RU2833828C2 - Novel compounds for inhibition of janus kinase 1 - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: present invention relates to novel selective Janus kinase 1 (JAK1) inhibitors, methods of producing said inhibitors, a pharmaceutical composition containing said inhibitors and use thereof.

EFFECT: development of new compounds as selective JAK1 inhibitors.

10 cl, 2 dwg, 4 tbl, 8 ex

Description

FIELD OF INVENTION

The invention relates to Janus kinase 1 (JAK1) inhibitors, a method for synthesizing the compounds of the present invention, a composition containing these compounds, and the use of these compounds for inhibiting JAK1.

PRIOR ART

Cytokines are key stimulants of several biological pathways, and when a specific pathway is dysregulated, anticytokine therapy is indicated. More than 50 cytokines, interleukins, interferons, colony-stimulating factors, and hormones participate in receptor-mediated signaling pathways, the type I and type II cytokine receptor families. Like other receptor superfamilies, the type I and type II cytokine receptors are similar in their intracellular signaling: they all use JAKs. Janus kinases (JAKs) are intracellular tyrosine kinases that bind to the intracellular domains of many cytokine receptors. There are four isoforms of JAKs: JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) bind directly to the intracellular domains of type I/II cytokine receptors but not to receptors of other classes of cytokines. Different families of cytokine receptors use specific JAK isoforms for signal transduction. Phosphorylation of JAKs, when a cytokine binds to its receptor, leads to phosphorylation of other intracellular molecules, which ultimately leads to gene transcription. JAK-dependent cytokines are major contributors to immunopathology, and blockade of such cytokines by biologically active substances may be useful in immune-mediated diseases and cancer, as well as in several other important diseases and disorders.

There are several JAK kinase inhibitors. They block different JAKs and therefore inhibit the action of a wide range of cytokines, and several pan-JAK inhibitors are under development. JAK isoforms differ in function, and there is a need in the art for isoform-specific inhibitors that can reduce the undesirable effects of universal JAK inhibitors. JAK1 plays a key role in interferon type I and II signaling and is involved in signaling from the interleukin-2, interleukin-4, glycoprotein 130 (gp130), and class II receptor families. Therefore, inhibition of JAK1 by small molecules may impact signaling pathways in cancer, inflammation, and autoimmune diseases. However, to minimize adverse effects, especially those resulting from JAK2 inhibition, the development of selective inhibitors is essential to maintain efficacy and improve safety.

PURPOSE OF THE INVENTION

The aim of the present invention is to develop compounds as selective inhibitors of JAK1, a method for producing these inhibitors, a composition containing such compounds, and the use of these compounds.

BRIEF DESCRIPTION OF THE ESSENCE OF THE INVENTION

The present invention describes 1H-imidazo[4,5-b]pyridin-2(3H)-one as a selective inhibitor of JAK 1, its pharmaceutically acceptable salts and isomers of formula I:

Where

A is a 5-membered or 6-membered carbocycle or heterocycle containing 1-3 heteroatoms selected from the group consisting of O, N, S, optionally substituted by a _CH3 , F or Cl group;

B is H, or alkoxy, or O, -CO-, an optionally substituted 3-8-membered carbocyclic ring, a 3-8-membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S,

X independently represents H, (CH ₂ )n, -CO-, OCO, COO; CO(CH ₂ )n, (NH ₂ )n; (CH ₂ )n(NH ₂ )n; (CH ₂ )n(NH ₂ )nCN; CONH; CONR ₁ R ₂ , CO(NH ₂ )n; (CH ₂ )nCO(NH ₂ )n, CO(NH ₂ )n(CH ₂ )CF ₃ , SO ₂ (CH ₂ )n, NH(CH ₂ )nCN, an unsubstituted or substituted 3-8-membered carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S and SO ₂ , and the substituents on the carboxyl or heterocyclic ring can be selected from halogen, alkoxy, CHMe, -CH(CF ₃ ), -C(CF ₃ )(OH), C(CF ₃ )(OMe), -CH(CN), CHOH, CH(R ₅ ),

Y may be absent or may be selected from H, _R1 , _R2 , halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, CN, -CO-, _COR1 , ( _CH2 )n, -( _CH2 )nCN-, CH2CF3 _{, COOH} , OR1, NR1R2, _-COOR1 , -CON( _R1 ) ₂ , -SO2( _CH2 )n, -SO2N _{( R1 ) 2} , _{-OCOR1 , CONHCH ( CH3 )} -CF3 _{, CH2CN} , _CH2SO2CH3 , _-NR1COR1 , _{-CONH , CONR1R2} , _-CO ( _NH2 )n( _CH2 ) _nSO2 ; -CONH(CH ₂ )nOH, CONH(CH ₂ )nSO ₂ R ₁ R ₂ , -CONH-(CH ₂ )nCF ₃ , -CONH(CH ₂ )nCF ₃ , -NHCONH(CH ₂ )nCF ₃ , NHCONHR ₁ , -NHCOR ₁ R ₂ , NR ₁ CONR ₁ R ₂ , (NH ₂ )n, -NH ₂ CH ₂ , NH ₂ CH ₂ CF ₃ , -CH(CF ₃ )-(CH)n-CO-NR ₁ R ₂ , CH(CF ₃ )-(CH)n-SO ₂ , (CH)n; a CH(OH)( _CF3 )(heterocycle) _R1 group, an optionally substituted 3-8-membered carbocyclic ring or a 3-8-membered saturated mono-, condensed or bridged heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S or _SO2 , an optionally substituted 3-8-membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S or _SO2 , wherein the substitution can independently be _R1 and _R2 at any position of this ring; _C1-6 alk-aryl, _ArC1-6 alkyl;

R ₁ and R ₂ are independently selected from the group consisting of H, halogen, CN, CF ₃ , hydroxyl, amino, SO ₂ , SO ₂ , C ₁ -C ₆ alkyl, SO ₂ -C ₃ -C ₈ cycloalkyl, CH ₂ CN, CH ₂ CF ₃ , unsubstituted or substituted straight or branched C ₁ -C ₆ alkyl, wherein the substituents are selected from halogen, OH, CN, C ₁ -C ₆ alkoxy optionally substituted with NH ₂ , C ₁ -C ₆ alkylsulfonyl optionally substituted with CONH ₂ , unsubstituted or substituted C ₃ -C ₈ carbocyclyl or a 3-8-membered heterocyclic ring with 1-3 heteroatoms selected from O, N and S, SO ₂ , straight or branched C ₁ -C ₆ alkenyl, straight or branched C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonyl, C(O)-C ₃ -C ₈ cycloalkyl, heteroalkyl optionally substituted with CONH ₂ , C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, C ₃ -C ₈ heterocycloalkyl, C ₃ -C ₈ heterocycloalkenyl, carbocyclyl, aryl and heteroaryl, -CH(CF ₃ )-(CH)n-CON-R ₃ R ₄ , -CH(CF ₃ )-(CH)n-SO ₂ -NR ₃ R ₄ , CH(CF ₃ )-(CH)n-NR ₃ R ₄ , CH(CF ₃ )-NR ₃ R ₄ , CH(CF ₃ )-(CH)n-SO ₂ -CHR ₃ R ₄ , wherein cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, carbocyclyl, aryl and heteroaryl groups are optionally substituted;

R ₃ and R ₄ are H, independently represent CH ₃ , C ₃ -C ₈ cycloalkyl;

R ₅ is an unsubstituted or substituted 3-8-membered carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S, SO ₂ ;

R ₆ independently represents H, straight or branched C ₁ -C ₆ alkyl, halogen;

X can be combined with Y at any atom to form a chemically feasible bond;

n is 0-3.

The present invention also describes a method for preparing the compounds of the present invention, a composition containing the compounds of the present invention, and the use of the compounds of the present invention as selective JAK1 inhibitors.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows the results of cumulative psoriasis score and body weight change for the compounds of Examples 1133 and 1215 in the imiquimod (IMQ)-induced psoriasis mouse model. The results shown in Fig. 1a are based on the psoriasis severity score. Data are shown as mean ± S.E.M. (n=8), * indicates significant difference compared to vehicle-treated control group. # indicates significant difference compared to untreated control group. Two-way ANOVA was followed by Bonferroni test. ** P<0.01 and ###/*** P<0.001. Fig. 1b refers to body weight. Data are shown as mean ± S.E.M. (n=8), # indicates significant difference compared to untreated control. Two-way ANOVA was followed by the Bonferroni test. # P<0.05.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes 1H-imidazo[4,5-b]pyridin-2(3H)-one as a selective inhibitor of JAK 1, its pharmaceutically acceptable salts

and isomers of formula I:

,

Where

A is a 5-membered or 6-membered carbocycle or heterocycle containing 1-3 heteroatoms selected from the group consisting of O, N, S, optionally substituted by a _CH3 , F or Cl group;

B is H, or alkoxy, or O, -CO-, an optionally substituted 3-8-membered carbocyclic ring, a 3-8-membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S,

X independently represents H, (CH ₂ )n, -CO-, OCO, COO; CO(CH ₂ )n, (NH ₂ )n; (CH ₂ )n(NH ₂ )n; (CH ₂ )n(NH ₂ )nCN; CONH; CONR ₁ R ₂ , CO(NH ₂ )n; (CH ₂ )nCO(NH ₂ )n, CO(NH ₂ )n(CH ₂ )CF ₃ , SO ₂ (CH ₂ )n, NH(CH ₂ )nCN, an unsubstituted or substituted 3-8-membered carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S and SO ₂ , and the substituents on the carboxyl or heterocyclic ring can be selected from halogen, alkoxy, CHMe, -CH(CF ₃ ), -C(CF ₃ )(OH), C(CF ₃ )(OMe), -CH(CN), CHOH, CH(R ₅ ),

Y may be absent or may be selected from H, _R1 , _R2 , halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, CN, -CO-, _COR1 , ( _CH2 )n, -( _CH2 )nCN-, CH2CF3 _, COOH, OR1, NR1R2, _-COOR1 , -CON _{( R1} ) ₂ , _-SO2 ( _CH2 ) _n , -SO2N(R1) ₂ , _{-OCOR1 , CONHCH ( CH3} ) _-CF3 , _{CH2CN , CH2SO2CH3} , _-NR1COR1 , _-CONH , CONR1R2 _{, -CO} ( _NH2 )n( _CH2 ) _{nSO2 ;} -CONH(CH ₂ )nOH, CONH(CH ₂ )nSO ₂ R ₁ R ₂ , -CONH-(CH ₂ )nCF ₃ , -CONH(CH ₂ )nCF ₃ , -NHCONH(CH ₂ )nCF ₃ , NHCONHR ₁ , -NHCOR ₁ R ₂ , NR ₁ ONR ₁ R ₂ , (NH ₂ )n, -NH ₂ CH ₂ , NH ₂ CH ₂ CF ₃ , -CH(CF ₃ )-(CH)n-CO-NR ₁ R ₂ , CH(CF ₃ )-(CH)n-SO ₂ , (CH)n; a CH(OH)( _CF3 )(heterocycle) _R1 group, an optionally substituted 3-8-membered carbocyclic ring or a 3-8-membered saturated mono-, condensed or bridged heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S or _SO2 , an optionally substituted 3-8-membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S or _SO2 , wherein the substitution can independently be _R1 and _R2 at any position of this ring; _C1-6 alk-aryl, _ArC1-6 alkyl;

R ₁ and R ₂ are independently selected from the group consisting of H, halogen, CN, CF ₃ , hydroxyl, amino, SO ₂ , SO ₂ , C ₁ -C ₆ alkyl, SO ₂ -C ₃ -C ₈ cycloalkyl, CH ₂ CN, CH ₂ CF ₃ , unsubstituted or substituted straight or branched C ₁ -C ₆ alkyl, wherein the substituents are selected from halogen, OH, CN, C ₁ -C ₆ alkoxy optionally substituted with NH ₂ , C ₁ -C ₆ alkylsulfonyl optionally substituted with CONH ₂ , unsubstituted or substituted C ₃ -C ₈ carbocyclyl or a 3-8-membered heterocyclic ring with 1-3 heteroatoms selected from O, N and S, SO ₂ , straight or branched C ₁ -C ₆ alkenyl, straight or branched C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonyl, C(O)-C ₃ -C ₈ cycloalkyl, heteroalkyl optionally substituted with CONH ₂ , C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, C ₃ -C ₈ heterocycloalkyl, C ₃ -C ₈ heterocycloalkenyl, carbocyclyl, aryl and heteroaryl, -CH(CF ₃ )-(CH)n-CO-NR ₃ R ₄ , -CH(CF ₃ )-(CH)n-SO ₂ -NR ₃ R ₄ , CH(CF ₃ )-(CH)n-NR ₃ R ₄ , CH(CF ₃ )-NR ₃ R ₄ , CH(CF ₃ )-(CH)n-SO ₂ -CHR ₃ R ₄ , wherein cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, carbocyclyl, aryl and heteroaryl groups are optionally substituted;

R ₃ and R ₄ are H, independently represent CH ₃ , C ₃ -C ₈ cycloalkyl;

R ₅ is an unsubstituted or substituted 3-8-membered carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S, SO ₂ ;

R ₆ independently represents H, straight or branched C ₁ -C ₆ alkyl, halogen;

X can be combined with Y at any atom to form a chemically feasible bond;

n is 0-3.

The compounds described in this application and their pharmaceutically acceptable salts may exist as individual stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds described in this application may also exist as geometric isomers. All such individual stereoisomers, racemates, and mixtures and geometric isomers thereof are intended to be included within the scope of the compounds described in this application.

Typical compounds of formula I of the present invention are illustrated herein below in Table 1.

The compounds of the present invention include:

1001. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)benzamide;

1002. 1-(1,1,1-trifluoropropan-2-yl)-3-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)phenyl)urea;

1003. 1-(2,2,2-trifluoroethyl)-3-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)phenyl)urea;

1004. 1-(2,2,2-trifluoroethyl)-3-(5-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)pyrimidin-2-yl)urea;

1005. 1-(2,2,2-trifluoroethyl)-3-(5-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)pyridin-2-yl)urea;

1006. 1-(5-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)pyrazin-2-yl)-3-(2,2,2-trifluoroethyl)urea;

1007. N-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-3,3-dimethylazetidine-1-carboxamide;

1008. N-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)phenyl)morpholine-4-carboxamide;

1009. 1-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-3-(pyridin-4-yl)urea;

1010. 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)phenyl)-3-(2,2,2-trifluoroethyl)urea;

1011. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazine-1-carboxamide;

1012. N-(cyanomethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazine-1-carboxamide;

1013. 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(2-(methylsulfonyl)ethyl)piperazine-1-carboxamide;

1014. 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(pyridin-4-yl)piperazin-1-carboxamide;

1015. N-(2-fluoropyridin-4-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazine-1-carboxamide;

1016. N-(1-(methylsulfonyl)piperidin-4-yl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-carboxamide;

1017. N-(cyclopentylmethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-carboxamide;

1018. 7-(4-(1,1-dioxidothiomorpholine-4-carbonyl)piperazin-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1019. 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(2-methoxypyridin-4-yl)piperazine-1-carboxamide;

1020. N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-carboxamide;

1021. N-(1,1,1-trifluoropropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-carboxamide;

1022. N-(2,2,2-trifluoroethyl)-4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-carboxamide;

1023. 7-(4-(3,3-dimethylazetidine-1-carbonyl)piperazin-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1024. 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(2-methyl-4-(methylsulfonyl)phenyl)piperazine-1-carboxamide;

1025. N-(2,2,2-trifluoroethyl)-2-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)acetamide;

1026. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1027. N-(cyanomethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1028. N-(2,2,2-trifluoroethyl)-3-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrrole-1-carboxamide;

1029. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1030. N-(1,1,1-trifluoropropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1031. 7-(1-(4,4,4-trifluorobutanoyl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1032. N-(1-cyanocyclopropyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1033. N-(2-cyanopropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1034. N-(cyclopentylmethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1035. N-(cyanomethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide hydrochloride;

1036. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)-1H-pyrazol-1-carboxamide;

1037. 7-(1-(3,3-dimethylazetidine-1-carbonyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1038. N-(cyano(cyclopentyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1039. N-(2-cyano-1-cyclopentylethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1040. N-(2-cyanobutan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1041. N-(1-cyclopentyl-2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1042. 4-(1-ethyl-2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide;

1043. N-(cyano(cyclopropyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1044. N-(1-cyano-2-methylpropyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1045. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-carboxamide;

1046. N-(1-cyanopropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1047. N-((S)-1-cyano-2-methylpropyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1048. 1-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)azetidine-3-carbonitrile;

1049. N-((R)-1-cyano-2-methylpropyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1050. N-(3-cyano-1,1,1-trifluoropropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1051. N-(2-cyano-1-cyclopropylethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1052. N-(1-cyanopropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1053. N-(1-cyanopropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1054. N-((R)-cyano(cyclopropyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1055. 1-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)pyrrolidine-3-carbonitrile;

1056. N-(3-cyanocyclobutyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1057. 2-(1-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)pyrrolidin-3-yl)acetonitrile;

1058. N-(1-(3-cyanoazetidin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1059. N-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1060. N-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1061. 3-(1-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)pyrrolidin-3-yl)propanenitrile;

1062. N-(2-cyano-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1063. N-(cyano(phenyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1064. N-(2,2,2-trifluoroethyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1065. N-(2-cyano-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1066. N-(2-cyanocyclohexyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1067. 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)piperidine-4-carbonitrile;

1068. N-(1-(3-cyanoazetidin-1-yl)propan-2-yl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1069. N-(1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)pyrrolidin-3-yl)propan-1-sulfonamide;

1070. N-(cyano(phenyl)methyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1071. N-(1-cyano-3-methoxypropyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1072. N-(1-cyano-3-(methylsulfonyl)propyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1073. N-((S)-1-cyano-2-methylpropyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide;

1074. 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)-4-methylpyrrolidine-3-carbonitrile;

1075. 2-(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile;

1076. 2-(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)thiazol-4-yl)acetonitrile;

1077. 7-(1-((oxazol-5-yl)methyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1078. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile;

1079. 6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridine-3-carbonitrile;

1080. 7-(1-(5-((methylsulfonyl)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1081. 7-(1-(5-((oxetan-3-yl)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1082. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile hydrochloride;

1083. (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methanol;

1084. 7-(1-(5-(2,2,2-trifluoroethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1085. 7-(1-(5-(morpholinomethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1086. 4-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)thiomorpholine-1,1-dioxide;

1087. 1-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)azetidin-3-carbonitrile;

1088. 6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-N-(cyanomethyl)pyridine-3-carboxamide;

1089. N-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)methanesulfonamide;

1090. N-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)methanesulfonamide;

1091. N-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-cyanoacetamide;

1092. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)acetamide;

1093. 2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-N-(cyanomethyl)pyrimidine-5-carboxamide;

1094. N-(2,2,2-trifluoroethyl)-4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide;

1095. 4-(2-ethoxy-3H-imidazo[4,5-b]pyridin-7-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide;

1096. 4-(2-cyclopropyl-3H-imidazo[4,5-b]pyridin-7-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide;

1097. 3-(4-(2-(4-chloro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-tetrahydro-2H-pyran-4-carbonitrile;

1098. 4-(2-(1-acetylpiperidin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide;

1099. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)acetonitrile;

1100. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2-cyclopropylacetonitrile;

1101. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2-morpholinoacetonitrile;

1102. N-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2-cyanoacetamide;

1103. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-3-fluorophenyl)acetonitrile;

1104. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-2-fluorophenyl)acetonitrile;

1105. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-2-methoxyphenyl)acetonitrile;

1106. 2-(3-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)acetonitrile;

1107. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanenitrile;

1108. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide;

1109. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)cyclopropanecarbonitrile;

1110. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropylacetonitrile;

1111. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(3,3-difluoroazetidin-1-yl)acetonitrile;

1112. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-morpholinoacetonitrile;

1113. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile;

1114. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1-(methylsulfonyl)azetidin-3-yl)acetonitrile;

1115. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1-(methylsulfonyl)azetidin-3-yl)acetonitrile;

1116. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)butanenitrile;

1117. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-2-yl)acetonitrile;

1118. 2-(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-4-yl)acetonitrile;

1119. 7-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1120. 7-(1-(5-(1-chloro-2,2,2-trifluoroethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1121. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-N,N-dimethylethanamine;

1122. 7-(1-(5-(1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1123. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutanenitrile;

1124. 7-(1-(5-(2,2,2-trifluoro-1-isopropoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1125. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol;

1126. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol;

1127. 7-(1-(5-(1-cyclopropyl-2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1128. 7-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1129. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoro-3-methylbutan-2-ol;

1130. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclohexyl-2,2,2-trifluoroethanol;

1131. 1-(4-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)ethanone;

1132. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopentyl-2,2,2-trifluoroethanol;

1133. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methyl piperidin-4-yl)ethanol;

1134. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(tetrahydro-2H-pyran-4-yl)ethanol;

1135. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(piperidin-4-yl)ethan-1-ol

1135. 7-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1136. 7-(1-(5-(2,2,2-trifluoro-1-morpholinoethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1137. 7-(1-(5-(1,1,1-trifluoro-3-(methylsulfonyl)propan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1138. 7-(1-(5-(4-(cyclopropylsulfonyl)-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1139. 7-(1-(5-(1-((methylsulfonyl)methoxy)-2,2,2-trifluoroethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1140. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutane-1-sulfonamide;

1141. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-sulfonamide;

1142. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide;

1143. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N,N-dimethylbutanamide;

1144. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutanamide;

1145. 1-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea;

1146. 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1147. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-N-methylpentanamide;

1148. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)cyclopropanecarboxamide;

1149. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide;

1150. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)cyclopentanecarboxamide;

1151. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine;

1152. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)cyclopropanamine;

1153. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutan-1-ol;

1154. 7-(1-(5-(1,1,1-trifluoro-4-methoxybutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1155. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoropentannitrile;

1156. 2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile;

1157. 7-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1158. (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(cyclopropyl)methanol;

1159. 7-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1160. 7-(1-(5-(1-methoxy-3-(methylsulfonyl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1161. 7-(1-(5-(1-fluoro-3-(methylsulfonyl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1162. 7-(1-(5-(4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1163. (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanol;

1164. (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-methylpiperidin-4-yl)methanol;

1165. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)-2-hydroxyacetamide;

1166. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide;

1167. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyano-N-(2,2,2-trifluoroethyl)acetamide;

1168. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethanol;

1169. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-2-yl)-2,2,2-trifluoroethanol;

1170. 7-(1-(6-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1171. 1 -(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-4-yl)-2,2,2-trifluoroethanol;

1172. 1-(5-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-2-yl)-2,2,2-trifluoroethanol;

1173. 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1174. 7-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1175. 7-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1176. 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)pyrrolidine-3-carbonitrile;

1177. 1-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea;

1178. 1-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropyl urea;

1179. 3-cyclopentyl-3-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)propanenitrile;

1180. 3-cyclopentyl-3-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)propanenitrile;

1181. 7-(1-(5-((S)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1182. 7-(1-(5-((R)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1183. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol;

1184. 7-(1-(5-((R)-2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1185. 7-(1-(5-((S)-2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1186. 7-(1-(5-(1,1,1-trifluoro-4-(isopropylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1187. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-(methylsulfonyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethanamine;

1188. 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-(cyclopropylaminosulfonyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1189. 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1190. 7-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)phenyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1191. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(trifluoromethyl)propan-1-ol;

1192. N-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-2-cyanoacetamide;

1193. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-2-methylpentan-2-ol;

1194. 7-(1-(5-(3,3,3-trifluoro-2-((methylsulfonyl)methyl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1195. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-N-methylcyclopropanamine;

1196. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-2,2-dimethylbutan-1-ol;

1197. N-(2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)ethyl)cyclopropanamine;

1198. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine;

1199. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)cyclohexanamine;

1200. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine;

1201. 7-(1-(5-(1,1,1-trifluoro-4-morpholinobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1202. 1-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)azetidine-3-carbonitrile;

1203. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-isopropylbutan-1-amine;

1204. 7-(1-(5-(4-(cyclopropylmethylsulfonyl)-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1205. 7-(1-(5-(3-(cyclopropylmethylsulfonyl)-1,1,1-trifluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1206. 7-(1-(5-(1,1,1-trifluoro-3-morpholinopropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1207. (S)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-isopropylbutan-1-amine;

1208. (R)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-isopropylbutan-1-amine;

1209. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-(methylsulfonyl)-1H-pyrazol-1-yl)pyridin-3-yl)-3,3,3-trifluoropropan-1-amine;

1210. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-N-isopropylpentanamide;

1211. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N,N-diisopropylbutan-1-amine;

1212. N-(2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-3,3,3-trifluoropropyl)cyclopropanamine;

1213. (R)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutanamide;

1214. (S)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutanamide;

1215. (S)-4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-N-isopropylpentanamide;

1216. 7-(1-(5-((S)-4-(cyclopropylsulfonyl)-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1217. (S)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine, TFA salt;

1218. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-3,3,3-trifluoro-N-isopropylpropan-1-amine;

1219. 7-(1-(5-(1,1,1-trifluoro-4-(4-methylpiperazin-1-yl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1220. (4-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)(cyclopropyl)methanone;

1221. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-ethylpiperidin-4-yl)-2,2,2-trifluoroethanol;

1222. 7-(1-(5-(1,1,1-trifluoro-3-(4-methylpiperazin-1-yl)propan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1223. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-ol;

1224. 5-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-6,6,6-trifluorohexane-2-amine, TFA salt;

1225. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol;

1226. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol;

1227. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-4-hydroxypentanenitrile;

1228. 2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)-N-methylethanamine;

1229. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoro-3-morpholinopropan-2-ol;

1230. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoro-4-morpholinobutan-2-ol;

1231. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylazetidin-3-yl)ethanol;

1232. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-ethylpyrrolidin-3-yl)-2,2,2-trifluoroethanol;

1233. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-ethylpyrrolidin-3-yl)-2,2,2-trifluoroethanol;

1234. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpyrrolidin-3-yl)ethanol;

1235. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpyrrolidin-3-yl)ethanol;

1236. 1-(3-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)azetidin-1-yl)ethanone;

1237. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylazetidin-3-yl)ethanol;

1238. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-4-hydroxy-N-isopropylpentanamide;

1239. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-ethylazetidin-3-yl)-2,2,2-trifluoroethanol;

1240. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpiperidin-4-yl)ethanol;

1241. N-(2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)ethyl)propan-2-amine, TFA salt;

1242. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)ethanol;

1243. (3)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)ethanol;

1244. 7-(1-(5-(2,2,2-trifluoro-1-methoxy-1-(1-methylpiperidin-4-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1245. 3-(3-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)azetidin-1-yl)-3-oxopropanenitrile;

1246. 3-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-N-methylazetidine-1-carboxamide;

1247. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)isobutyramide;

1248. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-2-cyanoacetamide;

1249. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-1-morpholinobutan-1-one;

1250. 1-(4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoropentanoyl)azetidine-3-carbonitrile;

1251. (S)-1-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol;

1252. (R)-1-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol.

The present invention describes novel 1H-imidazo[4,5-b]pyridin-2(3H)-one compounds, their pharmaceutically acceptable salts and isomers of formula II:

Where

B represents H;

X independently represents H, (CH ₂ )n, -CO-, OCO, COO; CO(CH ₂ )n, (NH ₂ )n; (CH ₂ )n(NH ₂ )n; (CH ₂ )n(NH ₂ )nCN; CONH; CONR ₁ R ₂ , CO(NH ₂ )n; (CH ₂ )nCO(NH ₂ )n, CO(NH ₂ )n(CH ₂ )CF ₃ , SO ₂ (CH ₂ )n, NH(CH ₂ )nCN, an unsubstituted or substituted 3-8-membered carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S and SO ₂ , and the substituents on the carboxyl or heterocyclic ring can be selected from halogen, alkoxy, CHMe, -CH(CF ₃ ), -C(CF ₃ )(OH), C(CF ₃ )(OMe), -CH(CN), CHOH, CH(R ₅ ),

H, R ₁ , R ₂ , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkox, CN, -CO-, COR ₁ , (CH ₂ )n, -(CH ₂ )nCN-, CH ₂ CF ₃ , COOH, OR ₁ , NR ₁ R ₂ , -COOR ₁ , -CON(R ₁ ) ₂ , -SO ₂ (CH ₂ ) _n , -SO ₂ N(R ₁ ) ₂ , -OCOR ₁ , CONHCH(CH ₃ )-CF ₃ , CH ₂ CN, CH ₂ SO ₂ CH ₃ , -NR ₁ COR ₁ , -CONH, CONR ₁ R ₂ , -CO(NH ₂ )n(CH ₂ )nSO ₂ ; -CONH(CH ₂ )nOH, CONH(CH ₂ )nSO ₂ R ₁ R ₂ , -CONH-(CH ₂ )nCF ₃ , -CONH(CH ₂ )nCF ₃ ,

-NHCONH(CH ₂ )nCF ₃ , NHCONHR ₁ , -NHCOR ₁ R ₂ , NR ₁ CONR ₁ R ₂ , (NH ₂ )n, -NH ₂ CH ₂ , NH ₂ CH ₂ CF ₃ , -CH(CF ₃ )-(CH)n-CO-NR ₁ R ₂ ,, CH(CF ₃ )-(CH)n-SO ₂ , (CH)n; CH(OH)( _CF3 )(heterocycle) _R1 , an optionally substituted 3-8-membered carbocyclic ring or a 3-8-membered saturated mono-, condensed or bridged heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, _S or SO2, an optionally substituted 3-8-membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S or _SO2 , wherein the substitution can independently be _R1 and _R2 at any position on the ring; _O1-6alk -aryl, _ArC1-6alkyl ;

R ₁ and R ₂ are independently selected from the group consisting of H, halogen, CN, CF ₃ , hydroxyl, amino, SO ₂ , SO ₂ -C ₁ -C ₆ alkyl, SO ₂ -C ₃ -C ₈ cycloalkyl, CH ₂ CN, CH ₂ CF ₃ , unsubstituted or substituted straight or branched C ₁ -C ₆ alkyl, wherein the substituents are selected from halogen, OH, CN, C ₁ -C ₆ alkoxy optionally substituted with NH ₂ , C ₁ -C ₆ alkylsulfonyl optionally substituted with CONH ₂ , unsubstituted or substituted C ₃ -C ₈ carbocyclyl or a 3-8-membered heterocyclic ring with 1-3 heteroatoms selected from O, N and S, SO ₂ , straight or branched C ₁ -C ₆ alkenyl, straight or branched C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonyl, C(O)-C ₃ -C ₈ cycloalkyl, heteroalkyl optionally substituted with CONH ₂ , C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, C ₃ -C ₈ heterocycloalkyl, C ₃ -C ₈ heterocycloalkenyl, carbocyclyl, aryl and heteroaryl, -CH(CF ₃ )-(CH)n-CO-NR ₃ R ₄ , -CH(CF ₃ )-(CH)n-SO ₂ -NR ₃ R ₄ , CH(CF ₃ )-(CH)n-NR ₃ R ₄ , CH(CF ₃ )-NR ₃ R ₄ , CH(CF ₃ )-(CH)n-SO ₂ -CHR ₃ R ₄ , wherein cycloalkyl, cycloalkenyl, hetero cycloalkyl, heterocycloalkenyl, carbocyclyl, aryl and heteroaryl groups are optionally substituted;

R ₃ and R ₄ are H, independently represent CH ₃ , C ₃ -C ₈ cycloalkyl;

R ₅ is an unsubstituted or substituted 3-8-membered carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of O, N, S, SO ₂ ;

R ₆ independently represents H, straight or branched C ₁ -C ₆ alkyl, halogen;

X can be combined with Y at any atom to form a chemically feasible bond;

n is 0-3.

The present invention describes novel 1H-imidazo[4,5-b]pyridin-2(3H)-one compounds, their pharmaceutically acceptable salts and isomers of formula III:

Where

Y can be in any position of the pyridine ring, preferably in position 4 or 5 of pyridine;

Y represents H, R ₁ , R ₂ , halogen, CN, -CO-, COR ₁ , (CH ₂ )n, -(CH ₂ )nCN-, CH ₂ CF ₃ , COOH, -COOR ₁ , -CON(R ₁ ) ₂ , -SO ₂ (CH ₂ )n, -SO ₂ N(R ₁ ) ₂ , -OCOR ₁ , -NR ₁ COR ₁ , -CONH, CONR ₁ R ₂ , -CO(NH ₂ )n(CH ₂ )nSO ₂ ; -CONH(CH ₂ )nOH, CONH(CH ₂ )nSO ₂ R ₁ R ₂ , -CONH-(CH ₂ )nCF ₃ , -CONH(CH ₂ )nCF ₃ , -NHCONH(CH ₂ )nCF ₃ , -CH(CF ₃ )-(CH)n-CO-NR ₁ R ₂ , CH(CF ₃ )-(CH)n-SO ₂ -(CH)n; group CH(OH)(CF ₃ )(heterocycle)R ₁ , NHCONHR ₁ , -NHCOR ₁ R ₂ , NR ₁ CONR ₁ R ₂ , (NH ₂ )n, -NH ₂ CH ₂ -, NH ₂ CH ₂ CF ₃ ,

wherein the heterocycle is a possibly substituted 3-8-membered saturated mono-, condensed or bridged heterocyclic ring containing 1-3 heteroatoms selected from the group containing O, N, S;

wherein the substitution can independently be R ₁ and R ₂ at any position of the heterocyclic ring; C _1-6 alk-aryl, ArC _1-6 alkyl;

R ₁ and R ₂ are absent or independently selected from the group consisting of H, halogen, CN, CF ₃ , hydroxyl, amino, SO ₂ , SO ₂ -C ₁ -C ₆ alkyl, CH ₂ CF ₃ , straight or branched C ₁ -C ₆ alkyl, straight or branched C ₁ -C ₆ alkenyl, straight or branched C ₁ -C ₆ alkynyl, halo-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkylamino,

n is 0-3.

The present invention describes typical compounds of formula III as follows:

1133. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1 -(1 -methyl piperidin-4-yl)ethanol;

1134. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(tetrahydro-2H-pyran-4-yl)ethanol;

1176. 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)pyrrolidine-3-carbonitrile;

1181. 7-(1-(5-((S)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1182. 7-(1-(5-((R)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine;

1225. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol;

1226. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol;

1231. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylazetidin-3-yl)ethanol.

In one embodiment of the present invention, a method for preparing the compounds of the present invention is also described. The compounds of the present invention can be prepared according to the general synthesis schemes 1-4 presented in this description below.

General scheme of synthesis 1

Where

X represents C, N,

R ₂ and R ₃ represent H,

R ₁ :

Where

X represents C, N,

R ₁ is CN, and R ₂ is H,

R ₃ :

Where

X represents C, N,

R ₁ is CF ₃ , and R ₂ is H,

R ₃ :

Where

X represents C, N,

R ₁ is CF ₃ , and R ₂ is OH,

R ₃ :

Where

1 represents C, N,

R ₁ is CF ₃ , and R ₂ is OCH ₃ ,

R ₃ :

General scheme of synthesis 2

Where

X ₁ is O or H, R ₂ is H or -CH ₃ , R ₃ is H or -CH ₃ ,

R ₁ :

R ₄ :

General scheme of synthesis 3

Where

X ₁ , Y, Z represent C, N,

R ₃ is H, O, carbocycle,

General scheme of synthesis 4

Where

X represents C, N,

R ₂ is H, O, carbocycle,

R ₁ is

The present invention also includes, as another embodiment, a composition comprising a JAK1 inhibitory compound according to any of the preceding embodiments together with a pharmaceutically acceptable diluent, excipient and/or carrier. The compositions will include a conventional pharmaceutical carrier, excipient and/or diluent and a compound of the present invention as an active agent, and may further include carriers and adjuvants, etc. Pharmaceutically acceptable compositions will contain from about 1% to about 99% (by weight) of the compound(s) of the present invention or a pharmaceutically acceptable salt thereof and from 99% to 1% (by weight) of a suitable pharmaceutical excipient.

The administration of the compounds of the invention or their pharmaceutically acceptable salts in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration or means for achieving similar purposes. Thus, the administration can be carried out, for example, orally, nasally, parenterally (intravenously, intramuscularly or subcutaneously), locally, transdermally, intravaginally, intravesically, intracisternally or rectally in the form of solid, semi-solid, lyophilized powder or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions or aerosols or the like, preferably in unit dosage forms suitable for easy administration of precise dosages.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. The solid dosage forms described above can be prepared containing coatings and shells, such as enteric coatings. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Compositions for rectal administration are, for example, suppositories, which can be prepared by mixing the compounds of this invention, for example, with suitable non-irritating excipients or carriers. They are also provided for parenteral administration and administration in the form of sterile powders for reconstitution into sterile injection solutions or dispersions. Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays. Ophthalmic compositions, eye ointments, powders, inhalation compositions and solutions also include the compounds of this invention. Compressed gases can be used to disperse the compound of this invention in aerosol form.

The present invention includes, as another embodiment, a method of treating a disease mediated by or associated with JAK1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a JAK1 inhibitory compound according to any of the preceding embodiments or a composition comprising a JAK1 inhibitor according to any of the preceding embodiments together with a pharmaceutically acceptable diluent, excipient and/or carrier. Diseases mediated by or associated with JAK1 that can be treated include, but are not limited to, cancer, inflammatory disorders and autoimmune diseases.

The selective JAK1 inhibitors of the present invention may be effective in the treatment of cancer, including, but not limited to, carcinomas, sarcomas, lymphomas, leukemias, myelomas, germ cell tumors, blastomas, tumors of the central and peripheral nervous system and other tumors, including melanomas, seminoma and Kaposi's sarcoma and the like.

The compounds of the present invention may also be useful in disorders and diseases associated with acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, asthma, autoimmune hemolytic anemia, autoimmune thyroiditis, Crohn's disease, episodic lymphopenia with lymphocytotoxins, hemolytic jaundice of the newborn, Goodpasture's syndrome, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome and other internal bowel diseases, lupus, myasthenia gravis, myocardial or pericardial inflammation, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, scleroderma, systemic anaphylactic reaction, ulcerative colitis, nephritis (including including glomerulonephritis), gout, arthritis (such as rheumatoid arthritis and osteoarthritis), erythema, dermatitis, dermatomyositis, bronchitis, cholecystitis, sepsis and gastritis.

Without wishing to be bound by theory, it is noted that the compounds of the present invention exhibit selective inhibition of JAK1 over JAK 2, JAK 3 and TYK 2. Thus, it appears that the compounds of the present invention exhibit selective inhibition and are therefore more specific and preferred than other compounds of the prior art, as they are expected to cause fewer adverse effects.

The following examples and schemes illustrate a general procedure for synthesizing the compounds described in this application. The synthesis of the compounds of formula I described in this application and their variants is not limited by these examples and schemes. One skilled in the art will recognize that other procedures can be used to synthesize the compounds of formula I described in this application and that the procedures described in the examples and schemes represent only one such procedure. From the following description, one of ordinary skill in the art will recognize that the specific reaction conditions, added reagents, solvents, and reaction temperatures can be varied in the case of synthesizing specific compounds that fall within the scope of this invention. All intermediates described in the following examples for which there is no description of how to synthesize such intermediates are commercially available, unless otherwise noted.

Synthesis of compound No. 1177: 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile

Step 1: synthesis of trego-butyl-3-hydroxypyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (0.50 g, 2.699 mmol) in ethanol (5 mL) was added sodium borohydride (0.20 g, 5.399 mmol) at 0 °C and the mixture was stirred at room temperature (RT) for 4 h. The reaction progress was monitored using thin layer chromatography (TLC). After completion of the reaction, water (10 mL) was added to the reaction mixture and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.5 g, 99%) as a yellow solid.

MS (mass spectrometry): 188.24 [M+1].

Step 2: Synthesis of 1-(tert-butoxycarbonyl)pyrrolidin-3-ylmethanesulfonate

To a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.347 mmol) in dichloromethane (DCM; 10.0 mL) at 0 °C was added MsCl (0.673 g, 5.882 mmol) under nitrogen atmosphere. To the resulting reaction mixture was added dropwise a solution of diisopropylethylamine (DIPEA; 0.898 g, 6.951 mmol) in DCM (1.0 mL), stirred for 4 h at RT and the reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 10% ethyl acetate in hexane as eluent to give 1-(tert-butoxycarbonyl)pyrrolidin-3-ylmethanesulfonate (0.25 g, 25%) as a crude yellow oil. MS: 266.33 [M+1].

Step 3: synthesis of tert-butyl-3-cyanopyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butoxycarbonyl)pyrrolidin-3-ylmethanesulfonate (0.25 g, 0.9432 mmol) in dimethylformamide (DMF; 5 mL) and water (1 mL) was added KCN (0.138 g, 2.830 mmol) under nitrogen atmosphere and the resulting solution was heated overnight at 80 °C. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mixture was cooled to 0 °C and quenched with water. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 6% acetone in hexane as eluent to give tert-butyl 3-cyanopyrrolidine-1-carboxylate (0.15 g, 81%) as a yellow oil. MS: 197.25 [M+1].

Step 4: synthesis of pyrrolidine-3-carbonitrile trifluoroacetate

To a stirred solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (0.15 g, 0.765 mmol) in DCM (5 mL) was added TFA (0.8 mL) at 0 °C and the reaction mixture was allowed to stir at room temperature for 4 h. The reaction progress was monitored using TLC. After completion of the reaction, the volatiles were evaporated under reduced pressure, the residue was triturated with diethyl ether, filtered and dried to give pyrrolidine-3-carbonitrile trifluoroacetate (0.1 g, 62.2%) as a brownish solid.

MS: 194.15 [M+1].

Step 5: Synthesis of 4-nitroPhenyl-3-cyanocyclopentanecarboxylate

To a stirred solution of pyrrolidine-3-carbonitrile trifluoroacetate (0.05 g, 0.238 mmol) in acetonitrile (ACN; 5.0 mL) was added trimethylamine (0.072 g, 0.714 mmol) followed by 4-nitrophenyl chloroformate (0.047 g, 0.238 mmol) at 0 °C. The resulting reaction mixture was stirred for 4 h at room temperature. The completion of the reaction was monitored using TLC. After completion of the reaction, the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-nitrophenyl 3-cyanocyclopentanecarboxylate (0.05 g, 80.5%) as a white solid.

MS: 261.25 [M+1].

Step 6: Synthesis of 1-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazole-1-carbonyl)pyrrolidine-3-carbonitrile

To a stirred solution of 3-nitro-4-(1 H-pyrazol-4-yl)pyridin-2-amine (0.05 g, 0.2439 mmol) in DMF (2 mL) at 0 °C was added NaH (0.02 g, 0.4878 mmol) under nitrogen atmosphere and stirred for 30 min at the same temperature. To the resulting reaction mass was added a solution of 4-nitrophenyl 3-cyanocyclopentanecarboxylate (0.094 g, 0.7894 mmol) in DMF at 0 °C and stirred for 4 h at RT. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 0.5% methanol in DCM as eluent to give 1-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazole-1-carbonyl)pyrrolidine-3-carbonitrile (0.03 g, 37.6%) as a yellow solid.

MS: 328.3 [M+1].

Step 7: Synthesis of 1-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazole-1-carbonyl)pyrrolidine-3-carbonitrile

A stirred solution of 1-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazole-1-carbonyl)pyrrolidine-3-carbonitrile (0.03 g, 0.0917 mmol) in methanol (5 mL) was hydrogenated in the presence of 10% Pd/C (0.003 g, 10% w/w) using a hydrogen balloon. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile (0.02 g, 73.5%) as a brown solid.

MS: 298.3 [M+1].

Step 8: Synthesis of 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)pyrrolidine-3-carbonitrile

To a stirred solution of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile (0.025 g, 0.0841 mmol) in tetrahydrofuran (THF) was added trimethyl orthoformate (1.0 mL). The resulting reaction mixture was added p-toluenesulfonic acid (PTSA; 0.004 g) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. After completion, the reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh): eluent 3% to 5% MeOH in DCM, to give 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)pyrrolidine-3-carbonitrile (0.01 g, 40%) as an off-white solid.

MS: 308.3 [M+1].

Synthesis of Compound No. 1056: N-(3-cyanocyclobutyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide

Step 1: synthesis of tert-butyl-3-carbamoylcyclobutylcarbamate

To a stirred solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (0.500 g, 2.325 mmol) in THF (15 mL) was added ethyl chloroformate (0.301 mg, 2.79 mmol) at 0 °C and the reaction mixture was allowed to stir at room temperature for 1 h. To the resulting reaction mass was added ammonium hydroxide solution (5.0 mL) at 0 °C and stirred for 4 h at RT. The reaction progress was monitored using TLC. After completion of the reaction, the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 3-carbamoylcyclobutylcarbamate (0.430 g, 85.65%) as a colorless liquid.

MS: 215.12 [M+1].

Step 2: Synthesis of tert-butyl 3-cyanocyclobutylcarbamate

To a stirred solution of tert-butyl 3-carbamoylcyclobutylcarbamate (0.400 g, 1.869 mmol) in pyridine (5.0 mL) was added _POCl3 (1.84 g, 1.200 mmol) at 0 °C and the reaction mixture was allowed to stir at room temperature for 1 h. The reaction progress was monitored using TLC. After completion of the reaction, the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 3-cyanocyclobutylcarbamate (0.340 g, 98.8%) as a colorless liquid.

MS: 197.15 [M+1].

Step 3: Synthesis of 3-aminocyclobutanecarbonitrile hydrochloride

To a stirred solution of tert-butyl 3-cyanocyclobutylcarbamate (0.300 g, 1.522 mmol) in DCM (5 mL) was added dioxane-HCl (2.5 mL) at 0 °C and the reaction mixture was allowed to stir at room temperature for 4 h. The reaction progress was monitored using TLC. Upon completion, all volatiles were evaporated under reduced pressure, the residue was triturated with diethyl ether, filtered and dried to give 3-aminocyclobutanecarbonitrile hydrochloride (0.240 g, 94.63%) as an off-white solid.

MS: 133.05 [M+1].

Step 4: synthesis of 4-nitrophenyl-3-cyanocyclobutylcarbamate

To a stirred solution of 3-aminocyclobutanecarbonitrile hydrochloride (0.300 g, 2.247 mmol) in ACN (5.0 mL) was added trimethylamine (0.493 g, 4.89 mmol) followed by 4-nitrophenyl chloroformate (0.544 g, 2.706 mmol) at 0 °C. The resulting reaction mixture was stirred for 4 h at room temperature. The completion of the reaction was monitored using TLC. After completion of the reaction, the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-nitrophenyl 3-cyanocyclobutylcarbamate (0.250 g, 42.23%) as a yellowish solid.

MS: 262.05 [M+1].

Step 5: synthesis of N-(3-cyanocyclobutyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide

To a stirred solution of 7-(1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.05 g; 0.210 mmol) in ACN (2.5 ml) at 0 °C was added triethylamine (TEA; 0.053 g; 0.527 mmol) under nitrogen atmosphere and stirred for 30 min at the same temperature. To the resulting reaction mass was added a solution of 4-nitrophenyl-3-cyanocyclobutylcarbamate (0.081 g; 0.315 mmol) in ACN at 0 °C, then TEA (0.035 g; 0.315 mmol) under nitrogen atmosphere and stirred for 4 h at RT. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 3-5% methanol in DCM as eluent to give N-(3-cyanocyclobutyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide (0.03 g, 37.6%) as an off-white solid.

MS: 324.11 [M+1].

Synthesis of Compound No. 1063: N-(cyano(phenyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide

Step 1: 2-amino-2-phenylacetonitrile

To a stirred solution of benzaldehyde (1.0 g, 0.934 mmol) in ethanol (20 mL) were added ammonium chloride (0.99 g, 1.86 mmol), ammonium hydroxide (12.5 mL, 25% solution) and potassium cyanide (0.78 g, 1.21 mmol) at room temperature. The resulting reaction mixture was stirred at the same temperature for 4 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 2-amino-2-phenylacetonitrile (0.600 g, 48.3%) as an orange solid.

MS: 133.04 [M+1].

Step 2: 4-nitrophenyl cyano(phenyl)methylcarbamate

To a stirred solution of 2-amino-2-phenylacetonitrile (0.200 g, 1.515 mmol) in chloroform (5.0 mL) was added pyridine (Pyr; 0.3 g, 3.03 mmol) followed by 4-nitrophenyl chloroformate (0.3 g, 1.515 mmol) at 0 °C. The resulting reaction mixture was stirred for 4 h at room temperature. The completion of the reaction was monitored using TLC. Upon completion, the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-nitrophenyl cyano(phenyl)methylcarbamate (0.200 g, 44.4%) as a white solid.

MS: 298.25 [M+1].

Step 3: Synthesis of N-(cyano(phenyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide

To a stirred solution of 7-(1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.030 g, 0.0127 mmol) in DMF (2.0 mL) were added trimethylamine (0.038 g, 0.0381 mmol) and 4-nitrophenyl cyano(phenyl)methylcarbamate (0.037 g, 0.0127 mmol). The resulting reaction mixture was stirred for 6 h at room temperature. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give N-(cyano(phenyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide (0.004 g, 8.7%) as an off-white solid.

MS: 360.1 [M+1].

Synthesis of Compound No. 1064: N-(2,2,2-trifluoroethyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide

Step 1: synthesis of 4-(2-amino-3-nitropyridin-4-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.150 g, 0.073 mmol) in acetonitrile (10 mL) and trimethylamine (0.147 g, 0.146 mmol) was added 4-nitrophenyl 2,2,2-trifluoroethylcarbamate (0.231 g, 0.087 mmol) at room temperature. The resulting reaction mixture was stirred at 60 °C for 6 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 3-4% methanol in DCM to give 4-(2-amino-3-nitropyridin-4-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide (0.160 g; 67%) as a yellow solid.

MS: 331.04 [M+1].

Step 2: synthesis of 4-(2,3-diaminopyridin-4-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide

To a stirred solution of 4-(2-amino-3-nitropyridin-4-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide (0.080 g, 0.024 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.064 g, 0.12 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-(2,3-diaminopyridin-4-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide (0.045 g, 62.5%) as a dark brown solid.

MS: 301.2 [M+1].

Step 3: synthesis of N-(2,2,2-trifluoroethyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide

To a stirred solution of 4-(2,3-diaminopyridin-4-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide (0.045 g, 0.015 mmol) in THF (1.0 mL) was added trimethyl orthoformate (2.0 mL). The resulting reaction mixture was added PTSA (0.0051 g, 0.0030 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give N-(2,2,2-trifluoroethyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide (0.023 g, 50%) as an off-white solid.

MS: 311.1 [M+1].

Synthesis of Compound No. 1119: 7-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Step 1: synthesis of 6-bromopyridine-3-carbaldehyde

To a stirred solution of 2,5-dibromopyridine (26.0 g, 109.75 mmol) in diethyl ether (500 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (66 mL, 164.63 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then DMF (13 mL, 164.63 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4% ethyl acetate in hexane as eluent to give 6-bromopyridine-3-carbaldehyde (12.20 g, 59.8%) as a yellow oil.

MS: 187.0 [M+1].

Step 2: synthesis of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol

To a stirred solution of 6-bromopyridine-3-carbaldehyde (2.0 g, 10.75 mmol) in 1,2-dimethoxyethane (DME; 50 mL) at 0 °C was added trifluoromethyltrimethylsilane (TMSCF ₃ ; 1.61 g, 16.12 mmol) under nitrogen atmosphere, then CsF (2.44 g, 16.12 mmol) was added portionwise and stirred for 1 h at the same temperature. It was allowed to warm to RT and stirred for 6 h. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 20% ethyl acetate in hexane as eluent to give 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (1.24 g, 47.69%) as a yellow oil.

MS: 257.8 [M+1].

Step 3: Synthesis of 2-bromo-5-(2,2,2-trifluoro-1-methoxyethyl)pyridine

To a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (0.40 g, 15.56 mmol) in THF (5.0 mL) at 0 °C was added NaH (0.081 g, 20.23 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. To the resulting reaction mass was added a solution of Mel (0.232 g, 20.23 mmol) in THF (3.0 mL). The reaction was allowed to warm to RT and stirred for 1 h. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 10% acetone in hexane as eluent to give 2-bromo-5-(2,2,2-trifluoro-1-methoxyethyl)pyridine (0.39 g, 92.19%) as a colorless oil.

MS: 271.0 [M+1].

Step 4: synthesis of 4-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.15 g, 0.73 mmol) and 2-bromo-5-(2,2,2-trifluoro-1-methoxyethyl)pyridine (0.278 g, 1.02 mmol) in dimethyl sulfoxide (DMSO; 5 mL) was added K ₂ CO ₃ (0.251 g, 1.825 mmol), followed by Cul (0.013 g, 0.073 mmol) and L-proline (0.056 g, 0.365 mmol). The reaction mixture was heated at 110 °C for 16 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 40-60% acetone in n-hexane) to give 4-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.075 g, 37.87%) as a yellow solid.

MS: 394.4 [M+1].

Step 5: synthesis of 4-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2,3-diamine

To a stirred solution of 4-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.070 g, 1.77 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.025 g, 0.45 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.035 g, 53.03%) as a dark brown solid.

MS: 364.2 [M+1].

Step 6: synthesis of 7-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.035 g, 0.093 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.002 g, 0.018 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 3% to 5% MeOH in DCM) to give 7-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.07 g, 19.44%) as an off-white solid.

MS: 375.9 [M+1].

Synthesis of compound No. 1126: 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol

Step 1: Synthesis of N-methoxy-N-methylcyclopropanecarboxamide

To a stirred solution of cyclopropanecarbonyl chloride (10.0 g, 961.5 mmol) and N-methoxymethanamine hydrochloride (11.20 g, 1153.8 mmol) in THF (150 mL) was added dropwise TEA (24.20 g, 2403.8 mmol) at 0 °C and stirred for 30 min. The resulting reaction mass was then transferred to RT and stirred for 4 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 5% ether in n-hexane to give N-methoxy-N-methylcyclopropanecarboxamide (7.45 g; 60%) as a colorless oily mass.

MS: 130.07 [M+1].

Step 2: Synthesis of (6-bromopyridin-3-yl)(cyclopropyl)methanone

To a stirred solution of 2,5-dibromopyridine (12.0 g, 50.63 mmol) in diethyl ether (250 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (24.30 mL, 65.81 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then N-methoxy-N-methylcyclopropanecarboxamide (7.1 g, 55.69 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4% ethyl acetate in hexane as eluent to give (6-bromopyridin-3-yl)-(cyclopropyl)methanone (6.46 g, 68.07%) as a yellow oil.

MS: 227.1 [M+1].

Step 3: Synthesis of 1-(6-bromopyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol

To a stirred solution of (6-bromopyridin-3-yl)-(cyclopropyl)methanone (2.0 g, 88.49 mmol) in DME (25 mL) at 0 °C was added _TMSCF3 (1.86 g, 132.74 mmol) under nitrogen atmosphere, then CsF (2.01 g, 132.74 mmol) was added portionwise and the mixture was stirred for 1 h at the same temperature. The mixture was allowed to warm to RT and stirred for 6 h. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 15-20% ethyl acetate in hexane as eluent to give 1-(6-bromopyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (1.45 g, 55.76%) as a yellow oil.

MS: 297.4 [M+1].

Step 4: Synthesis of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.15 g, 0.73 mmol) and 1-(6-bromopyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (0.320 g, 1.02 mmol) in DMSO (5 mL) was added K ₂ CO ₃ (0.251 g, 1.825 mmol), followed by Cul (0.013 g, 0.073 mmol) and L-proline (0.056 g, 0.365 mmol). The reaction mixture was heated at 110 °C for 12 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 40-60% acetone in n-hexane) to give 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (0.065 g, 21.10%) as a yellow solid.

MS: 421.37 [M+1].

Step 5: synthesis of 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol

To a stirred solution of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (0.065 g, 1.54 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.043 g, 7.8 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (0.035 g, 57.37%) as a dark brown solid.

MS: 391.2 [M+1].

Step 6: synthesis of 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol

To a stirred solution of 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (0.035 g, 0.089 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0017 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 3% to 5% MeOH in DCM) to give 7-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.06 g, 17.19%) as an off-white solid.

MS: 400.9 [M+1].

Synthesis of Compound No. 1128: 7-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Step 1: Synthesis of 1-(6-bromopyridin-3-yl)ethanone

To a stirred solution of 2,5-dibromopyridine (12.0 g, 50.63 mmol) in diethyl ether (250 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (24.30 mL, 65.81 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then dimethylacetamide (DMA; 7.89 g, 60.75 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4% ethyl acetate in hexane as eluent to give 1-(6-bromopyridin-3-yl)ethanone (4.5 g, 44.03%) as a yellow oil.

MS: 201.1 [M+1].

Step 2: Synthesis of 2-(6-bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol

To a stirred solution of 1-(6-bromopyridin-3-yl)ethanone (2.0 g, 11.00 mmol) in DME (50 mL) at 0 °C was added _TMSCF3 (2.33 g, 14.30 mmol) under nitrogen atmosphere, then CsF (2.50 g, 16.50 mmol) was added portionwise and the mixture was stirred for 1 h at the same temperature. The mixture was allowed to warm to RT and stirred for 6 h. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 15-20% ethyl acetate in hexane as eluent to give 2-(6-bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol (1.45 g, 53.50%) as a yellow oil.

MS: 271.0 [M+1].

Step 3: Synthesis of 2-bromo-5-(1,1,1,2-tetrafluoropropan-2-yl)pyridine

To a stirred solution of 2-(6-bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol (1.45 g, 53.70 mmol) in 1,2-dichloroethane (DCE; 35 mL) at 0 °C was added diethylaminosulfur trifluoride (DAST; 1.12 g, 69.81 mmol) under nitrogen atmosphere, then stirred for 15 min at the same temperature. It was allowed to warm to RT and stirred for 1 h. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 15-20% ethyl acetate in hexane as eluent to give 2-bromo-5-(1,1,1,2-tetrafluoropropan-2-yl)pyridine (1.1 g, 75.86%) as a yellow oil.

MS: 273.04 [M+1].

Step 4: synthesis of 4-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.15 g, 0.73 mmol) and 2-bromo-5-(1,1,1,2-tetrafluoropropan-2-yl)pyridine (0.298 g, 1.09 mmol) in DMSO (5 mL) was added K ₂ CO ₃ (0.251 g, 1.825 mmol), followed by Cul (0.013 g, 0.073 mmol) and L-proline (0.056 g, 0.365 mmol). The reaction mixture was heated at 110 °C for 16 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 40-60% acetone in n-hexane) to give 4-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.065 g, 22.49%) as a yellow solid.

MS: 397.1 [M+1].

Step 5: synthesis of 4-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2,3-diamine

To a stirred solution of 4-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.065 g, 0.16 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.041 g, 0.82 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.035 g, 58.32%) as a dark brown solid.

MS: 367.4 [M+1].

Step 6: Synthesis of 7-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.035 g, 0.095 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0017 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 3% to 5% MeOH in DCM) to give 7-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.06 g, 16.67%) as an off-white solid.

MS: 377.2 [M+1].

Synthesis of Compound No. 1164: (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanol

Step 1: Synthesis of N-methoxy-N-methylcyclopropanecarboxamide

To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.0 g, 43.66 mmol) and N-methoxymethanamine hydrochloride (5.56 g, 56.76 mmol) in DMF (35 mL) were added dicyclohexylcarbodiimide (DCC; 13.51 g, 65.49 mmol) and dimethylaminopyridine (DMAP; 1.60 g, 13.98 mmol) successively at 0 °C and left under stirring for 30 min. The resulting reaction mass was allowed to warm to RT and stirred for 4 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with 1 N HCl in water and extracted with EtOAc. The organic layer was washed with bicarbonate water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 20% acetone in n-hexane) to give tert-butyl 4-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (7.45 g, 60%) as a colorless oily mass.

MS: 273.1 [M+1].

Step 2: synthesis of tert-butyl 4-(6-bromonicotinoyl)piperidine-1-carboxylate

To a stirred solution of 2,5-dibromopyridine (5.0 g, 21.18 mmol) in diethyl ether (100 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (8.47 mL, 21.18 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then tert-butyl 4-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (6.36 g, 23.29 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with 10% MeOH in DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-(6-bromonicotinoyl)piperidine-1-carboxylate (5.8 g, 67.12%) as a colorless oily mass.

MS: 371.0 [M+1].

Step 3: Synthesis of (6-bromopyridin-3-yl)(piperidin-4-yl)methanone

To a stirred solution of tert-butyl 4-(6-bromonicotinoyl)piperidine-1-carboxylate (5.0 g, 13.51 mmol) in THF (50 mL) was added 4 M HCl in dioxane (25 mL) at 0 °C under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 10 h. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with 10% MeOH in DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4-5% MeOH in DCM as eluent to give (6-bromopyridin-3-yl)(piperidin-4-yl)methanone (3.45 g, 94.52%) as a colorless crystalline solid.

MS: 271.0 [M+1].

Step 4: Synthesis of (6-bromopyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanone

To a stirred solution of (6-bromopyridin-3-yl)(piperidin-4-yl)methanone (2.0 g, 7.44 mmol) in anhydrous DCM (20 mL) at 0 °C was added MsCl (1.11 g, 9.66 mmol) under nitrogen atmosphere. To the resulting reaction mixture was added dropwise TEA (1.12 g, 11.16 mmol), stirred for 1 h at 0 °C, allowed to warm to RT and stirred for 1 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 2-3% MeOH in DCM as eluent to give (6-bromopyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanone (1.40 g, 56.00%) as an off-white solid.

MS: 349.01 [M+1].

Step 5: Synthesis of (6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanone

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.15 g, 0.73 mmol) and (6-bromopyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanone (0.254 g, mmol) in DMA (5 mL) was added K ₂ CO ₃ (0.251 g, 1.825 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 4-5% MeOH in DCM as eluent to give (6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanone (0.065 g, 18.84%) as a yellow solid.

MS: 472.02 [M+1].

Step 6: synthesis of 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol

To a stirred solution of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (0.065 g, 1.37 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.037 g, 6.8 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. After completion of the reaction, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (0.035 g, 57.37%) as a dark brown solid.

MS: 442.0 [M+1].

Step 7: synthesis of (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanone

To a stirred solution of 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (0.035 g, 7.93 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0017 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water, extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 5-6% MeOH in DCM as eluent to give (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanone (0.006 g, 17.41%) as an off-white solid.

MS: 452.0 [M+1].

Step 8: synthesis of 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol

To a stirred solution of (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanone (0.006 g, 0.013 mmol) in THF (1.0 mL) was added NaBH ₄ (0.001 g, 0.026 mmol) and stirred for 2 h at 0 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanol (0.03 g, 50.00%) as an off-white solid.

MS: 454.0 [M+1].

Synthesis of compound No. 1166: 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile

Step 1: synthesis of 6-bromopyridine-3-carbaldehyde

To a stirred solution of 2,5-dibromopyridine (26.0 g, 109.75 mmol) in diethyl ether (500 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (66 mL, 164.63 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then DMF (13 mL, 164.63 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4% ethyl acetate in hexane as eluent to give 6-bromopyridine-3-carbaldehyde (12.20 g, 59.8%) as a yellow oil.

MS: 187.0 [M+1].

Step 2: Synthesis of 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carbaldehyde

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.075 g, 0.36 mmol) and 6-bromopyridine-3-carbaldehyde (0.075 g, 0.40 mmol) in DMA (5 mL) was added K ₂ CO ₃ (0.124 g, 0.90 mmol) and the reaction mixture was heated at 110 °C for 16 h. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 1% to 3% MeOH in DCM) to give 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carbaldehyde (0.065 g, 51.58%) as a yellow solid.

MS: 311 [M+1].

Step 3: 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile

To a stirred solution of 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carbaldehyde (0.065 g, 0.20 mmol) in AcOH (5 mL) was added trimethylsilyl cyanide (TMSCN) (0.031 g, 0.31 mmol) and TMSCN (0.051 g, 0.38 mmol) in AcOH (1 mL) at 0 °C and allowed to warm to RT. The mixture was stirred for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with bicarbonate water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 2-3% MeOH in DCM as eluent to give 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile (0.045 g, 47.36%) as a yellow solid.

MS: 454 [M+1].

Step 4: 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile

To a stirred solution of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile (0.045 g, 0.09 mmol) in EtOH (10 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.027 g, 0.49 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with 5:5 H ₂ O : EtOAc (50 mL) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile (0.016 g, 37.20%) as a dark brown solid.

MS: 425.1 [M+1].

Step 5: 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile

To a stirred solution of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile (0.016 g, 0.037 mmol) in THF (3.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.07 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water, extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4-6% MeOH in DCM as eluent to give 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile (0.03 g, 58.82%) as an off-white solid.

MS: 435.2 [M+1].

Synthesis of compound No. 1116: 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)-butanenitrile

Step 1: Synthesis of 1-(6-bromopyridin-3-yl)-3-(methylthio)propan-1-ol

To a stirred solution of 2,5-dibromopyridine (1.5 g, 6.32 mmol) in diethyl ether (25 ml) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (2.5 ml, 6.32 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then 3-(methylthio)propanal (0.73 g, 6.965 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4% ethyl acetate in hexane as eluent to give 1-(6-bromopyridin-3-yl)-3-(methylthio)propan-1-ol (0.580 g, 35.15%) as a colorless oil.

MS: 264.0 [M+1].

Step 2: Synthesis of 1-(6-bromopyridin-3-yl)-3-(methylsulfonyl)propan-1-ol

To a stirred solution of 1-(6-bromopyridin-3-yl)-3-(methylthio)propan-1-ol (0.58 g, 2.19 mmol) in acetone: _H2O (50 mL, 7:3) at 0°C was added oxone (1.68 g, 5.49 mmol) under nitrogen atmosphere and stirred for 16 h at the same temperature. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 3% MeOH in DCM as eluent to give 1-(6-bromopyridin-3-yl)-3-(methylsulfonyl)propan-1-ol (0.60 g, 93.02%) as a colorless oil.

MS: 296.0 [M+1].

Step 3: Synthesis of 1-(6-bromopyridin-3-yl)-3-(methylsulfonyl)propyl methanesulfonate

To a stirred solution of 2,5-dibromopyridine (0.30 g, 1.02 mmol) in DCM (5.0 mL) at 0 °C was added MsCl (0.151 g, 1.32 mmol) under nitrogen atmosphere. To the resulting reaction mixture was added dropwise a solution of TEA (0.153 g, 1.52 mmol) in DCM (1.0 mL) and stirred for 15 min at 0 °C. The reaction mixture was allowed to warm slowly to RT and the reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The aqueous layer was basified with sodium bicarbonate until basic as indicated by pH indicator paper and then extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure to give 1-(6-bromopyridin-3-yl)-3-(methylsulfonyl)propyl methanesulfonate (0.320 g; 84.43%) as a crude yellow oily mass.

MS: 374.02 [M+1].

Step 4: Synthesis of 2-(6-bromopyridin-3-yl)-4-(methylsulfonyl)butanenitrile

To a stirred solution of 2,5-dibromopyridine (0.320 g, 8.56 mmol) in DMSO (1.5 mL) at RT was added potassium cyanide (0.067 g, 10.27 mmol) under nitrogen atmosphere and stirred for 1 h at 80 °C. The reaction progress was monitored using TLC. Upon completion, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 2-3% MeOH in DCM as eluent to give 2-(6-bromopyridin-3-yl)-4-(methylsulfonyl)butanenitrile (0.120 g, 46.15%) as a dark brown viscous mass.

MS: 305.01 [M+1].

Step 5: synthesis of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)butanenitrile

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.07 g, 0.34 mmol) and 2-(6-bromopyridin-3-yl)-4-(methylsulfonyl)butanenitrile (0.155 g, 0.51 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.166 g, 0.78 mmol), then CuI (0.006 g, 0.034 mmol) and N,N'-dimethylethylenediamine (DMEDA; 0.015 g, 0.175 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 2-3% MeOH in DCM) to give 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)butanenitrile (0.030 g, 20.54%) as a yellow solid.

MS: 428.1 [M+1].

Step 6: synthesis of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)butanenitrile

To a stirred solution of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)butanenitrile (0.030 g, 0.070 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (1.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.019 g, 0.35 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O : EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.015 g, 53.57%) as a dark brown solid.

MS: 398.2 [M+1].

Step 7: synthesis of 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)butanenitrile

To a stirred solution of 4-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.015 g, 0.037 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0012 g, 0.018 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 3% to 5% MeOH in DCM) to give 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)butanenitrile (0.004 g, 25.92%) as an off-white solid.

MS: 408.0 [M+1].

Synthesis of compound No. 1089: 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile

Step 1: synthesis of methyl 6-bromopyridine-3-carboxylate

To a stirred solution of 6-bromopyridine-3-carbaldehyde (1.5 g, 0.810 mmol) in methanol (45 mL) at RT were added N-iodosuccinimide (2.72 g, 1.210 mmol) and basic potassium carbonate (1.66 g, 1.210 mmol) in the dark and stirred for 6 h at the same temperature. The reaction progress was monitored using TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 8-12% ethyl acetate in hexane as eluent to give methyl 6-bromopyridine-3-carboxylate (1.05 g, 59.8%) as a white solid.

MS: 215.0 [M+1].

Step 2: synthesis of methyl 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-carboxylate

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.300 g, 0.138 mmol) and methyl 6-bromopyridine-3-carboxylate (0.44 g, 0.207 mmol) in DMA (7 mL) was added K ₂ CO ₃ (0.381 g, 0.276 mmol) at RT. The reaction mixture was heated at 110 °C for 16 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 40-60% acetone in n-hexane) to give methyl 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carboxylate (0.210 g, 42.85%) as a yellow solid.

MS: 341.09 [M+1].

Step 3: 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carboxylic acid

To a stirred solution of methyl 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carboxylate (0.2 g, 0.058 mmol) in a mixture of THF:MeOH: _H2O (18 mL, 5:3:1) was added LiOH (0.044 g, 0.117 mmol) and the mixture was stirred for 2 h at room temperature. After completion of the reaction, all volatiles were evaporated under reduced pressure. The reaction mixture was diluted with water, acidified with 6 N HCl solution to adjust the pH to 6 and extracted with EtOAc. The organic phases were combined, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carboxylic acid (0.170 g; 89%) as a yellow solid.

MS: 327 [M+1].

Step 4: 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile

To a stirred solution of 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carboxylic acid (0.080 g, 0.0271 mmol) and azetidine-3-carbonitrile hydrochloride (0.039 g, 0.049 mmol) in DMF (3 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; (0.139 g, 0.036 mmol) and DIPEA (0.063 g, 0.049 mmol). The reaction mixture was then stirred at room temperature for 6 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure to give the crude product. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh; eluent 4% MeOH in DCM) to give 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile (0.055 g; 58%) as a light yellow solid.

MS: 391.09 [M+1].

Step 5: 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile

To a stirred solution of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile (0.050 g, 0.012 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.033 g, 0.064 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O : EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile (0.035 g, 76%) as a dark brown solid.

MS: 361.2 [M+1].

Step 6: 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile

To a stirred solution of 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile (0.035 g, 0.097 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0017 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 5% to 6% MeOH in DCM) to give 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)nicotinoyl)azetidine-3-carbonitrile (0.018 g, 51.42%) as an off-white solid.

MS: 371.1 [M+1].

Synthesis of compound No. 1107: 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanenitrile

Step 1: Synthesis of 2-(6-bromopyridin-3-yl)propanenitrile

To a stirred solution of 1-(6-bromopyridin-3-yl)ethanone (0.4 g, 0.20 mmol) in DME (12 mL) at 0 °C under an inert gas atmosphere was added toluenesulfonylmethyl isocyanide (TosMIC; 0.585 g, 0.30 mmol). Then a solution of potassium tert-butoxide base (0.336 g, 0.30 mmol) in tert-butanol was added dropwise to the reaction mixture. After the addition, the mixture was stirred for 6 h at room temperature. The reaction progress was monitored using TLC. Upon completion, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 15% ethyl acetate in hexane as eluent to give 2-(6-bromopyridin-3-yl)propanenitrile (0.240 g, 57.14%) as a colorless oil.

MS: 211 [M+1].

Step 2: Synthesis of 2-(6-bromopyridin-3-yl)propanamide

To a stirred solution of 2-(6-bromopyridin-3-yl)propanenitrile (0.240 g, 0.114 mmol) and DMSO (4 mL) at 0 °C under N ₂ was added potassium carbonate base (0.315 g, 0.228 mmol). Hydrogen peroxide (0.7 mL) was added dropwise at 0 °C and the resulting mixture was stirred at RT for 4 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure product 2-(6-bromopyridin-3-yl)propanamide (0.230 g, 88.46%) as an off-white solid.

MS: 228 [M+1].

Step 3: Synthesis of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.160 g, 0.078 mmol) and 2-(6-bromopyridin-3-yl)propanamide (0.200 g, 0.078 mmol) in DMSO (5 mL) was added K ₂ CO ₃ (0.215 g, 0.156 mmol), then CuI (0.029 g, 0.00156 mmol) and L-proline (0.017 g, 0.00156 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide (0.140 g, 45.45%) as a yellow solid.

MS: 354.1 [M+1].

Step 4: synthesis of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide

To a stirred solution of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide (0.140 g, 0.039 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.105 g, 0.198 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O : EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide (0.090 g, 70%) as a dark brown solid.

MS: 324.2 [M+1].

Step 5: Synthesis of 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide

To a stirred solution of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide (0.090 g, 0.0278 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0095 g, 0.0055 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water, extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide (0.048 g, 52.17%) as an off-white solid.

MS: 334.1 [M+1].

Step 6: Synthesis of 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanenitrile

To a stirred solution of 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide (0.040 g, 0.0120 mmol) in pyridine (3.0 mL) was added dropwise _POCl3 (0.091 g, 0.60 mmol) at 0 °C. After complete addition, the mixture was stirred for 4 h at room temperature. The reaction was monitored for completion using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 4 to 6% MeOH in DCM) to give 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanenitrile (0.021 g, 56.7%) as an off-white solid.

MS: 316.1 [M+1].

Synthesis of Compound No. 1167: 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide

Step 1: Synthesis of 2-(6-bromopyridin-3-yl)-2-cyclopropylacetonitrile

To a stirred solution of (6-bromopyridin-3-yl)(cyclopropyl)methanone (1.0 g, 0.442 mmol) in DME (12 mL) at 0 °C under an inert gas atmosphere was added TosMIC (1.29 g, 0.663 mmol). Then a solution of potassium tert-butoxide base (0.991 g, 0.884 mmol) in tert-butanol (1.0 mL) was added dropwise to the reaction mixture. After complete addition, the mixture was stirred for 6 h at room temperature. The reaction progress was monitored using TLC. Upon completion, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 15% ethyl acetate in hexane as eluent to give 2-(6-bromopyridin-3-yl)-2-cyclopropylacetonitrile (0.6 g, 56.60%) as a colorless oil.

MS: 239 [M+2].

Step 2: Synthesis of 2-(6-bromopyridin-3-yl)-2-cyclopropylacetic acid

To a stirred solution of 2-(6-bromopyridin-3-yl)-2-cyclopropylacetonitrile (0.500 g, 0.210 mmol) was added 4 M HCl (5.0 mL) at room temperature. The resulting reaction mixture was stirred for 4 h at 100 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water, extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the pure desired product 2-(6-bromopyridin-3-yl)-2-cyclopropylacetic acid (0.320 g, 59.25%) as a thick oil.

MS: 258 [M+2].

Step 3: Synthesis of 2-(6-bromopyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide

To a stirred solution of 2-(6-bromopyridin-3-yl)-2-cyclopropylacetic acid (0.32 g, 0.125 mmol) and azetidine-3-carbonitrile hydrochloride (0.185 g, 0.187 mmol) in DMF (3 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 0.357 g, 0.187 mmol), 1-hydroxybenzotriazole (HOBT; 0.252 g, 0.187 mmol) and DIPEA (0.322 g, 0.250 mmol). The reaction mixture was then stirred at room temperature for 12 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure to give the crude product. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh; eluent 30% ethyl acetate in hexane) to give 2-(6-bromopyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (0.260 g; 61.90%) as an off-white solid.

MS: 339.09 [M+2].

Step 4: Synthesis of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.100 g, 0.0487 mmol) and 2-(6-bromopyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (0.163 g, 0.0487 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.206 g, 0.0974 mmol), followed by CuI (0.018 g, 0.00974 mmol) and DMEDA (0.085 g, 0.0974 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 4-6% MeOH in DCM) to give 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (0.130 g, 59%) as a yellow solid.

MS: 462.1 [M+1].

Step 5: synthesis of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide

To a stirred solution of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (0.080 g, 0.0173 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.045 g, 0.0867 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O : EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (0.061 g, 82.43%) as a dark brown solid.

MS: 432.2 [M+1].

Step 6: synthesis of 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide

To a stirred solution of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (0.060 g, 0.0139 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0046 g, 0.0027 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 7-8% MeOH in DCM) to give 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (0.035 g, 57.37%) as an off-white solid.

MS: 442.1 [M+1].

Synthesis of Compound No. 1136: 7-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Step 1: synthesis of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol

To a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanone (2.5 g, 0.984 mmol) in MeOH (50 mL) was added NaBH ₄ (0.744 g, 1.962 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 4 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (2.3 g, 91%) as a white solid.

MS: 256.2 [M+1].

Step 2: Synthesis of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate

To a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (2.3 g, 0.898 mmol) in DCM (46 mL) was added DIPEA (2.31 g, 1.796 mmol) at 0 °C. To the resulting reaction mass was added dropwise at 0 °C over 10 min and the reaction mixture was stirred at the same temperature for 4 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with water, brine, dried over sodium sulfate, concentrated under reduced pressure to obtain the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 10% acetone in n-hexane to give 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (2.5 g; 72%) as a white solid.

MS: 388 [M+1].

Step 3: synthesis of diethyl 2-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)malonate

To a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (2.4 g, 0.620 mmol) in THF (50 mL) was added diethyl malonate (1.63 g, 1.240 mmol) at room temperature and cooled to 10 °C. Potassium tert-butoxide base (1.38 g, 1.240 mmol) was added portionwise at 10 °C and stirring was continued at room temperature for 6 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 15% ethyl acetate in n-hexane to give diethyl 2-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)malonate (1.6 g; 70%) as a yellow oil.

MS: 398.2 [M+1].

Step 4: Synthesis of 2-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)propane-1,3-diol

To a stirred solution of diethyl 2-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)malonate (1.6 g, 0.402 mmol) in EtOH (32 mL) was added NaBH ₄ (0.450 g, 1.206 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 30% acetone in n-hexane to give 2-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)propane-1,3-diol (0.460 g; 35%) as a clear oil.

MS: 314 [M+1].

Step 5: synthesis of 2-bromo-5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridine

To a stirred solution of 2-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)propane-1,3-diol (0.450 g, 0.143 mmol) in anhydrous THF (20 mL) at 0 °C under N ₂ was added dropwise at 0 °C n-butyl lithium (1.6 M solution in hexane) (0.890 mL, 0.143 mmol) and stirred for 30 min. A solution of p-toluenesulfonyl chloride (0.271 g, 0.143 mmol) in anhydrous THF was added slowly. The mixture was stirred at 0 °C for 1 h and a second portion of n-butyl lithium (1.6 M solution in hexane) (0.890 mL, 0.143 mmol) was added dropwise. After the addition was complete, the mixture was heated at 60 °C and stirred for 4 h. The reaction was monitored for completion using TLC. Upon completion of the reaction, the reaction mixture was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 10% acetone in n-hexane to give 2-bromo-5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridine (0.130 g, 31%) as a clear oil.

MS: 296.1 [M+1].

Step 6: synthesis of 4-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.088 g, 0.0429 mmol) and 2-bromo-5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridine (0.128 g, 0.0429 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.182 g, 0.0864 mmol), then CuI (0.016 g, 0.00864 mmol) and DMEDA (0.076 g, 0.0864 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 4-5% MeOH in DCM) to give 4-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.085 g, 47.22%) as a yellow solid.

MS: 421.1 [M+1].

Step 7: synthesis of 4-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2,3-diamine

To a stirred solution of 4-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.050 g, 0.0119 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (1.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.031 g, 0.0591 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O : EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.032 g, 69.56%) as a dark brown solid.

MS: 391.2 [M+1].

Step 8: synthesis of 7-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.030 g, 0.0076 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.004 g, 0.0015 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 3% to 5% MeOH in DCM) to give 7-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.021 g, 70%) as an off-white solid.

MS: 401.0 [M+1].

Synthesis of Compound No. 1158: 7-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Step 1: Synthesis of 1-(6-bromopyridin-3-yl)ethanol

To a stirred solution of 1-(6-bromopyridin-3-yl)ethanone (0.5 g, 0.250 mmol) in MeOH (20 mL) was added NaBH ₄ (0.190 g, 0.500 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 4 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 25% ethyl acetate in n-hexane to give 1-(6-bromopyridin-3-yl)ethanol (0.450 g; 89.10%) as a clear oil.

MS: 202.1 [M+1].

Step 2: Synthesis of 2-bromo-5-(1-bromoethyl)pyridine

To a stirred solution of 1-(6-bromopyridin-3-yl)ethanol (0.400 g, 0.198 mmol) in DCE (20 mL) was added triphenylphosphine (TPP; 0.778 g, 0.297 mmol) followed by the addition of carbon tetrabromide (0.932 g, 0.297 mmol) portionwise at 0 °C. The resulting reaction mixture was stirred at room temperature for 6 h. The reaction was monitored for completion using TLC. Upon completion, the reaction was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 12% ethyl acetate in hexane as eluent to give 2-bromo-5-(1-bromoethyl)pyridine (0.290 g, 55.98%) as a white solid.

MS: 263.1 [M+1].

Step 3: Synthesis of 2-bromo-5-(1-(methylsulfonyl)ethyl)pyridine

To a stirred solution of 2-bromo-5-(1-bromoethyl)pyridine (0.280 g, 0.106 mmol) in DMSO (3.0 mL) was added sodium methanesulfinate (0.163 g, 0.160 mmol). The resulting reaction mixture was stirred for 3 h at 90 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the pure desired product 2-bromo-5-(1-(methylsulfonyl)ethyl)pyridine (0.155 g, 55.35%) as a clear oil.

MS: 263 [M+1].

Step 4: synthesis of 4-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.117 g, 0.057 mmol) and 2-bromo-5-(1-(methylsulfonyl)ethyl)pyridine (0.150 g, 0.057 mmol) in dioxane (7 mL) was added K ₃ PO ₄ (0.241 g, 0.114 mmol), then CuI (0.021 g, 0.0114 mmol) and DMEDA (0.100 g, 0.114 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 5-6% MeOH in DCM) to give 4-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.095 g, 42.79%) as a yellow solid.

MS: 389.1 [M+1].

Step 5: synthesis of 4-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2,3-diamine

To a stirred solution of 4-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.095 g, 0.024 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.064 g, 0.122 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O : EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.060 g, 68.96%) as a dark brown solid.

MS: 359.2 [M+1].

Step 6: synthesis of 7-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.060 g, 0.0136 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0046 g, 0.0027 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 7-8% MeOH in DCM) to give 7-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.027 g, 44.26%) as an off-white solid.

MS: 369.1 [M+1].

Synthesis of compound No. 1142: 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutane-1-sulfonamide

Step 1: Synthesis of 3-3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl ethanethioate

To a stirred solution of 2-bromo-5-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridine (0.300 g, 0.086 mmol) in DMF (5 mL) was added potassium thioacetate (0.197 g, 0.172 mmol) under nitrogen atmosphere and stirred for 12 h at room temperature. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 18% ethyl acetate in hexane as eluent to give 8-3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl ethanethioate (0.200 g, 68.96%) as a black solid.

Step 2: synthesis of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutane-1-sulfonyl chloride

To a stirred solution of N-chlorosuccinamide (NCS; 0.470 g, 0.350 mmol) and 2 N HCl (0.5 mL) in ACN at 0 °C under N ₂ was added dropwise a solution of S-3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl ethanethioate (0.300 g, 0.877 mmol) in ACN. The resulting mixture was stirred at RT for 4 h at room temperature. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 9-15% ethyl acetate (EA) in hexane) to give 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutane-1-sulfonyl chloride (0.225 g, 72.58%) as a yellow oil.

MS: 366 [M+1].

Step 3: synthesis of 3-(6-bromopyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-sulfonamide

To a stirred solution of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutane-1-sulfonyl chloride (0.150 g, 0.0409 mmol) in MeOH (7 mL) was added trimethylamine base (0.124 g, 0.122 mmol). Then methylamine was added. HCl (0.082 g, 0.122 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , evaporated under reduced pressure to give pure compound 3-(6-bromopyridin-3-yl)-4,4,4-trifluoro-N-methylbutane-1-sulfonamide (0.130 g; 87.83%) as a clear oil.

MS: 361 [M+1].

Step 4: Synthesis of 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4.4.4-trifluoro-N-methylbutane-1-sulfonamide

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.073 g, 0.036 mmol) and 3-(6-bromopyridin-3-yl)-4,4,4-trifluoro-N-methylbutane-1-sulfonamide (0.130 g, 0.036 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.152 g, 0.072 mmol), followed by CuI (0.013 g, 0.0072 mmol) and DMEDA (0.0066 g, 0.072 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutane-1-sulfonamide (0.09 g, 45%) as a yellow solid.

MS: 486.1 [M+1].

Step 5: synthesis of 3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-sulfonamide

To a stirred solution of 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutane-1-sulfonamide (0.070 g, 0.0144 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.40 g, 0.76 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O : EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutane-1-sulfonamide (0.045 g, 69.23%) as a dark brown solid.

MS: 456.2 [M+1].

Step 6: synthesis of 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-sulfonamide

To a stirred solution of 3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutane-1-sulfonamide (0.045 g, 0.0098 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0034 g, 0.0019 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutane-1-sulfonamide (0.021 g, 46.66%) as an off-white solid.

MS: 466.1 [M+1].

Synthesis of Compound No. 1160: 7-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Step 1: Synthesis of 2-bromo-5-(1-bromo-3-(methylthio)propyl)pyridine

To a stirred solution of 1-(6-bromopyridin-3-yl)-3-(methylthio)propan-1-ol (3.5 g, 1.33 mmol) in DCE (70 mL) was added TPP (4.5 g, 1.73 mmol) followed by portionwise addition of carbon tetrabromide (5.7 g, 1.73 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 7 h. The reaction was monitored for completion using TLC. Upon completion, the reaction was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4% ethyl acetate in hexane as eluent to give 2-bromo-5-(1-bromo-3-(methylthio)propyl)pyridine (2.65 g, 61.05%) as a yellow oil.

MS: 326.1 [M+1].

Step 2: synthesis of diethyl 2-(1-(6-bromopyridin-3-yl)-3-(methylthio)propyl)malonate

To a stirred solution of 2-bromo-5-(1-bromo-3-(methylthio)propyl)pyridine (2.34 g, 0.720 mmol) in THF (50 mL) was added diethyl malonate (1.72 g, 1.08 mmol) at room temperature and the solution was cooled to 10 °C. Sodium hydride base (0.420 g, 1.08 mmol) was added portionwise at 10 °C and stirring was continued at room temperature for 6 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 15% ethyl acetate in n-hexane to give diethyl 2-(1-(6-bromopyridin-3-yl)-3-(methylthio)propyl)malonate (1.05 g; 37.5%) as a yellow oil.

MS: 404.2 [M+1].

Step 3: synthesis of 2-(1-(6-bromopyridin-3-yl)-3-(methylthio)propyl)propane-1,3-diol

To a stirred solution of diethyl 2-(1-(6-bromopyridin-3-yl)-3-(methylthio)propyl)malonate (1.05 g, 0.259 mmol) in EtOH (20 mL) was added NaBH ₄ (0.290 g, 0.777 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 30% acetone in n-hexane to give 2-(1-(6-bromopyridin-3-yl)-3-(methylthio)propyl)propane-1,3-diol (0.500 g; 60.16%) as a clear oil.

MS: 320 [M+1].

Step 4: Synthesis of 2-bromo-5-(3-(methylthio)-1-(oxetan-3-yl)propyl)pyridine

To a stirred solution of 2-(1-(6-bromopyridin-3-yl)-3-(methylthio)propyl)propane-1,3-diol (0.470 g, 0.146 mmol) in anhydrous THF (30 mL) at 0 °C under N ₂ was added dropwise n-butyl lithium (1.6 M solution in hexane) (0.908 mL, 0.146 mmol) and stirred for 30 min. A solution of p-toluenesulfonyl chloride (0.277 g, 0.146 mmol) in anhydrous THF was added slowly. The mixture was stirred at 0 °C for 1 h and a second portion of n-butyl lithium (1.6 M solution in hexane) (0.908 mL, 0.146 mmol) was added dropwise. After addition, the mixture was heated at 60 °C and stirred for 4 h. The completion of the reaction was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 11% acetone in n-hexane to give 2-bromo-5-(3-(methylthio)-1-(oxetan-3-yl)propyl)pyridine (0.160 g, 36.1%) as a clear oil.

MS: 302.1 [M+1].

Step 5: Synthesis of 2-bromo-5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridine

To a stirred solution of 2-bromo-5-(3-(methylthio)-1-(oxetane-3-propyl)pyridine (0.160 g, 0.0520 mmol) in acetone: _H2O (20 mL, 7:3) at 0°C was added oxone (0.487 g, 0.158 mmol) under nitrogen atmosphere and stirred for 12 h at the same temperature. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 3% MeOH in DCM as eluent to give 2-bromo-5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridine (0.130 g, 73.86%) as a colorless oil.

MS: 334.0 [M+1].

Step 6j synthesis of 4-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol4-yl)-3-nitropyridin-2-amine

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.079 g, 0.0389 mmol) and 2-bromo-5-(3-(methylsulfonyl)-1-(octetan-3-yl)propyl)pyridine (0.130 g, 0.0389 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.164 g, 0.0778 mmol), then CuI (0.014 g, 0.0077 mmol) and DMEDA (0.068 g, 0.0778 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 4-5% MeOH in DCM) to give 4-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.005 g, 47.22%) as a yellow solid. MS: 459.1 [M+1].

Step 7: synthesis of 4-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol4-yl)pyridin-2,3-diamine

To a stirred solution of 4-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.060 g, 0.0131 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.034 g, 0.06591 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.045 g, 80.35%) as a dark brown solid.

MS: 429.2 [M+1].

Step 8j synthesis of 7-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.045 g, 0.0105 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0036 g, 0.0021 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 7-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.025 g, 54%) as an off-white solid.

MS: 439.0 [M+1].

Synthesis of Compound No. 1175: 7-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Step 1: synthesis of 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanone

To a stirred solution of 2,6-dibromopyridine (5.0 g, 2.12 mmol) in THF (50 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (12.5 mL, 3.18 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then 2,2,2-trifluoro-1-morpholinoethanone (5.06 g, 2.76 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 18% ethyl acetate in hexane as eluent to give 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanone (3.5 g, 64.81%) as a colorless oil.

Step 2: synthesis of (E/Z)-ethyl-3-(6-bromopyridin-2-yl)-4,4,4-trifluorobut-2-enoate

To a stirred solution of triethyl phosphonoacetate (3.9 g, 1.77 mmol) and THF (60 mL) at 0 °C under _N2 was added potassium tert-butoxide base (1.98 g, 1.77 mmol) in portions. The resulting mixture was stirred at RT for 1 h to form the anion. A solution of 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanone (3.0 g, 1.18 mmol) in THF (15 mL) was added slowly. After addition, the mixture was stirred for 6 h at RT. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 9-15% EA in hexane) to give (E/Z)-ethyl 3-(6-bromopyridin-2-yl)-4,4,4-trifluorobut-2-enoate (1.5 g; 40%) as a yellow oil.

MS: 324 [M+1].

Step 3: synthesis of 3-(6-bromopyridin-2-yl)-4,4,4-trifluorobutan-1-ol

To a stirred solution of (E/7)-ethyl 3-(6-bromopyridin-2-yl)-4,4,4-trifluorobut-2-enoate (1.5 g, 462 mmol) in EtOH (30 mL) was added NaBH ₄ (0.520 g, 1380 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 14 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 30% ethyl acetate in n-hexane to give 3-(6-bromopyridin-2-yl)-4,4,4-trifluorobutan-1-ol (0.610 g; 46.5%) as a clear oil.

MS: 284 [M+1].

Step 4: synthesis of 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-2-yl)-4,4,4-trifluorobutan-1-ol

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.253 g, 123 mmol) and 3-(6-bromopyridin-2-yl)-4,4,4-trifluorobutan-1-ol (0.350 g, 123 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.521 g, 246 mmol), then CuI (0.046 g, 0.246 mmol) and DMEDA (0.216 g, 246 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-2-yl)-4,4,4-trifluorobutan-1-ol (0.250 g; 50%) as a yellow solid.

MS: 409.1 [M+1].

Step 5: synthesis of 4-(1-(6-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-2-yl)-4,4,4-trifluorobutan-1-ol (0.120 g, 0.29 mmol) in DCE (10 mL) was added TPP (0.115 g, 0.44 mmol) followed by portionwise addition of carbon tetrabromide (0.145 g, 0.44 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 7 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 2-3% methanol in DCMA as eluent to give 4-(1-(6-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.065 g, 47.05%) as a yellow solid.

MS: 471.1 [M+1].

Step 6: synthesis of 4-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 4-(1-(6-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.065 g, 0.130 mmol) in DMSO (3.0 mL) was added sodium methanesulfinate (0.027 g, 0.20 mmol). The resulting reaction mixture was stirred for 3 h at 90 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 4-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.052 g, 81.20%) as a yellow solid.

MS: 471 [M+1].

Step 7: synthesis of 4-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2,3-diamine

To a stirred solution of 4-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.052 g, 0.11 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.029 g, 0.55 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.036 g; 75%) as a dark brown solid.

MS: 441.2 [M+1].

Step 8: synthesis of 7-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.035 g, 0.079 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0027 g, 0.015 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give 7-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.021 g, 60%) as an off-white solid.

MS: 451.1 [M+1].

Synthesis of Compound No. 1176: 7-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Step 1: synthesis of 1-(2-bromopyridin-4-yl)-2,2,2-trifluoroethanone

To a stirred solution of 2,4-dibromopyridine (5.0 g, 2.12 mmol) in THF (50 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (12.5 mL, 3.18 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then 2,2,2-trifluoro-1-morpholinoethanone (5.06 g, 2.76 mmol) was added dropwise to the reaction mixture, stirred for 1 h at -78 °C and the reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 18% ethyl acetate in hexane as eluent to give 1-(2-bromopyridin-4-yl)-2,2,2-trifluoroethanone (3.5 g, 64.81%) as a colorless oil.

Step 2: synthesis of (E/Z-ethyl-3-(2-bromopyridin-4-yl)-4,4,4-trifluorobut-2-enoate

To a stirred solution of triethyl phosphonoacetate (3.9 g, 1.77 mmol) and THF (60 mL) at 0 °C under _N2 was added potassium tert-butoxide base (1.98 g, 1.77 mmol) in portions. The resulting mixture was stirred at RT for 1 h to form the anion. A solution of 1-(2-bromopyridin-4-yl)-2,2,2-trifluoroethanone (3.0 g, 1.18 mmol) in THF (15 mL) was added slowly. After addition, the mixture was stirred for 6 h at RT. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 9 to 15% EA in hexane) to give (E/Z-ethyl 3-(2-bromopyridin-4-yl)-4,4,4-trifluorobut-2-enoate (1.5 g; 40%) as a yellow oil.

MS: 324 [M+1].

Step 3: synthesis of 3-(2-bromopyridin-4-yl)-4,4,4-trifluorobutan-1-ol

To a stirred solution of (E/Z-ethyl 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobut-2-enoate (1.5 g, 462 mmol) in EtOH (30 mL) was added NaBH ₄ (0.520 g, 1380 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 14 h. The progress of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 30% ethyl acetate in n-hexane to give 3-(2-bromopyridin-4-yl)-4,4,4-trifluorobutan-1-ol (0.610 g; 46.5%) as a clear oil.

MS: 284 [M+1].

Step 4: synthesis of 3-(2-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-4-yl)-4,4,4-trifluorobutan-1-ol

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.253 g, 123 mmol) and 3-(2-bromopyridin-4-yl)-4,4,4-trifluorobutan-1-ol (0.350 g, 123 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.521 g, 246 mmol), then CuI (0.046 g, 0.246 mmol) and DMEDA (0.216 g, 246 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 3-(2-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-4-yl)-4,4,4-trifluorobutan-1-ol (0.250 g; 50%) as a yellow solid.

MS: 409.1 [M+1].

Step 5: synthesis of 4-(1-(4-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 3-(2-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-4-yl)-4,4,4-trifluorobutan-1-ol (0.120 g, 0.29 mmol) in DCE (10 mL) was added TPP (0.115 g, 0.44 mmol) followed by portionwise addition of carbon tetrabromide (0.145 g, 0.44 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 7 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 2-3% methanol in DCMA as eluent to give 4-(1-(4-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.065 g, 47.05%) as a yellow solid.

MS: 471.1 [M+1].

Step 6: synthesis of 4-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 4-(1-(4-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.065 g, 0.130 mmol) in DMSO (3.0 mL) was added sodium methanesulfinate (0.027 g, 0.20 mmol). The resulting reaction mixture was stirred for 3 h at 90 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6 to 7% MeOH in DCM) to give 4-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.052 g, 81.20%) as a yellow solid.

MS: 471 [M+1].

Step 7: synthesis of 4-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2,3-diamine

To a stirred solution of 4-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.052 g, 0.11 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.029 g, 0.55 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.036 g, 75%) as a dark brown solid.

MS: 441.2 [M+1].

Step 8: synthesis of 7-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.035 g, 0.079 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0027 g, 0.015 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give 7-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.021 g, 60%) as an off-white solid.

MS: 451.1 [M+1].

Synthesis of compound No. 1178: 1-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea

Step 1: synthesis of 4-nitrophenyl cyclopropylcarbamate

To a stirred solution of cyclopropanamine (2.0 g, 3.508 mmol) in DCM (60.0 mL) was added trimethylamine (5.3 g, 5.26 mmol) followed by 4-nitrophenyl chloroformate (9.1 g, 4.55 mmol) at 0 °C. The resulting reaction mixture was stirred for 6 h at room temperature. The completion of the reaction was monitored using TLC. Upon completion of the reaction, the precipitated solid was immediately filtered on a Buchner funnel and then washed with DCM to yield the pure product (1.2 g, 15.58%) as a white solid.

MS: 223 [M+1].

Step 2: Synthesis of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanamine

To a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.650 g, 0.167 mmol) in DMF (5 mL) was added sodium azide (0.108 g, 0.167 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 6 h. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the pure intermediate compound. To a solution of the intermediate azide (0.550 g, 0.192 mmol) was added TPP (0.512 g, 0.192 mmol) in THF: _H2O (8:2 ml) at RT and stirring was continued at 60 °C for 12 h. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 20-30% acetone in hexane) to give 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanamine (0.160 g, 32%) as a yellow oil.

MS: 255.1 [M+1].

Step 3: Synthesis of 1-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropyl urea

To a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanamine (0.200 g, 0.078 mmol) in THF (10.0 mL) was added potassium carbonate (0.107 g, 0.078 mmol), followed by 4-nitrophenylcyclopropylcarbamate (0.248 g, 0.011 mmol). The resulting reaction mixture was stirred for 6 h at 60 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 15-20% acetone in hexane) to give 1-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea (0.120 g, 50.84%) as a white solid.

MS: 338 [M+1].

Step 4: synthesis of 1-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropyl urea

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.090 g, 0.0443 mmol) and 1-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea (0.150 g, 0.0443 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.122 g, 0.0886 mmol), then CuI (0.016 g, 0.00886 mmol) and DMEDA (0.077 g, 0.0886 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 9-10% MeOH in DCM) to give 1-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea (0.090 g; 45%) as a yellow solid.

MS: 463.1 [M+1].

Step 5: synthesis of 1-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropyl urea

To a stirred solution of 1-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea (0.085 g, 0.0183 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.048 g, 0.0919 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 1-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea (0.045 g, 56.96%) as a dark brown solid.

MS: 433.2 [M+1].

Step 6: synthesis of 1-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea

To a stirred solution of 1-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea (0.045 g, 0.0104 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0035 g, 0.0020 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 10-11% MeOH in DCM) to give 1-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea (0.023 g, 51%) as an off-white solid.

MS: 443.1 [M+1].

Synthesis of compound No. 1179: 1-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea

Step 1: Synthesis of 1-(3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropyl urea

To a stirred solution of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-amine (0.130 g, 0.045 mmol) in ACN (10.0 mL) was added trimethylamine (0.136 g, 0.135 mmol), followed by 4-nitrophenyl cyclopropylcarbamate (0.152 g, 0.068 mmol). The resulting reaction mixture was stirred for 6 h at 60 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 25-30% acetone in hexane) to give (0.140 g, 83.83%) as a thick oil.

MS: 367 [M+2].

Step 2: Synthesis of 1-(3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropyl urea

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.073 g, 0.0356 mmol) and 1-(3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea (0.130 g, 0.0356 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.150 g, 0.0712 mmol), then CuI (0.013 g, 0.00712 mmol) and DMEDA (0.062 g, 0.0712 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 7-8% MeOH in DCM) to give 1-(3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea (0.080 g, 45.97%) as a yellow solid.

MS: 491.1 [M+1].

Step 3: synthesis of 1-(3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4A4-trifluorobutyl)-3-cyclopropyl urea

To a stirred solution of 1-(3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea (0.060 g, 0.0122 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.032 g, 0.0612 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 1-(3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea (0.042 g; 75%) as a dark brown solid.

MS: 461.2 [M+1].

Step 4: synthesis of 1-(3-(6-(4-(3H-imidazo[4,5-b]iridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea

To a stirred solution of 1-(3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea (0.042 g, 0.0091 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0031 g, 0.0018 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give 1-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea (0.021 g, 48.83%) as an off-white solid.

MS: 471.1 [M+1].

Synthesis of compound No. 1075: 2-(2-(4-(3H-imidazo[4,5-b]iridin-7-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile

Step 1: Synthesis of ethyl 2-aminooxazole-4-carboxylate

To a stirred solution of ethyl 3-bromo-2-oxopropanoate (1.0 g, 5.128 mmol) in ethanol (20 mL) was added urea (0.462 g, 7.692 mmol) at room temperature. The resulting reaction mixture was stirred at reflux overnight. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 40% ethyl acetate in n-hexane to give ethyl 2-aminooxazole-4-carboxylate (0.700 g; 87.5%) as a cream-colored solid.

MS: 157.2 [M+1].

Step 2: Synthesis of ethyl 2-chlorooxazole-4-carboxylate

To a stirred solution of CuCl ₂ (1.29 g, 9.609 mmol) in ACN (20 mL) was added tert-butyl nitrile (0.991 g, 9.609 mmol) at room temperature. The resulting reaction mixture was heated at 65 °C. Ethyl 2-aminooxazole-4-carboxylate (1.0 g, 6.406 mmol) was added portionwise at 65 °C and stirring was continued for 2 h. The completion of the reaction was monitored using TLC. The reaction mixture was cooled to 0 °C, acidified with 6 N HCl solution and extracted with ether. The organic layer was washed with water, brine, dried over sodium sulfate, concentrated under reduced pressure to obtain the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 18% ethyl acetate in n-hexane to give ethyl 2-chlorooxazole-4-carboxylate (0.500 g; 44.6%) as a brown solid.

MS: 176 [M+1].

Step 3: Synthesis of (2-chlorooxazol4-yl)methanol

A stirred solution of ethyl 2-chlorooxazole-4-carboxylate (0.400 g, 2.271 mmol) in DCM (10 mL) was cooled to -78 °C under an inert atmosphere. Diisobutylaluminum hydride (DIBAL-H; 3.4 mL, 3.410 mmol) was added at -78 °C and stirring was continued for 1 h at the same temperature. After this, stirring was continued at room temperature for 16 h. The completion of the reaction was monitored using TLC. The reaction mixture was quenched with crushed ice, then 1 N HCl solution, and extracted with ether. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude (2-chlorooxazol-4-yl)methanol (0.250 g, 82.5%) as a yellow liquid, which was used as such in the next step.

MS: 134.1 [M+1].

Step 4: synthesis of (2-chloroxazol-4-yl)methylmethanesulfonate

To a stirred solution of (2-chlorooxazol-4-yl)methanol (0.10 g, 0.749 mmol) in DCM (10 mL) was added triethylamine base (0.114 g, 1.123 mmol) at room temperature and cooled to 0 °C. Mesyl chloride (0.103 g, 0.898 mmol) was added dropwise at 0 °C and stirring was continued for 6 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with DCM. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give pure (2-chlorooxazol-4-yl)methyl methanesulfonate (0.155 g, 97.77%) as an off-white solid.

MS: 211.1 [M+1].

Step 5: synthesis of 2-(2-chloroxazol-4-yl)acetonitrile

To a stirred solution of (2-chlorooxazol-4-yl)methyl methanesulfonate (0.500 g, 2.362 mmol) in ACN (10 mL) was added 1 M tetrabutylammonium fluoride (TBAF) in THF (4.72 mL, 4.725 mmol) at room temperature, followed by the addition of TMSCN (0.469 g, 4.725 mmol). The resulting reaction mixture was stirred for 6 h at room temperature. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 18% ethyl acetate in n-hexane to give pure 2-(2-chlorooxazol-4-yl)acetonitrile (0.210 g, 62.31%) as a white solid.

MS: 143.2 [M+1].

Step 6: synthesis of 2-(2-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.040 g, 0.195 mmol) was added DMF (4 mL), potassium tert-butoxide (0.022 g, 0.195 mmol) and the compound 2-(2-chlorooxazol-4-yl)acetonitrile (0.028 g, 0.39 mmol) at room temperature. The reaction mixture was heated at 80 °C for 12 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 5-6% MeOH in DCM) to give 2-(2-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile (0.030 g, 49.45%) as a yellow solid.

MS: 312.1 [M+1].

Step-7: Synthesis of 2-(2-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile

To a stirred solution of 2-(2-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile (0.030 g, 0.096 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.017 g, 0.48 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 2-(2-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile (0.025 g, 92%) as a dark brown solid.

MS: 283.2 [M+1].

Step 8: synthesis of 2-(2-(4-(3H-imidazo[4,5-b]iridin-7-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile

To a stirred solution of 2-(2-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile (0.025 g, 0.088 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0017 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water, extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 2-(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile (0.011 g, 44%) as an off-white solid.

MS: 293.1 [M+1].

Synthesis of compound No. 1078: 2-(6-(4-(3H-imidazo[4,5-b]iridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile

Step 1: Synthesis of (6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methanol

To a stirred solution of 6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridine-3-carbaldehyde (0.50 g, 1.612 mmol) in methanol/THF (10 mL, 1:1) was added sodium borohydride (0.069 g, 1.612 mmol) at 0 °C and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored using TLC. Upon completion of the reaction, water (10 mL) was added to the reaction mixture and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give (6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methanol (0.5 g, 100%) as a yellow solid.

MS: 313.28 [M+1].

Step 2: synthesis of (6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methylmethanesulfonate

To a stirred solution of (6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methanol (0.15 g, 0.480 mmol) in DCM (5.0 mL) at 0 °C was added MsCl (0.06 g, 0.528 mmol) under nitrogen atmosphere. To the resulting reaction mixture was added dropwise a solution of TEA (0.063 g, 0.629 mmol) in DCM (1.0 mL), stirred for 15 min at 0 °C, then warmed to RT and the reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give (6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl methanesulfonate (0.19 g, 100%) as a crude yellow oil.

MS: 391.37 [M+1].

Step 3: Synthesis of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile

To a stirred solution of (6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl methanesulfonate (0.25 g, 0.641 mmol) in ACN (5 mL) at 0 °C was added TMSCN (0.13 g, 1.282 mmol) under nitrogen atmosphere, then TBAF (1 M solution in THF, 1.3 mL, 1.282 mmol) and the resulting solution was heated overnight at 50 °C. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was cooled to 0 °C and quenched with 1 M HCl solution. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 1% MeOH in DCM as eluent to give 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile (0.08 g, 40%) as a yellow oil.

MS: 322.29 [M+1].

Step 4: synthesis of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile

A stirred solution of 2-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile (0.05 g, 0.1557 mmol) in methanol (5 mL) was hydrogenated in the presence of 10% Pd/C (0.005 g, 10% w/w) using a hydrogen balloon. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile (0.044 g, 99%) as a brown solid.

MS: 292.31 [M+1].

Step 5: Synthesis of 2-(6-(4-(3H-imidazo[4,5-b]iridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile

To a stirred solution of 2-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile (0.045 g, 0.1512 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.0 mL). The resulting reaction mixture was added PTSA (0.005 g, 0.0302 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 3% to 5% MeOH in DCM) to give 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile (0.05 g; 10%) as an off-white solid.

MS: 302.31 [M+1].

Synthesis of Compound No. 1094: N-(2,2,2-trifluoroethyl)-4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide

Step 1: synthesis of 1M-(2.2.2-trifluoroethyl)-4-(2-phenyl-3H-imidazoG4.5-Npyridin-7-yl)-1H-pyrazol-1-carboxamide

To a stirred solution of tert-butyl 2-phenyl-7-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride (0.015 g, 0.05042 mmol) and 4-nitrophenyl 2,2,2-trifluoroethylcarbamate (0.013 g, 0.05042 mmol) in anhydrous ACN (3 mL) was added triethylamine (0.01 g, 0.1008 mmol) and stirred at RT overnight. The reaction progress was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 2% methanol in DCM as eluent to give N-(2,2,2-trifluoroethyl)-4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide (0.004 g, 20%) as a white solid.

MS: 387.33 [M+1].

Synthesis of Compound No. 1180: 3-cyclopentyl-3-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)propanenitrile

Step 1: synthesis of tert-butyl 4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazole-1-carboxylate

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (1 g, 4.878 mmol) in DCM (10 mL) was added dropwise TEA (2.0 mL, 14.634 mmol) at room temperature and the reaction mixture was allowed to stir for 15 min. After 15 min, tert-butoxycarbonyl(Boc) anhydride (1.59 g, 7.317 mmol) was added and stirred for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with water, NaHCO ₃ , brine, dried over Na ₂ SO ₄ , and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh; eluent 1% MeOH in DCM) to give tert-butyl 4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazole-1-carboxylate (1.2 g, 81.0%) as a yellow solid.

MS: 306.29 [M+1].

Step 2: Synthesis of goret-butyl 4-(2,3-diaminopyridin-4-yl)-1H-pyrazole-1-carboxylate

A stirred solution of tert-butyl 4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazole-1-carboxylate (0.5 g, 1.639 mmol) in methanol (5 mL) was hydrogenated in the presence of 10% Pd/C (0.05 g, 10% w/w) using a hydrogen balloon. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give tert-butyl 4-(2,3-diaminopyridin-4-yl)-1H-pyrazole-1-carboxylate (0.45 g, 99.8%) as a brown solid.

MS: 276.31 [M+1].

Step 3: synthesis of gogo-butyl-4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxylate

To a stirred solution of tert-butyl 4-(2,3-diaminopyridin-4-yl)-1H-pyrazole-1-carboxylate (0.4 g, 1.452 mmol) and benzaldehyde (0.15 g, 1.452 mmol) in DCE (5 mL) at 0 °C was added AcOH (0.4 mL) and stirred for 30 min. Sodium triacetoxyborohydride (STAB; 0.13 g, 2.179 mmol) was then added and the resulting mixture was heated overnight at 60 °C. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was cooled to 0 °C and quenched with ice water. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 1% MeOH in DCM as eluent to give tert-butyl 4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxylate (0.3 g, 57.1%) as a white solid.

MS: 362.4 [M+1].

Step 4: Synthesis of tert-butyl-2-phenyl-7-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride

To tert-butyl 4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxylate (0.3 g, 0.831 mmol) was added 4 M HCl in dioxane (3 mL) and stirred at room temperature for 3 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, washed with diethyl ether and dried to give tert-butyl 2-phenyl-7-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride (0.25 g, 100%) as a white solid.

MS: 298.4 [M+1].

Step 5: Synthesis of 3-cyclopentyl-3-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)propanenitrile

To a stirred solution of tert-butyl 2-phenyl-7-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride (0.03 g, 0.115 mmol) and 3-cyclopentylacrylonitrile (0.015 g, 0.126 mmol) in anhydrous ACN (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 0.052 g, 0.3448 mmol) and heated overnight at 90 °C. The reaction progress was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 3% methanol in DCM as eluent to give 3-cyclopentyl-3-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)propanenitrile (0.005 g, 11.3%) as a white solid.

MS: 383.46 [M+1].

Synthesis of Compound No. 1174: 7-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Step 1: synthesis of (E/Z)-ethyl-3-(6-bromopyridin-3-yl)-4.4.4-triFluorobut-2-enoate

To a stirred solution of triethyl phosphonoacetate (3.9 g, 1.77 mmol) and THF (60 mL) at 0 °C under _N2 was added potassium tert-butoxide base (1.98 g, 1.77 mmol) in portions. The resulting mixture was stirred at RT for 1 h to form the anion. A solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanone (3.0 g, 1.18 mmol) in THF (15 mL) was added slowly. After addition, the mixture was stirred for 6 h at RT. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 9-15% EA in hexane) to give (E/Z)-ethyl 3-(6-bromopyridin-2-yl)-4,4,4-trifluorobut-2-enoate (1.5 g; 40%) as a yellow oil.

MS: 324 [M+1].

Step 2: synthesis of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-ol

To a stirred solution of (E/7)-ethyl 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobut-2-enoate (1.5 g, 462 mmol) in EtOH (30 mL) was added _NaBH4 (0.520 g, 1380 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 14 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4, and evaporated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 30% ethyl acetate in n-hexane to give 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-ol (0.610 g; 46.5%) as a clear oil.

MS: 284 [M+1].

Step 3: synthesis of 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutan-1-ol

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.253 g, 123 mmol) and 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-ol (0.350 g, 123 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.521 g, 2.46 mmol), then CuI (0.046 g, 0.246 mmol) and DMEDA (0.216 g, 0.246 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutan-1-ol (0.250 g; 50%) as a yellow solid.

MS: 409.1 [M+1].

Step 4: synthesis of 4-(1-(5-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutan-1-ol (0.120 g, 0.29 mmol) in DCE (10 mL) was added TPP (0.115 g, 0.44 mmol) followed by portionwise addition of carbon tetrabromide (0.145 g, 0.44 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 7 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 2-3% methanol in DCMA as eluent to give 4-(1-(5-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.065 g, 47.05%) as a yellow solid.

MS: 471.1 [M+1].

Step 5: synthesis of 4-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution of 4-(1-(5-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.065 g, 0.130 mmol) in DMSO (3.0 mL) was added sodium methanesulfinate (0.027 g, 0.20 mmol). The resulting reaction mixture was stirred for 3 h at 90 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give 4-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.052 g, 81.20%) as a yellow solid.

MS: 471 [M+1].

Step 6: synthesis of 4-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2,3-diamine

To a stirred solution of 4-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (0.052 g, 0.11 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.029 g, 0.55 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.036 g, 75%) as a dark brown solid.

MS: 441.2 [M+1].

Step 7: synthesis of 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.035 g, 0.079 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0027 g, 0.015 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (0.021 g, 60%) as an off-white solid.

MS: 451.1 [M+1].

Synthesis of compound No. 1157: 2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile

Step 1: Synthesis of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethanol

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.500 g, 2.439 mmol) and 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (0.68 g, 2.682 mmol) in DMSO (5 mL) was added K ₂ CO ₃ (1.0 g, 7.317 mmol), followed by Cul (0.045 g, 0.243 mmol) and s-proline (0.146 g, 1.219 mmol). The reaction mixture was heated at 110 °C for 16 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 2-3% MeOH in DCM) to give 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethanol (0.35 g, 37.8%) as a yellow solid.

MS: 381.28 [M+1].

Step 2: Synthesis of 2-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile

To a stirred solution of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethanol (0.3 g, 0.7894 mmol) in DMF (10 mL) at 0 °C was added NaH (0.31 g, 0.7894 mmol) under nitrogen atmosphere and stirred for 30 min at the same temperature. To the resulting reaction mass was added 2-bromoacetonitrile (0.094 g, 0.7894 mmol) and stirred for 4 h at RT. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 1% methanol in DCM as eluent to give 2-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile (0.14 g, 42.4%) as a yellow solid.

MS: 420.32 [M+1].

Step 3: synthesis of 2-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile

To a stirred solution of 2-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile (0.050 g, 0.119 mmol) in EtOH (10 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.033 g, 0.59 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and filtered through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 2-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile (0.040 g, 86.9%) as a dark brown solid.

MS: 389.33 [M+1].

Step 4: synthesis of 2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile

To a stirred solution of 2-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile (0.040 g, 0.102 mmol) in THF (3.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0205 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh) using 3% to 5% MeOH in DCM as eluent to give 2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile (0.008 g, 19.5%) as an off-white solid.

MS: 400.33 [M+1].

Synthesis of Compound No. 1150: 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide

Step 1: Synthesis of 4-(6-bromopyridin-3-yl)-5,5,5-trifluoropentanenitrile

To a stirred solution of 2-bromo-5-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridine (2.0 g, 5.797 mmol) in DMSO (10 mL) and water (2 mL) at RT was added potassium cyanide (0.75 g, 11.594 mmol) under nitrogen atmosphere and heated overnight at 80 °C. The reaction progress was monitored using TLC. Upon completion, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 15% acetone in hexane as eluent to give 4-(6-bromopyridin-3-yl)-5,5,5-trifluoropentanenitrile (1.1 g, 65.08%) as a dark brown viscous mass.

MS: 293.08 [M+1].

Step 2: Synthesis of 4-(6-bromopyridin-3-yl)-5,5,5-trifluoropentanoic acid

Conc. HCl (10 mL) was added to 4-(6-bromopyridin-3-yl)-5,5,5-trifluoropentanenitrile (1.0 g, 3.412 mmol) in a sealed tube and heated to 80 °C for 5 h. Upon completion, the reaction was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-(6-bromopyridin-3-yl)-5,5,5-trifluoropentanoic acid (0.6 g, 56.6%) as a dark brown viscous mass.

MS: 312.08 [M+1].

Step 3: Synthesis of 4-(6-bromopyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide

To a stirred solution of 4-(6-bromopyridin-3-yl)-5,5,5-trifluoropentanoic acid (0.15 g, 0.4823 mmol) and cyclopropylamine (0.033 g, 0.5787 mmol) in DMF (5 mL) were added EDCI (0.110 g, 0.5787 mmol), HOBT (0.097 g, 0.723 mmol) and N-methylmorpholine (NMM; 0.146 g, 1.446 mmol) at 10 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, concentrated under reduced pressure to give 4-(6-bromopyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide as a crude yellow oil (0.150 g; 88.8%).

MS: 351.16 [M+1].

Step 4: Synthesis of 4-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.06 g, 0.292 mmol) and 4-(6-bromopyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide (0.150 g, 0.536 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.124 g, 0.585 mmol), followed by Cul (0.011 g, 0.0585 mmol) and DMEDA (0.128 g, 1.463 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh) using 2% MeOH in DCM as eluent to give 4-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide (0.05 g, 35.9%) as a yellow solid.

MS: 476.42 [M+1].

Step 5: synthesis of 4-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide

To a stirred solution of 4-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide (0.050 g, 0.105 mmol) in EtOH (10 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.029 g, 0.526 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and filtered through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure 4-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide (0.040 g, 85.4%) as a dark brown solid.

MS: 446.44 [M+1].

Step 6: synthesis of 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide

To a stirred solution of 4-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide (0.040 g, 0.0898 mmol) in THF (3.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0179 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh) using 3%-5% MeOH in DCM as eluent to give 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide (0.020 g, 49.0%) as an off-white solid.

MS: 456.44 [M+1].

Synthesis of compound No. 1131: 1-(4-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)ethanone

Step 1: Synthesis of N-methoxy-N-methylcyclopropanecarboxamide

To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.0 g, 43.66 mmol) and N-methoxymethanamine hydrochloride (5.56 g, 56.76 mmol) in DMF (35 mL) were added DCC (13.51 g, 65.49 mmol) and DMAP (1.60 g, 13.98 mmol) sequentially at 0 °C and stirred for 30 min. The resulting reaction mixture was allowed to warm to RT and stirred for 4 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with 1 N HCl in water and extracted with EtOAc. The organic layer was washed with bicarbonate water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 20% acetone in n-hexane) to give tert-butyl 4-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (7.45 g, 60%) as a colorless oily mass.

MS: 273.1 [M+1].

Step 2: synthesis of tert-butyl 4-(6-bromonicotinoyl)piperidine-1-carboxylate

To a stirred solution of 2,5-dibromopyridine (5.0 g, 21.18 mmol) in diethyl ether (100 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (8.47 mL, 21.18 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then tert-butyl 4-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (6.36 g, 23.29 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with 10% MeOH in DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-(6-bromonicotinoyl)piperidine-1-carboxylate (5.8 g, 67.12%) as a colorless oily mass.

MS: 371.0 [M+1].

Step 3: Synthesis of tert-butyl 4-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate

To a stirred solution of tert-butyl 4-(6-bromonicotinoyl)piperidine-1-carboxylate (1 g, 2.71 mmol) in DME (50 mL) was added _TMSCF3 (0.77 g, 5.43 mmol) at 0 °C under nitrogen atmosphere, then CsF (0.82 g, 5.43 mmol) was added portionwise to the reaction mixture. The reaction mixture was allowed to warm to RT and stirred for 10 h. Upon completion of the reaction, the reaction mixture was quenched with 0.1 N HCl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 10% acetone in hexane as eluent to give tert-butyl 4-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate (0.52 g, 45.45%) as a white solid.

MS: 440 [M+2].

Step 4: Synthesis of tert-butyl 4-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.20 g, 0.975 mmol) and compound 4-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate (0.428 g, 0.975 mmol) in DMSO (6 mL) was added K ₂ CO ₃ (0.403 g, 2.92 mmol), then Cul (0.016 g, 0.0975 mmol) and L-proline (0.056 g, 0.487 mmol). The reaction mixture was heated at 110 °C for 16 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 40-60% acetone in n-hexane) to give tert-butyl 4-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate (0.075 g, 15.12%) as a yellow solid.

MS: 564.02 [M+1].

Step 5: Synthesis of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(piperidin-4-yl)ethanol

To a stirred solution of tert-butyl 4-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate (0.075 g, 13.51 mmol) in DCM (50 mL) was added TFA (0.2 g, 13.51 mmol) dropwise at RT under nitrogen atmosphere. The reaction mixture was allowed to warm to RT and stirred for 6 h. Upon completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with 10% MeOH in DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4-5% MeOH in DCM as eluent to give (6-bromopyridin-3-yl)(piperidin-4-yl)methanone (43 g, 74.52%) as a yellow solid.

MS: 364.16 [M+1].

Step 6: synthesis of 1-(4-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1hydroxyethyl)piperidin-1-yl)ethanone

To a stirred solution of (6-bromopyridin-3-yl)(piperidin-4-yl)methanone-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(piperidin-4-yl)ethanol (0.040 g, 0.109 mmol) in anhydrous DCM (5 mL) at 0 °C was added Et ₃ N (0.033 g, 0.329 mmol) under nitrogen atmosphere. To the resulting reaction mixture was added dropwise acetyl chloride (0.005 g, 0.109 mmol), stirred for 1 h at 0 °C. The mixture was allowed to warm to RT and stirred for 1 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mixture was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 2-3% MeOH in DCM as eluent to give 1-(4-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1hydroxyethyl)piperidin-1-yl)ethanone (0.035 g, 63.63%) as a yellow solid.

MS: 506.01 [M+1].

Step 7: synthesis of 1-(4-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)ethanone

To a stirred solution of 1-(4-(1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1hydroxyethyl)piperidin-1-yl)ethanone (0.035 g, 0.0693 mmol) in EtOH (3.0 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.019 g, 0.346 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 1-(4-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)ethanone (0.025 g, 78.12%) as a dark brown solid.

MS: 476.19 [M+1].

Step 8: synthesis of 1-(4-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)ethanone

To a stirred solution of 1-(4-(1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)ethanone (0.025 g, 0.05263 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0052 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water, extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 5-6% MeOH in DCM as eluent to give 1-(4-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)ethanone (0.006 g, 17.41%) as an off-white solid.

MS: 486.02 [M+1].

Synthesis of compound No. 1133: 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol

Step 1: Synthesis of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol

To a stirred solution of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(piperidin-4-yl)ethanol (0.110 g, 0.023 mmol) in anhydrous methanol (5 mL) were added formic acid (FCOOH; 0.030 g, 0.071 mmol) and formaldehyde (FCHO; 0.021 g, 0.071 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 70 °C for 6 h. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 5-6% MeOH in DCM as eluent to give 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol (0.060 g, 53.63%) as a yellow solid.

MS: 478.01 [M+1].

Step 2: 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol

To a stirred solution of 1-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol (0.060 g, 0.0125 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.5 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.033 g, 0.062 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol (0.040 g, 71.4%) as a dark brown solid.

MS: 448.19 [M+1].

Step 3: Synthesis of 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol

To a stirred solution of 1-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol (0.040 g, 0.0089 mmol) in THF (1.0 mL) was added trimethyl orthoformate (2.0 mL). The resulting reaction mixture was added PTSA (0.003 g, 0.0052 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water, extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography and column chromatography on silica gel (100-200 mesh) using 5-6% MeOH in DCM as eluent to give 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol (0.014 g, 34.41%) as an off-white solid.

MS: 458.02 [M+1].

Synthesis of Compound No. 1146: N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide

Step 1: synthesis of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanone

To a stirred solution of 2,5-dibromopyridine (5.0 g, 2.12 mmol) in THF (50 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (12.5 mL, 3.18 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then 2,2,2-trifluoro-1-morpholinoethanone (5.06 g, 2.76 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 18% ethyl acetate in hexane as eluent to give 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanone (3.5 g, 64.81%) as a colorless oil.

Step 2: synthesis of (E/Z)-ethyl-3-(6-bromopyridin-3-yl)-4,4,4-trifluorobut-2-enoate

To a stirred solution of triethyl phosphonoacetate (3.9 g, 1.77 mmol) and THF (60 mL) at 0 °C under _N2 was added potassium tert-butoxide base (1.98 g, 1.77 mmol) in portions. The resulting mixture was stirred at RT for 1 h to form the anion. A solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanone (3.0 g, 1.18 mmol) in THF (15 mL) was added slowly. After addition, the mixture was stirred for 6 h at RT. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 9-15% EA in hexane) to give (E/Z)-ethyl 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobut-2-enoate (1.5 g; 40%) as a yellow oil.

MS: 324 [M+1].

Step 3: synthesis of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-ol

To a stirred solution of (E/Z)-ethyl 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobut-2-enoate (1.5 g, 462 mmol) in EtOH (30 mL) was added NaBH ₄ (0.520 g, 1380 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 14 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 30% ethyl acetate in n-hexane to give 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-ol (0.610 g; 46.5%) as a clear oil.

MS: 284 [M+1].

Step 4: synthesis of 2-(3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl)isoindoline-1,3-dione

To an ice-cooled stirred solution of isoindolin-1,3-dione (0.774 g, 5.28 mmol), 3-(6-bromopyridin-2-yl)-4,4,4-trifluorobutan-1-ol (1 g, 3.53 mmol) and TPP (1.3 g, 5.28 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD) (0.919 g, 5.28 mmol). The reaction mixture was stirred at RT for 16 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 20% acetone in hexane) to give 2-(3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl)isoindolin-1,3-dione (0.600 g, 42%) as a free-flowing yellowish solid.

MS: 409.1 [M+1].

Step 5: synthesis of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-amine

To a stirred solution of 2-(3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl)isoindolin-1,3-dione (0.500 g, 0.29 mmol) in MeOH (10 mL) was added dropwise hydrazine hydrate (3 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 4 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mass was quenched with 1 N NaOH solution. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-amine (0.200 g; 47.05%) was obtained as a reddish semi-solid, which was used as such in the next step.

MS: 284.09 [M+1].

Step 6: Synthesis of N-(3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide

To an ice-cold stirred solution of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-amine (0.080 g, 0.282 mmol) in DCM (4.0 mL) was added trimethylamine (0.057 mL, 0.424 mmol) followed by MsCl (0.035 g, 0.252 mmol). The resulting reaction mixture was stirred for 3 h at RT. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 10-15% acetone in hexane) to give N-(3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide (0.070 g, 81.20%) as a reddish semi-solid.

MS: 363 [M+2].

Step 7: Synthesis of N-(3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.040 g, 0.195 mmol) and N-(3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide (0.070 g, 0.195 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.080 g, 0.585 mmol), followed by Cul (0.005 g, 0.0195 mmol) and DMEDA (0.017 g, 0.195 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 6-7% MeOH in DCM) to give N-(3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide (0.035 g; 50%) as a yellow solid.

MS: 466.1 [M+1].

Step 8: synthesis of N-(3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide

To a stirred solution of N-(3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide (0.035 g, 0.11 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.029 g, 0.55 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure N-(3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide (0.025 g, 75%) as a dark brown solid.

MS: 456.2 [M+1].

Step 9: synthesis of N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide

To a stirred solution of N-(3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide (0.025 g, 0.079 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0027 g, 0.015 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide (0.006 g; 60%) as an off-white solid.

MS: 466.45 [M+1].

Synthesis of Compound No. 1152: 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine

Step 1: synthesis of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanone

To a stirred solution of 2,5-dibromopyridine (5.0 g, 2.12 mmol) in THF (50 mL) at -78 °C was added n-butyl lithium (2.5 M solution in hexane) (12.5 mL, 3.18 mmol) under nitrogen atmosphere and stirred for 1 h at the same temperature. Then 2,2,2-trifluoro-1-morpholinoethanone (5.06 g, 2.76 mmol) was added dropwise to the reaction mixture and stirred for 1 h at -78 °C. The reaction progress was monitored using TLC. Upon completion of the reaction, the reaction mass was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 18% ethyl acetate in hexane as eluent to give 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanone (3.5 g, 64.81%) as a colorless oil.

Step 2: synthesis of (E/Z)-ethyl-3-(6-bromopyridin-3-yl)-4,4,4-trifluorobut-2-enoate

To a stirred solution of triethylphosphonoacetate (3.9 g, 1.77 mmol) and THF (60 mL) at 0 °C under N2 was added potassium tert-butoxide base (1.98 g, 1.77 mmol) portionwise. The resulting mixture was stirred at RT for 1 h to form the anion. A solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanone (3.0 g, 1.18 mmol) in THF (15 mL) was added slowly. After addition, the mixture was stirred for 6 h at RT. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 9-15% EA in hexane) to give (E/Z)-ethyl 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobut-2-enoate (1.5 g; 40%) as a yellow oil.

MS: 254 [M+2].

Step 3: synthesis of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-ol

To a stirred solution of (E/Z)-ethyl 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobut-2-enoate (1.5 g, 462 mmol) in EtOH (30 mL) was added NaBH ₄ (0.520 g, 1380 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 14 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give the crude reaction mass. Purification of the crude product was accomplished by column chromatography on silica gel (100-200 mesh) and the desired compound was eluted with 30% ethyl acetate in n-hexane to give 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-ol (0.610 g; 46.5%) as a clear oil.

MS: 284 [M+1].

Step 4: Synthesis of 2-bromo-5-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridine

To a stirred solution of 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutan-1-ol (0.500 g, 1.76 mmol) in DCM (20 mL) was added TPP (0.922 g, 3.52 mmol) followed by portionwise addition of carbon tetrabromide (1.16 g, 3.521 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 7 h. The reaction was monitored for completion using TLC. Upon completion, the reaction was quenched with ice-cold water. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 5-7% acetone in hexane as eluent to give 2-bromo-5-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridine (0.300 g, 47.05%) as a reddish semi-solid.

MS: 346.97 [M+1].

Step 5: synthesis of tert-butyl-3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutylmethylcarbamate

To a stirred solution of 2-bromo-5-(4-bromo-1,1,1-trifluorobutan-2-yl)pyridine (0.300 g, 0.867 mmol) in THF (10 mL) was added methylamine in THF (3 mL), followed by _Et3N (0.262 g, 2.60 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 4 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mass was quenched with water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained 3-(6-bromopyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine (93.75%) (0.240 g, 0.8080 mmol) was dissolved in DCM (10 mL), Boc anhydride (0.264 g, 1.21 mmol) was added, then _Et3N (0.204 g, 2.02 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 6 h. The completion of the reaction was monitored using TLC. Upon completion, the reaction mass was quenched with water. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Tert-butyl 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate (0.200 g; 49.05%) was obtained as an off-white solid, which was used as such in the next step.

MS: 397.09 [M+1].

Step 6: Synthesis of tert-butyl 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate

To a stirred solution of 3-nitro-4-(1H-pyrazol-4-yl)pyridin-2-amine (0.100 g, 0.487 mmol) and tert-butyl 3-(6-bromopyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate (0.193 g, 0.48 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (0.305 g, 1.44 mmol), followed by Cul (0.009 g, 0.048 mmol) and DMEDA (0.042 g, 0.48 mmol). The reaction mixture was heated at 110 °C for 6 h. The reaction progress was monitored using TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 3-5% MeOH in DCM) to give tert-butyl 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate (0.070 g; 50%) as a yellow solid.

MS: 522.1 [M+1].

Step 7: Synthesis of tert-butyl 3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate

To a stirred solution of tert-butyl 3-(6-(4-(2-amino-3-nitropyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate (0.052 g, 1.91 mmol) in EtOH (7.0 mL) was added NH ₄ Cl (2.0 mL) at room temperature. To the resulting reaction mixture was added Fe powder (0.52 g, 9.51 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was diluted with H ₂ O:EtOAc (50 mL, 5:5) and passed through celite to remove inorganic impurities from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give pure tert-butyl 3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate (0.036 g, 75%) as a dark brown solid.

MS: 492.2 [M+1].

Step 8: Synthesis of tert-butyl 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate

To a stirred solution of tert-butyl 3-(6-(4-(2,3-diaminopyridin-4-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutylmethylcarbamate (0.035 g, 0.079 mmol) in THF (1.0 mL) was added trimethyl orthoformate (1.5 mL). The resulting reaction mixture was added PTSA (0.0027 g, 0.015 mmol) and stirred for 4 h at 70 °C. The completion of the reaction was monitored using TLC. Upon completion, the reaction mixture was quenched with bicarbonate water and extracted with 10% MeOH in DCM. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude desired product, which was purified by column chromatography on silica gel (100-200 mesh; eluent 8-9% MeOH in DCM) to give tert-butyl 3-(6-(4-(3H-imidazo[4,5-i]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate (0.021 g, 60%) as an off-white solid.

MS: 502.1 [M+1].

Step 9: Synthesis of 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine

To a stirred solution of tert-butyl 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl methylcarbamate (0.021 g, 0.0419 mmol) in DCM (50 mL) was added dropwise TFA (0.004 g, 0.0419 mmol) at RT under nitrogen atmosphere. The reaction mixture was kept at RT and stirred for 6 h. Upon completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with 10% MeOH in DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 4-5% MeOH in DCM as eluent to give 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine (0.05 g, 31.25%) as an off-white solid.

MS: 402.1 [M+1].

The compounds of the present invention were tested for their activity and were found to be active. A description of the assays and results are provided below in this application.

Biological example 1: biochemical analysis of JAK

For the development of biochemical assays, recombinant JAK1, JAK2, JAK3, and TYK2 (Carna Biosciences) were used in a solution containing 50 mM N-2-hydroxyethyl-piperazine-N-2-ethanesulfonic acid (HEPES), pH 7.5, 1 mM ethylene glycol tetraacetic acid (EGTA), 10 mM _MgCl2 , 2 mM dithiothreitol (DTT), and 0.01% Tween-20. The intended amounts of enzyme and the concentrations of substrate (ULight-JAK-1 (Tyr1023) peptide) and ATP were determined for each kinase assay using appropriate titration and Michaelis constant (Km) measurements. The assay was developed using LANCE Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) technology (Perkin Elmer). The enzyme and compounds were incubated at 22°C for 60 min in a white 384-well OptiPlate (Perkin Elmer). Substrate and ATP were added to the above mixture and incubated for 90 min. The reaction was stopped by adding ethylenediaminetetraacetic acid (EDTA) and detection antibody (europium-labeled anti-phospho-tyrosine (PT66) antibody) was added. The assay was read in TR-FRET mode on a FLUOstar multi-mode reader from BMG. After irradiation at 320 nm, energy from the Eu donor is transferred to the ULight™ acceptor dye, which in turn generates light at 665 nm. The intensity of this light emission is proportional to the level of ULight™ substrate phosphorylation. Compounds that interfere with JAK enzymatic activity show lower levels of substrate phosphorylation and are reported as % inhibition relative to the vehicle control.

Biological example 2: cell-based JAK assays - phosphorylation of signal transducers and activators of transcription 3 (STAT3) and STAT5 by interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GMCSF)

TF-1 cells were starved overnight in OptiMEM medium containing 0.5% charcoal-stripped fetal calf serum, 0.1 mM non-essential amino acids (NEAA), 1 mM sodium pyruvate, and phenol red-free in a _CO2 incubator maintained at 37°C. The next day, cells were resuspended in phenol red-free Roswell Park Memorial Institute (RPMI) medium and dispensed into 96-well plates at a final cell density of 120,000 cells/well. Compounds were diluted in DMSO, added to cells, and incubated for 30 min in a _CO2 incubator maintained at 37°C. The final DMSO concentration in the cell-based assay was 0.2%. Recombinant human cytokines IL-6 (30 ng/ml) and GMCSF (5 ng/ml) were added to the plate containing the cells along with the compound and incubated for 20 min with gentle tapping once every 5 min. Compound-mediated effects on STAT3 and STAT5 phosphorylation were measured in lysates prepared using CISBIO STAT3 (pSTAT3) and pSTAT5 phosphorylated forms detection kits using homogeneous time-resolved fluorescence (HTRF) assay. Background signal obtained from cells not subjected to cytokine activation was subtracted from signals for vehicle control and compound-treated wells. Percent inhibition of pSTAT3/5 levels by compounds was calculated relative to the signal for the vehicle control, which was considered 100% pSTAT3/5.

Biological example 3: STAT5 phosphorylation by IL-2

HT-2 cells were starved overnight in RPMI medium with phenol red containing 10% fetal bovine serum for 4 hours in a _CO2 incubator maintained at 37°C. Compounds were diluted in DMSO and added to the wells of a 96-well plate at a final cell density of 120,000 cells/well. Cells and compounds were incubated for 30 minutes in a _CO2 incubator maintained at 37°C, and the final DMSO concentration in the cell-based assay was 0.2%. Recombinant human cytokine IL-2 (50 U/mL) was added to the plate containing cells and compound and incubated for 20 minutes with gentle tapping/shaking once every 5 minutes. Compound-mediated effects on STAT5 phosphorylation were measured in lysates prepared with CISBIO pSTAT5 detection kits using the HTRF method. The background signal from cells not subjected to cytokine activation was subtracted from the signals for vehicle control and compound-treated wells. Percent inhibition of pSTAT5 levels by compounds was calculated relative to the signal for the vehicle control, which was considered 100% pSTAT5.

Biological example 4: production of interferon-γ (IFN-γ) in natural killer cell line 92 (NK 92) under the influence of IL-12

NK 92 cells were cultured in IL-2-free medium overnight. The next day, NK 92 cells were seeded at 5000 cells per well in a 96-well plate. Compounds were added to the cells and incubated for 1 hour. Afterwards, IL-12 (10 U/ml) was added to the cells and incubated overnight. The supernatant was collected from the wells and the level of IFN-γ secretion was measured using a human IFN-γ enzyme-linked immunosorbent assay (ELISA) kit.

Absorbance was measured at 450 nm using a FLUOstar instrument from BMG. The background signal from cells not subjected to cytokine activation was subtracted from the signals for vehicle control-treated wells and the signals for compound-treated wells. The percentage inhibition of IFN-γ secretion levels by the compounds was calculated relative to the signal for the vehicle control, which was considered to represent 100% of IFN-γ secretion.

The compounds of the present invention were tested as described in Biological Examples 1-4 and the results are shown below in Table 2.

From the data in Table 2, it can be clearly seen that all the compounds of the present invention have selective JAK1 inhibitory activity.

Biological example 5: comparison with existing JAK inhibitors

As an illustration, some of the compounds from the examples were tested for their activity relative to an existing JAK inhibitor. The results for compounds from examples 1133, 1181, and 1215 were compared with the results for the existing JAK inhibitor under the same experimental conditions and are shown in Table 3.

The data thus obtained for the compounds were compared with two reference standards, filgotinib, a selective JAK1 inhibitor, and tofacitinib, a pan-JAK inhibitor. The compounds of Examples 1133, 1181, and 1215 demonstrated improved potency as well as selectivity for JAK1 (7-80-fold selectivity for JAK1 over JAK2; 3-22-fold selectivity for JAK1 over JAK3) compared to filgotinib (having 0.9-fold selectivity for JAK1 over JAK2; 12-fold selectivity for JAK1 over JAK3). These compounds also have significantly superior selectivity for JAK1 compared to a pan-inhibitor such as tofacitinib.

Biological example 6: mouse model of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease that can cause joint pain and systemic dysfunction. Several cytokines, such as IL-6 and IFN-γ, activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Inhibition of the JAK/STAT pathway is considered as one of the therapeutic options for the treatment of rheumatoid arthritis. Rodent arthritis models can be used to evaluate the therapeutic potential of compounds administered for preventive or therapeutic purposes. These models include, but are not limited to, collagen-induced arthritis in mice or rats, adjuvant-induced arthritis in rats, and anti-collagen antibody-induced arthritis.

The compounds described in this application were tested for efficacy related to inhibition of the JAK/STAT pathway in a collagen-induced arthritis model in mice. The compounds were administered orally once daily (1×/day) for 21 days and clinical signs, body weight, and histopathology of the ankles and paws were assessed at the end of the study. Arthritis scores were calculated for the compounds as well as the reference standard filgotinib. As an example, compounds from Examples 1215, 1181, and 1133 showed very good efficacy, greater than or comparable to filgotinib.

Biological example 7: mouse model of imiquimod-induced psoriasis

Imiquimod (IMQ)-induced dermatitis closely resembles human psoriasis lesions not only in phenotypic and histological characteristics but also in the developmental pattern of such lesions. IMQ is a ligand for toll-like receptor 7 (TLR7) and TLR8 and is a potent activator of the immune system. The immunomodulatory effects of IMQ in the initiation of psoriasis are attributed to stimulation of TLR7 and TLR8 on plasmacytoid dendritic cells (pDC) and activation of the type I interferon pathway. Migration of activated dermal dendritic cells to lymph nodes in the skin initiates a sequence of events leading to the late phase of psoriasis. The compounds described in this application are tested for their efficacy as JAK inhibitors in imiquimod-induced dermatitis in mice.

Female BALB/c mice were treated topically with a 3% cream formulation containing the test compounds. For five days, 5% imiquimod was applied to the skin of the back and right ear, four hours after administration of the test compounds. On the 6th day after administration of the test compounds, the severity of psoriasis was monitored and assessed according to the Psoriasis Area and Severity Index (PASI). The efficacy of the compounds was assessed using the PASI score. Redness, thickness, and scaling of the skin of the back and ear were assessed in the scoring groups.

The compounds of the present invention, for example, the compound of Example 1133, the compound of Example 1215, and filgotinib, showed statistically significant reduction in the cumulative psoriasis score compared to the vehicle. Significant reductions in back skin thickness and ear thickness were observed with the administration of the compounds of Examples 1133, 1215, and filgotinib (3%, topical, 1×/day). The compound of Example 1215 showed better efficacy compared to the compound of Example 1133 and the reference compound filgotinib. The data are shown in Fig. 1. From this figure, it can be clearly seen that the compounds of the Examples of the present invention show improved efficacy compared to commercially available compounds such as filgotinib.

Biological example 8: mouse model of oxazolone-induced colitis

The animal in which colitis is to be induced may be any mammal and may include, but is not limited to, a mouse, rat, guinea pig, hamster, rabbit, cat, dog, goat, monkey, and chimpanzee. Colitis may be induced in an animal by any method known in the art. A mouse model of oxazolone-induced colitis was used to study the efficacy of JAK inhibitors. Histological studies have shown that oxazolone-induced colitis is similar to human ulcerative colitis. Increased levels of proinflammatory cytokines in ulcerative colitis are dependent on signaling involving the JAK family of tyrosine kinases. It has been suggested that inhibition of JAK may be useful for the treatment of ulcerative colitis.

In this study, 10- to 12-week-old male BALB/c mice were treated with 4% oxazolone (formulated in 4:1 acetone:olive oil) or vehicle intershoulderly on day 1 of anesthetized animals. After 7 days of skin sensitization, mice were fasted for 6 hours and then treated intrarectally with 1% oxazolone (formulated in 1:1 ethanol:water). Drug or vehicle treatment (oral (p.o.), twice daily (2×/d)) was initiated on day 6, the day before intrarectal oxazolone administration. Animals were treated with test compounds or vehicle until day 9. The disease activity index (DAI) was scored for each mouse by experimenters blinded to treatment. The DAI scale was used to assess weight loss (0 = no weight loss, 2 = more than 5-10% weight loss, 4 = more than 20% weight loss), stool consistency (0 = normal, 2 = soft, non-lumpy stool, 4 = severe diarrhea), and rectal bleeding (0 = no blood, 2 = bloody stool, 4 = blood sticking to the anus and part of the tail).

Table 4 below provides the scores for the compounds according to the disease activity index scores compared to the vehicle-treated group.

The compounds of the present invention, such as the compounds of Examples 1181, 1215, and filgotinib, demonstrated statistically significant reductions in disease activity index compared to vehicle. Significant reductions in stool consistency, rectal bleeding, and weight loss were observed with the compounds of Examples 1181, 1215, and filgotinib (30 mg/kg, p.o., twice daily). The compound of Example 1215 demonstrated superior efficacy compared to the commercially available compound filgotinib.

Claims (311)

1. A 1H-imidazo[4,5-b]pyridin-2(3H)-one compound exhibiting selective inhibition of Janus kinase 1 (JAK 1), a pharmaceutically acceptable salt or isomer thereof, selected from the group consisting of: 1011. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazine-1-carboxamide; 1012. N-(cyanomethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazine-1-carboxamide; 1013. 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(2-(methylsulfonyl)ethyl)piperazine-1-carboxamide; 1014. 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(pyridin-4-yl)piperazin-1-carboxamide; 1015. N-(2-fluoropyridin-4-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazine-1-carboxamide; 1017. N-(cyclopentylmethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-carboxamide; 1018. 7-(4-(1,1-dioxidothiomorpholine-4-carbonyl)piperazin-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 1019. 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(2-methoxypyridin-4-yl)piperazine-1-carboxamide; 1020. N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-carboxamide; 1021. N-(1,1,1-trifluoropropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-carboxamide; 1023. 7-(4-(3,3-dimethylazetidine-1-carbonyl)piperazin-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 1024. 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(2-methyl-4-(methylsulfonyl)phenyl)piperazine-1-carboxamide; 1025. N-(2,2,2-trifluoroethyl)-2-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)acetamide; 1026. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1027. N-(cyanomethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1028. N-(2,2,2-trifluoroethyl)-3-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrrole-1-carboxamide; 1029. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1030. N-(1,1,1-trifluoropropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1031. 7-(1-(4,4,4-trifluorobutanoyl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one; 1032. N-(1-cyanocyclopropyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1033. N-(2-cyanopropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1034. N-(cyclopentylmethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1035. N-(cyanomethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide hydrochloride; 1036. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1038. N-(cyano(cyclopentyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1039. N-(2-cyano-1-cyclopentylethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1040. N-(2-cyanobutan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1041. N-(1-cyclopentyl-2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1042. 4-(1-ethyl-2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide; 1043. N-(cyano(cyclopropyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1044. N-(1-cyano-2-methylpropyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1045. N-(2,2,2-trifluoroethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1046. N-(1-cyanopropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1047. N-((S)-1-cyano-2-methylpropyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1048. 1-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)azetidine-3-carbonitrile; 1049. N-((R)-1-cyano-2-methylpropyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1050. N-(3-cyano-1,1,1-trifluoropropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1051. N-(2-cyano-1-cyclopropylethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1052. N-(1-cyanopropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1053. N-(1-cyanopropan-2-yl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1054. N-((R)-cyano(cyclopropyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1055. 1-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)pyrrolidine-3-carbonitrile; 1056. N-(3-cyanocyclobutyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1057. 2-(1-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)pyrrolidin-3-yl)acetonitrile; 1058. N-(1-(3-cyanoazetidin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1059. N-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1060. N-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1061. 3-(1-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)pyrrolidin-3-yl)propanenitrile; 1062. N-(2-cyano-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1063. N-(cyano(phenyl)methyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1064. N-(2,2,2-trifluoroethyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1065. N-(2-cyano-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1066. N-(2-cyanocyclohexyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1067. 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carbonyl)piperidine-4-carbonitrile; 1068. N-(1-(3-cyanoazetidin-1-yl)propan-2-yl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1069. N-(1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)pyrrolidin-3-yl)propan-1-sulfonamide; 1070. N-(cyano(phenyl)methyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1071. N-(1-cyano-3-methoxypropyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1072. N-(1-cyano-3-(methylsulfonyl)propyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1073. N-((S)-1-cyano-2-methylpropyl)-4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazole-1-carboxamide; 1074. 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)-4-methylpyrrolidine-3-carbonitrile; 1075. 2-(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)oxazol-4-yl)acetonitrile; 1076. 2-(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)thiazol-4-yl)acetonitrile; 1077. 7-(1-((oxazol-5-yl)methyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1078. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile; 1079. 6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridine-3-carbonitrile; 1080. 7-(1-(5-((methylsulfonyl)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1081. 7-(1-(5-((oxetan-3-yl)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1082. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)acetonitrile hydrochloride; 1083. (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methanol; 1084. 7-(1-(5-(2,2,2-trifluoroethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1085. 7-(1-(5-(morpholinomethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1086. 4-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)thiomorpholine-1,1-dioxide; 1087. 1 -((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)azetidin-3-carbonitrile; 1088. 6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-N-(cyanomethyl)pyridine-3-carboxamide; 1089. N-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)methanesulfonamide; 1090. N-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)methanesulfonamide; 1091. N-((6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-cyanoacetamide; 1092. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)acetamide; 1093. 2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-N-(cyanomethyl)pyrimidine-5-carboxamide; 1094. N-(2,2,2-trifluoroethyl)-4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carboxamide; 1095. 4-(2-ethoxy-3H-imidazo[4,5-b]pyridin-7-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide; 1096. 4-(2-cyclopropyl-3H-imidazo[4,5-b]pyridin-7-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide; 1097. 3-(4-(2-(4-chloro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-tetrahydro-2H-pyran-4-carbonitrile; 1098. 4-(2-(1-acetylpiperidin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxamide; 1099. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)acetonitrile; 1100. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2-cyclopropylacetonitrile; 1101. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2-morpholinoacetonitrile; 1102. N-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2-cyanoacetamide; 1103. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-3-fluorophenyl)acetonitrile; 1104. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-2-fluorophenyl)acetonitrile; 1105. 2-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)-2-methoxyphenyl)acetonitrile; 1106. 2-(3-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)acetonitrile; 1107. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanenitrile; 1108. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)propanamide; 1109. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)cyclopropanecarbonitrile; 1110. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropylacetonitrile; 1111. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(3,3-difluoroazetidin-1-yl)acetonitrile; 1112. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-morpholinoacetonitrile; 1113. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1,1-dioxidothiomorpholino)acetonitrile; 1114. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1-(methylsulfonyl)azetidin-3-yl)acetonitrile; 1115. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(1-(methylsulfonyl)azetidin-3-yl)acetonitrile; 1116. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4-(methylsulfonyl)butanenitrile; 1117. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-2-yl)acetonitrile; 1118. 2-(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-4-yl)acetonitrile; 1119. 7-(1-(5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1120. 7-(1-(5-(1-chloro-2,2,2-trifluoroethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1121. 1-(6-(4-(H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-N,N-dimethylethanamine; 1122. 7-(1-(5-(1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1123. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutanenitrile; 1124. 7-(1-(5-(2,2,2-trifluoro-1-isopropoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1125. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol; 1126. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol; 1127. 7-(1-(5-(1-cyclopropyl-2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1128. 7-(1-(5-(1,1,1,2-tetrafluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1129. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoro-3-methylbutan-2-ol; 1130. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclohexyl-2,2,2-trifluoroethanol; 1131. 1-(4-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)ethanone; 1132. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-cyclopentyl-2,2,2-trifluoroethanol; 1133. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol; 1134. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(tetrahydro-2H-pyran-4-yl)ethanol; 1135. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(piperidin-4-yl)ethan-1-ol; 1136. 7-(1-(5-(2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1137. 7-(1-(5-(2,2,2-trifluoro-1-morpholinoethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1138. 7-(1-(5-(1,1,1-trifluoro-3-(methylsulfonyl)propan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1139. 7-(1-(5-(4-(cyclopropylsulfonyl)-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1140. 7-(1-(5-(1-((methylsulfonyl)methoxy)-2,2,2-trifluoroethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1141. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutane-1-sulfonamide; 1142. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-sulfonamide; 1143. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)methanesulfonamide; 1144. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N,N-dimethylbutanamide; 1145. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutanamide; 1146. 1-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea; 1147. 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one; 1148. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-N-methylpentanamide; 1149. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)cyclopropanecarboxamide; 1150. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-5,5,5-trifluoropentanamide; 1151. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)cyclopentanecarboxamide; 1152. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine; 1153. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)cyclopropanamine; 1154. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutan-1-ol; 1155. 7-(1-(5-(1,1,1-trifluoro-4-methoxybutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1156. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoropentannitrile; 1157. 2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)acetonitrile; 1158. 7-(1-(5-(1-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1159. (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(cyclopropyl)methanol; 1160. 7-(1-(5-(3-(methylsulfonyl)-1-(oxetan-3-yl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1161. 7-(1-(5-(1-methoxy-3-(methylsulfonyl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1162. 7-(1-(5-(1-fluoro-3-(methylsulfonyl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1163. 7-(1-(5-(4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1164. (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-(methylsulfonyl)piperidin-4-yl)methanol; 1165. (6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)(1-methylpiperidin-4-yl)methanol; 1166. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)-2-hydroxyacetamide; 1167. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide; 1168. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-cyano-N-(2,2,2-trifluoroethyl)acetamide; 1169. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethanol; 1170. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-2-yl)-2,2,2-trifluoroethanol; 1171. 7-(1-(6-(2,2,2-trifluoro-1-methoxyethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1172. 1-(2-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-4-yl)-2,2,2-trifluoroethanol; 1173. 1-(5-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-2-yl)-2,2,2-trifluoroethanol; 1174. 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1175. 7-(1-(6-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1176. 7-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1177. 1-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-carbonyl)pyrrolidine-3-carbonitrile; 1178. 1-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-cyclopropylurea; 1179. 1-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-3-cyclopropylurea; 1180. 3-cyclopentyl-3-(4-(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)propanenitrile; 1181. 7-(1-(5-((S)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1182. 7-(1-(5-((R)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1183. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol; 1184. 7-(1-(5-((R)-2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1185. 7-(1-(5-((S)-2,2,2-trifluoro-1-(oxetan-3-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1186. 7-(1-(5-(1,1,1-trifluoro-4-(isopropylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1187. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-(methylsulfonyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethanamine; 1188. 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-(cyclopropylaminosulfonyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1189. 7-(1-(5-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one; 1190. 7-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)phenyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1191. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-(trifluoromethyl)propan-1-ol; 1192. N-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethyl)-2-cyanoacetamide; 1193. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-2-methylpentan-2-ol; 1194. 7-(1-(5-(3,3,3-trifluoro-2-((methylsulfonyl)methyl)propyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1195. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-N-methylcyclopropanamine; 1196. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-2,2-dimethylbutan-1-ol; 1197. N-(2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)ethyl)cyclopropanamine; 1198. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine; 1199. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)cyclohexanamine; 1200. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine; 1201. 7-(1-(5-(1,1,1-trifluoro-4-morpholinobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1202. 1-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)azetidine-3-carbonitrile; 1203. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-isopropylbutan-1-amine; 1204. 7-(1-(5-(4-(cyclopropylmethylsulfonyl)-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1205. 7-(1-(5-(3-(cyclopropylmethylsulfonyl)-1,1,1-trifluoropropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1206. 7-(1-(5-(1,1,1-trifluoro-3-morpholinopropan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1207. (S)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-isopropylbutan-1-amine; 1208. (R)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-isopropylbutan-1-amine; 1209. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-(methylsulfonyl)-1H-pyrazol-1-yl)pyridin-3-yl)-3,3,3-trifluoropropan-1-amine; 1210. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-N-isopropylpentanamide; 1211. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N,N-diisopropylbutan-1-amine; 1212. N-(2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-3,3,3-trifluoropropyl)cyclopropanamine; 1213. (R)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutanamide; 1214. (S)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutanamide; 1215. (S)-4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-N-isopropylpentanamide; 1216. 7-(1-(5-((S)-4-(cyclopropylsulfonyl)-1,1,1-trifluorobutan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1217. (S)-3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-N-methylbutan-1-amine, trifluoroacetic acid (TFA) salt; 1218. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-3,3,3-trifluoro-N-isopropylpropan-1-amine; 1219. 7-(1-(5-(1,1,1-trifluoro-4-(4-methylpiperazin-1-yl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1220. (4-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)(cyclopropyl)methanone; 1221. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-ethylpiperidin-4-yl)-2,2,2-trifluoroethanol; 1222. 7-(1-(5-(1,1,1-trifluoro-3-(4-methylpiperazin-1-yl)propan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1223. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-ol; 1224. 5-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-6,6,6-trifluorohexane-2-amine, TFA salt; 1225. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol; 1226. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol; 1227. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-4-hydroxypentanenitrile; 1228. 2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)-N-methylethanamine; 1229. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoro-3-morpholinopropan-2-ol; 1230. 2-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1,1,1-trifluoro-4-morpholinobutan-2-ol; 1231. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylazetidin-3-yl)ethanol; 1232. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-ethylpyrrolidin-3-yl)-2,2,2-trifluoroethanol; 1233. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-ethylpyrrolidin-3-yl)-2,2,2-trifluoroethanol; 1234. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpyrrolidin-3-yl)ethanol; 1235. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpyrrolidin-3-yl)ethanol; 1236. 1-(3-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)azetidin-1-yl)ethanone; 1237. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylazetidin-3-yl)ethanol; 1238. 4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoro-4-hydroxy-N-isopropylpentanamide; 1239. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-ethylazetidin-3-yl)-2,2,2-trifluoroethanol; 1240. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpiperidin-4-yl)ethanol; 1241. N-(2-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoroethoxy)ethyl)propan-2-amine, TFA salt; 1242. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)ethanol; 1243. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)ethanol; 1244. 7-(1-(5-(2,2,2-trifluoro-1-methoxy-1-(1-methylpiperidin-4-yl)ethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1245. 3-(3-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)azetidin-1-yl)-3-oxopropanenitrile; 1246. 3-(1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-N-methylazetidine-1-carboxamide; 1247. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)isobutyramide; 1248. N-(3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluorobutyl)-2-cyanoacetamide; 1249. 3-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-4,4,4-trifluoro-1-morpholinobutan-1-one; 1250. 1-(4-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-5,5,5-trifluoropentanoyl)azetidine-3-carbonitrile; 1251. (S)-1-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol; 1252. (R)-1-(4-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol. 2. A 1H-imidazo[4,5-b]pyridin-2(3H)-one compound exhibiting selective inhibition of Janus kinase 1 (JAK 1), a pharmaceutically acceptable salt or isomer thereof of formula III: Where Y can be in any position of the pyridine ring, preferably in position 4 or 5 of pyridine; Y represents H, R ₁ , R ₂ , halogen, CN, -CO-, COR ₁ , -(CH ₂ )nCN, -CH ₂ CF ₃ , COOH, -COOR ₁ , -CON(R ₁ ) ₂ , -SO ₂ N(R ₁ ) ₂ , -OCOR ₁ , -NR ₁ COR ₁ , -CONH ₂ , CONR ₁ R ₂ , -CONH(CH ₂ )nOH, -CONH(CH ₂ )nSO ₂ R ₁ R ₂ , -CONH-(CH ₂ )nCF ₃ , -NHCONH(CH ₂ )nCF ₃ , -CH(CF ₃ )-(CH ₂ )n-CO-NR ₁ R ₂ , CH(CF ₃ )-(CH ₂ )n-SO ₂ -CH ₃ ; CH(OH)(CF ₃ )heterocycle-R ₁ , NHCONHR ₁ , -NHCOR ₁ R ₂ , NR ₁ CONR ₁ R ₂ , NH ₂ , NH ₂ CH ₂ -, NHCH ₂ CF ₃ , wherein the heterocycle is an unsubstituted or substituted 3-8-membered saturated mono-, condensed or bridged heterocyclic ring containing 1-3 heteroatoms selected from the group containing O, N, S; wherein the substitution can independently be R ₁ and R ₂ at any position of the heterocyclic ring; C _1-6 alk-aryl, arylC _1-6 alkyl; R ₁ and R ₂ are absent or independently selected from the group consisting of H, halogen, CN, CF ₃ , hydroxyl, amino, SO ₂ -C ₁ -C ₆ alkyl, CH ₂ CF ₃ , straight or branched C ₁ -C ₆ alkyl, straight or branched C ₁ -C ₆ alkenyl, straight or branched C ₁ -C ₆ alkynyl, halo-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy; C ₁ -C ₆ alkylamino, n is 0-3. 3. A compound of formula III according to claim 2, selected from the group containing: 1133. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylpiperidin-4-yl)ethanol; 1134. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(tetrahydro-2H-pyran-4-yl)ethanol; 1176. 7-(1-(4-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1181. 7-(1-(5-((S)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1182. 7-(1-(5-((R)-1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine; 1225. (R)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol; 1226. (S)-1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-isopropylpyrrolidin-3-yl)ethanol; 1231. 1-(6-(4-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,2,2-trifluoro-1-(1-methylazetidin-3-yl)ethanol. 4. A method for producing compounds according to any of paragraphs 1-3, comprising the steps of: Where the atom of the X cycle is C, N, R ₂ and R ₃ represent H, R ₁ : Where the atom of the X cycle is C, N, R ₁ is CN and R ₂ is H, R ₃ : Where the atom of the X cycle is C, N, R ₁ is CF ₃ , and R ₂ is H, R ₃ : Where the atom of the X cycle is C, N, R ₁ is CF ₃ , and R ₂ is OH, R ₃ : Where the atom of the X cycle is C, N, R ₁ is CF ₃ , and R ₂ is OCH ₃ , R ₃ : 5. A method for obtaining compounds according to item 1, comprising the following stages: Where X ₁ is O or H, R ₂ is H or -CH ₃ , R ₃ is H or -CH ₃ , R ₁ : R ₄ : 6. A method for obtaining compounds according to item 1, comprising the steps of: Where the atom of the X ₁ cycle is C, the atoms of the Y,Z cycle are C,N, R ₃ is H, O, carbocycle, 7. A method for producing compounds according to item 1, comprising the following stages: Where the atom of the X cycle is N, R ₂ is H, O, carbocycle, R ₁ is 8. A pharmaceutical composition for selectively inhibiting Janus kinase 1 (JAK 1), comprising a compound according to any one of claims 1-3 together with pharmaceutically acceptable excipients. 9. A pharmaceutical composition according to claim 8, administered orally, nasally, parenterally - intravenously, intramuscularly or subcutaneously, locally, transdermally, intravaginally, intravesically, intracisternally or rectally in the form of solid, semi-solid, lyophilized powder or liquid dosage forms. 10. Use of a compound according to any of paragraphs. 1-3 for the treatment of a JAK-1-mediated disease selected from cancer including carcinomas, sarcomas, lymphomas, leukemias, myelomas, germ cell tumors, blastomas, tumors of the central and peripheral nervous system and other tumors including melanomas, seminoma and Kaposi's sarcoma, acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, asthma, autoimmune hemolytic anemia, autoimmune thyroiditis, Crohn's disease, episodic lymphopenia with lymphocytotoxins, hemolytic jaundice of the newborn, Goodpasture's syndrome, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, visceral bowel disease, lupus, myasthenia gravis, myocardial inflammation or pericarditis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, scleroderma, systemic anaphylactic reaction, ulcerative colitis, nephritis including glomerulonephritis, gout, arthritis such as rheumatoid arthritis and osteoarthritis, erythema, dermatitis, dermatomyositis, bronchitis, cholecystitis, sepsis and gastritis.

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