RU2575635C2 - Derivative 6-carbonitrile dipyridopyrroles and application thereof in cancer treatment - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of general formula

or to its pharmaceutically acceptable salts, where X is CR⁴; Z is CR⁸; R² is H; R³ is H, halo or R⁹; R⁴: H, -(CR¹⁴R¹⁵)_nNR¹¹R¹², -(CR¹⁴R¹⁵)_nOR¹¹, monocycle, possessing 4-6 ring members, 1-2 of which represent heteroatoms, selected from nitrogen and oxygen, or bicycle, possessing 7-8 ring atoms, 1-2 of which represent heteroatoms, selected from nitrogen, where said monocycle and bicycle are optionally substituted by one group R¹³; each n independently represents 0-2; R⁵: H, -(CR¹⁴R¹⁵)_nNR¹¹R¹², -(CR¹⁴R¹⁵)_nOR¹¹; R⁶: H, CN or pyrazolyl, optionally substituted by one group R¹³; R⁸ is H; R⁹ is C1-6-alkyl; R¹¹ and R¹²: H, C1-6-alkyl, C3-6-cycloalkyl, monocycle, possessing 4-7 ring members, 1 of which represents heteroatom, selected from nitrogen and oxygen, or bicycle, possessing 7-8 ring atoms, 1 of which represents nitrogen heteroatom, where said alkyl, cycloalkyl, monocycle and bicycle are optionally substituted by from one to two groups R¹³; R¹¹ and R¹² together with N atom, which they are bound to, optionally form 4-7-membered monocyclic or bicyclic ring, possessing additional 0-1 heteroatoms, selected from O and N, said ring can be optionally substituted by from one to two groups R¹³; R¹³ represents halo, oxo, -(CR¹⁴R¹⁵)_nC(=Y')R¹⁶, -(CR¹⁴R¹⁵)_nNR¹⁶R¹⁷, -(CR¹⁴R¹⁵)_nOR¹⁶, -(CR¹⁴R¹⁵)_nNR¹⁶C(=Y')R¹⁷ or R¹⁶; R¹⁴ and R¹⁵ are H; R¹⁶ and R¹⁷: H, C1-6-alkyl, monocycle, possessing 4-6 ring members, 1-2 of which represent heteroatoms, selected from nitrogen and oxygen, or bicycle, possessing 7-8 ring atoms, 1 of which represents nitrogen heteroatom, where said alkyl, monocycle or bicycle are optionally substituted by from one to three groups R¹⁸; R¹⁶ and R¹⁷ together with N atom, which they are bound to, optionally form 5-6-membered ring, possessing additional 0-1 heteroatoms, selected from O, said ring can be optionally substituted by from one to two groups R¹⁸; R¹⁸: C1-6-alkyl, C3-6-cycloalkyl, monocycle, possessing 4-5 ring members, 1 of which represents heteroatom, selected from nitrogen and oxygen, or bicycle, possessing 7-8 ring atoms, 1-2 of which represent heteroatoms, selected from nitrogen, halo, CF₃, -(CR¹⁹R²⁰)_nOR²³, -(CR¹⁹R²⁰)_nS(O)₂R²³ or -(CR¹⁹R²⁰)_nS(O)₂NR²³R²⁴, where said alkyl is optionally substituted by one group R²¹; R¹⁹ and R²⁰ are H; R²³ and R²⁴: H, C1-6-alkyl; each R²¹ independently represents H or halogen; Y' represents O. Invention also relates to intermediate compounds, pharmaceutical composition based on formula (i) compound, method of inhibiting abnormal cell growth or treatment of hyperproliferative disorders and method for treatment of tumour disease, based on application of formula (I) compound, application of formula (I) compound.

EFFECT: obtained are novel compounds, useful in treatment of hyperproliferative disorders.

29 cl, 1 dwg, 7 tbl, 180 ex

Description

The present invention relates to 1,7-diazacarbazole compounds that are useful as kinase inhibitors, more particularly as checkpoint kinase 1 (chk1) inhibitors, and thus are useful as antitumor drugs. The present invention also relates to compositions, more specifically to pharmaceutical compositions comprising these compounds, and methods for using them to treat various forms of cancer or hyperproliferative diseases, as well as to methods of using said compounds for in vitro, in situ and in vivo diagnosis or treatment mammalian cells or related pathological conditions.

Individual cells divide by creating an exact copy of their chromosomes, and then dividing them into separate cells. This cycle of DNA replication, separation and separation of chromosomes is regulated by intracellular mechanisms that support the sequence of stages and control the exact execution of each stage. In this process, there are control points (checkpoints) of the cell cycle (Hartwell et al., Science, Nov. 3, 1989, 246 (4930): 629-34), in which cells can stop the division process to allow time for DNA repair mechanisms before going through through a cycle into mitosis. There are two such control points in the cell cycle - the control point G1 / S, which is regulated by the p53 protein, and the control point G2 / M, which is controlled by the serine / threonine kinase - checkpoint kinase 1 (chk1).

Chk1 and chk2 are structurally unrelated but functionally overlapping serine / threonine kinases activated by genotoxic stimuli (reviewed by Bartek et al., Nat. Rev. Mol. Cell Biol. 2001, vol. 2, pp. 877-886). Chk1 and chk2 will switch checkpoint signals from ATM and ATR protein kinases, which phosphorylate and activate them. Chk2 is a stable protein expressed during the cell cycle, mainly activated by ATM in response to double-stranded DNA breaks. In contrast, Chk1 protein expression is significantly reduced at the S and G2 phases of the cell cycle. In response to DNA damage, Chk1 is phosphorylated and activated via ATM / ATR, leading to arrest of the cell cycle in S and G2 / M phases to repair DNA damage (described in Cancer Cell, Bartek and Lukas, Volume 3, Issue 5, May 2003, Pages 421-429). Inhibition of Chk1 has been shown to remove cell cycle arrest, leading to an increase in cancer cell death, accompanied by DNA damage by various chemotherapeutic agents. Cells with missing intact G1 checkpoints are partially dependent on S and G2 / m checkpoints, and thus are thought to be more sensitive to chemotherapeutic treatment in the presence of a Chk1 inhibitor, while normal cells with a functioning checkpoint in G1 phase are expected to be less prone to cell death.

The present invention relates to 1,7-diazacarbazoles of Formula (I), (Ia), and / or (Ib) (and / or their solvates, hydrates and / or salts) having inhibitory activity against kinases, more specifically inhibitory activity in against kinase chk1. The compounds of the present invention are also useful as inhibitors of kinase-3-glycogen synthase (GSK-3), KDR kinase, and FMS-like tyrosine kinase 3 (FLT3). Accordingly, the compounds of the present invention and their compositions are useful in the treatment of hyperproliferative diseases, such as tumors.

X represents CR ² or N;

Y represents CR ⁴ or N;

Z represents CR ⁸ or N; with the proviso that at least one of X, Y or Z simultaneously represents N;

R ² represents H, halogen, CN, CF ₃ , —OCF ₃ , OH, —NO ₂ , C ₁ -C ₅ alkyl, —O (C ₁ -C ₅ alkyl), —S (C ₁ -C ₅ alkyl) or N (R ²² ₂ ;,

R ³ represents H, halogen, CN, —OR ⁹ , —N (R ²² ) —R ⁹ , —S (O) _p —R ⁹ or R ⁹ ;

p represents 0, 1 or 2;

R ⁴ represents H, halogen, CN, CF ₃ , —OCF ₃ , OH, —NO ₂ , - (CR ¹⁴ R ¹⁵ ) _n C (= Y ′) OR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n C ( = Y ') NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n OR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n S (O) _p R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² C (= Y ') R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² C (= Y') OR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² C (= Y ') NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² SO ₂ R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n OC (= Y) R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n OC (= Y ') NR ¹¹ R ^12, - (CR ¹⁴ R ¹⁵⁾ _n S (O) ₂ NR ¹¹ R ^12, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one to four R ¹³ groups;

each n independently represents 0-5;

R ⁵ represents H, halogen, CN, CF ₃ , —OCF ₃ , OH, —NO ₂ , - (CR ¹⁴ R ¹⁵ ) _n C (Y ′) OR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n C (= Y ') _n NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² C (= Y') R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n OR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n S (O) _p R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² C (= Y ') OR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² C (= Y ') NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² SO ₂ R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n OC (= Y') R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n OC ( = Y ') NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n S (O) ₂ NR ¹¹ R ¹² , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,

wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one to four R ¹³ groups;

R ⁶ is H, CN, —CF ₃ , —OCF ₃ , halogen, —C (= Y ′) OR ¹¹ , —C (= Y ′) NR ¹¹ R ¹² , —OR ¹¹ , —OC (= Y ′ ) R ¹¹ , -NR ¹¹ R ¹² , -NR ¹² C (= Y ') R ¹¹ , -NR ¹² C (= Y') NR ¹¹ R ¹² , -NR ¹² S (O) _q R ¹¹ , -SR ¹¹ , -S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -OC (= Y ') NR ¹¹ R ¹² , -S (O) ₂ NR ¹¹ R ¹² , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one to four R ¹³ groups;

R ⁷ represents H, OH, CN, O (C ₁ -C ₃ alkyl) or C ₁ -C ₄ alkyl, where each specified alkyl is optionally substituted with one to three groups independently selected from halogen, N (R ²² ) ₂ or OR ²² ;

R ⁸ represents H, halogen, CN, NO ₂ , N (R ²² ) ₂ , OH, O (C ₁ -C ₃ alkyl), or C ₁ -C ₃ alkyl, wherein each said alkyl is optionally substituted with one to three fluoride groups;

each R ⁹ group independently represents alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, where each member of R ^{9 is} independently substituted with one to three R ¹⁰ groups;

each R ¹⁰ group independently represents H, CN, —CF ₃ , —OCF ₃ , —NO ₂ , halogen, R ¹¹ , —OR ¹¹ , —NR ¹² C (= Y ′) R ¹¹ , —NR ¹² C (= NR ¹² ) R ¹¹ , -NR ¹² S (O) _q R ¹¹ , -SR ¹¹ , -NR ¹¹ R ¹² , oxo, -C (= Y ') OR ¹¹ , -C (= Y') NR ¹¹ R ¹² , -S (O) _q R ¹¹ , -NR ¹² C (= Y ') OR ¹¹ , -NR ¹² C (= Y') NR ¹¹ R ¹² , -OC (= Y ') R ¹¹ , -OC (= Y ') NR ¹¹ R ¹² or -S (O) ₂ NR ¹¹ R ¹² ;

each q independently represents 1 or 2;

R ¹¹ and R ¹² independently represent H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one to four R ¹³ groups, and where two geminal groups of R ^{13 are} optionally taken together with the atom to which they are attached, form a 3-6 membered ring having an additional 0-2 heteroatoms selected from O, S and N, while this ring may optionally be substituted with one to four R ¹⁸ groups;

R ¹¹ and R ¹² optionally taken together with the attached N atom form a 4-7 membered ring having an additional 0-2 heteroatoms selected from O, S and N, wherein said ring may optionally be substituted with one to four R ¹³ groups;

each R ¹³ group independently represents halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, - (CR ¹⁴ R ¹⁵ ) ₂ C = (Y ′) R ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹⁶ R ¹⁷ , - (CR ¹⁴ R ¹⁵ ) _n OR ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n SR ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹⁶ C (= Y ') R ¹⁷ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹⁶ C (= Y') OR ¹⁷ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹⁷ C (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n OC (= Y') R ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁴ R ¹⁵ ) _n S (O) R ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ or R ¹⁶ ;

R ¹⁴ and R ^{15 are} independently selected from H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one to four R ¹⁸ groups;

R ¹⁶ and R ¹⁷ independently represent H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one to four R ¹⁸ groups;

R ¹⁶ and R ¹⁷ R ¹² optionally taken together with the attached N atom form a 5-6 membered ring having an additional 0-2 heteroatoms selected from O, S and N, wherein said ring may optionally be substituted with one to four R groups ¹⁸ ;

each R ¹⁸ group independently represents H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, - (CR ¹⁹ R ²⁰ ) _n C (= Y ′) R ²³ , - (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ²³ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ²³ R ²⁴ , - (CR ¹⁹ R ²⁰ ) _n NR ²³ R ²⁴ , - (CR ¹⁹ R ²⁰ ) _n OR ²³ , - (CR ¹⁹ R ²⁰ ) _n -SR ²³ . - (CR ¹⁹ R ²⁰ ) _n NR ²⁴ C (= Y ') R ²³ , - (CR ¹⁹ R ²⁰ ) _n NR ²⁴ C (= Y') OR ²³ , - (CR ¹⁹ R ²⁰ ) _n NR ²² C ( = Y ') NR ²³ R ²⁴ , - (CR ¹⁹ R ²⁰ ) _n NR ²⁴ SO ₂ R ²³ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') R ²³ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ²³ R ²⁴ , - (CR ¹⁹ R ²⁰ ) _n S (O) R ²³ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ²³ or - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ²³ R ²⁴ , wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R ²¹ groups;

R ¹⁹ and R ²⁰ independently represent H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one to four R ²⁵ groups;

R ²³ and R ²⁴ independently represent H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R ²¹ groups;

R ²³ and R ²⁴ R ¹² optionally taken together with the attached N atom form a 5-6 membered ring having an additional 0-2 heteroatoms selected from O, S and N, wherein said ring may optionally be substituted with one to four R groups ²¹ ;

each R ²¹ group independently represents H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, —C (= Y ′) R ²⁵ , —C (= Y ') OR ²⁵ , -C (= Y') NR ²⁵ R ²⁶ , -NR ²⁵ R ²⁶ , -OR ²⁵ , -SR ²⁵ , -NR ²⁶ C (= Y ') R ²⁵ , -NR ²⁶ C (= Y ') OR ²⁵ , -NR ²² C (= Y') NR ²⁵ R ²⁶ , -NR ²⁶ R ²⁵ , -OC (= Y ') R ²⁵ , -OC (= Y') NR ²⁵ R ²⁶ , -S (O) R ²⁵ , —S (O) ₂ R ^25, or —S (O) ₂ NR ²⁵ R ²⁶ , wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R ²⁵ groups;

each group R ²⁵ and R ²⁶ independently represents H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four groups selected from halogen, —CN, —OCF ₃ , -CF ₃ , -NO ₂ , -C ₁ -C ₆ alkyl, -OH, oxo, -SH, -O (C ₁ -C ₊ alkyl), -S (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -SO ₂ (C ₁ -C ₆ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) SO ₂ (C ₁ -C ₆ alkyl), -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) ₂ , -OC (O) NH ₂ , -OC (O) NH (C ₁ -C ₆ alkyl), -OC (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) NH (C ₁ -C ₆ alkyl), -NHC (O) N (C ₁ -C ₆ alkyl) ₂ , -N (C ₁ -C ₆ alkyl) C (O) NH (C ₁ - C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) NH (C ₁ -C ₆ alkyl), -NHC (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) O (C ₁ -C ₆ alkyl) and -N (C ₁ -C ₆ alkyl) C (O) O (C ₁ -C ₆ alkyl);

R ²⁵ and R ²⁶ is optionally taken together with the attached N atom form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S and N, wherein said ring may be optionally substituted by one to four groups selected from the following: halogen, —CN, —OCF ₃ , CF ₃ , —NO ₂ , —C ₁ -C ₆ alkyl, —OH, oxo, —SH, —O (C ₁ -C ₆ alkyl), —S (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -SO ₂ (C ₁ -C ₆ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) SO ₂ (C ₁ -C ₆ alkyl), -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) ₂ , -OC (O) NH ₂ , -OC (O) NH (C ₁ -C ₆ alkyl ), -OC (O) N ( C ₁ -C ₆ alkyl) _2, -NHC (O) NH (C ₁ -C ₆ alkyl), -NHC (O) N ( C ₁ -C ₆ alkyl) 2 - N (C ₁ -C ₆ alkyl) C (O) NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) NH (C ₁ -C ₆ alkyl), -NHC (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) O (C ₁ -C ₆ alkyl) and -N (C ₁ - C ₆ alkyl) C (O) O (C ₁ -C ₆ alkyl);

Y 'is independently O, NR ²² or S;

each R ²² group independently is H or C ₁ -C ₆ alkyl; and

despite the fact that (1) R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁸ are not simultaneously H; and (2) when X represents CH, Y represents CH, R ⁵ represents H, Z represents CR ⁸ and R ³ represents H or alkyl, then R ^{6 is} not —C (= Y ′) OR ¹¹ .

The present invention includes compositions (eg, pharmaceutical compositions) comprising the compounds of Formulas (I), (Ia) and / or (Ib) (and / or their solvates, hydrates and / or salts) and a carrier (pharmaceutically acceptable carrier). The present invention also includes compositions (eg, pharmaceutical compositions) comprising compounds of formula (I), (Ia) and / or (Ib) (and / or their solvates, hydrates and / or salts) and a carrier (pharmaceutically acceptable carrier), further comprising a second therapeutic agent. The compositions of the present invention are also useful for inhibiting abnormal cell growth or in treating hyperproliferative diseases in mammals (e.g., humans), such as tumors.

The present invention includes a method of inhibiting abnormal cell growth or treating hyperproliferative diseases in mammals (e.g., humans), such as tumors, comprising administering to said mammal a therapeutically effective amount of compounds of formula (I), (Ia) and / or (Ib) (and / or their solvates, hydrates and / or salts) or their compositions, alone or in combination with a second chemotherapeutic agent.

The present invention includes a method of using the claimed compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells, organisms or associated pathological conditions.

Next will be disclosed in detail certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. Although the invention will be described in relation to the listed embodiments, it is understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that may be included in the scope of the present invention as defined by the claims. A person skilled in the art will recognize many methods and materials similar or equivalent to those described in the present invention that can be used in the practice of the present invention. The present invention is in no way limited to the described methods and materials. In the case where one or more of the used literary sources of information, patents and similar materials differ from or contradict the present description, including, but not limited to, the disclosed terms, the use of terms, described methods, etc., the interpretation according to the present invention is the main one.

The term “alkyl” as used in the present invention refers to saturated, linear or branched chain monovalent hydrocarbon radicals comprising from one to twelve carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH _3), ethyl (Et, -CH ₂ CH _3), 1-propyl (n-Pr, n-propyl, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, isopropyl, -CH (CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, i-butyl, isobutyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, sec-butyl, - CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl (f-Bu, f-butyl, tert-butyl, -C (CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH ₃ ) cH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2- butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-hexi l (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) ( CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ ) (CH ₂ CH ₃ ) _2), 2-methyl-3-pentyl (-CH (CH ₂ CH ₃₎ CH (CH _{3) 2),} 2,3-dimethyl-2-butyl (-C (CH _{3) 2} CH (CH _{3) 2} ), 3,3-dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ ) ₃ , 1-heptyl, 1-octyl, and the like.

The term "alkenyl" refers to a linear or branched chain monovalent hydrocarbon radicals containing from one to twelve carbon atoms and containing at least one unsaturated carbon-carbon bond, sp ² double bond, while the alkenyl radical includes radicals having "cis-" and a "trans" orientation, or alternatively a "Y" and "Z" orientation. Examples include, but are not limited to, ethenyl or vinyl (—CH = CH ₂ ), allyl (—CH ₂ CH = CH ₂ ), and the like.

The term "alkynyl" refers to linear or branched monovalent hydrocarbon radicals containing from one to twelve carbon atoms and containing at least one unsaturated carbon-carbon bond, sp triple bond. Examples include, but are not limited to, ethynyl (—C = CH), propynyl (propargyl, —CH ₂ C = CH), and the like.

The term “cycloalkyl” refers to monovalent non-aromatic, saturated or unsaturated rings consisting of 3-12 carbon atoms in the case of monocyclic rings and from 6 to 12 carbon atoms in the case of bicyclic rings. Bicyclic carbon ring structures having from 6 to 12 carbon atoms can exist, for example, in the form of a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can exist in the form of [5,6] or [6,6] systems, or in the form of bridging systems such as bicyclo [2.2.1] heptane, bicyclo [2.2.2] oxian and bicyclo [3.2 .2] nonane. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1 -cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclodedecyl and the like.

“Aryl” means a monovalent hydrocarbon radical of 6-14 atoms obtained by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. Some aryl groups are designated in the structure of examples as “Ar”. Aryls include bicyclic radicals containing aromatic rings fused to saturated or unsaturated rings or aromatic carbocyclic or heterocyclic rings. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.

The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” are used interchangeably and mean saturated or unsaturated (ie, having at least one double bond inside the ring) carbocyclic radical of 3-14 ring atoms in which at least one the ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms are carbon, with at least one ring atom optionally independently substituted with one or more substituents, op further. The heterocycle may be a monocycle having 3-7 ring members (from 2 to 6 carbon atoms and from 1 to 4 heteroatoms selected from N, O and S) or a bicycle having 6-10 ring members (from 4 to 9 carbon atoms and from 1 to 6 heteroatoms selected from N, O and S), for example, bicyclo [4,5], [5,5], [5,6] or [6,6] systems or bridging [2.1.1] , [2.2.1], [2.2.2] or [3.2.2] of the system. Heterocycles are described by Paquette, Leo A .; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), in particular in Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular, Issues 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82: 5566. "Heterocyclyl" also includes radicals in which heterocyclic radicals are fused to saturated or unsaturated rings or aromatic carbocyclic or heterocyclic rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, tioksanil, piperazinyl, homopiperazinyl, azetidinyl, Occitania, thietanyl, homopiperidinyl, oksipanil, tiepanil, oxazepinyl, diazepinyl , thiazepinyl, 2-pyrroinyl, 3-pyrroinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianil, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl idazolinil, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl and azabicyclo [2.2.2] hexanyl. Spiro residues are also included in the scope of the definition of this term. Examples of heterocyclic groups in which ring atoms are replaced by oxo (= O) residues are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.

The term “heteroaryl” refers to monovalent aromatic radicals of 5-6 membered rings and includes fused ring systems (at least one of which is aromatic) of 5-16 atoms containing at least one heteroatom independently selected from nitrogen, oxygen and sulfur.

Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolazole, thiazolazole pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolisinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, benzothiothianothiaziolazothiazioiaziol nzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and fluoropyridinyl.

Heterocyclic or heteroaryl groups may be attached via carbon (carbon-linked) or nitrogen (nitrogen-linked) where possible. As an example, and not for the purpose of limitation, carbon-bound heterocycles and heteroaryls are attached at the 2, 3, 4, 5, or 6 position of pyridine, at the 3, 4, 5, or 6 position of pyridazine, the 2, 4, 5, or 6 position of pyrimidine , at 2, 3, 5 or 6 positions of pyrazine, at 2, 3, 4 or 5 positions of furan, tetrahydrofuran, thiophene, tetrahydrothiophene, pyrrole or pyrrolidine, at 2, 4 or 5 positions of oxazole, imidazole or thiazole, 3, 4 or 5 positions of isoxazole, pyrazole or isothiazole, 2 or 3 positions of aziridine, 2, 3 or 4 positions of azetidine, 2, 3, 4, 5, 6, 7 or 8 positions of quinoline or 1, 3, 4, 5 6,7 or 8 positions of isoquinoline.

For the purpose of illustration, and not limitation, nitrogen-bound heterocycles or heteroaryls can be attached at the 1st position for aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-oxo-1,2-dihydropyridine or 4-oxo-1,4-dihydropyridine; on the 2nd position of isoindole or isoindoline; on the 4th position of morpholine and on the 9th position of carbazole or (3-carboline.

The term "halo" means F, Cl, Br or I. The heteroatoms present in heteroaryl or heterocyclyl composition include the oxidized forms such as ^{N + → O -, S (} O) and S (O) ^2.

The terms “treat” and “treatment” refer to both therapeutic treatment and prophylactic or preventative measures in which an object prevents or reduces unwanted physiological changes or disorders, such as the development or growth of a tumor. As purposes of the present invention, beneficial or desirable results include, but are not limited to, alleviating symptoms, reducing the degree of disease, stabilizing (i.e., not worsening) the condition of the disease, delaying or slowing the progression of the disease, improving or temporarily weakening the condition of the disease, and remission (partial or complete), both identifiable and non-identifiable. “Treatment” can also mean life extension compared to life expectancy without treatment. Those in need of treatment include those who are already in a condition or disease, as well as those who are at risk of developing a condition or disease, or those in whom such conditions or diseases are prevented.

The phrase “therapeutically effective amount” means an amount of a compound of the present invention that 1) treats or prevents a particular disease, condition or disorder, 2) alleviates, improves or alleviates one or more symptoms of a particular disease, condition or disorder, or 3) prevents or delays the onset of at least one symptom of a particular disease, condition or disorder described in the present invention. In the case of tumors, a therapeutically effective amount of the drug can reduce the number of cancer cells, reduce the size of the tumor, inhibit (i.e. delay, to some extent, or preferably stop the growth) of tumor metastases, inhibit, to some extent, tumor growth, and / or remove, to some extent, at least one symptom associated with the tumor. With regard to the volume of a drug capable of preventing the growth or destruction of existing cancer cells, it may be cytostatic and / or cytotoxic. In the case of tumor therapy, the effectiveness can be measured, for example, by estimating the time of development of the disease (TTR) and / or determining the response rate (RR).

The terms "abnormal cell growth" and "hyperproliferative disease" are used interchangeably in the present invention. "Abnormal cell growth" is used here, unless otherwise indicated, in relation to cell growth, which occurs independently of normal regulatory mechanisms. Which includes, for example, the abnormal growth of: (1) tumor cells (tumors) that proliferate by expression of a mutated tyrosine kinase or overexpression of tyrosine kinase receptors; (2) benign and malignant cells in other proliferative diseases in which abnormal tyrosine kinase activation occurs; (3) any tumors that proliferate through tyrosine kinase receptors; (4) any tumors that proliferate through abnormal activation of serine / threonine kinase, and (5) benign and malignant cells in other proliferative diseases in which abnormal activation of serine / threonine kinase occurs.

The term “tumor” and “tumor” refers to or describes the physiological conditions in mammals, which are usually characterized by unregulated cell growth. A “tumor” contains one or more cancer cells. The tumor includes liquid and solid tumors. Examples of tumors include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, myelomas, and leukemia or lymphoid malignancies. More specific examples of such tumors include squamous cell carcinoma (e.g., squamous cell carcinoma of the skin), lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and squamous cell lung cancer, peritoneal cancer, hepatocellular cancer, gastric cancer, including a gastrointestinal tumor tract, pancreatic tumor, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colon cancer, colorectal cancer, malignant thyroid tumors of the brain, melanoma, endometrial or uterine carcinoma, salivary carcinoma, kidney cancer, prostate cancer, cancer of the female genital organs, thyroid cancer, hepatocarcinoma, anal carcinoma, penile carcinoma, neck and head cancer, as well as acute myelocytic leukemia (AML).

A “chemotherapeutic agent” is a chemical compound useful in the treatment of tumor diseases. Examples of chemotherapeutic agents include Ertolinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novmatis) mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016bline, Glax) SCH 66336), Sorafenib (BAY43-9006, Bayer Labs) and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkyl sulfonates such as busulfan, improsulfane and piposulfan; aziridines, such as benzodopa, carboxwon, meturedopa and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylene melamine, triethylene phosphoride, triethylene thiophosphoramide and trimethyl melamine; acetogenins (especially bullatacin and bullatacinone); bryostatin; callistatin; CC-1065 (including its synthetic analogs, adozelesin, carzelesin and biselezin); cryptophycins (in particular cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pankratistatin; sarcodictin; spongistatin; folic acid analogues such as denopterin, methotrexate, pteropterin, trimethixate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, karmofur, cytarabine, dideoxyuridine, doxyfluridine, enocytabine, phloxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostan, testolactone; anti-adrenergic drugs such as aminoglutthymidine, mitotan, trilostane; folic acid enhancers such as frolinic acid; Aceglaton; aldophosphamide glycoside; aminolevulinic acid; enyluracil; bestrabucil; bisanthrene; edatraxate; defofamine; Demecolcin; diaziquon; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; lentinan; lonidine; maytansinoids such as maytansine and anzamitocins; mitoguazone; mittoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pyrarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; PSK (polysaccharide complex (JHS Natural Products, Eugene, OR); rasoxane; rhizoccin; sisofiran; spirogermanium; tenuazonic acid; triaziquon; 2,2 ', 2 ”trichlorotriethylamine; trichotecenes (especially T-2 toxin, verracurin A, roridine A and anguidine); urethane; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobromane; gacitosin; arabinoside ("Ara-C"); chloranbucil; 6-thioguanine; mercapturine; ifosfamide; Aphosphonide; amindecrine; amindecrine; ®); ibandronate; CPT-11; difluoromethylornithine (DMFO); and pharmaceutically acceptable salts, acids, or other derivatives of any of the foregoing compounds.

The term “chemotherapeutic agent” also includes: (i) anti-hormonal agents that act as regulators or inhibitors of hormonal effects on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® ; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxy tamoxifen, trioxifene, keoxifen, LY117018, onapriston and FARESTON ((toremifine citrate); (ii) aromatase inhibitors that inhibit the aromatase enzyme that regulates estrogen production in the adrenal gland such as, for example, 4 (5) -imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN ((extremum; Pfizer), formestane, fadrazole, RIVISOR ((Vorozol), FEMARA ((letrozole; Novartis) and ARIMIDEX ((anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxocitabine (a 1,3-dioxalane nucleoside analog of cytosine); (iv) protein kinase inhibitors; (v ) lipid kinase inhibitors; (vi) antisense oligonucleotides, in particular those that suppress the expression of signaling pathway genes involved in abnormal cell proliferation, such as, for example, PKC alpha, Ralf and H-Ras; (vii) ribozymes, such as a VEGF expression inhibitor (e.g. ANGIOZYME®) and HER2 gene expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example ALLOVECTIN®, LEUVECTIN (and VAXID®, PROLEUKIN (rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABARELIX (rmRH; (ix) antiangiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids or derivatives of any of the above compounds.

Other examples of “chemotherapeutic agents” can be used in combination with the present compounds, including MEK inhibitors (MAP kinase kinases), such as XL518 (Exelixis, Inc.) and AZD6244 (Astrazeneca); Raf inhibitors such as XL281 (Exelixis, Inc.), PLX4032 (Plexxikon) and ISIS5132 (Isis Pharmaceuticals); mTor inhibitors (mammalian rapamycin targets) such as rapamycin, AP23573 (Ariad Pharmaceuticals), temsirolimus (Wyeth Pharmaceuticals) and RAD001 (Novartis); PI3K inhibitors (phosphoinositide-3 kinase) such as SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.) and GDC-0941 (Genentech ); cMet inhibitors such as PHA665752 (Pfizer), XL-880 (Exelixis, Inc.), ARQ-197 (ArQule) and CE-355621; and pharmaceutically acceptable salts, acids or derivatives of any of the above compounds.

Examples of “chemotherapeutic agents” also include DNA damaging agents, such as thiotepa and CYTOXAN (cyclophosphamide; alkylating agents (eg cisplatin; carboplatin; cyclophosphamide; nitrogen mustards, such as chlorambucil, chlorofazamide, chlorofazamide, esteramtamide mechlorfamide, mechthloromethine mech, chlorofosfamide, mesthramistine mechmefinemech, mechthloromethine mech, chlorofosfamide, mestramistine mechmefide and hydrochloride, melphalan, novembikhine, phenesterol, prednimustine, trophosphamide, uramustine; busulfan; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine and temozolomide); antimetabolites (n for example, antifolates such as 5-fluorouracil (5-FU) fluoropyrimidines and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and GEMZAR ((gemcitabine); antitumor antibiotics such as potassium endeic antibiotics, e.g. and calicheamicin omega II (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); anthracyclines such as adriamycin; dinemycin, including dinemycin A; bisphosphonates, such as clodronate; esperamycin; as well as neocarcinostatin chromophore and the associated chromophores of chromoprotein enediin antibiotics), aclacinomisins, actinomycin, autramycin, azaserin, bleomycin, cactinomycin, carabicin, carminomycin, carcinofilin, dactin-dactin-dactin-dactin -norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mytomycin, mytomycin, mitomycin amitsin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubitsin, streptonigrin, streptozocin, tubercidin, ubenimex, tsinostatin and zorubicin; antimitotic agents (e.g. vinca alkaloids such as vincristine, vinblastine, vindesine and NAVELBINE® (vinorelbine) and taxoids such as TAXOL ((paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ((free from cream) - nanoparticle-containing compositions of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois) and TAXOTERE ((doxetaxel; Rhone-Poulenc Rorer, Antony, France); topoisomerase inhibitors (e.g., RFS 2000, epipodophyllotoxins like etoposide and teniposide, amc, amc synthetic analogues of topotecan), and irinotecan and SN-38) and agents cell differentiation (e.g. retinoids such as all trans-retinoic acids, 13-cis-retinoic acid and phenretinide); and pharmaceutically acceptable salts, acids or derivatives of any of the above compounds.

“Chemotherapeutic agents” also include agents that modulate the apoptotic response, including IAP inhibitors (apoptosis protein inhibitors) such as AEG40826 (Aegera Therapeutics); and bcl-2 inhibitors such as GX15-070 (Gemin X Biotechnologies), CND0103 (apogossypol; Coronado Biosciences), HA14-1 (ethyl-2-amino-6-bromo-4- (1-cyano-2-ethoxy- 2-oxoethyl) -4H-chromene-3-carboxylate), AT101 (Ascenta Therapeutics), ABT-737 and ABT-263 (Abbott) and pharmaceutically acceptable salts, acids or derivatives of any of the above compounds.

The term “prodrug” as used in the present invention refers to precursors or derivative forms of the compounds of the present invention that are capable of enzymatic or hydrolytic activation or conversion to a more active parent form. For example, see Wilman, "Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions, 14, cc. 375-382, 615th Meeting Belfast (1986) and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al., (Ed.), Cc. 247-267, Humana Press (1985). Prodrugs of the present invention include, but are not limited to, ether-containing Prodrugs, phosphate-containing Prodrugs, thiophosphate-containing Prodrugs, sulfate-containing Prodrugs, peptide-containing Prodrugs modified by D-amino acids Prodrugs, glycosylated Prodrugs, β-lactam-containing Prodrugs, optionally substituted phenoxyacetamide-containing prodrugs, optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine and other 5-fluoruridine proletar substances that can be converted into more active non-cytotoxic drugs. Examples of cytotoxic drugs that can be modified into prodrug form include, but are not limited to, the compounds of the present invention and chemotherapeutic agents, such as described above.

A "metabolite" is a product produced in the body from a specific compound or its salt. Metabolites of the compounds can be identified using conventional methods known in the art, and their activity is determined using tests that are, for example, described in the present invention. Such products can be formed as a result of oxidation, hydroxylation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. the introduced compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds resulting from a process comprising contacting a compound of the present invention with a mammal for a time sufficient to form its metabolic product.

A “liposome” is a small vesicle composed of various kinds of lipids, phospholipids and / or surfactant that is useful for delivering a drug (such as the chk inhibitors disclosed in the present invention and, optionally, a chemotherapeutic agent) to a mammal. The components of liposomes are often organized as a bilayer, similar to the organization of lipids in biological membranes.

The term “package leaflet” is used to refer to the instructions included in the package with the therapeutic product that contains information about the indication, use, doses, administration, contraindications and / or warnings regarding the use of such a therapeutic product.

The term "chiral" refers to molecules that have the property of being unable to overlap mirror partners, while the term "chiral" refers to molecules that are superimposed on their partners in mirror image.

The term “stereoisomer” refers to compounds that have identical chemical composition and bonds, but the different orientation of their atoms in space cannot be interchangeable by rotation around single bonds.

"Diastereomer" refers to a stereoisomer with two or more centers of chirality, while their molecules are not mirror images of each other. Diastereomers have various physical properties, for example, melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high resolution analytical methods such as crystallization, electrophoresis and chromatography.

"Enantiomers" refer to two stereoisomers of compounds that are not mutually adjustable mirror images of each other.

The stereochemical definitions and conventions used in the present invention are mainly taken from S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain centers of asymmetry or chirality and, therefore, exist as different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are part of the present invention. Many organic compounds exist in the form of optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light. In the description of optically active compounds, the prefixes D and L, or R and S are used to indicate the absolute configurations of the molecules around their chiral center (s).

The prefixes d and 1 or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by a compound, where (-) or 1 means that the compound is levorotatory. A connection prefixed with (+) or d is dextrorotatory. For these chemical structures, these stereoisomers are identical, except that they are mirror images of each other. Certain stereoisomers may also be referred to as enantiomers, and a mixture of such isomers is often referred to as a mixture of enantiomers. A mixture with an enantiomer ratio of 50:50 is called a racemic mixture or racemate, which can be formed in the case of non-stereoselectivity or non-stereospecificity of a chemical reaction or process. The terms “racemic mixture” and “racemate” mean an optically inactive equimolar mixture of two types of enantiomers.

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies, which are mutually transitive into each other through a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversion via proton migration, such as keto-enol or iminaminamine isomerization. Valence tautomers encompass interconversion by reorganizing certain binding electrons. For example, any mention of the structure of 2-hydroxypyridine includes its tautomer-2-oxo-1,2-dihydropyridine, also known as 2-pyridone.

The expression "pharmaceutically acceptable salt" is used in the present invention with respect to pharmaceutically acceptable organic or inorganic salts of the compounds of the invention. Examples of such salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotyanates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisinates, fumarates, gluconates, glucuronates, sugars, formates, benzoates, glutamates, methanesulfonates, mesylates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, pamoates (that is, 1,1'-methyl-salts -hydroxy-3-naphthoate)), alkali metal salts (n example, sodium or potassium) salts, alkaline earth metal (e.g. magnesium) and ammonium salts. Pharmaceutically acceptable salts may include other molecules such as acetate ion, succinate ion or other counterion. The counterion can be any organic or inorganic residue that stabilizes the charge of the parent compound. Moreover, pharmaceutically active salts may have more than one charged atom in their structure. Structures in which multiply charged atoms are part of a pharmaceutically acceptable salt may have several counterions. Accordingly, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

If the compound of the invention is a base, the desired pharmaceutically acceptable salts can be prepared by any suitable method known in the art, for example by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or by treatment with an organic acid, such as acetic acid, methanesulfonic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, small new acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids, such as glucuronic acid or galacturonic acid, alpha-acids, such as citric acid or tartaric acid, amino acids, such as aspartic acid or glutamic acid, aromatic acids, such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid or the like.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salts can be prepared by any suitable means, for example, by treating the free acid with an organic or inorganic base, such as amines (primary, secondary or quaternary), alkali metal hydroxides or alkaline earth metal hydroxides or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine or arginine, urea, primary, secondary or quaternary amines and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts prepared with sodium , calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The expression "pharmaceutically acceptable" indicates that the substance or composition should be chemically and / or toxicologically compatible with other ingredients containing the composition and / or a mammal that is treated with them.

“Solvate” means an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that can form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" means a complex in which the solvent molecule is water.

The term “protecting group” refers to a substituent, which is usually used to block or protect partial functionality for the reaction to proceed along another functional group of a compound. For example, an “amino protecting group” is a substituent attached to an amino group that blocks or protects the reactivity of the compound at the amino group. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), 2- (trimethylsilyl) ethoxymethyl (SEM) and 9-fluoroorenylmethyleneoxycarbonyl (Fmoc). Similarly, a “hydroxy protecting group” refers to a hydroxy substituent that blocks or protects the hydroxy group reactivity of the compound. Suitable protecting groups include acetyl and tert-butyldimethylsilyl. A “carboxy protecting group” refers to a substituent of a carboxy group that blocks or protects the reactivity of a carboxy group. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2- (trimethylsilyl) ethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphenylphenyl) nitroethyl and the like. For a general description of protective groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms “compound according to the present invention” and “compounds of the present invention”, “compounds of Formula (I), (Ia) or (Ib)” and “compounds of Formula (I), (Ia) and / or (Ib) "unless otherwise indicated, include compounds of Formula (I), (Ia) or (Ib), as well as their stereoisomers, structural isomers, tautomers, solvates, metabolites, salts (eg, pharmaceutically acceptable salts) and prodrugs. Unless indicated otherwise, the structures described in the present invention also imply the inclusion of compounds that differ only in the presence of one or more an isotope-enriched atom, for example, compounds of Formula (I), (Ia) or (Ib) in which one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by ¹³ C- or ¹⁴ C-enriched carbon are included in the scope of the present invention.

The present invention discloses 1,7-diazacarbazoles of the formula (I), (Ia) and / or (Ib) (and / or their solvates, hydrates and / or salts) as described above, having inhibitory activity against kinases such as chk1, GSK-3, KDR and / or FLT3. In particular, the compounds of the present invention are useful as chk1 kinase inhibitors.

In some embodiments of the present invention, the compounds are compounds of formula (Ia) (i.e., X is CH, Y is CR ⁴ , Z is CH, and R ⁵ is H), where R ³ , R ^4, and R ⁶ are as defined in formula (I); a R ³ , R ⁴ and R ⁶ are not simultaneously H; and where R ⁴ represents H and R ³ represents H or alkyl when R ^{6 is} not —C (= Y ′) OR ¹¹ .

In some embodiments of the present invention, the compounds are compounds of formula (Ib) (i.e., X is CH, Y is CH, Z is CH), where R ³ , R ⁵ and R ⁶ are as defined in formula (I); and R ³ , R ⁵ and R ⁶ are not simultaneously H; and when R ⁵ represents H and R ³ represents H or alkyl, then R ^{6 is} not —C (= Y ′) OR ¹¹ .

In some embodiments of the present invention, X represents CH (i.e., R ² represents H), Y represents CR ⁴ , and Z represents CH (i.e., R ⁸ represents H); and all other values are as defined in formula (I).

In some embodiments of the present invention, R ³ represents H, CH ₃ , or halo; and all other values are as defined in formula (I), (Ia) or (Ib), or as defined in any embodiment described herein. In some embodiments of the present invention, R ³ represents H; and all other values are as defined in formula (I), (Ia), or (Ib), or as defined in any embodiment described herein. In some embodiments of the present invention, R ³ is a halo (eg, F, Cl, or Br); and all other values are as defined in formula (I), (Ia), or (Ib), or as defined in any embodiment described herein. In some embodiments of the present invention, R ³ represents CH ₃ ; and all other values are as defined in formula (I) or (Ib), or as defined in any embodiment described herein.

In some embodiments of the present invention, R ⁴ is —NR ¹¹ R ¹² or —OR ¹¹ where R ¹¹ and R ^12, together with an attached N atom, optionally form a 4-7 membered ring having additional 0-2 heteroatoms selected from O , S and N, said ring may be optionally substituted with one to four R ¹³ groups; and all other meanings are as defined in formula (I) or (Ia), or as defined in any embodiment described herein.

In some embodiments of the present invention, R ⁴ is —NR ¹¹ R ¹² or —OR ¹¹ where R ¹¹ is alkyl or heterocyclyl and R ¹² is H or alkyl and said alkyl or heterocyclyl is optionally substituted with one or three R ¹³ groups and where R ¹¹ and R ^12, together with an attached N atom, optionally form a 4-7 membered ring having additional 0-2 heteroatoms selected from O, S and N, said ring may be optionally substituted with one to four R ¹³ groups ; and all other meanings are as defined in formula (I) or (Ia), or as defined in any embodiment described herein.

In some embodiments of the present invention, the R ⁴ group is selected from one of the following groups; and all other values are as defined in formula (I) or (Ia), or as defined in any embodiment described herein:

In some embodiments of the present invention, R ⁵ represents

-NR ¹¹ R ¹² or -OR ¹¹ wherein R ¹¹ and R ¹² together with the attached N atom optionally form a 4-7 membered ring having additional 0-2 heteroatoms selected from O, S and N, said ring may be optionally substituted by one to four groups R ¹³ ; and all other meanings are as defined in formula (I) or (Ia), or as defined in any embodiment described herein.

In some embodiments of the present invention, R ⁵ is —NR ¹¹ R ¹² or —OR ¹¹ where R ¹¹ is alkyl or heterocyclyl and R ¹² is H or alkyl, said alkyl or heterocyclyl is optionally substituted with one or three R ¹³ groups and where R ¹¹ and R ^12, together with an attached N atom, optionally form a 4-7 membered ring having additional 0-2 heteroatoms selected from O, S and N, said ring may be optionally substituted with one to four R ¹³ groups ; and all other meanings are as defined in formula (I) or (Ia), or as defined in any embodiment described herein.

In some embodiments of the present invention, the R ⁵ group is selected from one of the following groups; and all other values are as defined in formula (I) or (Ib), or as defined in any embodiment described herein:

In some embodiments of the present invention, R ⁶ is H, CN, or pyrrolyl optionally substituted with C ₁ -C ₃ alkyl; and all other values are as defined in formula (I), (Ia) or (Ib), or as defined in any embodiment described herein. In some embodiments of the present invention, R ⁶ is CN or pyrrolyl optionally substituted with C ₁ -C ₃ alkyl; and all other values are as defined in formula (I), (Ia) or (Ib), or as defined in any embodiment described herein. In some embodiments of the present invention, R ⁶ is CN; and all other values are as defined in formula (I), (Ia) or (Ib), or as defined in any embodiment described herein. In some embodiments of the present invention, R ⁶ represents N-methylpyrrolyl or pyrrolyl; and all other meanings are as defined in formula (Ia), or as defined in any embodiment described herein. In some embodiments of the present invention, R ⁶ is H; and all other values are as defined in formula (I), (Ia) or (Ib), or as defined in any embodiment described herein.

Another embodiment of the present invention includes any of the compounds listed in the title of Examples 1-178 (for example, any of the compounds listed in the names of Examples 1-32, 35-53, 55-109, 113, 115-116, 119-123, 125, 127-143, 145-146, 149, 153-154, 156, 159-167, 169-171 and 174-176).

The compounds of the present invention are prepared according to any of the methods described in the preparation schemes or in the examples, or by methods known in the art. The starting compounds and various intermediates can be purchased commercially, prepared from commercially available compounds, or prepared using well-known synthetic methods. Accordingly, methods for creating the present compounds of formula (I), (Ia) or (Ib) in accordance with one or more Schemes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11a, 11b, 11c, 11d, 11c, 11d, 11c, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 (27-1, 27-2 and 27-3), and / or 28-32 are included in the scope of the present invention ..

For example, compounds 914-dipyrido [2,3-b; 4 ', 3'-d] pyrrole (also referred to as diazocarbazole here) of formulas (1-4) can be obtained using the synthetic routes described in Scheme 1.

Scheme 1

Compounds of formula (1-1) can be prepared using published methods described in the literature.

Intermediates of formula (1-1) can then be brominated in the presence of a suitable brominating agent, such as bromine, in a suitable solvent, such as acetic acid, at a temperature between 20 ° C and 120 ° C, to obtain compounds of formula (1-2 )

Compounds of formula (1-3) can be prepared by reacting intermediate (1-2) with a suitable ammonia source, such as ammonia gas, in a suitable solvent, such as methanol, at a temperature between 20 ° C. and 65 ° C.

Intermediates of formula (1-3) can then be dehydrated in the presence of a suitable dehydrating agent, such as trifluoroacetic anhydride, in a suitable solvent, such as THF, at a temperature of from 20 ° C to the boiling point of the solvent, to obtain compounds of formula (1-4 )

Scheme 2

where X '= Cl, Br, I or Otf

The compounds of formula (2-4) can also be obtained in accordance with the reactions shown in Scheme 2 (where R ³ represents R ³ or an intermediate residue which can be acted upon to obtain R ³ , and R ⁶ represents R ⁶ or an intermediate residue that can be acted upon to obtain R ⁶ ). Boronic acid of formula (2-2, where R = H) can be prepared from compounds of formula (2-1) by treatment with a base such as butyllithium in the presence of an alkyl borate such as trimethyl borate in a suitable solvent such as THF, at a temperature between -78 ° C and room temperature.

Alternatively, a boronic ester of formula (2-2, where R = alkyl) can be prepared from compounds of formula (2-1) with a suitable alkylate dibor in the presence of a catalyst such as bis (diphenylphosphino) ferrocene palladium (II) dichloride using a suitable base , such as potassium acetate, in a solvent, such as dioxane, at a temperature from room temperature to the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of formula (2-4) can be prepared according to the reactions shown in Scheme 2, by reacting compounds of formula (2-2) with a suitable halide of formula (2-3) (including a suitable substituent R ^{3 '} ), in the presence of a catalyst such as bis (diphenylphosphino) ferrocene palladium (II) dichloride, with a base such as aqueous sodium carbonate in a suitable additional solvent, such as acetonitrile, at room temperature to the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

The protecting group (P ₁₎ of the compounds of formula (2-1), (2-2) and (2-4) may be manipulated at any stage of the synthesis. A protecting group such as SEM (trimethylsilylethoxymethyl) can be incorporated into the compound using an alkylating agent such as SEM chloride in a solvent such as DMF in the presence of a suitable base such as sodium hydride. Compounds of general formula (2-4) in which P ₁ represents a protecting group, such as SEM, may be deprived of the protecting group by a reagent similar to tetrabutylammonium fluoride in a solvent such as THF, at a temperature between -20 ° C and 50 ° C to obtain compounds in which P ₁ represents N.

Scheme 3

where X '= Cl, Br, I or Otf

Compounds of general formula (3-4) can also be prepared according to the reactions shown in Scheme 3 (wherein R ³ is R ³ or an intermediate residue that can be acted upon to produce R ³ and R ⁶ is R ⁶ or an intermediate residue that can be acted upon to obtain R ⁶ ). Stannanes of general formula (3-2) can be prepared from compounds of formula (3-1) with a base and a suitable tin halide in a suitable solvent such as THF.

Alternatively, stannanes of general formula (3-2) can be prepared from compounds of formula (3-1) with a suitable diol alkyl (containing a suitable R group) in the presence of a catalyst such as tetrakis (triphenylphosphate) palladium (0) in a suitable solvent, such like toluene, at a temperature from room temperature to the temperature of solvent evaporation, or under microwave radiation at a temperature between 70 ° C and 150 ° C.

Compounds of general formula (3-4) can be prepared from compounds of general formula (3-2) with a suitable halide or triflate of formula (3-3), in the presence of a catalyst such as tetrakis (triphenylphosphate) palladium (0) in a suitable solvent, such as dioxane at room temperature to the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Scheme 4

Compounds of general formula (4-6) can be obtained from commercial sources, or using published methods described in the literature. Compounds of general formula (4-6) can also be prepared according to the reactions shown in Scheme 4.

Compounds of general formula (4-3) can be prepared from compounds of formula (4-1) by reaction with a halogenated pyridine or triflate of formula (4-2) in the presence of a transition metal catalyst such as bis (triphenylphosphine) palladium (II) dichloride , a base, such as aqueous sodium carbonate, in a suitable solvent, such as acetonitrile at a temperature from room temperature to the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

2-cyanopyrimidines of formula (4-4) can be prepared from 2-halopyridines of formula (4-3) by reaction with inorganic cyanidines, such as zinc cyanide, in the presence of a transition metal catalyst such as tetrakis (triphenylphosphate) palladium (0 ), in a solvent, such as DMF, at a temperature of from 50 ° C to the evaporation temperature of one of the solvents, or under microwave radiation at a temperature between 70 ° C and 200 ° C. Aminopyridines (4-4) can then be halogenated with a halogenating agent such as N-bromosuccinimide in a solvent such as DMF at a temperature between room temperature and 50 ° C. to give intermediates of formula (4-5).

Cyclization of compounds of general formula (4-5) with a suitable base such as sodium hexamethyldisilazide in a suitable solvent such as THF at temperatures between 0 ° C and 50 ° C can give compounds of general formula (4-6).

Scheme 5

Compounds of general formula (5-2), (5-3) and (5-4) can be prepared using published methods described in the literature. Compounds of formulas (5-2), (5-3) and (5-4) can also be obtained using the synthetic routes depicted in Scheme 5 (where R ^{3 ′} is R ³ or an intermediate residue that can be acted upon, to get R ³ ).

Compounds of general formula (5-2) can be prepared from compounds of formula (5-1) by reaction with a reagent such as n-butyllithium in a polar aprotic solvent such as THF or diethyl ether at a temperature between -100 ° C and 0 ° C and quenching with boronic ester, such as trimethyl borate or triisopropyl borate.

Compounds of general formula (5-3) can be prepared from compounds of formula (5-1) by reaction with a reagent such as bis (pinacolato) dibor in the presence of a catalyst such as [1,1'-bis (diphenylphosphino) ferrocene-dichloropalladium (II) in the presence of a base such as potassium acetate in a suitable solvent such as dioxane, or a mixture of two or more suitable solvents, at a temperature between room temperature and the temperature of evaporation of the solvent or solvents, or under microwave conditions at a temperature between 70 ° C and 160 ° C.

Compounds of general formula (5-4) can be prepared from compounds of formula (5-1) by reaction with a reagent such as hexamethyldiol or triethyltin chloride in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (0), in the presence of a base such as as potassium carbonate in a suitable solvent, such as DMF, or a mixture of two or more suitable solvents, at a temperature between room temperature and the temperature of evaporation of the solvent or solvents, or under microwave conditions at a temperature of m between 70 ° C and 160 ° C. Alternatively, these compounds of general formula (5-4) can be prepared from compounds of formula (5-1) by reaction with a reagent such as n-butyllithium in a polar aprotic solvent such as THF at a temperature between -100 ° C and 25 ° C and subsequent reaction with a reagent such as hexamethyldiol or triethyl tin chloride in a suitable polar aprotic solvent such as THF at a temperature between -100 ° C and 50 ° C.

Scheme 6

Compounds of general formula (6-3) can be prepared using published methods described in the literature. Compounds of formula (6-3) can also be prepared using the synthetic routes depicted in Scheme 6 (wherein R ³ is R ³ or an intermediate residue that can be acted upon to produce R ³ and R ⁶ is R ⁶ or an intermediate residue that can be acted upon to obtain R ⁶ ). Compounds of general formula (6-3) can be prepared from compounds of formula (6-1) by reaction with boronic acid or boronic ester of formula (6-2) (containing a suitable substituent R ³ ), or by reaction with aryl or tin alkyl of the formula (6-4) (containing suitable R ³ substituents), in the presence of a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride, [1,1'-bis (diphenylphosphino) -ferrocene] dichloropalladium (II), an aqueous base such as sodium carbonate in a suitable solvent such as acetonitrile, or a combination of a solution This can be done at temperatures between room temperature and solvent evaporation temperature, or under microwave radiation at temperatures between 70 ° C and 150 ° C.

Scheme 7

Compounds of general formula (7-8) can be prepared using published methods described in the literature. Compounds of formula (7-8) can also be prepared using the synthetic routes depicted in Scheme 7 (wherein R ⁶ is R ⁶ or an intermediate residue that can be acted upon to produce R ⁶ ). Compounds of the general formula (7-3) can be prepared from compounds of the general formula (7-1) and a suitable alkyne (7-2) (containing the R ¹⁰ group, which can be stored without modifications after reaction, or can be further modified with the preparation of other R ¹⁰ groups) by reaction in the presence of a catalytic system such as tetrakis (triphenylphosphine) palladium (0) and copper (I) iodide in the presence of a base such as triethylamine and a suitable solvent such as N, N-dimethylformamide, temperature between room temperature temperature and solvent boiling point. Such an addition reaction can also be carried out in the presence of palladium on carbon, triphenylphosphine, copper (I) iodide and triethylamine in the presence of a suitable solvent, such as acetonitrile, at a temperature between room temperature and the temperature of evaporation of the solvent or solvents, or under microwave radiation at a temperature between 70 ° C and 160 ° C.

Compounds of general formula (7-6) can be prepared from compounds of general formula (7-3) and hydrogen in the presence of a suitable catalyst, such as a Lindlar or palladium catalyst on barium sulfate, in the presence of quinoline and a suitable solvent, such as methanol and ethanol. Compounds of general formula (7-6) can also be prepared by reacting compounds of general formula (7-1) with a suitable alkene (7-4) (containing a group R ¹⁰ which can be stored without modification after reaction, or may be further modified with obtaining other R ¹⁰ groups in the presence of a base such as triethylamine or potassium carbonate, phosphine such as triphenylphosphine, a metal such as palladium acetate and a solvent such as acetonitrile at a temperature between room temperature and the boiling point of the solution body. Compounds of general formula (7-6) can also be prepared by reacting a compound of general formula (7-1) by reaction with vinyl stannane (7-5) (containing a group R ¹⁰ that can be stored without modification after reaction, or can be modified further to give other groups R ¹⁰ ) in the presence of a metal compound such as tetrakis (triphenylphosphine) palladium (0) in a suitable solvent such as toluene.

Compounds of general formula (7-8) can be prepared from compounds of general formula (7-3) or (7-6) by reaction with hydrogen in the presence of a catalyst, such as palladium on carbon, or platinum oxide monohydrate in a suitable solvent, such as methanol or ethanol.

Compounds of general formula (7-8) can also be prepared by reacting compounds of general formula (7-1) with a suitable zinc zinc reagent (7-7) in the presence of a catalyst, such as dimer of allyl palladium (I) chloride or bis (tert-butylphosphine) ) palladium (0), and a suitable solvent, such as 1,4-dioxane, at a temperature between room temperature and the boiling point of the solvent.

Scheme 8

Compounds of general formula (8-3) can be prepared from compounds of general formula (8-1) by reaction with a suitable 1,3-dipole, such as trimethylsilyl azide in a suitable solvent, such as toluene at a temperature between room temperature and the boiling point of the solvent .

Compounds of general formula (8-2) can be prepared from compounds of general formula (8-1) and hydrogen in the presence of a suitable catalyst, such as a Lindlar catalyst or palladium on barium sulfate, in the presence of quinoline and a suitable solvent, such as methanol or ethanol.

Compounds of general formula (8-3) can be prepared by reacting compounds of general formula (8-2) with a suitable 1,3-dipole (or its precursor containing a group R ¹⁰ , which can be stored without modification after reaction, or can be modified further to give other groups R ¹⁰⁾ such as N-methoxymethyl-N- (trimethylsilylmethyl) benzylamine and lithium fluoride in a solvent such as acetonitrile with ultrasonic treatment, or nitroethane and phenyl isocyanate in a suitable solvent such as toluene, in the presence of bases Nia, such as triethylamine, at a temperature between 0 ° C and the boiling point temperature of the solvent.

Scheme 9

Compounds of general formula (9-2) can be prepared using published methods described in the literature. Compounds of formula (9-2) can be prepared using the synthetic routes depicted in Scheme 9 (wherein R ⁹ is R ⁹ or an intermediate residue that can be acted upon to produce R ⁹ and R ⁶ is R ⁶ or intermediate residue, which can act to receive R ^6).

Compounds of general formula (9-2) can be prepared from compounds of formula (9-1) by reaction with compounds of general formula (HY'-R ⁹ ') in the presence of reagents such as copper (II) iodide or copper powder, in the presence of base, such as cesium carbonate, in a suitable solvent, such as DMF, at a temperature between room temperature and the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 240 ° C, which may be similar to the conditions described in literature authored by Ullmann.

Compounds of general formula (9-2) can be prepared from compounds of formula (9-1) by reaction with compounds of general formula (HY'-R ⁹ ') in the presence of a catalyst such as [1,1'-bis (diphenylphosphino) ferrocene ] dichloropalladium (II), in the presence of a base such as potassium tert-butoxide, in a suitable solvent such as DME, or a mixture of two or more suitable solvents, at a temperature between room temperature and the temperature of evaporation of the solvent or solvents, or under microwave conditions at a temperature between 70 ° C and 160 ° C, which may be similar to the conditions described in the literature by Buchwald and Hartwig.

Pattern 10

Compounds of general formula (10-7), (10-8) and (10-9) can be prepared using published methods described in the literature (WO 2006001754). Compounds of formula (10-7), (10-8) and (10-9) can be prepared using the synthetic routes depicted in Scheme 10 (where R ³ is R ³ or an intermediate residue that can be acted upon to obtain R ³ and R ⁵ represents R ⁵ or an intermediate residue which can be acted upon to obtain R ⁵ ). Compounds of general formula (10-2) can be prepared from compounds of formula (10-1) by deprotonation using a suitable base, such as lithium diisopropylamide, in a suitable solvent, such as THF, at a temperature between -78 ° C and room temperature with subsequent addition of a suitable methylating agent such as methyl iodide. Intermediate (10-2) can then be brominated with a suitable brominating agent, such as N-bromosuccinimide, in a solvent such as carbon tetrachloride, at a temperature between room temperature and the evaporation temperature of the solvent to obtain compounds of formula (10-3).

Compounds of formula (10-3) can be converted to compounds of formula (10-4) by substituting tosylaminoacetonitrile for a suitable base such as sodium hydride in a solvent such as DMF at a temperature between -20 ° C and 50 ° C. Intermediates (10-4) can then be cyclized with a suitable base, such as lithium hexamethylsilylamide, in a solvent, such as THF, at a temperature between -20 ° C and 50 ° C to give compounds of general formula (10-5). Phenol (10-5) can then be reacted with a suitable alcohol (R ^{11 '} OH) using phosphine and a crosslinking agent, such as diisopropylazodicarboxylate, in a suitable solvent, such as THF, to give esters of general formula (10-7).

Alternatively, phenol intermediates (10-5) can be converted to triflates using a reagent such as trifluoromethanesulfonic anhydride in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane at a temperature between -50 ° C and 20 ° C. Triflates (10-6) can then be converted into compounds of general formula (10-9) by reaction with boronic acid or boronic ester of formula (10-10) in the presence of a transition metal catalyst such as bifriphenylphosphine) palladium (II) dichloride base, such as aqueous sodium carbonate, in a suitable solvent, such as acetonitrile, at room temperature to evaporate the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C. Alternatively, triflates can be converted to compounds of general formula (10-8) by substituting a suitable amino ester (HNR ^{11 '} R ^12' ) as a solvent or in a solvent such as 2-propanol at a temperature between ambient temperature and the point of evaporation of the solvent.

Compounds of general formula (10-8) can be prepared from compounds of formula (10-6) by reaction with compounds of general formula (HNR ^{11 '} R ^12' ) in the presence of a catalyst such as [1,1'-bis (diphenylphosphino) ferrocene ] dichloropalladium (II), in the presence of a base such as potassium tert-butoxide, in a suitable solvent, such as DME, or a mixture of two or more suitable solvents, at room temperature to the temperature of evaporation of the solvent or solvents, or under microwave conditions temperature between 70 ° C and 160 ° C, which can ut be similar to conditions described in the literature under the authorship of Buchwald and Hartwig.

Scheme 11a

Compounds of general formula (11-6) can be prepared using published methods described in the literature. Compounds of formula (11-6) can be prepared using the synthetic routes depicted in Scheme B (wherein R ³ is R ³ or an intermediate residue that can be acted upon to produce R ³ , and where R ⁶ is R ⁶ or an intermediate residue that can be acted upon to obtain R ⁶ ). Compounds of formula (11-1) can be converted via acyl hydrazide formation, diazotization and Curtius rearrangement to give compounds of formula (11-4), which can then be converted by means of the Sandmeyer reaction into compounds of formula (11-5). Similarly, compounds of formula (11-4) can undergo a Sandmeyer reaction to produce other 6-substituted derivatives, such as 6-fluoro (11-7), 6-chloro (11-8), 6-iodo (11-9) , 6-alkylthio (11-10), 6-hydroxy (11-11) and 6-cyano (11-12) as shown in Scheme 11b.

Scheme 11b

Compounds of formula (11-5) are useful for introducing an R ⁶ group (or an R ^{6 ′} group that can be converted to an R ⁶ group) in various ways to produce compounds of formula (11-6), for example, by crosslinking with organic boronic derivatives acids in the presence of a palladium catalyst. Similarly, organic stannanes (e.g., R ^{6 '} SnR ₃ ), organozinc (R ^6' ZnCl) and other reagents can be used in place of organic boronic acid. In particular, compounds of formula (11-6) in which R ^{6 ′} are groups such as alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl can be obtained in this way. Compounds of formula (11-5) can also be converted to organic boronic acid derivatives of the form (11-13), which can give compounds of formula (11-6) by reacting with organohalide or triflate derivatives in the presence of a palladium catalyst, as shown in Scheme 11 c. Analogously (11-5) can be converted to organic stannanes, organozinc or other derivatives used instead of organic boronic acid in addition reactions catalyzed by palladium to give compounds of formula (11-6).

11 s circuit

The compounds of general formula (11-5) are useful in the preparation of derivatives via aromatic nucleophilic substitution reactions using the R-NuH nucleophilic reagent, which can be facilitated in the presence of a base, as shown in Scheme Na. Examples of such reagents and reactions are alcohols giving compounds of formula (11-14), thiols giving compounds of formula (11-15), primary and secondary amines giving compounds of formula (11-16), and heterocycles such as imidazole, which give compounds of formula (11-17). The occurrence of such substitution reactions can also be facilitated in the presence of palladium, copper or other catalysts, giving compounds of general formula (11-18), as shown in Scheme 11d.

11d circuit

The compounds of general formula (11-5) are useful in the preparation of derivatives via aromatic nucleophilic substitution reactions using the nucleophilic reagent R-NuH, which can be facilitated in the presence of a base, as shown in Scheme 11d. Examples of such reagents and reactions are alcohols giving compounds of formula (11-14), thiols giving compounds of formula (11-15), primary and secondary amines giving compounds of formula (11-16), and heterocycles such as imidazole, which give compounds of formula (11-17). The occurrence of such substitution reactions can also be facilitated in the presence of palladium, copper or other catalysts, giving compounds of the general formula (11-18), as shown in Scheme 11d.

Circuit 11c

Compounds of formula (11-1) can also be used as intermediates in the preparation of benzene alcohols via nucleophilic addition of organometallic reagents or hydride transfer reagents to an ether group, for example methyl magnesium bromide, to produce tertiary alcohols of formula (11-19), as shown on Scheme Not. Compounds of formula (11-1) can also be partially reduced to an ether group to give aldehydes of formula (11-20), for example, using hydride transfer reagents such as diisobutylammonium chloride. Intermediates such as (11-20) can be transformed by nucleophilic addition with organometallic reagents of an aldehyde functional group, for example ethyl magnesium bromide, to give secondary alcohols of the formula (11-21). Such benzene alcohols can be further transformed by o-alkylation, for example using an alkyl halide and a base, as well as the transformation of compounds of formula (11-21) into ether products of general formula (11-22). Aldehydes of the formula (11-20) can also be reductively aminated using amines and hydride transfer reagents, such as sodium cyanoborohydride, to give benzene amines of the general formula (11-22), as shown in Scheme 11c.

The reagents and conditions given in Schemes 11a, 11b, 11c, 11d and 11c are given as examples of use, and comparable ways of using alternative reagents can be found in the literature.

Pattern 12

Compounds of general formula (12-1) can be prepared using the methods described herein, and compounds of formula (12-6) can be prepared using the synthetic routes depicted in Scheme 12 (wherein R ^{3 ′} is R ³ or an intermediate residue, which may be treated to obtain R ^3, and where E represents a generalization of functional group obtained by the reaction with an electrophilic reagent followed by suitable isolation procedures of the reaction product, and P represents a suitable protective group). Esters of carboxylic acids of formula (12-1) can be saponified to give compounds of general formula (12-2), for example using aqueous lithium hydroxide. Alternatively, compounds of formula (12-1) can be converted to carboxamides of formula (12-4) by treatment with, for example, pure tert-butylamine. Compounds such as (12-2) can be treated with two or more equivalents of a strong base, for example, lithium tetramethylpiperidine, and quenched with a wide range of electrophilic reagents to give derivatives of the general formula (12-3) in which the 5th position has been replaced by a functional group E, obtained from an electrophilic reagent. Examples of such a transformation are given in the literature (WO 2003022849). For example, suitable electrophilic reagents giving derivatives with functional group E include, respectively: ethyl iodide giving 5-ethyl; formaldehyde giving b-hydromethyl; 5-formyl dimethylformamide; trimethyl borate, giving 5-boronic acid ester, which can be further transformed into 5-hydroxy by oxidation using basic hydrogen peroxide.

Similarly, carboxamide compounds of formula (12-4) give products of formula (12-5) in a similar treatment, and these products can be further converted into 6-cyano derivatives of formula (12-6) by treatment with acid dehydrating agents, for example phosphorus oxychloride .

The reagents and conditions given in Scheme 12 are given as examples of use, and comparable methods of using alternative reagents can be found in the literature.

Pattern 13

Similarly to the methods shown in Scheme 14, compounds of the general formula (13-4) can be obtained using the synthetic pathways depicted in Scheme 13 (where R ^{3 '} is R ³ or an intermediate residue that can be acted upon to obtain R ³ , R ^{5 ′} represents R ⁵ or an intermediate residue that can be acted upon to obtain R ⁵ , R ^{6 ′} represents R ⁶ or an intermediate residue that can be acted upon to obtain R ⁶ , and R ^{8 ′} represents R ⁸ residue or intermediate, which can podeystvovat To receive the R ^8). For example, iodo-amino-heterocyclic compounds of formula (13-4) can be coupled to heterocycle-boronic acids of general formula (13-2) using a suitable palladium catalyst and base, for example dichlorobis (triphenylphosphine) palladium (0) and potassium acetate, in a suitable solvent to give diaryl compounds of formula (13-3). Such compounds can be further transformed by treatment with a base, for example sodium hexamethyldisilyazide, in a suitable solvent, to obtain tricyclic compounds of the general formula (13-4). So, further substitution of the tricycle, for example, at the 3-, 5-, 6- and 8-positions, can be carried out using compounds of the formula (13-1) and (13-2), in which one or more functional groups R ^{3 '} , R ^5' , R ^{6 '} or R ^{8' are} already present in the desired position.

Compounds of formula (14-7) and (14-9) can be prepared using the synthetic routes depicted in Scheme 14.

Compounds of general formula (14-3) can be prepared from compounds of formula (14-1) by reaction with boronic acid or boronic ester of formula (14-2), in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride, a base, such as aqueous sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between room temperature and the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C. Compounds of general formula (14-3) can be cyclized with gender cheniem compounds of formula (14-4) with a suitable base such as sodium hexamethyldisilazane in a suitable solvent such as THF, at a temperature between 0 ° C and 50 ° C.

Compounds of general formula (14-4) can then be converted to compounds of general formula (14-6) by reaction with boronic acid or boronic ester (containing suitable substituents R ⁶ '), in the presence of a catalyst such as bifriphenylphosphine) palladium ( I) a dichloride, of a base, such as aqueous sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between room temperature and the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C. Alternatively, with of the connections of the formula (14-4) may be paired with alkyl or aryl tin compounds (containing suitable substituents R ^{6 '),} in the presence of a catalyst such as bifrifenilfosfin) palladium (II) dichloride or [1,1'-bis (diphenylphosphino) ferrocene ] dichloropalladium (II), with or without an aqueous base, such as sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between room temperature and the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of general formula (14-6) can be prepared from compounds of formula (14-4) by reaction with compounds of general formula (HX-R ₆ ^' ) in the presence of a catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), in the presence of a base such as palladium tert-butoxide, in a suitable solvent, such as DME, or a mixture of two or more suitable solvents, at a temperature between room temperature and the temperature of evaporation of the solvent or solvents, or under microwave conditions temperature between 70 ° C and 160 ° C, which may be similar to the conditions described in the literature under the authorship of Buchwald and Hartwig.

Intermediates of formula (14-6) can then be halogenated in the presence of a suitable halogenating agent, such as bromine, in a solvent such as acetic acid, at a temperature between 20 ° C and 120 ° C, to obtain compounds of formula (14-7) . Compounds of formula (14-7) can then be converted into compounds of formula (14-9) using the methods described in Scheme 9.

Alternatively, compounds of formula (14-4) can be halogenated to give compounds of formula (14-5), then converted to compounds of formula (14-8) by reaction with boronic acid, boronic ester or stannane, and then converted to compounds of formula ( 14-9) using similar conditions as described for the introduction of the R ^{3 ′} group.

Scheme 15

Compounds (15-1) can be prepared using the methods described herein. Conducting the reaction of compounds of the general formula (15-1) with methanesulfonyl chloride in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane at a temperature between 0 ° C and the evaporation temperature of the solvent gives the compounds of formula (15-2).

Compounds of general formula (15-3) can be prepared from compounds (15-2) by reaction with an amine, in the presence of a base, such as triethylamine, in a suitable solvent, such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature.

Compounds of general formula (16-3) can be prepared according to the reactions shown in Scheme 16.

Pattern 16

Compounds (16-1) can be prepared using the methods described in Scheme 2. Conducting the reaction of compounds of general formula (16-1) with an oxidizing agent, such as N-methylmorpholine-N-oxide, in a suitable solvent, such as tetrahydrofuran, the temperature between the ambient temperature and the evaporation temperature of the solvent gives the compounds of formula (16-2).

Compounds of general formula (16-3) can be prepared from compounds (16-2) by reaction with an alkyl halide, in the presence of a catalyst such as (i) copper iodide, a ligand such as N, N-dimethyl glycine, a base such as carbonate cesium, in a suitable solvent, such as dioxane, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of General formula (17-13) can be obtained in accordance with the reactions shown in Scheme 17.

Scheme 17

Compounds (17-1) and (17-4) can be obtained from commercial sources or using published methods described in the literature. Compounds of general formula (17-2) can be prepared from compounds of formula (17-1) by reaction with an organometallic reagent such as boronic acid or its ester in the presence of a transition metal catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bases such as aqueous potassium fluoride, in a suitable solvent, such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of general formula (17-3) can be prepared from compounds of formula (17-2) by reaction with a base, such as lithium diisopropylamide, and a boronate source, such as triisopropyl borate, in a suitable solvent, such as THF, at a temperature between -78 ° C and ambient temperature.

5-bromo-6-chloro-4-iodonicotinic acid (17-5) can be obtained from 5-bromo-6-chloro-nicotinic acid (17-4) by reaction with a base such as n-butyllithium with an amine such as 2 , 2,6,6-tetramethylpiperidine, and a source of iodine, such as solid iodine, in a suitable solvent, such as THF, at a temperature between -78 ° C and ambient temperature. 5-bromo-6-chloro-4-iodopyridin-3-yl) -carbamic acid tert-butyl ether (17-6) can be obtained from 5-bromo-6-chloro-4-iodo-nicotinic acid (17-5 ) by reaction with diphenylphosphoryl azide in the presence of a base, such as triethylamine and tert-butanol, in a suitable solvent, such as toluene, at a temperature between ambient temperature and the temperature of evaporation of the solvent. 5-bromo-6-chloro-4-iodopyridin-3-ylamine (17-7) can be obtained from 5-bromo-6-chloro-4-iodopyridin-3-yl) -carbamic acid tert-butyl ether (17- 6) by reaction with trifluoroacetic acid in a suitable solvent, such as DCM at a temperature between -10 ° C and the evaporation temperature of the solvent.

Compounds of general formula (17-8) can be prepared from compounds of formula (17-3) by reaction with 5-bromo-6-chloro-4-iodopyridin-3-ylamine (xiii) in the presence of a transition metal catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), a base such as aqueous potassium fluoride, in a suitable solvent, such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave irradiation under temperature between 70 ° C and 150 ° C.

Cyclization of compounds with the general formula (17-8) with a suitable base, such as sodium hexamethylsilazide in a suitable solvent, such as THF, at a temperature between 0 ° C and 50 ° C, gives compounds of the general formula (17-9).

Compounds of general formula (17-10) can be prepared from compounds (17-8) by reaction with an organometallic reagent, such as boronic acid or its ester, in the presence of a transition metal catalyst such as [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (II), a base, such as aqueous potassium fluoride, in a suitable solvent, such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave conditions at a temperature between 70 ° C and 150 ° FROM.

Cyclization of compounds of general formula (17-10) with a suitable base, such as sodium hexamethylsilazide in a suitable solvent, such as THF, at temperatures between 0 ° C and 50 ° C gives compounds of general formula (17-12).

Compounds of general formula (17-13) can be prepared from compounds (17-12) by reaction with an organometallic reagent, such as boronic acid or its ester, in the presence of a transition metal catalyst such as [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (II), a base, such as aqueous potassium fluoride, in a suitable solvent, such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave conditions at a temperature between 70 ° C and 150 ° FROM.

Compounds of general formula (17-11) can be prepared from compounds (17-10) by reaction with an organometallic reagent, such as boronic acid or its ester, in the presence of a transition metal catalyst such as [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (II), a base such as aqueous potassium fluoride, in a suitable solvent such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave radiation at a temperature between 70 ° C and 150 ° FROM.

Cyclization of compounds with the general formula (17-11) with a suitable base, such as sodium hexamethylsilazide in a suitable solvent, such as THF at a temperature between 0 ° C and 50 ° C, can give compounds of the general formula (17-13).

Compounds of formula (18-8) can be prepared using the synthetic routes depicted in Scheme 18.

Scheme 18

Compounds (18-1) and (18-2) can be obtained from commercial sources, obtained using published methods described in the literature, or by the methods described in Scheme 3. 5-bromo-6'-chloro-2-fluoro- [3,4 '] bipyridinyl-3'-ylamine (18-3) can be prepared from 5-bromo-2-fluoropyridin-3-boronic acid (18-2) by reaction with 6-chloro-4-iodopyridin-3 -ylamine (18-1) in the presence of a transition metal catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (I), a base such as aqueous sodium carbonate, in a suitable solution a body, such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

3-bromo-6-chloro-1,7-diazacarbazole (18-4) can be prepared from 5-bromo-6'-chloro-2-fluoro- [3,4 '] bipyridinyl-3'-ylamine (18- 3) by cyclization with a suitable base, such as sodium hexamethylsilazide, in a suitable solvent, such as THF, at a temperature between 0 ° C and 50 ° C.

Compounds of general formula (18-5) can be prepared from compounds (18-4) by reaction with an organometallic reagent, such as boronic acid or its ester, in the presence of a transition metal catalyst such as [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (II), a base such as aqueous sodium carbonate, in a suitable solvent such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave conditions at a temperature between 70 ° C and 150 ° FROM.

Compounds of general formula (18-8) can be prepared from compound (18-5) by reaction with an organometallic reagent, such as boronic acid or its ester, in the presence of a transition metal catalyst such as [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (II), a base such as aqueous sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between ambient temperature and the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° FROM.

Compounds of general formula (18-6) can be prepared from compound (18-3) by reaction with an organometallic reagent, such as boronic acid or its ester, in the presence of a transition metal catalyst such as [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (II), a base such as aqueous sodium carbonate, in a suitable solvent such as acetonitrile, at a temperature between ambient temperature and solvent evaporation temperature, or under microwave conditions at a temperature between 70 ° C and 150 ° FROM.

Compounds of general formula (18-7) can be prepared from compound (18-6) by reaction with an organometallic reagent such as boronic acid or its ester in the presence of a transition metal catalyst such as [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (II), a base such as aqueous sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between ambient temperature and the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° FROM.

Cyclization of compounds of general formula (18-7) with a suitable base, such as sodium hexamethylsilazide, in a suitable solvent, such as THF, at temperatures between 0 ° C and 50 ° C, can give compounds of general formula (18-8).

Scheme 19

Compounds of formula (19-1) and (19-2) can be synthesized in accordance with the methods described in the literature, or in accordance with the paths given in Scheme 19. Compounds of formula (19-3) can be obtained from compounds of formula ( 19-1) by reaction with a boronic acid or its ester of formula (19-2), in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride, a base such as aqueous sodium carbonate, in a suitable solvent such as acetonitrile at a temperature between room temperature and the evaporation temperature of compound, or under microwave conditions between 70 ° C and 150 ° C. Compounds of general formula (19-3) can be cyclized to give compounds of formula (19-4) with a base such as sodium hexamethyldisiazane in a suitable solvent, such as THF, at a temperature between 0 ° C. and 50 ° C. The intermediates of formula (19-4) can then be halogenated in the presence of a suitable halogenating agent, such as iodine monochloride, in a solvent such as acetic acid, at a temperature between 20 ° С and solution evaporation point ator, to give compounds of formula (19-5).

Compounds of formula (19-5) can then be converted to compounds of formula (19-6) by reaction with boronic acid or its ester (containing suitable R ³ substituents) in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride , a base, such as aqueous sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between room temperature and the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C. and 150 ° C. Alternatively, the compounds of formula (19 -5) can be coupled with tin alkyl or aryl compounds (containing suitable R ^{3 ′} substituents), in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), with or without an aqueous base, such as sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between room temperature and the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of formula (19-6) can be converted into compounds of formula (19-8) by reaction with an iodine source, such as sodium iodide, using a copper catalyst, such as a mixture of copper (I) iodide and N, N'- dimethylethylenediamine, in a solvent such as 1,4-dioxane, at a temperature between room temperature and the point of evaporation of the solvent.

Compounds of formula (19-7) can be prepared from compounds of formula (19-6) and (19-8) by reaction with compounds of general formula (R ^{6 '} -M) by reaction with boronic acid, boronic ester or stannane under conditions similar to those previously described for the introduction of the group R ^{3 '} .

Scheme 20

The compounds of formula (20-1) can be synthesized in accordance with the methods described in the literature, or in accordance with the paths shown in schemes 1, 4, 10, 13, 14, 17 and 18. Compounds of formula (20-1) can be converted to compounds of formula (20-2) by reaction with a source of iodine, such as sodium iodide, using a copper catalyst, such as a mixture of copper (I) iodide and N, N'-dimethylethylenediamine, in a solvent such as 1 , 4-dioxane at a temperature between room temperature and the point of evaporation of the solvent.

Compounds of formula (20-1) can also be converted to compounds of general formula (20-3) using a catalyst, such as palladium in a solvent, such as ethanol, in a hydrogen atmosphere at a temperature from room temperature to 50 ° C.

Scheme 21

The compounds of formula (21-1) can be synthesized in accordance with the methods described in the literature, or in accordance with the paths shown in schemes 1, 4, 10, 13, 14, 17 and 18. Compounds of formula (21-1) ( where X represents a leaving group such as Br or I) can be converted into compounds of formula (21-2) using carbon monoxide sources such as molybdenum hexacarbonyl in the presence of a catalyst such as a Herman's catalyst containing a suitable amine (21-12) (HNR ¹¹ R ¹² ), a base such as 1,8-diazabicyclo [5.4.0] undets -7-ene, in a solvent such as 1,4-dioxane, at a temperature between room temperature and the point of evaporation of the solvent. Compounds of formula (21-1) can also be converted to compounds of formula (21-3) using carbon monoxide sources such as molybdenum hexacarbonyl in the presence of a catalyst such as a Herman catalyst containing a suitable alcohol (21-13) (HOR ¹¹ ), a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene in a solvent such as 1,4-dioxane at a temperature between room temperature and the point of evaporation of the solvent. Compounds of formula (21-1) can be converted to compounds of formula (21-4) using a reagent (21-14) such as zinc (II) cyanide in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (0), in a solvent, such as DMF, at a temperature between room temperature and the point of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of formula (21-1) can be converted to compounds of formula (21-5) using a reagent such as sodium trifluoroacetate, in the presence of a catalyst, such as copper (I) iodide, in a solvent such as DMF, at a temperature between room temperature temperature and solvent evaporation point.

Compounds of formula (21-6) can be prepared from compounds of formula (21-1) and a base such as n-butyllithium in a solvent such as THF with a suitable tin halide (21-15) (where X 'is a leaving a group such as Cl or Br). Alternatively, compounds of formula (21-6) can be prepared from compounds of formula (21-1) with a suitable alkyldiol (21-16) (containing suitable R groups) in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (0), in a suitable solvent, such as toluene, at room temperature to the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of formula (21-7) can be prepared from compounds of formula (21-1) by treatment with a base such as n-butyl lithium, in the presence of an alkyl borate (21-17) such as trimethyl borate, in a suitable solvent such as THF, temperatures between -78 ° C and ambient temperature. Alternatively, compounds of formula (21-7) can be prepared from compounds of formula (21-1) with a suitable alkylate diborum (21-18) in the presence of a catalyst such as bis (diphenylphosphino) ferrocene palladium (I) dichloride, using a suitable base, such as potassium acetate, in a solvent such as dioxane, at a temperature from room temperature to the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of formula (21-8) can be prepared from compounds of formula (21-1) by reaction with compounds of formula (21-19) (HSR ⁹ ) in the presence of a catalyst such as palladium (II) acetate / JOSIPHOS, using a base, such as potassium tert-butoxide in a suitable solvent, such as DME, at room temperature to the temperature of evaporation of the solvent or solvents, or under microwave conditions at a temperature between 70 ° C and 160 ° C.

Compounds of the formula (21-9) can be prepared from compounds of the formula (21-1) with a suitable alkyne (21-20) (containing the group R ¹⁰ ', which can be stored without modification after reaction, or can be further modified to obtain other R ¹⁰ groups) by reaction in the presence of a catalyst system such as tetrakis (triphenylphosphine) palladium (0) and copper (I) iodide in the presence of a base such as triethylamine and a suitable solvent such as N, N-dimethylformamide, at a temperature between room temperature and temperature swarm of solvent boiling point. This addition reaction can also be carried out in the presence of palladium on carbon, triphenylphosphine, copper (I) iodide and triethylamine, in the presence of a suitable solvent, such as acetonitrile, at a temperature between room temperature and the temperature of evaporation of the solvent or solvents, or under microwave conditions temperature between 70 ° C and 160 ° C.

Compounds of formula (21-1) can be converted to compounds of formula (21-10) by reaction with boronic acid or its ester (21-21) (containing suitable R ³ substituents), in the presence of a catalyst such as bis (triphenylphosphine) palladium (Ii) a dichloride base, such as aqueous sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between room temperature and the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C. and 150 ° C. Alternatively, the compounds formulas (21-1) can be coupled with tin alkyl or aryl compounds (21-21) (containing suitable R ³ substituents), in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), with or without an aqueous base, such as sodium carbonate, in a suitable solvent, such as acetonitrile, at a temperature between room temperature and the evaporation temperature of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of formula (21-11) can be prepared from compounds of formula (21-6) with a suitable halide or triflate of formula (21-22) (R ^{3 '} -X ”), in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium ( 0), in a suitable solvent, such as 1,4-dioxane, at room temperature to the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of formula (21-11) can also be prepared by reacting compounds of formula (21-7) with a suitable halide of formula (21-22) (R ^{3 '} -X "), (containing suitable substituents R ^3' ), in the presence of a catalyst, such as bis (triphenylphosphine) palladium (II) dichloride, with a base such as aqueous sodium carbonate, in a suitable cosolvent, such as acetonitrile, at room temperature to solvent evaporation temperature, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Scheme 22

Compounds of formula (22-1) can be synthesized in accordance with the methods described in the literature, or in accordance with the pathways shown in Scheme 9. Compounds of formula (22-1) can be converted into compounds of formula (22-2) by treatment with a suitable alkylating agent (22-11) R ^{9 '-X} or R ^22' -X (where X represents a suitable leaving group such as Cl, Br, I, OMs or OTf) using a suitable base such as cesium carbonate in a solvent such as acetonitrile at a temperature between room temperature and the vapor point dissolution of solvent. Alternatively, compounds of formula (22-1) can be converted to compounds of formula (22-3) by reaction with a suitable aldehyde (22-12) R ^{9 '} CHO or R ^22' CHO and a suitable hydrogen source such as sodium triacetoxyborohydride in a solvent such as 1,2-dichloroethane at a temperature between 0 ° C and 50 ° C.

Compounds of formula (22-1) can also be converted to compounds of formula (22-4) using a reagent such as sodium nitrite in an acid solution such as aqueous hydrochloric acid, aqueous hydrobromic acid or aqueous sulfuric acid. Compounds of formula (22-4) can then be converted to fluoro compounds of formula (22-10) with a reagent such as sodium tetrafluoroborate; to a chlorine derivative of the formula (22-9) with such a reagent as copper (I) chloride; in iodine compounds of the formula (22-8) with a reagent such as copper iodide; in the alkylthio compounds of formula (22-7) with a reagent such as NaSR ^{9 '} and cyano derivatives (22-5) with a reagent such as copper (I) cyanide and potassium cyanide all at a temperature between 0 ° C and the solvent evaporation point.

Scheme 23

The compounds of formula (23-1) can be synthesized in accordance with the methods described in the literature, or in accordance with the paths shown in Scheme 10. The compounds of formula (23-3), (23-4) and (-5) can be obtained using the synthetic routes shown in Scheme 23. Compounds of formula (23-1) can be converted to compounds of formula (23-4) by reaction with a suitable chlorine source, such as phosphorus pentachloride, in a suitable solvent, such as chlorobenzene, temperature from room temperature to the point of evaporation of the solvent.

Compounds of formula (23-1) can also be converted to compounds of formula (23-2) using a reagent such as nonafluorobutanesulfonic anhydride, in the presence of a base such as pyridine, in a suitable solvent such as dichloromethane, at a temperature between -50 ° C and 20 ° C. Compounds of formula (23-2) can be converted to compounds of formula (23-3) by reaction with a suitable bromine source, such as tetra-n-butylammonium bromide, in a solvent such as 1,4-dioxane , at a temperature from room temperature to the temperature of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of formula (23-2) can be converted to compounds of formula (23-5) by reaction with a suitable iodine source, such as tetra-n-butylammonium iodide, in a solvent, such as 1,4-dioxane, at room temperature solvent evaporation temperature, or under microwave radiation at a temperature between 70 ° C and 150 ° C.

Scheme 24

Compounds of formula (24-1) can be synthesized in accordance with the methods described in the literature, or in accordance with the pathways shown in Scheme 10. Compounds of formula (24-2) can be obtained by alkylation of compounds of formula (24-1) with a suitable alkylating agent (24-3) R ^{11 '-X} (where X represents a suitable leaving group such as Cl, Br, I, OMs or OTf) using a suitable base such as cesium carbonate in a solvent such as acetonitrile , at a temperature between room temperature and the point of evaporation of the solvent.

Pattern 25

The compounds of formula (25-1) can be synthesized in accordance with the methods described in the literature, or in accordance with the paths shown in Scheme 23. Compounds of formula (25-1) (where X represents a leaving group, such as Br or I ) can be converted into compounds of formula (25-2) by reaction with a suitable alkenyltin reagent of formula (25-10), such as phenyl tributyltin, in the presence of a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0), in a suitable solvent, such as 1,4-dioxane, at t temperature between room temperature and solvent evaporation point. Compounds of formula (25-2) can be converted to compounds of formula (25-3) by treatment with a reagent such as ozone in a suitable solvent such as methanol at a temperature between -78 ° C and room temperature, followed by decomposition of ozonide with such a reagent like dimethyl sulfide. Compounds of formula (25-3) can be converted into compounds of formula (25-4) by reaction with a suitable amine of formula (25-11) (HNR ^{16 '} R ^17' ) and a suitable hydrogen source such as sodium triacetoxyborohydride in a solvent such like 1,2-dichloroethane, at a temperature between 0 ° C and 50 ° C.

Compounds of formula (25-1) (where X is a leaving group such as Br or I) can be converted into compounds of formula (25-5) by reaction with potassium alkyl trifluoroborate or alkyl borate of formula (25-12) in the presence of a catalyst based a transition metal such as [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, a base such as aqueous potassium carbonate, in a suitable solvent such as DMF, at room temperature to a temperature of evaporation of the solvent, or conditions of microwave radiation at temperature e is between 70 ° and 150 ° C. Compounds of formula (25-5) may also be prepared from compounds of formula (25-1) by reaction with an aryl or alkyl tin compounds of formula (25-12) (containing suitable substituents R ^{5 '} ) in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or [1, G-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in an aqueous base such as sodium carbonate in a suitable solvent such as acetonitrile, or a combination of solvents, between room temperature and vapor temperature tions of the solvent, or under microwave irradiation at a temperature between 70 ° C and 150 ° C.

Alternatively, compounds of formula (25-7) can be prepared from compounds of formula (25-1) (where X is a leaving group such as Br or I) and a suitable alkyno (25-13) (containing a group R ^{10 '} , which can be saved without modifications after reaction, or can be further modified to give other groups R ¹⁰ ) by reaction in the presence of a catalyst system such as tetrakis (triphenylphosphine) palladium (0) and copper (I) iodide, in the presence of a base such like triethylamine, and a suitable solvent such as N, N -dimethylformamide at a temperature between room temperature and the boiling point of the solvent. This addition reaction can also be carried out in the presence of palladium on carbon, triphenylphosphine, copper (I) iodide and triethylamine in the presence of a suitable solvent, such as acetonitrile, at a temperature between room temperature and the temperature of evaporation of the solvent or solvents, or under microwave conditions at a temperature between 70 ° C and 160 ° C.

Compounds of formula (25-1) (where X is a leaving group such as F, Cl, Br or I) can be converted to compounds of formula (25-6) by substitution of a suitable amine of formula (25-11) (HNR ^{11 '} R ^{12 '} ) as a solvent or in a solvent such as NMP at a temperature between ambient temperature and the point of evaporation of the solvent. Compounds of formula (25-3) can also be prepared from compounds of formula (25-1) (where X is a leaving group such as Br or I) by reaction with compounds of formula (25-11) (HNR ^{11 '} R ¹² ' ) in the presence of a catalyst, such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), in the presence of a base such as potassium tert-butoxide in a suitable solvent such as DME, or a mixture of two or more suitable solvents, at room temperature to the temperature of evaporation of the solvent or solvents, or under microwave conditions of radiation at a temperature between 70 ° C and 160 ° C.

Compounds of formula (25-8) can be prepared from compounds of formula (25-1) (where X is a leaving group such as Br or I) by reaction with compounds of general formula (25-14) (HSR ^{11 ′} ) in the presence of a catalyst, such as palladium (II) acetate / JOAIPHOS, in the presence of a base such as potassium tert-butoxide in a suitable solvent, such as DME, or a mixture of two or more suitable solvents, at room temperature to the temperature of evaporation of the solvent or solvents, or under microwave radiation at temperature between 70 ° C and 160 ° C.

The sulfides of the intermediates of formula (25-8) can be converted to sulfoxides and sulfones of formula (25-9) by oxidation with a suitable oxidizing agent, such as oxone, in a solvent such as acetone, at a temperature between 0 ° C and 50 ° C.

The compounds of formula (26-1) can be synthesized in accordance with the methods described in the literature, or in accordance with the paths shown in Scheme 10. Compounds of formula (26-1) can be converted into compounds of formula (26-2) by treatment an acid such as hydrochloric acid in a solvent such as water, at a temperature between room temperature and the point of evaporation of the solvent, or in a closed vessel at a temperature between 70 ° C and 140 ° C.

The compounds of formula (26-2) can then be reacted with a suitable alcohol (26-10) (R ^{11 '} OH) using phosphine and a coupling reagent such as diisopropylazodicarboxylate in a suitable solvent such as THF to give esters of the general formula (26-3). Alternatively, compounds of formula (26-3) may be prepared by alkylation of compounds of general formula (26-2) with a suitable alkylating agent (26-11) R ^{11 '-X} (where X represents a suitable leaving group such as Cl, Br , I, OMs or OTf) using a suitable base such as cesium carbonate in a solvent such as acetonitrile, at a temperature between room temperature and the point of evaporation of the solvent.

Compounds of formula (26-2) can also be converted to nonaflates (26-5) using a reagent such as nonafluorobutanesulfonic anhydride, in the presence of a base such as pyridine, in a suitable solvent such as dichloromethane, at a temperature between -50 ° C. and 20 ° C.

Compounds of formula (26-5) can be converted to compounds of formula (26-4) by substitution of suitable amines of general formula (26-12) (HNR ^{11 '} R ^12' ) either as a solvent or in a solvent such as NMP, with temperature between ambient temperature and solvent evaporation point. Compounds of formula (26-4) can also be prepared from compounds of formula (26-5) by reaction with compounds of general formula (26-12) (HNR ^{11 '} R ^12' ) in the presence of a catalyst such as [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium (II), in the presence of a base such as potassium tert-butoxide, in a suitable solvent such as DME, or a mixture of two or more suitable solvents, at room temperature to the temperature of evaporation of the solvent or solvents, or under conditions of microwave radiation at a temperature between 70 ° C and 160 ° C.

Alternatively, compounds of formula (26-7) can be prepared from compounds of formula (26-5) with a suitable alkyno (26-14) (containing a group R ^{10 '} , which can be stored without modification after reaction, or may be further modified to produce other R ¹⁰ groups) by reaction in the presence of a catalyst system such as tetrakis (triphenylphosphine) palladium (0) and copper (I) iodide in the presence of a base such as triethylamine and a suitable solvent such as N, N-dimethylformamide at a temperature between room temperature swarm and temperature of the boiling point of the solvent. This addition reaction can also be carried out in the presence of palladium on carbon, triphenylphosphine, copper (I) iodide and triethylamine in the presence of a suitable solvent, such as acetonitrile, at a temperature between room temperature and the temperature of evaporation of the solvent or solvents, or under microwave conditions at a temperature between 70 ° C and 160 ° C.

Nonaflate intermediates (26-5) can be converted to compounds of formula (26-8) by reaction with potassium alkyl trifluoroborate or alkyl borate of formula (26-15) in the presence of a transition metal catalyst such as [1,1'-bis ( diphenylphosphino) ferrocene] palladium (II) dichloride, a base, such as aqueous potassium carbonate, in a suitable solvent, such as DMF, at room temperature to evaporate the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C. Compounds of general formulas You (26-8) can also be obtained from compounds of formula (26-5) by reaction with aryl or alkyl tin compounds (containing suitable substituents R ⁵ ), in the presence of a catalyst such as bifriphenylphosphine) palladium (II) dichloride or [1 , 1e-bis ^ diphenylphosphino) ferrocene] dichloropalladium (II), an aqueous base such as sodium carbonate, in a suitable solvent such as acetonitrile, or a combination of solvents, at a temperature between room temperature and the temperature of evaporation of the solvent, or under microwave conditions exercises at a temperature between 70 ° C and 150 ° C.

Compounds of formula (26-6) can be prepared from compounds of formula (26-5) (where X is a leaving group such as Br or I) by reaction with compounds of formula (26-13) (HSR ^{11 ′} ) in the presence of a catalyst such as palladium (II) acetate / JOSIPHOS in the presence of a base such as potassium tert-butoxide in a suitable solvent such as DME, or a mixture of two or more suitable solvents, at room temperature to the temperature of evaporation of the solvent or solvents, or microwave conditions at a temperature between 70 ° C and 160 ° C.

The sulfides of the intermediates of formula (26-6) can be converted to sulfoxides or sulfones of formula (26-9) by oxidation with a suitable oxidizing agent, such as oxone, in a solvent such as acetone at a temperature between 0 ° C and 50 ° C.

Scheme 27

Scheme 27-1

Scheme 27-2

Scheme 27-3

The compounds of formula (27-4) can be synthesized in accordance with the methods described in the literature, or in accordance with the pathways shown in Scheme 27-1. Compound (27-1) can be converted to compound (27-2) by treatment with urea in a suitable solvent, such as methanol, by heating in a closed vessel at temperatures above 150 ° C. Compound (27-2) can be converted into compound (27-3) by treatment with a dehydrating agent in a suitable solvent at the desired temperature, such as trifluoroacetic anhydride in the presence of triethylamine at a temperature between 0 ° C and ambient temperature. Compound (27-3) can be converted into a protected compound of formula (27-4) by methods described in the literature, where P ¹ is a suitable protecting group, such as a 2-trimethylsilanylethoxymethyl derivative, by treating 2-trimethylsilanylethoxymethyl with chloride and sodium hydride in tetrahydrofuran .

Compounds of formula (27-4) can also be synthesized from compounds of formula (27-5), as shown in Scheme 27-2, described in the literature, or other reduction methods, such as hydrogenation in the presence of a palladium catalyst on a carbon support in a suitable solvent such as tetrahydrofuran, or by treatment with powdered zinc and ammonium formate in tetrahydrofuran.

Compounds of formula (27-10) can be synthesized from compounds of formula (27-4) as shown in Scheme 27-2. Compounds of formula (27-4) can be converted into compounds of formula (27-6) by treatment with an oxidizing agent in a suitable solvent, such as hydroperitic adduct in chloroform at ambient temperature. Compounds (27-6) can be converted into compounds (27-7) by treatment with an electrophilic agent and a source of chloride, such as methanesulfonyl chloride in N, N-dimethylformamide at ambient temperature. Compounds (27-7) can be deoxygenated to compounds (27-8) by treatment with a suitable reducing agent, such as triethylamine, in the presence of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in acetonitrile under microwave irradiation .

Compounds of formula (27-8) can also be prepared by the methods depicted in Scheme 27-3. Compounds (27-4) can also be converted into compounds of formula (27-11) by treatment with an oxidizing agent in a suitable solvent, such as hydroperitic adduct in chloroform. Compounds (27-11) can be converted into compounds (27-8) by treatment with a suitable agent, such as methanesulfonyl chloride, in N, N-dimethylformamide at ambient temperature.

Compounds of formula (27-8) can be converted to compounds of formula (27-9) by treatment with an alcohol shown as R ⁹ OH in the presence of a suitable base such as sodium hydride in a suitable solvent such as tetrahydrofuran at a temperature between ambient temperature and the temperature of the boiling point of the solvent, or at a temperature greater than the boiling point of the solvent in a closed vessel. Compounds of formula (27-9) can be converted to compounds (27-10) by removing a protecting group shown as P ¹ , such as a 2-trimethylsilanylethoxymethyl protecting group, for example, by treating with tetrabutylammonium fluoride in tetrahydrofuran, or, as an additional example, by treatment with aqueous hydrobromic acid in dioxane followed by treatment with aqueous sodium hydroxide.

Scheme 28

Compounds of general formula (28-1) can be prepared using published methods described in the literature. Compounds of formula (28-11) and (28-13) can be prepared using the synthetic routes depicted in Scheme 28.

Compounds of general formula (28-2) (where X is H, F, Cl, and Br) can be prepared from compounds of general formula (28-1) and propine by reaction in the presence of a catalyst system such as bifriphenylphosphine) dichloropalladium (II) and copper (I) iodide, in the presence of a base such as triethylamine and a solvent such as THF, at a temperature between room temperature and the boiling point of the solvent.

Compounds of general formula (28-3) can be prepared from compounds of formula (28-2) by treatment with a suitable base, such as potassium tert-butoxide, in a suitable solvent such as mpem-butanol at a temperature between room temperature and the point of evaporation of the solvent .

Compounds of general formula (28-3) can then be converted to compounds of general formula (28-4) by treatment with an acid chloride such as trifluoroacetic acid chloride in the presence of a Lewis acid such as aluminum chloride in a suitable solvent such as dichloromethane at a temperature between room temperature and the evaporation point of the solvent, followed by hydrolysis of the base using a suitable base, such as sodium hydroxide in a suitable solvent, such as methanol at a temperature between room temperature temperature and solvent evaporation point.

Compounds of general formula (28-4) can then be brominated with a brominating agent such as N-bromosuccinimide in a solvent such as 1,2-dichloroethane at a temperature between room temperature and solvent evaporation temperature to give compounds of general formula (28-5) . Compounds of general formula (28-5) can be converted to compounds of general formula (28-6) by substituting tosylaminoacetonitrile (28-6) using a suitable base such as sodium hydride in a solvent such as DMF at a temperature between -20 ° C and 50 ° C. The compounds of general formula (28-7) can then be cyclized with a suitable base such as lithium hexamethylsilylamide in a solvent such as THF at a temperature between -78 ° C and room temperature to give compounds of the general formula ( 28-8). Compounds of general formula (28-8) can then be reacted with a suitable alcohol (28-12) (R ^{11 ′} OH) using phosphine and a coupling reagent such as diisopropylazodicarboxylate in a suitable solvent such as THF to give esters of general formula ( 28-13).

Alternatively, compounds of general formula (28-5) can be converted to compounds of general formula (28-9) using a chlorinating agent, such as phosphorus pentachloride, in a suitable solvent, such as chlorobenzene or phosphorus oxychloride, at a temperature between 50 ° C and solvent evaporation point.

Compounds of general formula (28-11) can be prepared from compounds of formula (28-9) by reaction with compounds of general formula (28-10) (HNR ^{11 '} R ^12' ) with or without the presence of a base such as N, N- diisopropylethylamine in a suitable solvent, such as NMP, at a temperature from room temperature to the evaporation temperature of the solvent.

Scheme 29

Compounds of the general formula (29-1) can be prepared using the synthesis pathways shown in Scheme 28. Compounds of the formula (29-4) can be made using the synthetic pathways shown in Scheme 29.

Compounds of general formula (29-1) can be converted to compounds of general formula (29-2) using a catalyst, such as palladium, in a solvent, such as ethanol, in a hydrogen atmosphere at room temperature to 50 ° C. Compounds of the formula ( 29-2) can then be reacted with a suitable alcohol (29-3) (R ^{11 '} OH) using phosphine and a coupling reagent such as diisopropyl azodicarboxylate in a suitable solvent such as THF to give esters of general formula (29-4) .

Scheme 30

Compounds of general formula (30-1) may be prepared using published methods described in the literature, or available from commercial sources.

Compounds of general formula (30-2) can be prepared from compounds of general formula (30-1) by treatment with a mixture of an aldehyde, such as formaldehyde, in the presence of an amine, such as dimethylamine, in a suitable solvent, such as 1-butanol, at a temperature between 50 ° C and the evaporation point of the solvent. Compounds of general formula (30-2) can be converted to compounds of general formula (30-3) by treatment with acetamidomalonate, such as diethylacetamidomalonate, in the presence of a base, such as sodium hydroxide, in a suitable solvent, such as xylene, at a temperature between 50 ° C and the evaporation point of the solvent.

Compounds of general formula (30-4) can be prepared from compounds of formula (30-3) by hydrolysis and decarboxylation using a suitable acid, such as concentrated hydrochloric acid, at a temperature between 50 ° C and the evaporation point of the solvent. Compounds of general formula (30-5) can be prepared from compounds of general formula (30-4) by treatment with a suitable acid, such as hydrochloric acid, in the presence of an alcoholic solvent, such as methanol, at a temperature between ambient temperature and the point of evaporation of the solvent. Compounds of general formula (30-5) can be converted to compounds of general formula (30-6) by treatment with an aldehyde, such as formaldehyde, in a suitable solvent, such as pyridine at a temperature between 50 ° C and the evaporation point of the solvent.

Compounds of general formula (30-7) can be prepared from compounds of general formula (30-6) by oxidation with a suitable oxidizing agent, such as silica, in a suitable solvent, such as 1,4-dioxane, at a temperature between 50 ° C and solvent evaporation point. Compounds of general formula (30-7) can then be saponified in the presence of a base, such as lithium hydroxide, in a mixture of suitable solvents such as THF and water, at a temperature of from 20 ° C. to 50 ° C., to give compounds of general formula (30 -8).

Compounds of general formula (30-9) can be prepared by decarboxylation of compounds of general formula (30-8) by heating in a suitable solvent, such as NMP, at a temperature between 100 ° C. and the boiling point of the solvent.

Compounds of general formula (30-9) can be converted to compounds of general formula (30-13) by substitution with a suitable amine of general formula (30-11) (HNR ^{11 '} R ^12' ) either as a solvent or in a solvent such as NMP, at a temperature between ambient temperature and the point of evaporation of the solvent. Compounds of general formula (30-13) can also be prepared from compounds of general formula (30-9) by reaction with compounds of general formula (30-11) (HNR ^{11 '} R ^12' ) in the presence of a catalyst such as [1,1 'bis (diphenylphosphino) ferrocene] dichloropalladium (II), in the presence of a base such as potassium tert-butoxide, in a suitable solvent such as DME, or a mixture of two or more suitable solvents, at room temperature to the temperature of evaporation of the solvent or solvents , or under microwave conditions at a temperature between 70 ° C 160 ° C.

Compounds of general formula (30-12) may be prepared by alkylation of compounds of general formula (30-9) with a suitable alkylating agent (30-10) R ^{11 '-OH} with a suitable base such as cesium carbonate in a solvent such as acetonitrile, at a temperature between room temperature and the point of evaporation of the solvent.

Scheme 31

Compounds of general formula (31-1) may be prepared using published methods described in the literature, or available from commercial sources. Compounds of formula (31-10) can be prepared using the synthetic routes depicted in Scheme 31.

Compounds of general formula (31-2) can be prepared from compounds of general formula (31-1) by reaction with carbamate. such as tert-butyl carbamate, in the presence of a catalyst such as Tris (dibenzylidine acetone) dipalladium (0) / XantPhos, a base such as cesium carbonate, in a suitable solvent such as 1,4-dioxane. at temperatures from 50 ° C to the temperature of solvent evaporation, or under microwave conditions at temperatures from 70 ° C to 150 ° C. Compounds of general formula (31-2) can be deprotonated with a suitable base such as n-butyllithium / TMEDA, in a suitable solvent, such as diethyl ether, between -78 ° C and -10 ° C, then halogenated with a suitable halogenating agent, such as iodine, to give compounds of general formula (31-3).

Compounds of general formula (31-3) may be deprotected using an acid such as TFA (trifluoroacetic acid) in a solvent such as dichloromethane to give compounds of general formula (31-4). Compounds of general formula (31-6) can be prepared from compounds of general formula (31-4) by reaction with boronic acid of general formula (31-5) in the presence of a catalyst such as Anphos2, a base such as aqueous potassium fluoride, in a suitable a solvent, such as acetonitrile, at a temperature of from 50 ° C and a temperature of evaporation of the solvent, or under microwave conditions at a temperature of from 70 ° C to 150 ° C.

Compounds of general formula (31-6) can be cyclized to give compounds of general formula (31-7) with a base such as sodium hexamethyldisilazane in a suitable solvent, such as THF, at a temperature between 0 ° C and 50 ° C. formulas (31-7) can be converted into compounds of general formula (31-10) using a reagent of general formula (31-8), such as zinc (II) cyanide in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0) in a solvent such as DMF, at a temperature between room temperature and the vapor point of the solvent, or under microwave irradiation at a temperature between 70 ° C and 150 ° C.

Alternatively, compounds of general formula (31-6) can be converted to compounds of general formula (31-9) using a reagent of general formula (31-8) such as zinc (II) cyanide, in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (0) in a solvent such as DMF, at a temperature between room temperature and the point of evaporation of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C. Compounds of the general formula (31-9) can be cyclized to obtain compounds of General formula (31-10) with a base such as sodium hexamethyldisilazane, in a suitable solvent, such as THF, at a temperature between 0 ° C and 50 ° C.

Scheme 32

Compounds of general formula (32-1) and (32-9) can be prepared using the synthetic routes shown in Scheme 31. Compounds of general formula (32-5), (32-8), (32-10) and (32 -11) can also be made using the synthetic routes shown in Scheme 32. Compounds of general formula (32-1) can be converted to compounds of general formula (32-3) by substitution of suitable amines of general formula (32-2) (HNR ^{11 '} R ^12' ) either as a solvent or in a solvent such as DMA, at a temperature between the ambient temperature and the evaporation point of the solvent.

Compounds of general formula (32-7) may be prepared by alkylation of compounds of general formula (32-1) with a suitable alkylating agent (32-6) R ^{11 '-OH,} using an appropriate base such as cesium carbonate in a solvent such as acetonitrile, at a temperature between room temperature and the point of evaporation of the solvent.

Compounds of general formula (32-5) and (32-8) can be converted into compounds of general formula (32-5) and (32-8) using a reagent of general formula (32-4), such as zinc (II) cyanide , in the presence of a catalyst such as tertrakis (triphenylphosphine) palladium (0) in a solvent such as DMF, at a temperature between room temperature and the evaporation point of the solvent, or under microwave conditions at a temperature between 70 ° C and 150 ° C.

Compounds of general formula (32-9) can be converted to compounds of general formula (32-10) by substitution of suitable amines of general formula (32-2) (HNR ^{11 '} R ^12' ) as a solvent or in a solvent such as DMA with temperature between ambient temperature and 60 ° C.

Compounds of general formula (32-11) may be prepared by alkylation of compounds of general formula (32-9) with a suitable alkylating agent (32-6) R ^{11 '-OH,} using an appropriate base such as sodium hydride in a solvent such as N, N-dimethylformamide at a temperature between 0 ° C and the point of evaporation of the solvent.

It should be borne in mind that where appropriate functional groups exist, the compounds described by the formulas of Schemes 1-32, or any intermediates used in their preparation, can be further derivatized by one or more standard synthetic methods using substitution, oxidation, reduction, or cleavage reactions. Specific substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfinylation, halogenation, nitration, formylation and coupling procedures.

For example, subsequently, the primary amine group (-NH2) can be alkylated by reductive alkylation using an aldehyde or ketone and borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example 1,2 dichloroethane, or an alcohol such like ethyl alcohol, where necessary in the presence of an acid, such as acetic acid, in the range of ambient temperature. Secondary amine groups (—NH—) can similarly be alkylated using aldehydes.

Further, by way of example, primary or secondary amino groups can be converted to amido groups (—NHCOR ′ or —NRCOR ′) by acylation. Acylation can be accomplished by reaction with a suitable acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reaction with a suitable carboxylic acid in the presence of a suitable binding agent, such as HATU (O- (7-azabenzotriazole-1 -yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate) in a suitable solvent such as dichloromethane. Similarly, amino groups can be converted to sulfonamide groups (—NHSO ₂ R ′ or —NR ”SO ₂ R ′) by reaction with a suitable sulfonyl chloride in the presence of a suitable base such as triethylamine in a suitable solvent such as dichloromethane. Primary or secondary amino groups can be converted into urea groups (-NHCONR'R "or -NRCONR'R") by reaction with a suitable isocyanate in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane.

Amines (-NH ₂ ) can be prepared by reduction of the nitro group (-NO ₂ ), for example, by catalytic hydrogenation, using, for example, hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, in a solvent such as ethyl acetate or alcohol, such as methanol. Alternatively, the transformation can be carried out by chemical reduction using, for example, a metal, for example tin or iron, in the presence of an acid such as hydrochloric acid.

As a further example, amino groups (—CH ₂ NH ₂ ) can be prepared by reduction of nitriles (—CN), for example, by catalytic hydrogenation using, for example, hydrogen in the presence of a metal catalyst, for example, palladium on a support such as carbon, or a Raney nickel catalyst, in a solvent, such as an ether, for example, a cyclic ether, such as tetrahydrofuran, at a temperature of from -78 ° C and to the temperature of evaporation of the solvent.

In a further example, amino groups (-NH ₂ ) can be obtained from carboxylic acid groups (-CO ₂ H) by rearrangement of the corresponding acyl azide (-CONs), Curtius rearrangement and hydrolysis of the resulting isocyanate (-N = C = O).

Aldehyde groups (—CHO) can be converted to amino groups (—CH ₂ NR′R ”)) by reductive amination using an amine and borohydride, for example sodium triacetoxy borohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example dichloromethane, or alcohol, such as ethanol, where necessary in the presence of an acid, such as acetic acid at a temperature close to ambient temperature.

In a further example, aldehyde groups can be converted to alkenyl groups (-CH = CHR ′) by the Witting or Horner-Wadsworth-Emmons reaction using suitable phosphorane or phosphonate under standard conditions known to the skilled person.

Aldehyde groups can be prepared by reducing ether groups (such as —CO ₂ Et) or nitriles (—CN) using diisobutyl aluminum hydride in a suitable solvent such as toluene. Alternatively, aldehyde groups can be prepared by oxidizing alcohol groups using any suitable oxidizing agents known to the skilled person.

The ester groups (—CO ₂ R ′) can be converted to the corresponding acid groups (—CO ₂ H) by acidic or basic catalyzed hydrolysis, depending on the nature of R. If R is tert-butyl, acid catalyzed hydrolysis can be carried out, for example by treating with an organic acid, such as trifluoroacetic acid, in an aqueous solvent, or by treating with an inorganic acid, such as hydrochloric acid, in an aqueous solvent.

Carboxylic acid groups (—CO ₂ H) can be converted to amides (CONHR ′ or —CONR′R ”) by reaction with a suitable amine in the presence of a suitable coupling agent, such as HATU, in a suitable solvent, such as dichloromethane.

In a further example, carboxylic acids can be converted into homologous acids by adding one carbon (for example, —CO ₂ H to —CH ₂ CO ₂ H) by converting the corresponding acid chloride (—COCl) followed by Arndt – Aistert synthesis.

In a further example, —OH groups can be prepared from the corresponding esters (eg, —CO ₂ R ′), or aldehydes (—CHO) by reduction using complex metal hydrides such as lithium aluminum hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol. Alternatively, alcohols can be prepared by reducing the corresponding acids (—CO ₂ H) using, for example, lithium aluminum hydride in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.

Alcohol groups can be converted to leaving groups, such as a halogen atom or sulfonyloxy groups, such as alkylsulfonyloxy, for example trifluoromethylsulfonyloxy or arylsulfonyloxy, for example, p-toluenesulfonyloxy group, using conditions known to those skilled in the art. For example, an alcohol may react with a thioyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to produce the corresponding chloride. Bases (e.g. triethylamine) can also be used in such reactions.

In another example, alcohol, phenolic or amide groups can be alkylated by coupling phenol or amide to an alcohol in a solvent such as tetrahydrofuran in the presence of phosphine, for example triphenylphosphine, and an activator, such as diethyl, diisopropyl or dimethylazodicarboxylate. Alternatively, alkylation may be carried out by deprotonation using a suitable base, for example sodium hydride, followed by the addition of an alkylating agent such as an alkyl halide.

Aromatic halogen substituents in the compounds can participate in the halogen-metal exchange by treatment with a base, for example, lithium base, such as n-butyl or tert-butyl lithium, optionally at a low temperature, for example, about -78 ° C, in a solvent such as tetrahydrofuran, followed by repayment by electrophile to introduce the necessary substituent. For example, a formyl group can be introduced using N, N-dimethylformamide as an electrophile. Aromatic halogen substituents can alternatively undergo a metal-catalyzed reaction (e.g., palladium or copper) to introduce, for example, acidic, ester, cyano, amide, aryl, heteroaryl, alkenyl, alkynyl, thio or amino substituents. Suitable methods can be carried out as described by Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogen substituents can also undergo nucleophilic substitution during the reaction with a suitable nucleophile, such as an amine or alcohol. Preferably, such reactions can be carried out at elevated temperatures in the presence of microwave radiation.

The compounds of the present invention are tested for their ability to inhibit the activity and activation of chk1 kinase (primary assays) and their biological effects on growing cells (secondary assays) as described below. Compounds having an IC ₅₀ value lower than 10 μM (more preferably less than 5 μM, more preferably less than 1 μM, most preferably less than 0.5 μM) in the activity analysis and activation of chk1 kinase in Example i, and EC ₅₀ less than 10 μM (more preferably less than 5 μM, most preferably less than 1 μM) in the cell assay of Example II are useful as a chk1 kinase inhibitor.

The present invention includes compositions (eg, pharmaceutical compositions) comprising a compound of Formula (I), (Ia) and / or (Ib), (and / or solvates, hydrates and / or salts thereof) and a carrier (pharmaceutically acceptable carrier) . The present invention also includes a composition (eg, a pharmaceutical composition) comprising a compound of Formula (I), (Ia) and / or (Ib) (and / or their solvates, hydrates and / or salts) and a carrier (pharmaceutically acceptable carrier), further containing a second chemotherapeutic agent, such as described in the present invention. The present invention also includes a composition (eg, a pharmaceutical composition) comprising a compound of Formula (I), (Ia) and / or (Ib) (and / or their solvates, hydrates and / or salts) and a carrier (pharmaceutically acceptable carrier), further containing a second chemotherapeutic agent, such as a DNA damaging agent, including those described herein. The compositions of the present invention are useful for inhibiting abnormal cell growth or for treating hyperproliferative diseases, such as tumors, in mammals (e.g., humans). For example, the compounds and compositions of the present invention are useful in the treatment of breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer, malignant brain tumors, sarcomas, melanoma, lymphoma, myeloma and / or leukemia in mammals (e.g., humans).

The present invention includes a method of inhibiting abnormal cell growth or treating hyperproliferative diseases such as cancer in mammals (e.g., humans), comprising administering to said mammal a therapeutically effective amount of a compound of Formula (I), (Ia) and / or (Ib) (and / or solvates, hydrates and / or salts thereof) or compositions thereof. For example, the present invention includes a method of treating breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer, malignant brain tumors, sarcoma, melanoma, lymphoma, myeloma and / or leukemia in mammals (e.g., humans), comprising administering to said mammal a therapeutically effective amount of a compound of Formula (I), (Ia) and / or (Ib) (and / or solvates, hydrates and / or salts thereof) or compositions thereof.

The present invention includes a method of inhibiting abnormal cell growth or treating hyperproliferative diseases, such as cancer, in mammals (e.g., humans), comprising administering to said mammal a therapeutically effective amount of a compound of Formula (I), (Ia) and / or (Ib) (and / or solvates, hydrates and / or salts thereof) or compositions thereof, in combination with a second chemotherapeutic agent, such as described in the present invention. The present invention also includes a method of inhibiting abnormal cell growth or treating hyperproliferative diseases, such as cancer, in mammals (e.g., humans), comprising administering to said mammal a therapeutically effective amount of a compound of Formula (I), (Ia) and / or (Ib) (and / or solvates, hydrates and / or salts thereof) or compositions thereof, in combination with a second chemotherapeutic agent, such as a DNA damaging agent, including those described herein. For example, the present invention includes a method for treating breast cancer, colorectal cancer, ovarian cancer, numbered lung cell carcinoma of the lung, malignant brain tumors, sarcoma, melanoma, lymphoma, myeloma and / or leukemia in mammals (e.g., human), comprising administering to said to a mammal a therapeutically effective amount of a compound of Formula (I), (Ia) and / or (Ib) (and / or their solvates, hydrates and / or salts) or compositions thereof, in combination with a second chemotherapeutic agent, such as described in the present invention . The present invention also includes a method of inhibiting abnormal cell growth or treating hyperproliferative diseases such as cancer in mammals (e.g., humans), comprising administering to said mammal a therapeutically effective amount of a compound of Formula (I), (Ia) and / or (Ib) (and / or their solvates, hydrates and / or salts) or compositions thereof, in combination with a second chemotherapeutic agent, such as a DNA damaging agent, including those described herein.

The present invention includes a method of using the present compounds for in vitro, in situ, and in vivo diagnosis and treatment of mammalian cells, an organism, or related pathological conditions.

The introduction of the compounds of the present invention (hereinafter "the active substance (a)") can be carried out by any means, which include the delivery of the compounds to their site of action. These methods include oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, inhalation, or rectal administration.

The amount of active substance will depend on the subject of treatment, the severity of the disease or pathological conditions, the speed of administration, availability of the substance and the doctor’s prescription. However, an effective dosage is in the range of from about 0.001 to about 100 mg per kg of body per day, preferably from about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg person, such an amount would be from about 0.05 to 7 g per day, preferably from about 0.05 to about 2.5 g / day. In some cases, dosage levels lower than the lower limit of the above range may be more than suitable, while in other cases even larger doses can be used without causing harmful side effects, provided that such large doses are first divided into several small doses for appointments throughout the day.

The active substance can be used as a single treatment or in combination with one or more chemotherapeutic agents, for example, which are described in the present invention. Such combined treatment can be achieved by simultaneous, sequential or separate dosing of the individual components of the treatment.

The pharmaceutical composition may, for example, be in the form suitable for oral administration in the form of a tablet, capsule, pill, powder, sustained-release preparation, solution, suspension, in the form of a sterile solution, suspension or emulsion for parenteral injection, for topical administration in the form of ointments or creams or for rectal administration in the form of suppositories. The pharmaceutical composition may be in unit dosage form suitable for single administration or for precise doses. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound of the present invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, excipients, etc.

Examples of forms for parenteral administration include solutions or suspensions of the active substances in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solution. Such dosage forms may be buffered, if necessary, in a suitable manner.

Suitable pharmaceutical carriers include inert diluents or excipients, water and various organic solvents. Pharmaceutical compositions, if desired, may contain additional components, such as flavorings, binders, excipients, and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid, can be used with various disintegrants, such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and gum. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful in the manufacture of tablets. Solid compositions of a similar type can also be used in soft and hard-filled gelatin capsules. Preferred materials thus include lactose or milk sugar and high molecular weight polyethylene glycols. When it is desirable to use aqueous suspensions or tinctures for oral administration, the active substance in their composition can be combined with various sweeteners or flavorings, pigments or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.

Methods of obtaining various pharmaceutical compositions with a certain amount of active substance are known, or will be obvious, to qualified specialists. For an example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

Examples

Abbreviations

AIBN 2,2'-Azobis (2-methylpropionitrile)

ATP Adenosine 5'-triphosphate

BiOtage BiOtage pre-filled silica gel cartridge ⁽ SNAP Cartridge for flash chromatography

CDCl ₃ Deuterated Chloroform

CD ₃ OD Deuterated methanol

DCM Dichloromethane

DCE Dichloroethane

DIPEA Diisopropylethylamine

DMAP 4-Dimethylaminopyridine

DMA Dimethylacetamide

DMAP 4-Dimethylaminopyridine

DME 1,2-Dimethoxyethane

DMF Dimethylformamide

DMSO Dimethyl Sulfoxide

DMSO-d ₆ Deuterated Dimethyl Sulfoxide

EtOAc Ethyl Acetate

EtOH Ethanol

h hour

HCl hydrochloric acid

HM-N IsOlute (HM-N is a modified form of diatomite that effectively absorbs aqueous samples

HOBt 1-Hydroxybenzotriazole

IMS Industrial Meth

HATU O- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

LCMS Liquid chromatography mass spectrometry

LDA Lithium Diisopropylamide

MeOH Methanol

mmol Millimoli

M Moli

n Normal (concentration)

NaHCO ₃ Sodium Bicarbonate

NaOH Sodium Hydroxide

NBS N-Bromosuccinimide

NMP N-Methyl-2-pyrrolidone

NMR Nuclear Magnetic Resonance

PyBOP (Benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate

SCX-2 Strong cation exchange resin

Si-SPE IsOlute Pre-Filled Silica Gel Cartridge (for flash chromatography

Si-ISCO ISCO® Flash Chromatography Pre-Filled Silica Gel Cartridge

TBAF tetrabutylammonium fluoride

THF Tetrahydrofuran

TFA Trifluoroacetic Acid

TLC Thin layer chromatography

TMS Trimethylsilyl

Basic experimental conditions

¹ H NMR spectra were recorded at ambient temperature using a Varian Unity Inova spectrometer (400 MHz) using a triple resonance of a 5 mm sample. The chemical shift is presented as ppm (ppm) relative to tetramethylsilane. The following abbreviations were used: br = wide signal, s = singlet, d = dipole, dd = double dipole, t = triplet, q = quartet, m = multiplet.

Liquid chromatography-mass spectrometry (LCMS) to determine the retention time (R-g) and the masses of bound ions was carried out using one of the following methods.

Method A: experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer coupled to a Waters Acquity UPLC system with a PDA UV detector using an Acquity UPLC BEN C18 (1.7 μm) 100 × 2.1 mm column and a flow rate of 0.4 ml / min. The solvent system consisted of 95% water containing 0.1% formic acid (Solvent A) and 5% acetonitrile containing 0.1% formic acid (Solvent B) for the first 0.40 min, followed by adjusting the gradient to 5% Solvent A and 95% Solvent B over the next 7 minutes The final solvent system was kept constant over the next 0.40 minutes.

Method B: experiments were performed on a Waters Platform LC quadrupole mass spectrometer coupled to a Hewlett Packard HP1100 LC system with a diode array detector and a 100-position autosampler using a Phenomenex Luna C18 (2) 30 × 4.6 mm column and a flow rate of 1 ml / min The solvent system consisted of 95% water containing 0.1% formic acid (Solvent A) and 5% methanol containing 0.1% formic acid (Solvent B) for the first 0.50 min, followed by adjusting the gradient to 5% solvent A and 95% solvent B over the next 4 minutes The final solvent system was kept constant over the next 0.50 minutes.

Method C: experiments were performed on a Waters Quattro Micro triple quadrupole mass spectrometer coupled to a Hewlett Packard HP1100 LC system with a diode array detector and a 100-position autosampler using a Higgins Clipeus 5 μm C18 100 × 3 mm column and a flow rate of 1 ml / min The solvent system consisted of 95% water containing 0.1% formic acid (Solvent A) and 5% methanol containing 0.1% formic acid (Solvent B) for the first 1.0 min, followed by adjusting the gradient to 5% solvent A and 95% solvent B over the next 20 minutes The final solvent system was kept constant for the next 1.0 min.

Method D: experiments were performed on an Agilent 1100 HPLC with an Agilent MSD mass spectrometer using an ESI as an ionization source, and using an Agilent ZORBAX SB-C18 100 × 3.0 mm column with a 0.7 ml / min flow rate. The solvent system was a gradient starting with 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B), with an increase of up to 5% solvent A and 95% solvent B over 25 minutes. The final solvent system was kept constant over the next 5.0 minutes.

Method E: experiments were performed on an Agilent 1100 HPLC with an Agilent MSD MSD mass spectrometer using an ESI "ionization source, and using an Agilent ZORBAX SB-C18 30 × 2.1 mm column and 0.6 ml / min flow rate. The solvent system was a gradient starting with 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B), with an increase of up to 5% solvent A and 95% solvent B over 9 minutes. the solvent system was kept constant for the next 1.0 min.

Method F: experiments were performed on a Waters Acquity UHPLC with a Waters-LCT Premier XE mass spectrometer using ESI as an ionization source, and using an Acquity UPLC BEN C18, 1.7 μm, 2.1 * 50 mm column and with a 0.6 ml / min speed flow. The solvent system was a gradient starting with 98% water 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B), bringing to 2% solvent A and 98% solvent B over 2.5 minutes . The final solvent system was kept constant for the next 1.0 min.

Method G: experiments were performed on a Waters Acquity UHPLC with a Waters -LCT Premier XE mass spectrometer using ESI as an ionization source, and using an Acquity UPLC BEN C18, 1.7 μm, 2.1 * 50 mm column and at 0.6 ml / min speed flow. The solvent system was a gradient starting with 98% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B), increasing to 2% solvent A and 98% solvent B over 17 minutes. The final solvent system was kept constant for the next 1.0 minutes.

Microwave experiments were performed using the Biotage Initiator 60 (which uses a single-mode resonator and dynamic tunneling. A temperature of 40-250 ° C was used and a pressure of more than 30 bar (3 MPa) could be set. Alternatively, a CEM Discover microwave was used in some experiments.

BASIC WAYS

Boronic acids and boronate esters have been prepared from suitable aryl halide intermediates using the basic coupling methods described below. All aryl halide intermediates were either commercially available or prepared using methods described in the literature, or may be prepared by a qualified professional. In some cases, intermediates were not isolated, and the coupling reaction was carried out with crude (crude) boronic acid / boronate ester. The Suzuki reaction was carried out using both commercially available boronic acids / boronate esters and compounds obtained using the methods described in detail below. If necessary, any protective groups were then removed using one of the deprotection conditions described below. The Stille reaction was carried out using both commercially available stannanes and compounds prepared using the methods detailed below. If necessary, any protective groups were then removed using one of the deprotection conditions described below.

The main methods for producing boronic acid / boronate ester Method A: a suitable aryl halide (1-3 eq.) Was suspended in a THF mixture in an inert atmosphere, then n-butyllithium (1-3 eq.) Was added at -78 ° C. After 5 -30 minutes at the indicated temperature, trialkyl borate (1-3 eq.) was added, then the reaction mixture was heated to ambient temperature and the reaction was quenched by the addition of ammonium chloride. The resulting precipitate was purified using one of the main purification methods described below, or was used crude in the next step.

Method B: a suitable aryl halide (1-3 eq.) Was suspended in a mixture of dioxane and DMSO before bis (pinacolato) dibor (1-2 eq.), Potassium acetate and 1,1'-bis (diphenylphosphino) -ferrocene] were added dichloropalladium (II) (5-10 mol%) and then the reaction mixture was heated under microwave conditions (100-160 ° C) for 1-20 minutes. The resulting precipitate was purified using one of the main purification methods described below, or used raw in the next stage.

Method C: A suitable (bromomethyl) phenylboronic acid (1 eq.) Was mixed with sodium iodide (0.05 eq.) And potassium carbonate (3.0 eq.) In acetonitrile and a suitable amine (1.2 eq.) Was added. The reaction mixture was heated to 50 ° C for 2 hours and then cooled to ambient temperature or stirred at room temperature until completion of the reaction, then the volatiles were removed in vacuo and the precipitate was resuspended in MeOH. The remaining precipitate was removed by filtration, then a methanol solution was collected and concentrated to dryness under reduced pressure. The resulting boronic acid was subsequently used without further purification.

Method D: A suitable electrophile (1-2 equiv.) And potassium carbonate (3-5 equiv.) Was added to 4,4,5,5-tetramethyl-2 (1H-pyrazol-4-yl) -1,3,2 -dioxaborolan in acetonitrile, then the mixture was stirred under reflux for 1-7 days. The resulting precipitate was purified using one of the main purification methods described below.

SYNTHESIS OF INTERMEDIATE COMPOUNDS

Preparation of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: 5-bromo-3-iodopyridin-2-ylamine

A mixed solution of 5-bromopyridin-2-ylamine (50 g, 289 mmol) in 2M sulfuric acid (500 ml) was treated with portions of potassium iodate (30.8 g, 144 mmol) and the mixture was heated to 100 ° C. Potassium iodide solution (26.5 g, 160 mmol) in water (50 ml) was added dropwise Over ca. 1 hour. The mixture was allowed to mix for 30 minutes, then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture was extracted with ethyl acetate (x3). The combined organic layers were washed with an aqueous sodium thiosulfate solution, water and brine, dried (Na ₂ SO ₄ ) and evaporated to give the title compound as a brown precipitate (77.4 g, 90%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.06 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 4.96 (s, 2H). Stage 2: 5-bromo-3-prop-1-ynylpyridin-2-ylamine

Propine (28 g, 700 mmol) was condensed in a pre-weighed flask cooled to ca. -40 ° C and containing THF (150 ml). The solution was added via cannula to a chilled (0-5 ° C), degassed mixture of 5-bromo-3-iodopyridin-2-ylamine (139 g, 465 mmol), bis (triphenylphosphine) dichloropalladium (0) (16.3 g, 23 , 2 mmol), copper (I) iodide (5.3 g, 27.9 mmol) and triethylamine (141 g, 194 ml, 1.4 mol) in THF (1.25 L). The mixture was stirred at 0-5 ° C. for 30 minutes, then at ambient temperature for the next 30 minutes. The precipitate was removed by filtration and the filtration residue was washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (x3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate, then extracted with diethyl ether (x3). The combined organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound as an orange-yellow precipitate (91 g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ): 8.01 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 4.96 (s, 2H), 2.11 (s, 3H).

Stage 3: 5-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine

5-bromo-3-prop-1-ynylpyridin-2-ylamine (91 g, 431 mmol) was treated with a 1M solution of potassium tert-butoxide in tert-butanol (700 ml) and the reaction mixture was heated at 85 ° C for 1 hour. The mixture was allowed to cool to ambient temperature and poured into a 1: 1 mixture of water / ice (ca. 1 L). The resulting precipitate was collected by filtration, washed with water and allowed to air dry. The resulting precipitate was dissolved in dichloromethane, dried (Na ₂ SO ₄ ) and evaporated, then triturated with diethyl ether to give the title compound as a brown precipitate (88.7 g, 97%). ¹ H NMR (400 MHz, CDCl ₃ ): 10.21 (s, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 6.13 (s, 1H), 2.52 (s, 3H).

Stage 4: 5-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester

Aluminum trichloride (179 g, 1.34 mol) was added to a mixture of 5-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine (81 g, 384 mmol) in dichloromethane (1.5 L) and stirred for 50 minutes . Trichloroacetyl chloride (238 g, 147 ml, 1.31 mol) was added and the reaction mixture was allowed to stir for 18 hours. The reaction mixture was cooled to 0 ° C and quenched by the addition of methanol (500 ml). The solvent was evaporated and the resulting residue was treated with a mixture of potassium hydroxide (320 g) in methanol (2 L) (carefully an exothermic reaction) and then the reaction mixture was heated under reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then evaporated. The resulting residue was treated with 2M hydrochloric acid to obtain an acidic solution. The resulting mixture was extracted with ethyl acetate (x5), the combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated, then triturated with diethyl ether to give the title compound as an orange-yellow precipitate (91 g, 88% ) ¹ H NMR (300 MHz, DMSO-D ₆ ): 12.63 (s, 1H), 8.31 (s, 2H), 3.83 (s, 3H), 2.68 (s, 3H).

Stage 5: 1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester

A cooled (0-5 ° C) suspension of 5-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (85 g, 316 mmol), powdered sodium hydroxide (38.1 g, 953 mmol) and benzyltriethylammonium chloride (1.46 g, 6.3 mmol) in dichloromethane (1 L) were treated through ca. for 5 minutes, benzenesulfonyl chloride (69.5 g, 51 ml, 394 mmol). The reaction mixture was allowed to stir at 0-5 ° C. for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The precipitate was removed by filtration through celite, and the filtration residue was washed with dichloromethane. The filtrate was evaporated and the resulting precipitate was triturated with diethyl ether to give the title compound as an orange-yellow precipitate (122 g, 94%). ¹ H NMR (400 MHz, CDCl ₃ ): 8.43 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 8.20-8.16 (m, 2H), 7.65-7.59 (m, 1H), 7.54-7.49 (m, 2H), 3.94 (s, 3H), 3.16 (s, 3H).

Stage 6: 1-benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester

A mixture of 1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (121 g, 296 mmol), NBS (63 g, 354 mmol) and 1, 1-azobis (cyclohexanecarbonitrile) (14.4 g, 59 mmol) in 1,2-dichloroethane (1.2 L) was heated under reflux for 90 minutes. The reaction mixture was allowed to cool to ambient temperature and washed with a saturated aqueous solution of sodium thiosulfate. The organic layer was dried (Na ₂ SO ₄ ) then filtered. The filtrate was stirred with flash silica gel, filtered and the filtrate was evaporated under reduced pressure. The resulting precipitate was triturated with diethyl ether / pentane (1: 1) to give the title compound as a white precipitate (130 g, 90%). ¹ H NMR (400 MHz, CDCl ₃ ): 8.47-8.46 (m, 4H), 7.64-7.64 (m, 1H), 7.54-7.53 (m, 2H), 5.67 (s, 2H), 4.00 (s, 3H )

Stage 7: 1-benzenesulfonyl-5-bromo-2 - {[cyanomethyl- (toluene-4-sulphonyl) amino1-methyl} -1H-pyrrolo [2,3-b] pyridin-3-carboxylic acid methyl ester

Sodium hydride (11.7 g, 60% dispersion in mineral oil, 293 mmol) was added dropwise to a cooled (0 ° C.) solution of 1-benzenesulfonyl-6-bromo-2-bromomethyl-1H-pyrrolo [2,3-b ] pyridine-3-carboxylic acid methyl ester (130 g, 266 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (61.5 g, 293 mmol) in DMF (1.25 L). The reaction mixture was stirred at 0 ° C for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into a cooled, stirred solution of 2M hydrochloric acid (1.25 L). The resulting precipitate was collected by filtration (slow) and the filtration residue was washed with water, then with methanol and after diethyl ether. The resulting filtration residue was dried to give the title compound as a gray precipitate (154 g, 94%). LCMS (Method B): R _T = 4.28 min, M + H ⁺ = 617/619. ¹ H NMR (400 MHz, CDCl _3): 8.49 (d, J = 2.3 Hz, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.33-8.33 (m, 2H) , 7.78-7.76 (m, 2H), 7.64-7.64 (m, 1H), 7.55-7.54 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.43 (s, 2H), 4.28 (s, 2H), 3.96 (s , 3H); 2.43 (s, 3H).

Stage 8: 9-benzenesulphonyl-3-bromo-5-hydroxy-9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Lithium bis (trimethylsilyl) amide (800 ml of a 1N solution in THF, 800 mmol) was added dropwise to a cooled (-78 ° C) suspension of 1-benzenesulfonyl-5-bromo-2 - {[cyanomethyl- (toluene-4-sulfonyl) ) amino] methyl] -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (154 g, 250 mmol) in dry THF (1.25 L). The reaction mixture was allowed to slowly warm to -10 ° C then was slowly quenched with cold 1M hydrochloric acid. The layers were separated, and the aqueous layer was then extracted with THF. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The resulting precipitate was triturated with methanol, then acetone, and dried in air to obtain the title compound as a beige precipitate (77.6 g, 72%). LCMS (Method B): R _T = 3.83 min, M + H ⁺ = 429/431. ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.22 (s, 1H), 8.83 (d, J = 2.3 Hz, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.19-8.16 (m, 2H), 7.75-7.74 (m, 1H), 7.65-7.59 (m, 2H).

Preparation of 9-benzenesulfonyl-5-hydroxy-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Mixture of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (9.91 g, 23.1 mmol), palladium carbon hydrogenation catalyst ( 10 wt.%, 1.0 g, 0.94 mmol), ethanol (250 ml), ethyl acetate (50 ml), DMF (50 ml) and triethylamine (50 ml) were stirred at room temperature in a hydrogen atmosphere for 16 hours. The catalyst was removed by filtration through Celite ⁽ and the filtrate was dried to dryness to obtain a resin, which was mixed with hydrochloric acid (1M, 100 ml) and sonicated in a laboratory ultrasonic bath for cleaning for 30 minutes. The resulting precipitate was collected by filtration, washed with water, then dried under under vacuum to obtain the title compound as a reddish precipitate (7.19 g, 89%). ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.27 (s, 1H), 8.71 (dd, J = 4.9, 1.7 Hz, 1H), 8.68 (dd, J = 7.9, 1.7 Hz, 1H), 8.20-8.20 (m, 2H), 7.74-7.73 (m, 1H), 7.60-7.59 (m, 3H).

Preparation of 9-benzenesulfonyl-3-bromo-5-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (2.0 g, 4.66 mmol) and phosphorus pentachloride (2.9 g, 14.0 mmol) in chlorobenzene (6 ml) was heated at 105 ° C for 1 hour. The reaction mixture was cooled to ambient temperature, and the solvent was removed in vacuo to give a precipitate. The resulting precipitate was dissolved in dichloromethane (300 ml) and the solution was treated with ice water (300 ml). The layers were separated and the aqueous layer was then extracted with dichloromethane (300 ml). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The resulting precipitate was triturated with methanol and dried to give the title compound as a reddish precipitate (1.1 g, 53%). ¹ H NMR (300 MHz, DMSO-d ₆ ): 9.70 (s, 1H), 9.06 (d, J = 2.2 Hz, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.27-8.22 (m, 2H), 7.77-7.76 (m, 1H), 7.67-7.60 (m, 2H).

Preparation of 9-benzenesulfonyl-3-fluoro-5-hydroxy-9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: 5-fluoro-3-iodopyridin-2-ylamine

A mixed solution of 5-fluoropyridin-2-ylamine (50 g, 0.45 mol) in 2M sulfuric acid (250 ml) was treated in portions with potassium iodate (48 g, 0.22 mol) and the mixture was heated to 100 ° C. Potassium iodide solution (41 g 0.24 mol) in water (100 ml) was added dropwise through ca. within 1 hour. The mixture was allowed to mix for 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture was extracted with ethyl acetate (x3). The combined organic layers were washed with an aqueous sodium thiosulfate solution, water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound as a yellow precipitate (61.2 g, 58%). ¹ H NMR (400 MHz, CDCl ₃ ): 7.94 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 7.2, 2.7 Hz, 1H), 4.85 (s, 2H).

Stage 2: 5-fluoro-3-prop-1-ynylpyridin-2-ylamine

Propine (15.4 g, 0.39 mol) was condensed in a pre-weighed flask cooled to ca. -40 OC and containing THF (80 ml). The solution was added via cannula to a chilled (0-5 OC), degassed mixture of 5-fluoro-3-iodopyridin-2-ylamine (61.0 g, 0.26 mol), bis (triphenylphosphine) dichloropalladium (0) (9.0 g, 13.0 mmol), copper (I) iodide (2.95 g, 15.6 mmol) and triethylamine (77.7 g, 107 ml, 0.78 mol) in THF (650 ml). The mixture was stirred at 0-5 ° C. for 30 minutes, then at ambient temperature for the next 30 minutes. The precipitate was removed by filtration, and the filtration residue was washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (x3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate, then extracted with diethyl ether (x3). The combined organic layer was dried (NS ₂ SO ₄ ), filtered and evaporated to give the title compound as a brown precipitate (32.2 g, 84%). ¹ H NMR (400 MHz, CDCl ₃ ): 7.90 (s, 1H), 7.24 (dd, J = 8.4.2.8 Hz, 1H), 4.84 (s, 2H), 2.11 (s, 3H).

Stage 3: 5-fluoro-2-methyl-1H-pyrrolo [2,3-b] iridine

5-fluoro-3-prop-1-ynylpyridin-2-ylamine (14.0 g, 90.0 mmol) was treated with a 1M solution of potassium tert-butoxide in tert-butanol (150 ml) and the reaction mixture was heated at 85 ° C for 1 hour. The mixture was allowed to cool to ambient temperature and poured into a mixture of water with ice 1: 1 (ca. 1 liter). The resulting precipitate was collected by filtration, washed with water and allowed to air dry. The resulting precipitate was dissolved in dichloromethane, dried (Na ₂ SO ₄ ), filtered and evaporated, then triturated with diethyl ether to give the title compound as an orange-yellow precipitate (9.2 g, 66%). ¹ H NMR (300 MHz, CDCl ₃ ): 10.61 (s, 1H), 8.12 (s, 1H), 7.51 (dd, J = 9.1, 2.3 Hz, 1H), 6.17 (s, 1H), 2.53 (d, J = 1.0 Hz, 3H).

Stage 4: 5-Fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester

Aluminum trichloride (28.0 g, 209.7 mmol) was added to a mixture of 5-fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridine (9.0 g, 59.9 mmol) in dichloromethane (150 ml) and stirred for 50 minutes . Trichloroacetyl chloride (37 g, 23 ml, 203.7 mmol) was added and the reaction mixture was allowed to stir for 18 hours. The reaction mixture was cooled to 0 ° C and quenched by the addition of methanol (50 ml). The solvent was evaporated and the resulting residue was treated with a mixture of potassium hydroxide (50 g) in methanol (150 ml) (carefully an exothermic reaction) and then the reaction mixture was heated under reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then evaporated. The resulting residue was treated with 2M hydrochloric acid to obtain an acidic solution. The resulting mixture was extracted with ethyl acetate (x5), the combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated, then triturated with diethyl ether to give the title compound as an orange-yellow precipitate (9.23 g, 74% ) ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.55 (s, 1H), 8.22 (dd, J = 2.8, 1.7 Hz, 1H), 7.95 (dd, J = 9.5, 2.8 Hz, 1H), 3.83 ( s, 3H); 2.68 (s, 3H).

Stage 5: 1-benzenesulfonyl-5-fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester

A cooled (0-5 ° C) suspension of 5-fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (9.0 g, 43.2 mmol), powdered sodium hydroxide (5.4 g, 133.9 mmol) and benzyltriethylammonium chloride (0.2 g, 0.86 mmol) in dichloromethane (100 ml) were treated through ca. 5 minutes benzenesulfonyl chloride (9.5 g, 6.9 ml, 54.0 mmol). The reaction mixture was allowed to stir at 0-5 ° C for 20 minutes, then allowed to warm to ambient temperature and was stirred for 24 hours. The precipitate was removed by filtration through celite, and the filtration residue was washed with dichloromethane. The filtrate was evaporated and the resulting precipitate was triturated with diethyl ether to give the title compound as a cream precipitate (14.0 g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ): 8.27 (dd, J = 2.8, 1.1 Hz, 1H), 8.18-8.18 (m, 2H), 7.97 (dd, J = 8.7, 2.8 Hz, 1H), 7.61- 7.61 (m, 1H), 7.52-7.51 (m, 2H), 3.94 (s, 3H), 3.16 (s, 3H).

Stage 6: 1-benzenesulfonyl-5-fluoro-2-bromomethyl-1H-pyrrolo [2,3-b] iridine-3-carboxylic acid methyl ester

Mixture of 1-benzenesulfonyl-5-fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (13.9 g, 39.9 mmol), 1,3-dibromo-5,5-dimethylhydantoin (12.6 g, 39.9 mmol) and 1,1-azobis (cyclohexanecarbonitrile) (1.95 g, 8.0 mmol) in 1,2-dichloroethane (150 ml) were heated under reflux for 90 minutes, then stirred at ambient temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium thiosulfate. The organic layer was dried (Na ₂ SO ₄ ) then filtered. The filtrate was stirred with flash silica gel, filtered and the filtrate was evaporated under reduced pressure. The resulting precipitate was triturated with diethyl ether / pentane (1: 1) to give the title compound as a cream precipitate (15.9 g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ): 8.47-8.44 (m, 2H), 8.32 (dd, J = 2.8, 1.1 Hz, 1H), 8.04 (dd, J = 8.5, 2.8 Hz, 1H), 7.64- 7.64 (m, 1H), 7.54-7.53 (m, 2H), 5.68 (s, 2H), 4.00 (s, 3H).

Stage 7: 1-benzenesulfonyl-5-fluoro-2 - {[cyanomethyl- (toluene-4-sulfonyl) amino1-methyl} -1H-pyrrolo [2.3-b] pyridin-3-carboxylic acid methyl ester

Sodium hydride (1.6 g, 60% dispersion in mineral oil, 40.5 mmol) was added dropwise to a cooled (0 ° C.) solution of 1-benzenesulfonyl-5-fluoro-2-bromomethyl-1H-pyrrolo [2,3-b] pyridine -3-carboxylic acid methyl ester (15.8 g, 36.9 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (8.5 g, 40.5 mmol) in DMF (150 ml). The reaction mixture was stirred at 0 ° C for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into a cooled, stirred solution of 2M hydrochloric acid (400 ml). The resulting precipitate was collected by filtration (slowly) and the filter residue was washed with water, then with methanol and then with diethyl ether. The resulting filtration residue was dried to give the title compound as a gray precipitate (16.7 g, 82%). ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.49 (dd, J = 2.8, 1.2 Hz, 1H), 8.24-8.24 (m, 2H), 8.14 (dd, J = 8.8, 2.8 Hz, 1H), 7.75-7.74 (m, 1H), 7.70-7.68 (m, 2H), 7.62-7.62 (m, 2H), 7.39-7.35 (m, 2H), 5.36 (s, 2H), 4.42 (s, 2H), 3.88 (s, 3H); 2.36 (s, 3H).

Stage 8: 9-benzenesulfonyl-3-fluoro-5-hydroxy-9H-dipyrido [2.3-b: 4 ', 3'-d] pyrrole-6-carbonitrile

Lithium bis (trimethylsilyl) amide (100 ml of a 1N solution in THF, 100 mmol) was added dropwise to a cooled (-78 ° C) suspension of 1-benzenesulfonyl-5-fluoro-2 - {[cyanomethyl- (toluene-4-sulfonyl) ) amino] methyl} -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (16.5 g, 29.6 mmol) in dry THF. (150 ml). The reaction mixture was allowed to slowly warm to -10 ° C, then slowly quenched with cold 1M hydrochloric acid. The layers were separated, and then the aqueous layer of THF was extracted. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The resulting precipitate was triturated with methanol, then acetonitrile and dried in air to give the title compound as a brown precipitate (8.2 g, 75%). ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.25 (s, 1H), 8.76 (dd, J = 2.8, 1.3 Hz, 1H), 8.50 (dd, J = 8.2, 2.8 Hz, 1H), 8.20- 8.17 (m, 2H), 7.75-7.75 (m, 1H), 7.63-7.62 (m, 2H).

Preparation of 9-benzenesulfonyl-5-chloro-3-fluoro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

A solution of 9-benzenesulfonyl-3-fluoro-5-hydroxy-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (500 mg, 1.36 mmol) and phosphorus pentachloride (708 mg, 3.4 mmol) in chlorobenzene (1.5 ml) was heated at 110 ° C for 1 hour. The reaction mixture was cooled to ambient temperature and then the solvent was removed in vacuo to give a precipitate. The resulting precipitate was dissolved in dichloromethane (50 ml) and then the solution was diluted with ice water (50 ml). The layers were separated and the aqueous layer was then extracted with dichloromethane (50 ml). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The resulting precipitate was triturated with diethyl ether and dried to give the title compound as a reddish precipitate (320 mg, 65%). ¹ H NMR (400 MHz, CDCl ₃ ): 9.81 (s, 1H), 8.69 (d, J = 2.8 Hz, 1H), 8.50 (dd, J = 7.6, 2.8 Hz, 1H), 8.24 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H).

Preparation of 9-benzenesulfonyl-3-chloro-5-hydroxy-9H-dipyrido [2.3-b: 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: 5-chloro-3-iodopyridin-2-ylamine

A mixed solution of 5-chloropyridin-2-ylamine (51.4 g, 0.40 mol) in 2M sulfuric acid (700 ml) was treated in portions with potassium iodate (43.7 g, 0.2 mol) and the mixture was heated to 100 ° C. A solution of potassium iodide (36.5 g, 0.55 mol) in water (100 ml) was added dropwise through ca. within 1 hour. The mixture was allowed to mix for 30 minutes, then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture was extracted with ethyl acetate (x3). The combined organic layers were washed with an aqueous sodium thiosulfate solution, water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound as a reddish precipitate (86.3 g, 84%). LCMS (Method B): R _T = 3.76 min, M + H ⁺ = 255/257. ¹ H NMR (400 MHz, CDCl ₃ ): 7.98 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 5.03 (s, 2H).

Stage 2: 5-chloro-3-prop-1-ynylpyridin-2-ylamine

Propine (35 g, 0.87 mol) was condensed in a pre-weighed flask cooled to ca. -40 ° C and containing THF (100 ml). The solution was added via cannula to a chilled (0-5 ° C), degassed mixture of 5-chloro-3-iodopyridin-2-ylamine (81.4 g, 0.32 mol), bis (triphenylphosphine) dichloropalladium (0) (4.49 g, 6.4 mmol) , copper (I) iodide (1.46 g, 7.67 mmol) and triethylamine (97.3 g, 134 ml, 0.98 mol) in THF (900 ml). The mixture was stirred at 0-5 ° C. for 30 minutes, then at ambient temperature for the next 30 minutes. The precipitate was removed by filtration, and the filtration residue was washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (x3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate, then extracted with diethyl ether (x3). The combined organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound as a brown precipitate (53.8 g, quantitative yield). LCMS (Method B): R _T = 3.55 min, M + H ⁺ = 167/169. ¹ H NMR (300 MHz, CDCl ₃ ): 7.92 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 5.00 (s, 2H), 2.10 (s, 3H).

Stage 3: 5-chloro-2-methyl-1H-pyrrolo [2,3-b] pyridine

5-chloro-3-prop-1-ynylpyridin-2-ylamine (53.7 g, 0.32 mol) was treated with a 1M solution of potassium tert-butoxide in tert-butanol (515 ml) and the reaction mixture was heated at 85 ° C for 1 hour. The mixture was allowed to cool to ambient temperature and poured into a 1: 1 mixture of water / ice (ca. 1 L). The resulting precipitate was collected by filtration, washed with water and allowed to air dry. The resulting precipitate was dissolved in dichloromethane, dried (Na ₂ SO ₄ ), filtered and evaporated, then triturated with diethyl ether to give the title compound as a gray precipitate (44.8 g, 83%). LCMS (Method B): R _T = 3.64 min, M + H ⁺ = 167/169. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.02 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 6.11 (d, J = 1.1 Hz, 1H), 2.40 (d, J = 1.0 Hz, 3H).

Stage 4: 5-chloro-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester

Aluminum trichloride (125 g, 0.94 mol) was added to a mixture of 5-chloro-2-methyl-1H-pyrrolo [2,3-b] pyridine (44.8 g, 0.27 mol) in dichloromethane (1.1 L) and stirred for 50 minutes . Trichloroacetyl chloride (166.2 g, 102 ml, 0.91 mol) was added and the reaction mixture was allowed to stir for 21 hours. The reaction mixture was cooled to 0 ° C and quenched by the addition of methanol (110 ml). The solvent was evaporated, and the resulting residue was treated with a mixture of potassium hydroxide (226 g) in methanol (900 ml) (carefully an exothermic reaction) and then the reaction mixture was heated under reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then evaporated. The resulting residue was treated with 2M hydrochloric acid to obtain an acidic solution. The resulting mixture was extracted with ethyl acetate (x5), the combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated, then triturated with diethyl ether to give the title compound as a reddish precipitate (57.1 g, 94%). LCMS (Method B): R _T = 4.15 min, M + H ⁺ = 225. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.32 (d, J = 0.7 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 3.83 (s, 3H); 2.68 (s, 3H).

Stage 5: 1-benzenesulfonyl-5-chloro-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester

A cooled (0-5 ° C) suspension of 5-chloro-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (57 g, 0.25 mol), powdered sodium hydroxide (30.45 g, 0.76 mol) and benzyltriethylammonium chloride (1.16 g, 5.1 mmol) in dichloromethane (800 ml) were treated through ca. for 5 minutes, benzenesulfonyl chloride (56.1 g, 40.5 ml, 0.32 mol). The reaction mixture was allowed to stir at 0-5 ° C for 15 minutes, then allowed to warm to ambient temperature and was stirred for 24 hours. The precipitate was removed by filtration through celite, and the filtration residue was washed with dichloromethane. The filtrate was evaporated and the resulting residue was triturated with diethyl ether to give the title compound as a brown precipitate (17.5 g, 30%). LCMS (Method B): R _T = 4.67 min, M + Na ⁺ = 381. ¹ H NMR (400 MHz, CDCl ₃ ): 8.34 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.18-8.18 (m, 2H), 7.61-7.61 (m, 1H), 7.51-7.50 (m, 2H), 3.94 (s, 3H), 3.15 (s, 3H).

Stage 6: 1-benzenesulfonyl-5-chloro-2-bromomethyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester

Mixture of 1-benzenesulfonyl-5-chloro-2-methyl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (16.9 g, 46.2 mmol), 1,3-dibromo-5,5-dimethylhydantoin (13.21 g, 46.2 mmol) and 1,1-azobis (cyclohexanecarbonitrile) (1.52 g, 9.3 mmol) in 1,2-dichloroethane (200 ml) were heated under reflux for 90 minutes, then stirred at ambient temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium thiosulfate. The organic layer was dried (Na ₂ SO ₄ ), then filtered. The filtrate was stirred with flash silica gel, filtered, and the filtrate was evaporated under reduced pressure. The resulting precipitate was triturated with diethyl ether / pentane (1: 1) to give the title compound as a white precipitate (13.7 g, 61%). LCMS (Method B): R _T = 4.35 min, M + H ⁺ = 443/445/447. ¹ H NMR (400 MHz, CDCl ₃ ): 8.46-8.46 (m, 2H), 8.39 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.64-7.64 (m, 1H), 7.55-7.52 (m, 2H), 5.67 (s, 2H), 4.00 (s, 3H).

Stage 7: 1-benzenesulfonyl-5-chloro-2 - {[cyanomethyl- (toluene-4-sulfonyl) amino] methyl} -1H-pyrrolo [2,3-b] pyridin-3-carboxylic acid methyl ester

Sodium hydride (4.1 g, 60% dispersion in mineral oil, 101 mmol) was added dropwise to a cooled (0 ° C.) solution of 1-benzenesulfonyl-5-chloro-2-bromomethyl-1H-pyrrolo [2,3-b] pyridine -3-carboxylic acid methyl ester (40.8 g, 91.9 mmol) and L / -cyanomethyl-4-methyl-benzenesulfonamide (21.3 g, 101 mmol) in DMF (400 ml). The reaction mixture was stirred at 0 ° C for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into a cooled, stirred solution of 2M hydrochloric acid (400 ml). The resulting precipitate was collected by filtration (slowly) and the filtration residue was washed with water, then with methanol and then with diethyl ether. The resulting filtration residue was dried to give the title compound as a reddish precipitate (39.6 g, 75%). LCMS (Method B: R _T = 4.58 min, M + H ⁺ = 573/575. ¹ H NMR (400 MHz, CDCl ₃ ): 8.40 (d, J = 2.4 Hz, 1H), 8.33-8.33 (m, 2H ), 8.27 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.64-7.64 (m, 1H), 7.55-7.54 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.43 (s, 2H), 4.28 (s, 2H), 3.96 (s, 3H), 2.43 (s, 3H).

Stage 8: 9-benzenesulfonyl-3-chloro-5-hydroxy-9H-dipyrido [2,3-b: 4 ', 3'-d] pyrrole-6-carbonitrile

Lithium bis (trimethylsilyl) amide (220 ml of a 1N solution in THF, 220 mmol) was added dropwise to a cooled (-78 ° C) suspension of 1-benzenesulfonyl-5-chloro-2 - {[cyanomethyl- (toluene-4-sulfonyl) ) amino] methyl] -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid methyl ester (39.6 g, 69.1 mmol) in dry THF (350 ml). The reaction mixture was allowed to slowly warm to -10 ° C, then slowly quenched with cold 1M hydrochloric acid. The layers were separated, and then the aqueous layer of THF was extracted. The combined organic layers were washed with brine, dried (Na2S04), filtered and evaporated. The resulting precipitate was triturated with methanol, then acetonitrile and dried in air to obtain the title compound as a reddish precipitate (7.37 g, 27%). LCMS (Method B): R _T = 5.11 min, M + H ⁺ = 385/387. ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.23 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.19-8.19 (m, 2H), 7.75-7.75 (m, 1H), 7.62-7.61 (m, 2H).

Preparation of 9-benzenesulphonyl-3.5-dichloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Solution of 9-benzenesulfonyl-3-chloro-5-hydroxy-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1.9 g, 4.94 mmol) and phosphorus pentachloride (3.1 g, 14.8 mmol) in phosphorus oxychloride (8 ml) was heated at 105 ° C for 2 hours. The reaction mixture was cooled to ambient temperature and then the solvent was removed in vacuo to give a precipitate. The resulting precipitate was dissolved in dichloromethane (300 ml), and then the solution was diluted with ice water (300 ml). The layers were separated and the aqueous layer was then extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The resulting precipitate was triturated with diethyl ether and dried to give the title compound as a reddish precipitate (1.17 g, 59%). ¹ H NMR (400 MHz, CDCl ₃ ): 9.81 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.26-8.22 (m, 2H) 7.66-7.66 (m, 1H); 7.53-7.53 (m, 2H).

Preparation of 5-Fluoro-9- (2-trimethylsilanylethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'] pyrrole-6-carbonitrile

Stage 1: (6-chloro-5-fluoropyridin-3-yl) -carbamic acid tert-butyl ether

Degassed mixture of 5-bromo-2-chloro-3-fluoropyridine (22.5 g, 107 mmol), tert-butyl carbamate (13.8 g, 117.5 mmol), Tris (dibenzylideneacetone) dipalladium (0) (2.95 g, 3.2 mmol), XantPhos (2.48 g, 4.28 mmol) and cesium carbonate (69.7 g, 214 mmol) in dioxane (340 ml) were heated at 85 ° C for 24 hours. The reaction mixture was cooled to ambient temperature, and the resulting precipitate was removed by filtration. The resulting precipitate was washed with ethyl acetate, then dichloromethane and the filtrate was combined and concentrated in vacuo to give a residue which was purified by flash chromatography (silica gel: cyclohexane to 25% ethyl acetate / cyclohexane) to give the title compound as a pale yellow precipitate ( 22.6 g, 86%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.04 (dd, J = 10.1, 2.4 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 6.62 (s, 1H), 1.53 (s, 9H) .

Stage 2: (6-chloro-5-fluoro-4-iodopyridin-3-yl) -carbamic acid tert-butyl ether

nBuli (107 ml, 2.5 M in hexanes, 268 mmol) was added dropwise to a cooled (-78 ° C) solution of (6-chloro-5-fluoropyridin-3-yl) -carbamic acid mpem-butyl ether (22 g, 89.2 mmol) and N, N, N ', N'-tetramethylethylenediamine (40.5 ml, 268 mmol) in anhydrous diethyl ether (400 ml) in an argon atmosphere, observing the internal reaction temperature below -60 ° C. Upon completion of the addition, the reaction mixture allowed to warm to -20 ° C and was stirred for 90 minutes. The reaction mixture was cooled to -78 ° C and after 15 minutes a solution of iodine (70 g, 280 mmol) in THF (125 ml) was added dropwise. The reaction mixture was allowed to gradually warm to ambient temperature and was stirred overnight. The reaction mixture was poured into 1M HCl (200 ml) and crushed ice (50 g), and the aqueous phase was extracted with ethyl ether (2 × 200 ml). The combined organic layer was washed with water (200 ml), aqueous potassium carbonate (150 ml), aqueous sodium thiosulfate (150 ml) and brine (150 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give draft. The resulting precipitate was triturated with ethanol, and the resulting precipitate was collected by filtration, washed with pentane and dried in vacuo to give the title compound as a white precipitate (27.2 g, 82%). The triturated solutions were concentrated and purified by flash chromatography (silica gel: toluene to 5% ethyl acetate / toluene) to give an additional amount of the title compound as a white precipitate (4.0 g, 12%). Total yield = 31.2 g, 94%. ¹ H NMR (400 MHz, CDCl ₃ ): 8.82 (s, 1H), 6.71 (s, 1H), 1.55 (s, 9H).

Stage 3: 6-chloro-5-fluoro-4-iodopyridin-3-ylamine

Trifluoroacetic acid (50 ml) was added to a solution of (6-chloro-5-fluoro-4-iodopyridin-3-yl) -carbamic acid tert-butyl ether (31 g, 83.2 mmol) in dichloromethane (150 ml) and the resulting reaction mixture mixed at ambient temperature for 90 minutes. The solvent was evaporated, and the resulting residue was treated with ice-water (200 ml), separated into layers with diethyl ether (300 ml) and the pH of the aqueous phase was adjusted to 10 by adding solid sodium carbonate solution. The organic phase was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a precipitate. The resulting precipitate was triturated with a mixture of pentane / diethyl ether (9: 1) to give the title compound as a cream-colored precipitate (22.3 g, 98%). ¹ H NMR (400 MHz, CDCl ₃ ): 7.63 (s, 1H).

Stage 4: 6'-chloro-2,5'-difluoro- [3,4 '] bipyridinyl-3'-ylamine

Degassed mixture of 6-chloro-6-fluoro-4-iodopyridin-3-ylamine (98.7 g, 362 mmol), 2-fluoropyridine 3-boronic acid (68.3 g, 485 mmol), bis [di-tert-butyl (4- dimethylaminophenyl) phosphine] dichloropalladium (II) (7.7 g, 10.9 mmol) and potassium fluoride (63 g, 1.09 mol) in a mixture of acetonitrile (900 ml) and water (275 ml) were heated at 90 ° C for 2 hours. The reaction mixture was allowed to cool to ambient temperature and was filtered through Celite ⁽ and washed with ethyl acetate. The filtrate was diluted with ethyl acetate and the organic layer was collected, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a precipitate. The resulting residue was triturated with diethyl ether with obtaining the title compound as a gray precipitate (65.8 g, 75%). The triturated solutions were concentrated and purified by flash chromatography (silica gel: dichloromethane to 20% ethyl acetate / dichloromethane) to give after additional trituration with ether, an additional amount of the compound indicated in the title was obtained as a gray precipitate (9.7 g, 11%). Total yield = 75.5 g, 86%. ¹ H NMR (400 MHz, CDCl ₃ ): 8.39 (ddd , J = 4.9, 2.0, 1.1 Hz, 1H), 7.86-7.84 (m, 2H), 7.39 (ddd, J = 7.4, 4.9, 1.9 Hz, 1H).

Stage 5: 6-chloro-5-fluoro-9H-dipyrido [2,3-b; 4'3'-d] pyrrole

A solution of 6'-chloro-2,5'-difluoro [3,4 '] bipyridinyl-3'-ylamine (70 g, 290 mmol) in THF (300 ml) was added dropwise to a solution of sodium bis (trimethylsilyl) amide ( 720 ml, 1 M in THF, 720 mmol) at such a rate that the reaction temperature was kept at 40 ° C. After the addition was complete, the mixture was stirred for ca. 1 hour at ambient temperature. The solvent was evaporated in vacuo and the residue was poured into ice-cold 1N. hydrochloric acid. The resulting suspension was filtered and the precipitate washed with water. The filtration residue was collected and triturated with acetone and then diethyl ether to give the title compound as a beige precipitate (40.9 g, 64%). The triturated solutions were evaporated and the residue was triturated with methanol followed by diethyl ether to give a second batch of the title compound as a brown precipitate (6.1 g, 10%). Total yield = 47 g, 74%. ¹ H NMR (400 MHz, DMSO-d ₆ ): 13.24 (s, 1H), 8.91 (d, J = 2.5 Hz, 1H), 8.77 (dd, J = 4.8, 1.7 Hz, 1H), 8.65 (dd, J = 7.9, 1.7 Hz, 1H), 7.50 (dd, J = 7.9, 4.8 Hz, 1H).

Stage 6: 6-chloro-5-fluoro-9- (2-trimethylsilanylethoxymethyl) -9H-dipyrido [2,3-b; 4'3-d] pyrrole

A suspension of 6-chloro-5-fluoro-9H-dipyrido [2,3-b; 4'3'-d] pyrrole (9 g, 40.6 mmol) in DMF (90 ml) was placed in an ice bath and partially treated with hydride sodium (60% suspension in mineral oil) (1.94 g, 48.5 mmol), keeping the internal temperature within 20-25 ° С. When gas evolution ceased (ca. 1 hour), the mixture was treated dropwise with 2- (trimethylsilyl) ethoxymethyl chloride (8.1 g, 8.7 ml, 48.5 mmol), keeping the internal temperature within 25-30 ° C. After further stirring for 1 hour , the mixture was partitioned between ethyl acetate and ice-cold 1N. hydrochloric acid. The aqueous phase was then extracted with ethyl acetate, and the combined organic phase was washed with water, an aqueous solution of potassium carbonate, water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The precipitate was triturated with a mixture of pentane / diethyl ether (ca. 20: 1) to give the title compound as a beige precipitate (11.4 g, 80%). The triturated solutions were evaporated and purified by chromatography to give a second batch of the title compound (0.85 g, 6%). Total yield = 12.3 g, 86%. ¹ H NMR (400 MHz, CDCl ₃ ): 8.68-8.68 (m, 2H), 8.52 (dd, J = 7.8, 1.7 Hz, 1H), 7.35 (dd, J = 7.8, 4.8 Hz, 1H), 5.95 ( s, 2H), 3.59 (t, J = 8.2 Hz, 2H), 0.92 (t, J = 8.2 Hz, 2H), -0.09 (d, J = 0.5 Hz, 9H).

Stage 7: 5-fluoro-9- (2-trimethylsilanylethoxymethyl) -9H-dipyrido [2,3-b; 4'3'-d] pyrrole-6-carbonitrile F

A solution of 6-chloro-5-fluoro-9- (2-trimethylsilanylethoxymethyl) -9H-dipyrido [2,3-b; 4'3'-d] pyrrole (12.2 g, 34.7 mmol) in DMF (120 ml) was treated with cyanide zinc (4.88 g, 41.7 mmol) and tetrakis (triphenylphosphine) palladium (0) (6 g, 5.2 mmol). The mixture was degassed and stirred in a nitrogen atmosphere at a temperature of 130 ° C for 3 hours. After cooling to ambient temperature, the mixture was filtered through Celite ⁽ and the filtration residue was washed with DMF (10 ml). The filtrate was partitioned between ethyl acetate and water and the aqueous phase was then extracted with ethyl acetate. The combined organic layer was washed with water (x2) and brine, dried (Na ₂ SO _4), filtered and evaporated. The resulting precipitate was dissolved in dichloromethane and stirred with flash silica gel, filtered to remove the precipitate, and the precipitate was washed well with dichloromethane. The filtrate was evaporated and the resulting residue was triturated with pentane / diethyl ether (ca. 4: 1) to give the title compound as a white precipitate (8.15 g, 68%). The triturated solutions were evaporated and the resulting residue was purified by flash chromatography to give a second batch of compound indicated in the title (0.92 g, 8%). Total yield = 9.07 g, 76%. ¹ H NMR (400 MHz, CDCl ₃ ): 8.99 (d, J = 2.1 Hz, 1H), 8.75 (dd, J = 4.8, 1.7 Hz, 1H), 8.57 (dd, J = 7.9, 1.7 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 6.02 (s, 2H), 3.63-3.56 (m, 2H ), 0.93 (t, J = 8.2 Hz, 2Н), -0.08 (d, J = 0.6 Hz, 9Н).

Preparation of 1-Oxetan-3-yl-piperidin-4-ylamine

Stage 1: (1-Oxetan-3-yl-piperidin-4-yl) -carbamic acid tert-butyl ether

to a suspension of piperidin-4-yl-caroamino acid tert-butyl ether (200 mg, 1.0 mmol) in DCE (6 ml) was added oxetanone (60 mg, 0.83 mmol) in DCE (2 ml). After 75 minutes, sodium triacetoborohydride (282 mg, 1.33 mmol) was added at a time. After 20 hours at ambient temperature, the reaction mixture was loaded directly onto 5 g SCX-2 cartridge, which was washed with methanol, then 2N. ammonia in methanol. Concentratedly combined the main fractions under vacuum of the obtained precipitate (silica gel, 5 g column, Si-SPE, 0-10% methanol in dichloromethane) gave the title compound as a white precipitate (141 mg, 67%). ¹ H NMR (300 MHz, CDCl ₃ ): 4.62-4.61 (m, 4H), 4.44 (s, 1H), 3.46-3.45 (m, 2H), 2.67 (d, J = 10.9 Hz, 2H), 2.02- 1.88 (m, 4H); 1.44 (s, 9H).

Stage 2: 1-0xetan-3-yl-piperidin-4-ylamine

To a solution of (1-oxetan-3-yl-piperidin-4-yl) -carbamic acid tert-butyl ether (134 mg, 0.52 mmol) in dichloromethane (2 ml) was added TFA (2 ml). After 15 minutes at ambient temperature, the reaction mixture was concentrated in vacuo and the residue was charged onto 5 g SCX-2 cartridge, which was washed with methanol, then 2N. ammonia in methanol. Concentratedly combined the main fractions under vacuum gave the title compound as a colorless gum (82 mg, 100%). ¹ H NMR (400 MHz, CDCl ₃ ): 4.63-4.63 (m, 4H), 3.47-3.45 (m, 1H), 2.69-2.68 (m, 3H), 1.90-1.81 (m, 4H), 1.41-1.40 (m, 2H).

Preparation of 1-Oxetan-3-yl-piperidin-4-ol

To a suspension of piperidin-4-ol (364 mg, 3.6 mmol) in DCE (30 ml) was added oxetanone (216 mg, 3.0 mmol). After 2 hours, sodium triacetoborohydride (1.02 g, 4.8 mmol) was added at a time. After 20 hours at ambient temperature, the reaction mixture was loaded directly onto 20 g of SCX-2 cartridge, which was washed with methanol, then 2N. ammonia in methanol. Concentration of the combined main fractions in vacuo followed by flash chromatography of the obtained residue (silica gel, 10 g column, Si-SPE, 0-10% methanol in dichloromethane) gave the title compound as a colorless oil (285 mg, 52%) . ¹ H NMR (300 MHz, CDCl ₃ ): 4.64-4.63 (m, 4H), 3.77-3.77 (m, 1H), 3.49-3.47 (m, 1H), 2.65-2.55 (m, 2H), 2.04 (t , J = 10.5 Hz, 2H), 1.94-1.93 (m, 2H), 1.62-1.61 (m, 2H), 1.47 (d, J = 4.5 Hz, 1H).

Preparation of 4-methyl- [1,4 '] bipiperidinyl-4-ol

To a suspension of piperidin-4-yl-carbamic acid tert-butyl ether (723 mg, 3.6 mmol) in DCE (20 ml) was added 4-methylpiperidin-4-ol (500 mg, 4.4 mmol). After 30 minutes, sodium triacetoborohydride (1.54 g, 7.3 mmol) was added in portions. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (50 ml) and dichloromethane (75 ml). The organic phase was separated, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting precipitate was purified by flash chromatography (silica gel, BiOtage 100 g column, 0-10% methanol in dichloromethane) to give crude 4-hydroxy-4-methyl- [1,4 '] bipiperidinyl-1'-carboxylic acid tert- butyl ether. This crude material was dissolved in dichloromethane (10 ml) and TFA (2 ml) was added. After 30 minutes at ambient temperature, the reaction mixture was concentrated in vacuo, and the resulting precipitate was loaded onto 20 g SCX-2 cartridge, which was washed with methanol, then 2N. ammonia in methanol. Concentratedly combined main fractions under vacuum gave the title compound as a colorless oil (285 mg, 40% in two steps). ¹ H NMR (300 MHz, CDCl ₃ ): 3.15 (d, J = 12.3 Hz, 2H), 2.62-2.60 (m, 6H), 2.42-2.39 (m, 1H), 1.84 (d, J = 12.6 Hz, 2H), 1.67-1.64 (m, 5H), 1.46-1.44 (m, 2H), 1.24 (s, 3H).

Preparation of (1-ethyl-piperidin-4-yl) methylamine

Stage 1: (1-Ethylpiperidin-4-yl) -methylcarbamic acid tert-butyl ether

Acetaldehyde (1.65 ml, 27.9 mmol) was added to a solution of methylpiperidin-4-yl-carbamic acid mpem-butyl ether (2.0 g, 9.4 mmol) in dichloromethane (50 ml). The resulting dark red solution was stirred for 10 minutes, then sodium triacetoborohydride (2.97 g, 14.0 mmol) was added in portions. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (100 ml) and dichloromethane (100 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 × 100 ml). The combined organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting precipitate was purified by flash chromatography (silica gel, 70 g column, Si-SPE, ethyl acetate followed by 10% methanol in dichloromethane) to give the title compound as an orange oil (1.64 g, 72%). ¹ H NMR (300 MHz, CDCl ₃ ): 3.01 (d, J = 11.3 Hz, 2H), 2.74 (s, 3H), 2.41 (q, J = 7.2 Hz, 2H), 1.98 (t J = 11.6 Hz, 2H), 1.76-1.72 (m, 5H), 1.46 (s, 9H), 1.08 (t, J = 7.2 Hz, 3H).

Stage 2: (1-ethyl-piperidin-4-yl) methylamine

To a solution of (1-ethylpiperidin-4-yl) -methylcarbamic acid tert-butyl ether (1.65 g, 6.8 mmol) in dichloromethane (15 ml) was added TFA (5 ml). After 1 hour at ambient temperature, the reaction mixture was concentrated in vacuo, and the residue was charged onto 70 g of SCX-2 cartridge, which was washed with methanol, then 2N. ammonia in methanol. Concentration of the combined basic fractions in vacuo afforded the title compound as an orange oil (900 mg, 94%). ¹ H NMR (300 MHz, CD ₃ OD): 2.95 (d, J = 11.6 Hz, 2H), 2.48-2.36 (m, 3H), 2.35 (s, 3H), 1.96-1.95 (m, 4H), 1.40 -1.38 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H).

Preparation of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: 9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Mixture of 3-bromo-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (5.6 g, 14 mmol), ammonium formate (8.8 g, 139 mmol) and zinc (9.1 g, 139 mmol) in tetrahydrofuran (85 ml) were heated at 75 ° C for 10 hours. The reaction mixture was allowed to cool, filtered through a pad of celite, and washed with dichloromethane (200 ml). The filtrate was concentrated in vacuo and then purified by flash chromatography (silica gel, 120 g, ISCO, 5-45% ethyl acetate in heptane) to give the title compound as a white precipitate (3.6 g, 80%). ¹ H NMR (400 MHz, CDCl ₃ ) (9.17 (s, 1H), 8.73 (dd, J = 4.8, 1.5, 1H), 8.46 (dd, J = 7.8, 1.5, 1H), 8.39 (s, 1H) , 7.39 (dd, J = 7.8, 4.8, 1 H), 6.01 (s, 2H), 3.60 (t, J = 8.0, 2H), 0.93 (t, J = 8.0, 2H), -0.09 (s, 9H )

Stage 2: 9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b: 4 ', 3'-d] pyrrole-6-carbonitrile-1,7-dioxide

To a suspension of the hydroperitic adduct (5.9 g, 62.2 mmol) in chloroform (40 ml) was added trifluoroacetic anhydride (8.7 ml, 61.6 mmol) dropwise over 10 minutes. The reaction mixture was stirred at ambient temperature for 5 minutes and then added to it. 9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (2.0 g, 6.0 mmol) as a solution in chloroform (30 ml). Note: an exothermic reaction was observed as a result of the addition of the substrate. The reaction mixture was stirred at ambient temperature for 10 minutes and then at 50 ° C for 30 minutes. The reaction mixture was cooled to ambient temperature, treated with saturated sodium thiosulfate solution (20 ml) and diluted with water (50 ml) with methanol (10 ml) ) The layers were separated and the organic layer was washed with 0.5N. hydrochloric acid (50 ml), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 80 g, ISCO, 0-10% methanol in dichloromethane) to give the title compound as pale yellow precipitate (930 mg, 40%). ¹ H NMR (400 MHz, CDCl ₃ ) (8.86 (s, 1H), 8.39 (d, J = 6.4, 1H), 8.27 (s, 1H), 7.94 (d, J = 8.1, 1H), 7.32 (dd , J = 7.9, 6.5, 1H), 6.55 (s, 2H), 3.73 (t, J = 8.0, 2H), 0.93 (t, J = 8.0, 2H), -0.04 (s, 9H).

Stage 3: 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile-7-oxide

A mixture of 9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile-1,7-dioxide (2.1 g, 5.9 mmol) in N, N-dimethylformamide (50 ml) was treated with methanesulfonyl chloride (0.78 ml, 10.0 mmol), and the reaction mixture was stirred at ambient temperature for 7 hours. The reaction mixture was then diluted with ethyl acetate (150 ml) and water (200 ml). The layers were separated and the organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 40 g, ISCO, 5-85% ethyl acetate in heptane) to give the title compound as 6.5: 1 mixture with 2-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile-7-oxide, respectively, in the form of a grayish-white precipitate (1.7 g, 77%). The mixture was triturated in ethyl acetate (10 ml) overnight and the remaining precipitate was collected by vacuum filtration and washed with ethyl acetate (5 ml) to give the title compound with> 98% purity. ¹ H NMR (400 MHz, CDCl ₃ ) 6 8.86 (s, 1H), 8.39 (d, J = 6.4, 1 H), 8.27 (s, 1 H), 7.94 (d, J = 8.1, 1 H), 7.32 (dd, J = 7.9, 6.5, 1 H), 6.55 (s, 2H), 3.73 (t, J = 8.0, 2H), 0.93 (t, J = 8.0, 2H), -0.04 (s, 9H) .

Stage 4: 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Solution of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile-7-oxide (1.3 g, 3.52 mmol) in dichloromethane (11 ml) was treated with phosphorus trichloride (2N solution in dichloromethane, 1.9 ml, 3.9 mmol), and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 40 g, ISCO, 0-40% ethyl acetate in heptane) to give the title compound as a white precipitate (1.2 g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ) (9.20 (d, J = 0.9, 1H), 8.74 (d, J = 0.9, 1H), 8.60 (d, J = 5.3, 1H), 7.39 (d, J = 5.3, 1H), 6.02 (s, 2H), 3.60 (t, J = 8.0, 2H), 0.94 (t, J = 8.0, 2H), -0.08 (s, 9H).

Preparation of (R) -tert-butyl 3- (hydroxymethyl) -4-methylpiperazine-1-carboxylate

To a solution of (R) -tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate (115 mg, 0.53 mmol) in acetonitrile (1.4 ml) and water (0.3 ml) was added formalin (0.11 ml, 1.6 mmol) followed by triacetoborohydride sodium (225 mg, 1.1 mmol). The reaction mixture was stirred for 20 minutes at ambient temperature. The reaction mixture was then alkalized by adding a saturated aqueous solution of sodium carbonate (1 ml), diluted with dichloromethane (50 ml) and methanol (5 ml) and washed with a saturated aqueous solution of sodium bicarbonate (2 × 15 ml). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to give a white crystalline precipitate, which was used in the next step without any further purification (120 mg, 98%).

Preparation of (S) -tert-butyl 3- (hydroxymethyl) -4-methylpiperazine-1-carboxylate

The title compound was prepared according to the methods of the preceding example using (S) -tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate.

Preparation of (S) -tert-butyl 2- (hydroxymethyl) -4-methylpiperazine-1-carboxylate

The title compound was prepared according to the methods of the preceding example using (S) -tert-butyl 2- (hydroxymethyl) piperazine-1-carboxylate.

Preparation of (R) -tert-butyl 2- (hydroxymethyl) -4-methylpiperazine-1-carboxylate

The title compound was prepared according to the methods of the preceding example using (R) -t-butyl 2- (hydroxymethyl) piperazine-1-carboxylate.

Preparation of (1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-ylmethanol

To a suspension of (1R, 3S, 4S) -2-azabicyclo [2.2.1] heptane-3-carboxylic acid hydrogen chloride (500 mg, 3 mmol) in tetrahydrofuran (4.6 ml) was added lithium tetrahydroaluminate (1N solution in tetrahydrofuran, 5.7 ml 6 mmol) dropwise over 10 minutes. The reaction mixture was stirred overnight at ambient temperature under nitrogen. The reaction was quenched with a few drops of water, diluted with diethyl ether (50 ml) and tetrahydrofuran (25 ml). The reaction mixture was alkalinized to pH ~ 11 by adding potassium hydroxide tablets and gently mixed for 30 minutes. The reaction mixture was filtered through sodium sulfate, concentrated in vacuo, redissolved in dichloromethane (10 ml), dried over sodium sulfate again, filtered and concentrated in vacuo to give a yellow crystalline precipitate, which was used in the next step without any further purification (400 mg, 100%).

Preparation of trans (3S, 4S) -tert-butyl 4-fluoro-3-hydroxypiperidin-1-carboxylate

The preparation of the title compound is described in WO 2008106692 (A1).

Preparation of 4-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole

Step 1: Preparation of (4-chloro-1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) dimethylamine

4-chloro-7-azaindole (7.32 g, 48 mmol), paraformaldehyde (1.59 g, 52.8 mmol) and dimethylamine hydrochloride (4.32 g, 52.8 mmol) were suspended in 1-butanol (30 ml) and the mixture was heated under reflux for 2 hours. The mixture was cooled to ambient temperature and diluted with diethyl ether (50 ml). The resulting precipitate was collected by filtration and washed with diethyl ether and allowed to air dry. The precipitate was dissolved in water (100 ml) and the pH of the solution was adjusted to 11 by portionwise addition of solid potassium carbonate. The aqueous phase was extracted with dichloromethane (3 × 40 ml). The combined organic phase was dried (MgSO ₄ ), filtered and evaporated to give the title compound as a pale yellow precipitate (7.12 g, 70%). ¹ H NMR (300 MHz, CDCl ₃ ): 11.19 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.32 (s, 1H), 7.08 (d, J = 5.2 Hz, 1H), 3.79 (s, 2H); 2.34 (s, 6H).

Stage 2: 2-acetylamino-2- (4-chloro-1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) malonic acid diethyl ether

(4-chloro-1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) dimethylamine (7.1 g, 34 mmol), powdered sodium hydroxide (0.21 g, 5.2 mmol) and diethylacetamidomalomonate (8.26 g, 38 mmol) were suspended in xylene (60 ml) and the mixture was heated under reflux for 4 hours. While the mixture was hot, it was filtered to remove the precipitate and the filtrate was allowed to cool to ambient temperature with stirring. The precipitate precipitated was collected by filtration, washed with xylene, then dissolved in dichloromethane and passed through a layer of silica gel (25 g). The layer was washed with a 1: 1 mixture of ethyl acetate: dichloromethane (100 ml) and then with ethyl acetate (2 × 100 ml). The combined filtrate was evaporated and the resulting residue was triturated with ethyl acetate (100 ml). The precipitate was collected by filtration and allowed to dry in air to give the title compound as a white precipitate (8.5 g, 65%). ¹ H NMR (400 MHz, CDCl ₃ ): 10.12 (S.1H), 8.13 (d, J = 5.2 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J = 5.2 Hz, 1H), 6.71 (s, 1H), 4.23-4.22 (m, 4H), 4.06 (s, 2H), 2.02 (s, 3H), 1.24 (t, J = 7.1 Hz, 6H).

Stage 3: 2-amino-3- (4-chloro-1H-pyrrolo [2.3-b] pyridin-3-yl) -propionic acid hydrochloride

2-Acetylamino-2- (4-chloro-1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) malonic acid diethyl ether (8.5 g, 22.3 mol) was dissolved in concentrated hydrochloric acid (45 ml) and the solution was heated at 100 ° C for 16 hours. The mixture was allowed to cool to ambient temperature and evaporated in vacuo. The resulting precipitate was azeotroped with methanol (100 ml) and toluene (2 × 100 ml) to give the crude title compound as a white precipitate. LCMS (Method B): R _T = 1.88 min, M + H ⁺ = 240.

Stage 4: 2-amino-3- (4-chloro-1H-pyrrolo [2.3-b] pyridin-3-yl) -prOpiOnic acid methyl ester - hydrOchlOride salt

Thionyl chloride (27.5 ml) was added dropwise after 15 minutes to a chilled (0 ° C.) suspension of 2-amino-3- (4-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -propionic acid hydrochloride (7.28 g, 22.3 mmol) in methanol (150 ml). Upon completion of the addition, the mixture was heated under reflux for 66 hours. The mixture was allowed to cool to ambient temperature and evaporated. The resulting precipitate was azeotroped with toluene (2 × 150 ml) to give the title compound as a beige precipitate (7.7 g, 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.06 (s, 1H), 8.39 (s, 3H), 8.17 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H) , 7.19 (d, J = 5.2 Hz, 1H), 4.07-4.06 (m, 1H), 3.54 (dd, J = 14.9, 5.8 Hz, 1H), 3.30 (dd, J = 14.9, 9.0 Hz, 1H).

Stage 5: 4-chloro-6,7,8,9-tetrahydro-5H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carboxylic acid methyl ester

A suspension of 2-amino-3- (4-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -propionic acid methyl ester (3.5 g, 10 mmol) in pyridine (25 ml) was treated with a solution of formaldehyde ( 37% in water, 0.90 ml) and the resulting mixture was heated to 100 ° C for 1.25 hours. The mixture was allowed to cool to ambient temperature then evaporated in vacuo. The resulting residue was treated with saturated aqueous sodium carbonate (15 ml) and the resulting precipitate was collected by filtration and washed with water (20 ml). The filtrate was extracted with 20% methanol in dichloromethane (6 × 25 ml). The combined organic phase was mixed with the precipitate and concentrated in vacuo to give the title compound as a brown precipitate (2.1 g, 87%). LCMS (Method B): R _T = 2.36 min, M + H ⁺ = 266. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.66 (s, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.06 (d, J = 5.1 Hz, 1H), 4.01-3.71 (m, 3H), 3.69 (s, 3H), 3.19 (dd, J = 15.4.4.7 Hz, 1H), 2.94 (dd, J = 15.4, 8.9 Hz, 1H).

Stage 6: 4-chloro-9H-dipyrido [2,3-b; 4 ', 3'] pyrrole-6-carboxylic acid methyl ester

A mixture of 4-chloro-6,7,8,9-tetrahydro-5H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carboxylic acid methyl ester (2.1 g, 7.9 mmol) and dioxide selenium (1.20 g, 11.1 mol) in 1,4-dioxane (50 ml) was heated at 100 ° C for 3.5 hours. The resulting gray suspension was filtered while it was hot through a celite filter and then the filter was washed with hot THF and 25% methanol in dichloromethane. The combined filtrate was concentrated in vacuo and the resulting precipitate was triturated with methanol (10 ml). The resulting precipitate was collected by filtration and allowed to air dry to give the title compound as a grayish-white precipitate (1.03 g, 48%). ¹ H NMR (400 MHz, DMSO-d ₆ ): 13.02 (s, 1H), 9.06 (d, J = 1.1 Hz, 1H), 8.94 (d, J = 1.0 Hz, 1H), 8.63 (d, J = 5.3 Hz, 1H), 7.54 (d, J = 5.3 Hz, 1H), 3.93 (s, 3H).

Stage 7: 4-chloro-9H-dipyrido-G2.3-b: 4'.CHP Pyrrole-6-carboxylic acid

A mixture of 4-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carboxylic acid methyl ester (0.73 g, 2.8 mol) and lithium hydroxide (0.38 g, 9.0 mmol) in tetrahydrofuran (15 ml) and water (3 ml) were heated at 50 ° C for 1.5 hours. The mixture was allowed to cool to ambient temperature, treated with hydrochloric acid (1M, 9 ml) and evaporated in vacuo to give a gray precipitate (0.68 g, 98%). LCMS (Method B): R _T = 2.98 min, M + H ⁺ = 248. ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.98 (s, 1H), 9.05 (d, J = 1.0 Hz, 1H), 8.95 (d, J = 1.0 Hz, 1H), 8.63 (d, J = 5.3 Hz, 1H), 7.54 (d, J = 5.3 Hz, 1H).

Stage 8: 4-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole

A mixture of 4-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carboxylic acid (390 mg, 1.57 mmol) in N-methylpyrrolidine (8 ml) was heated under reflux for 8 ocloc'k. The mixture was allowed to cool to ambient temperature. The compound was used as a solution in NMP for subsequent reactions. LCMS (Method B): R _T = 2.15 min, M + H ⁺ = 204.

The main methods of binding

Method A-1: Mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) alcohol (2-4 equiv.), and sodium hydride in the form of a 60% dispersion in mineral oil (2-8 equiv.) in tetrahydrofuran was heated at a temperature of 25 ° C to 55 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified by flash chromatography on silica gel using a gradient of either ethyl acetate in heptane or methanol in dichloromethane. The purified substance was then deprotected using the conditions described below.

Method B-1: Mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 eq.) And a suitable amine (2-4 equiv.) was heated in N, N-dimethylacetamide at a temperature of from 80 ° C to 120 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified by flash chromatography on silica gel using a gradient of either ethyl acetate in heptane or methanol in dichloromethane. The purified substance was then deprotected using the conditions described below.

Method C-1: Mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.), Hydrochloric salts of a suitable amine (2-4 equivalents) and triethylamine (5-10 equivalents) were heated in N, N-dimethylacetamide at a temperature of from 80 ° C to 120 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified by flash chromatography on silica gel using a gradient of either ethyl acetate in heptane or methanol in dichloromethane. The purified substance was then subjected to deprotection using the general conditions described below.

Method D-1: Mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) amine (5 equiv.), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.2 equiv.), tris (dibenzylideneacetone) dipalladium (0) (0.1 equiv.) and cesium carbonate (2 equiv.) , 4-dioxane was heated at a temperature of from 100 ° C to 110 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified by flash chromatography on silica gel using a gradient of either ethyl acetate in heptane or methanol in dichloromethane. The purified substance was then deprotected using the conditions described below.

Method E-1: 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-dpyrrole-6-carbonitrile (1 equiv.) Was heated in a suitable amine ( 1-5 eq) in DMA at a temperature of from 120 ° C to 140 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

Method F-1: 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 eq.) In THF was heated with a suitable alcohol (2-5 equivalents) and sodium hydride (2-5 equivalents) between ambient temperature and up to 100 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

Method A-2: A suitable 3-position substituted 9-benzenesulfonyl-5-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 eq.) Was heated in a suitable amine (3-5 equivalents) and triethylamine (10 equivalents) at a temperature between 140 ° C and 160 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

Method B-2: Suitable 3-position substituted 9-benzenesulfonyl-5-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) Or 3-substituted 5-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equivalent) was heated in a suitable amine (3-5 equivalent) and triethylamine (10 equiv.) at a temperature between 120 ° C. and 160 ° C. until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

Method C-2: A mixture of a suitable 3-position substituted 9-benzenesulfonyl-5-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) of a suitable amine (1-2 equivalents), cesium carbonate (1-3 equivalents) and sodium iodide (0.5-1 equivalents) in DMF were heated under microwave conditions (from 100 ° C to 160 ° C) in the range from 5 to 15 minutes. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

Method D-2: 5-fluoro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) Or 5- fluoro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) in DMA was heated with a suitable amine (2-5 equiv.) between ambient temperature and 160 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

Method E-2: 5-fluoro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) In NMP was heated with a suitable alcohol (2-5 equivalents) and sodium hydride (2-5 equivalents) between ambient temperature and 160 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

Method F-2: A solution of a suitable 3-position substituted 9-benzenesulfonyl-5-hydroxy-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) of a suitable alcohol (2-5 equivalents) and triphenylphosphine (2-5 equivalents) in anhydrous DMF or anhydrous THF was treated dropwise with diethyl azodicarboxylate (2-5 equivalents) and the mixture was stirred at a temperature between ambient temperature and 50 ° C in interval from 2 to 65 hours. The resulting reaction mixture was diluted with ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting precipitate was purified using the basic methods described below.

Method G-2: Chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole (1 eq.) In NMP was heated with a suitable amine (2-5 eq.) Between ambient temperature and 160 ° C until the reaction was considered complete. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

The main methods of hydrogenation

Method A-2: A solution of a suitable 5-position substituted 9-benzenesulfonyl-3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) or 5-position substituted 3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) in a mixture of ethanol and tetrahydrofuran (1: 1 vol. (vol.)) was treated with palladium-carbon (10 wt.%), then placed in a hydrogen atmosphere and the reaction mixture was stirred at ambient temperature until the reaction was considered complete. The reaction mixture was purged with argon, then the catalyst was removed by filtration and the filtrate was evaporated. The resulting precipitate was purified using one of the main purification methods described below.

Method B-2: A solution of a suitable 5-position substituted 9-benzenesulfonyl-3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) or 5-position substituted 3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.) in a mixture of ethanol, dichloromethane, triethylamine and DMF (2 : 2: 1: 2 v / v) was treated with palladium-carbon (10 wt.%), Then placed in a hydrogen atmosphere and the reaction mixture was stirred at ambient temperature until the reaction was considered complete. The reaction mixture was purged with argon, then the catalyst was removed by filtration and the filtrate was evaporated. The resulting precipitate was purified using one of the main purification methods described below.

The main methods of deprotection

Method A-1: A mixture of a suitable, substituted at the 4th position, 9- (2-trimethylsilanyl-ethoxymethyl) dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile was dissolved in 1.4 -dioxane and then treated with 48% HBr _(aq) and heated to a temperature between 50 ° C and 75 ° C until the reaction was considered complete. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide and purified using one of the basic methods described below. In some cases, the aqueous supernatant was purified by similar methods and combined.

Method B-1: 1n. TBAF in THF was added to the protected substrate mixture in a suitable solvent. The reaction mixture was stirred between ambient temperature and 55 ° C until the reaction was considered complete. The resulting solution was concentrated in vacuo before purification of the crude material through one of the main purification methods described below.

Method C-1: 6n. HCl was added to the protected substrate mixture in a suitable solvent. The reaction mixture was stirred between ambient temperature and 55 ° C until the reaction was considered complete. The resulting solution was concentrated in vacuo before purification of the crude material through one of the main purification methods described below.

Method D-1: 48% hydrobromic acid was added to a mixture of the protected substrate in acetic acid. The reaction mixture was stirred between ambient temperature and 55 ° C until the reaction was considered complete. The resulting solution was concentrated in vacuo before purification of the crude material through one of the main purification methods described below.

Method A-2: 1n. TBAF in THF was added to the protected substrate mixture in a suitable solvent. The reaction mixture was stirred between ambient temperature and 55 ° C until the reaction was considered complete. The resulting solution was concentrated in vacuo before purification of the crude material through one of the main purification methods described below. Alternatively, the crude material was partitioned between water and ethyl acetate, and the organic layer was dried, concentrated in vacuo, before the crude material was purified by one of the basic purification methods described below.

Method B-2: The tertiary amine was dissolved or suspended in dichloromethane and treated with an excess (at least 2 equivalents) of 1-chloroethyl chloroformate, DIPEA (at least 1 equivalent) was added and the resulting mixture was heated under reflux. When LCMS analysis showed that the starting materials (or any 1-chloroethyl carbamate starting material) had been consumed, the solution was cooled and concentrated in vacuo. The precipitate was placed in methanol and heated under reflux until LCMS analysis showed complete consumption of the intermediates. The reaction mixture was then cooled and concentrated in vacuo. The precipitate was purified using one of the main purification methods described below.

Method C-2: 2n. ammonia in methanol was added to the mixture of the protected substrate. The reaction mixture was stirred at ambient temperature until the reaction was considered complete. The resulting solution was concentrated in vacuo before purification of the crude material through one of the main purification methods described below.

Method D-2: TFA was added to a mixture of the protected substrate in a suitable solvent at ambient temperature. The mixture was stirred until the reaction was considered complete. The reaction mixture was concentrated in vacuo and purified using one of the main purification methods described below.

Method E-2: Triethylamine in methanol was added to the mixture of the protected substrate. The reaction mixture was stirred at ambient temperature until the reaction was considered complete. The resulting solution was concentrated in vacuo before purification of the crude material through one of the main purification methods described below.

Basic reductive amination / alkylation methods Method A-2: To a solution of a suitable 5-position substituted 9-benzenesulfonyl-3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 -carbonitrile (1 equiv.), sodium triacetoxyborohydride (1-2 equiv.) and acetic acid in methanol was added aqueous formaldehyde (2-4 equiv.) and then the reaction mixture was stirred at ambient temperature until the reaction considered complete. The reaction mixture was concentrated in vacuo and purified using one of the main purification methods described below.

Method B-2: To a solution of a suitable 5-position substituted 9-benzenesulfonyl-3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv. ), sodium triacetoborohydride (1-2 equivalents) and acetic acid in methanol, acetaldehyde (2-4 equivalents) was added, and then the reaction mixture was stirred at ambient temperature until the reaction was considered complete. The reaction mixture was concentrated in vacuo and purified using one of the main purification methods described below.

Method C-2: A mixture of a suitable 5-position substituted 9-benzenesulfonyl-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (1 equiv.), 2.2 -dimethyloxyran (1-2 equiv.), cesium carbonate (1-3 equiv.) in DMF was heated under microwave conditions (from 100 ° C to 160 ° C) in the interval between 5 and 15 minutes. The reaction mixture was cooled, then diluted with water and extracted with a suitable solvent. The resulting precipitate was purified using one of the main purification methods described below.

Basic cleaning methods

Method A-1: Compounds were usually purified by reverse phase HPLC using Gemini-NX columns (10 μM, 3 cm × 10 cm) manufactured by Phenomenex. Samples were loaded with a gradient of 5-50%, 5-85%, or 20-60% acetonitrile or methanol in water with 0.1% ammonium hydroxide or 0.1% formic acid for 14 minutes at a flow rate of 60 ml / min. In some cases, pure racemic compounds were separated using a Berger MG2 semi-preparative system on Chiral Technologies AD, OD, OJ, AS, IA, IB or IB columns (5 μM, 21.2 mm × 250 m) at a flow rate of 50-70 ml / min. Typically, the following solvents were used: methanol, ethanol or IPA with 0.1% triethylamine.

Method A-2: Biotage, Snap KP-NH, Amino Silica-ISCO, methanol / dichloromethane gradient.

Method B-2: Si-SPE or Si-ISCO or hand-made silica gel collet, gradient methanol / dichloromethane.

Method C-2: A solution of the substrate in methanol was loaded onto an IsOlute cartridge (SCX-2. Then, the cartridge was washed with methanol before the desired material was eluted using 2N ammonia in MeOH.

Method D-2: Si-SPE or Si-ISCO, ethyl acetate / methanol gradient.

Method E-2: Si-SPE or Si-ISCO, gradient 2-propanol / dichloromethane.

Method F-2: Biotage, Snap KP-NH, Amino Silica-ISCO, gradient 2-propanol / dichloromethane.

Differences from the main cleaning methods:

¹ triturated in dichloromethane; ² triturated in methanol; ³ triturated in acetonitrile; ⁴ triturated in ethyl acetate.

The compounds of the examples in Table 1 were obtained by one of the main methods of binding, followed by deprotection mainly according to Method A-1 and purification mainly according to Method A-1, which are described above.

Table 1 Example Structure / Name Binding method LCMS R _T (min), M + H ⁺ , Method ¹ H NMR (ppm) one

D-1 2.397, 309.1, E ¹ H NMR (400 MHz, d ₆ -DMSO) (12.43 (s, 1H), 9.07 (s, 1H), 8.85 (s, 1H), 8.22 (d, J = 5.8, 1H), 7.01 (t, J = 6.0, 1H), 6.61 (d, J = 5.9, 1H), 3.90 (m, 1H), 3.85 (m, 1H), 3.58 (m, 1H), 3.51 (t, J = 6.0, 2H), 3.20 (m, 1H), 2.98 (m, 1H), 2.87 (m, 1H), 2.73 (m, 1H). 4-4- (N- (morpholin-2-ylmethyl)) - 9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 2

A-1 5.391, 280.1, D ¹ H NMR (400 MHz, d ₃ -DMSO) (8.98 (d, J = 0.9, 1H), 8.57 (d, J = 5.9, 1H), 8.38 (s, 1H), 7.05 (d, J = 5.9, 1H), 4.53 (d, J = 6.3, 2H), 3.97 (t, J = 8.9, 2H), 3.80-3.73 (m, 2H), NH signals were not observed. 4- (azetidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 3

(R) -4- (morpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile A-1 6.122, 310.1, D ¹ H NMR (400 MHz, d _6- DMSO) 6 8.98 (d, J = 0.9, 1H), 8.54 (d, J = 5.7, 1 H), 8.44 (d, J = 0.9, 1H), 7.05 (d , J = 5.8, 1H), 4.40-4.30 (m, 2H), 3.95 (m, 1H), 3.82 (m, 1H), 3.56 (m, 1H), 3.02 (m, 1H), 2.79-2.63 (m , 3H), NH signals were not observed. four

A-1 5.750, 310.1, D ¹ H NMR (400 MHz, d ₆ -DMSO) (8.95 (s, 1H), 8.52 (d, J = 5.7, 1H), 8.41 (d, J = 0.8, 1H), 6.98 (d, J = 5.7, 1H), 4.33 (3, 2H), 3.98-3.90 (m, 1H), 3.81 (m, 1H), 3.56 (m, 1H), 3.02 (m, 1H), 2.78-2.63 (m, 3H), NH no signals were observed. (S) -4- (morpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 5

A-1 2.747, 320.1, E ¹ H NMR (400 MHz, d _6- DMSO) (12.78 (s, 1H), 8.98 (d, J = 0.9, 1H), 8.53 (s, 1H), 8.52 (d, J = 4.4, 1H), 7.00 (d, J = 5.8, 1H), 5.04-4.95 (m, 1H), 3.48 (m, 1H), 3.07 (m, 2H), 2.95-2.76 (m, 3H), 2.35 (m, 1H), 1.98 (m, 1H), 1.76 (m, 2H), 1.55 (m, 1H). 4- (quinuclidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 6

A-1 3.147, 280.1, E ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.8, 1H), 8.53 (d, J = 0.8, 1H), 8.51 (d, J = 5.7, 1H), 6.87 (d, J = 5.7, 1H), 4.73 (m, 1H), 3.15-3.05 (m, 1H), 2.96-2.86 (m, 2H), 2.04 (m, 2H), no NH signal was observed. 4 - ((1s, 3s) -cyclobutanamine-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 7

(R) -4 - ((1-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-
d] pyrrole-6-carbonitrile A-1 2.966, 323.1, E ¹ H NMR (400 MHz, d ₆ -DMSO) (8.95 (s, 1H), 8.53 (d, J = 5.7, 1H), 8.44 (s, 1H), 7.01 (d, J = 5.7, 1H), 4.46 (m, 1H), 4.30 (m, 1H), 3.07 (m, 1H), 2.80 (m, 1H), 2.75-2.60 (m, 3H), 2.57-2.52 (m, 1H), 2.43-2.27 (s , 3H), 2.19 (m, 1H), NH signals were not observed. 8

A-1 6.039, 323.1, D ¹ H NMR (400 MHz, d ₆ -DMSO) (8.98 (d, J = 0.9, 1H), 8.55 (d, J = 5.7, 1 H), 8.47 (d, J = 0.8, 1H), 7.07 (d , J = 5.8, 1H), 4.47 (dd, J = 10.3, 4.2, 1H), 4.32 (dd, J = 10.2, 5.3, 1H), 3.07 (m, 1H), 2.81 (m, 1H), 2.70 ( m, 3H), 2.60-2.53 (m, 1H), 2.34 (s, 3H), 2.23-2.15 (m, 1H), NH signals were not observed. (S) -4 - ((1-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carboonitrile 9

A-1 2.664, 323.1, E ¹ H NMR (400 MHz, d ₆ -DMSO) (8.96 (d, J = 0.8, 1H), 8.53 (m, 2H), 7.03 (d, J = 5.8, 1H), 4: 32-4.23 (m, 2H), 2.91 (m, 1H), 2.86-2.74 (m, 2H), 2.60 (m, 1H), 2.19 (s, 3H), 1.98 (m, 1H), 1.90 (m, 1H), NH signals are not were observed. (R) -4 - ((4-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 10

BUT 6.327, 323.1, D ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.9, 1H), 8.55 (m, 2H), 7.05 (d, J = 5.8, 1H), 4.33-4.23 (m, 2H) , 2.91 (m, 1H), 2.87-2.74 (m, 2H), 2.60 (m, 1H), 1.98 (td, J = 10.6,3.0, 1H), 1.91 (t, J = 9.9, 1H), NH signals not observed. (S) -4 - ((4-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile eleven

(R) -4 - ((piperidin-2-one) -5-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-
carbonitrile A-1 7.026, 308.0, D ¹ H NMR (400 MHz, d ₆ -DMSO) (12.72 (s, 1H), 8.98 (d, J = 0.8, 1H), 8.56 (d, J = 5.8, 1H), 8.36 (d, J = 0.8, 1H), 7.60 (s, 1H), 7.17 (d, J = 5.9, 1H), 5.33-5.22 (m, 1H), 3.58 (m, 2H), 2.42-2.29 (m, 2H), 2.23 (m, 2H). 12

A-1 6.510, 322.1, D ¹ H NMR (400 MHz, d ₆ -DMSO) (12.77 (s, 1H), 8.98 (d, J = 0.9, 1H), 8.54 (d, J = 5.7, 1H), 8.42 (d, J = 0.9, 1H), 7.05 (d, J = 5.8, 1H), 4.25 (d, J = 6.3, 2H), 2.91 (m, 2H), 2.26 (s, 3H), 2.07 (m, 2H), 1.99 (m, 1H), 1.88 (m, 2H), 1.47 (m, 2H). 4 - ((1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 13

A-1 3.218, 336.1, E ¹ H NMR (400 MHz, d ₆ -DMSO) (12.78 (s, 1H), 8.99 (d, J = 0.8, 1H), 8.54 (d, J = 5.7, 1H), 8.37 (s, 1H), 7.08 (d, J = 5.8, 1H), 4.30 (d, J = 9.2, 1H), 4.22 (d, J = 9.3, 1H), 2.51 (m, 1H), 2.38 (m, 1H), 2.17 (m, 3H), 2.17 (s, 1H), 2.11 (m2, 1H), 1.74-1.55 (m, 3H), 1.34 (m, 1H), 1.19 (s, 3H). 4 - ((1,3-dimethylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile fourteen

B-1 6.140, 363.1, D ¹ H NMR (400 MHz, d ₆ -DMSO) (12.82 (s, 1H), 8.98 (s, 1H), 8.50 (d, J = 5.5, 1H), 8.21 (s, 1H), 6.92 (d, J = 5.6, 1H), 4.11 (m, 1H), 4.05 (m, 1H), 3.95 (t, J = 10.4, 1H), 3.78 (d, J = 12.5, 1H), 3.49 (d, J = 11.7, 1H), 3.17-3.06 (m, 1H), 2.78-2.52 (m, 7H), 1.69 (s, 4H). 4- (2- (pyrrolidin-1-ylmethyl) morpholino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile fifteen

(R) -4- (morpholin-3-
ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile A-1 6.907, 310.1, D ¹ H NMR (400 MHz, d ₆ -DMSO) (12.78 (s, 1H), 8.97 (d, J = 0.9, 1H), 8.58 (d, J = 0.9, 1H), 8.55 (d, J = 5.7, 1H), 7.05 (d, J = 5.8, 1H), 4.31-4.19 (m, 2H), 3.95 (m, 1H), 3.73 (m, 1H), 3.49-3.42 (m, 2H), 3.41-3.22 ( m, 2H), 2.92-2.78 (m, 2H), no morpholine NH signal was observed. 16

A-1 7.696, 334.1, D ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.9, 1H), 8.56 (d, J = 5.7, 1H), 8.40 (d, J = 0.9, 1H), 7.11 (d, J = 5.8, 1H), 4.38 (m, 2H), 3.20-3.12 (m, 1H), 2.78 (m, 4H), 2.61-2.53 (m, 1H), 2.44-2.34 (m, 1H), 1.96 ( m, 1H), 1.75 (m, 1H), 1.65 (m, 2H), 1.42 (m, 1H), no NH signal was observed. 4- (quinuclidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 17

A-1 7.490, 312.0, D ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.9, 1H), 8.62 (d, J = 0.9, 1H), 8.54 (d, J = 5.8, 1H), 7.15 (d, J = 5.9, 1H), 5.09 (m, 1H), 4.86-4.69 (m, 1H), 3.06-2.94 (m, 1H), 2.69 -2.52 (m, 3H), 2.25-2.13 (m, 1H), 1.78-1.61 (m, 1H), NH signals were not observed. trans-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile eighteen

A-1 1.48 min, 320.18, F ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.9, 1H), 8.53 (dd, J = 3.3, 2.3, 2H), 7.01 (d, J = 5.8, 1H), 4.14 ( m, 1H), 4.05-3.90 (m, 1H), 3.42 (m, 1H), 2.56-2.49 (m, 1H), 2.44 (m, 1H), 1.64 (m, 3H), 1.55-1.40 (m, 2H), 1.23 (m, 1H), NH signals were not observed. 4 - ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 19

(S) -4- (2 - ((dimethylamino) methyl) mo
rfolino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile B-1 5.081, 337.2, D ¹ H NMR (400 MHz, d ₆ -DMSO) (12.82 (s, 1H), 8.98 (d, J = 0.8, 1H), 8.49 (d, J = 5.6, 1H), 8.23 (d, J = 0.7, 1H), 6.91 (d, J = 5.6, 1H), 4.18-3.99 (m, 2H), 3.93 (m, 1H), 3.81 (d, J = 12.6, 1H), 3.49 (d, J = 12.6, 1H ), 3.18-3.01 (m, 1H), 2.64 (m, 1H), 2.41-2.36 (m, 2H), 2.25 (s, 6H). twenty

B-1 5.081, 337.2,
D ¹ H NMR (400 MHz, d ₆ -DMSO) δ (12.82 (s, 1H), 8.98 (d, J = 0.8, 1H), 8.49 (d, J = 5.6, 1H), 8.23 (d, J = 0.7 , 1H), 6.91 (d, J = 5.6, 1H), 4.18-3.99 (m, 2H), 3.93 (m, 1H), 3.81 (d, J = 12.6, 1H), 3.49 (d, J = 12.6, 1H), 3.18-3.01 (m, 1H), 2.64 (m, 1H), 2.41-2.36 (m, 2H), 2.25 (s, 6H). (R) -4- (2 - ((dimethylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 21

B-1 2.429, 323.2,
E ¹ H NMR (500 MHz, de-DMSO) δ (8.97 (s, 1H), 8.49 (d, J = 5.5, 1H), 8.20 (s, 1H), 6.92 (d, J = 5.6, 1H), 4.06 (m, 2H), 3.95 (m, 1H), 3.74 (d, J = 12.3, 1H), 3.56 (d, J = 12.8, 1H), 3.16-3.09 (m, 1H), 2.86-2.81 (m, 1H), 2.79 (m, 2H), 2.44 (s, 3H), no NH signal was observed. (S) -4- (2 - ((methylamino) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 22

B-1 2.402, 323.2, E ¹ H NMR (500 MHz, d ₆ -DMSO) δ (8.96 (s, 1H), 8.47 (d, J = 5.5, 1H), 8.20 (s, 1H), 6.90 (d, J = 5.6, 1H), 4.04 (m, 1H), 4.00-3.87 (m, 2H), 3.78 (d, J = 12.6, 1H), 3.53 (d, J = 12.1, 1H), 3.16-3.07 (m, 1H), 2.77 (m , 1H), 2.63 (m, 2H), 2.36 (s, 3H), no NH signal was observed. (R) -4- (2 - ((methylamino) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 23

A-1 5.298, 338.2, D ¹ H NMR (500 MHz, d _6- DMSO) (12.75 (s, 1H), 8.97 (d, J = 0.9, 1H), 8.66 (s, 1H), 8.54 (d, J = 5.7, 1H), 7.05 (d, J = 5.8, 1H), 4.92 (s, 1H), 4.16 (s, 2H), 2.61 (m, 2H), 2.42 (m, 2H), 2.26 (s, 3H), 1.77 (m, 4H ) 4 - ((4-hydroxy-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 24

A-1 6.49, 340.1, D ¹ H NMR (500 MHz, d ₆ -DMSO) (8.99 (d, J = 0.9, 1H), 8.57 (d, J = 5.7, 1 H), 8.34 (d, J = 0.9, 1H), 7.09 (d , J = 5.8, 1H), 4.53 (s, 1H), 4.49 (s, 1H), 2.68 (m, 2H), 2.25 (m, 2H), 2.23 (s, 3H), 2.04 (m, 2H), 2.00-1.84 (m, 2H), no NH signal was observed. H4 - ((4-fluoro-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 25

A-1 6.34, 352.1, D ¹ H NMR (500 MHz, d ₆ -DMSO) (8.97 (d, J = 0.9, 1H), 8.55 (d, J = 5.7, 1H), 8.32 (s, 1H), 7.07 (d, J = 5.8, 1H), 4.34 (s, 2H), 3.25 (s, 3H), 2.58-2.50 (m, 2H), 2.25 (m, 2H), 2.20 (s, 3H), 1.93 (m, 2H), 1.81-1.70 (m, 2H), NH signal was not observed. 4 - ((4-methoxy-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 26

IN 1 5.363, 321.1, D ¹ H NMR (500 MHz, d ₆ -DMSO) (12.71 (s, 1H), 8.95 (d, J = 0.7, 1H), 8.44 (d, J = 5.6, 1H), 8.19 (s, 1H), 6.90 (d, J = 5.6, 1H), 3.84 (d, J = 9.8, 1H), 3.60 (d, J = 12.7, 1H), 2.91 (m, 1H), 2.81-2.68 (m, 2H), 2.29 ( s, 6H), 2.08 (m, 1H), 1.95 (m, 1H), 1.80 (m, 1H), 1.44 (m, 1H). (R) -4- (3- (dimethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 27

IN 1 5.350, 321.2, D ¹ H NMR (500 MHz, d ₆ -DMSO) (12.71 (s, 1H), 8.95 (d, J = 0.7, 1H), 8.44 (d, J = 5.6, 1H), 8.19 (s, 1H), 6.90 (d, J = 5.6, 1H), 3.84 (d, J = 10.6, 1H), 3.60 (d, J = 12.6, 1H), 2.91 (m, 1H), 2.75 (m, 2H), 2.28 (s, 6H), 2.08 (m, 1H), 1.95 (m, 1H), 1.79 (m, 1H), 1.50-1.37 (m, 1H). S) -4- (3- (dimethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 28

A-1 6.465, 336.1, A ¹ H NMR (500 MHz, d ₆ -DMSO) (8.93 (s, 1H), 8.48 (d, J = 5.7, 1H), 8.43 (s, 1H), 7.04 (d, J = 5.8, 1H), 4.74 (m, 1H), 2.28 (m, 3H), 2.21 (s, 6H), 1.90 (m, 2H), 1.73-1.62 (m, 2H), 1.47 (m, 2H), no NH signal was observed. 4 - ((1r, 4r) -4- (dimethylamino) cyclohexyloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

EXAMPLE 29

(R) -4 - ((1-methylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (R) -tert-butyl 3 - ((6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H- [2,3-b; 4 ', 3'-d] pyrrole -4-yloxy) methyl) piperidin-1-carboxylate

To a solution of (R) -tert-butyl 3- (hydroxymethyl) piperidine-1-carboxylate (120 mg, 0.56 mmol) in tetrahydrofuran (1.8 ml) was added sodium hydride as a 60% dispersion in mineral oil (22 mg, 0.56 mmol) . The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 β-carbonitrile (100 mg, 0.3 mmol) was added at a time. The reaction mixture was stirred at ambient temperature for 10 minutes before being heated at 40 ° C. for 2 hours. The mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 4 g, ISCO, 5-75% ethyl acetate in heptane) to give the title compound as a colorless oil which was used in the next step without any further purification (105 mg).

Stage 2; (R) -4- (piperidin-3-ylmethoxy) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6- carbonitrile

A solution of (R) -tert-butyl 3 - ((6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H- [2,3-b; 4 ', 3'-d] pyrrole-4 -yloxy) methyl) piperidine-1-carboxylate (105 mg, 0.21 mmol) in dichloromethane (2 ml) was treated with trifluoroacetic acid (0.3 ml, 4.0 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium carbonate (10 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 4 g, ISCO, 0-10% dichloromethane in methanol) to give the title compound as a yellow foam which was used in the next step without any further purification (60 mg, 50% in two steps).

Stage 3: (R) -4- (1-methylpiperidin-3-ylmethoxy) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d ] pyrrole-6-carbonitrile

To a solution of (R) -4- (piperidin-3-ylmethoxy) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole- 6-carbonitrile (50 mg, 0.1 mmol) in acetonitrile (0.5 ml) and water (0.1 ml) were added formalin (0.024 ml, 0.3 mmol) and then sodium triacetoborohydride (48 mg, 0.2 mmol). The reaction mixture was stirred for 20 minutes at ambient temperature and then alkalized by adding saturated aqueous sodium carbonate (1 ml), diluted with dichloromethane (50 ml) and methanol (5 ml), and washed with saturated aqueous sodium bicarbonate (2 × 15 ml). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give a pale yellow precipitate, which was used in the next step without any further purification (45 mg).

Stage 4: (R) -4 - ((1-methylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

(R) -4- (1-methylpiperidin-3-ylmethoxy) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole- 6-carbonitrile (45 mg, 0.1 mmol) was dissolved in 1,4-dioxane (0.2 ml) and then treated with 48% HBr _(aq) (0.2 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH 8-9 by adding dropwise concentrated hydrochloric acid to give a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml), and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound, as a pale yellow precipitate (26 mg, 70% in two stages). ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.7, 1H), 8.54 (d, J = 5.7, 1H), 8.44 (s, 1H), 7.04 (d, J = 5.8, 1H), 4.28 (d, J = 6.4, 2H), 2.88 (m, 1H), 2.65 (m, 1H), 2.27 (m, 1H), 2.19 (s, 3H), 1.97 (m, 2H), 1.83 (m, 1H), 1.74-1.66 (m, 1H), 1.59 (m, 1H), 1.28-1.18 (m, 1H), NH signal was not observed. LCMS (Method D): R _T = 7.182 min, M + H ⁺ = 322.1.

EXAMPLE 30

(R) -4- (4-methylmorpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (R) -t-butyl 2- (hydroxymethyl) morpholine-4-carboxylate. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.8, 1H), 8.54 (d, J = 5.7, 1H), 8.46 (d, J = 0.8, 1H), 7.03 (d, J = 5.8, 1H), 4.39 (d, J = 4.8, 2H), 4.11-4.00 (m, 1H), 3.92 - 3.84 (m, 1H), 3.64 (m, 1H), 2.90 (m, 1H), 2.66 (m, 1H), 2.24 (s, 3H), 2.11-1.99 (m, 2H), no NH signal was observed LCMS (Method D): R _T = 6.372 min, M + H ⁺ = 324.0.

EXAMPLE 31

(R) -4- (1-ethylpyrrolidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (R) -tert-butyl 3-hydroxypyrrolidine-1-carboxylate and acetaldehyde. ¹ H NMR (400 MHz, d _6- DMSO) 612.75 (8, 1H), 8.97 (d, J = 0.9, 1H), 8.53 (d, J = 5.7, 1H), 8.50 (d, J = 0.9, 1H ), 6.96 (d, J = 5.8, 1H), 5.25 (m, 1H), 2.99 (m, 1H), 2.89 (m, 1H), 2.83 (m, 1H), 2.57-2.37 (m, 4H), 2.15-2.05 (m, 1H), 1.07 (t, J = 7.2, 3H). LCMS (Method E): R _T = 3.868 min, M + H ⁺ = 308.1.

EXAMPLE 32

(S) -4 - ((1-ethylpyrrolidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -tert-butyl 2- (hydroxymethyl) pyrrolidine-1-carboxylate and acetaldehyde. ¹ H NMR (400 MHz, d _6- DMSO) 6 12.76 (s, 1H), 8.97 (d, J = 0.9, 1H), 8.54 (d, J = 5.7, 1H), 8.42 (d, J = 0.9, 1H), 7.06 (d, J = 5.8, 1H), 4.32 (m, 1H), 4.24-4.13 (m, 1H), 3.10 (m, 1H), 3.07-2.94 (m, 2H), 2.47-2.41 ( m, 1H), 2.29 (m, 1H), 2.14-2.00 (m, 1H), 1.83-1.72 (m, 3H), 1.05 (m, 3H). LCMS (Method E): R _T = 3.933 min, M + H ⁺ = 322.1. LCMS (Method D): R ^T = 7.696 min, M + H ′ = 334.1.

EXAMPLE 33

(S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-4- il) piperidin-3-ylcarbamate

A mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (100 mg, 0.3 mmol) and (5) - tert-butylpiperidin-3-ylcarbamate (167 mg, 0.9 mmol) in N, N-dimethylacetamide (1.3 ml) was heated at 100 ° C for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 4 g, ISCO, 0-60% ethyl acetate in heptane) to give the title compound as a white precipitate, which was used in the next step without any further purification (130 mg, 90%).

EXAMPLE 34

Tert-butyl 4- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrol-4-yl) piperazin-1- carboxylate

The title compound was prepared according to the methods of the preceding example using tert-butyl piperazine-1-carboxylate and was used in the next step without any further purification.

EXAMPLE 35

(S) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole -4-yl) piperidin-3-yl (ethyl) carbamate

To a solution of (S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole- 4-yl) piperidin-3-ylcarbamate (130 mg, 0.25 mmol) in tetrahydrofuran (2 ml) was added sodium hydride as a 60% dispersion in mineral oil (20 mg, 0.5 mmol) and then iodoethane (0.06 ml, 0.75 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction was quenched with water (30 μl), diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-60% ethyl acetate in heptane) to give the title compound as a colorless oil, which used in the next step without any further purification (90 mg).

Stage 2: (S) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-4- il) piperidin-3-yl (ethyl) carbamate (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane (0.3 ml) and then treated with 48% HBr _(aq) (0.3 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml), and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound, in the form of a white precipitate (30 mg, 40% in two stages). ¹ H NMR (500 MHz, D _6- DMSO) (8.94 (s, 1H), 8.45-8.39 (m, 2H), 6.87 (d, J = 5.6, 1H), 3.71 (d, J = 11.1, 1H) , 3.51 (d, J = 12.0, 1H), 3.08-2.99 (m, 1H), 2.99-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.72-2.66 (m, 1H), 2.62 ( m, 1H), 2.01 (m, 1H), 1.93 (m, 1H), 1.78 (m, 1H), 1.37 (m, 1 H), 1.05 (t, J = 7.1, 3H), no NH signal was observed. LCMS (Method E): R _T = 2.576 min, M + H ⁺ = 321.1.

EXAMPLE 36

(R) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (R) -tert-butylpiperidin-3-ylcarbamate. ¹ H NMR (500 MHz, d ₆ -DMSO) (8.94 (s, 1H), 8.43 (d, J = 5.6, 1H), -8.41 (s, 1H), 6.87 (d, J = 5.6, 1H), 3.71 (d, J = 10.9, 1H), 3.51 (d, J = 11.7, 1H), 3.08-2.99 (m, 1H), 2.94 (m, 1H), 2.80-2.73 (m, 1H), 2.69 (m , 1 H), 2.62 (m, 1H), 2.00 (m, 1H), 1.92 (m, 1H), 1.78 (m, 1H), 1.37 (m, 1H), 1.06 (t, J = 7.1, 3H) , NH signal was not observed LCMS (Method D): R _T = 5.537 min, M + H ⁺ = 321.1.

EXAMPLE 37

(S) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-6- carbonitrile

Stage 1: 4- (piperazin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

Solution tert-butyl 4- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-4-yl) piperazine -1-carboxylate (440 mg, 0.8 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (0.6 ml, 8.0 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium carbonate (10 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-10% dichloromethane in methanol) to give the title compound as a white foam, which was used in the next step without any further purification (200 mg, 60%).

Stage 2: (S) -tert-butyl 2- (2- (4- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-4-yl) piperazin-1-yl) -2-oxoethyl) pyrrolidin-1-carboxylate

Mixture of 4- (piperazin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (100 mg, 0.2 mmol), (S) -2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) acetic acid (220 mg, 1.0 mmol), 1-hydroxybenzotriazole (50 mg, 0.4 mmol), (3- dimethylaminopropyl) ethyl carbodiimide hydrochloride (70 mg, 0.4 mmol) and triethylamine (0.1 ml, 0.7 mmol) in dichloromethane (2.5 ml) were stirred at ambient temperature overnight. The reaction mixture was diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 4 g, ISCO, 0-70% ethyl acetate in heptane) to give the title compound as a white foam which was used in the next step without any further purification (140 mg).

Stage 3: (S) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H- [2,3-b; 4 ', 3'-d] pyrrole- 6-carbonitrile

(S) -tert-butyl 2- (2- (4- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3-d ] pyrrol-4-yl) piperazin-1-yl) -2-oxoethyl) pyrrolidin-1-carboxylate (140 mg, 0.18 mmol) was dissolved in 1,4-dioxane (0.4 ml) and then treated with 48% HBr _(aq) (0.4 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (54 mg, 60% in two stages). ¹ H NMR (500 MHz, d ₆ -DMSO) (8.97 (s, 1H), 8.48 (d, J = 5.4, 1 H), 8.23 (s, 1 H), 6.91 (d, J = 5.6, 1 H ), 3.82 (m, J = 4.6, 4H), 3.41-3.34 (m, 4H), 2.94 -2.85 (m, 1H), 2.80 (m, 1H), 2.65-2.53 (m, 3H), 1.94-1.82 (m, 1H), 1.79-1.59 (m, 2H), 1.34 (m, 1H), NH signal was not observed. LCMS (Method D): R _T = 5.419 min, M + H ⁺ = 390.2.

EXAMPLE 38

(R) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (R) -2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) acetic acid. ¹ H NMR (500 MHz, d ₆ -DMSO) (8.97 (s, 1H), 8.47 (d, J = 5.5, 1H), 8.23 (s, 1H), 6.91 (d, J = 5.6, 1H), 3.82 (m, 4H), 3.34 (m, 4H), 2.87 (m, 1H), 2.76 (m, 1H), 2.60-2.52 (m, 3H), 1.86 (m, 1H), 1.75-1.58 (m, 2H ), 1.31 (m, 1H), no NH signal was observed LCMS (Method D): R _T = 5.486 min, M + H ⁺ = 390.2.

EXAMPLE 39

bis-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile

Stage 1: 4-hydroxy-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile (100 mg, 0.3 mmol) in tetrahydrofuran (1.8 ml ) Sodium hydride was added as a 60% dispersion in mineral oil (22 mg, 0.56 mmol) and then a few drops of water. The reaction mixture was stirred at ambient temperature for 5 minutes and then at 40 ° C for 2 hours. The mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 5-100% ethyl acetate in heptane) to give the title compound as a pale yellow oil, which was used in the next step without any further purification (70 mg).

Stage 2: bis- (3S, 4R) -tert-butyl 3- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3' -d] pyrrole-4-yloxy) -4-fluoropiperidin-1-carboxylate

A mixture of 4-hydroxy-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (70 mg, 0.2 mmol), trans- (3S, 4S) tert-butyl 4-fluoro-3-hydroxypiperidin-1-carboxylate (68 mg, 0.3 mmol) and triphenylphosphine (135 mg, 0.5 mmol) in tetrahydrofuran (1.7 ml) were stirred at ambient temperature. After 3 minutes, the reaction mixture was treated with diisopropyl azodicarboxylate (0.1 ml, 0.5 mmol) and heated at 50 ° C for 4 hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-70% ethyl acetate in heptane) to give the title compound as a pale yellow precipitate which was used in the next step without any further purification (55 mg).

Stage 3: yis-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

cis- (3S, 4R) -tert-butyl 3- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-4-yloxy) -4-fluoropiperidin-1-carboxylate (55 mg, 0.1 mmol) was dissolved in 1,4-dioxane (0.2 ml) and then treated with 48% HBr _(aq) (0.2 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (10 mg, 12% in three stages). ¹ H NMR (400 MHz, D _6- DMSO) (12.90-12.68 (s, 1H), 8.98 (d, J = 0.9, 1H), 8.54 (d, J = 5.8, 1H), 8.48 (s, 1H) , 7.16 (d, J = 5.9, 1H), 5.13 (m, 2H), 3.20-3.10 (m, 1H), 2.98 (m, 1H), 2.74-2.62 (m, 2H), 2.06 (m, 1H) , 1.93 (m, 1H), no piperidine NH was observed LCMS (Method F): R _T = 1.47 min, M + H ′ = 312.15.

EXAMPLE 40

3-bromo-4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b: 4 ', 3'-d] pyrrole-6-carbonitrile

Mixture of 4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (50 mg, 0.16 mmol), acetate sodium (26 mg, 0.3 mmol) and bromine (32 μl, 0.6 mmol) in acetic acid (1 ml) were stirred at ambient temperature for 10 minutes. The reaction mixture was diluted with water (1 ml) and alkalized to pH ~ 8 by adding dropwise 6N. sodium hydroxide to obtain a yellow precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (25 mg, 38%). ¹ H NMR (500 MHz, d ₆ -DMSO) (9.02 (d, J = 8.7, 1H), 8.70 (d, J = 9.9, 1H), 8.43 (s, 1H), 4.21 (s, 2H), 2.81 (m, 2H), 2.62 (m, 2H), 2.45 (s, 3H), 1.97 (m, 2H), 1.68 (m, 2H), 1.30 (s, 3H), NH signal was not observed. ): R _T = 8.660 min, M + H ⁺ = 414.0 / 416.0.

EXAMPLE 41

3-chloro-4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Mixture of 4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (50 mg, 0.16 mmol), N -chlorosuccinimide (60 mg, 0.45 mmol) in acetonitrile (0.8 ml) and isopropyl alcohol (0.23 ml) was stirred at 40 ° C for 16 hours. The reaction mixture was diluted with acetonitrile (1 ml) and the precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min ] to give the title compound as a white precipitate (12 mg, 20%). ¹ H NMR (500 MHz, d _6- DMSO) (9.04 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 4.28 (s, 2H), 2.51-2.46 (m, 2H), 2.28 (m, 2H), 2.22 (s, 3H), 1.82 (m, 2H), 1.51 (m, 2H), 1.19 (s, 3H), NH signal was not observed. LCMS (Method D): R _T = 8.445 min, M + H ⁺ = 370.1.

EXAMPLE 42

1- [4- (3-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-4-yl) piperazin-1-yl] -2- (R) pyrrolidin- 2-yl ethanone

The title compound was prepared according to the methods of the preceding example using 1- [4- (9H-dipyrido [2,3b; 4 ', 3'-d] pyrrol-4-yl) piperazin-1-yl ] -2- (R) -pyrrolidin-2-yl-ethanone. ¹ H NMR (400 MHz, CD ₃ OD): 9.17 (s, 1H), 8.76 (d, 1H, J = 6.36 Hz), 8.68 (s, 1H), 8.60 (d, 1H, J = 6.37 Hz), 3.98-3.96 (m, 3H), 3.89 (t, 2H, J = 4.92 Hz), 3.77-3.75 (m, 2H), 3.67 (t, 2H, J = 5.15 Hz), 3.33-3.32 (m, 2H) , 3.17 (dd, 1H, J = 17.53, 3.65 Hz), 2.97 (dd, 1H, J = 17.52, 10.07 Hz), 2.30-2.29 (m, 1H), 2.13-2.13 (m, 1H), 2.02-2.01 (m, 1H), 1.81-1.80 (m; 1H). LCMS (Method A): R _T = 1.84 min, M + H ⁺ = 399.

EXAMPLE 43

(S) -3-chloro-4- (3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (S) -4- (3-hydroxypyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d ] pyrrole-6-carbonitrile

A mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (130 mg, 0.36 mmol) and (S) - 3-hydroxypyrrolidinol (91 mg, 1.04 mmol) in N, N-dimethylacetamide (1.6 ml) was heated at 100 ° C for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-100% ethyl acetate in heptane) to give the title compound as a white wax, which used in the next step without further purification (140 mg, 94%).

Stage 2: (S) -3-chloro-4- (3-hydroxypyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Mixture of (S) -4- (3-hydroxypyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole -6-carbonitrile (140 mg, 0.34 mmol) and N-chlorosuccinimide (137 mg, 1.02 mmol) in acetonitrile (1.3 ml) and isopropyl alcohol (0.4 ml) were stirred at 35 ° C for 5 hours. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate (1 ml), diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-50% ethyl acetate in heptane) to give the title compound as a pale yellow precipitate, which was used in the next step without any further purification (100 mg).

Stage 3: (S) -3-chloro-4- (3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

(S) -3-chloro-4- (3-hydroxypyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'- d] pyrrole-6-carbonitrile (100 mg, 0.2 mmol) was dissolved in 1,4-dioxane (0.3 ml) and then treated with 48% HBr _(aq) (0.3 ml) and heated at 55 ° C for 20 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a pale gray-white precipitate (40 mg, 60% in two stages). ¹ H NMR (400 MHz, d ₆ -DMSO) (8.95 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 5.27 (s, 1H), 4.54 (s, 1H), 3.88 ( m, 1H), 3.78 (dd, J = 10.5, 4.6, 1H), 3.66 (td, J = 9.0, 4.5, 1H), 3.50 (d, J = 10.3, 1H), 2.34-2.19 (m, 1H) , 2.06-1.95 (m, 1H), NH signals were not observed LCMS (Method D): R _T = 8.57 min, M + H ⁺ = 314.0.

EXAMPLE 44

3-chloro-4 - ((3S, 4S) -3,4-dihydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (3S, 4S) -pyrrolidin-3,4-diol. ¹ H NMR (400 MHz, d _6- DMSO) 5 12.85 (s, 1H), 8.95 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 5.42 (d, J = 3.1, 2H ), 4.20 (s, 2H), 4.00 (dd, J = 10.5, 4.2, 2H), 3.50 (d, J = 10.8, 2H). LCMS (Method D): R _T = 6.847 min, M + H ⁺ = 330.0.

EXAMPLE 45

3-chloro-4 - ((3R, 4R) -3,4-dihydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b: 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (3R, 4R) -pyrrolidin-3,4-diol. ¹ H NMR (400 MHz, d ₆ -DMSO) (12.88 (s, 1H), 8.95 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 5.44 (d, J = 3.1, 2H ), 4.20 (s, 2H), 4.00 (dd, J = 10.6, 3.8, 2H), 3.50 (d, J = 10.9, 2H). LCMS (Method D): R _T = 6.902 min, M + H ⁺ = 330.0

EXAMPLE 46

3-chloro-4- (3-hydroxyazetidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using azetidin-3-ol. ¹ H NMR (400 MHz, d _6- DMSO) (12.63 (s, 1H), 8.84 (s, 1H), 8.48 (s, 1H), 8.20 (s, 1H), 5.75 (d, J = 5.2, 1H ), 5.05-4.88 (m, 2H), 4.53 (d, J = 15.7, 1H), 4.41 (dd, J = 9.0, 4.3, 2H). LCMS (Method D): R _T = 6.880 min, M + H ⁺ = 300.0.

EXAMPLE 47

(5) -3-chloro-4- (3-hydroxy-3-methylpyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -3-methylpyrrolidin-3-ol. ¹ H NMR (400 MHz, d ₆ -DMSO) (12.88 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 5.14 (s, 1H), 3.95 ( dd, J = 17.5, 7.9, 1H), 3.71-3.65 (m, 1H), 3.63 (d, J = 10.1, 1H), 3.52 (d, J = 9.9, 1H), 2.15-2.01 (m, 2H) , 1.44 (s, 3H). LCMS (Method G): R _T = 5.81 min, M + H ⁺ = 328.12.

EXAMPLE 48

(R) -3-chloro-4- (3-hydroxy-3-methylpyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (R) -3-methylpyrrolidin-3-ol. ¹ H NMR (400 MHz, d _6- DMSO) (12.88 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 5.14 (s, 1 H), 3.95 (dd, J = 17.5, 7.9, 1H), 3.71-3.65 (m, 1H), 3.63 (d, J = 10.1, 1H), 3.52 (d, J = 10.0, 1H), 2.15-2.02 (m, 2H ), 1.44 (s, 3H). LCMS (Method G): R _T = 5.82 min, M + H ⁺ = 328.12.

EXAMPLE 49

(S) -3-chloro-4- (3-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -piperidin-3-ol. Proton NMR of this compound showed a mixture of two isomers. ¹ H NMR (400 MHz, d _6- DMSO) (12.93 (s, 1H), 9.27 (s, 0.2H), 8.97 (s, 0.8H), 8.73 (s, 0.2H), 8.68 (s, 0.8H ), 8.57 (s, 0.2H), 8.50 (s, 0.8H), 4.99 (d, J = 3.8, 1H), 3.82 (m, 1H), 3.56 (m, 1H), 3.42 (m, 2H), 3.26 (m, 1H), 2.06 - 1.89 (m, 2H), 1.76 (m, 1H), 1.54 (m, 1H). LCMS (Method D): R _T = 10.265 min, M + H ⁺ = 328.0.

EXAMPLE 50

(S) -3-chloro-4- (3-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (R) -piperidin-3-ol. Proton NMR of this compound showed a mixture of two isomers. ¹ H NMR (400 MHz, d _6- DMSO) (13.29-12.45 (s, 1H), 9.27 (s, 0.4H), 8.97 (s, 0.6H), 8.73 (s, 0.4H), 8.67 (s, 0.6H), 8.58 (s, 0.4H), 8.49 (s, 0.6H), 4.99 (s, 1H), 3.86 (m, 1H), 3.55 (m, 1H), 3.43 (m, 2H), 3.26 ( m, 1H), 2.06-1.88 (m, 2H), 1.76 (m, 1H), 1.62-1.46 (m, 1H). LCMS (Method D): R _T = 10.259 min, M + H ⁺ = 328.0.

EXAMPLE 51

3-chloro-4- (4-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using piperidin-4-ol. ¹ H NMR (400 MHz, d ₆ -DMSO) (12.95 (s, 1H), 8.98 (s, 1H), 8.50 (s, 2H), 4.92 (d, J = 4.2, 1H), 3.83 (d, J = 4.1, 1H), 3.60 (m, 2H), 3.49 (m, 2H), 1.99 (m, 2H), 1.69 (m, 2H). LCMS (Method D): R _T = 9.499 min, M + H ⁺ = 328.0.

EXAMPLE 52

(S) -3-chloro-4- (3-aminopyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -tert-butyl pyrrolidin-3-ylcarbamate. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.7, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 3.92 - 3.79 (m, 3H), 3.65 (m , 1H), 3.46 (m, 1H), 2.31 (m, 1H), 1.93 (m, 1H), NH signals were not observed LCMS (Method D): R _T = 6.620 min, M + H ⁺ = 313.0.

EXAMPLE 53

(S) -3-chloro-4- (3- (methylamino) pyrrolidin-1-yl) -9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -tert-butyl methyl (pyrrolidin-3-yl) carbamate. ¹ H NMR (500 MHz, d ₆ -DMSO) (8.95 (s, 1H), 8.79 (s, 1H), 8.45 (s, 1H), 3.78 (dd, J = 14.4, 8.5, 2H), 3.73-3.67 (m, 1H), 3.63 (m, 1H), 3.54 (m, 1H), 3.38 (m, 1H), 2.40 (s, 3H), 2.33-2.23 (m, 2H), 1.89 (m, 1H), No NH signals were observed LCMS (Method D): R _T = 6.863 min, M + H ⁺ = 327.0.

EXAMPLE 54

(S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrol-4-yl) pyrrolidin-3-yl (ethyl) carbamate

Stage 1: (S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrole-4 -yl) pyrrolidin-3-ylcarbamate

A mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (590 mg, 1.6 mmol) and (S) - tert-butyl pyrrolidin-3-ylcarbamate (918 mg, 4.9 mmol) in N, N-dimethylacetamide (7.6 ml) was heated at 100 ° C for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (40 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 12 g, ISCO, 0-90% ethyl acetate in heptane) to give the title compound as a white precipitate, which used in the next step without any further purification (530 mg, 63%).

Stage 2: (S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole -4-yl) pyrrolidin-3-yl (ethyl) carbamate

To a solution of (S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole- 4-yl) pyrrolidin-3-yl carbamate (700 mg, 1.0 mmol) in tetrahydrofuran (11 ml) was added sodium hydride as a 60% dispersion in mineral oil (140 mg, 3.4 mmol) and then iodoethane (0.77 ml, 9.4 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction was quenched with water (0.1 ml), diluted with ethyl acetate (100 ml) and washed with water (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-60% ethyl acetate in heptane) to give the title compound as a white precipitate, which used in the next step without any further purification (560 mg.80%).

EXAMPLE 55

(S) -3-chloro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

Stage 1: (S) -tert-butyl 1- (3-chloro-6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-, b; 4 ', 3 '-d] pyrrol-4-yl) pyrrolidin-3-yl (ethyl) carbamate

A mixture of (S) -tert-butyl 1 - (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-4 -yl) pyrrolidin-3-yl (ethyl) carbamate (100 mg, 0.2 mmol) and N-chlorosuccinimide (75 mg, 0.56 mmol) in acetonitrile (0.75 ml) and isopropyl alcohol (0.2 ml) was stirred at 35 ° C for 5 o'clock. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate, diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-50% ethyl acetate in heptane) to give the title compound as a pale yellow foam which was used in the next step without any further purification (100 mg).

Stage 2: (S) -3-chloro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(S) -tert-butyl 1- (3-chloro-6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-4-yl) pyrrolidin-3-yl (ethyl) carbamate (100 mg, 0.18 mmol) was dissolved in 1,4-dioxane (0.3 ml) and then treated with 48% HBr _(aq) (0.3 ml) and heated at 55 ° C for 20 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml), and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound, in the form of a pale yellow precipitate (40 mg, 60% in two stages). ¹ H NMR (500 MHz, d _6- DMSO) (8.96 (s, 1H), 8.70 (s, 1H), 8.46 (s, 1H), 3.79 (m, 1H), 3.73 (m, 1H), 3.66- 3.60 (m, 1H), 3.55-3.47 (m, 2H), 2.65 (m, 2H), 2.26 (m, 1H), 1.98-1.88 (m, 1H), 1.13 (t, J = 7.1, 3H), No NH signal was observed LCMS (Method D): R _T = 7.287 min, M + H ⁺ = 341.0.

EXAMPLE 56

(S) -3-bromo-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (S) -tert-butyl 1- (3-bromo-6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3' -d] pyrrol-4-yl) pyrrolidin-3-yl (ethyl) carbamate

A mixture of (5) -tert-butyl 1 - (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-4 -yl) pyrrolidin-3-yl (ethyl) carbamate (125 mg, 0.23 mmol), sodium acetate (38 mg, 0.46 mmol) and bromine (36 μl, 0.7 mmol) in acetic acid (1 ml) were stirred at ambient temperature within 1 minute. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-50% ethyl acetate in heptane) to give the title compound as a pale yellow oil, which was used in the next step without any further purification (65 mg).

Stage 2: (S) -3-bromo-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(S) -tert-butyl 1- (3-bromo-6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-4-yl) pyrrolidin-3-yl (ethyl) carbamate (65 mg, 0.1 mmol) was dissolved in 1,4-dioxane (0.3 ml) and then treated with 48% HBr _(aq) (0.3 ml) and heated at 55 ° C for 20 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a pale yellow precipitate (23 mg, 26% in two stages). ¹ H NMR (500 MHz, d ₆ -DMSO) (8.97 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 3.79-3.73 (m, 2H), 3.62-3.51 (m, 3H ), 3.43 (m, 1H), 2.72-2.59 (m, 2H), 2.26 (m, 1H), 1.97 (m, 1H), 1.14 (t, J = 7.1, 3H), no NH signal was observed. Method D): R _T = 7.535 min, M + H ⁺ = 385.0 / 387.0.

EXAMPLE 57

(S) -3-fluoro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (S) -tert-butyl 1- (3-fluoro-6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3' -d] pyrrol-4-yl) pyrrolidin-3-yl (ethyl) carbamate

Mixture of (S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-4 -yl) pyrrolidin-3-yl (ethyl) carbamate (290 mg, 0.54 mmol) and SelectfluOr ((957 mg, 2.7 mmol) in acetonitrile (4.5 ml) were stirred at 0 ° C for 5 minutes. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate, diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-50% ethyl acetate in heptane) to irradiation of the title compound as a pale yellow foam, which was used in the next step without any further purification (120 mg).

Stage 2: (S) -3-fluoro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(S) -tert-butyl 1- (3-fluoro-6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-4-yl) pyrrolidin-3-yl (ethyl) carbamate (120 mg, 0.2 mmol) was dissolved in 1,4-dioxane (0.3 ml) and then treated with 48% HBr _(aq) (0.3 ml) and heated at 55 ° C for 20 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a pale yellow precipitate (50 mg, 30% in two stages). ¹ H NMR (500 MHz, d ₆ -DMSO) (8.87 (s, 1H), 8.49 (s, 1H), 8.32 (d, J = 7.0, 1H), 3.91-3.84 (m, 1H), 3.83-3.76 (m, 2H), 3.58 (m, 1H), 3.43 (m, 1H), 2.67-2.56 (m, 2H), 2.19 (m, 1H), 1.83 (m, 1H), 1.07 (t, J = 7.1 , 3H), NH signal was not observed LCMS (Method D): R _T = 6.033 min, M + H ⁺ = 325.1.

EXAMPLE 58

4 - ((3-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1; 4 - ((3-methylpiperidin-3-yloxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of 3-methylpiperidin-3-ol (99 mg, 0.86 mmol) in tetrahydrofuran (3.2 ml) was added sodium hydride as a 60% dispersion in mineral oil (35 mg, 0.86 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6- carbonitrile (141 mg, 0.39 mmol) was added at a time and the reaction mixture was stirred at this temperature for 10 minutes before being heated at 40 ° C. for 5 hours. The mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 40 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as an orange precipitate which was used in the next step without any further purification (52 mg, 30%).

Stage 2: 4 - ((3-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

4 - ((3-methylpiperidin-3-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (52 mg, 0.12 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 10 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in a grayish-white precipitate (11 mg, 31%). ¹ H NMR (400 MHz, d ₆ -DMSO) 6 12.18 (s, 1H), 8.70 (d, J = 0.9, 1H), 8.51 (d, J = 0.9, 1H), 8.27 (d, J = 9.0, 1H), 6.90 (d, J = 9.1, 1H), 4.48 (s, 1H), 3.93-3.84 (m, 1H), 3.64 (d, J = 13.0, 1H), 3.55-3.40 (m, 2H), 1.79 (m, 1H), 1.67-1.57 (m, 2H), 1.52 (m, 1H), 1.13 (s, 3H). LCMS (Method E): R _T = 3.73 min, M + H ⁺ = 308.2.

EXAMPLE 59

4- (3- (dimethylamino) -2,2-dimethylpropoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example with 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 -carbonitrile using 3- (dimethylamino) -2,2-dimethylpropan-1-ol. ¹ H NMR (400 MHz, d ₆ -DMSO) (12.78 (s, 1H), 8.99 (d, J = 0.8, 1H), 8.55 (d, J = 5.7, 1H), 8.39 (d, J = 0.8, 1H), 7.06 (d, J = 5.8, 1H), 4.12 (s, 2H), 2.41 (s, 2H), 2.24 (s, 6H), 1.10 (s, 6H). LCMS (Method E): R _T = 3.58 min, M + H ⁺ = 324.1.

EXAMPLE 60

(S) -4- (piperidin-3-yloxy) -9H-dipyrido [2.3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -piperidin-3-ol. ¹ H NMR (400 MHz, d _6- DMSO) 6 8.96 (d, J = 0.9, 1H), 8.57 (d, J = 0.9, 1H), 8.52 (d, J = 5.8, 1H), 7.08 (d, J = 5.9, 1H), 4.84-4.74 (m, 1H), 3.22 (m, 1H), 2.93 (m, 1H), 2.89-2.78 (m, 1H), 2.77-2.64 (m, 1H), 2.12 ( m, 1H), 1.94-1.85 (m, 1H), 1.85-1.73 (m, 1H), 1.57 (m, 1H). LCMS (Method E): R _T = 6.98 min, M + H ⁺ = 294.1.

EXAMPLE 61

4 - ((4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (4-methylpiperidin-4-yl) methanol. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.99 (s, 1H), 8.56 (d, J = 5.6, 1H), 8.41 (s, 1H), 8.40 (s, 1 H), 7.10 (d, J = 5.8, 1H), 4.17 (s, 2H), 3.08-2.90 (m, 4H), 1.87-1.71 (m, 2H), 1.59 (m, 2H), 1.24 (s, 3H). ): R _T = 7.78 min, M + H ⁺ = 322.1.

EXAMPLE 62

4- (1- (3-fluoropropyl) -4-methylpiperidin-4-yl) methoxy1-9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile f

Stage 1: tert-butyl 1-benzyl-4-methylpiperidin-4-carboxylate

To a solution of N, N-diisopropylamine (3.1 ml, 22 mmol) in tetrahydrofuran (60 ml) cooled to -78 ° C was added n-butyllithium (2.5 N solution in hexanes, 8.9 ml, 22 mmol) dropwise over 5 minutes and the mixture was stirred for 30 minutes at -78 ° C. A solution of tert-butyl 1-benzylpiperidin-4-carboxylate (5.0 g, 20 mmol) in tetrahydrofuran (40 ml) was then added dropwise to the reaction mixture over 10 minutes, and the temperature was maintained at −78 ° C. for 30 minutes before methyl iodide (1.3 ml, 21 mmol) was added at a time. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction was quenched with water (100 ml) and diluted with ethyl acetate (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x50 ml). The combined organic parts were dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 40 g, ISCO, 0-100% ethyl acetate in heptanes) to give the title compound as a colorless oil, which used in the next step without any further purification (5.3 g, 90%).

Stage 2: (1-benzyl-4-methylpiperidin-4-yl) methanol

A solution of tert-butyl 1-benzyl-4-methylpiperidin-4-carboxylate (4.7 g, 18 mmol) in diethyl ether (47 ml) was cooled to 0 ° C and lithium tetrahydroaluminate (990 mg, 25 mmol) was added in portions. The reaction mixture was warmed to ambient temperature and gently stirred for 1 hour. The mixture was then cooled to 0 ° C. and 1N was added dropwise to the reaction mixture. sodium hydroxide solution (6 ml) to obtain a white precipitate. The mixture was filtered and the precipitate was washed with ethyl acetate (100 ml). The combined filtrate was separated and the aqueous portion was extracted with ethyl acetate (2 × 50 ml). The combined organics were dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 80 g, ISCO, 45-100% ethyl acetate in heptane) to give the title compound as a white precipitate, which used in the next step without any further purification (2.7 g, 67%).

Stage 3: (4-methylpiperidin-4-yl) methanol

To a solution of (1-benzyl-4-methylpiperidin-4-yl) methanol (2.7 g, 12 mmol) in methanol (34 ml) was added ammonium formate (8.6 g, 135 mmol) and then palladium on carbon (10% w / w) mass., 3.6 g, 1.7 mmol). The reaction mixture was stirred for 18 hours in a flask with hydrogen, then degassed, purged with nitrogen, and filtered through a pad of celite. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography (silica gel, 40 g, ISCO, 0-20% methanol in dichloromethane) to give the title compound as a colorless oil, which was used in the next step without any additional purification (1.2 g, 76%).

Stage 4: 4 - ((4-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6- carbonitrile

To a solution of (4-methylpiperidin-4-yl) methanol (989 mg, 7.7 mmol) in 1,4-dioxane (18 ml) and N, N-dimethylformamide (12 ml) was added sodium hydride as a 60% dispersion in mineral oil (670 mg, 28 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 was added β-carbonitrile (428 mg, 1.2 mmol) at a time, and the reaction mixture was heated at 40 ° C. for 18 hours. The cooled reaction mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 40 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as grayish - white precipitate, which was used in the next step without any further purification (300 mg, 56%).

Step 5: 4- (1- (3-fluoropropyl) -4-methylpiperidin-4-yl) methoxy] -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3' -d] pyrrole-6-carbonitrile

To a solution of 4 - ((4-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (77 mg, 0.17 mmol) in 1,4-dioxane (2.6 ml) and N, N-dimethylformamide (0.5 ml) was added sodium hydride as a 60% dispersion in mineral oil (20 mg, 0.85 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 3-fluoropropyl trifluoromethasulfonate (46 mg, 0.22 mmol) was added at a time, and the reaction mixture was heated at 40 ° C. for 18 hours. The cooled reaction mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 1-15% methanol in dichloromethane) to give the title compound as an oil, which used in the next step without any further purification (59 mg, 68%).

Stage 6: 4- (1- (3-fluoropropyl) -4-methylpiperidin-4-yl) methoxy] -9H-dipyrido [2,3-b, 4 ', 3'-d] pyrrole-6-carbonitrile

4- (1- (3-fluoropropyl) -4-methylpiperidin-4-yl) methoxy] -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (59 mg, 0.11 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound ( 17 mg, 38%). ¹ H NMR (500 MHz, d ₆ -DMSO) (8.98 (d, J = 0.9, 1H), 8.54 (d, J = 5.7, 1H), 8.35 (d, J = 0.9, 1H), 7.06 (d, J = 5.8, 1H), 4.54 (t, J = 6.1, 1H), 4.45 (t, J = 6.0, 1H), 4.13 (s, 2H), 2.62-2.55 (m, 2H), 2.42 (t, J = 7.1, 2H), 2.33 (m, 2H), 1.86 (m, 2H), 1.78 (m, 2H), 1.54 (m, 2H), 1.20 (s, 3H). LCMS (Method D): R _T = 7.43 min, M + H ′ = 382.2.

EXAMPLE 63

4 - ((1- (2-hydroxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using 2-iodoethyl trifluoromethasulfonate. ¹ H NMR (500 MHz, d ₆ -DMSO) (8.99 (s, 1H), 8.55 (d, J = 5.7, 1H), 8.45 (s, 2H), 8.35 (s, 1H), 7.07 (d, J = 5.8, 1H), 4.15 (s, 2H), 3.51 (t, J = 6.4, 2H), 2.61 (m, 2H), 2.44 (t, J = 6.4, 2H), 2.38 (m, 2H), 1.73 (m, 2H), 1.56 (m, 2H), 1.19 (s, 3H). LCMS (Method D): R _T = 6.66 min, M + H ′ = 366.0.

EXAMPLE 64

4 - ((1- (2-methoxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: 4 - ((1- (2-methoxyethyl) -4-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3 '-d] pyrrole-6-carbonitrile

To a solution of 4 - ((4-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (74 mg, 0.16 mmol) in acetonitrile (1.7 ml) was added sodium iodide (26 mg, 0.17 mmol) and 1-bromo-2-methoxyethane (16 μp, 0.17 mmol). The reaction mixture was heated at 50 ° C for 18 hours. The mixture was allowed to cool and then 1-bromo-2-methoxyethane (65 μl, 0.69 mmol) and N, N-diisopropylethylamine (29 μl, 0.16 mmol) were added, after which the mixture was heated at 50 ° C for an additional 4 hours. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate (10 ml), water (20 ml) and dichloromethane (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as an oil, which used in the next step without any further purification (36 mg, 43%).

Stage 2: 4 - ((1- (2-methoxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

4 - ((1- (2-methoxyethyl) -4-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d ] pyrrole-6-carbonitrile (36 mg, 0.07 mmol) was dissolved in 1,4-dioxane (0.3 ml) and then treated with 48% HBr _(aq) (0.3 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (1 ml), and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound, as a white precipitate (7 mg, 25%). ¹ H NMR (500 MHz, d ₆ -DMSO) (8.99 (s, 1H), 8.55 (d, J = 5.7, 1H), 8.35 (s, 1H), 8.31 (s, 1H), 7.08 (d, J = 5.8, 1H), 4.13 (s, 2H), 3.44 (t, J = 6.4, 2H), 3.24 (s, 3H), 2.66 - 2.58 (m, 2H), 2.52 (t, J = 6.4, 2H) , 2.39 (m, 2H), 1.74 (m, 2H), 1.53 (m, 2H), 1.18 (s, 3H). LCMS (Method G): R _T = 3.92 min, M + H ⁺ = 380.0.

EXAMPLE 65

4 - ((1-ethyl-4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

Stage 1: 4 - ((1-ethyl-4-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of 4 - ((4-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (75 mg, 0.17 mmol) in dichloromethane (1.1 ml) was added acetaldehyde (14 μl, 0.25 mmol) and sodium triacetoborohydride (53 mg, 0.25 mmol), the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 ml) and dichloromethane (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-20% methanol in dichloromethane) to give the title compound as a yellow precipitate, which was used in the next step without any further purification (58 mg, 73%).

Stage 2: 4 - ((1-ethyl-4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

4 - ((1-ethyl-4-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 β-carbonitrile (58 mg, 0.12 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (13 mg, 30%). ¹ H NMR (400 MHz, d ₆ -DMSO) (8.98 (d, J = 0.8, 1H), 8.54 (d, J = 5.7, 1H), 8.35 (d, J = 0.8, 1H), 7.06 (d, J = 5.8, 1H), 4.12 (s, 2H), 2.56 (m, 2H), 2.42-2.25 (m, 4H), 1.75 (m, 2H), 1.54 (m, 2H), 1.19 (s, 3H) 1.08-0.97 (m, 3H). LCMS (Method D): R _T = 8.49 min, M + H ⁺ = 450.1.

EXAMPLE 66

(P) -4- (1-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (R) -4- (piperidin-3-yloxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of (R) -piperidin-3-ol hydrochloride (169 mg, 1.2 mmol) in tetrahydrofuran (4.5 ml) and N, N-dimethylformamide (1 ml) was added sodium hydride as a 60% dispersion in mineral oil (200 mg, 5.0 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 was added β-carbonitrile (200 mg, 0.56 mmol) at a time, and the reaction mixture was stirred at this temperature for 10 minutes before being heated at 40 ° C. for 4 hours. The cooled reaction mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 40 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as a yellow precipitate which was used in the next step without any further purification (236 mg, 100%).

Stage 2: (R) -4- (1-methylpiperidin-3-yloxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 carbonitrile

To a solution of (R) -4- (1-methylpiperidin-3-yloxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6- carbonitrile (101 mg, 0.24 mmol) in acetonitrile (1.0 ml) and water (0.21 ml) were added formalin (20 μl, 0.71 mmol) and then sodium triacetoborohydride (101 mg, 0.48 mmol), the mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 ml) and dichloromethane (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 4 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as a white precipitate which was used in the next step without any further purification (93 mg, 89%).

Stage 3: (R) -4- (1-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(R) -4- (1-methylpiperidin-3-yloxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile ( 93 mg, 0.21 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (18 mg, 27%). ¹ H NMR (400 MHz, d ₆ -DMSO) (12.74 (s, 1H), 8.96 (d, J = 0.8, 1 H), 8.52 (d, J = 5.8, 1H), 8.46 (d, J = 0.9 , 1H), 7.10 (d, J = 5.9, 1H), 4.93-4.82 (m, 1H), 2.93 (m, 1H), 2.57-2.51 (m, 1H), 2.44 (m, 1H), 2.24 (s , 3H), 2.19 (m, 1H), 2.08 (m, 1H), 1.83 (m, 1H), 1.68 (m, 2H). LCMS (Method D): R _T = 7.08 min, M + H ′ = 308.1 .

EXAMPLE 67

4 - ((R) -1-ethylpiperidin-3-hydroxy) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile

Stage 1: (R) -4- (1-ethylpiperidin-3-yloxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 carbonitrile

To a solution of (R) -4- (piperidin-3-hydroxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile ( 84 mg, 0.20 mmol) in acetonitrile (1.0 ml) was added iodoethane (24 μl, 0.30 mmol), and the mixture was heated at 50 ° C for 18 hours. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 ml) and dichloromethane (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as a yellow oil, which was used in the next step without any further purification (46 mg, 51%).

Stage 2: (R) -4- (1-ethylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

(R) -4- (1-ethylpiperidin-3-hydroxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile ( 46 mg, 0.10 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (12 mg, 37%). ¹ H NMR (400 MHz, d ₆ -DMSO) (12.78 (s, 1H), 8.96 (d, J = 0.9, 1H), 8.54-8.51 (d, J = 5.9, 1H), 8.50 (d, J = 0.9, 1H), 7.11 (d, J = 5.9, 1H), 4.93-4.83 (m, 1H), 2.98 (d, J = 8.9, 1H), 2.61 (m, 1H), 2.52 (m, 2H), 2.44 (q, J = 7.2, 2H), 2.26 (t, J = 8.8, 1H), 2.07 (m, 1H), 1.86-1.75 (m, 1H), 1.66 (m, 2H), 1.04 (t, J = 7.1, 3H). LCMS (Method E): R _T = 7.33 min, M + H ⁺ = 322.1.

EXAMPLE 68

(R) -4- (1- (2-hydroxyethyl) piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using 2-iodoethanol. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.95 (d, J = 0.8, 1H), 8.50 (d, J = 5.8, 1H), 8.47 (d, J = 0.8, 1H), 7.06 (d, J = 5.9, 1 H), 4.84 (m, 1H), 4.37 (s, 1H), 3.53 (t, J = 6.2, 2H), 3.08 (m, 1H), 2.67 (m, 1H), 2.54 (m , 3H), 2.32 (m, 1H), 2.09 (m, 1H), 1.85-1.73 (m, 1H), 1.73-1.55 (m, 2H). LCMS (Method G): R _T = 3.06 min, M + H ⁺ = 338.1.

EXAMPLE 69

(R) -4- (1- (2-methoxyethyl) piperidin-3-hydroxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using 1-bromo-2-methoxyethane. ¹ H NMR (400 MHz, d ₆ -DMSO) (12.73 (s, 1H), 8.97 (s, 1H), 8.52 (d, J = 5.6, 1H), 8.50 (s, 1H), 7.10 (d, J = 5.8, 1H), 4.87 (s, 1H), 3.48 (m, 2H), 3.24 (s, 3H), 3.00 (m, 1H), 2.65 (m, 3H), 2.38 (m, 1H), 2.04 ( m, 1H), 1.85-1.56 (m, 3H). LCMS (Method D): R _T = 7.09 min, M + H ⁺ = 352.1.

EXAMPLE 70

4 - ((4-ethyl-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

Stage 1: (4-ethyl-1-methylpiperidin-4-yl) methanol

To a mixed suspension of di-tert-butyl 4-ethylpiperidin-1,4-dicarboxylate (1.1 g, 3.7 mmol) in tetrahydrofuran (13 ml) was added lithium tetrahydroaluminate (1.0 N solution in tetrahydrofuran, 15 ml, 15 mmol), and the mixture stirred at ambient temperature for 6 hours. The mixture was diluted with 1N. sodium hydroxide solution (5 ml), was filtered through Whatman filter paper, and the precipitate was washed with ethyl acetate (50 ml). The combined filtrate was separated and the organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white precipitate, which was used in the next step without any further purification (506 mg, 57%).

Stage 2: 4 - ((4-ethyl-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of (4-ethyl-1-methylpiperidin-4-yl) methanol (223 mg, 1.4 mmol) in tetrahydrofuran (3.2 ml) was added sodium hydride as a 60% dispersion in mineral oil (57 mg, 1.4 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before adding 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (150 mg, 0.42 mmol) at a time, and the reaction mixture was stirred at this temperature for 10 minutes, then heated at 40 ° C. for 4 hours. The mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-10% methanol in dichloromethane) to give the title compound as a white foam, which was used in the next step without any further purification (152 mg, 76%).

Stage 3: 4 - ((4-ethyl-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

4 - ((4-ethyl-1-methylpiperidin-4-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 β-carbonitrile (152 mg, 0.32 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (44 mg, 40%). ¹ H NMR (500 MHz, d ₆ -DMSO) (8.98 (s, 1H), 8.55 (d, J = 5.7, 1H), 8.32 (s, 1H), 7.12 (d, J = 5.8, 1H), 4.18 (s, 2H), 2.37 (m, 4H), 2.19 (s, 3H), 1.75-1.68 (m, 2H), 1.67 (m, 2H), 1.65-1.57 (m, 2H), 0.86 (t, J = 7.5, 3H). LCMS (Method D): R _T = 7.36 min, M + H ⁺ = 350.2.

EXAMPLE 71

4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (1.4-dimethylpiperidin-4-yl) methanol

To a mixed suspension of 1,4-dimethylpiperidin-4-carboxylic acid hydrochloride (1.0 g, 5.17 mmol) in tetrahydrofuran (18.9 ml) was added lithium tetrahydroaluminate (1.0 N solution in tetrahydrofuran, 20.7 ml, 20.7 mmol) dropwise over 5 minutes . The reaction mixture was stirred at ambient temperature for 12 hours and then diluted with water (20 ml), alkalized to pH ~ 12 by adding sodium hydroxide tablets and then diluted with diethyl ether (100 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless oil (543 mg, 73%). ¹ H NMR (400 MHz, d ₆ -DMSO) (4.44 (m, 1H), 3.12 (d, J = 5.4, 2H), 2.50 (m, 2H), 2.39 - 2.31 (m, 2H), 2.13 (s , 3H), 2.12-2.09 (m, 1H), 1.42 (m, 2H), 1.16 (m, 2H), 0.82 (s, 3H).

Stage 2: 4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (1,4-dimethylpiperidin-4-yl) methanol. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.99 (d, J = 0.8, 1H), 8.55 (d, J = 5.7, 1H), 8.35 (d, J = 0.9, 1H), 7.08 (d, J = 5.8, 1H), 4.13 (s, 2H), 2.54-2.51 (m, 2H), 2.30 (m, 2H), 2.21 (s, 3H), 1.81-1.68 (m, 2H), 1.55 (m, 2H), 1.19 (s, 3H). LCMS (Method D): R _T = 6.68 min, M + H ⁺ = 336.2.

EXAMPLE 72

(R) -4- (piperidin-2-ylmethoxy) -9H-dipyrido Г2.3-b: 4'.3 '^ 1 pyrrole-6-carbonitrile

Stage 1: (R) -piperidin-2-ylmethanol hydrochloride

A mixture of (R) -tert-butyl 2- (hydroxymethyl) piperidine-1-carboxylate (840 mg, 3.9 mmol) in 1, 4-dioxane (15 ml) was treated with hydrochloric acid (4.0N solution in dioxane, 9.8 ml, 39 mmol) and stirred at ambient temperature for 3 hours. The solvent was evaporated in vacuo to give the title compound as a white precipitate (594 mg). ¹ H NMR (400 MHz, d ₆ -DMSO) (8.75 (s, 1H), 4.72 (t, J = 5.3, 1H), 3.35 (m, 1H), 3.28-3.15 (m, 3H), 2.72 (m , 1H), 2.59-2.52 (m, 1H), 1.88-1.72 (m, 2H), 1.72-1.53 (m, 2H), 1.16 (m, 1H).

Stage 2: (R) -4- (piperidin-2-ylmethoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6- carbonitrile

To a solution of (R) -piperidin-2-ylmethanol hydrochloride (510 mg, 3.4 mmol) in tetrahydrofuran (12 ml) was added sodium hydride as a 60% dispersion in mineral oil (270 mg, 6.8 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before adding 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (550 mg, 1.5 mmol) at a time, and the reaction mixture was stirred at this temperature for 10 minutes, then heated to 40 ° C. for 5 hours. The cooled mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 40 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as a white precipitate, which was used in the next step without any further purification (470 mg, 70%).

Stage 3: (R) -4- (piperidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(R) -4- (piperidin-2-ylmethoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (467 mg 1.1 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (122 mg, 37%). ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (d, J = 0.7, 1H), 8.54 (m, 2H), 7.05 (d, J = 5.8, 1H), 4.30-4.18 (m, 2H) , 3.11 (m, 1H), 3.03 (m, 1H), 2.69-2.60 (m, 1H), 1.79 (m, 2H), 1.58 (m, 1H), 1.45-1.33 (m, 2H), 1.33-1.21 (m, 1H). LCMS (Method D): R _T = 7.41 min, M + H ⁺ = 308.1.

EXAMPLE 73

(S) -4- (piperidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -tert-butyl 2- (hydroxymethyl) piperidine-1-carboxylate. ¹ H NMR (400 MHz, d _6- DMSO) (8.97 (d, J = 0.8, 1H), 8.54 (dd, J = 3.3, 2.4, 2H), 7.05 (d, J = 5.8, 1H), 4.29- 4.17 (m, 2H), 3.08 (m, 1H), 3.03 (m, 1H), 2.70-2.62 (m, 1H), 1.79 (m, 2H), 1.58 (m, 1H), 1.46-1.33 (m, 2H), 1.32-1.19 (m, 1H). LCMS (Method D): R _T = 7.38 min, M + H ⁺ = 308.1.

EXAMPLE 74

(R) -4 - ((1-ethylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile

Stage 1: (R) -4 - ((1-ethylpiperidin-2-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of (R) -4- (piperidin-2-ylmethoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile ( 96 mg, 0.22 mmol) in dichloromethane (1.4 ml) was added acetaldehyde (19 μl, 0.33 mmol) followed by sodium triacetoborohydride (70 mg, 0.33 mmol) and the reaction mixture was stirred at ambient temperature for 5 minutes. The mixture was diluted with saturated aqueous sodium bicarbonate (50 ml) and dichloromethane (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 1-15% methanol in dichloromethane) to give the title compound as a yellow precipitate, which used in the next step without any further purification (64 mg, 87%).

Stage 2: (R) -4 - ((1-ethylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(R) -4 - ((1-ethylpiperidin-2-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 β-carbonitrile (64 mg, 0.14 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a precipitate (15 mg, 32%). ¹ H NMR (500 MHz, d ₆ -DMSO) (12.81 (s, 1H), 8.98 (s, 1H), 8.55 (d, J = 5.7, 1H), 8.43 (s, 1H), 7.05 (d, J = 5.8, 1H), 4.27 (m, 3H), 3.05 (m, 1H), 2.77 (m, 1H), 2.36 (m, 1H), 2.25 (m, 1H), 1.99 (m, 1H), 1.83 ( m, 1H), 1.70 (m, 1H), 1.57 (m, 1H), 1.23 (m, 1H), 1.03 (t, J = 7.1, 3H), 0.92 (d, J = 6.6, 1H). Method D): R _T = 6.63 min, M + H ⁺ = 336.2.

EXAMPLE 75

(R) -4 - ((1-methylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

Stage 1: (R) -4 - ((1-methylpiperidin-2-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of (R) -4- (piperidin-2-ylmethoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile ( 220 mg, 0.50 mmol) in acetonitrile (2.2 ml) and water (0.45 ml) formalin (41 μl, 1.5 mmol) was added followed by sodium triacetoborohydride (210 mg, 1.0 mmol), and the reaction mixture was stirred at ambient temperature for 20 minutes. The mixture was diluted with saturated aqueous sodium bicarbonate (50 ml) and dichloromethane (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as a yellow precipitate, which was used in the next step without any further purification (197 mg, 87%).

Stage 2: (R) -4 - ((1-methylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(R) -4 - ((1-methylpiperidin-2-yl) methoxy) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 β-carbonitrile (197 mg, 0.44 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a white precipitate (39 mg, 28%). ¹ H NMR (400 MHz, d ₆ -DMSO) (12.80 (s, 1H), 8.98 (d, J = 0.9, 1H), 8.55 (d, J = 5.7, 1H), 8.47 (d, J = 0.9, 1H), 7.07 (d, J = 5.8, 1H), 4.39 (ddd, J = 35.9, 10.4, 4.4, 2H), 2.84 (m, 1H), 2.34 (s, 3H), 2.16 (td, J = 11.4 , 3.3, 1H), 1.92-1.82 (m, 1H), 1.76 (m, 1H), 1.62 (m, 1H), 1.58-1.43 (m, 2H), 1.43-1.29 (m, 1H), 1.23 (s , 1H). LCMS (Method D): R _T = 7.48 min, M + H ⁺ = 322.1.

EXAMPLE 76

(S) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (S) -4- (tert-butyl 2-methoxyethyl (pyrrolidin-3-yl) carbamate) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3 '-d] pyrrole-6-carbonitrile

To a solution of (S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole- 4-yl) pyrrolidin-3-yl carbamate (73 mg, 28 mmol) in tetrahydrofuran (17 ml) and N, N-dimethylformamide (0.5 ml) sodium hydride was added as a 60% dispersion in mineral oil (34 mg, 1.4 mmol) . The reaction mixture was stirred at ambient temperature for 5 minutes before 1-bromo-2-methoxyethane (18 μl, 0.19 mmol) was added and the mixture was heated at 40 ° C. for 4 hours. The cooled reaction mixture was diluted with water (10 ml) and ethyl acetate (30 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 1-100% ethyl acetate in heptane) to give the title compound as a yellow precipitate, which was used in the next step without any further purification (58 mg, 71%).

Stage 2: (S) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(S) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole -6-carbonitrile (58 mg, 0.10 mmol) was dissolved in 1,4-dioxane (0.5 ml), treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml), and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound, as a yellow precipitate (12 mg, 35%). ¹ H NMR (400 MHz, d ₆ -DMSO) (8.82 (s, 1H), 8.50 (s, 1H), 8.15 (d, J = 5.9, 1H), 6.46 (d, J = 6.0, 1H), 3.93 (dd, J = 9.8, 5.6, 1H), 3.82 (m, 1H), 3.74-3.66 (m, 1H), 3.59 (dd, J = 9.7, 4.0, 1H), 3.48 (s, 1H), 3.41 ( t, J = 5.5, 2H), 3.24 (s, 3H), 2.77 (m, 2H), 2.16 (m, 1H), 1.94 (m, 1H). LCMS (Method D): R _T = 6.05 min, M + H ⁺ = 337.1.

EXAMPLE 77

(S) -4- (N- (3-fluoropropyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using 3-fluoropropyl trifluoromethasulfonate. ¹ H NMR (500 MHz, d ₆ -DMSO) (8.83 (s, 1H), 8.49 (s, 1H), 8.18 (d, J = 5.9, 1H), 8.13 (s, 1H), 6.50 (d, J = 5.9, 1H), 4.57 (t, J = 6.0, 1H), 4.47 (t, J = 5.9, 1H), 3.97 (m, 1H), 3.87 (m, 1H), 3.78-3.68 (m, 1H) , 3.61 (m, 2H), 2.82 (m, 2H), 2.22 (m, 1H), 2.03 (m, 1H), 1.87 (m, 2H). LCMS (Method D): R _T = 4.72 min, M + H ⁺ = 339.1.

EXAMPLE 78

(R) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (R) -3- (BOc-amino) pyrrolidine. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.79 (s, 1H), 8.46 (s, 1H), 8.13 (d, J = 5.9, 1H), 6.41 (d, J = 5.9, 1H), 3.90 (dd, J = 9.6, 5.6, 1H), 3.79 (m, 1H), 3.68 m, 1H), 3.55 (dd, J = 9.7, 4.4, 2H), 3.47-3.41 (m, 1H), 3.42-3.37 (m, 2H), 3.23 (s, 3H), 2.73 (m, 2H), 2.13 (m, 1H), 1.91 (m, 1H). LCMS (Method D): R _T = 6.03 min, M + H ⁺ = 337.1.

EXAMPLE 79

(S) -4- (M-ethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: (S) -4- (N-ethylpyrrolidin-3-amino) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 carbonitrile

A mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (89 mg, 0.25 mmol), (S) - N-ethylpyrrolidin-3-amine (140 mg, 1.23 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (21 mg, 0.037 mmol), cesium carbonate (161 mg, 0.49 mmol) and tris (dibenzylideneacetone ) dipalladium (0) (17 mg, 0.018 mmol) was heated in a closed flask at 110 ° C for 2 hours. The mixture was diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as an orange precipitate, which was used in the next step without any further purification (75 mg, 70%).

Stage 2: (S) -4- (M-ethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

(S) -4- (M-ethylpyrrolidin-3-amino) -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile ( 75 mg, 0.17 mmol) was dissolved in 1,4-dioxane (0.5 ml) and then treated with 48% HBr _(aq) (0.5 ml) and heated at 75 ° C for 15 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a reddish precipitate (25 mg, 48%). ¹ H NMR (400 MHz, d _6- DMSO) (8.81 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 5.9, 1H), 6.46 (d, J = 6.0, 1H), 3.91 (dd, J = 9.7, 5.6, 1H), 3.83 (m, 1H), 3.71 (m, 1H), 3.53 (dd, J = 9.6, 4.3, 1H), 3.43 (m, 1H), 2.59 (m, 2H), 2.13 (m, 1H), 1.96-1.83 (m, 1H), 1.03 (t, J = 7.1, 3H). LCMS (Method G): R _T = 1.97 min, M + H ⁺ = 307.1.

EXAMPLE 80

4- (4- (pyrrolidin-3-yl) morpholino) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using 4- (pyrrolidin-3-yl) morpholine. ¹ H NMR (400 MHz, d _6- DMSO) (12.53 (s, 1H), 8.82 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 5.9, 1H), 6.51 (d, J = 6.0, 1H), 3.99-3.88 (m, 1H), 3.79 (m, 2H), 3.68-3.55 (m, 5H), 3.02-2.91 (m, 1H), 2.58-2.41 (m, 4H), 2.27 (m, 1H), 1.94-1.82 (m, 1H). LCMS (Method D): R _T = 5.16 min, M + H ⁺ = 349.1.

EXAMPLE 81

4- (2,5-diazabicyclo [2.2.1] heptan-2-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using mpem-butyl 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.82 (s, 1H), 8.31 (s, 1H), 8.15 (d, J = 5.9, 1H), 6.53 (d, J = 5.9, 1H), 4.69 (s, 1H), 4.19 (d, J = 6.5, 1H), 3.73 (s, 1H), 3.32 (m, 1H), 3.11 (d, J = 9.9, 1H), 3.00 (d, J = 9.7, 1H), 1.97 (d, J = 9.7, 1H), 1.79 (d, J = 9.2, 1H). LCMS (Method D): R _T = 4.38 min, M + H ⁺ = 291.1.

EXAMPLE 82

4- (N-methylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using mpem-butyl methyl (pyrrolidin-3-yl) carbamate. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.81 (s, 1H), 8.49 (s, 1H), 8.14 (d, J = 5.9, 1 H), 6.45 (d, J = 6.0, 1H), 3.91 (m, 1H), 3.83 (m, 1H), 3.73-3.64 (m, 1H), 3.51 (dd, J = 9.7, 3.9, 2H), 2.31 (s, 3H), 2.11 (m, 1H), 1.92 (m, 1H). LCMS (Method D): R _T = 5.38 min, M + H ⁺ = 293.1.

EXAMPLE 83

(R) -4- (N, N-dimethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example with 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 -carbonitrile (101 mg, 0.28 mmol) using (R) -N, N-dimethylpyrrolidin-3-amine. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.80 (s, 1H), 8.43 (s, 1H), 8.15 (d, J = 5.8, 1H), 6.45 (d, J = 5.9, 1H), 3.88 (m, 1H), 3.77 (m, 2H), 3.65-3.54 (m, 1H), 2.88-2.77 (m, 1H), 2.52 (m, 1H), 2.24 (s, 6H), 1.94-1.80 (m , 1 N). LCMS (Method D): R _T = 4.24 min, M + H ⁺ = 307.1.

EXAMPLE 84

(S) -4- (N, N-dimethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -N, N-dimethylpyrrolidin-3-amine. ¹ H NMR (400 MHz, d ₆ -DMSO) (8.81 (s, 1H), 8.46 (s, 1H), 8.16 (d, J = 5.9, 1H), 6.49 (d, J = 5.9, 1H), 3.90 (m, 1H), 3.79 (m, 2H), 3.61 (t, J = 8.8, 1H), 2.89-2.77 (m, 1H), 2.52 (m, 1H), 2.24 (s, 6H), 1.95-1.80 (m, 1H). LCMS (Method D): R _T = 4.17 min, M + H ⁺ = 307.1.

EXAMPLE 85

4- (octahydropyrrolo [3,4-b] pyrrole) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using mpem-butyl hexahydro-pyrrolo [3,4-b] pyrrole-5 (1H) -carboxylate. ¹ H NMR (500 MHz, d _6- DMSO) (8.85 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.20 (d, J = 5.9, 1H), 6.63 (d, J = 5.9, 1H), 4.65-4.57 (m, 1H), 4.19 (m, 1H), 3.64-3.57 (m, 1H), 3.05 (m, 1H), 2.97 (m, 1H), 2.93-2.84 (m , 2H), 2.78 (d, J = 11.9, 1H), 2.09-1.96 (m, 2H). LCMS (Method D): R _T = 4.57 min, M + H ⁺ = 305.1.

EXAMPLE 86

4 - ((2aS, 6aS) -1-methyl-octahydropyrrolo [3,4-b] pyrrole) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (3aS, 6aS) -1-methyl-octahydropyrrolo [3,4-b] pyrrole. ¹ H NMR (500 MHz, d ₆ -DMSO) (12.58 (s, 1H), 8.89 (s, 1 H), 8.65 (s, 1 H), 8.31 (d, J = 5.6, 1 H), 6.68 ( d, J = 5.7, 1H), 3.87 (d, J = 11.0, 1H), 3.48 (dd, J = 9.7, 7.3, 1H), 3.37 (dd, J = 9.8, 2.8, 1H), 3.11-3.01 ( m, 2H), 3.01-2.89 (m, 2H), 2.35-2.25 (m, 1H), 2.16-2.06 (m, 1H), 1.74-1.62 (m, 1H). LCMS (Method D): R _T = 4.28 min, M + H ⁺ = 319.2.

EXAMPLE 87

4 - ((R) -piperidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (R) -tert-butyl 3-aminopiperidine-1-carboxylate. ¹ H NMR (400 MHz, d _6- DMSO) (8.99 (s, 1H), 8.84 (s, 1H), 8.20 (d, J = 5.9, 1H), 6.61 (d, J = 6.0, 1H), 6.33 (d, J = 8.3, 1H), 3.72-3.61 (m, 1H), 3.13 (m, 1H), 2.88 (m, 1H), 2.61 (m, 1H), 2.02 (m, 1H), 1.79-1.65 (m, 2H), 1.52 (m, 1H). LCMS (Method E): R _T = 3.62 min, M + H ⁺ = 293.1.

EXAMPLE 88

3-chloro-4-piperazine-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: 4- (tert-butylpiperazine-1-carboxylate) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 carbonitrile

A mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (126 mg, 0.35 mmol) and tert-butylpiperazine- 1-carboxylate (196 mg, 1.05 mmol) in N, N-dimethylacetamide (1.6 ml) was heated at 120 ° C for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-100% ethyl acetate in heptane) to give the title compound as a yellow oil, which used in the next step without any further purification (203 mg, 100%).

Stage 2: 3-chloro-4- (tert-butylpiperazine-1-carboxylate) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d ] pyrrole-6-carbonitrile

A mixture of 4- (tert-butylpiperazine-1-carboxylate) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (178 mg, 0.35 mmol) and N-chlorosuccinimide (140 mg, 1.05 mmol) in acetonitrile (1.4 ml) and isopropyl alcohol (0.4 ml) were stirred at 35 ° C for 1 hour. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate (1 ml), diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-100% ethyl acetate in heptane) to give the title compound as a pale yellow foam, which was used in the next step without any further purification (142 mg, 75%).

Stage 3: 3-chloro-4-piperazin-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

3-chloro-4- (tert-butyl-piperazine-1-carboxylate) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (142 mg, 0.26 mmol) was dissolved in 1,4-dioxane (0.4 ml) and then treated with 48% HBr _(aq) (0.4 ml) and heated at 60 ° C for 20 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a light yellow precipitate (19 mg, 22%). ¹ H NMR (400 MHz, d ₆ -DMSO) (8.95 (s, 1H), 8.53 (s, 1H), 8.48 (d, J = 6.2, 1H), 3.43 (m, 4H), 3.02-2.97 (m , 4H). LCMS (Method G): R _T = 3.80 min, M + H ⁺ = 313.0.

EXAMPLE 89

3-chloro-4- (1-ethylpiperazine) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using N-ethylpiperazine. ¹ H NMR (400 MHz, d _6- DMSO) (8.92 (s, 1H), 8.48 (s, 1H), 8.43 (s, 1H), 3.52 (s, 4H), 2.67 (s, 4H), 2.54- 2.44 (m, 4H), 1.09 (t, J = 7.2, 3H). LCMS (Method D): R _T = 6.84 min, M + H ⁺ = 341.0.

EXAMPLE 90

Stage 1: (S) -Benzyl 3- (tert-butoxycarbonylamino) pyrrolidine-1-carboxylate

A solution of (S) -tert-butyl-pyrrolidin-3-ylcarbamate (4.2 g, 22 mmol) in dichloromethane (49 ml) was cooled to 0 ° C and treated with pyridine (2.2 ml, 29 mmol) and benzyl chloroformate (3.8 ml, 29 mmol) ) The mixture was stirred at 0 ° C. for 30 minutes and then warmed to ambient temperature and stirred for 4 hours. The reaction mixture was diluted with water (100 ml) and dichloromethane (100 ml), the organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 40 g, ISCO, 1-100% ethyl acetate in heptanes ) to give the title compound as a white precipitate, which was used in the next step without any further purification (5.2 g, 73%).

Stage 2: (S) -benzyl 3- (tert-butoxycarbonyl (3-fluoropropyl) amino) pyrrolidine-1-carboxylate

To a mixture of (S) -benzyl 3- (tert-butoxycarbonylamino) pyrrolidine-1-carboxylate (400 mg, 1.2 mmol) and 3-fluoropropyl trifluoromethasulfonate (433 mg, 2.1 mmol) in tetrahydrofuran (10 ml) was added 60% sodium hydride dispersions in mineral oil (146 mg, 3.6 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with water (20 ml) and dichloromethane (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 40 g, ISCO, 1-20% methanol in dichloromethane) to give the title compound as a colorless oil which was used in the next step without any further purification (475 mg, 100%).

Stage 3: (S) -tert-butyl-3-fluoropropyl (pyrrolidin-3-yl) carbamate

To a solution of (S) -benzyl 3- (tert-butoxycarbonyl (3-fluoropropyl) amino) pyrrolidine-1-carboxylate (611 mg, 1.6 mmol) in methanol (6.5 ml) was added ammonium formate (1.1 g, 18 mmol) followed by the addition of palladium on charcoal (10% w / w, 479 mg, 0.22 mmol). The reaction mixture was stirred at ambient temperature for 1 hour in a flask with hydrogen, then degassed and filtered through a pad of celite. The filtrate was concentrated in vacuo to give a precipitate, which was used in the next step without any further purification.

Stage 4: (S) -4- (benzyl 3- (tert-butoxycarbonyl (3-fluoropropyl) amino) pyrrolidine-1-carboxylate) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2 , 3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

A mixture of 4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (135 mg, 0.38 mmol) and (S) - tert-butyl-3-fluoropropyl (pyrrolidin-3-yl) carbamate (557 mg, 2.3 mmol) in N, N-dimethylacetamide (1.8 ml) was heated at 120 ° C for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-20% methanol in dichloromethane) to give the title compound as a yellow oil, which used in the next step without any further purification (214 mg, 100%).

Step 5: (S) -3-chloro-4- (benzyl 3- (tert-butoxycarbonyl (3-fluoropropyl) amino) pyrrolidine-1-carboxylate) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H -dipyrido [2,3-b; 4 ', 3'-a] pyrrole-6-carbonitrile

A mixture of (S) -4- (benzyl 3- (tert-butoxycarbonyl (3-fluoropropyl) amino) pyrrolidine-1-carboxylate) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3 -b; 4 ', 3'-d] pyrrole-6-carbonitrile (214 mg, 0.38 mmol) and N-chlorosuccinimide (151 mg, 1.1 mmol) in acetonitrile (1.5 ml) and isopropyl alcohol (0.4 ml) were stirred at 35 ° C for 1 hour. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate, diluted with ethyl acetate (50 ml) and washed with water (20 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-100% ethyl acetate in heptane) to give the title compound as the oil that was used in the next step without any further purification (125 mg, 55%).

Stage 6: (S) -3-chloro-4- (N- (3-fluoropropyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6- carbonitrile

(S) -3-chloro-4- (benzyl 3- (tert-butoxycarbonyl (3-fluoropropyl) amino) pyrrolidine-1-carboxylate) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [ 2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (125 mg, 0.21 mmol) was dissolved in 1,4-dioxane (0.4 ml) and then treated with 48% HBr _(aq) (0.4 ml) and heated at 60 ° C for 20 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in a grayish-white precipitate (18 mg, 23%). ¹ H NMR (400 MHz, d ₆ -DMSO) (8.97 (s, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 4.61 (t, J = 6.0, 1H), 4.49 (t, J = 5.9, 1 H), 3.80 (m, 2H), 3.64 (m, 1H), 3.51 (m, 2H), 2.70 (m, 2H), 2.31 (m, 1H), 1.94 (m, 2H), 1.89 -1.83 (m, 1H). LCMS (Method E): R _T = 3.16 min, M + H ⁺ = 373.1.

EXAMPLE 91

(S) -3-chloro-4- (3- (2,2-difluoroethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using 2,2-difluoroethyl trifluoromethasulfonate. ¹ H NMR (400 MHz, d _6- DMSO) (12.88 (s, 1H), 8.96 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 6.05 (s, 1H), 3.87- 3.75 (m, 2H), 3.67-3.54 (m, 2H), 3.48 (m, 1H), 3.00 (m, 2H), 2.51 (m, 1H), 2.27 (m, 1H), 1.95 (m, 1H) LCMS (Method D): R _T = 7.27 min, M + H ⁺ = 377.0.

EXAMPLE 92

(S) -3-chloro-4- (N- (pyrrolidin-3-yl) isobutyramide) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The title compound was prepared according to the methods of the preceding example using (S) -4- (3-aminopyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [ 2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile and isobutyryl chloride. ¹ H NMR (400 MHz, d _6- DMSO) (8.97 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.18 (d, J = 6.2, 1H), 4.45 (dd, J = 11.9, 5.6, 1H), 3.94 (dd, J = 9.9,6.5, 1H), 3.81 (dd, J = 16.3, 7.5, 1H), 3.64 (dd, J = 15.2, 8.6, 1H), 3.45 (dd , J = 10.0, 4.6, 1H), 2.48-2.42 (m, 1H), 2.42-2.29 (m, 1H), 2.11-1.97 (m, 1H), 1.03 (dd, J = 16.5, 6.8, 6H). LCMS (Method G): R _T = 6.53 min, M + H ⁺ = 382.9.

EXAMPLE 93

(S) -3-chloro-4- (N- (2,2,2-trifluoroethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 carbonitrile

Stage 1: (S) -4- (3-aminopyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d ] pyrrole-6-carbonitrile

To a solution of (S) -tert-butyl-1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole -4-yl) pyrrolidin-3-ylcarbamate (401 mg, 0.79 mmol) in dichloromethane (9.0 ml) trifluoroacetic acid (9.0 ml) was added and the mixture was stirred at ambient temperature for 10 minutes. The solvent was evaporated in vacuo, the resulting precipitate was dissolved in dichloromethane and treated with saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo to give the title compound as a yellow foam, which was used in the next step without any further purification (268 mg, 83%).

Stage 2: (S) -4- (3- (2,2,2-trifluoroethylamino) pyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3- b; 4 ', 3'-d] pyrrole-6-carbonitrile

Mixture of (S) -4- (3-aminopyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole -6-carbonitrile (131 mg, 0.32 mmol), 2,2,2-trifluoroethyl trifluoromethasulfonate (490 mg, 2.1 mmol) and N, N-diisopropylethylamine (365 μl, 2.1 mmol) in dichloromethane (15 ml) were heated at 40 ° C. within 4 hours. The cooled reaction mixture was diluted with water (20 ml) and dichloromethane (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-20% methanol in dichloromethane) to give the title compound as the oil that was used in the next step without any further purification (156 mg, 100%).

Stage 3: (S) -4- (3- (2,2,2-trifluoroethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6- carbonitrile

(S) -4- (3- (2,2,2-trifluoroethylamino) pyrrolidin-1-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (156 mg, 0.32 mmol) was dissolved in 1,4-dioxane (0.4 ml) and then treated with 48% HBr _(aq) (0.4 ml) and heated at 60 ° C for 20 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a yellow precipitate (5.0 mg, 5%). ¹ H NMR (400 MHz, d _6- DMSO) (8.81 (s, 1H), 8.47 (s, 1H), 8.15 (d, J = 5.8, 1H), 6.43 (d, J = 5.8, 1H), 3.95 (m, 1H), 3.81 (m, 1H), 3.68 (m, 1H), 3.60-3.50 (m, 2H), 2.81 (m, 1H), 2.14 (m, 1H), 2.02-1.88 (m, 1H ) LCMS (Method D): R _T = 7.71 min, M + H ⁺ = 361.0.

EXAMPLE 94

(R) -4- (Piperidin-3-yloxy) -6- (1-methyl-1H-pyrazol-4-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole

Stage 1: 6-bromo-3-iodo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole

A solution of iodine chloride (32.5 g, 200 mmol) in acetic acid (120 ml) was added in parts over 2 hours to a mixture of 6-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole ( 5.0 g, 20 mmol) and sodium acetate (18.2 g, 221 mmol) in acetic acid (120 ml) at 100 ° C. The reaction mixture was cooled to ambient temperature and poured into a saturated solution of sodium metabisulfite (20% wt./mass. 400 ml). The resulting precipitate was collected by filtration, and the precipitate was washed with water (50 ml) and diethyl ether (2 × 50 ml), then dried at 45 ° C to obtain a stable weight, to obtain the title compound as a gray precipitate (6.3 g, 83%). ¹ H NMR (DMSO-d ₆ , 300 MHz) 12.49 (s, 1H); 9.14 (d, J = 2.1 Hz, 1H); 8.79 (d, J = 2.1 Hz, 1H); 8.71 (s, 1H); 8.49 (s, 1H). LCMS (Method B): R _T = 3.40 min, M + H ⁺ = 374/376.

Stage 2: 3-bromo-3-iodo-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole

To a suspension of 6-bromo-3-iodo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole (10 g, 24 mmol) in DMF (100 ml), sodium hydride was added in an inert atmosphere ( 1.4 g, 36 mmol) and the reaction mixture was allowed to mix at ambient temperature for 30 minutes. The reaction mixture was cooled to 0 ° C. and 2- (trimethylsilyl) ethoxymethyl chloride (6.4 ml, 36 mmol) was added dropwise, then the resulting suspension was allowed to warm to room temperature. Water (150 ml) was added to the resulting suspension in order to quench the reaction, the solvent was removed in vacuo, and the resulting precipitate was purified by flash chromatography (silica gel, 120 g column, ISCO, 0-15% ethyl acetate in cyclohexane) to give the compound indicated in the title as a grayish-white crystalline precipitate (7.2 g, 59%). ¹ H NMR (400 MHz, CDCl ₃ ) (8.94 (s, 1H), 8.88 (d, J = 1.9, 1H), 8.74 (d, J = 1.9, 1H), 8.16 (s, 1H), 5.98 (s , 2H), 3.70-3.58 (m, 2H), 1.04-0.92 (m, 2H), -0.00 (s, 9H).

Stage 3: 6-bromo-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b: 4 ', 3'-d] pyrrole

A solution of 6-bromo-3-iodo-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole (3.0 g, 5.95 mmol) in tetrahydrofuran (40 ml) was cooled to -78 ° C. Isopropyl magnesium chloride (2.On solution in tetrahydrofuran, 3.12 ml, 6.2 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred at this temperature for 1.5 hours, and then the reaction was quenched with a saturated aqueous solution of ammonium chloride (1 ml). The reaction mixture was then diluted with 25 ml of water and extracted with ethyl acetate (150 ml). The organic layer was separated, washed with water (50 ml) then brine (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil, which was used in the next step without any further purification (2.2 g, 100% )

Stage 4: 6-bromo-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-1,7-dioxide

To a suspension of the hydroperitic adduct (4.2 g, 45 mmol) in chloroform (37 ml) was added trifluoroacetic anhydride (6.3 ml, 44.4 mmol) dropwise over 10 minutes. The reaction mixture was stirred at ambient temperature for 5 minutes and then 6-bromo-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole ( 2.1 g, 5.6 mmol) as a solution in chloroform (15 ml). Note: an exothermic reaction was observed as a result of the addition of the substrate. The reaction mixture was stirred at ambient temperature for 10 minutes and then at 50 ° C for 30 minutes. The reaction mixture was cooled to ambient temperature, treated with saturated sodium thiosulfate solution (20 ml) and diluted with water (50 ml) and methanol (10 ml). The layers were separated, and the organic layer was washed with 0.5n. hydrochloric acid (50 ml), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 80 g, ISCO, 0-10% methanol in dichloromethane) to give the title compound as pale yellow precipitate that was used in the next step without any further purification (1 g, 44%).

Stage 5: 6-bromo-4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-7-oxide

A mixture of 6-bromo-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-1,7-dioxide (1 g, 2.4 mmol) in N, N-dimethylformamide (19 ml) was treated with methanesulfonyl chloride (0.38 ml, 4.9 mmol) and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate (150 ml) and water (200 ml). The layers were separated, and the organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 40 g, ISCO, 5-85% ethyl acetate in heptane) to give the title compound as a mixture 4: 1 with 6-bromo-2-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-7-oxide, respectively, in the form of grayish off-white precipitate (100 mg, 10%). The mixture was used in the next step without any further purification.

Stage 6: 6-bromo-4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole

Solution of 6-bromo-4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-7-oxide with 6-bromo-2-chloro -9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-7-oxide (4: 1, 90 mg, 0.2 mmol), 1.1' - [bis (diphenylphosphino) ferrocene] dichloropalladium (II) (8.5 mg, 0.012 mmol), and triethylamine (0.1 ml, 0.7 mmol) in acetonitrile (1.2 ml) was heated under microwave irradiation at 130 ° C for 10 minutes. the reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 40 g, ISCO, 0-40% ethyl acetate in heptane) to give m of the title compound as a 4: 1 mixture of the title compound with 6-bromo-2-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole as a grayish-white precipitate (60 mg, 70%). The mixture was used in subsequent steps without any further purification.

Stage 7: (R) -tert-butyl-3- (6-bromo-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-4-yloxy) piperidin-1-carboxylate

To a solution of (R) -tert-butyl-3-hydroxypiperidin-1-carboxylate (64 mg, 0.32 mmol) in tetrahydrofuran (1.2 ml) was added sodium hydride as a 60% dispersion in mineral oil (13 mg, 0.32 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before a mixture of 6-bromo-4-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'- was added d] pyrrole with 6-bromo-2-chloro-9- (2-trimethylsilanyl-ethoxymethyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole (4: 1, 60 mg, 0.1 mmol) at a time, and the reaction mixture was stirred at this temperature for 10 minutes before being heated at 40 ° C for 2 hours. The cooled reaction mixture was then diluted with water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-65% ethyl acetate in heptane) to give the title compound as a colorless oil, which was used in the next step without any further purification (60 mg, 70%).

Stage 8: (R) -tert-butyl-3- (6- (1-methyl-1H-pyrazol-4-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2, 3-b; 4 ', 3'-d] pyrrole-4-yloxy) piperidin-1-carboxylate

A mixture of (R) -tert-butyl-3- (6-bromo-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole- 4-yloxy) piperidin-1-carboxylate (50 mg, 0.09 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (90 mg, 0.43 mmol), 1,1 '- [bis (diphenylphosphino) ferrocene] dichloropalladium (II) (6.3 mg, 0.009 mmol) and a saturated aqueous solution of sodium carbonate (0.1 ml) in acetonitrile (0.9 ml) were heated under microwave radiation at 130 ° C for 30 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 4 g, ISCO, 0-90% ethyl acetate in heptane) to give the title compound as a light brown oil, which was used in the next step without any any additional purification (50 mg).

Step 9: (R) -4- (Piperidin-3-yloxy) -6- (1-methyl-1H-pyrazol-4-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d ]pyrrol

(R) -tert-butyl-3- (6- (1-methyl-1H-pyrazol-4-yl) -9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b ; 4 ', 3'-d] pyrrole-4-yloxy) piperidine-1-carboxylate (50 mg, 0.09 mmol) was dissolved in 1,4-dioxane (0.2 ml) and then treated with 48% HBr _(aq) (0.2 ml ) and heated at 75 ° C for 5 minutes. Then, the cooled reaction mixture was alkalized to pH ~ 12 by dropwise adding 6N. sodium hydroxide and then immediately acidified to pH ~ 8-9 by adding dropwise concentrated hydrochloric acid to obtain a whitish precipitate. The precipitate was collected by centrifugation, dissolved in dimethyl sulfoxide (2 ml) and purified using preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) for 30 min, 35 ml / min] to obtain the title compound in as a pale yellow precipitate (10 mg, 30% in two stages). ¹ H NMR (400 MHz, d ₆ -DMSO) (11.95 (s, 1H), 8.77 (s, 1H), 8.39 (d, J = 5.7, 1H), 8.21 (s, 1H), 8.12 (s, 1H ), 7.94 (s, 1H), 6.95 (d, J = 5.9, 1H), 4.77-4.67 (m, 1H), 3.91 (s, 3H), 3.10-3.25 (m, 1H), 2.90-2.83 (m , 2H), 2.67 (m, 1H), 2.19 (m, 1H), 1.91-1.78 (m, 2H), 1.67-1.53 (m, 1H), piperidine NH was not observed LCMS (Method D): R _T = 5.567 min, M + H ⁺ = 349.1.

The compounds of the examples in Table 2 were obtained by one of the main 20 methods of binding, followed by deprotection mainly according to the main methods of deprotection and purification according to the main methods of purification, which are described above.

table 2 Example Structure / Name Binding method The method of deprotection Cleaning Method (s) LCMS R _T (min), M + H ⁺ , Method ¹ H NMR (ppm) 95

дипиридо[2,3b;4',3'-d]пиррол-4-ил)-пиперазин-1-ил]-2-(R)-пирролидин-2-ил-этанон

dipyrido [2,3b; 4 ', 3'-d] pyrrol-4-yl) piperazin-1-yl] -2- (R) pyrrolidin-2-yl ethanone G-2 D-2 B-2 ³ 1.42, 365, A (400 MHz, CD ₃ OD): 9.17 (s, 1H), 8.76 (d, J = 6.4 Hz, 1H), 8.68 (s, 1H), 8.60 (d, J = 6.4 Hz, 1H), 3.98-3.96 (m, 3H), 3.89 (t, J = 4.9 Hz, 2H), 3.77-3.75 (m, 2H), 3.67 (t, J = 5.2 Hz, 2H), 3.33-3.32 (m, 2H), 3.17 ( dd, J = 17.5, 3.7 Hz,
1H), 2.97 (dd, J = 17.5, 10.1 Hz, 1H), 2.30-2.29 (m, 1H), 2.13-2.13 (m, 1H), 2.02-2.01 (m, 1H), 1.81-1.80 (m, 1H). 96

G-2 D-2 B-2 ³ 0.62, 282, A (400 MHz, CD ₃ OD): 8.73 (s, 1H), 8.26 (d, J = 5.7 Hz, 1H), 11.11-8.05 (m, 2H), 6.51 (d, J = 6.1 Hz, 1H), 3.97 (dd, J = 9.9, 6.3 Hz, 1H), 3.92-3.91 (m, 1H), 3.80-3.79 (m, 1H), 3.64 (dd, J = 9.8, 6.0 Hz, 1H), 3.55-3.54 (m , 1H), 2.74-2.73 (m, 2H), 2.36-2.35 (m, 1H), 1.98-1.97 (m, 1H), 1.18 (t, J = 7.17 Hz, 3H). [(S) -1- (9H-Dipyrido [2,3-b; 4 ', 3'-d] pyrrol-4-yl) -pyrrolidin-3-yl] ethylamine

The compounds of the examples in Table 3 were obtained by one of the main methods of binding, followed by deprotection mainly according to the main methods of deprotection and purification according to the main methods of purification, which are described above.

Table 3 Example Structure / Name Binding method The method of deprotection Cleaning Method (s) LCMS RT (min), M + H ⁺ , Method ¹ H NMR (ppm) 97

4-(1-этил
пиперидин-4-иламино)-9Н-дипиридо[2,3-b;4',3'-d]пиррол-6-карбонитрил

4- (1-ethyl
piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile E-1 B-1 S-2 ³ 1.08, 321, C (300 MHz, DMSO-d ₆ ): 12.40 (s, 1H), 9.07 (s, 1H), 8.83 (s, 1H), 8.19 (d, J = 5.9 Hz, 1H), 6.60 (d, J = 6.0 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 3.77-3.52 (m, 1H), 2.94 (d, J = 11.1 Hz, 2H), 2.36 (q, J = 7.2 Hz, 2H),
2.03-2.01 (m, 4H), 1.84-1.76 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H). 98

F-1 B-1 B-2 ³ 4.44, 320, C (400 MHz, CDCl ₃ ): 8.95 (d, J = 1.0H4, 1H), 8.47 (d, J = 5.9 Hz, 1H), 8.41 (d, J = 1.0 Hz, 1H), 6.70 (d, J = 5.9 Hz, 1H), 4.84-4.83 (m, 1H), 3.50 (ddd, J = 14.6, 8.0, 2.1 Hz, 1H), 3.14-3.02 (m, 3H), 3.03-2.83 (m, 2H), 2.45 -2.42 (m, 1H), 2.18-2.17 (m, 1H), 1.94-1.93 (m, 1H), 1.82-1.68 (m, 2H). 4 - [(S) - (1-azabicyclo- [2.2.2] oct-3-yl) oxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 99

E-1 B-1 S-2 ³ 1.45, 321, C (400 MHz, DMSO-d ₆ ): 12.44 (s, 1H), 8.95 (s, 1H), 8.84 (d, J = 0.9 Hz, 1H), 8.21 (d, J = 5.9 Hz, 1H), 6.60 ( d, J = 6.0 Hz, 1H), 6.34 (d, J = 8.5 Hz, 1H), 3.80 (s, 1H), 2.99 (d, J = 10.7 Hz, 1H), 2.77 (d, J = 10.8 Hz, 1H), 2.42 (q, J = 7.2 Hz, 2H), 2.16 (t, J = 10.1 Hz, 1H), 2.07-1.89 (m, 2H), 1.80-1.68 (m, 1H), 1.61-1.59 (m , 2H), 1.04 (t, J = 7.1 Hz, 3H). 4 - ((S) -1-ethylpiperidin-3-ylamino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile one hundred

F-1 S-1 C-2 ² 4.01, 312, C (400 MHz, CDCl ₃ ): 12.14 (s, 1H), 8.97 (d, J = 1.1 Hz, 1H), 8.51 (d, J = 5.8 Hz, 1H), 8.45 (d, J = 1.1 Hz, 1H) , 6.81 (d, J = 5.9 Hz, 1H), 5.09-4.87 (m, 2H), 3.45-3.44 (m, 1H), 3.28-3.18 (m, 1H), 3.08-3.07 (m, 1H), 2.91 -2.82 (m, 1H), 2.20-2.09 (m, 2H). cis- (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 101

E-1 B-1 B-2 1.91, 307, A (400 MHz, CD ₃ OD): 8.94 (d, J = 0.9 Hz, 1H), 8.44 (d, J = 5.7 Hz, 1H), 8.21 (d, J = 1.0 Hz, 1H), 6.96 (d, J = 5.7 Hz, 1H), 3.48-3.47 (m, 4H), 2.92-2.80 (m, 4H), 2.63 (q, J = 7.3 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H). 4- (4-ethylpiperazin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 102

E-1 IN 1 C-2 ³ 1.87, 347, A (400 MHz, DMSO-d ₆ ): 8.95 (d, J = 0.8 Hz, 1Н), 8.43 (d, J = 5.6 Hz, 1Н), 8.14 (d, J = 1.0 Hz, 1Н), 6.88 (d, J = 5.6 Hz, 1H), 3.66 (d, J = 12.5 Hz, 2H), 3.04 (t, J = 11.8 Hz, 2H), 2.57 (s, 4H), 2.31-2.22 (m, 1H), 2.09 ( d, J = 12.5 Hz, 2H), 1.76-1.68 (m, 6H). 4- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 103

E-1 B-1 B-2 ¹ 1.79, 362, A (400 MHz, DMSO-d ₆ ): 8.95 (d, J = 0.9 Hz, 1Н), 8.43 (d, J = 5.6 Hz, 1Н), 8.15 (d, J = 1.0 Hz, 1Н), 6.88 (d, J = 5.6 Hz, 1H), 3.74 (d, J = 12.5 Hz, 2H), 3.62 (t, J = 4.3 Hz, 4H), 2.99 (t, J = 12.2 Hz, 2H), 2.56 (t, J = 4.2 Hz, 4H), 2.44-2.41 (m, 1H), 2.04 (d, J = 12.4 Hz, 2H), 1.87-1.59 (m, 2H). 4- (4-morpholin-4-yl-piperidin-1-yl) -9H-dipyrido [2,3b; 4 ', 3'd] pyrrole-6-carbonitrile 104

E-1 D-1 C-2 ³ 1.68, 321, A (400 MHz, DMSO-d ₆ ): 12.44 (s, 1H), 8.95 (s, 1H), 8.84 (d, J = 0.9 Hz, 1H), 8.21 (d, J = 5.9 Hz, 1H), 6.60 ( d, J = 6.0 Hz, 1H), 6.35 (d, J = 8.5 Hz, 1H), 3.87-3.74 (m, 1H), 3.00 (d, J = 10.8 Hz, 1H), 2.77 (d, J = 10.9 Hz, 1H), 2.42 (q, J = 7.2 Hz, 2H), 2.16 (t, J = 10.1 Hz, 1H), 2.07-1.91 (m, 2H), 1.80-1.69 (m, 1H), 1.67-1.56 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H). 4 - ((R) -1-ethyl-piperidin-3-ylamino) -9H-dipyrido- [2,3b; 4 ', 3'-d] pyrrole-6-carbonitrile 105

E-1 C-1 C-2 ³ 1.70, 3.07, A (400 MHz, CD ₃ OD): 8.93 (d, J = 0.9 Hz, 1H), 8.41 (d, J = 5.7 Hz, 1H), 8.21 (d, J = 1.0 Hz, 1H), 6.94 (d, J = 5.8 Hz, 1H), 3.85 (d, J = 12.9 Hz, 2H), 3.11 (t, J = 12.3 Hz, 2H), 2.79 (3, 1H), 2.51 (s, 3H), 2.23 (d, J = 12.4 Hz, 2H), 1.79-1.69 (m, 2H). 4- (4-Methylaminopiperide in-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile 106

E-1 B-1 B-2 1.93, 280, A (400 MHz, DMSO-d ₆ ): 8.80 (3, 1H), 8.46 (s, 1H), 8.14 (d, J = 5.8 Hz, 1H), 6.42 (d, J = 5.9 Hz, 1H), 4.48 ( s, 1H), 4.01 (dd, J = 10.2, 4.3 Hz, 1H), 3.89-3.80 (m, 1H), 3.70-3.62 (m, 1H), 3.53 (d, J = 10.4 Hz, 1H), 3.45 -3.20 (2H, overlapped by solvent peak), 2.08-2.07 (m, 1H), 2.04-1.94 (m, 1H). 4 - ((R) -3-hydroxypyrrolidine -1-yl) -9H-dipyrido [2,3b; 4 ', 3'-d] pyrrole-6-carbonitrile 107

E-1 IN 1 IN 2 1.93, 280, A (400 MHz, DMSO-d ₆ ): 8.79 (s, 1H), 8.43 (s, 1H), 8.14 (d, J = 5.8 Hz, 1H), 6.39 (d, J = 5.6 Hz, 1H), 4.48 ( s, 1H), 3.99 (dd, J = 10.2, 4.2 Hz, 1H), 3.88-3.79 (m, 1H), 3.66-3.62 (m, 1H), 3.53 (d, J = 10.6 Hz, 1H), 3.46 -3.20 (2H, overlapped by solvent peak), 2.08-2.07 (m, 1H), 2.04-1.94 (m, 1H). 4 - ((S) -3-hydroxypyrrolidine -1-yl) -9H-dipyrido [2,3b; 4 ', 3'-d] pyrrole-6-carbonitrile 108

E-1 B-1, C-1 C-2 ² 2.05, 312, A (400 MHz, DMSO-d ₆ ): 8.80 (d, J = 1.0 Hz, 1H), 8.36-8.34 (m, 2Н), 6.76 (d, J = 5.6 Hz, 1Н), 4.80-4.79 (m, 2Н ), 3.53-3.12 (1H, overlapped by solvent peak), 2.93-2.88 (m, 1H), 2.65-2.62 (m, 2H), 2.22-2.19 (m, 1H), 1.68-1.57 (m, 1H). trans- (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile

The compounds of the examples of Table 4 were obtained by hydrogenation of the corresponding 3-Br intermediates.

Table 4 Example Structure / Name 3-x Binding method Hydrogenation method The method of deprotection Cleaning method LCMS R _T , M + H ⁺ , Method ¹ H NMR (ppm) 109

5-(пиперидин-4-илметокси)-9Н-дипиридо[2,3-b;4',3'-d]пиррол-6-карбонитрил

5- (piperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 A-2 C-2, D-2 C-2 ¹ 2.27, 308, A (400 MHz, CD ₃ OD / CDCl ₃ ): 8.73 (s, 1H), 8.66-8.61 (m, 2H), 7.45 (dd, J = 7.9, 4.9 Hz, 1H), 4.46 (d, J = 6.2 Hz , 2H), 3.17 (d, J = 12.6 Hz, 2H), 2.74 (td, J = 12.4, 2.7 Hz, 2H), 2.23-2.20 (m, 1H), 2.02 (d, J = 13.2 Hz, 2H) 1.52 (qd, J = 12.4, 4.0 Hz, 2H). 110

5- (pyrrolidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 A-2 C-2, D-2 B-2 ¹ 2.20, 294, A (300 MHz, CD ₃ OD / CDCl ₃ ): 8.73 (s, 1H), 8.66 (dd, J = 4.9, 1.7 Hz, 1H), 8.62 (dd, J = 7.9, 1.7 Hz, 1H), 7.45 (dd , J = 7.9, 4.9 Hz, 1H), 4.57-4.56 (m, 2H), 3.27-3.26 (m, 1H), 3.03-3.02 (m, 3H), 2.89 (d, J = 9.5 Hz, 1H), 2.16-2.15 (m, 1H), 1.78 (t, J = 6.8 Hz, 1H). 111

5 - ((8) -piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-
carbonitrile Br F-2 A-2 C-2, D-2 C-2 ³ 2.23, 294, A (400 MHz, CD ₃ OD / CDCl ₃ ): 8.75 (s, 1H), 8.66-8.66 (m, 2H), 7.46-7.45 (m, 1H), 4.78-4.77 (m, 1H), 3.35-3.31 ( m, 1H), 3.02 (dd, J = 12.5, 8.3 Hz,
1H), 2.91 (d, J = 12.8 Hz, 1H), 2.73 (t, J = 5.5 Hz, 1H), 2.31-2.21 (m, 1H), 1.94-1.93 (m, 2H), 1.59-1.59 (m , 1H). 112

5 - ((R) -1-pyrrolidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 A-2 S-2, D-2 S-2 2.09, 294 A (400 MHz, DMSO-d ₆ ): 8.80 (dd, J = 7.9, 1.7 Hz, 1H), 8.76 (s, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 7.45 (dd, J = 7.9, 4.8 Hz, 1H), 4.33 (d, J = 6.2 Hz, 2H), 3.62-3.61 (m, 1H), 2.86-2.85 (m, 2H), 1.95-1.95 (m, 1H), 1.71- 1.70 (m, 2H); 1.56-1.55 (m, 1H). 113

5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br IN 2 A-2 NA S-2 4.81, 389, C (400 MHz, CD ₃ OD): 8.60 (s, 1H), 8.59 (dd, J = 4.1, 1.5 Hz, 1H), 8.47 (s, 1H), 7.42 (dd, J = 7.7, 5.2 Hz, 1H) , 4.14-4.13 (m, 1H), 3.04 (d, J = 11.3 Hz, 2H), 3.03-2.38 (m, 2H), 2.41-2.40 (m, 2H), 2.33-2.30 (m, 2H), 2.25 (d, J = 13.4 Hz, 3H), 1.85-1.83 (m, 2H). 114

5 - ((S) -1-ethyl-piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 A-2 E-2 B-2 ⁴ 4.60, 322, C (400 MHz, DMSO-d ₆ ): 12.92 (s, 1H), 8.78 (s, 1H), 8.74 (dd, J = 7.9, 1.7 Hz, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H ), 7.45 (dd, J = 7.9, 4.8 Hz, 1H), 4.82-4.76 (m, 1H), 2.93 (d, J = 11.0 Hz, 1H), 2.56-2.44 (m, 2H), 2.36 (q, J = 7.2 Hz, 2H), 2.26 (t, J = 10.0 Hz, 1H), 2.06-2.00 (m, 1H), 1.87-1.75 (m, 2H), 1.49-1.48 (m, 1H), 0.97 (t , J = 7.2 Hz, 3P). 115

5- [1- (2-methoxy-ethyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br A-2 B-2 NA S-2 ³ 4.64, 351, C (400 MHz, CD ₃ OD): 8.68 (dd, J = 8.0, 1.5 Hz, 1H), 8.6 (dd, J = 4.9, 1.51 Hz, 1H), 8.4 (s, 1H), 7.43 (dd, J = 8.0, 4.9 Hz, 1H), 4.13-4.12 (m, 1H), 3.55 (t, J = 5.5 Hz, 2H), 3.35 (s, 3H), 3.06-3.03 (m, 2H), 2.63 (t, J = 5.5 Hz, 2H), 2.25 (t, J = 12.0 Hz, 2H), 2.19-2.15 (m, 2H), 1.85 (q, J = 6.1 Hz, 2H). 116

5- (1-Cyclopropylmethyl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 A-2 C-2 B-2, C-2 2.54, 348, A (400 MHz, CD ₃ OD): 8.75 (s, 1H), 8.67-8.67 (m, 2H), 7.46 (dd, J = 7.9, 4.9 Hz, 1H), 4.97-4.87 (m, 1H), 3.17- 3.07 (m, 2H), 2.34-2.32 (m, 4H), 2.26-2.16 (m, 2H), 2.13-2.12 (m, 2H), 0.92-0.92 (m, 1H), 0.56-0.55 (m, 2H ), 0.16-0.16 (m, 2H). 117

5- (cis) - (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 A-2 E-2 C-2 ³ 5.13, 312, C (400 MHz, CDCl ₃ ): 8.79 (dd, J = 7.9, 1.7 Hz, 1H), 8.76 (s, 1H), 8.63 (dd, J = 4.9, 1.7 Hz, 1H), 7.38 (dd, J = 7.9 , 4.9 Hz, 1H), 5.18-4.92 (m, 2H), 3.41-3.41 (m, 1H), 3.21-3.18 (m, 1H), 2.87 (dd, J = 35.6, 14.8 Hz, 1H), 2.78- 2.69 (m, 1H), 2.18-2.07 (m, 2H). 118

5 - ((S) -1-pyrrolidin-2-
ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 B-2 D-2 A-2 2.09, 294, A (300 MHz, DMSO-d ₆ ): 8.81 (dd, J = 7.93, 1.70 Hz, 1H), 8.77 (d, J = 0.51 Hz, 1H), 8.69 (dd, J = 4.79, 1.66 Hz, 1H), 7.45 (dd, J =
7.90, 4.79 Hz, 1H), 4.33 (d, J = 6.2 Hz, 2H), 3.62-3.61 (m, 1H), 2.86-2.85 (m, 2H), 1.97-1.93 (m, 1H), 1.67-1.66 (m, 3H). 119

5 - [(1-ethyl-piperidin-4-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br IN 2 IN 2 NA A-2 ² 2.22, 335, A (300 MHz, DMSO-d ₆ ): 8.98 (dd, J = 8.0, 1.5 Hz, 1H), 8.61 (dd, J = 4.8, 1.5 Hz, 1H), 8.40 (8, 1H), 7.42 (dd, J = 8.0, 4.8 Hz, 1H), 6.49 (t, J = 6.5 Hz, 1H), 3.84-3.64 (m, 2H), 3.04-3.04 (m, 2H), 2.89-2.83 (m, 2H), 2.03- 2.02 (m, 4H), 1.50-1.45 (m, 2H), 1.19 (t, J = 7.3 Hz, 3H). 120

Br A-2 IN 2 NA ^one 5.16, 335, C (400 MHz, CD ₃ OD / CDCl ₃ ): 8.83 (s, 1H), 8.69-8.67 (m, 2H), 7.48-7.46 (m, 1H), 4.02-3.83 (m, 1H), 3.72-3.53 ( m, 2H), 3.24-3.10 (m, 5H), 3.10-2.92 (m, 2H), 2.24-2.10 (m, 4H), 1.35 (t, J = 7.3 Hz, 3H). 5 - [(1-ethyl-piperidin-4-yl) methyl-amino] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

The compounds of the examples in Table 5 were prepared by basic methods. described above.

Table 5 Example Structure / Name 3-x Binding method The method of deprotection Cleaning method LCMS R _T , M + H ⁺ , Method ¹ H NMR (ppm) 121

5-(1-бутилпиперидин-4-илокси)-9Н-дипиридо[2,3-b;4',3'-d]пиррол-6-карбонитрил

5- (1-butylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N A-2 NA S-2 ³ 6.14, 350, C (300 MHz, CD ₃ OD): 8.74 (s, 1H), 8.67-8.62 (m, 2H), 7.56 (s, 1H), 7.43-7.42 (m, 1H), 4.98-4.89 (m, 1H), 3.05-2.92 (m, 2H), 2.44-2.42 (m, 2H), 2.23-2.16 (m, 6H), 1.52-1.51 (m, 2H), 1.41-1.31 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 122

5- (1-methyl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N E-2 A-2 B-2 ³ 4.87, 308, C (400 MHz, DMSO-d ₃ ): 8.79 (s, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.59 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 (dd, J = 7.9, 4.8 Hz, 1H), 4.71-4.69 (m, 1H), 2.76 (d, J = 10.9 Hz, 2H), 2.18 (s, 3H), 2.06 (t, J = 10.1 Hz, 4H), 1.96 -1.94 (m, 2H). 123

trifluoropropyl) -piperidin-4-
ilamino] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 NA B-2 ³ 4.81, 389, C (400 MHz, CD ₃ OD): 8.60 (s, 1H), 8.59 (dd, J = 4.1, 1.5 Hz, 1H), 8.47 (s, 1H), 7.42 (dd, J = 7.7, 5.2 Hz, 1H) , 4.14-4.13 (m, 1H), 3.04 (d, J = 11.3 Hz, 2H), 3.03-2.38 (m,
2H), 2.41-2.40 (m, 2H), 2.33-2.30 (m, 2H), 2.25 (d, J = 13.4 Hz, 3H), 1.85-1.83 (m, 2H). 124

5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) amino] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 NA S-2 ³ 3.99, 319, C (400 MHz, CD ₃ OD): 8.65 (dd, J = 8.0, 1.5 Hz, 1H), 8.61 (dd, J = 4.9, 1.5 Hz, 1H), 8.47 (s, 1H), 7.45 (dd, J = 8.0, 4.9 Hz, 1H), 4.44 (s, 1H), 3.57 (ddd, J = 14.0, 9.4, 2.3 Hz, 1H), 3.14-3.07 (m, 1H), 2.90-2.89 (m, 4H), 2.11 -2.10 (m, 2H), 2.04-1.54 (m, 2H), 1.62-1.61 (m, 1H). 125

5- (2-pyrrolidin-1-yl-ethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N S-2 S-2 B-2 ² 4.16, 308, C (400 MHz, CD ₃ OD): 8.78 (dd, J = 7.9, 1.6 Hz, 1H), 8.74 (s, 1H), 8.65 (dd, J = 4.9, 1.6 Hz, 1H), 7.44 (dd, J = 7.9, 4.9 Hz, 1H), 4.70 (t, J = 5.7 Hz, 2H), 3.15 (t, J = 5.7 Hz, 2H), 2.73-2.72 (m, 4H), 1.83-1.82 (m, 4H). 126

5- (trans) - (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-
b; 4 ', 3'-d] pyrrole-6-carbonitrile N F-2 E-2 IN 2 2.16, 312, A (400 MHz, DMSO-d ₆ ): 8.80 (s, 1H), 8.71 (dd, J = 6.2, 1.7 Hz, 1H), 8.67 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 7.9 , 4.7 Hz, 1H), 4.82-4.81 (m, 2H), 3.25-3.23 (m, 2H), 2.90 (d, J = 13.1 Hz, 1H), 2.42-2.41 (m,
1H), 2.23-2.15 (m, 1H), 1.81 (qd, J = 11.9.4.4 Hz, 1H). 127

5 - [(4-ethyl-morpholin-2-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 NA S-2 2.16, 337, A (400 MHz, CDCl ₃ ): 11.12 (s, 1H), 8.67 (dd, J = 4.9, 1.5 Hz, 1H), 8.55 (s, 1H), 8.39 (dd, J = 8.0, 1.5 Hz, 1H), 7.40 (dd, J = 7.9, 4.9 Hz, 1H), 5.25 (dd, J = 7.1, 4.0 Hz, 1H), 4.10-4.09 (m, 2H), 3.95-3.95 (m, 1H), 3.84 (td, J = 11.3, 2.5 Hz, 1H), 3.72 (ddd, J = 12.7, 8.0, 4.0 Hz, 1H), 2.93 (d, J = 11.3 Hz, 1H), 2.83 (d, J = 11.7 Hz, 1H), 2.48-2.46 (m, 2H), 2.24 (td, J = 11.4, 3.3 Hz, 1H), 2.06 (t, J = 10.7 Hz, 1H), 1.11 (t, J = 7.2 Hz, 3H). 128

5- (4-ethylamino-piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 D-2, A-2 IN 2 2.24, 321, A (400 MHz, CD ₃ OD): 8.74 (s, 1H), 8.71 (dd, J = 8.0, 1.6 Hz, 1H), 8.64 (dd, J = 4.9, 1.6 Hz, 1H), 7.45 (dd, J = 8.0, 4.9 Hz, 1H), 3.64-3.59 (m, 4H), 3.11-3.00 (m, 1H), 2.94 (q, J = 7.2 Hz, 2H), 2.28-2.19 (m, 2H), 1.92-1.83 (m, 2H), 1.28-1.26 (m, 3H). 129

5- (1-oxetan-3-yl-piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 NA S-2, D-2 2.03, 349, A (400 MHz, DMSO-d ₆ ): 12.68 (s, 1H), 8.78 (dd, J = 8.0, 1.6 Hz, 1H), 8.61 (dd, J = 4.8, 1.5 Hz, 1H), 8.44 (s, 1H ), 7.41 (dd, J = 8.0, 4.9 Hz, 1H), 5.72 (d, J = 9.4 Hz, 1H), 4.53 (, J = 6.5 Hz t, 2Н), 4.43 (t, J = 6.0 Hz, 2Н ), 4.00-3.98 (m, 1H), 3.40-3.39 (m, 1H), 2.74 (d, J = 8.9 Hz, 2H), 2.03 (d, J = 10.5 Hz, 2H), 1.99-1.74 (m, 4H). 130

5- (1-Cyclopropylmethyl-piperidin-4-ylamino) -9H-dipyrido [2,3-d; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 C-2 ¹ 2.35, 347, A (400 MHz, CDCl ₃ ): 10.77 (s, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.59 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 7.9, 4.9 Hz, 1H), 4.48 (d, J = 9.9 Hz, 1H), 4.17-4.17 (m, 1H), 3.21 (d, J = 11.4 Hz, 2H), 2.36-2.31 (m, 6H ), 1.95-1.91 (m, 2H), 0.96-0.96 (m, 1H), 0.60-0.55 (m, 2H), 0.18-0.16 (m, 2H). 131

5-
[1,3 '] Bipyrrolidinyl-1'-yl-9H-dipyrido [2,3-b; 4', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 IN 2 2.20, 333, A (400 MHz, DMSO-d ₆ ): 12.78 (s, 1H), 8.66 (s, 1H), 8.65 (dd, J = 4.8, 1.5 Hz, 1H), 8.48 (dd, J = 8.0, 1.6 Hz, 1H ), 7.43 (dd, J = 8.0, 4.8 Hz, 1H), 3.71-3.69 (m, 4H), 3.13
(s, 1H), 2.60 (d, J = 26.2 Hz, 3H), 2.33-2.30 (m, 1H), 2.09-2.07 (m, 1H), 1.76 (s, 4H). 132

5- [1- (3-fluoropropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile N E-2 A-2 S-2 ³ 2.38, 354, A (300 MHz, CD ₃ OD): 8.75 (s, 1H), 8.68-8.62 (m, 2H), 7.44 (dd, J = 7.9, 5.0 Hz, 1H), 4.96-4.94 (m, 1H), 4.52 ( dt, J = 47.3, 5.8 Hz, 2H), 3.06-2.93 (m, 2H), 2.58 (t, J = 7.7 Hz, 2H), 2.35 (t, J = 10.8 Hz, 2H), 2.04-2.03 (m , 6H). 133

5- [4- (3-fluoroazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 B-2 ³ 2.22, 351, A (400 MHz, CD ₃ OD): 8.71 (s, 1H), 8.69 (dd, J = 8.0, 1.6 Hz, 1H), 8.63 (dd, J = 4.9, 1.6 Hz, 1H), 7.44 (dd, J = 8.0, 4.9 Hz, 1H), 5.33-5.04 (m, 1H), 3.74-3.73 (m, 2H), 3.64-3.56 (m, 2H), 3.52-3.51 (m, 2H), 3.37-3.36 (m, 2H), 2.51-2.50 (m, 1H), 2.09-1.99 (m, 2H), 1.68-1.67 (m, 2H). 134

5- [4- (3-hydroxyazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 A-2 ³ 2.13, 349, A (400 MHz, CD ₃ OD): 8.72 (s, 1H), 8.69 (dd, J = 8.0, 1.6 Hz, 1H), 8.63 (dd, J = 4.9, 1.6 Hz, 1H), 7.44 (dd, J = 8.0, 4.9 Hz, 1H), 4.41 (p, J = 6.3 Hz, 1H), 3.74 (td, J = 6.5, 2.2 Hz, 2H), 3.55-3.54 (m, 4H), 3.02 (td, J = 6.6 , 2.1 Hz, 2Н), 2.45-2.38 (m, 1Н), 2.10-1.99 (m, 2Н), 1.67 (q, J = 6.1 Hz, 2Н). 135

5- [4 - ((S) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 B-2 ³ 2.24, 365, A (300 MHz, CD ₃ OD): 8.74 (s, 1H), 8.72 (dd, J = 8.0, 1.6 Hz, 1H), 8.64 (dd, J = 4.9, 1.6 Hz, 1H), 7.44 (dd, J = 8.0, 4.9 Hz, 1H), 5.27 (dt, J = 55.1, 5.5 Hz, 1H), 3.61-3.58 (m, 4H), 3.14 (s, 2H), 2.84 (ddd, J = 32.0, 11.8, 4.9 Hz , 1H), 2.62 (q, J = 7.9 Hz, 1H), 2.50-2.44 (m, 1H), 2.12-2.07 (m, 6H). 136

5- (4-azetidin-1-yl-piperidin-1-yl) -
9H-dipyrido [2 carbonitrile, 3-b; 4 ', 3'-d] pyrrole-6- N D-2 A-2 B-2 ³ 2.19, 333, A (400 MHz, CD ₃ OD): 8.73 (s, 1H), 8.64 (t, J = 7.4 Hz, 2H), 7.56 (s, 1H), 7.42 (dd, J = 7.8, 4.8 Hz, 1H), 3.57 (d, J = 13.8 Hz, 4H), 3.39 (t, J = 7.3 Hz, 4H), 2.44 (t, J = 10.4 Hz, 1H), 2.20-2.18 (m, 2H), 2.04 (d, J =
12.5 Hz, 2H), 1.65 (d, J = 12.6 Hz, 2H). 137

5- [4 - ((R) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 B-2 ³ 2.24, 365, A (300 MHz, CD ₃ OD): 8.74 (s, 1H), 8.71 (dd, J = 8.0, 1.6 Hz, 1H), 8.64 (dd, J = 4.9, 1.6 Hz, 1H), 7.43 (dd, J = 8.0, 4.9 Hz, 1H), 5.28 (dt, J = 55.1, 5.4 Hz, 1H), 3.62-2.59 (m, 4H), 3.30-3.15 (m, 2H), 2.87 (ddd, J = 32.0, 11.8, 4.9 Hz, 1H), 2.70-2.60 (m, 1H), 2.58-2.45 (m, 1H), 2.41-1.90 (m, 6H). 138

5- [4 - ((S) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br IN 2 NA B-2 ³ 2.11, 363, A (400 MHz, DMSO-d ₆ ): 12.88 (s, 1H), 8.79 (s, 1H), 8.71 (d, J = 4.3 Hz, 1H), 8.59 (d, J = 7.5 Hz, 1H), 7.47 ( dd, J = 7.7, 4.8 Hz, 1H), 5.49 (s, 1H), 4.48 (s, 1H), 3.80-3.39 (m, 8H, overlapped by solvent peak), 2.38-2.18 (m, 3H), 2.18- 1.73 (m, 4H). 139

5- [4 - ((R) -3-hydroxy-pyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6- carbonitrile Br IN 2 NA B-2 ³ 2.10, 363, A (400 MHz, DMSO-d ₆ ): 8.80 (s, 1H), 8.72 (dd, J = 4.7, 1.6 Hz, 1H), 8.60 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 (dd, J = 7.9, 4.8 Hz, 1H), 5.67-5.38 (m, 1H),
4.50 (s, 1H), 3.75-3.31 (m, 8H), 2.40-2.21 (m, 3H), 2.09-1.92 (m, 4H). 140

5- (4-hydroxy-piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 E-April ² 2.81, 294, A (400 MHz, CD ₃ OD): 8.72 (dd, J = 8.0, 1.6 Hz, 1H), 8.72 (s, 1H), 8.64 (dd, J = 4.9, 1.6 Hz, 1H), 7.46 (dd, J = 8.0, 4.9 Hz, 1H), 4.09-3.81 (m, 1H), 3.67-3.66 (m, 2H), 3.52-3.50 (m, 2H), 2.20-2.13 (m, 2H), 1.92-1.91 (m, 2H), 1.45 (s, 1H). 141

5- (4-hydroxy- [1,4 '] bipiperidinyl-1'-yl) -9H-dipyrido [2,3-b; 4', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 2 2.14, 377, A (400 MHz, CD ₃ OD): 8.72 (s, 1H), 8.70 (dd, J = 8.0, 1.6 Hz, 1H), 8.64 (dd, J = 4.9, 1.6 Hz, 1H), 7.46 (dd, J = 8.0, 4.9 Hz, 1H), 3.68-3.64 (m, 3H), 3.61-3.53 (m, 2H), 3.14-2.99 (m, 2H), 2.65 (t, J = 11.2 Hz, 1H), 2.49 (t , J = 10.7 Hz, 2H), 2.17 (d, J = 12.3 Hz, 2H), 1.97-1.95 (m, 4H), 1.66-1.65 (m, 2H). 142

5- (4-fluoro- [1,4 '] bipiperidinyl-1'-yl) -9H-dipyrido [2,3-b; 4', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 E-2 ⁴ 2.41, 379, A (400 MHz, CD ₃ OD): 8.77 (s, 1H), 8.72 (dd, J = 8.0, 1.6 Hz, 1H), 8.66 (dd, J = 4.9, 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 4.9 Hz, 1H), 4.96 (d, J = 50.8 Hz, 1H), 3.70-3.68 (m, 4H), 3.46 (s, 5H), 2.37 (d, J = 11.8 Hz, 2H), 2.20- 2.20 (m, 6H). 143

5- (4-hydroxy-4-methylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 B-2 3.16, 308, A (400 MHz, DMSO-d ₆ ): 8.73 (s, 1H), 8.67 (dd, J = 4.8, 1.5 Hz, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.0 , 4.8 Hz, 1H), 3.70 (td, J = 11.2, 2.8 Hz, 2Н), 3.34-3.24 (m, 2Н), 1.87-1.85 (m, 2Н), 1.75 (d, J = 13.0 Hz, 2Н) 1.30 (s, 3H). 144

5- (1-Azabicyclo [2.2.2] oct-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 B-2 ² 2.28, 320, A (300 MHz, DMSO-d ₆ ): 8.83 (s, 1H), 8.78 (dd, J = 8.0, 1.7 Hz, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 7.45 (dd, J = 8.0, 4.8 Hz, 1H), 2.88 (t, J = 7.2 Hz, 6H), 1.93 (t, J = 7.2 Hz, 6H). 145

5- (1,4-Dimethyl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N E-2 A-2 B-2 ³ 2.19, 322, A (400 MHz, DMSO-d ₆ ): 8.81 (s, 1H), 8.70-8.70 (m, 2H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 2.72-2.70 (m, 2H), 2.27 -2.19 (m, 4H), 2.18 (s, 3H), 1.92-1.89 (m, 2H), 1.34 (s, 3H). 146

5- (4-hydroxy-4-methyl [1,4 '] bipiperidinyl-1'-yl) -9H-dipyrido [2,3 b; 4', 3'-d] pyrrole-6-carbonitrile N D-2 A-2 B-2 ³ 2.22, 319, A (400 MHz, DMSO-d ₆ ): 8.73 (s, 1H), 8.67 (dd, J = 4.8, 1.5 Hz, 1H), 8.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (dd, J = 8.0, 4.8 Hz, 1H), 4.09 (s, 1H), 1.99 (d, J = 12.2 Hz, 2H), 3.59 (d, J = 11.8 Hz, 2H), 3.40 (t, J = 11.9 Hz, 2H ), 2.60-2.58 (m, 5H), 1.85-1.82 (m, 2H), 1.53-1.47 (m, 4H), 1.12 (s, 3H). 147

3-bromo-5- (piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Vg IN 2 IN 2 S-2 ³ 5.66, 370/372, C (400 MHz, CDCl ₃ / CD ₃ OD): 8.72 (s, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 3.62-3.57 (m, 4H ), 3.05-3.04 (m, 1H), 2.16-2.13 (m, 2H), 1.80-1.79 (m, 2H). 148

3-bromo-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 D-2, C-2 B-2 2.55, 372, A (400 MHz, DMSO-d ₆ ): 8.78 (s, 1H), 8.76 (d, 1H, J = 2.3 Hz), 8.58 (d, 1H, J = 2.3 Hz), 4.78-4.77 (m, 1H), 3.08 (dt, 2H, J = 13.0, 4.2 Hz), 2.58 (ddd, 2H, J = 12.8, 10.7, 2.7 Hz), 2.06 (d, 2H, J = 12.1 Hz), 1.85-1.74 (m, 2H) . 149

3-bromo-5- (1-oxetan-3-yl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br F-2 E-2 A-2 ³ 2.59, 428, A (400 MHz, DMSO-d ₆ ): 8.80 (d, J = 1.9 Hz, 2H), 8.66 (d, J = 2.3 Hz, 1H), 4.81 (s, 1H), 4.49 (dt, J = 36.1, 6.3 Hz, 4H), 3.43-3.41 (m, 1H), 2.69-2.68 (m, 2H), 2.05-2.02 (m, 6H). 150

3-bromo-5- (1-ethyl-piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br B-2 NA B-2 2 52 399/401, A (400 MHz, CDCl ₃ ): 8.62 (d, J = 2.0 Hz, 2H), 8.44 (s, 1H), 4.17 (s, 1H), 3.05 (s, 2H), 2.52 (s, 2H), 2.23 ( d, J = 13.0 Hz, 4H), 1.82 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H). 151

5- (1-ethyl-piperidin-4-yloxy) -3-fluoro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile F F-2 E-2 B-March ² 2.41, 340, A (400 MHz, DMSO-d ₆ ): 8.79 (s, 1H), 8.74-8.73 (m, 1H), 8.37 (dd, J = 8.5, 2.8 Hz, 1H), 4.79-4.71 (m, 1H), 2.86 -2.82 (m, 2H), 2.34 (q, J = 7.2 Hz, 2H), 2.07-2.04 (m, 4H), 1.97-1.95 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 152

5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -3-fluoro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 carbonitrile F F-2 E-2 B-2 ³ 2.38, 338, V (400 MHz, DMSO-d ₆ ): 8.77 (s, 1H), 8.76-8.74 (m, 1H), 8.28 (dd, J = 8.5, 2.8 Hz, 1H), 5.09-5.07 (m, 1H), 3.47 -3.21 (m, 1H, overlapped by solvent peak), 3.05-3.02 (m, 2H), 2.87-2.76 (m, 1H), 2.67-2.66 (m, 2H), 2.23-2.22 (m, 1H), 2.05 ( s, 1H), 1.69-1.68 (m, 1H), 1.50-1.49 (m, 2H). 153

3-fluoro-5- (4-morpholin-4-yl-piperidin-1-yl) -9H-dipyrido [2,3-
b; 4 ', 3'-d] pyrrole-6-carbonitrile F B-2 NA S-2 ³ 2.29, 381, A (400 MHz, DMSO-d ₆ ): 12.96 (s, 1H), 8.75 (s, 1H), 8.73 (dd, J = 2.8, 1.5 Hz, 1H), 8.28 (dd, J = 9.0, 2.8 Hz, 1H ), 3.62-3.61 (m, 6H), 3.41 (t, J = 11.7 Hz, 2H), 2.58 (t, J = 4.3 Hz, 4H), 2.50-2.39 (m, 1H), 2.06 (d, J = 12.4 Hz
2H), 1.76 (qd, J = 11.6.3.7 Hz, 2H). 154

3-chloro-5- (4-morpholin-4-yl-piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Cl B-2 NA C-2 ³ 2.49, 397/399, A (400 MHz, DMSO-d ₆ ): 8.75 (s, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 3.69-3.57 (m, 6H), 3.42 (t, J = 12.2 Hz, 2H), 2.57 (t, J = 4.3 Hz, 4H), 2.46-2.39 (m, 1H), 2.08 (d, J = 12.2 Hz, 2H), 1.72 (qd, J = 11.7, 3.7 Hz, 2H). 155

3-fluoro-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile F F-2 E-2, D-2 B-2 ⁴ 2.30, 312, A (400 MHz, DMSO-d ₆ ): 8.79 (s, 1H), 8.73 (dd, J = 2.8, 1.7 Hz, 1H), 8.31 (dd, J = 8.5, 2.8 Hz, 1H), 4.75-4.74 (m , 1H), 3.09-3.00 (m, 2H), 2.55-2.54 (m, 2H), 2.06-2.05 (m, 2H), 1.85-1.73 (m, 2H). 156

3-bromo-5- (4-morpholin-4-yl-piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br B-2 E-2 C-April ² 2.51, 441, A (400 MHz, CDCl ₃ ): 8.72 (s, 1H), 8.66-8.65 (m, 2H), 3.83 (s, 4H), 3.70-3.52 (m, 4H), 2.71 (s, 4H), 2.58-2.44 (s, 1H), 2.21 (d, J = 12.2 Hz, 2H), 1.88-1.84 (m, 2H). 157

5 - [(S) - (1-azabicyclo [2.2.2] ok t-3-yl) oxy] -3-chloro-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole- 6-carbonitrile Cl F-2 E-2 B-2 ⁴ 2.61, 354/356, A (400 MHz, DMSO-d ₆ ): 8.77 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 5.07-5.06 (m, 1H), 3.44-3.20 (m, 1H, overlapped by solvent peak), 3.04-2.99 (m, 2H), 2.85-2.82 (m, 1H), 2.74-2.59 (m, 2H), 2.24-2.21 (m, 1H), 2.11 -1.99 (m, 1H), 1.70-1.69 (m, 1H), 1.51-1.50 (m, 2H). 158

3-chloro-5- (1-ethyl-piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Cl B-2 NA F-2 2.47, 355, A (400 MHz, CD ₃ OD): 8.72 (d, J = 2.3 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.42 (s, 1H), 4.18-4.14 (m, 1H), 3.09 -3.05 (m, 2H), 2.51 (q, J = 7.3 Hz, 2H), 2.21-2.17 (m, 4H), 1.90-1.81 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H). 159

3-chloro-5- (4-pyrrolidin-1-yl-piperidin-1-yl) -9H-dipyrido [2,3-
b; 4 ', 3'-d] pyrrole-6-carbonitrile Cl IN 2 NA S-2 ⁴ 2.56, 381/383, A (400 MHz, CD ₃ OD): 8.73 (s, 1H), 8.63-8.62 (m, 2H), 3.59-3.58 (m, 4H), 2.89-2.66 (m, 4H), 2.48-2.41 (m, 1H ), 2.27 (d, J = 12.7 Hz, 2H), 1.91-1.90 (m, 6H).

The compounds of the examples in Table 6 were obtained by the basic methods described above.

Table 6 Example Structure / Name 3-x Binding method The method of deprotection The method of reductive amination Cleaning method LCMS R _T , M + H ⁺ , Method ¹ H NMR (ppm) 160

N F-2 D-2 IN 2 C ³ 2.39, 336, A (400 MHz, CDCl ₃ ): 8.80 (s, 1H), 8.70 (dd, J = 4.9, 1.6 Hz, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 7.9, 4.9 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 3.36 (s, 1H), 3.02 (s, 1H), 2.57 (s, 2H), 2.50 (s, 2H), 2.10 (s, 2H) ), 1.98 (m, 1H), 1.84 (s, 2H), 1.31-1.27 (m, 1H), 1.17 (t, J = 7.0 Hz, 3H). 5- (1-ethyl-piperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'd] pyrrole-6-carbonitrile 161

5- (1-ethyl-piperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N F-2 D-2 IN 2 S-2 ³ 2.40, 336 A (400 MHz, CD ₃ OD): 8.73 (s, 1H), 8.67 (q, J = 1.8 Hz, 1H), 8.65 (s, 1H), 7.46-7.46 (m, 1H), 4.48 (d, J = 6.1 Hz, 2H), 3.16-3.08 (m, 2H), 2.53 (q, J = 7.3 Hz, 2H), 2.22-2.02 (m, 5
H), 1.63 (q, J = 12.6 Hz, 2H), 1.15 (t, J = 7.3 Hz, 3H). 162

5 - ((S) -1-ethyl-piperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N F-2 D-2 IN 2 S-2 ³ 2.39, 336, A (400 MHz, CD ₃ OD): 8.73 (s, 1H), 8.65-8.65 (m, 2H), 7.46 (dd, J = 7.8, 5.0 Hz, 1H), 4.54-4.40 (m, 2H), 3.40- 3.29 (m, 1H), 3.00 (d, J = 11.4 Hz, 1H), 2.52-2.52 (m, 2H), 2.40-2.32 (m, 1H), 2.05-2.04 (m, 3H), 1.87-1.80 ( m, 1H), 1.74-1.73 (m, 1H), 1.30-1.29 (m, 1H), 1.13 (t, J = 7.3 Hz, 3H). 163

5- (1-methylazepan-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N F-2 D-2 A-2 IN 2 2.30, 322, A (400 MHz, DMSO-de): 8.77 (s, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.56 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 (dd, J = 7.9, 4.8 Hz, 1H), 4.98-4.97 (m, 1H), 2.68 (ddd, J = 13.4, 7.3, 3.0 Hz, 1H), 2.58 (ddd, J = 12.4, 8.7, 3.4 Hz, 1H), 2.45 -2.44 (m, 2H), 2.26 (s, 3H), 2.25-1.99 (m, 4H), 1.83-1.82 (m, 1H), 1.56-1.54 (m, 1H). 164

5- [1- (2-hydroxy-2-methylpropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N F-2 D-2 C-2 B-2 ⁴ 2.36, 366, A (400 MHz, DMSO-d ₆ ): 8.78 (s, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.58 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 (dd, J = 7.9, 4.8 Hz, 1H), 5.75 (s, 1H), 4.68-4.66 (m, 1H), 2.99-2.95 (m, 2 H), 2.27 (t, J = 11.2 Hz, 2H), 2.21 (s , 2H), 2.09-1.98 (m, 2H), 2.02-1.90 (m, 2H), 1.09 (s, 6H). 165

5- (1-ethyl-azetidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile N F-2 D-2, E-2 B-2 B-2 ⁴ 3.92, 294, C (400 MHz, DMSO-d ₆ ): 8.78 (s, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.63 (dd, J = 7.9, 1.7 Hz, 1H), 7.46 (dd, J = 7.9, 4.8 Hz, 1H), 5.31-5.30 (m, 1H), 3.69-3.68 (m, 2H), 3.35-3.33 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H). 166

3-fluoro-5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile F F-2 D-2, E-2 B-2 S- ^2-3 2.33, 326, A (400 MHz, CDCl ₃ ,): 8.72 (s, 1H), 8.57-8.47 (m, 1H), 8.36-8.22 (m, 1H), 5.10-4.95 (m, 1H), 3.06-2.77 (s, 2H ), 2.64 (s, 3H), 2.38-2.24 (m, 4H), 2.18-2.01 (m, 2H). 167

3-chloro-5- (1-methyl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Cl F-2 D-2, E-2 A-2 B-2 ⁴ 2.51, 342/344, A (400 MHz, DMSO-d ₆ ): 8.80 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 4.81-4.76 (m, 1H), 2.75-2.73 (m, 2H), 2.19 (s, 3H), 2.10-2.07 (m, 4H), 2.00-1.89 (m, 2H). 168

3-chloro-5- (1-ethyl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Cl F-2 D-2, E-2 B-2 B-2 ⁴ 2.62, 356/358, A (400 MHz, DMSO-d ₆ ): 8.80 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 4.86-4.73 (m, 1H), 2.86-2.81 (m, 2H), 2.35 (q, J = 7.2 Hz, 2H), 2.16-2.01 (m, 4H), 1.96-1.94 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H) .

The compounds of the examples in Table 7 were obtained by hydrogenation of the corresponding 3-Br analogues.

Table 7 Example Structure / Name 3-x Binding method The method of deprotection Cleaning Method (s) LCMS R _T (min), M + H ⁺ , Method ¹ H NMR (ppm) 169

5-(1-метил-пиперидин-4-иламино)-9Н-дипиридо[2,3-b;4',3'-d]пиррол-6-карбонитрил

5- (1-methyl-piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br A-2 NA 3.99, 307, C (400 MHz, CD ₃ OD): 8.69 (dd, J = 8.0, 1.5 Hz, 1H), 8.62 (dd, J = 4.9, 1.5 Hz, 1H), 8.53 (s, 1H), 7.44 (dd, J = 8.0, 4.9 Hz, 1H), 4.35-4.22 (m, 1H), 3.56 (d, J = 12.9 Hz, 2H), 3.23-3.07 (s, 2H), 2.87 (s, 3H), 2.42 (d, J = 14.0 Hz, 2H), 2.10-2.05 (m, 2H). 170

5- (4-pyrrolidin-1-yl-piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br A-2 NA 4.92, 347, C (400 MHz, CD ₃ OD): 8.77 (s, 1H), 8.72 (dd, J = 8.0, 1.6 Hz, 1H), 8.66 (dd, J = 4.9, 1.6 Hz, 1H), 7.46 (dd, J = 8.0, 4.9 Hz, 1H), 3.67 (dd, J = 8.2, 2.4 Hz, 4H), 3.58-3.36 (s, 5H), 2.45-2.36 (m, 2H), 2.20-2.05 (s, 6H). 171

5- (4-morpholin-4-yl-piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br A-2 NA 4.39, 363, C (400 MHz, CD ₃ OD): 8.77 (s, 1H), 8.71 (dd, J = 8.0, 1.6 Hz, 1H), 8.66 (dd, J = 4.9, 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 4.9 Hz, 1H), 3.94 (s, 4H), 3.55-3.02 (m, 5H, overlapped by solvent peak), 3.73-3.60 (m, 4H), 2.45-2.31 (m, 2H), 2.20-2.00 ( m, 2H). 172

5- (piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br. A-2 IN 2 B-2 ² 4.17, 293, C (400 MHz, CD ₃ OD / CDCl ₃ ): 8.69 (dd, J = 8.0, 1.5 Hz, 1H), 8.62 (dd, J = 4.9, 1.5 Hz, 1H), 8.54 (s, 1H), 7.44 (dd , J = 8.0, 4.9 Hz,
1H), 4.35-4.33 (m, 1H), 3.59-3.49 (m, 2H), 3.15 (td, J = 12.9, 3.0 Hz, 2H), 2.50-2.39 (m, 2H), 2.14-2.02 (m, 2H). 173

5-piperazin-1-yl-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile Br A-2 IN 2 2 3.08, 279, C (400 MHz, CD ₃ OD): 8.98-8.91 (m, 1H), 8.91 (s, 1H), 8.73 (d, J = 5.1 Hz, 1H), 7.63-7.57 (m, 1H), 3.85-3.80 ( m, 4H), 3.64-3.59 (m, 4H).

Example 174: 5- [1- (2,2-difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Stage 1: 4- (9-benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-5-yloxy) piperidine-1-carboxylic acid tert- butyl ether

Solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (15.8 g, 36.8 mmol), 4-hydroxypiperidin-1- carboxylic acid mpem-butyl ether (18.5 g, 92.0 mmol) and triphenylphosphine (24.1 g, 92.0 mmol) in anhydrous THF (100 ml) were treated dropwise with diethyl azodicarboxylate (18.1 ml, 92.0 mmol) and the mixture was heated at 50 ° C for 40 minutes. After that, the reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography (silica gel, 2 × 330 g column, ISCO, 0-10% ethyl acetate in dichloromethane). The resulting product was purified by trituration with diethyl ether to give the title compound as a grayish-white precipitate (17.6 g, 78%). ¹ H NMR (300 MHz, CDCl ₃ ): 9.57 (s, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.23-8.22 (m, 2H) , 7.64-7.63 (m, 1H), 7.53-7.51 (m, 2H), 5.20-5.20 (m, 1H), 4.07 (d, J = 13.6 Hz, 2H), 3.06 (t, J = 12.1 Hz, 2H ), 2.20-2.19 (m, 2H), 1.85-1.85 (m, 2H), 1.47 (s, 9H).

Stage 2: 9-benzenesulfonyl-3-bromo-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

To a solution of 4- (9-benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrol-5-yloxy) piperidine-1-carboxylic acid mpem-butyl ether (12.6 g, 20.6 mmol) in dichloromethane (36 ml) was added TFA (36 ml). After 1 hour at ambient temperature, the reaction mixture was concentrated in vacuo and the precipitate was partitioned between saturated aqueous sodium carbonate (800 ml) and dichloromethane (2 L). The organic phase was separated, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give the title compound as a grayish-white precipitate (8.8 g, 84%), which was used without further purification. ¹ H NMR (300 MHz, DMSO-d ₆ ): 9.46 (s, 1H), 8.90 (d, J = 2.3 Hz, 1H), 8.64 (d, J = 2.3 Hz, 1H), 8.23-8.22 (m, 2H), 7.78 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.8 Hz, 2H), 4.85-4.85 (m, 1H), 3.17 (s, 1H), 3.00 (dt, J = 13.0 , 4.1 Hz, 2H), 2.50-2.49 (m, 2H is overlapped by the peak of the solvent), 2.15-1.97 (m, 2H), 1.75-1.75 (m, 2H).

Stage 3: 9-benzenesulfonyl-3-bromo-5- [1- (2,2-difluoroethyl) piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole -6-carbonitrile

To a suspension of 9-benzenesulfonyl-3-bromo-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (450 mg, 0.88 mmol) in THF (8 ml), 2,2-difluoroethyl trifluoromethasulfonate (282 mg, 1.32 mmol) in THF (1 ml) was added, followed by DIPEA (250 μl). The resulting reaction mixture was heated at 65 ° C for 7 hours, then concentrated in vacuo. The precipitate was triturated with ethyl acetate to give the title compound as a pale yellow precipitate (485 mg, 96%). ¹ H NMR (300 MHz, DMSO-d ₆ ): 9.46 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.24-8.23 (m, 2H), 7.78 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.8 Hz, 2H), 6.13 (tt, J = 55.8, 4.3 Hz, 1H), 4.85-4.85 (m, 1H), 3.17-3.12 (m, 2H), 2.75 (td, J = 15.7, 4.3 Hz, 2H), 2.37 (t, J = 10.9 Hz, 2H), 2.08-2.07 (m, 2H), 1.96-1.95 (m, 2H).

Stage 4: 9-benzenesulfonyl-5- [1- (2,2-difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Suspension of 9-benzenesulfonyl-3-bromo-5- [1- (2,2-difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6 β-carbonitrile (240 mg, 0.42 mmol) and palladium-carbon (10 wt.%, 50 mg) in technical denatured alcohol (5 ml) and dichloromethane (5 ml) were stirred at ambient temperature in a hydrogen atmosphere for 5 days. The reaction vessel was purged with nitrogen, then the reaction mixture was filtered through a PTFE (polytetrafluoroethylene) filter cup. The filtrate was evaporated in vacuo and the resulting residue was purified by flash chromatography (silica gel, 10 g column, ISCO, 0-2% methanol in dichloromethane) to give the title compound as a grayish-white precipitate (66 mg, 32% ) LCMS (Method B): R _T = 3.74 min, M + H ⁺ = 518.

Step 5: 5- [1- (2,2-Difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of 9-benzenesulfonyl-5- [1- (2,2-difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile ( 68 mg, 0.14 mmol) in methanol (5 ml) was added potassium carbonate (193 mg, 1.4 mmol), and the resulting suspension was heated at 40 ° C for 4 hours. After that, the reaction mixture was loaded directly onto a 5 g SPE NH ₂ cartridge, which was eluted with a 1: 1 mixture of methanol: dichloromethane. The appropriate fractions were concentrated in vacuo and the resulting residue was purified by flash chromatography (silica gel, 10 g column, Si-SPE, 0-4% 2N NH ₃ in methanol and dichloromethane) to give the title compound as a pale yellow precipitate (36 mg, 73%). LCMS (Method C): R _T = 6.07 min, M + H ⁺ = 358. ¹ H NMR (300 MHz, CD ₃ OD): 8.74 (s, 1H), 8.64-8.64 (m, 2H) , 7.58 (s, 1H), 7.43 (dd, J = 7.9, 4.9 Hz, 1H), 5.94 (tt, J = 55.8, 4.2 Hz, 1H), 4.93-4.92 (m, 1H), 3.11-2.99 (m, 2H), 2.82 (td, J = 15.1, 4.3 Hz, 2H), 2.51-2.51 (m , 2H), 2.15-2.14 (m, 4H).

Example 175: 5- [1- (2-methanesulfonylethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

Stage 1: 9-benzenesulfonyl-3-bromo-5-P- (2-methanesulfonylethyl) piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6- carbonitrile

To a suspension of 9-benzenesulfonyl-3-bromo-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (400 mg, 0.78 mmol) in methanol (10 ml) methyl vinyl sulfone (207 mg, 1.95 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 24 hours, then concentrated in vacuo. The precipitate was triturated with ethyl acetate to give the title compound as a pale yellow precipitate (446 mg, 92%). ¹ H NMR (300 MHz, DMSO-d ₆ ): 9.46 (d, J = 0.4 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.3 Hz, 1H), 8.24 -8.24 (m, 2H), 7.78 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.8 Hz, 2H), 4.86-4.86 (m, 1H), 3.27 (t, J = 7.1 Hz, 2H is blocked by solvent peak), 3.03 (s, 3H), 2.92-2.80 (m, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.21 (t, J = 10.9 Hz, 2H), 2.22-1.98 ( m, 2H), 1.92-1.92 (m, 2H).

Stage 2: 9-benzenesulfonyl-5- [1- (2-methanesulfonylethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3-d] pyrrole-6-carbonitrile

Suspension of 9-benzenesulfonyl-3-bromo-5- [1- (2-methanesulfonylethyl) piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (245 mg, 0.39 mmol) and palladium on carbon (10 wt.%, 50 mg) in industrial denatured alcohol (5 ml), dichloromethane (5 ml) and triethylamine (3 ml) were stirred at ambient temperature in a hydrogen atmosphere for 24 hours. The reaction vessel was purged with nitrogen, then the reaction mixture was filtered through a PTFE filter cup. The filtrate was evaporated in vacuo and the resulting residue was purified by flash chromatography (silica gel, 10 g column, ISCO, 0-50% ethyl acetate in dichloromethane) to give the title compound as a grayish-white precipitate (140 mg, 65% ) LCMS (Method C): R _T = 4.97 min, M + H ⁺ = 400. ¹ H NMR (300 MHz, DMSO-d ₆ ): 9.49 (s, 1H), 8.76 (dd, J = 4.8, 1.6 Hz, 1H), 8.63 (dd, J = 7.9, 1.7 Hz, 1H), 8.25- 8.24 (m, 2H), 7.76 (t, J = 7.4 Hz, 1H), 7.64-7.63 (m, 3H), 4.76-4.75 (m, 1H), 3.26 (t, J = 7.4 Hz, 2H is blocked by the solvent peak ), 3.02 (s, 3H), 2.88 (d, J = 11.3 Hz, 2H), 2.72 (t, J = 6.8 Hz, 2H), 2.14-2.14 (m, 4H), 1.91-1.91 (m, 2H) .

Stage 3: 5- [1- (2-methanesulfonylethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a solution of 9-benzenesulfonyl-5- [1 - (2-methanesulfonylethyl) piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (6138 mg , 0.26 mmol) in methanol (10 ml) was added potassium carbonate (353 mg, 2.6 mmol), and the resulting suspension was heated at 40 ° C for 3 hours. After that, the reaction mixture was loaded directly onto a 5 g SPE NH ₂ cartridge, which was eluted with a 1: 1 mixture of methanol: dichloromethane. The appropriate fractions were concentrated in vacuo and the resulting residue was purified by flash chromatography (silica gel, 25 g column, Si-SPE, 0-5% 2N NH ₃ in methanol and dichloromethane) to give the title compound as a pale yellow precipitate (49 mg, 47%). ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.96 (s, 1H), 8.79 (s, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 8.59 (dd, J = 7.9, 1.6 Hz, 1H), 7.47 (dd, J = 7.9, 4.8 Hz, 1H), 4.87-4.57 (m, 1H), 3.28-3.26 (m, 2H is overlapped by solvent peak), 3.04 (s, 3H), 3.02-2.77 (m, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.20 (t, J = 10.8 Hz, 2H), 2.21-1.97 (m, 2H), 1.96-1.89 (m, 2H).

Example 176: 5- [1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile but

Stage 1: 9-benzenesulfonyl-3-bromo-5- {1- [2- (tetrahydropyran-2-yloxy) -ethyl] -piperidin-4-yloxy} -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

To a suspension of 9-benzenesulfonyl-3-bromo-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (789 mg, 1.54 mmol) sodium iodide (46 mg, 0.31 mmol) was added in acetonitrile (50 ml), and the resulting suspension was sonicated for 5 minutes. 2- (2-bromoethoxy) tetrahydropyran (483 mg, 2.31 mmol) was added, and the reaction mixture was heated at 50 ° C for 48 hours. The resulting precipitate was concentrated in vacuo, then dissolved in dichloromethane, diluted with 1N. aqueous sodium carbonate (50 ml) and was extracted with dichloromethane (3 × 50 ml). The combined organic layer was dried (Na ₂ SO ₄ ), filtered, evaporated in vacuo and the resulting residue was purified by flash chromatography (silica gel, 40 g column, ISCO, 0-30% ethyl acetate in dichloromethane) to give the title compound, as a pale yellow precipitate (330 mg, 33%). ¹ H NMR (300 MHz, CDCl ₃ ): 9.54 (s, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.23-8.22 (m, 2H) , 7.64-7.64 (m, 1H), 7.53-7.50 (m, 2H), 5.13-5.11 (m, 1H), 4.59 (t, J = 3.5 Hz, 1H), 3.87-3.86 (m, 2H), 3.54 -3.52 (m, 2H), 2.99 (d, J = 11.6 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 2.35 (t, J = 11.3 Hz, 2H), 2.22 (d, J = 12.3 Hz, 2H), 2.03-1.99 (m, 2H), 1.87-1.47 (m, 6H).

Stage 2: 9-benzenesulfonyl-3-bromo-5- {1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2.3-b; 4'.3'-d] pyrrole-6-carbonitrile

To a solution of 9-benzenesulfonyl-3-bromo-5- {1 - [2- (tetrahydropyran-2-yloxy) -ethyl] -piperidin-4-yloxy} -9H-dipyrido [2,3-b; 4 ', 3 '-d] pyrrole-6-carbonitrile (330 mg, 0.52 mmol) in dichloromethane (5 ml) and methanol (10 ml) was added n-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and the reaction mixture was heated at 40 ° C. for 4 hours, then concentrated in vacuo. The resulting precipitate was dissolved in dichloromethane, diluted with saturated aqueous sodium bicarbonate (20 ml) and extracted with dichloromethane (3 × 20 ml). The combined organic layer was dried (Na ₂ SO ₄ ), filtered, evaporated in vacuo to give the crude title compound as a pale yellow precipitate (312 mg), which was used without purification. ¹ H NMR (300 MHz, CDCl ₃ ): 9.56 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.23-8.22 (m, 2H) , 7.64-7.63 (m, 1H), 7.52-7.51 (m, 2H), 5.16-5.14 (m, 1H), 3.65 (t, J = 5.3 Hz, 2H), 2.96 (m, J = 11.5 Hz, 2H ), 2.61 (t, J = 5.3 Hz, 2H), 2.39 (t, J = 11.3 Hz, 2H), 2.25 (m, J = 12.5 Hz, 2H), 2.03-2.01 (m, 2H).

Stage 3: 9-benzenesulfonyl-5- {1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2.3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Suspension of 9-benzenesulfonyl-3-bromo-5- [1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (283 mg, 0.51 mmol) and palladium on carbon (10 wt.%, 50 mg) in technical denatured alcohol (3 ml) and dichloromethane (3 ml) were stirred at ambient temperature in a hydrogen atmosphere for 48 hours. The reaction vessel was purged with nitrogen, then the reaction mixture was filtered through a PTFE filter cup. The filtrate was evaporated in vacuo and the resulting precipitate was purified by flash chromatography (silica gel, 24 g column, ISCO, 0-30% methanol in dichloromethane) to give the title compound as a grayish-white precipitate (125 mg, 51% ) ¹ H NMR (300 MHz, CDCl ₃ ): 9.59 (s, 1H), 8.76 (dd, J = 4.9, 1.7 Hz, 1H), 8.54 (dd, J = 7.9, 1.7 Hz, 1H), 8.27-8.26 ( m, 2H), 7.62-7.61 (m, 1H), 7.56-7.44 (m, 3H), 5.04-5.03 (m, 1H), 3.70 (t, J = 5.2 Hz, 2H), 3.09-3.09 (m, 2H), 2.69 (t, J = 5.2 Hz, 2H), 2.51 (t, J = 11.0 Hz, 2H), 2.32-2.25 (m, 2H), 2.12-2.10 (m, 2H).

Stage 4: 5- [1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile

Solution of 9-benzenesulfonyl-5- [1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (125 mg, 0.26 mmol) and triethylamine (1 ml) in methanol (10 ml) were heated at 60 ° C for 3 hours. The mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (silica gel, 10 g column, ISCO, 0-8% methanol in dichloromethane). The resulting material was triturated with acetonitrile and methanol to give the title compound as a grayish-white precipitate (40 mg, 45%). LCMS (Method C): R _T = 4.83 min, M + H ⁺ = 338.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.79 (s, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.59 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 ( dd, J = 7.9.4.8 Hz, 1H), 4.71-4.69 (m, 1H), 4.38 (s, 1H), 3.49 (s, 2H), 2.93-2.81 (m, 2H), 2.40 (t, J = 6.3 Hz, 2H), 2.15 (t, J = 11.1 Hz, 2H), 2.06 (d, J = 12.0 Hz, 2H), 1.93-1.92 (m, 2H).

Example 177: 5- (1-ethyl-piperidin-4-yloxy) -3-methyl-9H-dipyrido [2,3-b; 4'.3'-d] pyrrole-6-carbonitrile

Mixture of 9-benzenesulfonyl-3-bromo-5- (1-ethyl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-6-carbonitrile (215 mg, 0.40 mmol), trimethylboroxine (167 μl, 1.2 mmol), cesium carbonate (156 mg, 0.48 mmol) and tetrakis (triphenylphosphine) palladium (0) (96 mg, 0.04 mmol) in dioxane (2.0 ml) were degassed with argon and heated under microwave radiation at 100 ° C for 90 minutes. The reaction mixture was allowed to cool to ambient temperature, diluted with saturated aqueous ammonium chloride (10 ml) and was extracted with dichloromethane (3 × 10 ml). The combined organic phase was washed with brine (2 × 10 ml) and concentrated in vacuo. The resulting precipitate was diluted with THF (10 ml), 1N was added. aqueous potassium hydroxide (1 ml), and the reaction mixture was then heated at 50 ° C. for 1 hour. The solvent was evaporated in vacuo and the resulting residue was purified by chromatography (silica gel, 2 g column, Si-SPE, 0-10% 2-propanol in dichloromethane). The appropriate fractions were combined and evaporated in vacuo, the resulting residue was triturated with pentane (2x2 ml) to give the title compound as a grayish-white precipitate (69 mg, 52%). LCMS (Method A): R _T = 2.46 min, M + H ⁺ = 336.2. ¹ H NMR (400 MHz, CD ₃ OD): 8.71 (s, 1H), 8.52 (dd, J = 2.1, 0.7 Hz, 1H), 8.47 (dd, J = 2.1, 0.9 Hz, 1H), 4.91-4.88 (m, 1H), 5 3.02-2.99 (m, 2H), 2.57 (s, 3H), 2.50 (q, J = 7.2 Hz, 2H), 2.26-2.19 (m, 4H), 2.12-2.11 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H).

Example 178: 5- (1-ethyl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole

Stage 1: 3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-5-ol

9-benzenesulfonyl-3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-5-ol (4.0 g, 9.32 mmol) was dissolved in concentrated hydrochloric acid (100 ml) and heated in autoclave at 125 ° C for 40 hours. The mixture was allowed to cool to ambient temperature and then evaporated in vacuo. The resulting precipitate was loaded onto a 50 g SCX-2 cartridge, which was washed with methanol, then 2N. ammonia in methanol. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a light brown precipitate (2.44 g, 99%). LCMS (Method B): R _T = 2.70 min, M + H ⁺ = 264/266. ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.25 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H) 8.04 (s, 1H).

Stage 2: 3-bromo-5-hydroxy-dipyrido [2,3-b; 4'.3'-d] pyrrole-9-carboxylic acid benzyl ether

Sodium hydride (167 mg, 4.17 mmol) was added to a chilled (0 ° C) mixture of 3-bromo-9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-5-ol (1.0 g, 3.79 mmol) in DMF (15 ml). Upon completion of the addition, the mixture was stirred for 15 minutes, then allowed to warm to ambient temperature and was stirred for 15 minutes. A solution of benzyl chloroformate (610 mg, 3.6 mmol) in DMF (1 ml) was added and stirring continued for 18 hours. The solvent was evaporated and the resulting precipitate was diluted with water, extracted with dichloromethane (5 × 50 ml) and ethyl acetate (3 × 30 ml). The combined organic layer was dried over (Na ₂ SO ₄ ), filtered and evaporated to give a precipitate. The resulting precipitate was purified using flash chromatography (silica gel, 12 g cartridge, ISCO, 0-7% methanol in dichloromethane). Suitable fractions were collected and evaporated to give the title compound as a pale yellow solid (240 mg, 17%). LCMS (Method B): R _T = 4.54 min, M + H ⁺ = 398/400. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.99 (s, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H) 7.63 (d, J = 7.5 Hz, 2H); 7.48-7.36 (m, 3H); 5.61 (s, 2H).

Stage 3: 3-bromo-5- (1-tert-butoxycarbonyl-piperidin-4-yloxy) dipyrido [2,3-b; 4'.3'-d] pyrrole-9-carboxylic acid benzyl ester

A solution of 3-bromo-5-hydroxy-dipyrido [2,3-b; 4 ', 3'-d] pyrrole-9-carboxylic acid benzyl ester (234 mg, 0.59 mmol), 4-hydroxypiperidin-1-carboxylic acid tert of butyl ether (295 mg, 1.47 mmol) and triphenylphosphine (390 mg, 1.47 mmol) in anhydrous THF (7 ml) were treated dropwise with diethyl azodicarboxylate (295 mg, 1.47 mmol). Upon completion of the addition, the mixture was heated at 50 ° C for 1 hour. The mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (silica gel, 12 g cartridge, ISCO, 0-7% methanol in dichloromethane). The appropriate fractions were collected and evaporated to give the title compound as an orange oil (0.34 g, 100%). LCMS (Method B): R _T = 4.76 min, M + H ⁺ = 581/583. ¹ H NMR (400 MHz, CDCl ₃ ): 9.27 (s, 1H), 8.80 (d, J = 2.3 Hz, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.32 (s, 1H), 7.60 (d, J = 7.3 Hz, 2H), 7.43-7.36 (m, 3H), 5.64 (s, 2H), 4.89 (m, 1H), 3.40-3.39 (m, 2H), 3.02 (ddd, J = 13.5 , 9.8, 3.4 Hz, 2H), 2.21-1.80 (m, 4H), 1.46 (s, 9H).

Stage 4: 3-bromo-5- (piperidin-4-yloxy) dipyrido [2,3-b; 4'.3'-d] pyrrole-9-carboxylic acid benzyl ester

Solution of 3-bromo-5- (1-tert-butoxycarbonyl-piperidin-4-yloxy) dipyrido [2,3-b; 4 ', 3'-d] pyrrole-9-carboxylic acid benzyl ether (0.34 g, 0.59 mmol ) in trifluoroacetic acid (2 ml) and dichloromethane (4 ml) was stirred at ambient temperature for 15 minutes. The solvent was evaporated and the resulting residue was treated with saturated sodium hydrogen carbonate solution (20 ml) and extracted with dichloromethane (3 × 30 ml). The combined organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated to give a precipitate. The resulting precipitate was purified by flash chromatography (silica gel, 12 g cartridge, ISCO, 0-10% methanol in dichloromethane, then 10% 2M NH ₃ in methanol and dichloromethane). The appropriate fractions were combined and evaporated to give the title compound as a yellow precipitate (118 mg, 42%). LCMS (Method B): R _T = 3.13 min, M + H ⁺ = 481/483. ¹ H NMR (400 MHz, CDCl ₃ ): 9.22 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 7.60 -7.59 (m, 2H), 7.40-7.40 (m, 3H), 5.63 (s, 2H), 4.86-4.82 (m, 1H), 3.26-3.25 (m, 2H), 2.95-2.94 (m, 2H) 2.29-2.25 (m, 2H); 1.99-1.97 (m, 2H).

Stage 5: 3-bromo-5- (1-ethyl-piperidin-4-yloxy) dipyrido [2,3-b; 4 ', 3'-d] pyrrole-9-carboxylic acid benzyl ether

Acetaldehyde (3M solution in dichloromethane, 0.16 ml, 0.48 mmol) was added to a mixture of 3-bromo-5- (piperidin-4-yloxy) dipyrido [2,3-b; 4 ', 3'-a] pyrrole-9- carboxylic acid benzyl ether (116 mg, 0.24 mmol), sodium triacetoborohydride (77 mg, 0.36 mmol) and acetic acid (17 μL, 0.29 mmol) in methanol (3 ml) and dichloromethane (1 ml), and the mixture was stirred for 18 hours. The solvent was evaporated, and the resulting residue was diluted with saturated aqueous sodium hydrogen carbonate (20 ml) and extracted with dichloromethane (3 × 30 ml). The combined organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to give a precipitate. The resulting precipitate was purified by flash chromatography (silica gel, 12 g cartridge, ISCO, 0-8% methanol in dichloromethane). Suitable fractions were collected and evaporated to give the title compound as a pale yellow precipitate (75 mg, 61%). LCMS (Method B): R _T = 3.43 min, M + H ⁺ = 509/511. ¹ H NMR (400 MHz, CDCl ₃ ): 9.23 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.62 (s, 1H), 8.31 (s, 1H), 7.60-7.60 (m, 2H), 7.40-7.40 (m, 3H), 5.63 (s, 2H), 4.85 (s, 1H), 2.91 (brs, 2H), 2.62 (br s, 2H), 2.33 (brs, 2H), 2.14 ( brs, 2H), 1.59 (brs, 2H), 1.23 (brs, 3H).

Stage 6: 5- (1-ethyl-piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ', 3'-d] pyrrole

Mixture of 3-bromo-5- (1-ethyl-piperidin-4-yloxy) dipyrido [2,3-b; 4 ', 3'-d] pyrrole-9-carboxylic acid benzyl ether (75 mg, 0.15 mmol) , palladium on charcoal (10 wt.%, 10 mg) and triethylamine (0.1 ml) in THF (5 ml) was stirred in a hydrogen atmosphere for 3 days. The catalyst was removed by filtration through Celite ^© , and the filtrate was evaporated to give a precipitate. The resulting precipitate was loaded onto a 2 g SCX-2 cartridge, which was washed with methanol, then 2N. ammonia in methanol. The main methanol fractions were evaporated and the resulting residue was purified by flash chromatography (silica gel, 4 g cartridge, ISCO, 0-7% methanol in dichloromethane). Suitable fractions were collected and evaporated to give the title compound as a white precipitate (33 mg, 75%). LCMS (Method A): R _T = 1.51 min, M + H ⁺ = 297. ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.13 (s, 1H), 8.53-8.53 (m, 3H), 8.21 (s, 1H), 7.32 (dd, J = 7.7, 4.8 Hz, 1H), 4.85-4.84 (m, 1H), 2.70-2.67 (m, 2H), 2.38-2.36 (m, 4H), 2.07-2.06 (m, 2H), 1.88-1.87 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H).

EXAMPLE i Chk1 and chk2 analysis (chk primary analysis)

A full-sized mutant recombinant human protein labeled with histidine and expressed in insect cells (Invitrogen, chk1 catalog number PV3982 and chk2 catalog number PV3983) was used as a source of enzymatic activity.

AlphaScreen chk1 kinase analysis was performed for 30 minutes in the presence of HumCM ATP using the Akt substrate-1 biotinylated peptide (Cell Signaling Technology, product # 1065) as a substrate. Phosphorylation of the substrate was detected and counted using AlphaScreen technology. It consists of an antibody to phospho-Akt substrate-1 (Cell Signing technOIOgy product # 9611) and two AlphaScreen beads (Perkin Elmer), one bead is coated with protein A, which binds the Ig chain of the antibody (Product 6760137), and one is coated with streptavidin, which binds biotin on the Akt substrate-1 biotinylated peptide (Product 6760002). The activity of chk1 kinase is manifested in the production of the phosphorylated peptide Akt substrate-1, an event that determines the presence of two types of beads very close to each other in the presence of antibodies, which leads to the generation of luminescence, which is detected on a Perkin Elmer reader (FusiOn).

ATP radiometric analysis of chk1 kinase was performed by incubation for 30 minutes in the presence of 10 μM ATP containing 0.3 μCi ³³ P-ATP per sample and using ChKTide (KKKVSRSGLYRSPSMPENLNRPR peptide sequence) as a substrate. After acidification with 1% phosphoric acid and washing to remove unbound ATP, substrate phosphorylation was detected and counted by measuring bound radioactive phosphorus using a Perkin Elmer TOpcOunt.

AlphaScreen chk2 kinase analysis was performed for 30 minutes in the presence of 30 μM ATP using the biotinylated tyrosine hydroxylase peptide (ser 40) (Cell Signing TechnOIOgy, product # 1132) as a substrate. Phosphorylation of the substrate was detected and counted using AlphaScreen technology. It consists of an antibody to the tyrosine hydroxylase phospho peptide (ser 40) (Cell Signing technOIOgy product # 2791) and two AlphaScreen beads (Perkin Elmer), one bead is coated with protein A, which binds the Ig chain of the antibody (Product 6760137), and one is coated streptavidin, which binds biotin on the biotinylated tyrosine hydroxylase peptide (ser 40) (Product 6760002). The activity of chk2 kinase is manifested in the production of the phosphorylated tyrosine hydroxylase peptide, an event that determines the presence of two types of beads very close to each other in the presence of an antibody, which leads to the generation of luminescence, which is detected on a Perkin Elmer reader (FusiOn).

ATP radiometric analysis of chk2 kinase was performed by incubation for 30 minutes in the presence of UumkM ATP containing 0.3 μCi ³³ P-ATP per sample and using ChKTide (KKKVSRSGLYRSPSMPENLNRPR peptide sequence) as a substrate. After acidification with 1% phosphoric acid and washing to remove unbound ATP, phosphorylation of the substrate was detected and counted by measuring the bound radioactive phosphorus using a Perkin Elmer TOpcOunt.

The tested compounds were diluted in DMSO before being added to the assay buffer; the final concentration of DMSO in the assay was 1%.

The IC ₅₀ value was determined as the concentration at which the test compound gave 50% inhibition compared to the control. IC ₅₀ values were calculated using the XLfit software package (version 2.0.5).

The tested compounds indicated in the names of examples 1-178 showed IC ₅₀ values less than 5 μM in the assay described in Example i with respect to chk1 kinase. For example, Examples 1-32, 35-50, 53, 55-57, 59-63, 65-73, 75-81, 83-112 and 114-178 showed ICso values lower than 5 μM in the assay described in Example i in relation to kinase chk1. In particular, the presented compounds (the numbering of the examples coincides with the above) had the following activity levels (in μM): Example 1: 0.016; 2: 0.0072; 3: 0.0026; 4: 0.0176; 5: 0.023; 6: 0.0021; 7: 0.0039; 8: 0.0506; 9: 0.0394; 10: 0.0155; 11: 0.106; 12: 0.006; 13: 0.0171; 14: 0.0157; 15: 0.0813; 16: 0.0338; 17: 0.0062; 18: 0.167; 23: 0.0013; 24: 0.0014; 25: 0.0004; 26: 0.068; 27: 0.0037; 28: 0.0172; 29: 0.0099; 30: 0.0088; 31: 0.0186; 32: 0.22; 36: 0.0096; 37: 0.0128; 39: 0.0012; 40: 0.0013; 42: 0.0152; 430.0073; 44: 0.0215; 46: 0.0176; 47: 0.0073; 48: 0.0193; 49: 0.0087; 50: 0.0234; 51: 0.0138; 52: 0.0001; 55: 0.0003; 56: 0.0001; 57: 0.0013; 59: 0.0151; 60: 0.0541; 61: 0.0012; 62: 0.0012; 63: 0.0041; 65: 0.0002; 66: 0.0344; 67: 0.104; 68: 0.0534; 69: 0.172; 70: 0.0021; 71: 0.001; 73: 0.0229; 75: 0.0014; 76: 0.0057; 77: 0.0035; 78: 0.226; 80: 0.113; 82: 0.0007; 83: 0.052; 84: 0.001; 85: 0.0024; 86: 0.0193; 87: 0.0046; 88: 0.0053; 89: 0.0223; 90: 0.0002; 91: 0.0088; 92: 0.0266; 93: 0.101; 94: 0.0011; 95: 0.529; 97: 0.0143; 98: 0.112; 99: 0.17; 100: 0.0082; 101: 0.0282; 102: 0.0175; 103: 0.0073; 104: 0.0568; 105: 0.0071; 106: 0.0362; 107: 0.0177; 108: 0.0197; 109: 0.0011; 110: 0.0028; 111: 0.0062; 122: 0.0654; 113: 0.0092; 114: 0.039; 115: 0.006; 116: 0.0034; 118: 0.0147; 119: 0.0097; 120: 0.0068; 121: 0.0018; 122: 0.0012; 124: 0.0051; 125: 0.0952; 126: 0.0036; 127: 0.0988; 128: 0.0003; 129: 0.0244; 130: 0.0086; 131: 0.0481; 132: 0.0009; 133: 0.0002; 134: 0.0001; 135: 0.0004; 136: 0.0001; 137: 0.0006; 138: 0.0001; 139: 0.0002; 140: 0.0181; 141: 0.0023; 142: 0.0032; 143: 0.0235; 146: 0.0015; 147: 0.0001; 148: 0.0039; 149: 0.039; 151: 0.0173; 152: 0.0047; 153: 0.005; 154: 0.0023; 155: 0.0044; 156: 0.0011; 157: 0.0008; 158: 0.0043; 159: 0.0002; 160: 0.0696; 161: 0.0037; 162: 0.059; 163: 0.0014; 164: 0.0167; 165: 0.063; 166: 0.0037; 167: 0.0017; 168: 0.0037; 169: 0.0068; 170: 0.0002; 171: 0.0024; 172: 0.0047; 173: 0.0079; 174: 0.064; 175: 0.017; 176: 0.0011; 177: 0.0021.

EXAMPLE ii Cell analysis (cancellation of checkpoints)

Compounds were tested in cell analysis using the HT-29 cell line (ATCC NTV-38) obtained from human colorectal adenocarcinoma.

The cell line was maintained in DMEM / F12 (1: 1) medium (Invitrogen GibcO, # 31331) with an additional 10% FCS at 37 ° C in a 5% CO ₂ humidification incubator.

Cells were plated on 96-well plates at a density of 30,000 cells / well and after 24 hours they were treated with 20nM SN-38 in 0.4% DMSO. One column of 8 wells on each plate was used to create control with the maximum signal. These cells were treated with 0.4% DMSO without SN-38. Cells grew for a further 16 hours, then the medium containing DMSO with or without SN-38 was removed and replaced with a medium containing 300 nM of single nocodazole (to determine the baseline) or in combination with 10 concentrations of chk1 inhibitors (final concentration of DMSO was 0.4% ) Cells grew for a further 24 hours. The medium was removed and replaced with 50 μl of lysis buffer containing protease inhibitors and phosphatase inhibitors. This buffer contained detergent for cell destruction. After complete destruction of the cells, 25 μl of the lysate was placed on a 96-well 4-point MesoScale plate coated with anti-histone H3 antibodies (MesoScale Discovery (MSD) product K110EWA-3), which was previously blocked with 3% bovine serum albumin in Tris buffer solution. Due to the transfer of the lysate to the MSD plate, histone H3 in the lysate was captured by the coated antibody as a result of incubation at room temperature for 2 hours. After the capture step, the plate was washed and then incubated with the anti-phosphorylated histone H3 antibody, which was conjugated to the Sulfo label. This mark gave a signal when it was near the electrode at the base of the MSD tablet. Linking the labeled antibody to the captured protein allowed detection on an MSD reader.

EC ₅₀ values were determined as the concentration at which the target compound gave a 50% decrease in the level of phosphorylated NS histone within the range of the normal sigmoidal dose-response curve in comparison with the signal generated by 300 nM nocodazole alone. EC ₅₀ values were calculated using the XLfit software package (version 2.0.5) or Graphpad Prism, (version 3.03) approximating a sigmoidal curve with a variable slope.

The tested compounds of Examples 1-178 showed EC ₅₀ values less than 10 μM when assayed in accordance with Example ii. For example, the compounds of Examples 1-4, 6-10, 12-15, 17, 19-31, 35-36, 39-50, 53, 55-57, 59-63, 65-67, 70-73, 75 -77, 79, 81, 83-92, 94, 96, 100-112 and 114-178 showed EC ₅₀ values less than 10 μM when analyzed in accordance with Example ii.

Claims (29)

1. The compound of formula (I) or its pharmaceutically acceptable salt:

X represents CR ² ;
Y represents CR ⁴ ;
Z represents CR ⁸ ;
R ² represents H;
R ³ represents H, halo or R ⁹ ;
R ⁴ represents H, - (CR ¹⁴ R ¹⁵ ) _n NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n OR ¹¹ , a monocycle having 4-6 ring members, 1-2 of which are heteroatoms selected from nitrogen and oxygen, or a bicycle having 7-8 ring atoms, 1-2 of which are heteroatoms selected from nitrogen, wherein said monocycle and bicycle are optionally substituted with one R ¹³ group;
each n independently represents 0-2;
R ⁵ represents H, - (CR ¹⁴ R ¹⁵ ) _n NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n OR ¹¹ ;
R ⁶ represents H, CN or pyrazolyl optionally substituted with one R ¹³ group;
R ⁸ represents H;
each R ⁹ group independently is C 1-6 alkyl;
R ¹¹ and R ¹² independently represent H, C1-6-alkyl, C3-6-cycloalkyl, a monocycle having 4-7 ring members, 1 of which is a heteroatom selected from nitrogen and oxygen, or a bicycle having 7- 8 ring atoms, 1 of which is a nitrogen heteroatom, wherein said alkyl, cycloalkyl, monocycle and bicycle are optionally substituted with one to two R ¹³ groups;
R ¹¹ and R ^12, together with the N atom to which they are attached, optionally form a 4-7 membered monocyclic or bicyclic ring having additional 0-1 heteroatoms selected from O and N, said ring may optionally be substituted with one to two groups R ¹³ ;
each group R ¹³ independently represents halo, oxo, - (CR ¹⁴ R ¹⁵ ) _n C (= Y ′) R ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹⁶ R ¹⁷ , - (CR ¹⁴ R ¹⁵ ) _n OR ¹⁶ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹⁶ C (= Y ′) R ¹⁷ or R ¹⁶ ;
R ¹⁴ and R ^{15 are} independently selected from H;
R ¹⁶ and R ¹⁷ independently represent H, C1-6-alkyl, a monocycle having 4-6 ring members, 1-2 of which are heteroatoms selected from nitrogen and oxygen, or a bicycle having 7-8 ring atoms, 1 of which is a nitrogen heteroatom, wherein said alkyl, monocycle or bicycle is optionally substituted with one to three R ¹⁸ groups;
R ¹⁶ and R ^17, together with the N atom to which they are attached, optionally form a 5-6 membered ring having additional 0-1 heteroatoms selected from O, said ring may optionally be substituted with one to two R ¹⁸ groups;
each R ¹⁸ independently represents C1-6 alkyl, C3-6 cycloalkyl, a monocycle having 4-5 ring members, 1 of which is a heteroatom selected from nitrogen and oxygen, or a bicycle having 7-8 ring atoms, 1-2 of which are heteroatoms selected from nitrogen, halo, CF ₃ , - (CR ¹⁹ R ²⁰ ) _n OR ²³ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ²³ or - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ²³ R ²⁴ , wherein said alkyl is optionally substituted with one R ²¹ group;
R ¹⁹ and R ²⁰ independently represent H;
R ²³ and R ²⁴ independently represent H, C 1-6 alkyl;
each R ²¹ independently represents H or halogen;
Y ′ represents O. 2. The compound according to claim 1, which is a compound of formula (I-a):

3. The compound according to claim 1, which is a compound of formula (Ib):

4. The compound according to claim 2, where R ³ represents H, CH ₃ or halo. 5. The compound according to claim 1, where R ⁴ represents —NR ¹¹ R ¹² or —OR ¹¹ , where R ¹¹ and R ^12, together with the N atom to which they are attached, optionally form a 4–7 membered ring having additional 0-1 heteroatoms selected from O and N, the specified ring may be optionally substituted by one to two groups R ¹³ . 6. The compound according to claim 1, where the group R ⁴ selected from one of the following groups:

7. The compound according to claim 1, where R ⁵ represents —NR ¹¹ R ¹² or —OR ¹¹ , where R ¹¹ and R ^12, together with the N atom to which they are attached, optionally form a 4-7 membered ring having additional 0-1 heteroatoms selected from O and N, the specified ring may be optionally substituted by one to two groups R ¹³ . 8. The compound according to claim 1, where the group R ⁵ selected from one of the following groups:

9. The compound according to claim 1, where R ⁶ represents H, CN or pyrazolyl, optionally substituted with C ₁ -C ₃ alkyl. 10. The compound according to claim 1, where R ⁶ represents H, CN, N-methylpyrazolyl or pyrazolyl. 11. The compound according to claim 1, where R ⁶ represents H or CN. 12. The compound according to claim 1, where R ⁶ represents CN. 13. The compound according to claim 1, which is selected from the group consisting of:
4- (N- (morpholin-2-ylmethyl)) - 9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (azetidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (morpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (morpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (quinuclidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1s, 3s) -cyclobutanamin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((1-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((4-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((4-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((piperidin-2-one) -5-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1,3-dimethylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (2- (pyrrolidin-1-ylmethyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (morpholin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (quinuclidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
trans-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (2 - ((dimethylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (2 - ((dimethylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (2 - ((methylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (2 - ((methylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-hydroxy-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-fluoro-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-methoxy-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (3- (dimethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (3- (dimethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1r, 4r) -4- (dimethylamino) cyclohexyloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (4-methylmorpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1-ethylpyrrolidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((1-ethylpyrrolidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-6- carbonitrile;
(R) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-6- carbonitrile;
cis-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
1- [4- (3-chloro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) -piperazin-1-yl] -2- (R) -pyrrolidin- 2-yl ethanone;
(S) -3-chloro-4- (3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((3S, 4S) -3,4-dihydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((3R, 4R) -3,4-dihydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (3-hydroxyazetidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-hydroxy-3-methylpyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -3-chloro-4- (3-hydroxy-3-methylpyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -3-chloro-4- (3-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (4-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-aminopyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (methylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-bromo-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-fluoro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (3-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (3- (dimethylamino) -2,2-dimethylpropoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (3-fluoropropyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (2-hydroxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (2-methoxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1-ethyl-4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -1-ethylpiperidin-3-hydroxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1- (2-hydroxyethyl) piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1- (2-methoxyethyl) piperidin-3-hydroxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-ethyl-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (piperidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (piperidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-ethylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N- (3-fluoropropyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N-ethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4- (pyrrolidin-3-yl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (2,5-diazabicyclo [2.2.1] heptan-2-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (N-methylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (N, N-dimethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N, N-dimethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (octahydropyrrolo [3,4-b] pyrrole) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((3aS, 6aS) -1-methyl-octahydropyrrolo [3,4-b] pyrrole) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -piperidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4-piperazine-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (1-ethylpiperazine) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (N- (3-fluoropropyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (2,2-difluoroethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile ;
(S) -3-chloro-4- (N- (pyrrolidin-3-yl) isobutyramide) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (N- (2,2,2-trifluoroethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
(R) -4- (piperidin-3-yloxy) -6- (1-methyl-1H-pyrazol-4-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole;
1- [4- (9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) piperazin-1-yl] -2- (R) pyrrolidin-2-yl- ethanone;
[(S) -1- (9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) pyrrolidin-3-yl] ethylamine;
4- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((S) -1-ethylpiperidin-3-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
cis- (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-ethylpiperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -1-ethylpiperidin-3-ylamino) -9H-dipyrido-[2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-methylaminopiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((S) -3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
trans- (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (piperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-methoxyethyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-cyclopropylmethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(1-ethylpiperidin-4-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(1-ethylpiperidin-4-yl) methyl-amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-butylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (2-pyrrolidin-1-yl-ethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(4-ethylmorpholin-2-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-ethylaminopiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-oxetan-3-ylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-cyclopropylmethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1,3 ′] bipyrrolidinyl-1′-yl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3-fluoropropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4- (3-fluoroazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4- (3-hydroxyazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((S) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-azetidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((R) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((S) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((R) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy- [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-fluoro- [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1,4-dimethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methyl [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (1-oxetan-3-ylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-fluoro-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidine-3-ylmethoxy) -9H-dipyrido [2,3-b; ^4,, 3'd] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-ethylpiperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylazepan-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-hydroxy-2-methylpropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylazetidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-fluoro-5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (1-ethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2,2-difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-methanesulfonylethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile. 14. The compound according to claim 1, which is selected from the group consisting of:
4- (N- (morpholin-2-ylmethyl)) - 9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (azetidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (morpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (morpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (quinuclidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1s, 3s) -cyclobutanamin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((1-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((4-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((4-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((piperidin-2-one) -5-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1,3-dimethylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (2- (pyrrolidin-1-ylmethyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (morpholin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (quinuclidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
trans-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (2 - ((dimethylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (2 - ((dimethylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (2 - ((methylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (2 - ((methylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-hydroxy-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-fluoro-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-methoxy-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (3- (dimethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (3- (dimethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-b] pyrrole-6-carbonitrile;
4 - ((1r, 4r) -4- (dimethylamino) cyclohexyloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (4-methylmorpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1-ethylpyrrolidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((1-ethylpyrrolidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-6- carbonitrile;
(R) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-6- carbonitrile;
cis-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
1- [4- (3-chloro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) -piperazin-1-yl] -2- (R) -pyrrolidin- 2-yl ethanone;
(S) -3-chloro-4- (3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((3S, 4S) -3,4-dihydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((3R, 4R) -3,4-dihydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (3-hydroxyazetidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-hydroxy-3-methylpyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -3-chloro-4- (3-hydroxy-3-methylpyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -3-chloro-4- (3-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (4-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-aminopyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (methylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-bromo-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-fluoro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (3-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (3- (dimethylamino) -2,2-dimethylpropoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (3-fluoropropyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (2-hydroxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (2-methoxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1-ethyl-4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -1-ethylpiperidin-3-hydroxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1- (2-hydroxyethyl) piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1- (2-methoxyethyl) piperidin-3-hydroxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-ethyl-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbrnitrile;
4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (piperidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (piperidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-ethylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N- (3-fluoropropyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N-ethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4- (pyrrolidin-3-yl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3 ^, -d] pyrrole-6-carbonitrile;
4- (2,5-diazabicyclo [2.2.1] heptan-2-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (N-methylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (N, N-dimethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N, N-dimethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (octahydropyrrolo [3,4-b] pyrrole) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((3aS, 6aS) -1-methyl-octahydropyrrolo [3,4-b] pyrrole) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -piperidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4-piperazine-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (1-ethylpiperazine) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (N- (3-fluoropropyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (2,2-difluoroethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile ;
(S) -3-chloro-4- (N- (pyrrolidin-3-yl) isobutyramide) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (N- (2,2,2-trifluoroethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
(R) -4- (piperidin-3-yloxy) -6- (1-methyl-1H-pyrazol-4-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole;
1- [4- (9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) piperazin-1-yl] -2- (R) pyrrolidin-2-yl- ethanone;
[(S) -1- (9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) pyrrolidin-3-yl] ethylamine;
4- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((S) -1-ethylpiperidin-3-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
cis- (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-ethylpiperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -1-ethylpiperidin-3-ylamino) -9H-dipyrido [2 _, 3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-methylaminopiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((S) -3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
trans- (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (piperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (pyrrolidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((R) -1-pyrrolidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-ethylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-methoxyethyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-cyclopropylmethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (cis) - (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-pyrrolidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(1-ethylpiperidin-4-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(1-ethylpiperidin-4-yl) methyl-amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-butylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (2-pyrrolidin-1-yl-ethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (trans) - (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(4-ethylmorpholin-2-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-ethylaminopiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-oxetan-3-ylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-cyclopropylmethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1,3 ′] bipyrrolidinyl-1′-yl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3-fluoropropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4- (3-fluoroazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4- (3-hydroxyazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((S) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-azetidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((R) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((S) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((R) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy- [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-fluoro- [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-azabicyclo [2.2.2] oct-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1,4-dimethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methyl [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (1-oxetan-3-ylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -3-fluoro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -3-fluoro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
3-fluoro-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-fluoro-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -3-chloro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
3-chloro-5- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-ethylpiperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylazepan-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-hydroxy-2-methylpropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylazetidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-fluoro-5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (1-ethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5-piperazin-1-yl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2,2-difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-methanesulfonylethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -3-methyl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole. 15. The compound according to claim 1, which is selected from the group consisting of:
4- (N- (morpholin-2-ylmethyl)) - 9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (azetidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (morpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (morpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (quinuclidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1s, 3s) -cyclobutanamin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((1-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((4-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((4-methylpiperazin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((piperidin-2-one) -5-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1,3-dimethylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (2- (pyrrolidin-1-ylmethyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (morpholin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (quinuclidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
trans-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (2 - ((dimethylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (2 - ((dimethylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (2 - ((methylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (2 - ((methylamino) methyl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-hydroxy-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-fluoro-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-methoxy-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (3- (dimethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (3- (dimethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1r, 4r) -4- (dimethylamino) cyclohexyloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperidin-3-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (4-methylmorpholin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1-ethylpyrrolidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4 - ((1-ethylpyrrolidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (3- (ethylamino) piperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-6- carbonitrile;
(R) -4- (4- (2- (pyrrolidin-2-yl) acetyl) piperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-6- carbonitrile;
cis-4- (4-fluoropiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
1- [4- (3-chloro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) -piperazin-1-yl] -2- (R) -pyrrolidin- 2-yl ethanone;
(S) -3-chloro-4- (3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((3S, 4S) -3,4-dihydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4 - ((3R, 4R) -3,4-dihydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (3-hydroxyazetidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-hydroxy-3-methylpyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -3-chloro-4- (3-hydroxy-3-methylpyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -3-chloro-4- (3-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (4-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3-aminopyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (methylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-bromo-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-fluoro-4- (3- (ethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (3-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (3- (dimethylamino) -2,2-dimethylpropoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (3-fluoropropyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (2-hydroxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1- (2-methoxyethyl) -4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1-ethyl-4-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1-methylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -1-ethylpiperidin-3-hydroxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1- (2-hydroxyethyl) piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (1- (2-methoxyethyl) piperidin-3-hydroxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((4-ethyl-1-methylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((1,4-dimethylpiperidin-4-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-b] pyrrole-6-carbonitrile;
(R) -4- (piperidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (piperidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-ethylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4 - ((1-methylpiperidin-2-yl) methoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N- (3-fluoropropyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (N- (2-methoxyethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N-ethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4- (pyrrolidin-3-yl) morpholino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (2,5-diazabicyclo [2.2.1] heptan-2-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (N-methylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(R) -4- (N, N-dimethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -4- (N, N-dimethylpyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (octahydropyrrolo [3,4-b] pyrrole) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((3aS, 6aS) -1-methyl-octahydropyrrolo [3,4-b] pyrrole) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -piperidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4-piperazine-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-4- (1-ethylpiperazine) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (N- (3-fluoropropyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (3- (2,2-difluoroethylamino) pyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile ;
(S) -3-chloro-4- (N- (pyrrolidin-3-yl) isobutyramide) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
(S) -3-chloro-4- (N- (2,2,2-trifluoroethyl) pyrrolidin-3-amino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
(R) -4- (piperidin-3-yloxy) -6- (1-methyl-1H-pyrazol-4-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole;
1- [4- (9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) piperazin-1-yl] -2- (R) -pyrrolidin-2-ylethanone;
[(S) -1- (9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) pyrrolidin-3-yl] ethylamine;
4- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((S) -1-ethylpiperidin-3-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
cis- (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-ethylpiperazin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′d] pyrrole-6-carbonitrile;
4 - ((R) -1-ethylpiperidin-3-ylamino) -9H-dipyrido-[2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4- (4-methylaminopiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((R) -3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
4 - ((S) -3-hydroxypyrrolidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
trans- (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′d] pyrrole-6-carbonitrile. 16. The compounds according to claim 1, selected from the group consisting of:
5- (piperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (pyrrolidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((R) -1-pyrrolidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-ethylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-methoxyethyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-cyclopropylmethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (cis) - (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-pyrrolidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(1-ethylpiperidin-4-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(1-ethylpiperidin-4-yl) methylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-butylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (2-pyrrolidin-1-yl-ethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (trans) - (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(4-ethylmorpholin-2-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-ethylaminopiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-oxetan-3-ylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-cyclopropylmethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1,3 ′] bipyrrolidinyl-1′-yl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3-fluoropropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4- (3-fluoroazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4- (3-hydroxyazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((S) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-azetidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((R) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((S) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((R) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy- [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-fluoro- [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-azabicyclo [2.2.2] oct-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1,4-dimethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methyl [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (1-oxetan-3-ylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -3-fluoro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -3-fluoro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
3-fluoro-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-fluoro-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -3-chloro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
3-chloro-5- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-ethylpiperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylazepan-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-hydroxy-2-methylpropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylazetidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-fluoro-5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (1-ethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5-piperazin-1-yl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2,2-difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-methanesulfonylethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -3-methyl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole. 17. The compound according to claim 1, which is selected from the group consisting of:
5- (piperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (pyrrolidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -piperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((R) -1-pyrrolidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-ethylpiperidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-cyclopropylmethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (cis) - (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-pyrrolidin-2-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-butylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (2-pyrrolidin-1-yl-ethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (trans) - (3-fluoropiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3-fluoropropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-azabicyclo [2.2.2] oct-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1,4-dimethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (1-oxetan-3-ylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -3-fluoro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -3-fluoro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
3-fluoro-5- (piperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) oxy] -3-chloro-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6 β-carbonitrile;
5- (1-ethylpiperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - ((S) -1-ethylpiperidin-3-ylmethoxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylazepan-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-hydroxy-2-methylpropyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylazetidin-3-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-fluoro-5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (1-methylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (1-ethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2,2-difluoroethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-methanesulfonylethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-hydroxyethyl) -piperidin-4-yloxy] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -3-methyl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-ethylpiperidin-4-yloxy) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole. 18. The compound according to claim 1, which is selected from the group consisting of:
5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (2-methoxyethyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(1-ethylpiperidin-4-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(1-ethylpiperidin-4-yl) methylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [1- (3,3,3-trifluoropropyl) -piperidin-4-ylamino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(S) - (1-azabicyclo [2.2.2] oct-3-yl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5 - [(4-ethylmorpholin-2-ylmethyl) amino] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-oxetan-3-ylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-cyclopropylmethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (1-ethylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (1-methylpiperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (piperidin-4-ylamino) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile. 19. The compound according to claim 1, which is selected from the group consisting of:
5- [4- (3-fluoroazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4- (3-hydroxyazetidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((S) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-azetidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((R) -3-fluoropyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((S) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- [4 - ((R) -3-hydroxypyrrolidin-1-yl) -piperidin-1-yl] -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxypiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy- [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-fluoro- [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-hydroxy-4-methyl [1,4 ′] bipiperidinyl-1′-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-fluoro-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-bromo-5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
3-chloro-5- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-pyrrolidin-1-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5- (4-morpholin-4-ylpiperidin-1-yl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile;
5-piperazin-1-yl-9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-6-carbonitrile. 20. A compound selected from the group consisting of:
(S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-4- il) piperidin-3-ylcarbamate,
tert-butyl 4- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrol-4-yl) piperazine- 1-carboxylate and
(S) -tert-butyl 1- (6-cyano-9 - ((2- (trimethylsilyl) ethoxy) methyl) -9H-dipyrido [2,3-b; 4 ′, 3′-d] pyrrole-4- il) pyrrolidin-3-yl (ethyl) carbamate. 21. A pharmaceutical composition for inhibiting abnormal cell growth or treating hyperproliferative disorders, comprising a compound according to any one of claims 1-19 and a pharmaceutically acceptable carrier. 22. The pharmaceutical composition according to item 21, additionally containing a second chemotherapeutic agent. 23. The pharmaceutical composition according to claim 22, wherein said second chemotherapeutic agent is a DNA damaging agent. 24. A method of inhibiting abnormal cell growth or treating hyperproliferative disorders in mammals, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition according to any one of claims 21-23. 25. A method of treating a tumorous disease in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition according to any one of claims 21-23. 26. The method according A.25, in which the tumor is selected from breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer, malignant brain tumors, sarcoma, melanoma, lymphoma, myeloma and leukemia. 27. The method according to any one of paragraphs.24-26, in which the specified second chemotherapeutic agent is administered to the specified mammal sequentially or simultaneously. 28. The compound according to any one of claims 1 to 19 for use in the treatment of breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer, malignant brain tumors, sarcomas, melanoma, lymphoma, myeloma and leukemia. 29. The use of a compound according to any one of claims 1-19 in the manufacture of a medicament for the treatment of breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer, malignant brain tumors, sarcoma, melanoma, lymphoma, myeloma and leukemia.

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