.

Yield: 54 mg, 92 µmol, 80% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 12.96 (s, 1H), 9.83 (s, 1H), 8.67 (d, J=1 .8 Hz, 1H), 8.60 (s, 1H), 8.18 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.51 (dd, J=15 ,0, 9.0 Hz, 1H), 7.43-7.30 (m, 5H), 7.23 (t, J=8.7 Hz, 1H), 7.09 (d, J=8, 7 Hz, 2H), 5.01 (d, J=4.9 Hz, 1H), 4.72 (s, 1H), 4.53 (s, 2H), 4.08 (dd, J=9, 8, 4.1 Hz, 1H), 3.94 (dd, J=9.8, 6.2 Hz, 1H), 3.84 (d.kv, J=10.6, 5.3 Hz, 1H ), 3.49 (t, J=5.2 Hz, 2H).

TLC-MS: % calculated for C ₃₀ H ₂₅ F ₂ N ₃ O ₆ S ([MH] ^- ): 592.1, found: 592.0.

Purity: 94%

Example 41: Synthesis of N-(3-(5-(2-chloro-4-(2,3-dihydroxypropoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluorophenyl)-1-phenylmethane sulfonamide

Method: The title compound was prepared according to Example 10.

Yield: 76 mg, 121 µmol, 77% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (s, 1H), 9.83 (s, 1H), 8.47 (s, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.23 (s, 1H), 7.55-7.44 (m, 2H), 7.43-7.30 (m, 5H) , 7.27-7.17 (m, 2H), 7.08 (dd, J=8.6, 2.4 Hz, 1H), 5.04 (d, J=4.9 Hz, 1H), 4.73 (s, 1H), 4.53 (s, 2H), 4.12 (dd, J=10.1, 3.9 Hz, 1H), 3.98 (dd, J=10.0, 6.2 Hz, 1H), 3.84 (d.kv, J=10.7, 5.3 Hz, 1H), 3.48 (t, J=5.2 Hz, 2H).

TLC-MS: m/z calculated for C ₃₀ H ₂₄ ClF ₂ N ₃ O ₆ S ([MH] ^- ): 626.1, found: 625.9.

Purity: >99%

Example 42: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-1-(4-fluorophenyl) )methanesulfonamide

Method: The title compound was prepared according to Example 6, Step 3.

Yield: 36 mg, 66 µmol, 31% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (s, 1H), 9.83 (s, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.80 (d, J=7.8 Hz, 2H), 7.81-7.48 (m, 3H), 7.48 -7.39 (m, 2H), 7.25 (t, J=8.8 Hz, 1H), 7.19 (t, J=8.4 Hz, 2H), 4.55 (s, 2H) .

TLC-MS: m/z calculated for C ₂₇ H ₁₇ ClF ₃ N ₃ O ₃ S ([MH] ^- ): 554.1, found: 553.8.

Purity: 96%

Example 43: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-1-(3-fluorophenyl) )methanesulfonamide

Method: The title compound was prepared according to Example 6, Step 3.

Yield: 53 mg, 66 µmol, 45% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (s, 1H), 9.83 (s, 1H), 8.72 (s, 1H), 8.87 (s, 1H), 8.24 (s, 1H), 7.80 (d, J=7.8 Hz, 2H), 7.81-7.48 (m, 3H), 7.46 -7.39 (m, 2H), 7.25 (t, J=8.8 Hz, 1H), 7.19 (t, J=8.4 Hz, 2H), 4.55 (s, 2H) .

TLC-MS: m/z calculated for C ₂₇ H ₁₇ ClF ₃ N ₃ O ₃ S ([MH] ^- ): 554.1, found: 553.9.

Purity: 97%

Example 44: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-1-(2-fluorophenyl) )methanesulfonamide

Method: The title compound was prepared according to Example 8, Step 3.

Yield: 52 mg, 93 µmol, 44% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.04 (s, 1H), 10.02 (s, 1H), 8.72 (d, J=2 ,1 Hz, 1H), 8.67 (s, 1H), 8.21 (s, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.61-7.52 (m , 3H), 7.51-7.38 (m, 2H), 7.31-7.15 (m, 3H), 4.60 (s, 2H).

TLC-MS: % calculated for C ₂₇ H ₁₇ ClF ₃ N ₃ O ₃ S ([MH] ^- ): 554.1, found: 553.9.

Purity: 95%

Example 45: Synthesis of N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Step 1: 5-Bromo-2-cyclopropylpyrimidine

Method: The title compound was prepared according to Gabos et al. [WO 2006004532 A1].

Yield: 403 mg, 2.2 mmol, 13% after two steps (colorless oil).

TLC: nHex/EE 10%

Analytical data: ¹ H-NMR (CDCl _3, 200 MHz, ppm): δ 8.58 (s, 2H), 2.31-2.12 (m, 1H), 1.13-1.05 (m, 4H). ¹³ C-NMR (CDCl _3, 50 MHz, ppm): δ 170.7, 157.5, 116.7, 18.0, 11.4.

Step 2: N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Method: The title compound was prepared according to Example 4, Step 3.

Yield: 51 mg, 103 µmol, 47% (white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.08 (s, 1H), 9.77 (s, 1H), 9.03 (s, 2H), 8.75 (d, J=1.9 Hz, 1H), 8.70 (s, 1H), 8.28 (s, 1H), 7.59 (td, J=8.9, 6.2 Hz , 1H), 7.28 (t, J=8.6 Hz, 1H), 3.17-3.09 (m, 2H), 2.28 (ddd, J=12.6, 7.9, 5 .0 Hz, 1H), 1.80-1.68 (m, 2H), 1.14-1.02 (m, 4H), 0.96 (t, J=7.4 Hz, 3H).

TLC-MS: m/z calculated for C ₂₄ H ₂₁ F ₂ N ₅ O ₃ S ([MH] ^- ): 496.1, found: 496.1.

Purity: 97%

Example 46: Synthesis of N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-1-phenylmethanesulfonamide

Step 46-1: N-(3-(5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-1 -phenylmethane sulfonamide was prepared according to Example 4, Step 1.

Yield: 2.1 g, 3.12 mmol, 93% (white solid).

TLC: nHex/EE 25%

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 9.93 (s, 1H), 8.88 (s, 1H), 8.75 (d, J=1 .8 Hz, 1H), 8.34 (s, 1H), 7.66 (s, 3H), 7.60 (dd, J=14.6, 8.6 Hz, 1H), 7.41 (d , J=3.7 Hz, 2H), 7.36-7.33 (m, 3H), 7.28 (t, J=9.0 Hz, 1H), 4.57 (s, 2H).

TLC-MS: m/z calculated for C ₂₈ H ₁₆ BrCl ₂ F ₂ N ₃ O ₄ S ([MH] ^- ): 675.9, found: 675.4.

Step 46-2: N-(3-(1-(2,6-dichlorobenzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo [2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-1-phenylmethanesulfonamide was prepared according to Example 4, Step 2.

Yield: 1.2 g, 1.7 mmol, 75% (off-white solid).

TLC: nHex/EE 25%

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 9.91 (s, 1H), 8.86 (d, J=1.6 Hz, 1H), 8. 83 (s, 1H), 8.33 (s, 1H), 7.65 (s, 3H), 7.63-7.55 (m, 1H), 7.43-7.32 (m, 5H) , 7.28 (t, J=8.9 Hz, 1H), 4.57 (s, 2H), 1.30 (s, 12H).

TLC-MS: m/z calculated for C ₃₄ H ₂₈ BCl ₂ F ₂ N ₃ O ₆ S ([MH] ^- ): 724.1, found: 723.6.

Step 46-3: N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-1-phenylmethane -sulfonamide was prepared in accordance with Example 4, step 3.

Yield: 53 mg, 97 µmol, 47% (off-white solid).

TLC: nHex/EE (1:1)

Analytical data: ¹ H-NMR (DMSO-d _6, 400 MHz, ppm): δ 13.10 (s, 1H), 9.83 (s, 1H), 9.04 (s, 2H), 8.76 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 7.51 (dd, J=14.8, 8.8 Hz, 1H), 7.43 -7.31 (m, 5H), 7.24 (t, J=8.6 Hz, 1H), 4.54 (s, 2H), 2.33-2.24 (m, 1H), 1, 14-1.03 (m, 4H).

TLC-MS: m/z calculated for C ₂₈ H ₂₁ F ₂ N ₅ O ₃ S ([MH] ^- ): 544.1, found: 544.0.

Purity: 97%

In accordance with Example 4, steps 2 and 3, illustrated in the diagram below, the compounds shown in Table 2 were prepared.

Table 2: Examples 47-57 were prepared by analogy with Example 4, stages 2 and 3.

Example R ₁ -Br Product Analytical data 47 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 9.77 (s, 1H), 9.12 (s, 2H), 8.73 (d, J=4 ,1 Hz, 1H), 8.25 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.93 (t, J=6.9 Hz, 1H), 7, 59 (dd, J=14.9, 9.0 Hz, 1H), 7.41 (dd, J=7.3, 4.9 Hz, 1H), 7.29 (t, J=8.6 Hz , 1H), 3.19-3.06 (m, 2H), 1.74 (d.kv, J=15.0, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass for C ₂₂ H ₁₈ F ₂ N ₄ O ₃ S: 456.1
MS(ESI ⁺ ): 457.05 for [M+H] ⁺ . 48 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.12 (s, 1H), 9.79 (s, 1H), 9.26 (dd, J=4.9, 1.4 Hz, 1H ), 9.21 (s, 1H), 9.17 (d, J=2.1 Hz, 1H), 8.40 (dd, J=8.6, 1.3 Hz, 1H), 8.32 (s, 1H), 7.84 (dd, J=8.6, 4.9 Hz, 1H), 7.60 (dd, J=14.9, 9.0 Hz, 1H), 7.29 ( t, J=8.4 Hz, 1H), 3.19-3.06 (m, 2H), 1.74 (dd, J=15.1, 7.5 Hz, 2H), 0.96 (t , J=7.4 Hz, 3H).
Calculated exact mass for C ₂₁ H ₁₇ F ₂ N ₅ O ₃ S: 457.46.
MS(ESI ⁺ ): 458.10 for [M+H] ⁺ . 49 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.16 (s, 1H), 9.75 (s, 2H), 9.31 (d, J=5.5 Hz, 1H), 8, 94 (d, J=2.2 Hz, 1H), 8.89 (s, 1H), 8.33 (s, 1H), 8.15 (dd, J=5.4, 2.5 Hz, 1H ), 7.60 (dd, J=15.0, 9.0 Hz, 1H), 7.29 (t, J=8.6 Hz, 1H), 3.20-3.06 (m, 2H) , 1.74 (dd, J=15.2, 7.5 Hz, 2H), 0.97 (t, J=7.4 Hz, 3H).
Calculated exact mass: 457.10 (C ₂₁ H ₁₇ F ₂ N ₅ O ₃ S);
MS(ESI ⁺ ): 458.05 for [M+H] ⁺ . 50 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8, 28 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.58 (dd, J=14 ,8, 8.9 Hz, 1H), 7.28 (t, J=8.8 Hz, 1H), 6.58 (d, J=8.6 Hz, 1H), 6.14 (s, 2H ), 3.18-3.06 (m, 2H), 1.74 (dd, J=15.1, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H) .
Calculated 471.48 for C ₂₂ H ₁₉ F ₂ N ₅ O ₃ S. Measured 472.05 for [M+H] ⁺ . 51 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.79 (s, 1H), 8.79 (d, J=2.0 Hz, 1H), 8, 72 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.81 (d, J=5 .4 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.58 (dd, J=14.8, 8.9 Hz, 1H), 7.51 (d, J =5.4 Hz, 1H), 7.28 (t, J=8.6 Hz, 1H), 3.17-3.07 (m, 2H), 1.73 (d.kv, J=14, 9, 7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H).
_{Calculated 511.56 for C25H19F2N3O3S2 . ​} Measured 512.05 for [M+H] ⁺ . 52 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.98 (s, 1H), 9.76 (s, 1H), 8.76 (s, 1H), 8.66 (s, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68-7.52 (m, 2H), 7.27 (t, J=8.7 Hz, 1H), 7.02 (s, 1H), 3.16-3.05 (m, 2H), 1.73 (dd, J=15.0, 7.5 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H).
Calculated exact mass for C ₂₅ H ₁₉ F ₂ N ₃ O ₄ S: 495.11; MS(ESI ⁺ ): 496.10 for [M+H] ⁺ . 53 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.28-12.91 (m, 1H), 10.04-9.62 (m, 1H), 9.14 (d, J=1, 8 Hz, 1H), 8.85 (d, J=2.2 Hz, 1H), 8.79 (s, 1H), 8.46 (dd, J=8.2, 2.2 Hz, 1H) , 8.31 (s, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.65-7.51 (m, 3H), 7.29 (t, J=8.3 Hz, 1H), 3.18-3.07 (m, 2H), 1.74 (d.kv, J=15.0, 7.5 Hz, 2H), 0.97 (t, J=7, 4 Hz, 3H).
Calculated exact mass for C ₂₂ H ₁₉ F ₂ N ₅ O ₅ S ₂ : 535.08. MS(ESI+): 536.1 for [M+H] ⁺ . 54 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (d, J=2.1 Hz, 2H), 8.72 (s, 2H), 8.33 (s, 1H), 8, 23 (s, 2H), 8.05 (s, 6H), 7.55 (dd, J=15.1, 9.1 Hz, 2H), 7.20 (t, J=8.6 Hz, 2H ), 3.28 (s, 5H), 3.09-2.99 (m, 4H), 1.72 (d.kv, J=15.0, 7.5 Hz, 4H), 0.95 ( t, J=7.4 Hz, 5H). 55 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.03-12.77 (m, 1H), 10.25-10.00 (m, 1H), 8.69 (d, J=2, 2 Hz, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.56 (dd, J=15, 1, 9.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.23 (t, J=8.8 Hz, 1H), 3.13-3.00 ( m, 2H), 2.53 (d, J=4.5 Hz, 3H), 1.73 (dt, J=15.2, 7.4 Hz, 2H), 0.95 (t, J=7 ,4 Hz, 3H).
Calculated exact mass for C ₂₄ H ₂₁ F ₂ N ₃ O ₃ S ₂ : 501.57; MS(ESI+): 502.2 for [M+H] ⁺ . 56 ^1H -NMR (400 MHz, CDCl ₃ ) δ 10.20-10.05 (m, 1H), 8.85 (s, 1H), 8.62 (s, 1H), 7.87 (s, 1H ), 7.72 (t, J=11.8 Hz, 2H), 7.57 (s, 1H), 7.08 (t, J=8.6 Hz, 1H), 6.83 (s, 1H ), 6.48 (s, 1H), 3.13 (dd, J=9.1, 6.6 Hz, 2H), 1.91 (dt, J=15.1, 7.6 Hz, 2H) , 1.08 (t, J=7.4 Hz, 3H).
Calculated exact mass for C ₂₁ H ₁₇ F ₂ N ₃ O ₄ S: 445.09. MS(ESI ⁺ ): 446 for [M+H] ⁺ . 57 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.98 (s, 1H), 9.84 (s, 1H), 9.28 (s, 1H), 9.05 (d, J=12 .3 Hz, 2H), 8.36 (d, J=11.8 Hz, 1H), 8.20 (d, J=14.4 Hz, 1H), 7.58 (dd, J=14.8 , 8.7 Hz, 1H), 7.27 (t, J=8.6 Hz, 1H), 3.12 (dd, J=18.6, 11.1 Hz, 2H), 1.72 (dt , J=14.7, 7.4 Hz, 2H), 0.91 (dd, J=39.4, 32.0 Hz, 3H).
Calculated exact mass for C ₂₀ H ₁₆ F ₂ N ₄ O ₃ S ₂ : 462.06.
MS(ESI ⁺ ): 463.15 for [M+H] ⁺ .

Compounds 58 and 59 were prepared by analogy with Example 7.

Example Reagent Product ¹ H-NMR/MS 58 ¹ H-NMR (400 MHz, DMSO) δ 13.06 (s, 1H), 9.77 (s, 1H), 8.98 (s, 1H), 8.76 (d, J=2.1 Hz , 1H), 8.69 (s, 1H), 8.64 (d, J=4.3 Hz, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.21 (d , J=7.9 Hz, 1H), 7.66-7.50 (m, 2H), 7.29 (t, J=8.8 Hz, 1H), 3.17-3.08 (m, 2H), 1.73 (dt, J=14.9, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass for C ₂₂ H ₁₈ F ₂ N ₄ O ₃ S: 456.11. MS(ESI ⁺ ): 457.10 for [M+H] ⁺ . 59 ¹ H-NMR (400 MHz, DMSO) δ 8.85 (d, J=2.0 Hz, 1H), 8.77 (s, 1H), 8.69 (d, J=5.8 Hz, 2H ), 8.29 (s, 1H), 7.83 (d, J=5.7 Hz, 2H), 7.64-7.54 (m, 1H), 7.28 (t, J=8, 4 Hz, 1H), 3.18-3.06 (m, 2H), 1.74 (dd, J=15.3, 7.6 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass for C ₂₂ H ₁₈ F ₂ N ₄ O ₃ S: 456.11. MS(ESI ⁺ ): 457.10 for [M+H] ⁺ .

Example 60: Synthesis of N-(4-bromo-3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluorophenyl)propane-1-sulfonamide

Step 60-1: Synthesis of 6-bromo-2-fluoro-3-nitrobenzoic acid (2)

4-Bromo-2-fluoro-1-nitrobenzene (1.1 eq., 4 g, 18.18 mmol) was dissolved in anhydrous tetrahydrofuran (THF, 100 ml) and cooled to -78°C. Lithium diisopropylamide (2M in THF, 2 eq., 18.18 mL, 36.36 mmol) was added dropwise and the reaction mixture was stirred at -78°C for 1 hour and then quenched by the addition of carbon dioxide gas. The reaction mixture was heated to room temperature and the solvents were removed under vacuum. The resulting residue was extracted with 0.5 M aqueous sodium hydroxide (20 ml x 3). The combined aqueous layers were washed with ethyl acetate (EtOAc, 30 ml x 2), acidified to approximately pH 1 by adding concentrated hydrochloric acid, and then extracted with diethyl ether (30 ml x 2). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the desired 6-bromo-2-fluoro-3-nitrobenzoic acid (1.3 g, 4.92 mmol, 27% yield) as a white solid, which used in the next step without further purification.

Step 60-2: Synthesis of 6-bromo-2-fluoro-3-nitrobenzoic acid chloride (3)

To a solution of 6-bromo-2-fluoro-3-nitrobenzoic acid (1 equiv., 1.3 g, 4.92 mmol) in DCM (25 ml) at 0°C was added oxalyl chloride (2.5 equiv., 1. 55 g, 12.3 mmol) and then dimethylformamide (0.5 ml) was added. The resulting reaction mixture was stirred for approximately 3 hours at ambient temperature. The solvents were evaporated under reduced pressure to give the acid chloride (3, 1.3 g, crude product), which was used without further purification.

Step 60-3: Synthesis of (6-bromo-2-fluoro-3-nitrophenyl)(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (4)

At k.t. in an argon atmosphere 5 equiv. AlCl ₃ (4.39 g, 32.94 mmol) was stirred in 30 ml anhydrous DCM. After 1 hour, 5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine 2 (1 eq., 1.5 g, 6.588 mmol) was added. The mixture was stirred at room temperature. for an additional hour and then cooled to 0°C. Freshly obtained 6-bromo-2-fluoro-3-nitrobenzoyl chloride (3, 1.3 g, crude product) was dissolved in 15 ml of DCM and added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature. within 3 days. The progress of the reaction was monitored by TLC (40% EtOAc in hexane). The resulting mixture was then carefully quenched at 0°C by adding cold acetonitrile:H ₂ O (1:1, 30 ml). The precipitated solid was filtered and the filtrate was extracted with DCM (25 ml). The filter cake and DCM extract were combined and purified by FCC using 20% EtOAc in hexanes to give (3-nitro-6-bromo-2-fluorophenyl)(5-(4-chlorophenyl)-1H-pyrrolo[2,3- b]pyridin-3-yl)methanone (4.610 mg, 1.29 mmol, 19.50% yield) as an off-white solid.

Step 60-4: Synthesis of (3-amino-6-bromo-2-fluorophenyl)(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (5)

To a stirred solution of 3-nitro-6-bromo-2-fluorophenyl)(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (4.1 eq., 610 mg , 1.285 mmol) in THF (15 ml) at RT. stannous chloride (3 eq., 731 mg, 3.85 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The progress of the reaction was monitored by TLC (30% EtOAc in hexane). After completion, the reaction mixture was quenched by adding 20% aq. K ₂ CO ₃ solution (10 ml) and stirred for 10 minutes. The mixture was filtered through a layer of Celite, and the layer was washed with Celite THF (25 ml). The resulting organic layer was evaporated under vacuum, and the resulting residue was dissolved in EtOAc (20 ml). The mixture was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (3-amino-6-bromo-2-fluorophenyl)(5-(4-chlorophenyl)-1H-pyrrolo[2,3 -b]pyridin-3-yl)methanone 3 (560 mg, crude product), which was used in the subsequent reaction without further purification.

Step 60-5: Synthesis of N-(4-bromo-3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-fluorophenyl)propane-1-sulfonamide (6)

To a stirred solution of (3-amino-6-bromo-2-fluorophenyl)(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone 5 (1 equiv., 400 mg , 0.90 mmol) pyridine (5 ml) and DMAP (0.05 eq., 5.48 mg, 0.045 mmol) were added. When stirring at room temperature. propanesulfonyl chloride (1.5 eq., 202 mg, 1.35 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature. for 16 hours. The development of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under vacuum, water (5 ml) was added and extracted with DCM (10 ml x 2). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude compound, which was purified by FCC to give the target N-(4-bromo-3-(5-(4-chlorophenyl)- 1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-fluorophenyl)propane-1-sulfonamide (6, 120 mg, 0.22 mmol, 24.4%).

Example 61: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-4-cyano-2-fluorophenyl)propane-1-sulfonamide

N-(4-bromo-3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-fluorophenyl)propane-1-sulfonamide was added to the microwaving vial (1 eq., 50 mg, 0.09 mmol), and dissolved it in NMP (2 ml). The mixture was degassed with argon for 10 min, and CuCN (5 eq., 40.64 mg, 0.045 mmol), CuI (0.1 eq., 1.73 mg, 0.009 mmol) were added thereto. The reaction mixture was heated at 120°C under microwave conditions for 2 hours. The reaction mixture was filtered through Celite and concentrated in vacuo to give the crude product, which was purified by SFC to give N-(3-(5-(4-chlorophenyl) -1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-4-cyano-2-fluorophenyl)propane-1-sulfonamide (17 mg, 0.03 mmol, 37.69%) as off-white solid matter.

Analytical data: ^1H -NMR (400 MHz, DMSO) δ 13.12 (s, 1H), 10.51 (s, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 7.80 (dt, J=16.0, 10.1 Hz, 4H), 7.58 (d, J=8.3 Hz, 2H), 1.74 (dd , J=15.1, 7.2 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H).

Calculated exact mass for C ₂₄ H ₁₈ ClFN ₄ O ₃ S: 496.08. MS(ESI+): 497.05 for [M+H] ⁺ .

Example 62: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-dicyanophenyl)propane-1-sulfonamide

To a stirred solution of N-(2,4-dibromo-3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide (5) ( 1 equiv., 100 mg, 0.16 mmol), copper cyanide (4 equiv., 58.48 mg, 0.65 mmol) was added to DMF (2 ml) and the reaction mixture was heated at 120 ° C in a sealed tube for 5 hours After completion of the reaction, the reaction mixture was poured into ice water (20 ml), the resulting precipitate was filtered, washed with water (10 ml × 3), and then diluted with aqueous ammonia (5 ml × 2). The mixture was dried under vacuum and the crude product was purified by preparative HPLC to give N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4- dicyanophenyl)propane-1-sulfonamide (15 mg, 0.03 mmol, 18% yield) as a white solid.

Analytical data: ¹ H-NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 8.71 (d, J=47.9 Hz, 2H), 8.29 (s, 1H), 7. 95 (s, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.67 (s, 1H), 7.57 (d, J=8.3 Hz, 2H), 3, 12 (s, 2H), 1.76 (d, J=7.1 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H).

Calculated exact mass for C ₂₅ H ₁₈ ClN ₅ O ₃ S: 503.08.

MS(ESI ⁺ ): 504.10 for [M+H] ⁺ .

Example 63: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-cyanophenyl)propane-1-sulfonamide

The synthesis was carried out as shown in the diagram below. The individual steps were carried out in analogy with the steps described in Examples 60 and 61.

Example 64: Synthesis of N-(3-(4-chloro-5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Step 64-1: 5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propyl-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (2)

To a solution of compound 1 (1 equiv., 500 mg, 1.02 mmol) in THF (10 ml) at 0°C, m-CPBA (211.31 mg, 1.22 mmol) was added portionwise. The resulting suspension was left to warm to room temperature. and stirred at the same temperature for 18 hours. The reaction mixture was concentrated to dryness on a rotary evaporator under reduced pressure. We were added to the resulting crude product. aq. NaHCO ₃ (20 ml), which was extracted with DCM (3x80 ml). The combined organic layer was dried and concentrated in vacuo to give 5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-7- oxide (500 mg, crude) as a white solid, which was used in the next step without purification.

Step 64-2: N-(3-(4-chloro-5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1- sulfonamide (3)

To a stirred solution of 5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (2) (1 eq. , 250 mg, 0.49 mmol) to THF (10 ml) was added dropwise methanesulfonyl chloride (1.5 eq., 84.9 mg, 0.74 mmol) at 0°C. After addition was complete, the reaction mixture was heated to 70°C and stirred for 12 hours. The reaction was monitored by LCMS. After completion of the reaction, the volatiles were removed under reduced pressure to obtain a residue. The residue was diluted with water (20 ml) and extracted with DCM (50 ml x 3). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give N-(3-(4-chloro-5-(4-chlorophenyl)- 1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (70 mg, 0.13 mmol, 26.5% yield).

Analytical data: ^1H -NMR (400 MHz, DMSO) δ 13.45-12.72 (m, 1H), 10.09-9.49 (m, 1H), 8.40 (s, 1H), 8 .32 (s, 1H), 7.64-7.51 (m, 5H), 7.28 (t, J=8.7 Hz, 1H), 3.17-3.06 (m, 2H), 1.81-1.66 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Example 65: Synthesis of N-(3-(5-(4-chlorophenyl)-4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

N-(3-(4-chloro-5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (Example 50) (1 eq., 300 mg, 0.57 mmol) was dissolved in DMA (3 ml). Added zinc (0.1 eq., 3.74 mg, 0.057 mmol), zinc cyanide (2 eq., 134.38 mg, 1.14 mmol), Pd(dppf)Cl ₂ (0.035 eq., 16.74 mg, 0.02 mmol) and Pd ₂ (dba) ₃ (0.0175 eq., 10.48 mg, 0.01 mmol), the reaction mixture was degassed with argon for 20 min and stirred under microwave conditions at 120°C for 1.5 hours. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The Celite layer was washed with EtOAc (20 ml), the filtrate was concentrated under vacuum to leave a residue, which was dissolved in EtOAc (50 ml), washed with water, dried over Na ₂ SO ₄ , concentrated under reduced pressure to give the crude compound. The crude compound was purified by reverse phase preparative HPLC to give N-(3-(5-(4-chlorophenyl)-4-cyano-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4- difluorophenyl)propane-1-sulfonamide (100 mg, 0.19 mmol, 34% yield).

Analytical data: ^1H -NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.78 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.64-7.52 (m, 5H), 7.28 (t, J=8.4 Hz, 1H), 3.18-3.06 (m, 2H), 1.74 (d.kv, J=15.1, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).

Calculated exact mass for C ₂₄ H ₁₇ ClF ₂ N ₄ O ₃ S: 514.07. MS(ESI ⁺ ): 515.0 for [M+H] ⁺ .

Example 66: Synthesis of N-(3-(5-(4-chlorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Step 66-1: 5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propyl-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (2)

To a solution of compound 1 (1 eq., 1 g, 2.04 mmol) in THF (20 mL) at 0°C was added m-CPBA (1.2 eq., 422.61 mg, 2.45 mmol). The resulting suspension was left to warm to room temperature. and stirred overnight. The reaction mixture was concentrated to dryness using a rotary evaporator under reduced pressure conditions. The thus obtained crude product was triturated with DCM to obtain a solid, which was filtered and dried to obtain 5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2. 3-b]pyridine-7-oxide 2 (700 mg, 1.38 mmol, 68% yield) as a white solid.

Step 66-2: N-(3-(5-(4-chlorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1- sulfonamide (3)

A suspension of N-oxide 2 (1 eq., 500 mg, 0.988 mmol) and dimethyl sulfate (1.1 eq., 137.11 mg, 1.08 mmol) in anhydrous acetonitrile (15 ml) was stirred overnight under a nitrogen atmosphere at 60-65°C. After cooling to room temperature, a solution of NaOMe in MeOH (25 wt%, 4 ml) was added and the cloudy mixture was stirred overnight at 60-65°C. After neutralization by addition of AcOH and dilution with MeOH (5 ml), the mixture was evaporated to dryness. The resulting residue was dissolved in EtOAc (40 ml) and washed with aq. NaHCO ₃ (5 ml × 2). The aqueous layer was extracted with EtOAc (10 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification by preparative HPLC provided 22 (30 mg, 0.0576 mmol, 5.85%) as a white solid.

Analytical data: ^1H -NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 9.75 (s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.55 (dd, J=8.9, 3.0 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H ), 7.24 (t, J=8.6 Hz, 1H), 3.94 (s, 3H), 3.15-3.04 (m, 2H), 1.73 (d.q., J= 15.0, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).

Example 67: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-hydroxypropane-1-sulfonamide

Step 67-1: 3-(chlorosulfonyl)propyl acetate (2)

Step 67-1i: To a stirred solution of 3-bromopropan-1-ol 1 (1 eq., 3.0 g, 21.6 mmol) in DCM (50 mL) was added TEA (3 eq., 6.5 g, 64 .8 mmol) and 4-DMAP (0.1 eq., 0.264 g, 2.15 mmol), and cooled the reaction mixture to 0°C. At the same temperature, acetyl chloride (1.5 eq., 2.54 g, 32.4 mmol) was added dropwise to the solution over 15 min. The development of the reaction was monitored by TLC. After completion of the reaction (TLC), water (100 ml) was added, and the reaction mixture was extracted with DCM (20 ml x 2). The organic layer was separated, washed with 2N HCl (10 ml) and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the product of Step 1 (4 g, crude product), which was used in the next step without further purification.

Step 67-1ii: To a stirred solution of the product from Step 1 (1 eq., 4.0 g, crude product) in DMF (50 mL) was added potassium thioacetate (1.2 eq., 3.02 g, 26.51 mmol) , and the reaction mixture was stirred for 4 hours at room temperature. The development of the reaction was monitored by TLC. After completion of the reaction, ice water (150 ml) was added, and the reaction mixture was extracted with diethyl ether (20 ml x 3). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the product of step 2 (3 g, crude product), which was used in the next step without any further purification.

Step 67-1iii: To a stirred solution of the product from Step 2 (1 eq., 3.0 g, 17.023 mmol) in acetonitrile (30 mL) at 0°C was added 2N HCl (4 mL). NCS (4 eq., 9 g, 68.09 mmol) was added in portions over 30 min. The reaction mixture was stirred for 3 hours at room temperature. The development of the reaction was monitored by TLC. After completion of the reaction, the acetonitrile was evaporated under vacuum, water (100 ml) was added, and the reaction mixture was extracted with diethyl ether (50 ml x 3). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 3-(chlorosulfonyl)propyl acetate 2 (2 g, crude product), which was used in the next step without any further purification.

Step 67-2: 3-(N-(3-(5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2 ,4-difluorophenyl)sulfamoyl)propyl acetate (4)

To a stirred solution of (3-(3-amino-2,6-difluorobenzoyl)-5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone 3 (1 eq., 199.8 mg, 0.359 mmol) in DCM (10 ml) was added TEA (10 eq., 362.59 mg, 3.59 mmol) and DMAP (0.1 eq., 4.38 mg , 0.0359 mmol), and cooled the reaction mixture to 0°C. To this was added 3-(chlorosulfonyl)propyl acetate 2 (4 eq., 287.2 mg, 1.436 mmol). The development of the reaction was monitored by TLC. After completion of the reaction (16 h), the reaction mixture was quenched by adding 1N HCl (2 ml), and the reaction mixture was extracted with DCM (10 ml x 2). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude residue, which was purified by FCC to obtain the disulfonamide intermediate as the product of Step 4 (150 mg).

To a stirred solution of the product obtained in step 4 (1 eq., 150 mg, 0.169 mmol) in THF (2.5 ml) was added aq. NaOH (4 eq., 27.08 mg, 0.677 mmol), and the reaction mixture was stirred at room temperature. for 2 hours. The development of the reaction was monitored by TLC. After completion of the reaction, THF was removed under vacuum, water (5 ml) was added and the reaction mixture was neutralized by adding 5N HCl. The mixture was extracted with EtOAc (10 ml x 3). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give compound 4 (100 mg, crude product), which was used in the next step without any further purification.

Step 67-3: N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-hydroxypropane-1 -sulfonamide

To a stirred solution of 3-(N-(3-(5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4 -difluorophenyl)sulfamoyl)propyl acetate 4 (100 mg, 0.147 mmol, crude product) in THF (2 ml) was added aq. ammonia (2 ml), and stirred the reaction mixture at room temperature. for 12 hours. The solvent was evaporated under vacuum to leave a residue, which was further purified by preparative HPLC to give the product (25 mg, 0.05 mmol, 34% yield) as a white solid.

Analytical data: ¹ H-NMR (400 MHz, DMSO) δ 13.12-12.92 (m, 1H), 9.87-9.70 (m, 1H), 8.71 (d, J=2, 2 Hz, 1H), 8.65 (s, 1H), 8.22 (s, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.59 (t, J=10, 0 Hz, 3H), 7.28 (t, J=8.8 Hz, 1H), 4.64 (s, 1H), 3.47 (t, J=5.9 Hz, 2H), 3.17 (dd, J=10.3, 5.2 Hz, 2H), 1.87 (dd, J=15.5, 6.2 Hz, 2H).

Calculated exact mass for C ₂₃ H ₁₈ ClF ₂ N ₃ O ₄ S: 505.07.

MS(ESI ⁺ ): 506.0 for [M+H] ⁺ .

Example 68: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-hydroxypropane-1-sulfonamide

Step 68-1: 2-oxopropane-1-sulfonyl chloride (2)

Chloroacetone (1 equiv., 3 g, 32.425 mmol), Na ₂ SO ₃ (1 equiv., 4.085 g, 32.425 mmol) and water (30 ml) were mixed in a flask equipped with a reflux condenser. The mixture was refluxed with stirring for 20 hours, after which the mixture was evaporated to dryness. The resulting white solid (product of step 1) was used in the next step without further purification.

To a stirred solution of the product of step 1 (3 g, crude product) in toluene (15 ml) was added POCl ₃ (15 ml), and the reaction mixture was stirred at 110°C for 4 hours. The solvent was removed by rotary evaporation, diethyl ether ( 50 ml), and the mixture was further stirred for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (2) as a dark brown liquid (3 g, crude), which was used in the next step without further purification.

Step 68-2: N-(3-(5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4- difluorophenyl)-2-oxopropane-1-sulfonamide (4)

To a stirred solution of compound 3 (1 eq., 200 mg, 0.359 mmol) in dioxane (4 mL) was added pyridine (1 mL) and 4-DMAP (0.1 eq., 4.38 mg, 0.0359 mmol). When stirring at room temperature. 2-oxopropanesulfonyl chloride 2 (4 eq., 224.32 mg, 1.438 mmol) was added dropwise. The reaction mixture was stirred at room temperature. for 8 hours. The development of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under vacuum, water (5 ml) was added and extracted with EtOAc (3 x 10 ml). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude compound, which was purified by FCC to give compound 4 (199.75 mg, 0.295 mmol, 82% yield).

Step 68-3: N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-hydroxypropane-1 -sulfonamide

Step 68-3i: To a stirred solution of N-(3-(5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2 ,4-difluorophenyl)-2-oxopropane-1-sulfonamide 4 (1 equiv., 200 mg, 0.295 mmol) in MeOH (2 ml) at 0°C was added dropwise to a methanol solution of sodium borohydride (1 equiv., 11.22 mg, 0.295 mmol, 1 ml), and the reaction mixture was stirred for 1 hour. The development of the reaction was monitored by TLC. Once complete, the reaction mixture was added to water (20 ml) and extracted with EtOAc (3×5 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by FCC using 25% EtOAc in hexane to give the product of step 4 (70 mg, 0.1 mmol, 33.89% ).

Step 68-3ii: To a stirred solution of the product from Step 71-4i (70 mg, 0.103 mmol) in THF:MeOH (2 mL, 1:1) was added aq. ammonia (1 ml), and stirred the reaction mixture at room temperature. for 4 hours. The solvent was evaporated under vacuum and water (10 ml) was added. The mixture was neutralized to pH 7 by adding 5N HCl and extracted with EtOAc (3×5 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude product, which was purified by SFC to obtain the target N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-hydroxypropane-1-sulfonamide (15.99 mg, 0.0316 mmol, 21.50%).

Analytical data: ¹ H-NMR (400 MHz, DMSO) δ 13.02 (s, 1H), 9.86 (s, 1H), 8.71 (d, J=2.1 Hz, 1H), 8, 64 (s, 1H), 8.22 (s, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.66-7.53 (m, 3H), 7.28 (t , J=8.7 Hz, 1H), 5.01 (d, J=4.7 Hz, 1H), 4.12 (d, J=5.7 Hz, 1H), 3.23 (dd, J =10.2, 6.0 Hz, 2H), 1.20 (d, J=6.3 Hz, 3H).

Calculated exact mass for C ₂₃ H ₁₈ ClF ₂ N ₃ O ₄ S: 505.07.

MS(ESI ⁺ ): 506.0 for [M+H] ⁺ .

Example 69: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-2-oxopropane-1-sulfonamide

Analytical data: ¹ H-NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 10.08 (s, 1H), 8.72 (d, J=2.1 Hz, 1H), 8, 68 (s, 1H), 8.25 (s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.59 (t, J=10.2 Hz, 3H), 7, 29 (t, J=8.8 Hz, 1H), 4.45 (s, 2H), 2.27 (s, 3H).

Calculated exact mass for C ₂₃ H ₁₆ ClF ₂ N ₃ O ₄ S: 503.05. MS(ESI+): 504.05 for [M+H] ⁺ .

Example 70: Synthesis of N-(2,4-difluoro-3-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide

To a degassed stirred solution of RuPhos (0.1 eq, 20.38 mg, 0.04 mmol) in dioxane (2 mL) was added palladium acetate (0.05 eq, 4.89 mg, 0.02 mmol), and the reaction mixture was again degassed with argon for 15 minutes. To this mixture was added N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (1) (1 eq., 200 mg, 0.44 mmol) and morpholine (2 eq., 76.04 mg, 0.87 mmol), and then add 1 M solution of LiHMDS (4 eq., 1.7 mL, 1.7 mmol) in THF . The reaction mixture was further degassed with argon for 10 min and then heated at 100°C in a sealed tube for 12 h. The reaction mixture was diluted with water (10 ml) and adjusted to pH 6 by adding 5 N HCl. The reaction mixture was extracted with EtOAc (10 ml x 3). The combined organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude residue, which was further purified by SFC to obtain N-(2,4-difluoro-3-(5-morpholino-1H-pyrrolo[2,3 -b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide (35 mg, 0.08 mmol, 17%) as a white solid.

Analytical data: ¹ H-NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 9.74 (s, 1H), 8.28 (d, J=2.7 Hz, 1H), 8, 02 (d, J=3.0 Hz, 1H), 7.92 (s, 1H), 7.61-7.50 (m, 1H), 7.26 (t, J=8.6 Hz, 1H ), 3.99-3.62 (m, 19H), 3.21-3.06 (m, 5H), 1.73 (dt, J=15.0, 7.5 Hz, 2H), 0, 96 (t, J=7.4 Hz, 3H).

Example 71: Synthesis of N-(2,4-difluoro-3-(5-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide

Step 71-1: tert -butyl 4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazine-1-carboxylate (2)

To a degassed stirred solution of Ruphos (0.1 eq, 20.36 mg, 0.04 mmol) in NMP (2 mL) was added Pd ₂ dba ₃ (0.05 eq, 19.97 mg, 0.02 mmol) , and again degassed the reaction mixture with argon for 15 minutes. To this mixture was added N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide 1 (1 eq., 200 mg , 0.436 mmol) and 1-Boc-piperazine (1.5 eq., 121.81 mg, 0.65 mmol), and then sodium tert- butoxide (3 eq., 125.66 mg, 1.31 mmol) was added. . The reaction mixture was further degassed with argon for 10 min and then heated at 100°C in a microwave oven for 1 h. The reaction mixture was diluted with water (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was then FCCed with 30% EtOAc in hexanes to give tert- butyl-4-(3-(2,6-difluoro-3-( propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazine-1-carboxylate (2) (70 mg, 0.12 mmol, 28% yield) as a white solid.

Step 71-2: N-(2,4-difluoro-3-(5-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide hydrochloride

To tert -butyl-4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-carboxylate (2) (70 mg, 0.12 mmol) HCl in dioxane (3 mL, 4M) was added at 0°C and the reaction mixture was further stirred at room temperature. for 1 hour. After completion of the reaction, the dioxane was removed under vacuum to obtain a crude residue. This residue was triturated with diethyl ether to give N-(2,4-difluoro-3-(5-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane- 1-sulfonamide hydrochloride (25 mg, 0.05 mmol, 43%) as a white solid.

Analytical data: ¹ H-NMR (400 MHz, DMSO) δ 8.29 (d, J=2.4 Hz, 1H), 8.00 (s, 2H), 7.55 (dd, J=14.8 , 8.9 Hz, 1H), 7.25 (t, J=8.7 Hz, 1H), 3.37 (m, 4H), 3.30 (m, 4H), 3.14-3.06 (m, 2H), 1.72 (dd, J=15.0, 7.4 Hz, 2H), 0.94 (t, J=7.4 Hz, 3H).

Synthesis of 5-substituted N-(2,x - difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)alkyl-1-sulfonamide derivatives

5-Substituted N-(2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)alkyl-1-sulfonamide derivatives according to the formula

prepared according to the following examples.

Example 72: N-(2,4-difluoro-3-(5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide

N-[3-[1-(2,6-dichlorobenzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine -3-carbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (150 mg, 0.221 mmol, prepared by analogy with Example 4, steps 4-1 and 4-2), 5-bromo-2-chloropyrimidine (64 .2 mg, 0.332 mmol) and potassium carbonate (62.0 mg, 0.442 mmol) were suspended in 1,4-dioxane (0.600 ml) and water (0.300 ml) and degassed with argon for 5 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (Pd(dppf)Cl ₂ , 8.09 mg, 0.0111 mmol) was added and the mixture was heated to 60°C for 2 hours. The solvent was removed by evaporation, and the residue was dissolved in 10 ml of MeOH. Potassium carbonate (1 g) was added and the mixture was stirred at 50°C. After 2 hours, water was added and adjusted to pH~7 by adding aqueous HCl (1N). The aqueous phase was extracted three times with EtOAc, the combined organic phases were dried over sodium sulfate, and the solvent was removed under vacuum. The product was purified by flash chromatography using DCM/EtOAc/MeOH (92/8/0-88/8/4) as eluent. Along with the potassium carbonate-catalyzed removal of the dichlorobenzoyl protecting group, the chlorine in 5-bromo-2-chloropyrimidine was replaced by a methoxy group.

Analytical data:

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ 13.05 (s, 1H), 9.77 (s, 1H), 9.00 (s, 2H), 8.72 (d, J= 1.4 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.59 (dd, J=14.7, 8.8 Hz, 1H), 7.28 ( t, J=8.6 Hz, 1H), 3.99 (s, 3H), 3.15-3.07 (m, 2H), 1.74 (d.kv, J=14.8, 7, 3 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).

Calculated exact mass: 487.1; MS(ESI-): 486.3 for [MH] ^- .

By analogy with Example 72, compounds of Examples 73-95 were obtained, presented in Table 3.

Table 3: Examples 73-95 were prepared according to the procedure described in Example 72.

Example Reagent Product Analytical data 73 N-(2,4-difluoro-3-(5-(4-((trifluoromethyl)-sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H18F5N3O5S2/587.54 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.19-12.82 (m, 1H), 10.03-9.70 (m, 1H), 8.88 (d, J=2, 2 Hz, 1H), 8.82 (s, 1H), 8.31 (s, 1H), 8.26 (kV, J=8.7 Hz, 3H), 7.65-7.54 (m, 1H), 7.28 (t, J=8.8 Hz, 1H), 3.16-3.06 (m, 2H), 1.74 (d.kv, J=14.8, 7.4 Hz , 2H), 0.96 (t, J=7.4 Hz, 2H).
Calculated exact mass: 587.06
MS(ESI ⁺ ): 588 for [M+H] ⁺ . 74 N-(3-(5-(4-((difluoromethyl)-sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide
C24H19F4N3O5S2/569.55 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.10 (s, 1H), 9.97-9.66 (m, 1H), 8.82 (d, J=2.2 Hz, 1H ), 8.76 (s, 1H), 8.28 (s, 1H), 8.17 (d, J=8.5 Hz, 2H), 8.06 (d, J=8.5 Hz, 2H ), 7.56 (td, J=9.0, 6.0 Hz, 1H), 7.35 (s, 1H), 7.24 (dd, J=15.3, 6.2 Hz, 1H) , 3.15-3.03 (m, 2H), 1.71 (d.kv, J=15.0, 7.4 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H ).
Calculated exact mass: 569.07;
MS(ESI ⁺ ): 570.15 for [M+H] ⁺ . 75 N-(2,4-difluoro-3-(5-(4-(methylsulfinyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C24H21F2N3O4S2/517.57 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.06 (s, 1H), 9.78 (s, 1H), 8.77 (d, J=2.2 Hz, 1H), 8, 70 (s, 1H), 8.27 (s, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7, 59 (td, J=9.0, 5.9 Hz, 1H), 7.32-7.25 (m, 1H), 3.34 (s, 3H), 3.106-3.144 (m, 2H), 1 .73-1.75 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 517.09; MS(ESI ⁺ ): 518.1 76 N-(3-(5-(4-((2-aminoethyl)thio)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C25H24F2N4O3S2/530.61 ¹ H-NMR (400 MHz, DMSO) δ 8.70 (d, J=2.1 Hz, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 8.19 (s , 1H), 7.73 (d, J=8.3 Hz, 2H), 7.55 (dd, J=12.1, 6.0 Hz, 1H), 7.50 (d, J=8, 3 Hz, 2H), 7.21 (t, J=8.5 Hz, 1H), 3.15-3.10 (m, 2H), 3.08-3.03 (m, 2H), 2, 87 (t, J=7.0 Hz, 2H), 1.73 (dt, J=15.2, 7.5 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H).
Calculated 530.13 for C25H24F2N4O3S2. Measured 531.1 for [M+H] ⁺ . 77 N-(2,4-difluoro-3-(5-(6-(methylsulfonyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C23H20F2N4O5S2/534.55 ¹ H-NMR (400 MHz, DMSO) δ 13.16 (s, 1H), 9.76 (s, 1H), 9.22 (d, J=2.0 Hz, 1H), 8.86 (d , J=2.2 Hz, 1H), 8.81 (s, 1H), 8.56 (dd, J=8.2, 2.2 Hz, 1H), 8.31 (s, 1H), 8 .16 (d, J=8.2 Hz, 1H), 7.59 (td, J=9.0, 6.0 Hz, 1H), 7.29 (t, J=8.8 Hz, 1H) , 3.18-3.09 (m, 2H), 1.74 (d.kv, J=15.0, 7.4 Hz, 2H), 0.97 (t, J=7.4 Hz, 3H ).
Calculated 534.08 for C23H20F2N4O5S2. Measured 535.15 for [M+H] ⁺ . 78 N-(2,4-difluoro-3-(5-(4-((trifluoromethyl)thio)-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H18F5N3O3S2/555.54 ¹ H-NMR (400 MHz, DMSO) δ 13.07 (s, 1H), 9.78 (s, 1H), 8.78 (d, J=2.2 Hz, 1H), 8.71 (s , 1H), 8.28 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.59 (td , J=9.0, 5.9 Hz, 1H), 7.29 (t, J=8.1 Hz, 1H), 3.13 (dd, J=14.9, 7.3 Hz, 2H) , 1.74 (d.kv, J=15.0, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated 555.07 for C24H18F5N3O3S2. Measured 556.0 for [M+H] ⁺ . 79 N-(2,4-difluoro-3-(5-(6-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3,3,3-trifluoropropane -1-sulfonamide
C26H22F5N5O4S/595.55 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (d, J=3.1 Hz, 1H), 10.04 (s, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.60 (d, J=2.3 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.08 (d, J=2.9 Hz, 1H), 7.95 (dd, J=8.8, 2.6 Hz, 1H), 7.69 (td, J=8.2, 6.1 Hz, 1H), 7.38 (t, J =8.9 Hz, 1H), 6.97 (d, J=8.9 Hz, 1H), 3.73 (t, J=4.8 Hz, 4H), 3.54-3.50 (m , 4H), 3.49-3.45 (m, 2H), 2.93-2.76 (m, 2H).
MS(ESI ^- ): 594.3 for [MH] ^- . 80 N-(2,4-difluoro-3-(5-(6-thiomorpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3,3,3-trifluoropropane -1-sulfonamide
C26H22F5N5O3S2/611.61 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.85 (d, J=3.1 Hz, 1H), 10.03 (s, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.49 (d, J=2.6 Hz, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.92 (dd, J=8.9, 2.6 Hz, 1H), 7.68 (td, J=8.3, 6.2 Hz, 1H), 7.38 (t, J =8.8 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 4.01-3.94 (m, 4H), 3.52-3.43 (m, 2H) , 2.92-2.76 (m, 2H), 2.66-2.61 (m, 4H).
MS(ESI ^- ): 610.6 for [MH] ^- . 81 N-(3-(5-(6-(1,1-dioxidothiomorpholino)-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)- 3,3,3-trifluoropropane-1-sulfonamide
C26H22F5N5O5S2/643.60 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.87 (d, J=3.1 Hz, 1H), 10.03 (s, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.54 (d, J=2.6 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 8.01 (dd, J=8.8, 2.6 Hz, 1H), 7.68 (td, J=8.2, 6.1 Hz, 1H), 7.38 (t, J =8.9 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 4.17-4.10 (m, 4H), 3.52-3.43 (m, 2H) , 3.19-3.08 (m, 4H), 2.92-2.76 (m, 2H).
MS(ESI ^- ): 642.6 for [MH] ^- . 82 N-(3-(5-(4-cyclobutylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C27H25F2N3O3S/509.57 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.98 (s, 1H), 9.76 (s, 1H), 8.69 (d, J=2.2 Hz, 1H), 8, 59 (s, 1H), 8.22 (s, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.58 (dd, J=14.9, 9.0 Hz, 1H ), 7.38 (d, J=8.1 Hz, 2H), 7.28 (t, J=8.8 Hz, 1H), 3.67-3.53 (m, 1H), 3.17 -3.07 (m, 2H), 2.39-2.29 (m, 2H), 2.14 (dd, J=15.1, 6.0 Hz, 2H), 2.07-1.93 (m, 1H), 1.85 (d, J=9.9 Hz, 1H), 1.74 (dd, J=15.2, 7.5 Hz, 2H), 0.96 (t, J= 7.4 Hz, 3H).
MS(ESI ⁺ ): 510.2 for [M+H] ⁺ 83 N-(3-(5-(1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C20H17F2N5O3S/445.44 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.91-8.87 (m, 1H), 8.80 (d, J=2.1 Hz, 1H), 8.75-8.72 (m, 1H), 8.00 (s, 1H), 7.61-7.52 (m, 1H), 7.29-7.22 (m, 1H), 3.12-3.06 (m , 2H), 1.78-1.65 (m, 2H), 0.93 (t, J=7.4 Hz, 3H).
MS(ESI ⁺ ): 446.0 for [M+H] ⁺ 84 N-(3-(5-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C20H17F2N5O3S/445.44 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 13.01 (s, 1H), 12.93 (s, 1H), 9.78 (s, 1H), 8.89 (s, 1H), 8.83 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.59 (dd, J=14.8, 8.8 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 6.85 (s, 1H), 3.18-3.07 (m, 2H), 1.74 (dd, J=14.9, 7.6 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H).
MS(ESI ⁺ ): 446.0 for [M+H] ⁺ 85 N-(3-(5-(1H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1 -sulfonamide
C19H16F2N6O3S/446.43 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 8.93 (s, 1H), 8.74 (s, 1H), 8.30 (s, 1H), 8.11 (s, 1H), 7.62-7.52 (m, 1H), 7.28-7.22 (m, 1H), 3.17-3.04 (m, 2H), 1.80-1.65 (m, 3H ), 0.96 (t, J=7.5 Hz, 3H). 86 N-(3-(5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C19H15F2N5O3S2/463.48 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 13.26 (s, 1H), 9.82 (s, 1H), 9.70 (s, 1H), 9.12-9.03 (m , 1H), 9.01 (s, 1H), 8.37 (s, 1H), 7.67-7.55 (m, 1H), 7.36-7.24 (m, 1H), 3, 18-3.07 (m, 2H), 1.83-1.65 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
MS(ESI ⁺ ): 464.50 for [M+H] ⁺ 87 N-(2,4-difluoro-3-(5-(2-(methylthio)thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1- sulfonamide
C21H18F2N4O3S3/508.58 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 9.77 (s, 1H), 9.00 (d, J=2.0 Hz, 1H), 8, 92 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 7.66-7.52 (m, 1H), 7.29 (t, J=8.6 Hz , 1H), 3.18-3.05 (m, 2H), 1.73 (d.kv, J=15.0, 7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H). Calculated 508.05 for C22H18F2N4O3S. Measured 509.0 for [M+H] ⁺ 88 N-(2,4-difluoro-3-(5-(5-oxo-4,5-dihydropyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-phenyl)propane -1-sulfonamide
C21H17F2N5O4S/473.45 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.95 (s, 1H), 12.79-12.59 (m, 1H), 9.76 (s, 1H), 8.91 (s , 2H), 8.19 (d, J=4.1 Hz, 2H), 7.58 (dd, J=14.9, 8.9 Hz, 1H), 7.28 (t, J=8, 6 Hz, 1H), 3.19-3.06 (m, 2H), 1.84-1.64 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). 89 N-(2,4-difluoro-3-(5-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C21H17F2N5O3S/457.46 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.11 (s, 1H), 9.78 (s, 1H), 9.37 (d, J=1.2 Hz, 1H), 9, 16 (s, 2H), 8.77 (dd, J=2.2, 1.6 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.27 (s, 1H ), 7.59 (td, J=9.0, 6.0 Hz, 1H), 7.29 (t, J=8.6 Hz, 1H), 3.14-3.10 (m, 2H) , 1.78-1.69 (m, 2H), 0.95 (t, J=7.4 Hz, 3H).
Calculated exact mass: 457.1
MS(ESI ^- ): 456.3 for [MH] ^- . 90 N-(2,4-difluoro-3-(5-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C21H17F2N5O3S/457.46 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.09 (s, 1H), 9.79 (s, 1H), 9.42 (s, 1H), 9.39 (d, J=2 .0 Hz, 1H), 8.92 (d, J=4.8 Hz, 2H), 8.21 (s, 1H), 7.58 (td, J=9.0, 5.9 Hz, 1H ), 7.46 (t, J=4.9 Hz, 1H), 7.28 (t, J=8.4 Hz, 1H), 3.12-3.08 (m, 2H), 1.75 -1.68 (m, 2H), 0.93 (t, J=7.5 Hz, 3H).
Calculated exact mass: 457.1
MS(ESI ^- ): 456.3 for [MH] ^- . 91 N-(2,4-difluoro-3-(5-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C21H17F2N5O3S/457.46 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 9.76 (s, 1H), 9.17 (s, 1H), 9.14 (s, 2H), 8.74 (d, J=2.2 Hz, 2H), 8.71 (s, 1H), 7.56 (td, J=9.0, 5.9 Hz, 1H), 7.24 (t , J=8.4 Hz, 1H), 3.10-3.04 (m, 2H), 1.73-1.66 (m, 2H), 0.92 (t, J=7.4 Hz, 3H).
Calculated exact mass: 457.1
MS(ESI ^- ): 456.3 for [MH] ^- . 92 N-(2,4-difluoro-3-(5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-1-phenylmethanesulfonamide
C26H19F2N5O4S/535.53 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.07 (d, J=1.5 Hz, 1H), 9.82 (s, 1H), 9.02 (s, 2H), 8, 74 (d, J=2.2 Hz, 1H), 8.70 (s, 1H), 8.24 (d, J=2.1 Hz, 1H), 7.51 (td, J=9.0 , 5.9 Hz, 1H), 7.40-7.38 (m, 2H), 7.36-7.33 (m, 3H), 7.24 (t, J=8.5 Hz, 1H) , 4.54 (s, 2H), 4.00 (s, 3H).
Calculated exact mass: 535.1
MS(ESI ^- ): 534.0 for [MH] ^- . 93 N-(3-(5-(4-(dimethylphosphoryl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C25H24F2N3O4PS/531.51 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.05 (s, 2H), 9.77 (s, 1H), 8.77 (d, J=1.8 Hz, 1H), 8, 69 (s, 1H), 8.27 (s, 1H), 7.97-7.86 (m, 4H), 7.59 (dd, J=14.8, 8.9 Hz, 1H), 7 .29 (t, J=8.7 Hz, 1H), 3.18-3.07 (m, 2H), 1.73 (dd, J=22.7, 10.4 Hz, 8H), 0, 96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 531.12
MS(ESI ⁺ ): 532.11 for [M+H] ⁺ . 94 3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-N-(2-hydroxyethoxy)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
C20H20F2N4O6S/558.56 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 11.85 (s, 1H), 9.80 (s, 1H), 8.77 (d, J=2 .0 Hz, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.89 (kv, J=8.4 Hz, 4H), 7.58 (dd, J=14 ,9, 9.0 Hz, 1H), 7.28 (t, J=8.7 Hz, 1H), 4.79 (s, 1H), 3.95 (t, J=4.8 Hz, 2H ), 3.63 (d, J=4.7 Hz, 2H), 3.15-3.09 (m, 2H), 1.73 (dd, J=15.1, 7.5 Hz, 2H) , 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 558.14
MS(ESI ⁺ ): 559.0 for [M+H] ⁺ . 95 N-(3-(5-(1,3-dimethyl-1-oxido-1H-benzo[e][1,2]thiazin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3 -carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C27H24F2N4O4S2/570.63 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.07 (s, 1H), 9.79 (s, 1H), 8.79 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.29 (t, J=8.8 Hz, 1H), 6.20 (s, 1H), 3.79 (s, 3H), 3.19-3.07 (m, 2H), 2.14 (s, 3H), 1.74 (dd, J=15.0, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 570.12
MS(ESI ⁺ ): 571.05 for [M+H] ⁺ .

Example 96: Synthesis of 4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide

N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (80.0 mg, 0.175 mmol), (4 β-sulfamoylphenyl)boronic acid (0.0456 g, 0.227 mmol) and potassium carbonate (0.0490 g, 0.349 mmol) were suspended in ethylene glycol dimethyl ether (1.60 ml)/water (0.400 ml), and degassed with argon for 5 minutes. Tetrakis-Pd (0.0121 g, 0.0105 mmol) was added and the resulting mixture was heated in the microwave at 130°C for 40 min. The crude materials were passed through a bed of Celite, which was washed with EtOAc. The organic phases were washed with water and brine, dried over Na ₂ SO ₄ , and the solvent was removed under vacuum. The product was purified by flash chromatography (SiO ₂ , DCM/EtOAc 20% - 50%).

Analytical data:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.08 (d, J=2.3 Hz, 1H), 9.78 (s, 1H), 8.78 (d, J=22 Hz, 1H), 8.71 (s, 1H), 8.29 (d, J=2.6 Hz, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.95 (d, J=8.7 Hz, 2H), 7.59 (td, J=9.0, 6.0 Hz, 1H), 7.45 (s, 2H), 7.32-7.25 (m, 1H ), 3.17-3.09 (m, 2H), 1.80-1.67 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Calculated exact mass for C ₂₃ H ₂₀ F ₂ N ₄ O ₅ S ₂ : 534.1 (molecular weight: 534.55)

MS(ESI-): 532.7 for [MH] ^- .

Example 97: Synthesis of N-(2,4-difluoro-3-(5-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide

N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (0.120 g, 0.262 mmol), [2-( trifluoromethyl)phenyl]boronic acid (0.0547 g, 0.288 mmol) and potassium carbonate (0.0734 g, 0.524 mmol) were suspended in 1,4-dioxane (0.900 ml) and water (0.450 ml) and degassed with argon for 5 min. XPhos Pd G3 (0.0111 g, 0.0131 mmol) was added and the mixture was heated to 110°C in the microwave for 45 min at 50 W. The crude material was filtered through a pad of Celite, washed with EtOAc, and the filtrate was washed with us. aq. NH ₄ Cl solution. The organic phase was dried over sodium sulfate, the solvent was removed under reduced pressure, and the product was purified by flash chromatography using DCM/MeOH (100/0 v/v - 97/3 v/v) as eluent.

Analytical data:

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.07 (s, 1H), 9.76 (s, 1H), 8.39 (s, 1H), 8.35 (d, J=1 .7 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.61-7.54 (m, 2H), 7.28 (t, J=8.6 Hz, 1H), 3.14-3.10 (m, 2H), 1.78-1.70 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Calculated exact mass for C ₂₄ H ₁₈ F ₅ N ₃ O ₃ S: 523.1 (molecular weight: 523.48)

MS(ESI ⁺ ): 521.9 for [MH] ^- .

Example 98: Synthesis of N-(3-(5-(4-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (0.120 g, 0.262 mmol), N, N- dimethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.0712 g, 0.288 mmol) and potassium carbonate (0.0734 g, 0.524 mmol) were suspended in 1,4-dioxane (0.900 ml) and water (0.450 ml) and degassed with argon for 5 min. XPhos Pd G3 (0.0111 g, 0.0131 mmol) was added and the mixture was heated to 110°C in the microwave for 45 min at 50 W. The crude material was filtered through a pad of Celite, washed with EtOAc, and the filtrate was washed with us. aq. NH ₄ Cl solution. The organic phase was dried over sodium sulfate, the solvent was removed under reduced pressure, and the product was purified by flash chromatography using DCM/MeOH (100/0 v/v - 95/5 v/v) as eluent.

Analytical data:

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 9.76 (s, 1H), 8.64 (d, J=2.2 Hz, 1H), 8, 52 (s, 1H), 8.17 (s, 1H), 7.62-7.53 (m, 3H), 7.28 (t, J=8.4 Hz, 1H), 6.86 (d , J=8.8 Hz, 2H), 3.12 (dd, J=8.6, 6.7 Hz, 2H), 2.96 (s, 6H), 1.74 (d.kv, J= 15.0, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).

Calculated exact mass for C ₂₅ H ₂₄ F ₂ N ₄ O ₃ S: 498.2 (molecular weight: 498.55); MS(ESI-): 497.0 for [MH] ^- .

By analogy with Examples 96-98, compounds of Examples 99-123 were obtained, presented in Table 4.

99 N-(2,4-difluoro-3-(5-(naphthalene-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C27H21F2N3O3S/505.54 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 9.78 (s, 1H), 8.87 (d, J=2.2 Hz, 1H), 8, 79 (s, 1H), 8.33 (s, 1H), 8.26 (d, J=1.5 Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7, 98 (d, J=7.9 Hz, 1H), 7.94 (dd, J=8.5, 1.5 Hz, 1H), 7.63-7.53 (m, 3H), 7.30 (t, J=8.5 Hz, 1H), 3.16-3.11 (m, 2H), 1.79-1.70 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
ESI-MS [MH] ^- : m/z calculated for C27H21F2N3O3S 504.1 found: 504.0. 100 N-(3-(5-(1H-pyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C21H18F2N4O3S/444.46 ¹ H-NMR (400 MHz, DMSO _- d6 ) δ 12.78 (s, 1H), 11.04 (s, 1H), 9.93 (s, 1H), 8.65 (d, J=1 .7 Hz, 1H), 8.44 (s, 1H), 8.08 (s, 1H), 7.57 (dd, J=14.8, 8.9 Hz, 1H), 7.32 (s , 1H), 7.27 (t, J=8.7 Hz, 1H), 6.86 (s, 1H), 6.50 (s, 1H), 3.18-3.02 (m, 2H) , 1.73 (d.kv, J=14.9, 7.3 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H). 101 N-(2,4-difluoro-3-(5-(3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C23H19F2N3O4S/471.48 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.98 (s, 1H), 9.76 (s, 1H), 9.61 (s, 1H), 8.65 (d, J=2 ,2 Hz, 1H), 8.59 (s, 1H), 8.22 (s, 1H), 7.59 (td, J=9.0, 5.9 Hz, 1H), 7.33-7 .26 (m, 2H), 7.16 (d, J=7.7 Hz, 1H), 7.11-7.09 (m, 1H), 6.82 (dd, J=8.1, 1 .7 Hz, 1H), 3.14-3.11 (m, 2H), 1.78-1.70 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 471.1
MS(ESI ^- ): 470.3 for [MH] ^- . 102 N-(2,4-difluoro-3-(5-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H21F2N3O4S/485.51 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.94 (s, 1H), 9.76 (s, 1H), 8.48 (d, J=1.8 Hz, 2H), 8, 21 (s, 1H), 7.64-7.52 (m, 3H), 7.43-7.37 (m, 2H), 7.28 (t, J=8.5 Hz, 1H), 7 .17 (d, J=8.1 Hz, 1H), 7.09 (td, J=7.4, 0.8 Hz, 1H), 3.80 (s, 3H), 3.14-3, 08 (m, 2H), 1.77-1.70 (m, 2H), 0.95 (t, J=7.4 Hz, 3H).
Calculated exact mass: 485.1
MS(ESI ^- ): 484.3 for [MH] ^- . 103 N-(2,4-difluoro-3-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-propane-1-sulfonamide
C24H21F2N3O4S/485.51 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 13.00 (s, 1H), 9.77 (s, 1H), 8.71 (d, J=2.2 Hz, 1H), 8, 61 (s, 1H), 8.24 (s, 1H), 7.59 (td, J=9.0, 5.9 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H ), 7.31-7.25 (m, 3H), 6.99 (ddd, J=8.2, 2.4, 0.6 Hz, 1H), 3.86 (s, 3H), 3, 15-3.10 (m, 2H), 1.77-1.70 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 485.1
MS(ESI ^- ): 484.3 for [MH] ^- . 104 N-(3-(5-(2,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide
C25H23F2N3O5S/515.53 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.90 (s, 1H), 9.76 (s, 1H), 8.43 (d, J=2.0 Hz, 2H), 8, 18 (d, J=1.2 Hz, 1H), 7.58 (td, J=9.0, 5.9 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.28 (t, J=8.7 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.67 (dd, J=8.4, 2.4 Hz, 1H ), 3.83 (s, 3H), 3.79 (s, 3H), 3.13-3.08 (m, 2H), 1.77-1.69 (m, 2H), 0.95 ( t, J=7.4 Hz, 3H).
Calculated exact mass: 515.1
MS(ESI ^- ): 514.3 for [MH] ^- . 105 N-(3-(5-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide
C25H23F2N3O5S/515.53 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.96 (s, 1H), 9.76 (s, 1H), 8.70 (d, J=2.2 Hz, 1H), 8, 55 (s, 1H), 8.21 (s, 1H), 7.59 (td, J=9.0, 6.0 Hz, 1H), 7.31-7.24 (m, 3H), 7 .09 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.14-3.10 (m, 2H), 1.80- 1.63 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 515.1
MS(ESI ^- ): 514.3 for [MH] ^- . 106 N-(2,4-difluoro-3-(5-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H18F5N3O3S/523.48 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 13.07 (s, 1H), 9.77 (s, 1H), 8.79 (d, J=2.2 Hz, 1H), 8, 72 (s, 1H), 8.28 (s, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.2 Hz, 2H), 7, 60 (td, J=9.0, 5.9 Hz, 1H), 7.29 (t, J=8.3 Hz, 1H), 3.15-3.10 (m, 2H), 1.78 -1.71 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 523.1
MS(ESI ^- ): 522.2 for [MH] ^- . 107 N-(2,4-difluoro-3-(5-(4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-propane-1-sulfonamide
C23H18F2N4O5S/500.48 ¹ H-NMR (600 MHz, DMSO -d ₆ ) δ 13.11 (s, 1H), 9.77 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8, 77 (s, 1H), 8.35 (d, J=8.8 Hz, 2H), 8.30 (s, 1H), 8.08 (d, J=8.8 Hz, 2H), 7, 57-7.53 (m, 1H), 7.29 (t, J=8.3 Hz, 1H), 3.15-3.12 (m, 2H), 1.78-1.71 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).
Calculated exact mass: 500.1
MS(ESI ^- ): 499.1 for [MH] ^- . 108 4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzoic acid
C24H19F2N3O5S/499.49 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 13.06 (s, 2H), 9.77 (s, 1H), 8.79 (d, J=2.2 Hz, 1H), 8, 71 (s, 1H), 8.27 (s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.3 Hz, 2H), 7, 60 (td, J=9.0, 5.9 Hz, 1H), 7.29 (t, J=8.3 Hz, 1H), 3.15-3.11 (m, 2H), 1.78 -1.69 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 499.1
MS(ESI ^- ): 498.1 for [MH] ^- . 109 4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide
C24H20F2N4O4S/498.50 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 13.04 (d, J=2.4 Hz, 1H), 9.77 (s, 1H), 8.78 (d, J=2.2 Hz, 1H), 8.69 (s, 1H), 8.26 (d, J=2.7 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.3 Hz, 2H), 7.59 (td, J=9.0, 6.0 Hz, 1H), 7.41 (s, 1H), 7.29 (t, J=8.4 Hz, 1H), 3.14-3.11 (m, 2H), 1.78-1.71 (m, 2H), 0.96 (t, J= 7.4 Hz, 3H).
Calculated exact mass: 498.1
MS(ESI ^- ): 496.9 for [MH] ^- . 110 N-(3-(5-(2-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C24H18F2N4O3S/480.49 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.96 (d, J=2.0 Hz, 1H), 9.76 (s, 1H), 8.51 (s, 1H), 8, 40 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 7.74 (s, 1H), 7.60-7.52 (m, 3H ), 7.50-7.45 (m, 2H), 7.35 (s, 1H), 7.27 (t, J=8.7 Hz, 1H), 3.16-3.08 (m, 2H), 1.79-1.69 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).
Calculated exact mass: 498.1
MS(ESI ^- ): 496.6 for [MH] ^- . 111 N-(2,4-difluoro-3-(5-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H18F5N3O4S/539.48 ¹ H-NMR (600 MHz, DMSO -d ₆ ) δ 13.03 (s, 1H), 9.76 (s, 1H), 8.73 (d, J=2.2 Hz, 1H), 8, 66 (s, 1H), 8.26 (s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.59 (td, J=9.0, 5.9 Hz, 1H ), 7.51 (d, J=8.1 Hz, 2H), 7.29 (t, J=8.4 Hz, 1H), 3.15-3.10 (m, 2H), 1.78 -1.71 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 539.1
MS(ESI ^- ): 537.8 for [MH] ^- . 112 N-(2,4-difluoro-3-(5-( para- tolyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H21F2N3O3S/469.51 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.97 (s, 1H), 9.76 (s, 1H), 8.68 (d, J=2.2 Hz, 1H), 8, 59 (s, 1H), 8.22 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.59 (td, J=9.0, 5.9 Hz, 1H ), 7.33 (d, J=7.9 Hz, 2H), 7.28 (t, J=8.5 Hz, 1H), 3.14-3.10 (m, 2H), 2.37 (s, 3H), 1.78-1.70 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 469.1
MS(ESI ^- ): 468.0 for [MH] ^- . 113 N-(3-(5-(4-( tert- butyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C27H27F2N3O3S/511.59 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.98 (s, 1H), 9.77 (s, 1H), 8.69 (d, J=2.2 Hz, 1H), 8, 60 (s, 1H), 8.22 (s, 1H), 7.67 (d, J=8.3 Hz, 2H), 7.59 (td, J=9.0, 6.0 Hz, 1H ), 7.54 (d, J=8.4 Hz, 2H), 7.29 (t, J=8.5 Hz, 1H), 3.14-3.10 (m, 2H), 1.79 -1.69 (m, 2H), 1.33 (s, 9H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 511.2
MS(ESI ^- ): 509.9 for [MH] ^- . 114 N-(2,4-difluoro-3-(5-( metatolyl )-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H21F2N3O3S/469.51 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.98 (d, J=1.8 Hz, 1H), 9.77 (s, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.61 (s, 1H), 8.23 (d, J=2.5 Hz, 1H), 7.64-7.51 (m, 3H), 7.41 (t, J =7.6 Hz, 1H), 7.29 (t, J=8.6 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 3.14-3.10 (m , 2H), 2.42 (s, 3H), 1.78-1.71 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 469.1
MS(ESI ^- ): 468.0 for [MH] ^- . 115 N-(2,4-difluoro-3-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-propane-1-sulfonamide
C23H18F3N3O3S/473.47 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 13.03 (s, 1H), 9.77 (s, 1H), 8.74 (d, J=2.2 Hz, 1H), 8, 66 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.65-7.54 (m, 4H), 7.29 (t, J=8.7 Hz, 1H ), 7.25 (td, J=8.7, 2.2 Hz, 1H), 3.14-3.11 (m, 2H), 1.79-1.66 (m, 2H), 0, 96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 473.1
MS(ESI ^- ): 472.0 for [MH] ^- . 116 N-(4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acetamide
C25H22F2N4O4S/512.53 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 12.96 (s, 1H), 10.07 (s, 1H), 9.76 (s, 1H), 8.69 (d, J=2 .0 Hz, 1H), 8.59 (s, 1H), 8.21 (s, 1H), 7.74 (d, J=8.5 Hz, 2H), 7.69 (d, J=8 .5 Hz, 2H), 7.62-7.55 (m, 1H), 7.28 (t, J=8.6 Hz, 1H), 3.15-3.10 (m, 2H), 2 .08 (s, 3H), 1.74 (d.kv, J=14.9, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 512.1
MS(ESI ^- ): 511.0 for [MH] ^- . 117 N-(2,4-difluoro-3-(5-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H18F5N3O3S/523.48 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 13.06 (s, 1H), 9.77 (s, 1H), 8.79 (d, J=2.2 Hz, 1H), 8, 70 (s, 1H), 8.27 (s, 1H), 8.08 (d, J=7.2 Hz, 2H), 7.77 (dt, J=15.3, 7.7 Hz, 2H ), 7.59 (td, J=9.0, 6.0 Hz, 1H), 7.29 (t, J=8.6 Hz, 1H), 3.16-3.05 (m, 2H) , 1.79-1.69 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 523.1
MS(ESI ^- ): 522.0 for [MH] ^- . 118 N-(3-(5-(2-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C24H18F2N4O3S/480.49 ¹ H-NMR (600 MHz, DMSO _- d6 ) δ 13.14 (s, 1H), 9.77 (s, 1H), 8.64 (s, 1H), 8.61 (d, J=2 ,2 Hz, 1H), 8.32 (s, 1H), 8.02 (dd, J=7.8, 0.8 Hz, 1H), 7.85 (td, J=7.7, 1, 2 Hz, 1H), 7.77 (d, J=7.4 Hz, 1H), 7.65 (td, J=7.7, 1.0 Hz, 1H), 7.59 (td, J= 9.0, 5.9 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 3.15-3.10 (m, 2H), 1.78-1.70 (m , 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 480.1
MS(ESI ^- ): 479.0 for [MH] ^- . 119 N-(3-(5-(4-((dimethyl(oxo)-l6-sulfaneylidene)amino)-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl )propane-1-sulfonamide
C25H24F2N4O4S2/546.61 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.94 (s, 1H), 9.77 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H), 7.57 (d, J=8.1 Hz, 3H), 7.28 (t, J=8.5 Hz, 1H), 7.07 (d, J=8 .2 Hz, 2H), 3.26 (s, 6H), 3.17-3.07 (m, 2H), 1.73 (d, J=7.3 Hz, 2H), 0.96 (t , J=7.3 Hz, 3H).
Calculated exact mass: 546.12; MS(ESI ⁺ ): 547.1 120 N-(3-(5-(3-chloropyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C21H16ClF2N5O3S/491.90 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.14 (s, 1H), 9.79 (s, 1H), 9.27 (s, 1H), 9.17 (s, 2H), 8.92 (s, 1H), 8.31 (s, 1H), 7.59 (dd, J=14.9, 8.8 Hz, 1H), 7.29 (t, J=8.7 Hz , 1H), 3.19-3.07 (m, 2H), 1.74 (d.kv, J=14.9, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H). 121 N-(3-(5-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C23H20F2N4O3S/470.49 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 9.75 (s, 1H), 8.59 (d, J=2.1 Hz, 1H), 8, 47 (s, 1H), 8.15 (s, 1H), 7.58 (td, J=8.9, 6.1 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H ), 7.28 (t, J=8.6 Hz, 1H), 6.70 (d, J=8.4 Hz, 2H), 5.28 (s, 2H), 3.15-3.09 (m, 2H), 1.74 (d.kv, J=15.0, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 470.1
MS(ESI ^- ): 469.0 for [MH] ^- . 122 N-(3-(5-(2-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide
C23H20F2N4O3S/470.49 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 9.75 (s, 1H), 8.47 (s, 1H), 8.40 (d, J=1 .9 Hz, 1H), 8.19 (s, 1H), 7.58 (dd, J=14.8, 8.9 Hz, 1H), 7.27 (t, J=8.6 Hz, 1H ), 7.12-7.08 (m, 1H), 7.05 (dd, J=7.4, 1.1 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H) , 6.68 (t, J=7.3 Hz, 1H), 4.87 (s, 2H), 3.15-3.09 (m, 2H), 1.78-1.71 (m, 2H ), 0.97 (t, J=7.4 Hz, 3H).
Calculated exact mass: 470.1
MS(ESI ^- ): 469.0 for [MH] ^- .

Example 123: Synthesis of N-(3-(5-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Example 123 was prepared according to the following synthesis method:

Analytical data:

Chemical purity (HPLC/UV): 99.7%

MS(ESI ⁺ ): 434.20 (calculated exact mass for C ₂₁ H ₂₁ F ₂ N ₃ O ₃ S: 433.13)

Synthesis of 5-substituted N-(2-fluorophenyl)alkyl-1-sulfonamide derivatives

5-Substituted N-(2-fluoro-(1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)alkyl-1-sulfonamide derivatives according to the formula

was prepared in accordance with Example 124, which is described below.

Example 124: Synthesis of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-fluorophenyl)-1-phenylmethanesulfonamide

To a solution of N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-fluorophenyl]-1-phenylmethanesulfonamide (0.1000 g, 0.205 mmol, prepared by analogy with Example 3) In 1,4-dioxane (0.700 ml) and water (0.350 ml), (4-chlorophenyl)boronic acid (0.0480 g, 0.307 mmol) and potassium carbonate (0.0574 g, 0.410 mmol) were added and degassed the mixture with argon for 5 min. Tetrakis-Pd (0.0237 g, 0.0205 mmol) was added and the reaction vial was irradiated in the microwave for 45 min at 110°C (50 W). After cooling to RT, the mixture was passed through a pad of Celite, which was washed with EtOAc (50 ml). The organic phase was washed with a saturated aqueous solution of NH ₄ Cl and water and dried after washing over sodium sulfate. The product was purified by flash chromatography using DCM/MeOH (0-3%) as eluent. N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2-fluorophenyl]-1-phenylmethanesulfonamide (0.0548 g, 0.0843 mmol, 41% yield) was obtained as an off-white solid.

Analytical data:

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 8.70 (d, J=2.2 Hz, 1H), 8.68 (d, J=2.2 Hz, 1H), 8.03 ( s, 1H), 7.85 (dd, J=20.1, 8.4 Hz, 1H), 7.78 (dd, J=8.7, 2.4 Hz, 2H), 7.57 (d , J=8.5 Hz, 2H), 7.51 (td, J=7.9, 1.4 Hz, 1H), 7.39-7.31 (m, 5H), 7.24 (t, J=7.8 Hz, 1H), 4.51 (s, 2H).

Calculated exact mass for C ₂₇ H ₁₉ ClFN ₃ O ₃ S: (molecular weight: 519.98)

MS(ESI-): 518.2 for [MH] ^- .

Table 5: Examples 125-133 were prepared by analogy with Example 124.

Example Chemical structure IUPAC Name/Molecular Weight Analytical data 125 N-(3-(5-(2-chloro-4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluorophenyl)-1-phenylmethanesulfonamide
C ₂₈ H ₂₁ ClFN ₃ O ₄ S/550.00 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 8.47 (d, J=2.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 7.96 ( s, 1H), 7.52 (td, J=8.2, 1.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.34-7.26 (m , 6H), 7.20 (d, J=2.6 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.06 (dd, J=8.5, 2, 6 Hz, 1H), 6.97 (t, J=6.0 Hz, 1H), 4.26 (s, 2H), 3.84 (s, 3H).
Calculated exact mass: 549.1
MS(ESI ^- ): 548.3 for [MH] ^- . 126 N-(2-fluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-1-phenylmethanesulfonamide
C28H21F2N3O3S/517.55 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 9.84 (s, 1H), 8.38 (d, J=1.5 Hz, 1H), 8, 35 (d, J=1.5 Hz, 1H), 8.04 (s, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.41-7.33 (m, 7H ), 7.26 (t, J=7.9 Hz, 1H), 7.23 (dd, J=10.1, 2.2 Hz, 1H), 7.14 (td, J=8.4, 2.3 Hz, 1H), 4.55 (s, 2H), 2.27 (s, 3H).
Calculated exact mass: 517.1
MS(ESI ^- ): 516.3 for [MH] ^- . 127 N-(3-(5-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)- 2-fluorophenyl)-1-phenylmethanesulfonamide
C29H21ClFN3O5S/578.01 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 9.83 (s, 1H), 8.48 (d, J=2.2 Hz, 1H), 8, 38 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 7.50 (td, J=7.9, 1.5 Hz, 1H), 7.40-7.33 (m, 6H), 7.26 (t, J=7.8 Hz, 1H), 7.14 (s, 1H), 7.04 (s, 1H), 4.55 (s, 2H), 4 .32 (s, 4H).
Calculated exact mass: 577.1
MS(ESI ^- ): 576.2 for [MH] ^- . 128 N-(3-(5-(6-chlorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-fluorophenyl)-1 -phenylmethanesulfonamide
C28H19ClFN3O5S/563.98 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 9.84 (s, 1H), 8.47 (d, J=2.1 Hz, 1H), 8, 37 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 7.62 (ddd, J=7.0, 5.6, 4.0 Hz, 1H), 7.50 (td, J=7.9, 1.5 Hz, 1H), 7.40-7.33 (m, 5H), 7.28-7.24 (m, 2H), 7.13 (s, 1H ), 6.15 (s, 2H), 4.55 (s, 2H).
Calculated exact mass: 563.1
MS(ESI ^- ): 562.2 for [MH] ^- . 129 N-(2-fluoro-3-(5-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-1-phenylmethanesulfonamide
C26H19FN4O3S/486.52 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.99 (s, 1H), 9.86 (s, 1H), 8.83 (d, J=2.3 Hz, 1H), 8, 82 (d, J=2.3 Hz, 1H), 8.68 (dd, J=4.5, 1.6 Hz, 2H), 8.08 (s, 1H), 7.82 (dd, J =4.5, 1.6 Hz, 2H), 7.51 (td, J=7.9, 1.5 Hz, 1H), 7.42-7.34 (m, 6H), 7.28 ( t, J=7.8 Hz, 1H), 4.56 (s, 2H).
Calculated exact mass: 486.1.
MS(ESI ^- ): 485.2 for [MH] ^- . 130 N-(2-fluoro-3-(5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-1-phenylmethanesulfonamide
C26H20FN5O4S/517.54 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.94 (d, J=1.9 Hz, 1H), 9.84 (s, 1H), 9.00 (s, 2H), 8, 72 (d, J=2.2 Hz, 1H), 8.71 (d, J=2.2 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H), 7.51 ( td, J=7.9, 1.4 Hz, 1H), 7.41-7.37 (m, 3H), 7.37-7.34 (m, 3H), 7.27 (t, J= 7.8 Hz, 1H), 4.56 (s, 2H), 3.99 (s, 3H).
Calculated exact mass: 517.1
MS(ESI ^- ): 516.2 for [MH] ^- . 131 N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2-fluorophenyl)-1-phenylmethanesulfonamide
C28H22FN5O3S/527.57 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 9.85 (s, 1H), 9.02 (s, 2H), 8.74 (d, J=2 .2 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.07 (d, J=1.1 Hz, 1H), 7.51 (td, J=7.9 , 1.4 Hz, 1H), 7.41-7.37 (m, 3H), 7.37-7.34 (m, 3H), 7.27 (t, J=7.8 Hz, 1H) , 4.56 (s, 2H), 2.28 (tt, J=8.0, 4.8 Hz, 1H), 1.12-1.08 (m, 2H), 1.08-1.05 (m, 2H).
Calculated exact mass: 527.1
MS(ESI ^- ): 526.3 for [MH] ^- . 132 N-(2-fluoro-3-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-1-phenylmethanesulfonamide
C26H19FN4O3S/486.52 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.95 (s, 1H), 9.85 (s, 1H), 8.97 (d, J=1.9 Hz, 1H), 8, 75 (d, J=2.2 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.63 (dd, J=4.7, 1.3 Hz, 1H), 8.20-8.16 (m, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.55 (dd, J=7.8, 4.8 Hz, 1H), 7 .51 (td, J=7.9, 1.4 Hz, 1H), 7.41-7.37 (m, 3H), 7.37-7.34 (m, 3H), 7.28 (t , J=7.8 Hz, 1H), 4.56 (s, 2H).
Calculated exact mass. 486.1
MS(ESI ^- ): 485.1 for [MH] ^- . 133 N-(5-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluorophenyl)-1-phenylmethanesulfonamide
C27H19ClFN3O3S/519.98 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 9.92 (s, 1H), 8.72 (d, J=2.2 Hz, 1H), 8, 68 (d, J=2.2 Hz, 1H), 8.17 (s, 1H), 7.90 (dd, J=7.7, 2.0 Hz, 1H), 7.77 (d, J =8.5 Hz, 2H), 7.73 (dd, J=8.2, 4.5, 2.1 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7 .47 (dd, J=10.0, 8.6 Hz, 1H), 3.18-3.14 (m, 2H), 1.80-1.73 (m, 2H), 0.98 (t , J=7.4 Hz, 3H).
Calculated exact mass: 519.08
MS(ESI ^- ): [MH] ^- .

Example 134: Synthesis of N-(2,4-difluoro-3-(5-(3-hydroxyazetidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1- sulfonamide

Example 134-1: Synthesis of 3-(benzyloxy)azetidine

Example 134-2: N-(2,4-difluoro-3-(5-(3-hydroxyazetidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1 -sulfonamide

Analytical data:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.57 (s, 1H), 9.70 (s, 1H), 7.93 (s, 1H), 7.70 (d, J=2 .6 Hz, 1H), 7.52 (td, J=9.0, 6.0 Hz, 1H), 7.38 (s, 1H), 7.22 (t, J=8.7 Hz, 1H ), 4.59 (dt, J=11.3, 5.6 Hz, 1H), 4.14 (t, J=6.9 Hz, 2H), 3.55-3.52 (m, 3H) , 3.13-3.03 (m, 2H), 1.70 (d.kv, J=15.0, 7.5 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H ).

Calculated exact mass: 450.12. MS(ESI ⁺ ): 551.0 for [M+H] ⁺ .

Examples 135 and 136: Synthesis of N-(2,4-difluoro-3-(5-(4-oxopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propan- 1-sulfonamide and N-(2,4-difluoro-3-(5-(4-hydroxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propan-1- sulfonamide

Analytical data:

Example 135:

¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.23 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.70 (dd, J=16.1 , 10.5 Hz, 2H), 7.07 (t, J=8.6 Hz, 1H), 6.60 (s, 1H), 3.67 (t, J=5.9 Hz, 4H), 3.17-3.09 (m, 2H), 2.68 (t, J=5.9 Hz, 4H), 1.92 (dd, J=15.3, 7.7 Hz, 2H), 1 .08 (t, J=7.4 Hz, 3H).

Calculated exact mass: 476.13 for C ₂₂ H ₂₂ F ₂ N ₄ O ₄ S. MS(ESI ⁺ ): 477.1 for [M+H] ⁺ .

Example 136:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.64 (s, 1H), 9.74 (s, 1H), 8.24 (d, J=2.7 Hz, 1H), 8, 00 (s, 1H), 7.90 (s, 1H), 7.56 (dd, J=14.9, 8.9 Hz, 1H), 7.26 (t, J=8.4 Hz, 1H ), 4.71 (d, J=4.2 Hz, 1H), 3.68-3.60 (m, 1H), 3.52-3.45 (m, 2H), 3.14-3, 07 (m, 2H), 2.88 (t, J=10.0 Hz, 2H), 1.87 (s, 2H), 1.74 (dd, J=15.3, 7.6 Hz, 2H ), 1.61-1.51 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Calculated exact mass: 478.15 for C ₂₂ H ₂₄ F ₂ N ₄ O ₄ S. MS(ESI ⁺ ) 479.1 for [M+H] ⁺ .

Example 137: Synthesis of 1-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidine-3-carboxylic acid

Example 137 was prepared by analogy with Example 134.

Analytical data:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 9.73 (s, 1H), 7.98 (s, 1H), 7.76 (d, J=2 .6 Hz, 1H), 7.55 (td, J=9.0, 6.0 Hz, 1H), 7.42 (s, 1H), 7.25 (t, J=8.6 Hz, 1H ), 4.11 (t, 3=7.8 Hz, 2H), 3.95 (t, J=6.5 Hz, 2H), 3.17-3.05 (m, 2H), 1.74 (d.kv, J=15.0, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).

Calculated exact mass for C ₂₁ H ₂₀ F ₂ N ₄ O ₅ S: 478.11 (molecular weight: 478.47).

MS(ESI+): 479.1 for [M+H] ⁺ .

Example 138: Synthesis of N-(3-(5-(2,6-dimethyl-morpholino)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

Example 138 was prepared by analogy with Example 134.

Analytical data:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.67 (s, 1H), 9.75 (s, 1H), 8.28 (d, J=2.6 Hz, 1H), 8, 01 (s, 1H), 7.88 (s, 1H), 7.554.9, 8.9 Hz, 1H), 7.25 (t, J=8.7 Hz, 1H), 4.11 (s, 1H), 3.84-3.72 (m, 2H), 3.57 (d, J=11.3 Hz (dd, J =1, 2H), 3.15-3.06 (m, 2H) , 2.33 (t, J=11.0 Hz, 2H), 1.74 (dd, J=15.1, 7.5 Hz, 2H), 1.26 (d, J=6.4 Hz, 1H), 1.18 (d, J=6.2 Hz, 4H), 0.96 (t, J=7.4 Hz, 3H).

Calculated exact mass for C ₂₃ H ₂₆ F ₂ N ₄ O ₄ S: 492.16; molecular weight: 492.54.

MS(ESI ⁺ ): 493.1 for [M+H] ⁺ .

Example 139: Synthesis of N-(2,4-difluoro-3-(5-(oxetan-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide

Example 139 was prepared by analogy with Example 134.

Analytical data:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.54 (s, 1H), 9.73 (s, 1H), 7.91 (s, 1H), 7.33 (d, J=2 .4 Hz, 1H), 7.55 (dd, J=14.9, 9.0 Hz, 1H), 7.40 (s, 1H), 7.25 (t, J=8.7 Hz, 1H ), 4.33 (t, J=6.3 Hz, 2H), 4.57 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.9 Hz, 2H), 3.12 (dd, J=17.4, 9.9 Hz, 2H), 1.74 (d.kv, J=15.0, 7.5 Hz, 2H), 0.96 (t, J= 7.4 Hz, 3H)

Calculated exact mass for C ₂₀ H ₂₀ F ₂ N ₄ O ₄ S: 450.12 (molecular weight: 450.46)

MS(ESI ⁺ ): 451.1 for [M+H] ⁺ .

Example 140: Synthesis of N-(2,4-difluoro-3-(5-(oxetan-3-ylamino)-1H-pyrrolo[2,3 b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide

Example 140 was prepared by analogy with Example 134.

Analytical data:

^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.82-12.67 (m, 1H), 9.75 (s, 1H), 8.31 (s, 1H), 3.06 (s , 1H), 7.56 (dd, J=14.9, 9.0 Hz, 1H), 7.26 (t, J=8.7 Hz, 1H), 3.22 (s, 4H), 3 .16-3.06 (m, 2H), 1.83-1.64 (m, 6H), 1.63-1.51 (m, 2H), 0.96 (t, J=7.4 Hz , 3H).

Calculated exact mass for C ₂₂ H ₂₄ F ₂ N ₄ O ₃ S: 462.15 (molecular weight: 462.52)

MS(ESI ⁺ ): 463.1 for [M+H] ⁺ .

Synthesis of 5-substituted N-(2,x - difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)alkyl-1-sulfonamide derivatives

5-Substituted N-(2,x-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)alkyl-1-sulfonamide derivatives according to the formula

prepared according to the following examples.

Example 141: Synthesis of N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)methanesulfonamide

N-[3-[1-(2,6-dichlorobenzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine -3-carbonyl]-2,6-difluorophenyl]-N-methylsulfonylmethanesulfonamide (150 mg, 0.206 mmol), 5-bromo-2-cyclopropylpyrimidine (0.0451 g, 0.227 mmol) and potassium carbonate (0.0578 g, 0.412 mmol) was dissolved in 1,4-dioxane (1.40 ml) and water (0.700 ml), and the mixture was degassed with argon. Pd(dppf)Cl was added₂ (0.00753 g, 0.0103 mmol) and heated the mixture to 60°C for 2 hours. The crude mixture was passed through a bed of Celite, washed with MeOH and EtOAc, and the solvent was removed under vacuum. The residue was dissolved in MeOH, potassium carbonate (500 mg) was added, and the suspension was stirred for 3 hours at room temperature. Water was added and adjusted to pH 6-8 by adding 1N aq. HCl, and the aqueous phase was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was prepurified by flash chromatography using DCM/EtOAc/MeOH (92/8/0-88/8/4) as eluent. Thereafter, the product was suspended in EtOAc and after addition of n-pentane, the product was filtered and dried under vacuum (yield: 59 mg (60%), chemical purity (HPLC/UV): 98%)

Analytical data:

^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.97 (s, 1H), 9.72 (s, 1H), 9.01 (s, 2H), 8.72 (s, 2H), 8.12 (d, J=2.6 Hz, 1H), 7.66 (kv, J=7.6 Hz, 1H), 7.36 (t, J=8.9 Hz, 1H), 3, 12 (s, 3H), 2.27 (td, J=8.0, 4.0 Hz, 1H), 1.13-1.01 (m, 4H).

Calculated exact mass for C ₂₂ H ₁₇ F ₂ N ₅ O ₃ S: 489.1 (molecular weight: 489.47)

MS (ESI-): 468.3 for [MH] ^- .

Example 144: Synthesis of N-(2,6-difluoro-3-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)- 3,3,3-trifluoropropane-1-sulfonamide

N-[3-[1-(2,6-dichlorobenzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine -3-carbonyl]-2,6-difluorophenyl]-3,3,3-trifluoro-N-(3,3,3-trifluoropropylsulfonyl)-propane-1-sulfonamide (200 mg, 0.224 mmol, prepared by analogy with Example 4, steps 4-1 and 4-2), 5-bromo-2-(trifluoromethyl)-pyrimidine (56.0 mg, 0.247 mmol) and potassium carbonate (62.8 mg, 0.448 mmol) were dissolved in 1,4- dioxane (1.50 ml) and water (0.750 ml), and the mixture was degassed with argon. Pd(dppf)Cl was added₂ (8.20 mg, 0.0112 mmol), and heated the mixture to 60°C for 2 hours. The crude mixture was passed through a pad of Celite, washed with MeOH and EtOAc, and the solvent was removed under vacuum. The residue was redissolved in MeOH, potassium carbonate (500 mg) was added, and the suspension was stirred for 3 hours at room temperature. Water was added and adjusted to pH 6-8 by adding 1N aq. HCl, the aqueous phase was extracted with EtOAc, the layers were separated, the organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was prepurified by flash chromatography using DCM/EtOAc/MeOH (92/8/0-88/8/4) as eluent. The prepurified product was suspended in EtOAc, precipitated with n-pentane, filtered and dried under vacuum (yield: 52 mg (40%), chemical purity (HPLC/UV: 99%).

Analytical data:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.09 (s, 1H), 10.05 (s, 1H), 9.50 (s, 2H), 8.89 (dd, J=9 ,9, 2.2 Hz, 2H), 8.21 (s, 1H), 7.76-7.64 (m, 1H), 7.40 (t, J=8.9 Hz, 1H), 3 .53-3.43 (m, 2H), 2.91-2.76 (m, 2H).

Example 143: Synthesis of N-(3-(5-(3-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide

N-[3-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-carbonyl]-2,6-difluorophenyl]propane-1-sulfonamide (0.150 g, 0.238 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.0599 g, 0.281 mmol) and potassium carbonate (0.0868 g, 0.475 mmol) suspended in 1,4-dioxane (1.20 ml) and water (0.600 ml), and degassed with argon for 5 minutes. Pd(dppf)Cl ₂ ) (0.0137 g, 0.0119 mmol) was added and the mixture was heated to 70°C for 2 hours. The crude material was filtered through a pad of Celite, washed with EtOAc, and the solvent was evaporated. The residue was suspended in MeOH (5 ml) and potassium carbonate (200 mg) was added. The mixture was stirred at room temperature. until complete (according to TLC) hydrolysis of the 2,6-dichlorobenzoyl protecting group. After dilution with water, 1N HCl (pH 6-7) was added and the product was extracted with EtOAc (3 x 50 ml). The organic phase was dried over sodium sulfate, the solvent was removed under reduced pressure, and the product was purified by flash chromatography using DCM/MeOH (100/0 v/v - 95/5 v/v) as eluent (yield : 52.8 g (45%); chemical purity (HPLC/UV): 97%).

Analytical data:

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.95 (s, 1H), 9.65 (s, 1H), 8.76 (d, J=1.9 Hz, 1H), 8, 74 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.10 (s, 2H), 7.87 (d, J=7.6 Hz, 1H), 7, 72 (t, J=7.8 Hz, 1H), 7.66 (dd, J=14.2, 7.6 Hz, 1H), 7.36 (t, J=8.8 Hz, 1H), 3.19-3.13 (m, 2H), 1.81 (d.kv, J=15.0, 7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) .

Calculated exact mass for C ₂₄ H ₁₈ F ₂ N ₄ O ₃ S: 480.1 (molecular weight: 480.49);

MS(ESI-): 479.0 for [MH] ^- .

By analogy with Examples 141-143, compounds of Examples 144-238 were obtained, presented in Table 5.

Table 5: Examples 144-238, obtained by analogy with Examples 141-143.

Example Reagent Product Analytical data 144 N-(2,6-difluoro-3-(5-(pyridazin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C21H17F2N5O3S/457.46 ¹ H-NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 9.77 (d, J=1.3 Hz, 1H), 9.67 (s, 1H), 9.33 (d , J=5.5 Hz, 1H), 8.93 (dd, J=8.2, 2.2 Hz, 2H), 8.22-8.14 (m, 2H), 7.67 (dd, J=14.5, 7.7 Hz, 1H), 7.36 (t, J=8.8 Hz, 1H), 3.21-3.10 (m, 2H), 1.81 (d.kv , J=14.9, 7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 457.10
MS(ESI ⁺ ): 458.1 for [M+H] ⁺ . 145 N-(2,6-difluoro-3-(5-(pyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C21H17F2N5O3S/457.46 ¹ H-NMR (400 MHz, DMSO) δ 9.25 (dd, J=6.6, 3.5 Hz, 2H), 9.14 (d, J=2.0 Hz, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.13 (s, 1H), 7.83 (dd, J=8.6, 4.9 Hz, 1H), 7.67-7.57 ( m, 1H), 7.33 (t, J=8.8 Hz, 1H), 3.15-3.09 (m, 2H), 1.79 (dt, J=15.1, 7.6 Hz , 2H), 0.99 (t, J=7.4 Hz, 3H).
Calculated 457.10 for C21H17F2N5O3S. Measured 457.9 for [M+H] ⁺ . 146 N-(3-(5-(2-cyclopropyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C ₂₄ H ₂₁ F ₂ N ₅ O ₃ S/497.52 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.98 (s, 1H), 9.65 (s, 1H), 9.02 (s, 1H), 8.72 (d, J=7 .4 Hz, 1H), 8.11 (s, 1H), 7.72-7.59 (m, 1H), 7.42-7.31 (m, 1H), 3.21-3.11 ( m, 1H), 2.31-2.24 (m, 1H), 1.81 (d, J=7.6 Hz, 2H), 1.16-1.04 (m, 4H), 1.00 (t, J=7.4 Hz, 3H). 147 N-(2,6-difluoro-3-(5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3,3,3-trifluoropropane -1-sulfonamide
C ₂₂ H ₁₆ F ₅ N ₅ O ₃ S/525.45 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.07 (s, 1H), 10.04 (s, 1H), 9.49 (s, 2H), 8.90 (d, J=2 .3 Hz, 1H), 8.87 (d, J=2.3 Hz, 1H), 8.20 (s, 1H), 7.70 (td, J=8.3, 6.2 Hz, 1H ), 7.39 (t, J=8.8 Hz, 1H), 3.51-3.43 (m, 2H), 2.91-2.76 (m, 2H). 148 N-(2,6-difluoro-3-(5-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3, 3,3-trifluoropropane-1-sulfonamide
C23H14F8N4O3S/578.44 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (d, J=3.0 Hz, 1H), 10.04 (s, 1H), 9.18 (d, J=2.3 Hz, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.48 (dd, J=8.1, 2 .3 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.70 (td, J=8.2, 6.1 Hz, 1H ), 7.39 (td, J=9.0, 1.4 Hz, 1H), 3.52-3.44 (m, 2H), 2.91-2.77 (m, 2H).
MS(ESI ^- ): Measured 577.3 for [MH] ^- . 149 N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)-methanesulfonamide
C21H14ClF2N3O3S/461.87 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 9.72 (s, 1H), 8.69 (sq, J=2.3 Hz, 2H), 8, 10 (d, J=1.5 Hz, 1H), 7.78 (d, J=8.6 Hz, 2H), 7.66 (td, J=8.3, 6.2 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.36 (td, J=8.9, 1.4 Hz, 1H), 3.12 (s, 3H).
Calculated exact mass: 461.0
MS(ESI ^- ): 460.3 for [MH] ^- . 150 N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)-3,3,3-trifluoropropane-1-sulfonamide
C23H15ClF5N3O3S/543.89 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (d, J=3.1 Hz, 1H), 10.03 (s, 1H), 8.69 (sq, J=2.3 Hz, 2H), 8.11 (s, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.69 (td, J=8.3, 6.2 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.38 (td, J=9.0, 1.4 Hz, 1H), 3.51-3.44 (m, 2H), 2 .92-2.76 (m, 2H).
Calculated exact mass: 543.0
MS(ESI ^- ): 542.2 for [MH] ^- . 151 N-(2,6-difluoro-3-(5-(4-(S-methylsulfonimidoyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H22F2N4O4S2/532.58 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 9.65 (s, 1H), 8.77 (d, J=4.4 Hz, 2H), 8, 12 (s, 1H), 8.05 (d, J=8.3 Hz, 2H), 7.99 (d, J=8.2 Hz, 2H), 7.66 (dd, J=14.2 , 7.5 Hz, 1H), 7.36 (t, J=8.8 Hz, 1H), 4.28 (s, 1H), 3.22-3.02 (m, 5H), 1.81 (dd, J=15.1, 7.5 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 532.11
MS(ESI ⁺ ): 533.98 for [M+H] ⁺ 152 N-(3-(5-(2-chloro-4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C23H18ClF2N3O4S/505.92 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 10.07 (s, 1H), 9.64 (s, 1H), 8.46 (d, J=2 .1 Hz, 1H), 8.38 (d, J=1.4 Hz, 1H), 8.06 (d, J=1.3 Hz, 1H), 7.65 (dd, J=14.4 , 7.7 Hz, 1H), 7.34 (t, J=8.2 Hz, 2H), 6.99 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8 ,4, 2.4 Hz, 1H), 3.18-3.13 (m, 2H), 1.81 (d.kv, J=15.0, 7.5 Hz, 2H), 1.00 ( t, J=7.4 Hz, 3H).
Calculated exact mass: 505.1
MS(ESI ^- ): 504.0 for [MH] ^- . 153 N-(3-(5-(2-chloro-4-(2,3-dihydroxypropoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane- 1-sulfonamide
C26H24ClF2N3O6S/580.00 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 9.64 (s, 1H), 8.49 (d, J=1.9 Hz, 1H), 8, 40 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.65 (dd, J=14.3, 7.6 Hz, 1H), 7.45 (d, J =8.5 Hz, 1H), 7.35 (t, J=8.7 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.07 (dd, J=8 .5, 2.4 Hz, 1H), 5.01 (d, J=5.1 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 4.11 (dd, J =10.0, 3.9 Hz, 1H), 3.97 (dd, J=10.0, 6.2 Hz, 1H), 3.83 (d.kv, J=10.8, 5.5 Hz, 1H), 3.47 (t, J=5.6 Hz, 2H), 3.18-3.12 (m, 2H), 1.81 (d.kv, J=14.9, 7, 4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 579.1
MS(ESI ^- ): 578.0 for [MH] ^- . 154 N-(3-(5-(4-(2,3-dihydroxypropoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C26H25F2N3O6S/545.56 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 9.65 (s, 1H), 8.65 (d, J=2.2 Hz, 1H), 8, 62 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 7.65 (dd, J=17.8, 8.2 Hz, 3H), 7.35 (t, J =8.7 Hz, 1H), 7.09 (d, J=8.7 Hz, 2H), 4.98 (d, J=5.2 Hz, 1H), 4.69 (t, J=5 .6 Hz, 1H), 4.07 (dd, J=9.9, 4.2 Hz, 1H), 3.93 (dd, J=9.9, 6.2 Hz, 1H), 3.83 (d.kv, J=10.9, 5.6 Hz, 1H), 3.48 (t, J=5.6 Hz, 2H), 3.18-3.13 (m, 2H), 1, 85-1.77 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 545.1
MS(ESI ^- ): 544.2 for [MH] ^- . 155 N-(2,6-difluoro-3-(5-(4-(pentafluoro-l6-sulfaneyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C23H18F7N3O3S2/581.52 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.99 (s, 1H), 9.66 (s, 1H), 8.83-8.72 (m, 2H), 8.12 (s , 1H), 8.02 (kv, J=9.1 Hz, 4H), 7.72-7.60 (m, J=6.7 Hz, 1H), 7.36 (t, J=8, 9 Hz, 1H), 3.21-3.11 (m, 2H), 1.81 (dd, J=15.2, 7.5 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 581.07
MS(ESI ⁺ ): 582.00 for [M+H] ⁺ . 156 N-(2,6-difluoro-3-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3,3,3-trifluoropropane-1 -sulfonamide
C22H15F5N4O3S/510.44 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 10.02 (s, 1H), 8.96 (s, 1H), 8.74 (d, J=2 .3 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.17 (dt, J=8.0 , 2.0 Hz, 1H), 8.14 (s, 1H), 7.69 (td, J=8.2, 6.1 Hz, 1H), 7.54 (dd, J=7.9, 4.7 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 3.51-3.43 (m, 2H), 2.92-2.74 (m, 2H).
Calculated exact mass: 510.1
MS(ESI ^- ): 509.3 for [MH] ^- . 157 N-(2,6-difluoro-3-(5-(6-fluoro-4-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3,3 ,3-trifluoropropane-1-sulfonamide
C23H16F6N4O3S/542.46 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.97 (d, J=1.3 Hz, 1H), 10.03 (s, 1H), 8.45 (d, J=2.1 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.15 (s, 2H), 7.69 (dd, J=14.4, 7.8 Hz, 1H), 7.38 (t, J=8.7 Hz, 1H), 7.23 (s, 1H), 3.50-3.44 (m, 2H), 2.89-2.77 (m, 2H) , 2.33 (s, 3H).
Calculated exact mass: 542.1
MS(ESI ^- ): 540.9 for [MH] ^- . 158 N-(2,6-difluoro-3-(5-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3,3,3-trifluoropropane -1-sulfonamide
C23H17F5N4O4S/540.47 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.91 (d, J=2.0 Hz, 1H), 10.04 (s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.64 (d, J=2.2 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 8.09 (dd, J=8.6, 2.6 Hz, 1H), 7.69 (dd, J=14.5, 7.8 Hz, 1H), 7.38 (t, J =8.8 Hz, 1H), 6.96 (dd, J=8.6, 0.3 Hz, 1H), 3.92 (s, 3H), 3.49-3.45 (m, 2H) , 2.88-2.79 (m, 2H).
Calculated exact mass: 540.1
MS(ESI ^- ): 539.0 for [MH] ^- . 159 N-(3-(5-(6-cyclopropylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C25H22F2N4O3S/496.53 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.92 (s, 1H), 9.65 (s, 1H), 8.76 (s, 1H), 8.72-8.60 (m , J=14.3 Hz, 2H), 8.08 (s, 1H), 8.04-7.98 (m, 1H), 7.71-7.58 (m, 1H), 7.43 ( d, J=8.0 Hz, 1H), 7.39-7.30 (m, 1H), 3.21-3.10 (m, 2H), 2.23-2.11 (m, 1H) , 1.88-1.74 (m, 2H), 1.10-0.89 (m, 7H).
Calculated exact mass: 496.14
MS(ESI ⁺ ): 497.10 for [M+H] ⁺ 160 N-(2,6-difluoro-3-(5-(6-(methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C23H21F2N5O3S/485.51 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 9.65 (s, 1H), 8.57 (d, J=21.7 Hz, 2H), 8, 36 (s, 1H), 8.02 (s, 1H), 7.81-7.73 (m, 1H), 7.69-7.58 (m, 1H), 7.38-7.30 ( m, 1H), 6.72-6.64 (m, 1H), 6.62-6.56 (m, 1H), 3.15 (s, 3H), 2.83 (d, J=4, 3 Hz, 3H), 1.88-1.75 (m, 2H), 1.00 (t, J=7.0 Hz, 3H).
Calculated exact mass: 485.13
MS(ESI ⁺ ): 486.0 for [M+H] ⁺ 161 N-(3-(5-(6-(dimethylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C24H23F2N5O3S/499.54 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.84-12.76 (m, 1H), 9.65-9.57 (m, 1H), 8.59 (s, 1H), 8 .54 (s, 1H), 8.43 (s, 1H), 7.99 (s, 1H), 7.90-7.82 (m, 1H), 7.64-7.57 (m, 1H ), 7.35-7.27 (m, 1H), 6.78-6.72 (m, 1H), 3.12 (s, 2H), 3.05 (s, 6H), 1.85- 1.73 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 499.15
MS(ESI ⁺ ): 500.10 for [M+H] ⁺ 162 N-(3-(5-(6-(azetidin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane- 1-sulfonamide
C25H23F2N5O3S/511.55 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 9.65 (s, 1H), 8.62 (d, J=2.1 Hz, 1H), 8, 56 (d, J=2.1 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.03 (s, 1H), 7.89 (dd, J=8.6 , 2.4 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.35 (s, 1H), 6.49 (d, J=8.6 Hz, 1H), 4.00 (t, J=7.4 Hz, 4H), 3.21-3.08 (m, 2H), 2.41-2.28 (m, 2H), 1.81 (dd, J= 15.1, 7.6 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 511.15
MS(ESI ⁺ ): 512.10 for [M+H] ⁺ 163 N-(2,6-difluoro-3-(5-(6-vinylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C24H20F2N4O3S/482.51 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 9.67 (s, 1H), 8.94 (s, 1H), 8.74 (d, J=16 .3 Hz, 2H), 8.17 (d, J=6.4 Hz, 1H), 8.11 (s, 1H), 7.66 (s, 2H), 7.36 (s, 1H), 6.99-6.81 (m, 1H), 6.31 (d, J=17.6 Hz, 1H), 5.52 (d, J=10.5 Hz, 1H), 3.16 (s , 2H), 1.82 (s, 2H), 0.99 (s, 3H).
Calculated exact mass: 482.12
MS(ESI ⁺ ): 483.0 for [M+H] ⁺ 164 N-(2,6-difluoro-3-(5-(6-(S-methylsulfonimidoyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1 -sulfonamide
C23H21F2N5O4S2/533.57 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 9.66 (s, 1H), 9.18-9.05 (m, 1H), 8.94-8 .68 (m, 2H), 8.55-8.41 (m, 1H), 8.29-8.01 (m, 2H), 7.74-7.58 (m, 1H), 7.45 -7.28 (m, 1H), 4.50 (s, 1H), 3.25-2.88 (m, 5H), 1.93-1.68 (m, 2H), 0.99 (t , 3H).
Calculated exact mass: 533.10
MS(ESI ⁺ ): 534.0 for [M+H] ⁺ 165 N-(3-(5-(2,6-dimethylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C24H22F2N4O3S/484.52 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.11-12.71 (m, 2H), 8.40 (d, J=5.8 Hz, 2H), 8.09 (s, 1H ), 7.70-7.56 (m, 2H), 7.34 (t, J=8.8 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 3.21 -3.00 (m, 5H), 1.81 (dd, J=15.0, 7.5 Hz, 2H), 1.00 (t, J=7.3 Hz, 3H).
Calculated exact mass: 484.14
MS(ESI ⁺ ): 485.0 for [M+H] ⁺ . 166 N-(3-(5-(2-chloro-6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C23H19ClF2N4O3S/504.94 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.99 (s, 1H), 9.66 (s, 1H), 8.54 (d, J=1.9 Hz, 1H), 8, 45 (d, J=1.9 Hz, 1H), 8.12 (s, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.70-7.62 (m, 1H ), 7.44 (d, J=7.7 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 3.20-3.10 (m, 2H), 1.81 (dd, J=15.0, 7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 504.08
MS(ESI ⁺ ): 505.05 for [M+H] ⁺ 167 N-(3-(5-(6-cyclopropyl-4-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C26H24F2N4O3S/510.56 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 9.66 (s, 1H), 8.39 (d, J=7.3 Hz, 2H), 8, 27 (s, 1H), 8.09 (s, 1H), 7.64 (dd, J=14.5, 7.4 Hz, 1H), 7.34 (t, J=8.9 Hz, 1H ), 7.29 (s, 1H), 3.20-3.09 (m, 2H), 2.25 (s, 3H), 2.11 (dt, J=12.8, 6.5 Hz, 1H), 1.86-1.72 (m, 2H), 1.40-1.38 (m, 1H), 1.05-0.91 (m, 7H).
Calculated exact mass: 510.15
MS(ESI ⁺ ): 511.10 for [M+H] ⁺ 168 N-(2,6-difluoro-3-(5-(2,4,6-trimethylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1- sulfonamide
C25H24F2N4O3S/498.55 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (s, 1H), 9.87-9.51 (m, 1H), 8.27 (d, J=2.0 Hz, 1H ), 8.21 (d, J=1.9 Hz, 1H), 8.08 (s, 1H), 7.71-7.61 (m, 1H), 7.34 (t, J=9, 0 Hz, 1H), 7.09 (s, 1H), 3.20-3.10 (m, 2H), 2.45 (s, 3H), 2.16 (s, 3H), 1.98 ( s, 3H), 1.81 (dd, J=15.1, 7.5 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 498.15
MS(ESI ⁺ ): 499.05 for [M+H] ⁺ 169 N-(3-(5-(2-chloro-6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C23H19ClF2N4O3S/504.94 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.65 (s, 1H), 8.56 (s, 2H), 8.46 (d, J=1 .4 Hz, 1H), 8.13 (s, 1H), 7.74-7.58 (m, 2H), 7.35 (t, J=8.8 Hz, 1H), 3.21-3 .09 (m, 2H), 2.56 (s, 3H), 1.80 (dt, J=14.5, 7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 504.08
MS(ESI ⁺ ): 505.1 for [M+H] ⁺ 170 N-(3-(5-(6-cyclopropyl-2-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C26H24F2N4O3S/510.56 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 9.64 (s, 1H), 8.39 (d, J=3.0 Hz, 2H), 8, 08 (s, 1H), 7.69-7.59 (m, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.34 (t, J=9.0 Hz, 1H ), 7.22 (d, J=7.8 Hz, 1H), 3.20-3.09 (m, 2H), 2.38 (s, 3H), 2.18-2.08 (m, 1H), 1.80 (dt, J=15.5, 7.8 Hz, 2H), 1.05-0.91 (m, 7H).
Calculated exact mass: 510.15
MS(ESI ⁺ ): 511.10 for [M+H] ⁺ 171 N-(3-(5-(4,6-dimethylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C24H22F2N4O3S/484.52 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 9.65 (s, 1H), 8.41 (d, J=2.1 Hz, 1H), 8, 39 (d, J=2.1 Hz, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.64 (d, J=7.1 Hz, 1H), 7, 34 (t, J=8.7 Hz, 1H), 7.26 (s, 1H), 3.30 (s, 3H), 3.19-3.10 (m, 2H), 2.26 (s , 3H), 1.87-1.75 (m, 2H), 0.99 (t, J=7.4 Hz, 3H). 172 N-(2,6-difluoro-3-(5-(3-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3,3,3-trifluoropropane -1-sulfonamide
C23H17F5N4O3S/524.47 ^1H -NMR (600 MHz, DMSO- _d6 ) δ 12.98 (s, 1H), 9.75 (s, 1H), 8.56 (s, 1H), 8.52-8.43 (m , 3H), 8.12 (s, 1H), 7.64 (dd, J=13.0, 7.5 Hz, 1H), 7.39-7.31 (m, 2H), 3.17- 3.10 (m, 2H), 2.30 (s, 3H), 1.85-1.76 (m, 2H), 1.00 (t, J=7.1 Hz, 3H).
Calculated exact mass: 524.1
MS(ESI ^- ): 523.0 for [MH] ^- . 173 N-(3-(5-(3-chloropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C22H17ClF2N4O3S/490.91 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 13.04 (s, 1H), 9.64 (s, 1H), 8.80 (s, 1H), 8.66-8.62 (m , 2H), 8.53 (d, J=2.1 Hz, 1H), 7.71-7.61 (m, 2H), 7.35 (t, 1H), 3.21-3.10 ( m, 2H), 1.87-1.75 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 490.07
MS(ESI ⁺ ): 491.00 for [M+H] ⁺ 174 N-(2,6-difluoro-3-(5-(3-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C22H17F3N4O3S/474.46 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 9.65 (s, 1H), 8.77 (s, 1H), 8.72 (d, J=2 ,2 Hz, 1H), 8.69 (s, 1H), 8.56 (d, J=4.8 Hz, 1H), 8.15 (s, 1H), 7.79 (s, 1H), 7.72-7.63 (m, 1H), 7.36 (s, 1H), 3.22-3.10 (m, 2H), 1.89-1.73 (m, 2H), 1. 00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 474.10
MS(ESI ⁺ ): 475.00 for [M+H] ⁺ 175 N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)-1-phenylmethanesulfonamide
C28H21F2N5O3S/545.56 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.99 (s, 1H), 9.75 (s, 1H), 9.02 (s, 2H), 8.73 (s, 2H), 8.12 (s, 1H), 7.69-7.59 (m, 1H), 7.47-7.42 (m, 2H), 7.41-7.31 (m, 4H), 4. 52 (s, 2H), 2.35-2.22 (m, 1H), 1.15-1.02 (m, 4H).
Calculated exact mass: 545.13
MS(ESI ⁺ ): 545.95 for [M+H] ⁺ 176 N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)-3,3,3-trifluoropropane- 1-sulfonamide
C24H18F5N5O3S/551.49 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (d, J=3.1 Hz, 1H), 10.03 (s, 1H), 9.01 (s, 2H), 8, 75-8.68 (m, 2H), 8.14 (d, J=2.6 Hz, 1H), 7.69 (td, J=8.2, 6.1 Hz, 1H), 7.39 (t, J=8.8 Hz, 1H), 3.52-3.43 (m, 2H), 2.84 (dtd, J=11.6, 8.5, 4.4 Hz, 2H), 2.28 (tt, J=7.8, 4.9 Hz, 1H), 1.12-1.04 (m, 4H).
Calculated exact mass: 551.1
MS(ESI ^- ): 550.3 for [MH] ^- . 177 N-(2,6-difluoro-3-(5-(2-(methylamino)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-3,3, 3-trifluoropropane-1-sulfonamide
C22H17F5N6O3S/540.47 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.88 (s, 1H), 10.04 (s, 1H), 8.67 (s, 2H), 8.63 (s, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 7.68 (dd, J=14.2, 7.3 Hz, 1H), 7.38 (t, J=8.7 Hz , 1H), 7.30 (dd, J=9.2, 4.7 Hz, 1H), 3.52-3.43 (m, 2H), 2.95-2.77 (m, 5H).
Calculated exact mass: 540.1
MS(ESI ^- ): 539.3 for [MH] ^- . 178 N-(3-(5-(2-(dimethylamino)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)-3,3,3 -trifluoropropane-1-sulfonamide
C23H19F5N6O3S/554.50 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (d, J=2.4 Hz, 1H), 10.04 (s, 1H), 8.73 (s, 2H), 8, 63 (d, J=2.1 Hz, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.68 ( dd, J=14.5, 7.8 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 3.52-3.42 (m, 2H), 3.19 (s , 6H), 2.91-2.76 (m, 2H).
Calculated exact mass: 554.1
MS(ESI ^- ): 553.4 for [MH] ^- . 179 N-(2,6-difluoro-3-(5-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)- 3,3,3-trifluoropropane-1-sulfonamide
C25H21F5N6O3S/580.53 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.95 (s, 1H), 10.47 (s, 1H), 8.72 (s, 2H), 8.62 (d, J=2 .2 Hz, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.07 (s, 1H), 7.66 (dd, J=14.4, 7.6 Hz, 1H ), 7.37 (t, J=8.8 Hz, 1H), 3.55 (t, J=6.6 Hz, 4H), 3.48-3.44 (m, 2H), 2.89 -2.79 (m, 2H), 1.99-1.94 (m, 4H).
Calculated exact mass: 580.1
MS(ESI ^- ): 579.2 for [MH] ^- . 180 N-(3-(5-(2-(azetidin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)-3 ,3,3-trifluoropropane-1-sulfonamide
C24H19F5N6O3S/566.51 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 10.03 (s, 1H), 8.72 (s, 2H), 8.62 (d, J=2 .2 Hz, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.09 (s, 1H), 7.65 (dd, J=14.3, 7.5 Hz, 1H ), 7.36 (t, J=8.8 Hz, 1H), 4.11 (t, J=7.5 Hz, 4H), 3.47-3.42 (m, 2H), 2.88 -2.78 (m, 2H), 2.38-2.32 (m, 2H).
Calculated exact mass: 566.1
MS(ESI ^- ): 565.1 for [MH] ^- . 181 N-(2,6-difluoro-3-(5-(2-(piperidin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)- 3,3,3-trifluoropropane-1-sulfonamide
C26H23F5N6O3S/594.56 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.88 (d, J=2.4 Hz, 1H), 10.03 (s, 1H), 8.72 (s, 2H), 8, 64 (d, J=2.2 Hz, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.67 ( dd, J=14.3, 7.7 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 3.83-3.79 (m, 4H), 3.49-3 .44 (m, 2H), 2.88-2.79 (m, 2H), 1.66 (dt, J=11.5, 5.8 Hz, 2H), 1.58-1.53 (m , 4H).
Calculated exact mass: 594.2
MS(ESI ^- ): 593.0 for [MH] ^- . 182 N-(3-(5-(2-(cyclopropylamino)-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)-3,3, 3-trifluoropropane-1-sulfonamide
C24H19F5N6O3S/566.51 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 10.04 (s, 1H), 8.69 (s, 2H), 8.63 (d, J=2 .2 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.08 (s, 1H), 7.66 (dd, J=14.4, 7.7 Hz, 1H ), 7.59 (d, J=3.5 Hz, 1H), 7.37 (t, J=8.8 Hz, 1H), 3.48-3.44 (m, 2H), 2.88 -2.79 (m, 2H), 2.79-2.74 (m, 1H), 0.72-0.68 (m, 2H), 0.53-0.49 (m, 2H).
Calculated exact mass: 566.1
MS(ESI ^- ): 565.1 for [MH] ^- . 183 N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)ethanesulfonamide
C23H19F2N5O3S/483.49 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 9.64 (s, 1H), 9.02 (s, 2H), 8.72 (d, J=6 ,0 Hz, 2H), 8.11 (s, 1H), 7.65 (dd, J=14.5, 7.5 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H ), 3.18 (dd, J=13.5, 6.2 Hz, 2H), 2.35-2.22 (m, 1H), 1.32 (t, J=7.2 Hz, 2H) , 1.16-1.00 (m, 3H).
Calculated exact mass: 483.12
MS(ESI ⁺ ): 484.40 for [M+H] ⁺ 184 N-(2,6-difluoro-3-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C22H16F5N5O3S/525.45 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.07 (s, 1H), 9.65 (s, 1H), 9.49 (s, 2H), 8.89 (d, J=6 ,2 Hz, 2H), 8.17 (s, 1H), 7.67 (dd, J=14.5, 7.5 Hz, 1H), 7.36 (t, J=8.9 Hz, 1H ), 3.22-3.01 (m, 2H), 1.91-1.70 (m, 2H), 1.14-0.83 (m, 3H).
Calculated exact mass: 525.09
MS(ESI ⁺ ): 526.0 for [M+H] ⁺ 185 N-(2,6-difluoro-3-(5-(2-(piperazin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane -1-sulfonamide
C25H25F2N7O3S/541.58 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.95 (s, 2H), 9.67 (s, 1H), 8.84 (s, 2H), 8.67 (s, 1H), 8.64 (s, 1H), 8.08 (s, 1H), 7.64 (d, J=6.7 Hz, 1H), 7.36 (t, J=8.8 Hz, 1H), 4.12-3.98 (m, 4H), 3.56 (s, 2H), 3.28-3.08 (m, 5H), 1.81 (dd, J=15.1, 7.5 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 541.17
MS(ESI ⁺ ): 542.05 for [M+H] ⁺ 186 N-(3-(5-(4-chloro-2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C22H18ClF2N5O3S/505.92 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 13.10-12.97 (m, 1H), 9.72-9.59 (m, 1H), 8.84 (s, 1H), 8 .62 (d, J=2.1 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.15 (s, 1H), 7.73-7.59 (m, 1H), 7.40-7.29 (m, 1H), 3.21-3.08 (m, 2H), 2.70 (s, 3H), 1.81 (d, J=7.6 Hz , 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 505.08
MS(ESI ⁺ ): 506.0 for [M+H] ⁺ 187 N-(2,6-difluoro-3-(5-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl) propane-1-sulfonamide
C24H24F2N6O4S/530.55 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 9.66 (s, 1H), 8.78 (s, 2H), 8.65 (d, J=2 ,0 Hz, 1H), 8.61 (s, 1H), 7.71-7.59 (m, J=6.8 Hz, 1H), 7.35 (t, J=8.6 Hz, 1H ), 3.77 (d, J=4.6 Hz, 4H), 3.70 (d, J=4.6 Hz, 4H), 3.20-3.08 (m, 2H), 1.81 (dd, J=15.0, 7.5 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H).
Calculated exact mass: 530.15
MS(ESI ⁺ ): 531.10 for [M+H] ⁺ 188 N-(2,6-difluoro-3-(5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C25H24F2N6O4S/542.56 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 9.66 (s, 1H), 8.78 (s, 2H), 8.65 (d, J=2 .0 Hz, 1H), 8.61 (s, 1H), 8.07 (s, 1H), 7.65 (d, J=6.8 Hz, 1H), 7.35 (t, J=8 .6 Hz, 1H), 3.77 (d, J=4.6 Hz, 4H), 3.70 (d, J=4.6 Hz, 4H), 3.22-3.09 (m, 2H ), 1.81 (dd, J=15.0, 7.5 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). Calculated exact mass: 542.15
MS(ESI ⁺ ): 543.10 for [M+H] ⁺ 189 N-(3-(5-(2-cyanopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C22H16F2N6O3S/482.47 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.08 (s, 1H), 9.65 (s, 1H), 9.48 (s, 1H), 8.90 (d, J=7 .2 Hz, 1H), 8.17 (s, 1H), 7.72-7.60 (m, 1H), 7.42-7.29 (m, 1H), 3.20-3.08 ( m, 2H), 1.81 (d, J=7.6 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 482.10
MS(ESI ⁺ ): 483.05 for [M+H] ⁺ 190 5-(3-(2,4-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-carboxamide
C22H18F2N6O4S/500.48 ¹ H-NMR (400 MHz, DMSO) δ 13.05 (s, 1H), 9.66 (s, 1H), 9.35 (s, 2H), 8.86 (d, J=2.1 Hz , 2H), 8.27 (s, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 7.73-7.62 (m, 1H), 7.36 (t, J=8.9 Hz, 1H), 3.20-3.11 (m, 2H), 1.81 (dd, J=15.1, 7.5 Hz, 2H), 1.00 (t, J =7.4 Hz, 3H).
Calculated exact mass: 500.11
MS(ESI ⁺ ): 501.05 for [M+H] ⁺ 191 N-(2,6-difluoro-3-(5-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane -1-sulfonamide
C25H24F2N6O3S/526.56 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 9.65 (s, 1H), 8.72 (s, 2H), 8.63 (d, J=1 .9 Hz, 1H), 8.58 (s, 1H), 8.06 (s, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.35 (t, J=8 .9 Hz, 1H), 3.56 (d, J=6.4 Hz, 4H), 3.20-3.10 (m, 2H), 1.98 (d, J=6.3 Hz, 4H ), 1.81 (dd, J=15.1, 7.5 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). Calculated exact mass: 526.16
MS(ESI ⁺ ): 527.05 for [M+H] ⁺ 192 N-(2,6-difluoro-3-(5-(2-((3-methoxypropyl)amino)-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl )propane-1-sulfonamide
C25H26F2N6O4S/544.58 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 9.64 (s, 1H), 8.64 (s, 1H), 8.58 (d, J=18 .8 Hz, 2H), 8.04 (s, 1H), 7.69-7.58 (m, 1H), 7.41-7.27 (m, 2H), 3.48-3.33 ( m, 4H), 3.23 (s, 3H), 3.19-3.09 (m, 2H), 1.87-1.72 (m, 4H), 0.98 (t, J=7, 3 Hz, 3H).
Calculated exact mass: 544.17
MS(ESI ⁺ ): 545.05 for [M+H] ⁺ 193 N-(2,6-difluoro-3-(5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C24H23F2N5O3S/499.54 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.66 (s, 1H), 9.13 (s, 2H), 8.75 (d, J=7 .6 Hz, 2H), 8.12 (s, 1H), 7.65 (s, 1H), 7.41-7.30 (m, 1H), 3.26-3.19 (m, 1H) , 3.19-3.07 (m, 2H), 1.93-1.70 (m, 2H), 1.34 (d, J=6.5 Hz, 6H), 1.00 (d, J =6.7 Hz, 3H).
Calculated exact mass: 499.15
MS(ESI ⁺ ): 499.99 for [M+H] ⁺ 194 N-(2,6-difluoro-3-(5-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl )propane-1-sulfonamide
C26H27F2N7O3S/555.60 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 9.67 (s, 1H), 8.76 (s, 2H), 8.62 (d, J=17 .9 Hz, 2H), 8.06 (s, 1H), 7.72-7.58 (m, 1H), 7.40-7.30 (m, 1H), 3.81 (s, 4H) , 3.20-3.10 (m, 2H), 2.43 (s, 3H), 2.26 (s, 2H), 1.90-1.74 (m, 2H), 1.00 (t , J=7.4 Hz, 3H).
Calculated exact mass: 555.19
MS(ESI ⁺ ): 556.05 for [M+H] ⁺ 195 N-(2,6-difluoro-3-(5-(2-(methylthio)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C22H19F2N5O3S2/503.54 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 9.67 (s, 1H), 9.05 (s, 2H), 8.74 (d, J=3 ,8 Hz, 2H), 8.11 (s, 1H), 7.61 (d, J=6.9 Hz, 1H), 7.33 (t, J=8.9 Hz, 1H), 3, 19-3.07 (m, 2H), 2.56 (s, 3H), 1.79 (dt, J=14.4, 7.2 Hz, 2H), 0.99 (t, J=7, 4 Hz, 3H).
Calculated exact mass: 503.09
MS(ESI ⁺ ): 504.00 for [M+H] ⁺ 196 N-(3-(5-(2-( tert- butyl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1- sulfonamide
C25H25F2N5O3S/513.56 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.66 (s, 1H), 9.14 (s, 2H), 8.75 (d, J=7 .9 Hz, 2H), 8.12 (s, 1H), 7.66 (dd, J=14.4, 7.6 Hz, 1H), 7.36 (t, J=8.9 Hz, 1H ), 3.20-3.10 (m, 2H), 1.81 (dd, J=15.0, 7.5 Hz, 2H), 1.42 (s, 9H), 1.00 (t, J=7.4 Hz, 2H).
Calculated exact mass: 513.16
MS(ESI ⁺ ): 514.10 for [M+H] ⁺ 197 N-(2,6-difluoro-3-(5-(2-(isopropylthio)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C24H23F2N5O3S2/531.60 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.67 (s, 1H), 9.04 (s, 2H), 8.74 (d, J=3 .3 Hz, 2H), 8.11 (s, 1H), 7.66-7.54 (m, 1H), 7.33 (s, 1H), 4.00-3.90 (m, 1H) , 3.18-3.06 (m, 2H), 1.90-1.70 (m, 2H), 1.42 (d, J=6.7 Hz, 6H), 0.99 (t, J =7.3 Hz, 3H).
Calculated exact mass: 531.12
MS(ESI ⁺ ): 532.0 [M+H] ⁺ 198 N-(2,6-difluoro-3-(5-(2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin- 3-carbonyl)phenyl)propane-1-sulfonamide
C27H29F2N7O4S/585.63 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.89 (s, 1H), 9.65 (s, 1H), 8.75 (s, 2H), 8.64 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.70-7.58 (m, 1H), 7.38-7.28 (m, 1H), 4.52-4, 40 (m, 1H), 3.80 (s, 3H), 3.60-3.49 (m, 2H), 3.20-3.10 (m, 2H), 2.46 (s, 2H) , 2.41-2.41 (m, 1H), 1.88-1.73 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 585.20
MS(ESI ⁺ ): 586.05 for [M+H] ⁺ 199 N-(3-(5-(2-(azetidin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane- 1-sulfonamide
C24H22F2N6O3S/512.54 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 9.65 (s, 1H), 8.72 (s, 2H), 8.63 (d, J=2 ,1 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.06 (s, 1H), 7.64 (dd, J=14.5, 7.7 Hz, 1H ), 7.35 (t, J=8.8 Hz, 1H), 4.11 (t, J=7.5 Hz, 4H), 3.20-3.11 (m, 2H), 2.35 (dt, J=14.7, 7.3 Hz, 2H), 1.82 (dt, J=15.0, 7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H)
Calculated exact mass: 512.14
MS(ESI ⁺ ): 513.10 for [M+H] ⁺ 200 N-(3-(5-(2-(3-(dimethylamino)propoxy)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl) propane-1-sulfonamide
C26H28F2N6O4S/558.60 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.98-12.89 (m, 1H), 8.98 (s, 2H), 8.77-8.63 (m, 2H), 8 .13-8.07 (m, 1H), 7.66-7.56 (m, 1H), 7.36-7.29 (m, 1H), 4.46-4.35 (m, 2H) , 3.18-3.07 (m, 2H), 2.46-2.37 (m, 2H), 2.20 (s, 6H), 1.98-1.87 (m, 2H), 1 .87-1.74 (m, 2H), 0.99 (s, 3H).
Calculated exact mass: 558.19
MS(ESI ⁺ ): 559.05 for [M+H] ⁺ 201 N-(2,6-difluoro-3-(5-(2-((2-hydroxyethyl)amino)-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl )propane-1-sulfonamide
C23H22F2N6O4S/516.52 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.88 (d, J=2.7 Hz, 1H), 9.65 (s, 1H), 8.66 (s, 2H), 8, 63 (d, J=2.2 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.65 ( dd, J=14.4, 7.7 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.27 (s, 1H), 3.56 (t, J=6 ,3 Hz, 2H), 3.42 (dd, J=9.8, 6.0 Hz, 2H), 3.17-3.14 (m, 2H), 1.85-1.77 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 516.1
MS(ESI ^- ): 515.0 for [MH] ^- . 201 N-(2,6-difluoro-3-(5-(2-((2-hydroxyethyl)-(methyl)amino)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3- carbonyl)phenyl)propane-1-sulfonamide
C24H24F2N6O4S/530.55 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 9.65 (s, 1H), 8.72 (s, 2H), 8.63 (d, J=2 .2 Hz, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 7.65 (dd, J=14.4, 7.7 Hz, 1H ), 7.35 (t, J=8.7 Hz, 1H), 4.73 (t, J=5.4 Hz, 1H), 3.73 (t, J=6.2 Hz, 2H), 3.63 (kv, J=6.0 Hz, 2H), 3.21 (s, 3H), 3.18-3.12 (m, 2H), 1.85-1.76 (m, 2H) , 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 530.2
MS(ESI ^- ): 528.9 for [MH] ^- . 203 (S)-N-(2,6-difluoro-3-(5-(2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3 -carbonyl)phenyl)propane-1-sulfonamide
C25H24F2N6O4S/542.56 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 9.65 (s, 1H), 8.72 (s, 2H), 8.63 (d, J=2 .2 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.05 (s, 1H), 7.65 (dd, J=14.4, 7.7 Hz, 1H ), 7.35 (t, J=8.7 Hz, 1H), 4.99 (d, J=3.5 Hz, 1H), 4.41 (s, 1H), 3.68-3.63 (m, 1H), 3.62-3.56 (m, 2H), 3.51 (d, J=11.6 Hz, 1H), 3.17-3.14 (m, 2H), 2, 07-2.01 (m, 1H), 1.95-1.89 (m, 1H), 1.85-1.77 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 542.2
MS(ESI ^- ): 540.9 for [MH] ^- . 204 (R)-N-(2,6-difluoro-3-(5-(2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3 -carbonyl)phenyl)propane-1-sulfonamide
C25H24F2N6O4S/542.56 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.88 (d, J=2.6 Hz, 1H), 9.65 (s, 1H), 8.72 (s, 2H), 8, 63 (d, J=2.2 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.65 ( dd, J=14.4, 7.7 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 4.99 (s, 1H), 4.41 (s, 1H), 3.68-3.63 (m, 1H), 3.62-3.56 (m, 2H), 3.51 (d, J=11.6 Hz, 1H), 3.18-3.14 ( m, 2H), 2.04 (dtd, J=13.2, 8.9, 4.6 Hz, 1H), 1.94-1.89 (m, 1H), 1.85-1.78 ( m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 542.2
MS(ESI ^- ): 540.9 for [MH] ^- . 205 N-(2,6-difluoro-3-(5-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl )propane-1-sulfonamide
C24H22F2N6O4S/528.53 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.89 (d, J=2.6 Hz, 1H), 9.65 (s, 1H), 8.72 (s, 2H), 8, 63 (d, J=2.2 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.64 ( dd, J=14.4, 7.7 Hz, 1H), 7.35 (t, J=8.7 Hz, 1H), 5.73 (d, J=6.5 Hz, 1H), 4, 63-4.57 (m, 1H), 4.32-4.28 (m, 2H), 3.85 (dd, J=9.9, 4.5 Hz, 2H), 3.17-3, 13 (m, 2H), 1.81 (d.kv, J=15.0, 7.5 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 528.1
MS(ESI ^- ): 527.1 for [MH] ^- . 206 N-(3-(5-(2-ethylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C23H21F2N5O3S/485.51 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.99 (s, 2H), 9.65 (s, 2H), 9.12 (s, 2H), 8.78-8.75 (m , 1H), 8.75-8.72 (m, 1H), 8.12 (s, 1H), 7.69-7.62 (m, 1H), 7.39-7.31 (m, 1H ), 3.21-3.10 (m, 2H), 3.04-2.93 (m, 2H), 1.86-1.75 (m, 2H), 1.34 (t, 3H), 1.00 (t, 3H).
Calculated exact mass: 485.13
MS(ESI ⁺ ): 486.05 for [M+H] ⁺ 207 N-(2,6-difluoro-3-(5-(2-(fluoromethyl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C22H18F3N5O3S/489.47 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 9.66 (s, 1H), 9.28 (s, 2H), 8.81 (s, 2H), 8.14 (s, 1H), 7.70-7.60 (m, 1H), 7.40-7.32 (m, 1H), 5.61 (d, J=46.5 Hz, 2H) , 3.21-3.07 (m, 2H), 1.91-1.73 (m, 2H), 1.08-0.92 (m, 3H).
Calculated exact mass: 489.11
MS(ESI ⁺ ): 490.05 for [M+H] ⁺ 208 N-(3-(5-(2-ethynylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C23H17F2N5O3S/481.48 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 9.66 (s, 1H), 9.24 (s, 2H), 8.82 (s, 2H), 8.15 (s, 1H), 7.66 (d, J=7.1 Hz, 1H), 7.36 (t, J=8.8 Hz, 1H), 4.48 (s, 1H), 3.22-3.09 (m, 2H), 1.89-1.74 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 481.10
MS(ESI ^- ): 480.0 for [MH] ^- 209 N-(2,6-difluoro-3-(5-(4-methyl-2-(methylthio)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane -1-sulfonamide
C23H21F2N5O3S2/517.57 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.97 (s, 1H), 9.64 (s, 1H), 8.53 (s, 1H), 8.48-8.46 (m , 1H), 8.45-8.43 (m, 1H), 8.11 (s, 1H), 7.68-7.58 (m, 1H), 7.34 (t, 1H), 3, 19-3.08 (m, 2H), 2.54 (s, 2H), 2.41 (s, 3H), 1.86-1.70 (m, 2H), 0.98 (t, J= 7.4 Hz, 3H).
Calculated exact mass: 517.11
MS(ESI ⁺ ): 518.05 for [M+H] ⁺ 210 N-(3-(5-(2-(1H-benzo[d]imidazol-6-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2, 6-difluorophenyl)propane-1-sulfonamide
C28H21F2N7O3S/573.58 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 12.70 (s, 1H), 9.30 (s, 2H), 8.85 (d, J=9 .6 Hz, 2H), 8.80-8.63 (m, 1H), 8.47-8.30 (m, 2H), 8.14 (s, 1H), 7.83-7.74 ( m, 1H), 7.70-7.62 (m, 1H), 7.40-7.32 (m, 1H), 3.22-3.11 (m, 2H), 1.88-1, 72 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 573.14
MS(ESI ⁺ ): 574.05 for [M+H] ⁺ . 211 N-(3-(5-(5-chloropyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C21H16ClF2N5O3S/491.90 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.25 (d, J=1.3 Hz, 1H), 9.20 (d, J=2.2 Hz, 1H), 9.14 ( d, J=2.2 Hz, 1H), 8.92 (d, J=1.3 Hz, 1H), 8.10 (s, 1H), 7.54-7.44 (m, 1H), 7.30-7.22 (m, 1H), 3.11-2.99 (m, 2H), 1.85-1.72 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).
Calculated exact mass: 491.06
MS(ESI ⁺ ): 492.05 for [M+H] ⁺ 212 (3-amino-2,4-difluorophenyl)(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone
C20H12ClF2N3O/383.78 ¹ H-NMR (700 MHz, DMSO-d ₆ ) δ 12.81 (s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 7.79-7.76 (m, 2H), 7.58-7.55 (m, 2H), 7.03 (t, J=9, 4 Hz, 1H), 6.76 (dd, J=14.0, 7.6 Hz, 1H), 5.45 (s, 2H).
Calculated exact mass: 383.1
MS(ESI ^- ): 381.9 for [MH] ^- . 213 N-(3-(5-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C23H18ClF2N3O3S/489.92 ¹ H-NMR (700 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 9.65 (s, 1H), 8.53 (d, J=2.2 Hz, 1H), 8, 44 (d, J=2.2 Hz, 1H), 8.11 (s, 1H), 7.66 (dd, J=14.4, 7.7 Hz, 1H), 7.64 (dd, J =7.4, 1.8 Hz, 1H), 7.55 (dd, J=7.1, 2.1 Hz, 1H), 7.48 (pd, J=7.4, 1.7 Hz, 2H), 7.35 (t, J=8.8 Hz, 1H), 3.17-3.14 (m, 2H), 1.84-1.78 (m, 2H), 1.00 (t , J=7.4 Hz, 3H).
Calculated exact mass: 489.1
MS(ESI ^- ): 487.8 for [MH] ^- . 214 N-(2,6-difluoro-3-(5-(naphthalene-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-methanesulfonamide
C25H17F2N3O3S/477.49 ¹ H-NMR (700 MHz, DMSO-d ₆ ) δ 12.99 (s, 1H), 9.66 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8, 49 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.67 (dd, J=14.4, 7.7 Hz, 1H), 7.64 (dd, J=8 ,1, 7.1 Hz, 1H), 7.58 (ddd, J=8.0, 6.7, 0.9 Hz, 1H), 7.56-7.52 (m, 2H), 7, 35 (t, J=8.8 Hz, 1H), 3.17-3.13 (m, 2H), 1.84-1.78 (m, 2H), 1.00 (t, J=7, 4 Hz, 3H).
Calculated exact mass: 505.1
MS(ESI ^- ): 504.0 for [MH] ^- . 215 N-(2,6-difluoro-3-(5-( ortho- tolyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C24H21F2N3O3S/469.51 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.00 (d, J=2.0 Hz, 1H), 9.76 (s, 1H), 8.39 (d, J=2.1 Hz, 1H), 8.35 (s, 1H), 8.24 (d, J=2.7 Hz, 1H), 7.64-7.53 (m, 2H), 7.37-7.30 (m, 4H), 7.28 (t, J=8.5 Hz, 1H), 3.15-3.06 (m, 2H), 2.26 (s, 3H), 1.78-1, 69 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 469.1
MS(ESI ^- ): 468.0 for [MH] ^- . 216 N-(2,6-difluoro-3-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C23H18F3N3O3S/473.47 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 9.65 (s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8, 65 (d, J=2.2 Hz, 1H), 8.07 (s, 1H), 7.80-7.76 (m, 2H), 7.66 (dd, J=14.4, 7. 7 Hz, 1H), 7.38-7.32 (m, 3H), 3.19-3.12 (m, 2H), 1.85-1.77 (m, 2H), 1.00 (t , J=7.4 Hz, 3H).
Calculated exact mass: 473.1
MS(ESI ^- ): 472.0 for [MH] ^- . 217 N-(2,6-difluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide
C24H20F3N3O3S/487.50 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 9.64 (s, 1H), 8.38 (d, J=2.2 Hz, 1H), 8, 35 (d, J=2.1 Hz, 1H), 8.08 (s, 1H), 7.65 (dd, J=14.4, 7.7 Hz, 1H), 7.37-7.29 (m, 2H), 7.23 (dd, J=10.1, 2.6 Hz, 1H), 7.14 (td, J=8.5, 2.7 Hz, 1H), 3.18- 3.12 (m, 2H), 2.26 (s, 3H), 1.85-1.77 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 487.1
MS(ESI ^- ): 486.0 for [MH] ^- . 218 N-(3-(5-(2-chloro-4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C24H20ClF2N3O4S/519.95 H-NMR (600 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 9.64 (s, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.08 (s, 1H), 7.65 (dd, J=14.4, 7.7 Hz, 1H), 7.46 (d, J= 8.5 Hz, 1H), 7.34 (t, J=8.8 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.07 (dd, J=8, 5, 2.6 Hz, 1H), 3.85 (s, 3H), 3.18-3.13 (m, 2H), 1.85-1.77 (m, 2H), 1.00 (t , J=7.4 Hz, 3H).
Calculated exact mass: 519.1
MS(ESI ^- ): 517.9 for [MH] ^- . 219 N-(3-(5-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1- sulfonamide
C24H19F2N7O3S/523.52 ¹ H-NMR (700 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 9.64 (b s, 2H), 8.77 (d, J=1.9 Hz, 1H), 8.75 (d, J=2.1 Hz, 1H), 8.16 (d, J=8.0 Hz, 2H), 8.09 (s, 1H), 7.89 (d, J=8 .2 Hz, 2H), 7.67 (dd, J=14.3, 7.7 Hz, 1H), 7.36 (t, J=8.7 Hz, 1H), 3.18-3.14 (m, 2H), 1.82 (d.kv, J=15.0, 7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 523.1
MS(ESI ^- ): 522.0 for [MH] ^- . 220 4-(3-(2,4-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide
C23H20F2N4O5S2/534.55 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 9.65 (s, 1H), 8.77 (d, J=2.2 Hz, 1H), 8, 75 (d, J=2.2 Hz, 1H), 8.11 (s, 1H), 7.98-7.94 (m, 4H), 7.66 (dd, J=14.4, 7. 7 Hz, 1H), 7.43 (s, 2H), 7.36 (t, J=8.7 Hz, 1H), 3.18-3.14 (m, 2H), 1.85-1, 78 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 534.1
MS(ESI ^- ): 533.0 for [MH] ^- . 221 N-(3-(5-(2-chloro-4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C23H17ClF3N3O3S/507.91 ¹ H-NMR (700 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 9.65 (s, 1H), 8.51 (d, J=2.2 Hz, 1H), 8, 42 (d, J=2.2 Hz, 1H), 8.11 (s, 1H), 7.68-7.62 (m, 2H), 7.61 (dd, J=8.5, 6, 2 Hz, 1H), 7.39-7.33 (m, 2H), 3.17-3.13 (m, 2H), 1.84-1.78 (m, 2H), 1.00 (t , J=7.4 Hz, 3H).
Calculated exact mass: 507.1
MS(ESI ^- ): 506.0 for [MH] ^- . 222 4-(3-(2,4-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzoic acid
C24H19F2N3O5S/499.49 ¹ H-NMR (700 MHz, DMSO-d ₆ ) δ 12.96 (s, 2H), 9.66 (s, 1H), 8.77 (d, J=2.2 Hz, 1H), 8, 75 (d, J=2.2 Hz, 1H), 8.11 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.67 (dd, J=14.3, 7.7 Hz, 1H), 7.36 (t, J=8.7 Hz, 1H), 3.18-3.14 (m , 2H), 1.84-1.78 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 499.1
MS(ESI ^- ): 497.9 for [MH] ^- . 223 3-(3-(2,4-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzoic acid
C24H19F2N3O5S/499.49 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.06 (s, 1H), 9.80 (s, 1H), 8.75 (d, J=2.2 Hz, 1H), 8, 68 (s, 1H), 8.27-8.24 (m, 2H), 8.03 (d, J=7.7 Hz, 1H), 8.01-7.98 (m, 1H), 7 .66 (t, J=7.7 Hz, 1H), 7.59 (td, J=9.0, 5.9 Hz, 1H), 7.29 (t, J=8.3 Hz, 1H) , 3.14-3.11 (m, 2H), 1.78-1.70 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
Calculated exact mass: 499.1
MS(ESI ^- ): 498.1 for [MH] ^- . 224 2-(3-(2,4-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzoic acid
C24H19F2N3O5S/499.49 ^1H -NMR (600 MHz, DMSO- _d6 ) δ 12.98 (s, 1H), 12.89 (s, 1H), 9.76 (s, 1H), 8.40 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.22 (s, 1H), 7.86 (dd, J=7.7, 1.1 Hz, 1H), 7.65 (td , J=7.5, 1.3 Hz, 1H), 7.58 (td, J=9.0, 5.9 Hz, 1H), 7.55-7.50 (m, 2H), 7, 28 (t, J=8.4 Hz, 1H), 3.14-3.10 (m, 2H), 1.78-1.71 (m, 2H), 0.97 (t, J=7, 4 Hz, 3H).
Calculated exact mass: 499.1
MS(ESI ^- ): 498.0 for [MH] ^- . 225 N-(3-(5-(4-chloro-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C24H20ClF2N3O3S/503.95 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 9.64 (s, 1H), 8.37 (dd, J=10.3, 2.1 Hz, 2H ), 8.09 (s, 1H), 7.69-7.60 (m, 1H), 7.46 (s, 1H), 7.41-7.26 (m, 3H), 3.17- 3.11 (m, 2H), 1.81 (dd, J=15.1, 7.6 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 503.09
MS(ESI ⁺ ): 504.05 for [M+H] ⁺ . 226 N-(3-(5-(2-chloro-4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,6-difluorophenyl)-1-sulfonamide
C25H22ClF2N3O4S/533.97 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 9.66 (s, 1H), 8.48 (d, J=2.1 Hz, 1H), 8, 39 (d, J=2.1 Hz, 1H), 8.08 (s, 1H), 7.65 (dd, J=14.3, 7.7 Hz, 1H), 7.46 (d, J =8.5 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.07 (dd, J=8 ,5, 2.6 Hz, 1H), 3.85 (s, 3H), 3.19-3.13 (m, 2H), 1.77 (dt, J=15.3, 7.7 Hz, 2H), 1.46-1.36 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).
Calculated exact mass: 533.1
MS(ESI ^- ): 532.0 for [MH] ^- . 227 N-(2,6-difluoro-3-(5-(4-fluoro-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)butane-1-sulfonamide
C25H22F3N3O3S/501.52 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 9.64 (s, 1H), 8.38 (d, J=2.1 Hz, 1H), 8, 35 (d, J=2.1 Hz, 1H), 8.08 (s, 1H), 7.65 (dd, J=14.4, 7.7 Hz, 1H), 7.36-7.32 (m, 2H), 7.23 (dd, J=10.1, 2.6 Hz, 1H), 7.14 (td, J=8.5, 2.7 Hz, 1H), 3.19- 3.13 (m, 2H), 2.26 (s, 3H), 1.80-1.73 (m, 2H), 1.45-1.37 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).
Calculated exact mass: 501.1
MS(ESI ^- ): 500.1 for [MH] ^- . 228 N-(2,6-difluoro-3-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-methanesulfonamide
C20H14F2N4O3S/428.41 ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.96 (s, 1H), 9.74 (s, 1H), 8.82-8.68 (m, 2H), 8.63 (d , J=3.8 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.12 (s, 1H), 7.65 (dd, J=14.2, 7, 4 Hz, 1H), 7.55 (dd, J=7.8, 4.7 Hz, 1H), 7.36 (t, J=8.8 Hz, 1H), 3.11 (s, 3H) .
Calculated exact mass: 428.08
MS(ESI ⁺ ): for [M+H] ⁺ 229 N-(2,6-difluoro-3-(5-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C23H20F2N4O3S/470.49 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 9.63 (s, 1H), 8.78 (s, 1H), 8.66 (d, J=12 .0 Hz, 2H), 8.06 (s, 1H), 8.05-8.00 (m, 1H), 7.68-7.58 (m, 1H), 7.40-7.28 ( m, 2H), 3.19-3.06 (m, 2H), 2.51 (s, 3H), 1.78 (d, J=7.6 Hz, 2H), 0.96 (t, J =7.4 Hz, 3H).
Calculated exact mass: 470.12
MS(ESI ⁺ ): 471.10 for [M+H] ⁺ 230 N-(2,6-difluoro-3-(5-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C23H17F5N4O3S/524.47 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 9.66 (s, 1H), 9.19 (s, 1H), 8.82 (dd, J=9 ,2, 2.0 Hz, 2H), 8.49 (d, J=8.1 Hz, 1H), 8.15 (s, 1H), 8.04 (d, J=8.2 Hz, 1H ), 7.67 (dd, J=14.5, 7.6 Hz, 1H), 7.36 (t, J=8.8 Hz, 1H), 3.21-3.11 (m, 2H) , 1.81 (d.kv, J=14.6, 7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 524.09
MS(ESI ⁺ ): 525.00 for [M+H] ⁺ 231 N-(2,6-difluoro-3-(5-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-ethanesulfonamide
C21H16F2N4O3S/442.44 ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.66 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8, 80 (d, J=2.3 Hz, 1H), 8.68 (d, J=4.8 Hz, 2H), 8.12 (s, 1H), 7.81 (dd, J=4.6 , 1.5 Hz, 2H), 7.67 (dd, J=14.4, 7.7 Hz, 1H), 7.36 (t, J=8.8 Hz, 1H), 3.19 (kv , J=7.3 Hz, 2H), 1.33 (t, J=7.3 Hz, 3H).
Calculated exact mass: 442.1
MS(ESI ^- ): 441.1 for [MH] ^- . 232 N-(2,6-difluoro-3-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C22H18F2N4O3S/456.47 ¹ H-NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 9.81 (s, 1H), 8.96 (s, 1H), 8.73 (dd, J=11.4, 2.1 Hz, 2H), 8.66-8.60 (m, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.11 (s, 1H), 7.63 ( dd, J=14.5, 7.5 Hz, 1H), 7.55 (dd, J=7.7, 4.9 Hz, 1H), 7.34 (t, J=8.9 Hz, 1H ), 3.19-3.08 (m, 2H), 1.80 (d.kv, J=14.9, 7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H).
Calculated exact mass: 456.
MS(ESI ⁺ ): 457.00 for [M+H] ⁺ . 233 N-(2,6-difluoro-3-(5-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C22H18F2N4O3S/456.47 ¹ H-NMR (400 MHz, DMSO) δ 13.07-12.84 (m, 1H), 10.05-9.75 (m, 1H), 8.82 (dd, J=9.5, 2 ,2 Hz, 2H), 8.68 (d, J=5.9 Hz, 2H), 8.13 (s, 1H), 7.82 (d, J=6.0 Hz, 2H), 7, 64 (dd, J=14.5, 7.5 Hz, 1H), 7.35 (t, J=8.7 Hz, 1H), 3.18-3.11 (m, 2H), 1.81 (dd, J=15.1, 7.6 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H).
Calculated exact mass: 456.11
MS(ESI ⁺ ): 457.1 for [M+H] ⁺ . 234 N-(2,6-difluoro-3-(5-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-methanesulfonamide
C20H14F2N4O3S/428.41 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.73 (s, 1H), 8.82 (dd, J=7.0, 2.2 Hz, 2H ), 8.76-8.57 (m, 2H), 8.14 (s, 1H), 7.82 (dd, J=4.6, 1.5 Hz, 2H), 7.65 (dd, J=14.4, 7.7 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 3.10 (s, 3H). 235 N-(2,6-difluoro-3-(5-(3-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C23H20F2N4O3S/470.49 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 9.66 (s, 1H), 8.52 (d, J=4.1 Hz, 1H), 8, 44 (d, J=4.3 Hz, 2H), 8.11 (s, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.66 (dd, J=14.3 , 7.5 Hz, 1H), 7.40-7.31 (m, 2H), 3.21-3.10 (m, 2H), 2.46 (s, 3H), 1.81 (dd, J=15.0, 7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Calculated exact mass: 470.12
MS(ESI ⁺ ): 471.0 for [M+H] ⁺ 236 N-(3-(5-(2,4-dimethoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C23H21F2N5O5S/517.51 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 9.65 (s, 1H), 8.57 (d, J=1.6 Hz, 1H), 8, 50 (d, J=1.9 Hz, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.65 (d, J=6.9 Hz, 1H), 7, 35 (t, J=8.8 Hz, 1H), 3.97 (s, 6H), 3.20-3.10 (m, 2H), 1.80 (dd, J=15.1, 7, 5 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H).
Calculated exact mass: 517.12
MS(ESI ⁺ ): 518.0 for [M+H] ⁺ 237 N-(3-(5-(2-chloropyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide
C21H16ClF2N5O3S/491.90 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 9.64 (s, 1H), 9.23 (d, J=26.5 Hz, 2H), 8, 76 (t, J=15.3 Hz, 2H), 8.13 (s, 1H), 7.64 (dd, J=14.4, 7.6 Hz, 1H), 7.34 (t, J =8.8 Hz, 1H), 3.15 (dd, J=14.6, 7.1 Hz, 2H), 1.78 (dt, J=14.8, 7.4 Hz, 2H), 0 .98 (t, J=7.4 Hz, 3H).
Calculated exact mass: 491.06
MS(ESI ⁺ ): 492.00 for [M+H] ⁺ 238 N-(2,6-difluoro-3-(5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide
C22H19F2N5O4S/487.48 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (s, 1H), 9.64 (s, 1H), 8.99 (s, 2H), 8.69 (d, J=5 .4 Hz, 2H), 8.09 (s, 1H), 7.64 (dd, J=14.1, 7.4 Hz, 1H), 7.34 (t, J=8.8 Hz, 1H ), 4.00 (d, J=20.7 Hz, 2H), 3.20-3.06 (m, 2H), 1.79 (dd, J=15.0, 7.5 Hz, 2H) , 0.98 (t, J=7.3 Hz, 3H).
Calculated exact mass: 487.11
MS(ESI ⁺ ): 488.00 for [M+H] ⁺

Example 239: Synthesis of N-(3-(5-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,6-difluorophenyl)propane-1-sulfonamide

Analytical data:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (s, 1 H), 9.65 (s, 1 H), 8.36 (s, 1 H), 8.27 (s, 1H), 7.96 (s, 1H), 7.70-7.56 (m, 1H), 7.33 (t, J=8.9 Hz, 1H), 3.80-3.60 (m, 1H), 3.20-3.11 (m, 2H), 2.44-2.29 (m, 3H), 2.25-2.11 (m, 2H), 2.10-1 .97 (m, 1 H), 1.88 (d, J=9.1 Hz, 1 H), 1.81 (dd, J=15.2, 7.6 Hz, 2H), 1.00 ( t, J=7.4 Hz, 3H).

Calculated exact mass: 433.13 for C ₂₁ H ₂₁ F ₂ N ₃ O ₃ S (molecular weight: 433.47)

MS(ESI ⁺ ): 434.2 for [M+H] ⁺ .

Example 240: Synthesis of N-(2,6-difluoro-3-(5-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)-1-phenylmethanesulfonamide

To a solution of (3-amino-2,4-difluorophenyl)-[1-(2,6-dichlorobenzoyl)-5-pyridin-4-ylpyrrolo[2,3-b]pyridin-3-yl]methanone (0.200 g, 0.382 mmol) in 1,4-dioxane (0.837 ml) and pyridine (0.837 ml), phenylmethanesulfonyl chloride (0.109 g, 0.573 mmol) and 4-dimethylaminopyridine (0.00467 g, 0.0382 mmol) were added successively. The mixture was stirred at 60°C until the reaction was complete according to TLC. The crude material was diluted with EtOAc (50 ml) and washed twice with 1M HCl (aq, 20 ml). The organic phase was dried over sodium sulfate and the solvent was removed under vacuum. The product was purified by flash chromatography using DCM/MeOH (0-5%) as eluent. N-[2,6-difluoro-3-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl]-1-phenylmethanesulfonamide (0.0840 g, 0. 1550 mmol, 41% yield was obtained as an off-white solid (yield: 84 mg (40%), chemical purity (HPLC/UV): 93%).

Analytical data:

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 9.75 (s, 1H), 8.83 (dd, J=5.4, 2.2 Hz, 2H ), 8.68 (dd, J=4.5, 1.6 Hz, 2H), 8.14 (s, 1H), 7.82 (dd, J=4.5, 1.6 Hz, 2H) , 7.68 (dd, J=14.4, 7.7 Hz, 1H), 7.45 (dd, J=7.8, 1.5 Hz, 2H), 7.41-7.35 (m , 4H), 4.54 (s, 2H).

Calculated exact mass _{: 504.1 for C26H18F2N4O3S} (molecular weight: _504.51 )

MS(ESI-): 503.2 for [MH] ^- .

Examples 241 and 242: Synthesis of N-(2,4-difluoro-3-(5-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1- sulfonamide and N-(2,4-difluoro-3-(5-(1,2,3,4-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl) propane-1-sulfonamide

Analytical data:

Example 241:

^1H -NMR (400 MHz, DMSO-d6) δ 8.36-8.32 (m, 1H), 8.32-8.29 (m, 1H), 8.09 (s, 1H), 7. 56-7.48 (m, 1H), 7.20-7.13 (m, 1H), 3.06-2.99 (m, 3H), 2.98-2.84 (m, 4H), 1.99-1.89 (m, 2H), 1.89 -1.78 (m, 2H), 1.77-1.66 (m, 2H), 0.95 (t, J=7.4 Hz, 3H).

Calculated exact mass _{: 460.14 for C22H24F2N4O3S} (molecular weight: _462.52 )

MS(ESI+): 463.20 for [M+H] ⁺

Example 242:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J=1.9 Hz, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 8, 14 (s, 1H), 7.61-7.49 (m, 1H), 7.22 (t, J=8.7 Hz, 1H), 6.28 (s, 1H), 3.61 (s , 2H), 3.18 (t, J=5.6 Hz, 2H), 3.12-3.02 (m, 2H), 2.62 (s, 2H), 1.73 (dd, J= 15.2, 7.6 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H).

Calculated exact mass: 460.14 for C ₂₂ H ₂₂ F ₂ N ₄ O ₃ S (molecular weight: 460.50)

MS(ESI ⁺ ): 461.20 for [M+H] ⁺ .

Example 243: Biological activity

Example 243-1: Binding Assay Methods

Kinase activities of the compounds of the present invention were measured using KINOMEscan™ Profiling Service at DiscoveRx 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 targeting the active site. The assay was performed by combining three components: DNA-labeled kinase; immobilized ligand; and the connection under test. The ability of the test compound to compete with the immobilized ligand was assessed by quantitative DNA tag PCR. The technology is described in detail in the documents of Fabian, M.A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol., 23, 329-336 (2005) and Karaman, M.W. et al. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol., 26, 127-132 (2008).

To study the affinity for MKK4, BRaf, MKK7 and JNK1, kinases were produced in HEK-293 cells, and then their DNA was labeled for qPCR. To prepare affinity resins for kinase assays, streptavidin-coated magnetic microbeads were treated with biotinylated small molecule ligands for 30 min at room temperature. Ligand microbeads were blocked with excess biotin and washed with blocking buffer (SEABLOCK™ (Pierce), 1% BSA, 0.05% TWEEN®20, 1 mM DTT) to remove unbound ligands and reduce nonspecific binding. Binding reactions were performed by coupling kinases, ligand 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 microbeads were washed with wash buffer (1× PBS, 0.05% TWEEN®20). The microbeads were then resuspended in elution buffer (1× PBS, 0.05% TWEEN®20, 0.5 11M non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The concentration of kinases in the eluates was determined by qPCR.

Average Z' values and standard deviations for each kinase were calculated from fourteen control wells for each experiment in over 135 independent experiments performed over a 16-month period. Average Z'=0.71.

Efficacy of tested compounds:

Compounds were screened at the indicated concentrations and binding interactions were reported as % of control, where lower values indicate stronger binding, i.e. higher efficiency.

Details regarding the kinases tested are presented below in Table 6.

Test compounds were provided as 10 mM stock solutions. Test solutions at the indicated final concentrations were prepared in DiscoverX. The results are presented in Table 7.

Table 6:

BRaf MKK4 MKK7 JNK1 Group S.T.E. S.T.E. CMCG Kinase construct Truncated Full size Full size Registration number NP_003001.1 NP_660186.1 NP_002741.1 View Human Human Human Kinase form Wild type Wild type Wild type Expression system Mammals Mammals Mammals Amino acid
start/stop S84/D399 M1/R419 M1/Q384

Binding affinity for MKK4 and selectivity for BRaf, MKK7 and JNK1

The potency of illustrative examples against the protein kinases MKK4, BRaf, MKK7 and JNK1 was expressed as the residual percentage of control binding (PoC), which was determined at a concentration of 100 nM. The identified efficiencies were categorized as follows:

PoC @ 100 nM category

PoC < 1 +++

1 ≤ PoC < 3 ++

3 ≤ PoC < 30 +

30 ≤ PoC O

The binding selectivity of illustrative examples for the protein kinases BRaf, MKK7 and JNK1, collectively referred to as “off-target”, was determined by the ratios PoC (non-target)/PoC (MKK4). The ratios were ordered by category as follows:

Value category

Ratio > 100 +++

100 ≥ Ratio > 10++

10 ≥ Ratio > 3 +

3 ≥ O ratio

Table 7: Binding affinity of exemplary Examples for MKK4 and selectivity for BRaf, MKK7 and JNK1 based on binding affinity values expressed as % of control.

Example MKK4 (% of control @100 nM) Selectivity (% to control @100 nM) regarding Braf regarding MKK7 relative to JNK1 2b O O O O 2c +++ +++ +++ +++ 2d + + + + 2f + O + + 13 O O O O 14 O O O O 15 O O O O 16 O O O O 17 O O O O 18 + O + + 19 + ++ ++ ++ 20 + + ++ ++ 21 ++ ++ ++ ++ 22 + O ++ ++ 23 + O ++ + 24 + O ++ + 25 + O + + 26 ++ ++ ++ ++ 27 +++ +++ +++ +++ 28 ++ ++ ++ ++ 29 + O ++ ++ thirty +++ ++ +++ +++ 31 +++ O +++ +++ 32 + O + + 33 + ++ ++ ++ 34 + ++ ++ ++ 35 +++ + +++ +++ 36 ++ ++ ++ ++ 37 + + + + 38 + + + + 39 + + ++ ++ 40 +++ +++ +++ +++ 41 ++ ++ ++ ++ 42 + + + + 43 + + + + 44 + ++ ++ ++ 45 +++ + +++ +++ 46 +++ +++ +++ +++ 47 ++ + ++ ++ 48 + O ++ ++ 49 +++ O +++ +++ 50 +++ O +++ +++ 51 + O + O 52 + O ++ ++ 53 +++ + +++ +++ 58 +++ ++ +++ +++ 59 +++ O +++ +++ 60 + ++ ++ ++ 61 o o + + 62 o o o o 63 o o o o 64 o o o o 65 o o o o 66 o o o o 67 o o o o 68 + o + + 69 + ++ ++ ++ 77 +++ O +++ +++ 79 +++ +++ +++ +++ 81 +++ +++ +++ +++ 82 +++ +++ +++ +++ 83 +++ O +++ +++ 84 +++ O +++ +++ 85 + O ++ ++ 86 + 0 ++ ++ 87 O O O O 88 +++ + +++ +++ 100 + O ++ ++ 101 ++ O ++ ++ 102 ++ ++ ++ ++ 103 + O ++ ++ 104 + + ++ ++ 105 ++ O ++ ++ 106 + O + + 107 + + ++ ++ 108 +++ ++ +++ +++ 109 +++ + +++ +++ 110 O O O O 111 O O O O 120 + O ++ ++ 123 +++ ++ +++ +++ 124 + ++ ++ ++ 125 ++ ++ ++ ++ 126 + ++ ++ ++ 127 ++ ++ ++ ++ 128 ++ ++ ++ ++ 129 +++ +++ +++ +++ 146 +++ +++ +++ +++ 148 +++ +++ +++ +++ 156 +++ +++ +++ +++ 157 +++ +++ +++ +++ 158 +++ +++ +++ +++ 159 +++ +++ +++ +++ 160 +++ +++ +++ +++ 161 +++ +++ +++ +++ 162 +++ +++ +++ +++ 163 +++ +++ +++ +++ 175 +++ +++ +++ +++ 176 +++ +++ +++ +++ 177 +++ +++ +++ +++ 178 +++ +++ +++ +++ 179 +++ +++ +++ +++ 180 +++ +++ +++ +++ 181 +++ +++ +++ +++ 182 +++ +++ +++ +++ 183 +++ +++ +++ +++ 184 +++ +++ +++ +++ 211 +++ +++ +++ +++ 228 +++ +++ +++ +++ 229 +++ +++ +++ +++ 230 +++ +++ +++ +++ 231 +++ +++ +++ +++ 232 +++ +++ +++ +++ 233 +++ +++ +++ +++ 234 +++ +++ +++ +++ 240 +++ +++ +++ +++ 241 + O + + 242 + O + +

Example 243-2: Enzyme Assay

The kinase activities of the compounds of the present invention were measured using the 33PanQinase® Assay Service provided by ProQinase GmbH, Freiburg, Germany. Details of assay conditions are disclosed on the ProQinase website (https://www.proginase.com/products-services-biochemical-assay-service/kinase-assays). Briefly, all kinase assays were performed in 96-well FlashPlates™ from PerkinElmer (Boston, MA, USA) in a 50 μl reaction volume. The reaction mixture was pipetted in four stages in the following order:

• 20 µl assay buffer (standard buffer)

• 5 µl of ATP solution (in H ₂ O)

• 5 µl of test compound (in 10% DMSO)

• 20 µl enzyme/substrate mixture

The analytical mixture for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM _MgCl2 , 3 mM _MnCl2 , 3 μM sodium orthovanadate, 1.2 mM DTT, 50 μg/ml PEG20000, ATP (at various concentrations corresponding apparent affinity constant of the corresponding kinase ATP-Km), [γ-33P]-ATP (approximately 8×1005 cpm per well), protein kinase and substrate.

Reaction mixtures were incubated at 30°C for 60 minutes. The reaction was stopped by adding 50 μl of 2% (v/v) H ₃ PO ₄ , the plates were aspirated and washed twice with 20 μl of 0.9% (w/v) NaCl. ³³ P incorporation was determined using a microplate scintillation counter (Microbeta, Wallac).

All studies were performed on BeckmanCoulter/SAGIANTM Core System.

In the case of a single concentration assay, the potency of the test compound was expressed as % residual activity. To determine IC ₅₀ values, serial dilutions were tested over a final concentration range of 100 μM to 3 nM (10 concentrations). The appropriate model for determining IC ₅₀ was the “sigmoidal response (variable slope)” with the parameters “upper bound” fixed at 100% and “lower bound” fixed at 0%. The approximation method used was the least squares method.

Efficacy against MCC4:

Inhibition efficacy against MKK4 was categorized as follows:

Single concentration assay (100 nM):

category

Residual activity <50%: +++

50% ≤ Residual activity < 70%: ++

70% ≤ Residual activity < 90% +

Residual activity ≥ 90% O

Analysis with determination of IC ₅₀ values:

category

IC ₅₀ <100 nM: +++

100 nM <IC _50<1 µM: ++

1 µM <IC _50<10 µM: +

IC ₅₀ > 10 µM: O

The selectivity of test compounds for BRaf, JNK1 and MKK7, collectively referred to as “non-target”, was determined by the ratio IC ₅₀ (non-target)/IC ₅₀ (MKK4) and categorized as follows:

Category

IC ₅₀ (non-target)/IC ₅₀ (MKK4) > 100 +++

100 ≥ IC ₅₀ (non-target)/IC ₅₀ (MKK4) > 10 ++

10 ≥ IC ₅₀ (non-target)/IC ₅₀ (MKK4) > 3 +

3 ≥ IC ₅₀ (non-target)/IC ₅₀ (MKK4) O

Table 8: Biochemical potency of the illustrative Examples for MKK4 and selectivity for BRaf, MKK7 and JNK1 based on inhibition of enzymatic activity, obtained as single concentrations or as IC ₅₀ values.

Table 8

Example Method of analysis Efficiency Selectivity MKK4 Braf JNK1 MKK7 2b 100 nM + N/D N/D N/D 2c IC ₅₀ +++ ++ ++ +++ 2d 100 nM + N/D N/D N/D 2e IC ₅₀ ++ ++ + +++ 2f 100 nM + N/D N/D N/D 2g IC ₅₀ ++ O + +++ 2h IC ₅₀ ++ + ++ ++ 27 IC ₅₀ ++ O o +++ 32 100 nM + N/D N/D N/D 33 100 nM + N/D N/D N/D 34 100 nM + N/D N/D N/D 35 100 nM ++ N/D N/D N/D 36 100 nM + N/D N/D N/D 37 100 nM + N/D N/D N/D 38 100 nM + N/D N/D N/D 39 100 nM + N/D N/D N/D 40 100 nM + N/D N/D N/D 41 100 nM + N/D N/D N/D 42 100 nM + N/D N/D N/D 43 100 nM + N/D N/D N/D 44 100 nM + N/D N/D N/D 45 IC ₅₀ ++ o ++ +++ 46 IC ₅₀ ++ + + +++ 47 IC ₅₀ + N/D N/D N/D 48 IC ₅₀ + O O ++ 49 IC ₅₀ + N/D ++ ++ 50 IC ₅₀ ++ O O +++ 51 100 nM + N/D N/D N/D 52 100 nM + N/D N/D N/D 53 IC ₅₀ ++ O O +++ 54 IC ₅₀ ++ O O +++ 55 IC ₅₀ ++ O + +++ 56 IC ₅₀ ++ O O +++ 57 IC ₅₀ ++ O O +++ 58 IC ₅₀ ++ N/D O ++ 59 IC ₅₀ ++ O + +++ 60 IC ₅₀ + N/D N/D N/D 61 100 nM O N/D N/D N/D 62 100 nM o N/D N/D N/D 63 100 nM ++ N/D N/D N/D 64 100 nM + N/D N/D N/D 65 100 nM o N/D N/D N/D 66 100 nM o N/D N/D N/D 67 100 nM o N/D N/D N/D 68 100 nM + N/D N/D N/D 69 100 nM ++ N/D N/D N/D 70 IC ₅₀ ++ O ++ +++ 71 IC ₅₀ + O O ++ 74 IC ₅₀ ++ O + +++ 75 IC ₅₀ ++ O + +++ 76 IC ₅₀ ++ O + +++ 77 IC ₅₀ ++ O + +++ 78 IC ₅₀ ++ O + +++ 79 IC ₅₀ +++ + ++ +++ 80 IC ₅₀ +++ ++ ++ +++ 81 IC ₅₀ +++ + ++ +++ 82 IC ₅₀ ++ O + +++ 83 IC ₅₀ ++ N/D O ++ 84 IC ₅₀ ++ N/D O +++ 85 IC ₅₀ + N/D O ++ 86 IC ₅₀ + N/D O ++ 87 IC ₅₀ O N/D O O 88 IC ₅₀ ++ N/D O ++ 89 IC ₅₀ + O O ++ 90 IC ₅₀ + O O ++ 91 IC ₅₀ + O O ++ 92 IC ₅₀ + O O ++ 92 IC ₅₀ ++ + + +++ 93 IC ₅₀ ++ O ++ +++ 94 IC ₅₀ +++ O + +++ 95 IC ₅₀ ++ O O +++ 96 100 nM ++ N/D N/D N/D 97 IC ₅₀ ++ O + +++ 98 IC ₅₀ + O + ++ 99 IC ₅₀ ++ O O +++ 100 IC ₅₀ O N/D O O 101 IC ₅₀ ++ O O +++ 102 IC ₅₀ ++ O + +++ 103 IC ₅₀ ++ O + +++ 105 IC ₅₀ ++ O ++ +++ 106 IC ₅₀ ++ O + +++ 107 IC ₅₀ ++ O + +++ 108 IC ₅₀ +++ O + +++ 109 IC ₅₀ ++ O + +++ 110 IC ₅₀ ++ O + +++ 111 IC ₅₀ ++ O + +++ 113 IC ₅₀ ++ O + +++ 114 IC ₅₀ ++ O + +++ 115 IC ₅₀ ++ O + +++ 116 IC ₅₀ ++ O O +++ 117 IC ₅₀ + O O +++ 118 IC ₅₀ ++ O + +++ 119 IC ₅₀ ++ O O +++ 120 IC ₅₀ ++ N/D O ++ 121 IC ₅₀ ++ O O +++ 122 IC ₅₀ ++ O O +++ 123 IC ₅₀ ++ N/D O +++ 124 IC ₅₀ ++ +++ O +++ 125 IC ₅₀ ++ +++ + +++ 126 IC ₅₀ ++ +++ + +++ 127 IC ₅₀ ++ +++ + +++ 128 IC ₅₀ ++ +++ + +++ 129 IC ₅₀ ++ ++ + +++ 130 IC ₅₀ ++ ++ ++ +++ 131 IC ₅₀ ++ ++ ++ +++ 132 IC ₅₀ ++ ++ O +++ 133 IC ₅₀ ++ ++ O +++ 134 IC ₅₀ + O O ++ 135 IC ₅₀ + O O ++ 136 IC ₅₀ + O O ++ 137 IC ₅₀ ++ O + +++ 138 IC ₅₀ + O O ++ 140 IC ₅₀ + O O ++ 141 IC ₅₀ ++ ++ +++ +++ 142 IC ₅₀ +++ +++ +++ +++ 143 IC ₅₀ +++ +++ ++ +++ 144 IC ₅₀ +++ ++ +++ +++ 145 IC ₅₀ ++ ++ ++ +++ 146 IC ₅₀ +++ +++ +++ +++ 147 IC ₅₀ +++ ++ +++ +++ 148 IC ₅₀ +++ ++ +++ +++ 149 IC ₅₀ ++ ++ ++ +++ 150 IC ₅₀ +++ +++ +++ +++ 151 IC ₅₀ ++ ++ ++ +++ 152 IC ₅₀ +++ +++ ++ +++ 153 IC ₅₀ +++ +++ ++ +++ 154 IC ₅₀ +++ ++ ++ +++ 155 IC ₅₀ +++ +++ ++ +++ 156 IC ₅₀ +++ ++ +++ +++ 157 IC ₅₀ +++ +++ +++ +++ 158 IC ₅₀ +++ ++ +++ +++ 159 IC ₅₀ +++ ++ +++ +++ 160 IC ₅₀ +++ ++ ++ +++ 161 IC ₅₀ +++ ++ ++ +++ 162 IC ₅₀ ++ ++ ++ +++ 163 IC ₅₀ +++ ++ ++ +++ 164 IC ₅₀ +++ ++ ++ +++ 165 IC ₅₀ +++ +++ +++ +++ 166 IC ₅₀ +++ +++ +++ +++ 167 IC ₅₀ +++ +++ +++ +++ 168 IC ₅₀ ++ +++ ++ +++ 169 IC ₅₀ +++ +++ +++ +++ 170 IC ₅₀ +++ +++ +++ +++ 171 IC ₅₀ +++ +++ +++ +++ 172 IC ₅₀ +++ +++ +++ +++ 173 IC ₅₀ +++ +++ ++ +++ 175 IC ₅₀ +++ ++ + +++ 176 IC ₅₀ +++ ++ +++ +++ 177 IC ₅₀ +++ N/D +++ +++ 178 IC ₅₀ +++ N/D +++ +++ 179 IC ₅₀ +++ +++ +++ +++ 180 IC ₅₀ +++ +++ +++ +++ 181 IC ₅₀ ++ +++ ++ +++ 182 IC ₅₀ +++ +++ +++ +++ 183 IC ₅₀ ++ +++ +++ +++ 184 IC ₅₀ ++ +++ ++ +++ 185 IC ₅₀ ++ + ++ +++ 186 IC ₅₀ +++ +++ +++ +++ 187 IC ₅₀ ++ +++ +++ +++ 188 IC ₅₀ +++ +++ +++ +++ 189 IC ₅₀ ++ ++ ++ +++ 190 IC ₅₀ +++ +++ +++ +++ 191 IC ₅₀ ++ +++ +++ +++ 192 IC ₅₀ ++ +++ ++ +++ 193 IC ₅₀ +++ ++ +++ +++ 194 IC ₅₀ ++ ++ ++ +++ 195 IC ₅₀ +++ +++ +++ +++ 196 IC ₅₀ +++ +++ +++ +++ 197 IC ₅₀ ++ +++ ++ +++ 198 IC ₅₀ ++ ++ ++ +++ 199 IC ₅₀ +++ ++ ++ +++ 200 IC ₅₀ + + + +++ 201 IC ₅₀ +++ +++ +++ +++ 202 IC ₅₀ +++ ++ +++ +++ 203 IC ₅₀ +++ ++ +++ +++ 204 IC ₅₀ ++ ++ +++ +++ 205 IC ₅₀ ++ ++ ++ +++ 206 IC ₅₀ +++ +++ +++ +++ 207 IC ₅₀ ++ +++ ++ +++ 208 IC ₅₀ +++ ++ +++ ++ 209 IC ₅₀ +++ +++ +++ +++ 210 IC ₅₀ + ++ + ++ 211 IC ₅₀ ++ +++ ++ +++ 212 IC ₅₀ ++ + O +++ 213 IC ₅₀ +++ +++ ++ +++ 214 IC ₅₀ ++ +++ ++ +++ 215 IC ₅₀ ++ O + +++ 216 IC ₅₀ +++ +++ +++ +++ 217 IC ₅₀ +++ +++ +++ +++ 218 IC ₅₀ +++ +++ ++ +++ 219 IC ₅₀ +++ +++ ++ +++ 220 IC ₅₀ +++ ++ ++ +++ 221 IC ₅₀ +++ +++ ++ +++ 222 IC ₅₀ +++ +++ ++ +++ 223 IC ₅₀ +++ + ++ +++ 224 IC ₅₀ + O O ++ 225 IC ₅₀ +++ +++ ++ +++ 226 IC ₅₀ +++ +++ ++ +++ 227 IC ₅₀ +++ +++ +++ +++ 228 IC ₅₀ ++ N/D ++ ++ 229 IC ₅₀ +++ +++ +++ +++ 230 IC ₅₀ +++ +++ +++ +++ 231 IC ₅₀ +++ ++ ++ +++ 232 IC ₅₀ +++ +++ ++ +++ 233 IC ₅₀ +++ ++ +++ +++ 234 IC ₅₀ +++ N/D +++ +++ 235 IC ₅₀ +++ +++ +++ +++ 236 IC ₅₀ +++ +++ +++ +++ 237 IC ₅₀ +++ +++ +++ +++ 238 IC ₅₀ +++ +++ +++ +++ 239 IC ₅₀ +++ +++ ++ +++ 240 IC ₅₀ +++ +++ + +++ 241 IC ₅₀ + N/D O + 242 IC ₅₀ O N/D O ++

Claims (15)

1. Connection selected from: or a pharmaceutically acceptable salt thereof. 2. A compound characterized by the formula or a pharmaceutically acceptable salt thereof. 3. Pharmaceutical composition for enhancing liver regeneration or preventing or reducing the death of hepatocytes associated with selective inhibition of protein kinase MKK4 relative to protein kinases JNK1 and MKK7, containing a compound according to any one of paragraphs. 1, 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 4. Pharmaceutical composition for selective inhibition of protein kinase MKK4 relative to protein kinases JNK1 and MKK7, containing a compound according to any one of paragraphs. 1, 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 5 Use of a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1, 2 or compositions according to claim 3 or 4 for obtaining a pharmaceutical composition for enhancing liver regeneration or preventing or reducing the death of hepatocytes associated with selective inhibition of protein kinase MKK4 relative to protein kinases JNK1 and MKK7. 6. A method of enhancing liver regeneration or preventing or reducing the death of hepatocytes associated with selective inhibition of protein kinase MKK4 relative to protein kinases JNK1 and MKK7, where the method includes administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in any one of paragraphs. 1, 2 or the composition defined in paragraph 3 or 4.