HK1217102B - Tetracyclic bromodomain inhibitors - Google Patents

Description

Tetracyclic bromodomain inhibitors

Background Art

Bromodomains refer to conservative protein structure folding, which is combined with the N-acetylated lysine residues present in some proteins. The BET family of proteins containing bromodomains includes four members (BRD2, BRD3, BRD4 and BRDt). Each member of the BET family uses two bromodomains to identify the N-acetylated lysine residues present mainly but not completely on the amino-terminal tail of histones. These interactions regulate gene expression by recruiting transcription factors to specific genomic locations within chromatin. For example, the BRD4 in combination with histones recruits transcription factor P-TEFb to promoters, resulting in the expression of a subset of genes involved in the cell cycle process (Yang et al., Mol. Cell. Biol. 28:967-976 (2008)). BRD2 and BRD3 also play a role as transcriptional regulators of growth-promoting genes (LeRoy et al., Mol. Cell 30: 51-60 (2008)). BET family members have recently been identified as important for the maintenance of several cancer types (Zuber et al., Nature 478: 524-528 (2011); Mertz et al., Proc. Nat'l. Acad. Sci. 108: 16669-16674 (2011); Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478: 529-533 (2011)). BET family members are also implicated in mediating acute inflammatory responses through the canonical NF-κB pathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)), leading to upregulation of genes involved in cytokine production (Nicodeme et al., Nature 468: 1119-1123, (2010)). It has been shown that in animal models, inhibition of cytokine induction by BET bromodomain inhibitors is an effective method for treating inflammation-mediated renal disease (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)). BRD2 function has been associated with an inappropriate regulation of dyslipidemia or fat formation, an elevated inflammatory profile, and a tendency to increased susceptibility to autoimmune diseases (Denis, Discovery Medicine 10: 489-499 (2010)). Human immunodeficiency virus utilizes BRD4 to initiate transcription of viral RNA from stably integrated viral DNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomain inhibitors have also been shown to reactivate HIV transcription in models of latent T cell infection and latent monocyte infection (Banerjee, et al., J. Leukocyte Biol. doi: 10.1189/jlb.0312165). BRDt plays an important role in spermatogenesis, which is blocked by BET bromodomain inhibitors (Matzuk, et al., Cell 150: 673-684 (2012)). Therefore, compounds that inhibit the binding of BET family bromodomains to their homologous acetylated lysine proteins are being sought for the treatment of cancer, inflammatory diseases, kidney diseases, diseases involving metabolism or fat accumulation, and some viral infections, as well as methods for male contraception. Therefore, there is a continued medical need for the development of new drugs for the treatment of these indications.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a compound of formula (I) or a salt thereof,

in

^Y1 is N or CH;

R ¹ is CD ₃ , C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl;

^R2 is H or C1 _{- C3} alkyl;

Y ³ is N or CR ³ ;

R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c , -S(O)R ^3d , -S(O) ₂ R ^3a , -S(O) ₂ NR ^3b R ^3c or G ¹ ; wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ¹ , -CN, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c , -C(O)N(R ^3d )NR ^3b R ^3c , -S(O)R ^3d , -S(O) ₂ R ^3a , -S(O) ₂ NR ^3b R ^3c , -OR ^3a , -OC(O)R ^3d , -NR ^3b R ^3c , N(R ^3b )C(O)R ^3d ,N(R ^3b )SO ₂ R ^3d ,N(R ^3b )C(O)OR ^3d , N(R ^3b )C(O)NR ^3b R ^3c , N(R ^3b )SO ₂ NR ^3b R ^3c and N(R ^3b )C(NR ^3b R ^3c )=NR ^3b R ^3c ;

Y ² is C(O), S(O) ₂ or CR ⁴ R ⁵ ;

R ⁴ is H, deuterium, C ₁ -C ₆ alkyl, halogen or C ₁ -C ₆ haloalkyl;

R ⁵ is H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -S(O)R ^5d , -S(O) ₂ R ^5a , -S(O) ₂ NR ^5b R ^5c or G ¹ ; wherein said C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ¹ , -CN, -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -C(O)N(R ^5b )NR ^5b R ^5c , -S(O)R ^5d , -S(O) ₂ R ^5a , -S(O) ₂ NR ^5b R ^5c , -OR ^5a , -OC(O)R ^5d , -NR ^5b R ^5c , N(R ^5b )C(O)R ^5d ,N(R ^5b )SO ₂ R ^5d ,N(R ^5b )C(O)OR ^5d , N(R ^5b )C(O)NR ^5b R ^5c , N(R ^5b )SO ₂ NR ^5b R ^5c and N(R ^5b )C(NR ^5b R ^5c )=NR ^5b R ^5c ;

R ^3a , R ^3b , R ^3c , R ^5a and R ^5b are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ or -(C ₁ -C ₆ alkylene)-G ¹ ;

R ^5c, at each occurrence, is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ , -(C ₁ -C ₆ alkylene)-G ¹ , -(C ₁ -C ₆ alkylene)-CN, -(C ₁ -C ₆ alkylene)-OR ^a , or -(C ₁ -C ₆ alkylene)-C(O)OR ^a ;

R ^3d, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ , or -(C ₁ -C ₆ alkylene)-G ¹ ;

R ^5d, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ , -(C ₁ -C ₆ alkylene)-G ¹ , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b );

G ^1, at each occurrence, is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ¹ is optionally substituted with 1, 2, 3, 4, or 5 R ^1g groups;

R ⁶ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , -S(O) ₂ R ^6a , -S(O) ₂ NR ^6b R ^6c or G ² ; wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ² , -CN, -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , -C(O)N(R ^6b )NR ^6b R ^6c , -S(O)R ^6d , -S(O) ₂ R ^6a , -S(O) ₂ NR ^6b R ^6c , -OR ^6a , -OC(O)R ^6d , -NR ^6b R ^6c ,N(R ^6b )C(O)R ^6d ,N(R ^6b )SO ₂ R ^6d ,N(R ^6b )C(O)OR ^6d , N(R ^6b )C(O)NR ^6b R ^6c , N(R ^6b )SO ₂ NR ^6b R ^6c and N(R ^6b )C(NR ^6b R ^6c )=NR ^6b R ^6c ;

R ^6a , R ^6b and R ^6c are each independently H, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, haloalkyl, G ² , -(C ₁ -C ₆ alkylene)-G ² , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

R ^6d is independently, at each occurrence, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, haloalkyl, G ² , -(C ₁ -C ₆ alkylene)-G ² , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C 6 ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

G ^2, at each occurrence, is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ² is optionally substituted with 1, 2, 3, 4, or 5 R ^2g groups;

^A1 is C( ^R7 ) or N; ^A2 is C( ^R8 ) or N; ^A3 is C( ^R9 ) or N; and ^A4 is C( ^R10 ) or N; wherein zero, one or two of ^A1 , ^A2 , ^A3 and ^A4 are N;

R ⁷ , R ⁸ and R ⁹ are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , -OR ^y1 , -OC(O)R ^y2 , -OC(O)NR ^y3 R ^y4 , -SR ^y1 , -S(O) ₂ R ^y1 , -S(O) ₂ NR ^y3 R ^y4 , -C(O)R ^y1 , -C(O)OR ^y1 , -C(O)NR ^y3 R ^y4 , -NR ^y3 R ^y4 , -N(R ^y3 )C(O)R ^y2 , -N(R ^y3 )S(O) ₂ R ^y2 , -N(R ^y3 )C(O)O(R ^y2 y1 、-(C ^{1 -C} 6 alkylene) ^{-C(O)R y2 、} -(C ₁ -C ₆ ^alkylene )-OC(O ⁾ NR y3 R ^y4 、-(C ₁ -C ₆ alkylene)-S(O) ² R ^y1 、-(C _{1 -C 6} alkylene)-S(O) ₂ NR ^{y3 R y4 、 -} (C ₁ -C ₆ alkylene)-C(O _{) R} ^y1 _、 -(C _{1 -C 6} alkylene)-C(O ⁾ OR ^y1 、-( _{C 1 -C 6 alkylene} )-C(O ⁾ -C ₁ -C 6 alkylene)-C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-CN or -(C ₁ -C ₆ alkylene)-G ³ ;

R ^y1 , R ^y3 and R ^y4 are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ³ , -(C ₁ -C ₆ alkylene)-G ³ , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C 6 alkylene)- ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O) _O (R ^{b )} , -(C ₁ -C ₆ alkylene)-N(R ^e ) ^C ( ^O )NR ^c R ^d , or -(C _{1 -C 6} alkylene)-N(R ^e )S( _{O) 2 NR} ^c R ^d ;

R ^y2 is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ³ , -(C ₁ -C ₆ alkylene)-G ³ , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

G ^3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclyl; and each G ³ group is optionally substituted with 1, 2, 3, 4, or 5 R ^4g groups;

R ¹⁰ is H, C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ haloalkyl or -CN;

R ^1g , R ^2g and R ^4g are independently selected at each occurrence from the group consisting of oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , G ^2a , -OR ^a , -OC(O)R ^b , -OC(O)NR ^c R ^d , -SR ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^c R ^d , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^c R ^d , -NR ^c R ^d , -N( ^Re )C(O)R ^b , -N( ^Re )S(O) ₂ R ^b , -N( ^Re )C(O)O(R ^b ), -N( ^Re )C(O)NR ^c R ^d -N(R ^e )S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-CN, -(C ₁ -C ₆ alkylene)-G ^2a , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-OC(O)R ^b , -(C ₁ -C ₆ alkylene)-OC(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C 6 alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C 1 -C ₆ alkylene)-S(O) ₂ R a _6alkylene )-NR ^c R ^d , -(C ₁ -C _6alkylene )-N(R ^e )C(O)R ^b , -(C ₁ -C _6alkylene )-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C _6alkylene )-N(R ^e )C(O)O(R ^b ), -(C ₁ -C _6alkylene )-N(R ^e )C(O)NR ^c R ^d , -(C ₁ -C _6alkylene )-N(R ^e )S(O) ₂ NR ^c R ^d , or -(C ₁ -C _6alkylene )-CN;

R ^a , R ^c , R ^d and ^Re are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ^2a , -(C ₁ -C ₆ alkylene)-OR ^z1 , -(C ₁ -C ₆ alkylene)-NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-C(O)NR ^z3 R ^z4 or -(C ₁ -C ₆ alkylene)-G ^2a ;

R ^b, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ^2a or -(C ₁ -C ₆ alkylene)-G ^2a ;

Each occurrence of G ^2a is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ^2a group is optionally substituted with 1, 2, 3, 4, or 5 R ^3g groups;

R ^3g at each occurrence is independently oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , -OR ^z1 , -OC(O)R ^z2 , -OC(O)NR ^z3 R ^z4 , -SR ^z1 , -S(O) ₂ R ^z1 , -S(O) ₂ NR ^z3 R ^z4 , -C(O)R ^z1 , -C(O)OR ^z1 , -C(O)NR ^z3 R ^z4 , -NR ^z3 R ^z4 , -N(R ^z3 )C(O)R ^z2 , -N(R ^z3 )S(O) ₂ R ^z2 , -N(R ^z3 )C(O)O(R ^z2 ), -N(R ^z3 )C(O)NR ^z3 R ^z4 , -N(R ^z3 )S(O) ₂ NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-OR ^z1 , -(C ₁ -C ₆ alkylene)-OC(O)R ^z2 , -(C ₁ -C ₆ alkylene)-OC(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^z1 , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-C(O)R ^z1 , -(C ₁ -C ₆ alkylene)-C(O)OR ^z1 , -(C ₁ -C ₆ alkylene)-C(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-NR ^z3 R ^z4 , -(C ₁ -C -(C 1 -C ₆ alkylene)-N(R ^z3 )C(O)R ^z2 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )S(O) ₂ R ^z2 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )C(O)O(R ^z2 ), -(C ₁ -C ₆ alkylene)-N(R ^z3 )C(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )S(O) ₂ NR ^z3 R ^z4 or -(C ₁ -C ₆ alkylene)-CN;

R ^z1 , R ^z3 and R ^z4 are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ haloalkyl at each occurrence; and

R ^z2, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ haloalkyl.

In another aspect, the present invention provides a method for treating or preventing a condition that is ameliorated by inhibiting BET, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) alone or in combination with a pharmaceutically acceptable carrier.

Some approaches are directed towards treating or preventing inflammatory diseases or cancer or AIDS.

In another aspect, the present invention relates to a method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphoblastic leukemia,

Acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngoduct cancer, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplasia (dysplasia) proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's carcinoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, blood cancer, liposarcoma, lung cancer, lymphangioendothelial sarcoma (lymphoblastoma) mpagiendotheliosarcoma), lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and proliferative diseases of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, malignant lymphoproliferative disorders of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC) ), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, benign synovioma, sweat gland cancer, radiation-induced thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is selected from cytarabine, bortezomib and 5-azacytidine.

On the other hand, the present invention relates to a method for treating a disease or condition in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin disease, cardiomyopathy, cardiac hypertrophy, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, heart failure, hepatitis, hypophysitis, inflammatory bowel disease ... Intestinal diseases, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis and Wegener's granulomatosis. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention relates to a method for treating a chronic kidney disease or condition in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change glomerulonephritis, polycystic kidney disease, and tubulointerstitial nephritis. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention relates to a method for treating acute kidney injury, disease, or condition in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the acute kidney injury, disease, or condition is selected from the group consisting of ischemia-reperfusion-induced kidney disease, cardiac and major surgery-induced kidney disease, percutaneous coronary intervention-induced kidney disease, radiocontrast agent-induced kidney disease, sepsis-induced kidney disease, pneumonia-induced kidney disease, and drug toxicity-induced kidney disease. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention relates to a method for treating AIDS in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

On the other hand, the present invention relates to a method for treating obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy in a patient, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention provides a method for contraception in male patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention further provides the use of a compound of formula (I) alone or in combination with another active agent in the preparation of a medicament (with or without a pharmaceutically acceptable carrier) for treating or preventing the diseases and conditions disclosed herein.

The present invention also provides pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with another active pharmaceutical agent. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Detailed Description of the Invention

Disclosed herein are compounds of formula (I)

wherein R ¹ , R ² , R ⁶ , Y ¹ , Y ² , Y ³ , A ¹ , A ² , A ³ and A ⁴ are defined in the Summary of the Invention above and the Detailed Description of the Invention below. Also disclosed are compositions comprising such compounds and methods of treating diseases and conditions with these compounds and compositions.

The compounds disclosed herein may contain one or more variables that occur more than once in any substituent or formula herein. The definition of a variable at each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents may be used only if such combinations form stable compounds. A stable compound is one that can be isolated from a reaction mixture.

a). Definition

It is important to note that, as used in this specification and the claims to be protected, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound as well as one or more of the same or different compounds, reference to "optionally a pharmaceutically acceptable carrier" refers to a single optional pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, etc.

When used in the specification and the appended claims, the following terms have the indicated meanings unless otherwise specified:

As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2 to 10 carbon atoms and at least one carbon-carbon double bond, optionally substituted with 1, 2, or 3 halogen atoms. The term " _C2 - _C6 alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term "alkenylene" refers to a divalent group derived from a straight or branched chain hydrocarbon of 2 to 4 carbon atoms and contains at least one carbon-carbon double bond. Representative examples of alkenylene include, but are not limited to, CH=CH and CH ₂ CH=CH.

As used herein, the term "alkyl" refers to a saturated, straight or branched hydrocarbon chain radical. In some cases, the number of carbon atoms in an alkyl group is indicated by the prefix " _Cx - _Cy ," where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent. Thus, for example, " _Ci - _C6 alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms, and " _Ci - _C3 alkyl" refers to an alkyl substituent containing from 1 to 3 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, 1,2,2-trimethylpropyl, 2-ethylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term "alkylene" or "alkylene" refers to a divalent group derived from a straight or branched saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or 1 to 6 carbon atoms ( _C1 - _C6 alkylene) or 1 to 4 carbon atoms or 2 to 3 carbon atoms ( _C2 - _C3 alkylene). Examples of alkylene and alkylene groups include, _{but are not} limited _{to , -CH2-} , _-CH2CH2- , _-CH2CH2CH2- , _{-CH2CH2CH2CH2-} , _{and -CH2CH} ( _CH3 ) _CH2- .

As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond, optionally substituted with 1, 2, or 3 halogen atoms. The term " _C2 - _C6 alkynyl" refers to an alkynyl group containing 2 to 6 carbon atoms. Representative examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl, and but-2-yn-1-yl.

As used herein, the term "aryl" refers to a phenyl or bicyclic aryl group. A bicyclic aryl group is a naphthyl group or a phenyl group fused to a monocyclic cycloalkyl group or a phenyl group fused to a monocyclic cycloalkenyl group. Non-limiting examples of aryl groups include dihydroindenyl (indanyl), indenyl, naphthyl, dihydronaphthyl, and tetrahydronaphthyl. Aryl groups are connected to the parent molecular moiety through any carbon atom contained in the bicyclic ring system and can be unsubstituted or substituted.

As used herein, the term "cycloalkyl" refers to a monocyclic cycloalkyl, a bicyclic cycloalkyl, or a spirocycloalkyl. A monocyclic cycloalkyl is a carbocyclic ring system containing 3-8 carbon atoms, zero heteroatoms, and zero double bonds, i.e., a _C3 - _C8 cycloalkyl. In certain embodiments, a cycloalkyl refers to a monocyclic _C3 - _C7 cycloalkyl. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring. Monocyclic and bicyclic cycloalkyl groups may contain one or two alkylene bridges, each consisting of one, two, three, or four carbon atoms in length, with each bridge connecting two non-adjacent carbon atoms of the ring system. Non-limiting examples of bicyclic ring systems include bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane, tricyclo[3.3.1.0 ^3,7 ]nonane (octahydro-2,5-methanopentalene or noradamantane) and tricyclo[3.3.1.1 ^3,7 ]decane (adamantane). Spiroalkyl is a monocyclic cycloalkyl group in which two substituents on the same carbon atom of the monocyclic cycloalkyl ring together with the carbon atom form a second monocyclic cycloalkyl ring. Monocyclic, bicyclic and spiroalkyl groups can be unsubstituted or substituted and are connected to the parent molecular moiety by any substitutable atom contained in the ring system.

As used herein, the term "cycloalkenyl" refers to a monocyclic or bicyclic hydrocarbon ring group. Monocyclic cycloalkenyl groups have four, five, six, seven, or eight carbon atoms and zero heteroatoms, i.e., _C4 - _C8 cycloalkenyl. Four-membered ring systems have one double bond, five-membered or six-membered ring systems have one or two double bonds, and seven- or eight-membered ring systems have one, two, or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Bicyclic cycloalkenyl groups are monocyclic cycloalkenyl groups fused to a monocyclic cycloalkyl group, or monocyclic cycloalkenyl groups fused to a monocyclic cycloalkenyl group. Monocyclic and bicyclic cycloalkenyl rings may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, and each connecting two non-adjacent carbon atoms of the ring system. Representative examples of bicyclic cycloalkenyls include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthyl, and 1,6-dihydro-pentalene. Monocyclic and bicyclic cycloalkenyls can be attached to the parent molecular moiety through any substitutable atom contained in the ring system and can be unsubstituted or substituted.

As used herein, the term "halo" or "halogen" refers to Cl, Br, I, and F.

As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein one, two, three, four, five, or six hydrogen atoms are replaced by halogen. The term " _Ci - _C6 haloalkyl" refers to a _C1 - _C6 alkyl group as defined herein, wherein one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen. The term " _Ci - _C3 haloalkyl" refers to a C1 _{- C3} alkyl group as defined herein, wherein one, two, three, four, five, or six hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 4-chlorobutyl, 2-chloro-3-fluoropentyl, trifluorobutyl, trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,3,3,4,4,4-heptafluorobutyl.

As used herein, the term "heterocyclyl" or "heterocyclic" refers to monocyclic heterocyclic groups, bicyclic heterocyclic groups, and spirocyclic heterocyclic groups. Monocyclic heterocyclic groups are three-, four-, five-, six-, seven-, or eight-membered carbocyclic rings that also contain at least one heteroatom independently selected from O, N, and S. Three- or four-membered rings contain zero or one double bond and one heteroatom selected from O, N, and S. When two O atoms or one O atom and one S atom are present in the heterocyclic ring, the two O atoms or one O atom and one S atom are not directly bonded to each other. Five-membered rings contain zero or one double bond and one, two, or three heteroatoms selected from O, N, and S. Examples of five-membered heterocyclic rings include those containing 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S and 2 N; 1 O and 1 N; or 1 O and 2 N in the ring. Examples of five-membered heterocyclic groups include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, and 3-pyrrolinyl. The six-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from O, N, and S. Examples of six-membered heterocyclic rings include those containing 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N in the ring. Examples of six-membered heterocyclic groups include tetrahydropyranyl, dihydropyranyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydropyrimidinyl, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, 1,1-dioxohexahydro-1-thiopyranyl, 1,1-dioxo-1λ ⁶ -thiomorpholinyl, thiomorpholinyl, thioxanyl, and trithianyl. Seven and eight-membered rings contain zero, one, two, or three double bonds and one, two, or three heteroatoms selected from O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolyl, oxadiazolidine ... The heterocyclic radicals include thiazolinyl, thiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. The bicyclic heterocyclic radical is a monocyclic heterocyclic radical fused to a phenyl group, a monocyclic heterocyclic radical fused to a monocyclic cycloalkyl group, a monocyclic heterocyclic radical fused to a monocyclic cycloalkenyl group, or a monocyclic heterocyclic radical fused to a monocyclic heterocyclic radical. Representative examples of bicyclic heterocyclyls include, but are not limited to, 1,3-benzodioxolyl, benzopyranyl, benzothiopyranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, 2,3-dihydro-1H-indolyl, dihydroisoindol-2-yl, isoindolyl, 3,4-dihydroisoquinolin-2(1H)-yl, 2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl, hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl. Monocyclic and bicyclic heterocyclyls may contain one or two alkylene or alkenylene bridges, or mixtures thereof, each consisting of no more than 4 carbon atoms and each linking two non-adjacent atoms of the ring system. Examples of such bridged heterocyclyls include, but are not limited to, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl)-8-azabicyclo[3.2.1]octan-8-yl, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methylenecyclopenta[b]furanyl, hexahydro-1H-1,4-methylenecyclopenta[c]furanyl, aza-adamantane (1-azatricyclo[3.3.1.1 ^3,7 ]decane) and oxa-adamantane (2-oxatricyclo[3.3.1.1 ^3,7 ]decane). Spirocyclic heterocyclyls are monocyclic heterocyclyls in which two cycloalkyls, bicyclic cycloalkyls, monocyclic heterocyclyls or bicyclic heterocyclyls are present on the same carbon atom of the monocyclic heterocyclyl ring. Examples of spirocyclic heterocyclic groups include, but are not limited to, 6-azaspiro[2.5]octan-6-yl, 1'H,4H-spiro[1,3-benzodioxane-2,4'-piperidinyl]-1'-yl, 1'H,3H-spiro[2-benzofuran-1,4'-piperidinyl]-1'-yl and 1,4-dioxa-8-azaspiro[4.5]dec-8-yl. The monocyclic, bicyclic and spiro heterocyclic groups may be unsubstituted or substituted. The monocyclic, bicyclic and spiro heterocyclic groups are attached to the parent molecular moiety via any carbon atom or any nitrogen atom contained in the ring system. The nitrogen and sulfur heteroatoms in the heterocyclic ring may optionally be oxidized (e.g., 1,1-dioxotetrahydrothienyl, 1,2-dioxo-1,2-thiazolidinyl, 1,1-dioxothiomorpholinyl), and the nitrogen atom may optionally be quaternized.

As used herein, the term "C ₄ -C ₆ heterocyclyl" or "C ₄ -C ₆ heterocyclic" refers to a 4-, 5-, or 6-membered monocyclic heterocyclyl, as defined herein above. Non-limiting examples of C ₄ -C ₆ heterocyclyl include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, and morpholinyl.

As used herein, the term "heteroaryl" refers to monocyclic heteroaryl and bicyclic heteroaryl groups. Monocyclic heteroaryl groups are five- or six-membered monocyclic rings. The five-membered ring contains two double bonds. The five-membered ring may contain one heteroatom selected from O or S, or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom. The six-membered ring contains three double bonds and one, two, three, or four nitrogen atoms. Representative examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl group consists of a monocyclic heteroaryl group fused to a phenyl group, or a monocyclic heteroaryl group fused to a monocyclic cycloalkyl group, or a monocyclic heteroaryl group fused to a monocyclic cycloalkenyl group, or a monocyclic heteroaryl group fused to a monocyclic heteroaryl group, or a monocyclic heteroaryl group fused to a monocyclic heterocyclyl group. Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl, 6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl, 6,7-dihydro-1,3-benzothiazolyl, imidazolyl, benzothia ... oxazolo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl and 5,6,7,8-tetrahydroquinolin-5-yl. Monocyclic and bicyclic heteroaryl groups can be substituted or unsubstituted and are attached to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained in the ring system. The nitrogen atom in the heteroaryl ring can be optionally oxidized and can be optionally quaternized.

As used herein, the term "heteroatom" refers to nitrogen, oxygen, and sulfur.

As used herein, the term "oxo" refers to =0.

If a group is described as "substituted," a non-hydrogen group is in the place of any substitutable hydrogen atom of the group. Thus, for example, a substituted heterocyclyl is a heterocyclyl group in which at least one non-hydrogen group replaces a hydrogen atom of the heterocyclyl group. It should be understood that if more than one substitution occurs on a group, the non-hydrogen groups may be the same or different (unless otherwise specified).

If a group is described as "optionally substituted," the group can be (1) unsubstituted or (2) substituted. If a group is said to be optionally substituted with up to a certain number of non-hydrogen groups, the group can be: (1) unsubstituted; or (2) substituted with up to the certain number of non-hydrogen groups, or with up to the maximum number of non-hydrogen substituents at the substitutable positions on the group, whichever is less. Thus, for example, if a group is described as being optionally substituted with up to three non-hydrogen groups, any heteroaryl group having fewer than three substitutable positions can be optionally substituted with up to as many non-hydrogen groups as the heteroaryl group has substitutable positions. For example, a tetrazolyl group (which has only one substitutable position) can be optionally substituted with up to one non-hydrogen group. As another example, if an amino nitrogen is described as being optionally substituted with up to two non-hydrogen groups, a primary amino nitrogen can be optionally substituted with up to two non-hydrogen groups, while a secondary amino nitrogen can be optionally substituted with only one non-hydrogen group.

The terms "treat," "treating," and "treatment" refer to a method of alleviating or eliminating a disease and/or its attendant symptoms.

The terms "prevent," "preventing," and "prevention" refer to methods of preventing the onset of a disease and/or its attendant symptoms or of inhibiting a subject from developing the disease. As used herein, "prevention" also includes delaying the onset of a disease and/or its attendant symptoms and reducing the risk of a subject developing the disease.

The phrase "therapeutically effective amount" refers to an amount of a compound or a pharmaceutically acceptable salt thereof, which, when administered alone or in combination with another pharmaceutical agent to treat a specific subject or population of subjects, is sufficient to prevent the development of or alleviate to some extent one or more symptoms of the disease or condition being treated. For example, in humans or other mammals, for a particular disease and subject being treated, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or can be an amount required by the guidelines of the U.S. Food and Drug Administration or equivalent foreign agencies.

The term "individual" or "subject" is defined herein as referring to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In preferred embodiments, the individual or subject is a human.

b. Compounds

The compounds of the present invention have the general formula (I) as described above.

Specific values for the variables in the compounds of formula (I) are as follows. Such values may be used, where appropriate, with any other values, definitions, claims or embodiments defined above or below.

In certain embodiments of Formula (I), Y ¹ is N or CH.

In certain embodiments Y ¹ is N.

In certain embodiments Y ¹ is CH.

In certain embodiments of formula (I), R ¹ is CD ₃ , C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl.

In certain embodiments, R ¹ is C ₁ -C ₃ alkyl. In some such embodiments, R ¹ is methyl.

In certain embodiments of formula (I), R ² is H or C ₁ -C ₃ alkyl.

In certain embodiments ^R2 is H or methyl.

In certain embodiments ^R2 is H.

In certain embodiments, R ² is C ₁ -C ₃ alkyl. In some such embodiments, R ² is methyl.

In certain embodiments of Formula (I), Y ³ is N or CR ³ .

In certain embodiments Y ³ is N.

In certain embodiments Y ³ is CR ³ .

In certain embodiments of formula (I), R ³ is H, -CN, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c , -S(O)R ^3d , -S(O) ₂ R ^3a , -S(O) ₂ NR ^3b R ^3c , or G ¹ ; wherein each of the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl is independently unsubstituted or substituted with one or two substituents independently selected from G ¹ , -CN, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c , -C(O)N(R ^3b )NR ^3b R ^3c , -S(O)R ^3d , -S(O) ₂ R ^3a , -S(O) ₂ NR ^3b R ^3c , -OR ^3a , -OC(O)R ^3d , -NR ^3b R ^3c ,N(R ^3b )C(O)R ^3d ,N(R ^3b )SO ₂ R ^3d , N(R ^3b )C(O)OR ^3d , N(R ^3b )C(O)NR ^3b R ^3c , N(R ^3b )SO ₂ NR ^3b R ^3c and N(R ^3b )C(NR ^3b R ^3c )=NR ^3b R ^3c .

In certain embodiments, R ³ is H, -CN, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c or C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with a substituent selected from the group consisting of G ¹ , -NR ^3b R ^3c , N(R ^3b )C(O)R ^3d , N(R ^3b )SO ₂ R ^3d , N(R ^3b )C(O)OR ^3d , N(R ^3b )C(O)NR ^3b R ^3c and N(R ^3b )SO ₂ NR ^3b R ^3c . In some such embodiments, the G ¹ group is an optionally substituted heterocyclyl. In some such embodiments, the C ₁ -C ₆ alkyl group is substituted with a G ¹ group, wherein the G ¹ group is piperidinyl, piperazinyl, or morpholinyl, each of which is optionally substituted with 1 or 2 C ₁ -C ₆ alkyl groups. In some such embodiments, the C ₁ -C ₆ alkyl group is substituted with a G ¹ group, wherein the G ¹ group is piperazinyl or morpholinyl, each of which is optionally substituted with 1 or 2 C ₁ -C ₆ alkyl groups.

In certain embodiments, R ³ is H, -C(O)NR ^3b R ^3c , -CN, or C ₁ -C ₆ alkyl, which is substituted by a G ¹ group. In some such embodiments, the C ₁ -C ₆ alkyl is substituted by a G ¹ group, wherein the G ¹ group is an optionally substituted C ₄ -C ₆ heterocyclyl. In some such embodiments, the C ₁ -C ₆ alkyl is substituted by a G ¹ group, wherein the G ¹ group is piperidinyl, piperazinyl, or morpholinyl, each of which is optionally substituted by 1 or 2 C ₁ -C ₆ alkyl groups.

In certain embodiments, R ^3a is H, -C(O)R ^3a , or -C(O)NR ^3b R ^3c . In some such embodiments, R ^3a is G ^1. In some such embodiments, R ^3a is G ¹ wherein G ¹ is optionally substituted heterocyclyl. In some such embodiments, R ^3a is G ¹ wherein G ¹ is piperidinyl, piperazinyl, or morpholinyl, each of which is optionally substituted with 1 or 2 C ₁ -C ₆ alkyl. In some such embodiments, R ^3a is G ¹ wherein G ¹ is piperazinyl, optionally substituted with 1 or 2 C ₁ -C ₆ alkyl.

In certain embodiments, R ³ is H or -C(O)NR ^3b R ^3c . In some such embodiments, R ^3b and R ^3c are each independently H or C ₁ -C ₆ alkyl.

In certain embodiments R ³ is H.

In certain embodiments, R ³ is -C(O)NR ^3b R ^3c . In some such embodiments, R ^3b and R ^3c are each independently H or C ₁ -C ₃ alkyl.

In certain embodiments, R ³ is G ¹ . In some such embodiments, G ¹ is optionally substituted monocyclic heteroaryl. In some such embodiments, G ¹ is optionally substituted pyrazolyl. In some such embodiments, G ¹ is pyrazolyl substituted with 1 or 2 C ₁ -C ₆ alkyl groups.

In certain embodiments of Formula (I), Y ² is C(O), S(O) ₂ or CR ⁴ R ⁵ .

In certain embodiments, Y ² is C(O).

In certain embodiments, Y ² is S(O) ₂ .

In certain embodiments, Y ² is CR ⁴ R ⁵ .

In certain embodiments of formula (I), R ⁴ is H, deuterium, C ₁ -C ₆ alkyl, halogen, or C ₁ -C ₆ haloalkyl.

In certain embodiments, R ⁴ is H or deuterium.

In certain embodiments, ^R4 is H.

In certain embodiments of Formula (I), R ⁵ is H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -S(O)R ^5d , -S(O) ₂ R ^5a , -S(O) ₂ NR ^5b R ^5c , or G ¹ ; wherein each of the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl is independently unsubstituted or substituted with one or two substituents independently selected from G ¹ , -CN, -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -C(O)N(R ^5b )NR ^5b R ^5c , -S(O)R ^5d , -S(O) ₂ R ^5a , -S(O) ₂ NR ^5b R ^5c , -OR ^5a , -OC(O)R ^5d , -NR ^5b R ^5c ,N(R ^5b )C(O)R ^5d ,N(R ^5b )SO ₂ R ^5d , N(R ^5b )C(O)OR ^5d , N(R ^5b )C(O)NR ^5b R ^5c , N(R ^5b )SO ₂ NR ^5b R ^5c and N(R ^5b )C(NR ^5b R ^5c )=NR ^5b R ^5c .

In certain embodiments, R ⁵ is H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, -C(O)R ^5a , -C(O)OR ^5a , or G ¹ ; wherein each of the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ¹ , -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -C(O)N(R ^5b )NR ^5b R ^5c , -OR ^5a , -OC(O)R ^5d , -NR ^5b R ^5c , N(R ^5b )C(O)R ^5d , N(R 5b ) ^5b )SO ₂ R ^5d , N(R ^5b )C(O)OR ^5d , N(R ^5b )C(O)NR ^5b R ^5c and N(R ^5b )SO ₂ NR ^5b R ^5c .

In certain embodiments, R ⁵ is C ₂ -C ₆ alkenyl optionally substituted by a G ¹ group, or R ⁵ is H, deuterium, C ₁ -C ₆ alkyl, -C(O)R ^5a , -C(O)OR ^5a , or G ¹ ; wherein the C ₁ -C ₆ alkyl is unsubstituted or substituted with a substituent selected from the group consisting of G ¹ , -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -C(O)N(R ^5b )NR ^5b R ^5c , -OR ^5a , -OC(O)R ^5d , -NR ^5b R ^5c , and N(R ^5b )C(NR ^5b R ^5c )═NR ^5b R ^5c .

In certain embodiments R ⁵ is H, deuterium, or C ₁ -C ₆ alkyl optionally substituted with a substituent selected from: -C(O)OR ^5a and OR ^5a . In some such embodiments, R ^5a is C ₁ -C ₆ alkyl.

In certain embodiments R ⁵ is H.

In certain embodiments of formula (I), ^R6 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, halogen, _C1 - _C6 haloalkyl, -C(O) ^R6a , -C(O)OR6a, -C(O) ^NR6bR6c , -S( _O ) ^2R6a , -S( _O ) ^2NR6bR6c , or ^{G2 ;} wherein said _C1 - _C6 alkyl, C2 _{- C6} alkenyl and _C2 - _C6 alkynyl are each independently unsubstituted or substituted with ¹ or 2 substituents independently selected from ^G2 , -CN, -C ⁽ O) ^R6a , -C(O) ^{OR6a, -C(O)NR6bR6c ,} -C(O) ^N ( ^R6b ) ^{NR6bR 6c} , -S(O)R ^6d , -S(O) ₂ R ^6a , -S(O) ₂ NR ^6b R ^6c , -OR ^6a , -OC(O)R ^6d , -NR ^6b R ^6c ,N(R ^6b )C(O)R ^6d ,N(R ^6b )SO ₂ R ^6d ,N(R ^6b )C(O)OR ^6d , N(R ^6b )C(O)NR ^6b R ^6c , N(R ^6b )SO ₂ NR ^6b R ^6c and N(R ^6b )C(NR ^6b R ^6c )=NR ^6b R ^6c .

In certain embodiments, R ⁶ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , -S(O) ₂ R ^6a , or G ² ; wherein the C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ² , -CN, -C(O)OR ^6a , -NR ^6b R ^6c , N(R ^6b )C(O)R ^6d , N(R ^6b )SO ₂ R ^6d , N(R ^6b )C(O)OR ^6d , N(R ^6b )C(O)NR ^6b R ^6c , and N(R ^6b )SO ₂ NR ^6b R ^6c .

In certain embodiments, R ⁶ is H, C ₁ -C ₆ alkyl, -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , -S(O) ₂ R ^6a , or G ² ; wherein the C ₁ -C ₆ alkyl is unsubstituted or substituted with a substituent selected from the group consisting of G ² and -C(O)OR ^6a .

In certain embodiments, R ⁶ is -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , G ² or C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a G ² group. In certain embodiments, R ^6a is G ² or unsubstituted C ₁ -C ₆ alkyl.

In certain embodiments, R ⁶ is -C(O)OR ^6a . In some such embodiments, R ^6a is C ₁ -C ₆ alkyl.

In certain embodiments, ^R is ^G or _C - _C alkyl, which is unsubstituted or substituted with a ^G group. In some such embodiments, ^R is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted _cycloalkyl ; or ^R is C- _C alkyl, which is unsubstituted or substituted with a substituent selected from heteroaryl, cycloalkyl, and heterocyclyl, each of which is optionally substituted. In some such embodiments, ^R is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted _{cycloalkyl; or R is C-C} ^alkyl _, which is unsubstituted or substituted with a substituent selected from cycloalkyl and heterocyclyl, each of which is optionally substituted. In some such embodiments, R ⁶ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazolyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or azepanyl, each of which is optionally substituted, or R ⁶ is C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a G ¹ group, wherein the G ¹ group is cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolane or pyrazolyl, each of which is optionally substituted. In some such embodiments, R ⁶ is optionally substituted phenyl, optionally substituted pyridinyl or optionally substituted cyclohexyl; or R ⁶ is C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a substituent selected from cyclopropyl and tetrahydrofuran, each of which is optionally substituted. In some such embodiments, the optional substituents are independently selected from halogen, -O(C ₁ -C ₃ alkyl), -O(C ₁ -C ₃ haloalkyl), -N(H)C(O)O(C ₁ -C ₆ alkyl), C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl. In some such embodiments, the optional substituents are halogen. In some such embodiments, the halogen is F or Cl.

In certain embodiments of Formula (I), ^A1 is C( ^R7 ) or N; ^A2 is C( ^R8 ) or N; ^A3 is C( ^R9 ) or N; and ^A4 is C( ^R10 ) or N; wherein zero, one, or two of ^A1 , ^A2 , ^A3 , and ^A4 are N.

In certain embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In certain embodiments, one of A ¹ , A ² , A ³ , and A ⁴ is N. In some such embodiments, A ¹ is N; A ² is C(R ⁸ ); A ³ is C(R ⁹ ); and A ⁴ is C(R ¹⁰ ).

In certain embodiments, two of A ¹ , A ² , A ³ , and A ⁴ are N. In some such embodiments, A ¹ is N; A ² is C(R ⁸ ); A ³ is N; and A ⁴ is C(R ¹⁰ ).

In certain embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N; ^A2 is C( ^R8 ); ^A3 is C(R9); and ^A4 is C( ^R10 ); or ^A1 is N; ^A2 is C( ^R8 ); ^A3 is N; and ^{A4 is} C( ^R10 ).

In certain embodiments of formula (I), R ⁷ , R ⁸ and R ⁹ are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , -OR ^y1 , -OC(O)R ^y2 , -OC(O)NR ^y3 R ^y4 , -SR ^y1 , -S(O) ₂ R ^y1 , -S(O) ₂ NR ^y3 R ^y4 , -C(O)R ^y1 , -C(O)OR ^y1 , -C(O)NR ^y3 R ^y4 , -NR ^y3 R ^y4 , -N(R ^y3 )C(O)R ^y2 , -N(R ^y3 )S(O) ₂ R ^y2 , -N(R ^y3 )C(O)O(R ^y2 ), -N(R ^y3 )C(O)NR ^y3 R ^y4 , -N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 , G ³ , -(C ₁ -C ₆ alkylene)-CN, -(C ₁ -C ₆ alkylene)-OR ^y1 , -(C ₁ -C ₆ alkylene)-OC(O)R ^y2 , -(C ₁ -C ₆ alkylene)-OC(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-C(O)R ^y1 , -(C ₁ -C _y3 )C(O)O( ^{R y2 )} , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)OR ^y1 , -(C ₁ -C ₆ alkylene)-C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O) _R y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) 2 R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R y2 ), -(C 1 -C 6 alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-CN or -(C ₁ -C ₆ alkylene)-G ³ .

In certain embodiments, R ⁷ is H, halogen, —CN, C ₁ -C ₃ alkyl, or optionally substituted cyclopropyl.

In certain embodiments, R ⁷ is H, halogen, C ₁ -C ₃ alkyl, or optionally substituted cyclopropyl. In some such embodiments, the cyclopropyl is optionally substituted with 1, 2, 3, 4, or 5 R ^4g groups, wherein R ^4g is C ₁ -C ₃ alkyl, halogen, or C ₁ -C ₃ haloalkyl.

In certain embodiments, R ⁷ is H or halogen. In some such embodiments, halogen is F or Cl. In some such embodiments, halogen is F.

In certain embodiments, ^R8 is H, _C1 - _C6 alkyl, halogen, _C1 - _C6 haloalkyl, -CN, optionally substituted heterocyclyl, -C(O) ^NRy3Ry4 , -( _C1 - _C6 alkylene) ^-NRy3Ry4 , -(C1- _C6 alkylene) ^-N ( ^Ry3 )C(O) ^Ry2 , -( _C1 - _C6 alkylene)-N( ^Ry3 )S(O) ^2Ry2 , -( _C1 - _C6 alkylene) ^-N ( ^Ry3 ₎ C(O) ^O ( ^Ry2 ), -( _C1 - _C6 alkylene)-N( ^Ry3 )C(O ₎ ^NRy3Ry4 , -( _C1 - _C6 ^alkylene )-N( ^Ry3 )S(O) _2NRy3 R ^y4 or -(C ₁ -C ₆ alkylene)-G ³ , wherein G ³ is an optionally substituted heterocyclic group.

In certain embodiments ^R8 is H.

In certain embodiments, R ⁹ is H, C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, -CN, -S(O) ₂ R ^y1 , -S(O) ₂ NR ^y3 R ^y4 , -C(O)NR ^y3 R ^y4 , -NR ^y3 R ^y4 , -N(R ^y3 )C(O)R ^y2 , -N(R ^y3 )S(O) ₂ R ^y2 , -N(R ^y3 )C(O)O(R ^y2 ), -N(R ^y3 )C(O)NR ^y3 R ^y4 , -N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-CN, -(-(C ₁ -C ₆ alkylene)-S(O) ₂ R ^{y1 y3} )C(O)R _y2 , -(C ₁ -C ₆ alkylene) ^-N (R y3 )C(O)O(R ^{y2 )} , -(C ₁ -C ₆ alkylene)-N( _R y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R y3 )C( ^O )R y2 _, -(C 1 -C 6 alkylene)-N(R y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 or -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 .

In certain embodiments R ⁹ is H, C ₁ -C ₆ alkyl, halogen, -S(O) ₂ R ^y1 , -S(O) ₂ NR ^y3 R ^y4 , -NR ^y3 R ^y4 , -N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-CN, or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 .

In certain embodiments, R ⁹ is H, C ₁ -C ₆ alkyl, halogen, -S(O) ₂ R ^y1 , -S(O) ₂ NR ^y3 R ^y4 , -NR ^y3 R ^y4 , -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 . In some such embodiments, R ^y1 , R ^y3 and R ^y4 are each independently H or C ₁ -C ₆ alkyl, and R ^y2 is C ₁ -C ₆ alkyl. In some such embodiments, R ^y1 and R ^y2 are C ₁ -C ₃ alkyl, and R ^y3 and R ^y4 are hydrogen.

In certain embodiments, R ⁹ is halogen, -NR ^y3 R ^y4 , -N(R ^y3 )C(O)R ^y2 , -N(R ^y3 )S(O) ₂ R ^y2 , or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 .

In certain embodiments, R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 . In some such embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl and R ^y3 is H. In some such embodiments, halogen is F. In some such embodiments, R ^y1 and R ^y2 are each independently methyl or ethyl, and R ^y3 is H.

In certain embodiments, R ⁹ is -(CH ₂ )-S(O) ₂ R ^y1 . In some such embodiments, R ^y1 is C ₁ -C ₆ alkyl. In some such embodiments, R ^y1 is methyl.

In certain embodiments of formula (I), R ¹⁰ is H, C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ haloalkyl, or —CN.

In certain embodiments, R ¹⁰ is H, C ₁ -C ₃ alkyl, or halogen.

In certain embodiments R ¹⁰ is H.

Various embodiments of the substituents R ¹ , R ² , R ⁶ , Y ¹ , Y ² , Y ³ , A ¹ , A ² , A ³ and A ⁴ have been discussed above. These substituent embodiments can be combined to form various embodiments of the compounds of formula (I). All embodiments of the compounds of formula (I) formed by combining the substituent embodiments discussed above are within the scope of the applicant's invention, and some illustrative embodiments of the compounds of formula (I) are provided below.

In certain embodiments,

Y ¹ is CH;

Y ³ is CR ³ ; and

Y ² is CR ⁴ R ⁵ .

In certain embodiments,

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ; and

R ³ is H, -CN, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c or C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with a substituent selected from the group consisting of G ¹ , -NR ^3b R ^3c , N(R ^3b )C(O)R ^3d , N(R ^3b )SO ₂ R ^3d , N(R ^3b )C(O)OR ^3d , N(R ^3b )C(O)NR ^3b R ^3c and N(R ^3b )SO ₂ NR ^3b R ^3c .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C(R8), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^{A4 is C(R10 )} .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^R4 is H or deuterium; and

R ⁵ is H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, -C(O)R ^5a , -C(O)OR ^5a or G ¹ ; wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ¹ , -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -C(O)N(R ^5b )NR ^5b R ^5c , -OR ^5a , -OC(O)R ^5d , -NR ^5b R ^5c , N(R ^5b )C(O)R ^5d , N(R ^5b )SO ₂ R ^5d , N(R ^5b )C(O)OR ^5d , N(R ^5b )C(O)NR ^5b R ^5c and N(R ^5b )SO ₂ NR ^5b R ^5c .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C(R8), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^{A4 is C(R10 )} .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ; and

R ⁶ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , -S(O) ₂ R ^6a or G ² ; wherein the C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ² , -CN, -C(O)OR ^6a , -NR ^6b R ^6c , N(R ^6b )C(O)R ^6d , N(R ^6b )SO ₂ R ^6d , N(R ^6b )C(O)OR ^6d , N(R ^6b )C(O)NR ^6b R ^6c and N(R ^6b )SO ₂ NR ^6b R ^6c .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C(R8), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^{A4 is C(R10 )} .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ; and

R ⁹ is H, C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, -CN, -S(O) ₂ R ^y1 , -S(O) ₂ NR ^y3 R ^y4 , -C(O)NR ^y3 R ^y4 , -NR ^y3 R ^y4 , -N(R ^y3 )C(O)R ^y2 , -N(R ^y3 )S(O) ₂ R ^y2 , -N(R ^y3 )C(O)O(R ^y2 ), -N(R ^y3 )C(O)NR ^y3 R ^y4 , -N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 or -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C(R8), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^{A4 is C(R10 )} .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ; and

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

^R1 is _C1 - _C3 alkyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ; and

Y ² is CR ⁴ R ⁵ .

In some further embodiments, R ¹ is methyl.

In certain embodiments,

^R1 is _C1 - _C3 alkyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^R4 is H or deuterium; and

R ⁵ is C ₂ -C ₆ alkenyl optionally substituted by a G ¹ group, or R ⁵ is H, deuterium, C ₁ -C ₆ alkyl, -C(O)R ^5a , -C(O)OR ^5a or G ¹ ; wherein the C ₁ -C ₆ alkyl is unsubstituted or substituted with a substituent selected from the group consisting of G ¹ , -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -C(O)N(R ^5b )NR ^5b R ^5c , -OR ^5a , -OC(O)R ^5d , -NR ^5b R ^5c and N(R ^5b )C(NR ^5b R ^5c )═NR ^5b R ^5c .

In some further embodiments, R ¹ is methyl.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C(R8), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^{A4 is C(R10 )} .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

^R1 is _C1 - _C3 alkyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ; and

R ³ is H; -C(O)R ^3a or -C(O)NR ^3b R ^3c .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C(R8), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^{A4 is C(R10 )} .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, A1 is N, A2 is C(R8), A3 is C(R9) and A4 is C(R10).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ¹ is methyl.

In some further embodiments, R ¹ is methyl and R ^3a is G ¹ .

In yet further embodiments, R ¹ is methyl, R ^3a is G ¹ , wherein G ¹ is optionally substituted heterocyclyl.

In certain embodiments,

^R1 is _C1 - _C3 alkyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ; and

^R6 is H, _C1 - _C6 alkyl, -C(O) ^R6a , -C(O) ^OR6a , -C(O) ^NR6bR6c , -S(O) _2R6a ^{or G2} ; wherein the _C1 - _C6 alkyl is unsubstituted or substituted with a substituent selected ^{from G2} and -C(O) ^OR6a .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C(R8), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^{A4 is C(R10 )} .

In some further embodiments, R ¹ is methyl.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

^R1 is _C1 - _C3 alkyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ; and

^R9 is H, _C1 - _C6 alkyl, halogen, -S(O) _2Ry1 , -S(O ₎ ^2NRy3Ry4 , ^-NRy3Ry4 , -N ^{( Ry3} ) ^S (O ⁾ _2Ry2 ^, or ^- ( _C1 - _C6 alkylene)-S(O) _2Ry1 .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C(R8), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^{A4 is C(R10 )} .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ¹ is methyl.

In certain embodiments,

^R1 is _C1 - _C3 alkyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ; and

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In yet further embodiments, R ¹ is methyl.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

R ⁷ is H, halogen, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H, C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, -CN, optionally substituted heterocyclyl, -C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 or -(C ₁ -C ₆ alkylene)-G ³ , wherein G ³ is an optionally substituted heterocyclyl; and

R ¹⁰ is H, C ₁ -C ₃ alkyl or halogen.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In one embodiment, the present invention relates to compounds of formula (I), wherein

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

R ⁷ is H, halogen, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H, C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, -CN, optionally substituted heterocyclyl, -C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 or -(C ₁ -C ₆ alkylene)-G ³ , wherein G ³ is an optionally substituted heterocyclyl;

R ¹⁰ is H, C ₁ -C ₃ alkyl or halogen; and

R ³ is H or -C(O)NR ^3b R ^3c .

In some further embodiments, R ^3b and R ^3c are each independently H or C ₁ -C ₆ alkyl.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In one embodiment, the present invention relates to compounds of formula (I), wherein

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

R ⁷ is H, halogen, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H, C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, -CN, optionally substituted heterocyclyl, -C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 or -(C ₁ -C ₆ alkylene)-G ³ , wherein G ³ is an optionally substituted heterocyclyl;

R ¹⁰ is H, C ₁ -C ₃ alkyl or halogen; and

R ⁵ is H, deuterium, or C ₁ -C ₆ alkyl optionally substituted with a substituent selected from the group consisting of —C(O)OR ^5a and OR ^5a .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In yet further embodiments, R ^5a is C ₁ -C ₆ alkyl.

In one embodiment, the present invention relates to compounds of formula (I), wherein

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

R ⁷ is H, halogen, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H, C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, -CN, optionally substituted heterocyclyl, -C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 or -(C ₁ -C ₆ alkylene)-G ³ , wherein G ³ is an optionally substituted heterocyclyl;

R ¹⁰ is H, C ₁ -C ₃ alkyl or halogen; and

R ⁶ is —C(O)R ^6a , —C(O)OR ^6a , —C(O)NR ^6b R ^6c , G ² or C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a G ² group.

In some further embodiments, R ^6a is G ² or unsubstituted C ₁ -C ₆ alkyl.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In one embodiment, the present invention relates to compounds of formula (I), wherein

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

R ⁷ is H, halogen, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H, C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, -CN, optionally substituted heterocyclyl, -C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 or -(C ₁ -C ₆ alkylene)-G ³ , wherein G ³ is an optionally substituted heterocyclyl;

R ¹⁰ is H, C ₁ -C ₃ alkyl or halogen; and

R ⁹ is halogen, -NR ^y3 R ^y4 , -N(R ^y3 )C(O)R ^y2 , -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 .

In some further embodiments, A ¹ is C(R ⁷ ), A ² is C(R ⁸ ), A ³ is C(R ⁹ ) and A ⁴ is C(R ¹⁰ );

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

^R7 is H or halogen;

^R8 is H; and

^R10 is H.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ); and

^R4 is H or deuterium;

^R7 is H or halogen;

R ⁸ is H;

^R10 is H; and

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 .

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl and R ^y3 is H.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

^R7 is H or halogen;

R ⁸ is H;

R ¹⁰ is H;

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ; and

R ⁶ is —C(O)R ^6a , —C(O)OR ^6a , —C(O)NR ^6b R ^6c , G ² or C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a G ² group.

In some further embodiments, R ^6a is G ² or unsubstituted C ₁ -C ₆ alkyl.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl and R ^y3 is H.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

^R7 is H or halogen;

R ⁸ is H;

R ¹⁰ is H;

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ;

^R6 is -C(O ^{) R6a} , -C(O) ^OR6a , -C(O) ^NR6bR6c , ^G2 or _C1 - _C6 alkyl, which is unsubstituted or substituted with a ^G2 group; and

R ⁵ is H, deuterium, or C ₁ -C ₆ alkyl optionally substituted with a substituent selected from the group consisting of —C(O)OR ^5a and OR ^5a .

In some further embodiments, R ^6a is G ² or unsubstituted C ₁ -C ₆ alkyl.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl and R ^y3 is H.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

^R7 is H or halogen;

R ⁸ is H;

R ¹⁰ is H;

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ;

R ⁶ is -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , G ² or C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a G ² group;

R ⁵ is H, deuterium, or C ₁ -C ₆ alkyl optionally substituted with a substituent selected from the group consisting of: -C(O)OR ^5a and OR ^5a ; and

R ³ is H or -C(O)NR ^3b R ^3c .

In some further embodiments, R ^6a is G ² or unsubstituted C ₁ -C ₆ alkyl.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

^R7 is H or halogen;

R ⁸ is H;

R ¹⁰ is H;

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ;

R ⁶ is -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , G ² or C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a G ² group;

R ⁵ is H, deuterium, or C ₁ -C ₆ alkyl optionally substituted with a substituent selected from the group consisting of: -C(O)OR ^5a and OR ^5a ;

R ³ is H or -C(O)NR ^3b R ^3c ;

R ^3b and R ^3c are each independently H or C ₁ -C ₆ alkyl;

R ^5a is C ₁ -C ₆ alkyl;

R ^y1 and R ^y2 are C ₁ -C ₆ alkyl; and

R ^y3 is H.

In some further embodiments, R ^6a is G ² or unsubstituted C ₁ -C ₆ alkyl.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

^R4 is H or deuterium;

^R7 is H or halogen;

R ⁸ is H;

R ¹⁰ is H;

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ;

R ⁶ is G ² or C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a G ² group;

R ⁵ is H, deuterium, or C ₁ -C ₆ alkyl optionally substituted with a substituent selected from the group consisting of: -C(O)OR ^5a and OR ^5a ;

R ³ is H or -C(O)NR ^3b R ^3c ;

R ^3b and R ^3c are each independently H or C ₁ -C ₆ alkyl;

R ^5a is C ₁ -C ₆ alkyl;

R ^y1 and R ^y2 are C ₁ -C ₆ alkyl; and

R ^y3 is H.

In some further embodiments, R ⁶ is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl; or R ⁶ is C ₁ -C ₆ alkyl, which is unsubstituted or substituted with a substituent selected from cycloalkyl and heterocyclyl, each of which is optionally substituted.

In some further embodiments, R ⁶ is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted pyridinyl, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with a G ² group, wherein G ² is cyclopropyl or tetrahydrofuranyl, each of which is optionally substituted.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

R ³ is H, -C(O)NR ^3b R ^3c , -CN, or a C ₁ -C ₆ alkyl group substituted by a G ¹ group; wherein G ¹ is an optionally substituted C ₄ -C ₆ heterocyclyl group;

^R4 is H or deuterium;

R ⁷ is H, halogen, -CN, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl.

R ⁸ is H;

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ; and

^R10 is H.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^3b is H or C ₁ -C ₆ alkyl; and R ^3c is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, G ¹ , or -(C ₁ -C ₆ alkylene)-G ¹ .

In some further embodiments, R ^3b and R ^3c are each independently H or C ₁ -C ₆ alkyl.

In some further embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl; and R ^y3 is H.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

R ³ is H, -C(O)NR ^3b R ^3c , -CN, or a C ₁ -C ₆ alkyl group substituted by a G ¹ group; wherein G ¹ is an optionally substituted C ₄ -C ₆ heterocyclyl group;

^R4 is H or deuterium;

R ⁷ is H, halogen, -CN, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H;

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ;

^R10 is H; and

^R5 is H.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^3b and R ^3c are each independently H or C ₁ -C ₆ alkyl.

In some further embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl; and R ^y3 is H.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

R ³ is H, -C(O)NR ^3b R ^3c , -CN, or a C ₁ -C ₆ alkyl group substituted by a G ¹ group; wherein G ¹ is an optionally substituted C ₄ -C ₆ heterocyclyl group;

^R4 is H or deuterium;

R ⁷ is H, halogen, -CN, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H;

R ⁹ is halogen, -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ;

R ¹⁰ is H;

^R5 is H; and

R ⁶ is phenyl, pyridyl, or cyclohexyl; each of which is optionally substituted; or R ⁶ is -C(O)O(C ₁ -C ₆ alkyl); or R ⁶ is -CH ₂ -(optionally substituted tetrahydropyranyl).

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^3b and R ^3c are each independently H or C ₁ -C ₆ alkyl.

In some further embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl; and R ^y3 is H.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

R ³ is G ¹ ;

^R4 is H or deuterium;

R ⁷ is H, halogen, -CN, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H;

R ⁹ is -S(O) ₂ R ^y1 , -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ; and

^R10 is H.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl; and R ^y3 is H.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

R ³ is G ¹ ; wherein G ¹ is optionally substituted heteroaryl;

^R4 is H or deuterium;

R ⁷ is H, halogen, -CN, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H;

R ⁹ is -S(O) ₂ R ^y1 , -N(R ^y3 )S(O) ₂ R ^y2 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 ;

^R10 is H; and

^R5 is H.

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^y1 and R ^y2 are C ₁ -C ₆ alkyl; and R ^y3 is H.

In certain embodiments,

^R1 is methyl;

^R2 is H;

Y ¹ is CH;

Y ³ is CR ³ ;

Y ² is CR ⁴ R ⁵ ;

^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ); or

^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 );

R ³ is G ¹ ; wherein G ¹ is optionally substituted pyrazolyl;

^R4 is H or deuterium;

R ⁷ is H, halogen, -CN, C ₁ -C ₃ alkyl or optionally substituted cyclopropyl;

R ⁸ is H;

R ⁹ is -S(O) ₂ R ^y1 ;

R ¹⁰ is H;

^R5 is H; and

R ⁶ is phenyl, pyridyl, or cyclohexyl; each of which is optionally substituted; or R ⁶ is -C(O)O(C ₁ -C ₆ alkyl); or R ⁶ is -CH ₂ -(optionally substituted tetrahydropyranyl).

In some further embodiments, ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ).

In some further embodiments, ^A1 is N, ^A2 is C( ^R8 ), ^A3 is N and ^A4 is C( ^R10 ).

In some further embodiments, R ^y1 is C ₁ -C ₆ alkyl.

In certain embodiments,

^Y1 is N or CH;

R ¹ is CD ₃ , C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl;

^R2 is H or C1 _{- C3} alkyl;

Y ³ is N or CR ³ ;

R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c , -S(O)R ^3d , -S(O) ₂ R ^3a , -S(O) ₂ NR ^3b R ^3c or G ¹ ; wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ¹ , -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c , -C(O)N(R ^3b )NR ^3b R ^3c , -S(O)R ^3d , -S(O) ₂ R ^3a , -S(O) ₂ NR ^3b R ^3c , -OR ^3a , -OC(O)R ^3d , -NR ^3b R ^3c ,N(R ^3b )C(O)R ^3d ,N(R ^3b )SO ₂ R ^3d ,N(R ^3b )C(O)OR ^3d , N(R ^3b )C(O)NR ^3b R ^3c , N(R ^3b )SO ₂ NR ^3b R ^3c and N(R ^3b )C(NR ^3b R ^3c )=NR ^3b R ^3c ;

Y ² is C(O), S(O) ₂ or CR ⁴ R ⁵ ;

R ⁴ is H, deuterium, C ₁ -C ₆ alkyl, halogen or C ₁ -C ₆ haloalkyl;

R ⁵ is H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -S(O)R ^5d , -S(O) ₂ R ^5a , -S(O) ₂ NR ^5b R ^5c or G ¹ ; wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ¹ , -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -C(O)N(R ^5b )NR ^5b R ^5c , -S(O)R ^5d , -S(O) ₂ R ^5a , -S(O) ₂ NR ^5b R ^5c , -OR ^5a , -OC(O)R ^5d , -NR ^5b R ^5c , N(R ^5b )C(O)R ^5d ,N(R ^5b )SO ₂ R ^5d ,N(R ^5b )C(O)OR ^5d , N(R ^5b )C(O)NR ^5b R ^5c , N(R ^5b )SO ₂ NR ^5b R ^5c and N(R ^5b )C(NR ^5b R ^5c )=NR ^5b R ^5c ;

R ^3a , R ^3b , R ^3c , R ^5a , R ^5b and R ^5c are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ or -(C ₁ -C ₆ alkylene)-G ¹ ;

R ^3d and R ^5d are each independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ or -(C ₁ -C ₆ alkylene)-G ¹ ;

G ¹ at each occurrence is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ¹ is optionally substituted with 1, 2, 3, 4, or 5 R ^1g groups;

R ⁶ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , -S(O) ₂ R ^6a , -S(O) ₂ NR ^6b R ^6c or G ² ; wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ² , -C(O)R 6a , -C(O)OR 6a , -C(O)NR 6b R ^6c , -C(O)N(R ^6b )NR ^6b R ^6c , -S(O)R 6a , -S( ^O ) 2 NR ^6b R ^6c or G 2 ; ^6d 、-S(O) ₂ R ^6a 、-S(O) ₂ NR ^6b R ^6c 、-OR ^6a 、-OC(O)R ^6d 、-NR ^6b R ^6c 、N(R ^6b )C(O)R ^6d 、N(R ^6b )SO ₂ R ^6d 、N(R ^6b )C(O)OR ^6d , N(R ^6b )C(O)NR ^6b R ^6c , N(R ^6b )SO ₂ NR ^6b R ^6c and N(R ^6b )C(NR ^6b R ^6c )=NR ^6b R ^6c ;

R ^6a , R ^6b and R ^6c are each independently H, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, haloalkyl, G ² , -(C ₁ -C ₆ alkylene)-G ² , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

R ^6d is independently, at each occurrence, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, haloalkyl, G ² , -(C ₁ -C ₆ alkylene)-G ² , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C 6 ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

G ^2, at each occurrence, is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ² is optionally substituted with 1, 2, 3, 4, or 5 R ^2g groups;

^A1 is C( ^R7 ) or N; ^A2 is C( ^R8 ) or N; ^A3 is C( ^R9 ) or N; and ^A4 is C( ^R10 ) or N; wherein zero, one or two of ^A1 , ^A2 , ^A3 and ^A4 are N;

R ⁷ , R ⁸ and R ⁹ are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , -OR ^y1 , -OC(O)R ^y2 , -OC(O)NR ^y3 R ^y4 , -SR ^y1 , -S(O) ₂ R ^y1 , -S(O) ₂ NR ^y3 R ^y4 , -C(O)R ^y1 , -C(O)OR ^y1 , -C(O)NR ^y3 R ^y4 , -NR ^y3 R ^y4 , -N(R ^y3 )C(O)R ^y2 , -N(R ^y3 )S(O) ₂ R ^y2 , -N(R ^y3 )C(O)O(R ^y2 y1 、-(C ^{1 -C} 6 alkylene) ^{-C(O)R y2 、} -(C ₁ -C ₆ ^alkylene )-OC(O ⁾ NR y3 R ^y4 、-(C ₁ -C ₆ alkylene)-S(O) ² R ^y1 、-(C _{1 -C 6} alkylene)-S(O) ₂ NR ^{y3 R y4 、 -} (C ₁ -C ₆ alkylene)-C(O _{) R} ^y1 _、 -(C _{1 -C 6} alkylene)-C(O ⁾ OR ^y1 、-( _{C 1 -C 6 alkylene} )-C(O ⁾ -C ₁ -C 6 alkylene)-C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-CN or -(C ₁ -C ₆ alkylene)-G ³ ;

R ^y1 , R ^y3 and R ^y4 are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ³ , -(C ₁ -C ₆ alkylene)-G ³ , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C 6 alkylene)- ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O) _O (R ^{b )} , -(C ₁ -C ₆ alkylene)-N(R ^e ) ^C ( ^O )NR ^c R ^d , or -(C _{1 -C 6} alkylene)-N(R ^e )S( _{O) 2 NR} ^c R ^d ;

R ^y2 is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ³ , -(C ₁ -C ₆ alkylene)-G ³ , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

G ^3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclyl; and each G ³ group is optionally substituted with 1, 2, 3, 4, or 5 R ^4g groups;

R ¹⁰ is H, C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ haloalkyl or -CN;

R ^1g , R ^2g and R ^4g are independently selected at each occurrence from oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , G ^2a , -OR ^a , -OC(O)R ^b , -OC(O)NR ^c R ^d , -SR ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^c R ^d , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^c R ^d , -NR ^c R ^d , -N( ^Re )C(O)R ^b , -N( ^Re )S(O) ₂ ^{R b} , -N(Re)C(O)O(R ^b ), -N( ^Re )C(O)NR ^c R ^d -N(R ^e )S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-CN, -(C ₁ -C ₆ alkylene)-G ^2a , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-OC(O)R ^b , -(C ₁ -C ₆ alkylene)-OC(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C 6 alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C 1 -C ₆ alkylene)-S(O) ₂ R a _6alkylene )-NR ^c R ^d , -(C ₁ -C _6alkylene )-N(R ^e )C(O)R ^b , -(C ₁ -C _6alkylene )-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C _6alkylene )-N(R ^e )C(O)O(R ^b ), -(C ₁ -C _6alkylene )-N(R ^e )C(O)NR ^c R ^d , -(C ₁ -C _6alkylene )-N(R ^e )S(O) ₂ NR ^c R ^d , or -(C ₁ -C _6alkylene )-CN;

R ^a , R ^c , R ^d and R ^e are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ^2a or -(C ₁ -C ₆ alkylene)-G ^2a ;

R ^b, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ^2a or -(C ₁ -C ₆ alkylene)-G ^2a ;

Each occurrence of G ^2a is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ^2a group is optionally substituted with 1, 2, 3, 4, or 5 R ^3g groups;

R ^3g at each occurrence is independently oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , -OR ^z1 , -OC(O)R ^z2 , -OC(O)NR ^z3 R ^z4 , -SR ^z1 , -S(O) ₂ R ^z1 , -S(O) ₂ NR ^z3 R ^z4 , -C(O)R ^z1 , -C(O)OR ^z1 , -C(O)NR ^z3 R ^z4 , -NR ^z3 R ^z4 , -N(R ^z3 )C(O)R ^z2 , -N(R ^z3 )S(O) ₂ R ^z2 , -N(R ^z3 )C(O)O(R ^z2 ), -N(R ^z3 )C(O)NR ^z3 R ^z4 , -N(R ^z3 )S(O) ₂ NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-OR ^z1 , -(C ₁ -C ₆ alkylene)-OC(O)R ^z2 , -(C ₁ -C ₆ alkylene)-OC(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^z1 , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-C(O)R ^z1 , -(C ₁ -C ₆ alkylene)-C(O)OR ^z1 , -(C ₁ -C ₆ alkylene)-C(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-NR ^z3 R ^z4 , -(C ₁ -C -(C 1 -C ₆ alkylene)-N(R ^z3 )C(O)R ^z2 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )S(O) ₂ R ^z2 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )C(O)O(R ^z2 ), -(C ₁ -C ₆ alkylene)-N(R ^z3 )C(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )S(O) ₂ NR ^z3 R ^z4 or -(C ₁ -C ₆ alkylene)-CN;

R ^z1 , R ^z3 and R ^z4 are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ haloalkyl at each occurrence; and

R ^z2, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ haloalkyl.

In certain embodiments,

^Y1 is N or CH;

R ¹ is CD ₃ , C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl;

^R2 is H or C1 _{- C3} alkyl;

Y ³ is N or CR ³ ;

R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c , -S(O)R ^3d , -S(O) ₂ R ^3a , -S(O) ₂ NR ^3b R ^3c or G ¹ ; wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ¹ , -CN, -C(O)R ^3a , -C(O)OR ^3a , -C(O)NR ^3b R ^3c , -C(O)N(R ^3d )NR ^3b R ^3c , -S(O)R ^3d , -S(O) ₂ R ^3a , -S(O) ₂ NR ^3b R ^3c , -OR ^3a , -OC(O)R ^3d , -NR ^3b R ^3c , N(R ^3b )C(O)R ^3d ,N(R ^3b )SO ₂ R ^3d ,N(R ^3b )C(O)OR ^3d , N(R ^3b )C(O)NR ^3b R ^3c , N(R ^3b )SO ₂ NR ^3b R ^3c and N(R ^3b )C(NR ^3b R ^3c )=NR ^3b R ^3c ;

Y ² is C(O), S(O) ₂ or CR ⁴ R ⁵ ;

R ⁴ is H, deuterium, C ₁ -C ₆ alkyl, halogen or C ₁ -C ₆ haloalkyl;

R ⁵ is H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -S(O)R ^5d , -S(O) ₂ R ^5a , -S(O) ₂ NR ^5b R ^5c or G ¹ ; wherein said C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ¹ , -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^5b R ^5c , -C(O)N(R ^5b )NR ^5b R ^5c , -S(O)R ^5d , -S(O) ₂ R ^5a , -S(O) ₂ NR ^5b R ^5c , -OR ^5a , -OC(O)R ^5d , -NR ^5b R ^5c , N(R ^5b )C(O)R ^5d ,N(R ^5b )SO ₂ R ^5d ,N(R ^5b )C(O)OR ^5d , N(R ^5b )C(O)NR ^5b R ^5c , N(R ^5b )SO ₂ NR ^5b R ^5c and N(R ^5b )C(NR ^5b R ^5c )=NR ^5b R ^5c ;

R ^3a , R ^3b , R ^3c , R ^5a and R ^5b are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ or -(C ₁ -C ₆ alkylene)-G ¹ ;

R ^5c, at each occurrence, is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ , -(C ₁ -C ₆ alkylene)-G ¹ , -(C ₁ -C ₆ alkylene)-CN, -(C ₁ -C ₆ alkylene)-OR ^a , or -(C ₁ -C ₆ alkylene)-C(O)OR ^a ;

R ^3d, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ , or -(C ₁ -C ₆ alkylene)-G ¹ ;

R ^5d, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ¹ , -(C ₁ -C ₆ alkylene)-G ¹ , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b );

G ¹ at each occurrence is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ¹ is optionally substituted with 1, 2, 3, 4, or 5 R ^1g groups;

R ⁶ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -C(O)R ^6a , -C(O)OR ^6a , -C(O)NR ^6b R ^6c , -S(O) ₂ R ^6a , -S(O) ₂ NR ^6b R ^6c or G ² ; wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G ² , -C(O)R 6a , -C(O)OR 6a , -C(O)NR 6b R ^6c , -C(O)N(R ^6b )NR ^6b R ^6c , -S(O)R 6a , -S( ^O ) 2 NR ^6b R ^6c or G 2 ; ^6d 、-S(O) ₂ R ^6a 、-S(O) ₂ NR ^6b R ^6c 、-OR ^6a 、-OC(O)R ^6d 、-NR ^6b R ^6c 、N(R ^6b )C(O)R ^6d 、N(R ^6b )SO ₂ R ^6d 、N(R ^6b )C(O)OR ^6d , N(R ^6b )C(O)NR ^6b R ^6c , N(R ^6b )SO ₂ NR ^6b R ^6c and N(R ^6b )C(NR ^6b R ^6c )=NR ^6b R ^6c ;

R ^6a , R ^6b and R ^6c are each independently H, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, haloalkyl, G ² , -(C ₁ -C ₆ alkylene)-G ² , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

R ^6d is independently, at each occurrence, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, haloalkyl, G ² , -(C ₁ -C ₆ alkylene)-G ² , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C 6 ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

G ^2, at each occurrence, is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ² is optionally substituted with 1, 2, 3, 4, or 5 R ^2g groups;

^A1 is C( ^R7 ) or N; ^A2 is C( ^R8 ) or N; ^A3 is C( ^R9 ) or N; and ^A4 is C( ^R10 ) or N; wherein zero, one or two of ^A1 , ^A2 , ^A3 and ^A4 are N;

R ⁷ , R ⁸ and R ⁹ are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , -OR ^y1 , -OC(O)R ^y2 , -OC(O)NR ^y3 R ^y4 , -SR ^y1 , -S(O) ₂ R ^y1 , -S(O) ₂ NR ^y3 R ^y4 , -C(O)R ^y1 , -C(O)OR ^y1 , -C(O)NR ^y3 R ^y4 , -NR ^y3 R ^y4 , -N(R ^y3 )C(O)R ^y2 , -N(R ^y3 )S(O) ₂ R ^y2 , -N(R ^y3 )C(O)O(R ^y2 y1 、-(C ^{1 -C} 6 alkylene) ^{-C(O)R y2 、} -(C ₁ -C ₆ ^alkylene )-OC(O ⁾ NR y3 R ^y4 、-(C ₁ -C ₆ alkylene)-S(O) ² R ^y1 、-(C _{1 -C 6} alkylene)-S(O) ₂ NR ^{y3 R y4 、 -} (C ₁ -C ₆ alkylene)-C(O _{) R} ^y1 _、 -(C _{1 -C 6} alkylene)-C(O ⁾ OR ^y1 、-( _{C 1 -C 6 alkylene} )-C(O ⁾ -C ₁ -C 6 alkylene)-C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ R ^y2 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)O(R ^y2 ), -(C ₁ -C ₆ alkylene)-N(R ^y3 )C(O)NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-N(R ^y3 )S(O) ₂ NR ^y3 R ^y4 , -(C ₁ -C ₆ alkylene)-CN or -(C ₁ -C ₆ alkylene)-G ³ ;

R ^y1 , R ^y3 and R ^y4 are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ³ , -(C ₁ -C ₆ alkylene)-G ³ , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C 6 alkylene)- ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O) _O (R ^{b )} , -(C ₁ -C ₆ alkylene)-N(R ^e ) ^C ( ^O )NR ^c R ^d , or -(C _{1 -C 6} alkylene)-N(R ^e )S( _{O) 2 NR} ^c R ^d ;

R ^y2 is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ³ , -(C ₁ -C ₆ alkylene)-G ³ , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C ₆ alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-NR ^c R ^d , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)O(R ^b ), -(C ₁ -C ₆ alkylene)-N(R ^e )C(O)NR ^c R ^d , or -(C ₁ -C ₆ alkylene)-N(R ^e )S(O) ₂ NR ^c R ^d ;

G ^3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclyl; and each G ³ group is optionally substituted with 1, 2, 3, 4, or 5 R ^4g groups;

R ¹⁰ is H, C ₁ -C ₃ alkyl, halogen, C ₁ -C ₃ haloalkyl or -CN;

R ^1g , R ^2g and R ^4g are independently selected at each occurrence from oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , G ^2a , -OR ^a , -OC(O)R ^b , -OC(O)NR ^c R ^d , -SR ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^c R ^d , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^c R ^d , -NR ^c R ^d , -N( ^Re )C(O)R ^b , -N( ^Re )S(O) ₂ ^{R b} , -N(Re)C(O)O(R ^b ), -N( ^Re )C(O)NR ^c R ^d -N(R ^e )S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-CN, -(C ₁ -C ₆ alkylene)-G ^2a , -(C ₁ -C ₆ alkylene)-OR ^a , -(C ₁ -C ₆ alkylene)-OC(O)R ^b , -(C ₁ -C ₆ alkylene)-OC(O)NR ^c R ^d , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^a , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^c R ^d , -(C ₁ -C ₆ alkylene)-C(O)R ^a , -(C ₁ -C 6 alkylene)-C(O)OR ^a , -(C ₁ -C ₆ alkylene)-C(O)NR ^c R ^d , -(C 1 -C ₆ alkylene)-S(O) ₂ R a _6alkylene )-NR ^c R ^d , -(C ₁ -C _6alkylene )-N(R ^e )C(O)R ^b , -(C ₁ -C _6alkylene )-N(R ^e )S(O) ₂ R ^b , -(C ₁ -C _6alkylene )-N(R ^e )C(O)O(R ^b ), -(C ₁ -C _6alkylene )-N(R ^e )C(O)NR ^c R ^d , -(C ₁ -C _6alkylene )-N(R ^e )S(O) ₂ NR ^c R ^d , or -(C ₁ -C _6alkylene )-CN;

R ^a , R ^c , R ^d and R ^e are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ^2a or -(C ₁ -C ₆ alkylene)-G ^2a ;

R ^b, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, G ^2a or -(C ₁ -C ₆ alkylene)-G ^2a ;

Each occurrence of G ^2a is independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; and each G ^2a group is optionally substituted with 1, 2, 3, 4, or 5 R ^3g groups;

R ^3g at each occurrence is independently oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -CN, NO ₂ , -OR ^z1 , -OC(O)R ^z2 , -OC(O)NR ^z3 R ^z4 , -SR ^z1 , -S(O) ₂ R ^z1 , -S(O) ₂ NR ^z3 R ^z4 , -C(O)R ^z1 , -C(O)OR ^z1 , -C(O)NR ^z3 R ^z4 , -NR ^z3 R ^z4 , -N(R ^z3 )C(O)R ^z2 , -N(R ^z3 )S(O) ₂ R ^z2 , -N(R ^z3 )C(O)O(R ^z2 ), -N(R ^z3 )C(O)NR ^z3 R ^z4 , -N(R ^z3 )S(O) ₂ NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-OR ^z1 , -(C ₁ -C ₆ alkylene)-OC(O)R ^z2 , -(C ₁ -C ₆ alkylene)-OC(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^z1 , -(C ₁ -C ₆ alkylene)-S(O) ₂ NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-C(O)R ^z1 , -(C ₁ -C ₆ alkylene)-C(O)OR ^z1 , -(C ₁ -C ₆ alkylene)-C(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-NR ^z3 R ^z4 , -(C ₁ -C -(C 1 -C ₆ alkylene)-N(R ^z3 )C(O)R ^z2 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )S(O) ₂ R ^z2 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )C(O)O(R ^z2 ), -(C ₁ -C ₆ alkylene)-N(R ^z3 )C(O)NR ^z3 R ^z4 , -(C ₁ -C ₆ alkylene)-N(R ^z3 )S(O) ₂ NR ^z3 R ^z4 or -(C ₁ -C ₆ alkylene)-CN;

R ^z1 , R ^z3 and R ^z4 are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ haloalkyl at each occurrence; and

R ^z2, at each occurrence, is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ haloalkyl.

Compounds of formula (I) may contain one or more asymmetrically substituted atoms. Compounds of formula (I) may also exist as individual stereoisomers (including enantiomers and diastereomers) and mixtures thereof. Individual stereoisomers of compounds of formula (I) may be synthesized from commercially available starting materials containing asymmetric or chiral centers, or by preparing a racemic mixture followed by resolution of the individual stereoisomers using methods known to those skilled in the art. Examples of resolution are, for example, (i) coupling a mixture of enantiomers to a chiral auxiliary and separating the resulting mixture of diastereomers by recrystallization or chromatography, followed by liberation of the optically pure product; or (ii) separation of a mixture of enantiomers or diastereomers on a chiral chromatographic column.

Compounds of formula (I) may also include various geometric isomers and mixtures thereof resulting from the arrangement of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen double bonds are designated as Z or E configurations and substituents around cycloalkyl groups or heterocyclic groups are designated as cis or trans configurations.

It is to be understood in the present invention that the compounds disclosed herein may exhibit tautomerism and that all tautomers are encompassed within the scope of the present invention.

Therefore, the structural formula figures in this specification may represent only one of the possible tautomers, geometric or stereoisomeric forms. However, it should be understood that the present invention includes any tautomers, geometric or stereoisomeric forms, and mixtures thereof, and is not limited to any one tautomer, geometric or stereoisomeric form used in the structural formula.

The compounds of the present invention were named using ChemDraw Ultra Version 12.0.

Exemplary compounds of formula (I) include, but are not limited to:

4-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(cyclopropylmethyl)-3-ethyl-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester;

4-(4-Fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(Cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-7-sulfonamide;

4-(4-Fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(Cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

Methyl 3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;

4-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

3-Benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

Methyl 3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;

10-methyl-7-((methylsulfonyl)methyl)-3-phenylethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

3-Isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(E)-3-(4-Fluorophenylvinyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

7-amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one;

N-(4-(4-Fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;

N-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;

4-Butyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

tert-Butyl 3-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)pyrrolidine-1-carboxylate;

10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-((4,4-difluorocyclohexyl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

tert-Butyl 4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)piperidine-1-carboxylate;

10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydro-2H-pyran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-Fluorophenyl)-(3,3- ² H ₂ )-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

7-Fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-Fluorophenyl)-7,10-dimethyl-3-phenyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester;

tert-Butyl 4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)piperazine-1-carboxylate;

10-methyl-7-((methylsulfonyl)methyl)-4-(pyrrolidin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(piperidin-4-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

7-Fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one;

7-Fluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester;

4-(4-Fluorophenyl)-3-(4-methoxypiperidine-1-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-Fluorophenyl)-10-methyl-3-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

5,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-Fluorophenyl)-7,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester;

N-cyclopentyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

4-Butyl-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

5,7-Difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(Cyclopropylmethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

Methyl 4-(5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)butanoate;

5,7-Difluoro-10-methyl-4-(3-phenylpropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(o-tolyl)-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

2-ethylhexyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;

4-isobutyryl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

5,7-Difluoro-10-methyl-4-phenylethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-((1Z,3E)-2,4-diphenylbuta-1,3-dien-1-yl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;

4-(4-chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;

4-(4-chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

N-(2,6-dimethylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(4-methoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(4-ethylphenethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(3-methoxybenzyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(2-chloroethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(cyclohexylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(4-isopropylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(2,6-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

Ethyl 4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4-carboxamido)methyl)cyclohexanecarboxylate;

N-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;

10-methyl-7-((methylsulfonyl)methyl)-4-toluenesulfonyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-([1,1'-biphenyl]-4-ylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-((4-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(phenylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-((2-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-((4-phenoxyphenyl)sulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-((4-Fluorophenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

Methyl 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;

4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo[cd,f]azulene-11(10H)-one;

(R)-ethyl 4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;

(S)-ethyl 4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;

2-Methoxyethyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;

10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid ethyl ester;

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid pentyl ester;

4-Chlorobutyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid naphth-2-yl ester;

10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid p-tolyl ester;

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid neopentyl ester;

10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid phenyl ester;

4-Fluorophenyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;

2-Methoxyphenyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;

2-Fluoroethyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;

4-Methoxyphenyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid but-2-yn-1-yl ester

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide;

4-(4-Fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(3-methoxypropionyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-([1,1'-biphenyl]-4-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(3-cyclopentylpropionyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2-(3-methoxyphenyl)acetyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-propionyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-4-(3-methylbutyryl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(3,3-dimethylbutyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(2-phenylacetyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-Benzoyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-methoxybenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

Methyl 4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)-4-oxobutanoate;

4-(2,4-difluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2-Fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(1-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(cyclopropylcarbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(3-phenylpropionyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-methylpropanamide;

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylpropionamide;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-morpholino-3-oxopropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(tetrahydro-2H-pyran-4-yl)propanamide;

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N'-methyl-N'-phenylpropionohydrazide;

N-Benzyl-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide;

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(1,1-dioxotetrahydrothiophen-3-yl)propanamide;

tert-Butyl 4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoyl)piperazine-1-carboxylate;

tert-Butyl 4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propionylamino)piperidine-1-carboxylate;

4-(4-Chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;

6-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)hexyl acetate;

3-(Aminomethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)(dimethylamino)methylene)-N-methylmethanammonium;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-oxo-3-(piperazin-1-yl)propyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(piperidin-4-yl)propanamide;

4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)butane-1,2-diyl diacetate;

Methyl 5-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pentanoate;

tert-Butyl (2-(((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)-2-oxoethyl)carbamate;

4-(2,4-difluorophenyl)-3-(6-hydroxyhexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)benzamide;

1-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)-3-phenylurea;

2-amino-N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)acetamide;

4-(2,4-difluorophenyl)-3-(3,4-dihydroxybutyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-difluorophenyl)-3-(3-hydroxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-3-(3-ethoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-Isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-((1-ethylpiperidin-3-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-ethoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

N-(2-cyanoethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

Methyl 2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamido)acetate;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-phenethyl-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

N-butyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

N-cyclohexyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

N-benzyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(3-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-Difluorophenyl)-N-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-Difluorophenyl)-N-(2-hydroxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-N-(oxazol-4-ylmethyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

N-(cyclopropylmethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-Difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-Difluorophenyl)-N-(1-(hydroxymethyl)cyclopropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-Difluorophenyl)-10-methyl-N-(1-methylcyclopropyl)-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(4-phenylbutyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;

4-(3,3-dimethylbutyryl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

tert-Butyl ((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;

4-((trans)-4-aminocyclohexyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(cyclopropylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

5,7-Difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid ethyl ester;

4-(2,4-difluorophenyl)-10-methyl-3-(3-(methylamino)propyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-3-(3-(dimethylamino)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

2-(4-(4-Fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-7-yl)acetonitrile;

4-(2,2-dimethyl-3-(pyrrolidin-1-yl)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

2-(3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)pyrrolidin-1-yl)acetic acid;

10-methyl-7-((methylsulfonyl)methyl)-4-(2-methyltetrahydrofuran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-4-(1-methylpiperidin-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-((1-isopropylpiperidin-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(1-(2-oxotetrahydrofuran-3-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(1-methoxypropan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-methoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-4-(1-methylpyrrolidin-3-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-4-(1-methylazepan-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(1-ethylpiperidin-3-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)benzonitrile;

4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;

5-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

tert-Butyl (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;

tert-Butyl (trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;

4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;

4-(2,4-difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-Chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;

4-(2,4-Difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;

4-(4-Cyanophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;

(S)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;

(R)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile;

10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid ethyl ester;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;

10-methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-aminocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(naphthalen-1-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;

4-(2,4-difluorophenyl)-(3,3- ² H ₂ )-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-neopentyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoindolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-3-(2,6-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-3-(3,5-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

3-(3,5-di-tert-butylphenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

Methyl (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carboxylate;

Methyl ((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carboxylate;

Methyl ((cis)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carboxylate;

2-(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)isoindoline-1,3-dione;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

Benzyl (2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)carbamate;

3-([1,1'-biphenyl]-2-yl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(quinolin-8-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

3-(4-(1H-imidazol-1-yl)phenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-(pyridin-2-yl)phenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile;

4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

Ethyl 4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;

4-(2,4-Difluorophenyl)-N,10-dimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;

4-(2,4-Difluorophenyl)-N,N,10-trimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;

N-(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)acetamide;

10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(1H-indazol-5-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-Benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(pyridazin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2-fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

2-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)-2-phenylacetonitrile;

2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)phenoxy)acetamide;

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid;

10-methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one;

(S)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(R)-methyl 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;

(S)-methyl 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;

4-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

4-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

(R)-N-ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;

10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one; and 4-(4-fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one;

or a pharmaceutically acceptable salt thereof.

The compounds of formula I can be used in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are described in S. M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.

The compounds of formula (I) may contain basic or acidic functional groups or both and may, when desired, be converted into pharmaceutically acceptable salts using appropriate acids or bases. Such salts may be prepared in situ during the final isolation and purification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothiosulfate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. Basic nitrogen-containing groups can also be quaternized using reagents such as lower alkyl halides, such as, but not limited to, the chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl; dialkyl sulfates, such as, but not limited to, dimethyl, diethyl, dibutyl, and diamyl sulfates; long-chain halides, such as, but not limited to, the chlorides, bromides, and iodides of decyl, lauryl, tetradecyl, and stearyl; aralkyl halides, such as, for example, the bromides of benzyl and phenethyl; and the like. Water- or oil-soluble or dispersible products are thereby obtained. Examples of acids useful for forming pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid, and citric acid.

Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting the carboxylic acid-containing group with a suitable base, such as, but not limited to, a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, salts based on alkali metal or alkaline earth metal cations, such as, but not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other examples of organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

The term "pharmaceutically acceptable prodrug" or "prodrug" refers to those prodrugs of the compounds of this invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The present invention includes compounds of formula (I) formed synthetically or by in vivo biotransformation of prodrugs.

The compounds described herein may exist in unsolvated as well as solvated forms, including hydrated forms such as hemihydrates. In general, solvated forms with pharmaceutically acceptable solvents such as water and ethanol are equivalent to the unsolvated forms for the purposes of the present invention.

General synthetic method

The compounds described herein, including compounds of Formula (I) and specific examples, can be prepared, for example, by the reaction routes shown in Schemes 1-6. Unless otherwise indicated, the variables ^A1 , ^A2 , A3, ^A4 , ^Y1 , ^Y2 , ^Y3 , ^R1 , ^R2 , ^R3 , R4, R5, ^R6 , ^R3b , ^R3c , ^R6a , ^R6b , and ^{R6c used} in ^{the following schemes have} the meanings described in the Summary of the Invention and Detailed Description of the Invention sections.

The abbreviations used in the description of the schemes and the specific examples have the following meanings: DMF is dimethylformamide, DMSO is dimethyl sulfoxide, mCPBA is 3-chloroperbenzoic acid, Pd(OAc) ₂ is palladium acetate, SFC is supercritical fluid chromatography, THF is tetrahydrofuran, TFA is trifluoroacetic acid, and HPLC is high performance liquid chromatography.

Reaction Scheme 1

As described in Reaction Scheme 1, compounds of formula (I) wherein Y ² is CR ⁴ R ⁵ can be prepared by treating compounds of formula (1) with an aldehyde or ketone (2) under acidic conditions. Typically, this cyclization reaction can be carried out in the presence of a reagent such as titanium tetrachloride in a solvent such as, but not limited to, tetrahydrofuran or dichloromethane at a temperature ranging from 0°C to 50°C. Alternatively, the cyclization reaction can be carried out in the presence of an acid such as acetic acid or hydrochloric acid in the presence of a solvent such as, but not limited to, methanol or ethanol, or in the absence of a solvent at a temperature ranging from 50°C to 150°C.

Reaction Scheme 2

As shown in Reaction Scheme 2, compounds of formula (1) wherein Y ¹ and Y ³ are CH and R ² is H can be prepared by general synthetic methods. Compounds of formula (4) wherein X is Br, Cl or I are treated with 1,1-dimethoxy-N,N-dimethylmethanamine at elevated temperature (e.g., about 60°C to about 100°C) in the absence or presence of a base and in a solvent such as, but not limited to, DMF to provide compounds of formula (5). Examples of suitable bases include, but are not limited to, lithium methoxide or sodium methoxide. Catalytic hydrogenation of (5) in the presence of a catalyst such as, but not limited to, Raney nickel and under a hydrogen atmosphere (about 30 psi) in a solvent such as, but not limited to, ethyl acetate at about room temperature generally provides compounds of formula (6). Protection of the nitrogen atom with a protecting group such as, but not limited to, a benzyl, tosyl or (trimethylsilyl)ethoxy)methyl group can be achieved by reaction with an appropriate halide in the presence of a strong base such as, but not limited to, sodium hydride to provide compounds of formula (7).

Treatment of (7) with an acid, such as, but not limited to, hydrochloric acid or hydrobromic acid, in a solvent, such as, but not limited to, dioxane or water, at about 40°C to about 100°C, typically provides a compound of formula (8).

Alkylation of (8) with a halide or mesylate in the presence of a base such as, but not limited to, sodium hydride, cesium carbonate or potassium carbonate in a solvent such as, but not limited to, dimethylformamide or dimethyl sulfoxide at a temperature of about 0°C to about 50°C provides a compound of formula (9).

The compound of formula (9) is treated with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) to obtain the compound of formula (10). In general, this transformation can be promoted by a palladium catalyst, such as, but not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) or palladium(II) acetate, an optional ligand such as, but not limited to, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), or 1,1'-bis(diphenylphosphino)ferrocene, and a base such as, but not limited to, carbonates, acetates or phosphates of sodium, potassium, cesium, and the like; and cesium fluoride. Non-limiting examples of suitable solvents include methanol, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran and water, or mixtures thereof. As shown in Reaction Scheme 2, compounds of formula (13) can be prepared by (a) treating a compound of formula (10) with a compound of formula (11) wherein X ¹⁰¹ is a halide, mesylate or triflate under Suzuki coupling conditions to obtain a compound of formula (12) (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148), and (b) removing the protecting group (PG). Removal of the protecting group can also occur in situ under Suzuki reaction conditions. Typically, the coupling reaction is carried out in the presence of a palladium catalyst and a base, and optionally in the presence of a ligand, and in a suitable solvent at an elevated temperature (e.g., at about 80° C. to about 150° C.). The reaction can be promoted by microwave irradiation. Examples of palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. Examples of suitable bases that may be used include, but are not limited to, carbonates or phosphates of sodium, potassium and cesium; and cesium fluoride. Examples of suitable ligands include, but are not limited to, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos) and 1,1'-bis(diphenylphosphino)ferrocene. Non-limiting examples of suitable solvents include methanol, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran and water, or mixtures thereof.

Alternatively, compounds of formula (9) wherein X is I, Br, Cl or triflate can be treated with a boronic acid or derivative thereof (e.g., a boronic ester) of formula (14) under Suzuki coupling conditions as described above to provide compounds of formula (12). Removal of the protecting group can be carried out under Suzuki reaction conditions to provide compounds of formula (13).

Reaction Scheme 3

Compounds of formula (11) wherein X ¹⁰¹ is I, Br or Cl, and compounds of formula (14) can be prepared according to the synthesis described in Reaction Scheme 3. Amines (15) wherein X ¹⁰¹ is I, Br or Cl are subjected to reductive amination with an aldehyde or ketone in the presence of a reducing agent, such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, and an acid (e.g., acetic acid) to provide compounds (11) wherein R ⁶ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each of which is optionally substituted, or R ⁶ is C ₁ -C ₆ haloalkyl. The reaction is typically carried out in a solvent, such as dichloromethane, methanol or ethanol, at a temperature of about 0° C. to about 100° C. Compounds of formula (14) can be prepared from compounds of formula (11) under Suzuki coupling conditions as described in Reaction Scheme 2.

Alternatively, the compound of formula (11) can be prepared using Buchwald reaction conditions. The halide (16) can be treated with a suitable amine (17) in the presence of a catalyst, a ligand, and a base in a solvent to obtain a compound of formula (18). Examples of catalysts that can be used include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) dichloride, and palladium(II) acetate. Examples of suitable bases that can be used include, but are not limited to, carbonates or phosphates of sodium, potassium, and cesium, and cesium fluoride. Examples of suitable ligands include, but are not limited to, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), and 1,1'-bis(diphenylphosphino)ferrocene. Non-limiting examples of suitable solvents include toluene, tert-butanol, methanol, ethanol, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran and water, or mixtures thereof. Compounds of formula (18) are halogenated by reaction with a reagent such as, but not limited to, N-bromosuccinimide or N-iodosuccinimide in a solvent such as, but not limited to, acetic acid at a temperature from about 0°C to about 50°C to obtain compounds of formula (11) wherein X ¹⁰¹ is I or Br.

Reaction Scheme 4

Compounds of formula (3) wherein ^R2 is H can be prepared according to the synthesis described in Reaction Scheme 4. Compounds of formula (20) can be prepared by treating compounds of formula (18) with (15) wherein ^X101 is a halide, mesylate or triflate under the Suzuki coupling conditions described in Reaction Scheme 2. Compounds of formula (20) can also be prepared by treating compounds of formula (21) wherein ^X103 is a halide, mesylate or triflate with boronic acid (or a boronic acid derivative) (22) under Suzuki coupling conditions. Deprotection of compound (20) under appropriate conditions affords compounds of formula (23). Compounds of formula (24) can be prepared by treating compounds of formula (23) with an aldehyde or ketone (2) using the conditions described in Reaction Scheme 1. Compounds of formula (25) wherein ^R6 is optionally substituted _C1 - _C6 alkyl, C2-C6 alkenyl or _C2 -C6 alkynyl, or ^R6 is _C1 - _{C6 haloalkyl} , _can be prepared by reductive amination of compounds of formula (24) with a suitable aldehyde or ketone using the reaction conditions described in Reaction Scheme _3. Similarly, reductive amination of compounds of formula (20) with a suitable aldehyde or ketone provides compounds of formula (26). Compounds of formula (25) wherein R ⁶ is C(O)OR ^6a , C(O)R ^6a , S(O) ₂ R ^6a and C(O)NR ^6b R ^6c can be prepared by reacting a compound of formula (24) with a chloroformate, an acid chloride, a sulfonyl chloride or an isocyanate in the presence of a base such as, but not limited to, diisopropylethylamine, triethylamine or cesium carbonate in a solvent such as dimethylformamide, dimethylacetamide, 1,2-dichloroethane or dichloromethane at a temperature ranging from ambient temperature to about 100° C. for about 2 to about 72 hours.

Reaction Scheme 5

Compounds of formula (21) wherein X ¹⁰³ is Cl, Y ¹ is N and Y ³ is CH can be prepared according to the synthesis described in Scheme 5. Treatment of (27) with ammonium hydroxide at about 100°C to about 150°C provides the amine of formula (28).

Iodination of (28) with N-iodosuccinimide in a solvent such as, but not limited to, acetonitrile or acetone at a temperature of about 40°C to about 85°C affords the compound of formula (29). This is then coupled with (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using Suzuki coupling conditions as described above to afford the compound of formula (30). Cyclization of (30) followed by nitrogen protection affords the compound of formula (31).

Cyclization of (30) can be achieved in the presence of an acid, such as, but not limited to, acetic acid or hydrochloric acid, and at elevated temperature (eg, about 50°C to about 100°C).

Reaction Scheme 6

Compounds of formula (38) can be prepared according to Reaction Scheme 6. Esters of formula (33) can be obtained by (a) treating formula (4) with diethyl oxalate in the presence of a base, such as, but not limited to, potassium ethoxide or sodium ethoxide, in a solvent such as, but not limited to, ethanol, dioxane, and diethyl ether, and at a temperature of about 40° C. to about 80° C., and (b) cyclizing the resulting intermediate (32) in the presence of iron in ethanol and acetic acid at a temperature of about 80° C. to about 100° C. The conversion of (33) to (36) can be achieved by employing the reaction conditions discussed above.

Intermediate (36) can be converted to compound (37) using the reaction conditions described in Schemes 1-5. Hydrolysis of the ester function of (37) followed by coupling of the resulting acid with a suitable amine of formula NHR ^3b R ^3c provides compounds of formula (38).

It should be appreciated that the synthetic reaction schemes and the specific examples illustrated in the synthetic examples section are illustrative and are not to be construed as limiting the scope of the invention as defined in the appended claims. All substitutions, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

The optimal reaction conditions and reaction times for each individual step may vary depending on the specific reactants employed and the substituents present in the reactants used. Unless otherwise stated, solvents, temperatures and other reaction conditions can be readily selected by one skilled in the art. Specific methods are provided in the Synthesis Examples section. Reactions can be worked up in conventional manner, for example by removing the solvent from the residue and further purified according to methodologies known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise stated, the starting materials and reagents are commercially available or can be prepared from commercially available materials by one skilled in the art using methods described in the chemical literature.

Routine experiments, including the appropriate operation of reaction conditions, reagents and synthetic route sequences, are all included within the scope of the present invention with the protection of any chemical functional group that is incompatible with reaction conditions and the deprotection at appropriate points in the reaction sequence of the method. Suitable blocking groups and the use of these suitable blocking groups for protecting and deprotecting different substituents are well known to those skilled in the art, and examples thereof are found in T.Greene and P.Wuts, Protecting Groups in Organic Synthesis (3 ^ed .), John Wiley & Sons, NY (1999), which are incorporated herein by reference in their entirety. The synthetic method of the compounds of this invention can be accomplished by being similar to the synthetic reaction routes described above and the method described in the specific embodiments.

Starting materials, if not commercially available, can be prepared by standard organic chemistry techniques analogous to those used to synthesize known, structurally similar compounds, or analogously to the methods described in the above schemes or in the Synthesis Examples section.

When an optically active form of a compound is required, it can be obtained by carrying out one of the methods described herein using optically active starting materials (e.g., prepared by asymmetric induction of an appropriate reaction step), or by resolving the stereoisomeric mixture of the compounds or intermediates using standard methods (e.g., chromatographic separation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, it can be prepared by carrying out one of the above methods using the pure geometric isomer as the starting material, or by resolving the mixture of geometric isomers of the compounds or intermediates using standard methods, such as chromatographic separation.

Pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. The phrase "pharmaceutically acceptable composition" refers to a composition suitable for administration for medical or veterinary purposes.

Pharmaceutical compositions comprising a compound of formula (I) alone or in combination with a second active agent can be administered orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (e.g., by powders, ointments, or drops), buccally, or as an oral or nasal spray to a subject. As used herein, the term "parenteral" refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intraarticular injection and infusion.

As used herein, the term "pharmaceutically acceptable carrier" refers to a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are: sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository wax; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffers such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffered solutions, and other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition at the discretion of the formulator.

The pharmaceutical composition for parenteral injection comprises a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder that is reconstituted into a sterile injectable solution or dispersion before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. For example, by using a coating material such as lecithin, by maintaining the desired particle size in the case of a dispersion and by using a surfactant, suitable fluidity can be maintained.

These compositions may also include adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Protection against the action of microorganisms may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents may also be included, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms may be achieved by including in the composition agents that delay absorption, such as aluminum monostearate and gelatin.

In some cases, to prolong the effect of a drug, it is desirable to slow its absorption from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of poorly water-soluble crystalline or amorphous material. The rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oily vehicle.

Injectable depot formulations are prepared by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the specific polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

The injectable compositions can be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, the solid dosage form may contain 1% to 95% (w/w) of the compound of Formula I. In certain embodiments, the compound of Formula I may be present in the solid dosage form in a ratio of 5% to 70% (w/w). In these solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retardants such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

The pharmaceutical composition can be in unit dosage form. In this form, the composition is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged composition, a package containing discrete quantities of the composition, such as packaged tablets, capsules, and powders in vials or ampoules. Additionally, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be a package of an appropriate number of any of these unit dosage forms. Depending on the specific application and the potency of the active ingredient, the amount of active ingredient in the unit dosage formulation can be varied or adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w/w) of the unit dose. The composition can, if desired, also contain other compatible therapeutic agents.

The dosage to be administered to a patient can be determined by the potency of the specific compound used and the patient's condition, weight, or surface area. The size of the dosage is also determined by the presence, nature, and extent of adverse side effects of the specific compound administered to a particular patient. When determining the effective amount of a compound to be administered for the treatment or prevention of a disease to be treated, the physician assesses factors such as the circulating plasma level of the compound, the toxicity of the compound, and/or the progression of the disease. In general, for a representative patient, the dosage of the compound is from about 1 microgram/kg to 100 milligrams/kg.

The frequency of administration of the compound of Formula I is determined by factors including, but not limited to, the compound's LD50, pharmacokinetic properties, contraindications, and side effects at various concentrations, as well as considerations of the patient's weight and overall health. The compound may be administered in a single dose or divided doses.

The compound used in the pharmaceutical method of the present invention can be administered at an initial dose of about 0.001 mg/kg to about 100 mg/kg per day. In certain embodiments, the daily dose range is from about 0.1 mg/kg to 10 mg/kg. However, the dosage can also vary depending on the patient's needs, the severity of the disease being treated, and the compound being used. The appropriate dosage for a particular situation is determined by the doctor. Treatment can begin with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small amounts until the optimal effect is achieved. If necessary, for convenience, the total daily dose can be divided into multiple portions and administered in batches within a day.

Solid compositions of a similar type may also be filled into soft and hard gelatin capsules using lactose or milk sugar as carriers as well as high molecular weight polyethylene glycols and the like.

Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents or may be compositions such that they release the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

If appropriate, the active compounds can be in micro-encapsulated form with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain an inert diluent commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitol and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of this invention with a suitable non-irritating carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

The compound of formula (I) can also be administered in the form of liposomes. Liposomes can generally be prepared from phospholipids or other lipid substances. Liposomes are formed by single or multi-layer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compound of formula (I), the composition of the present invention in liposome form may also contain stabilizers, preservatives, excipients, etc. Examples of lipids include, but are not limited to, natural and synthetic phospholipids and phosphatidylcholines (lecithins), used alone or together.

Methods for forming liposomes are described, for example, in Prescott, ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of the compounds described herein include powders, sprays, ointments, and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants that may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also encompassed within the scope of this invention.

How to use

The compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, can be administered to a patient suffering from a disorder or disease mediated by a bromodomain. The term "administering" refers to a method of administering a compound to a patient. Thus, the compound of formula I can be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, parenterally, or intraperitoneally. Furthermore, the compounds described herein can be administered by inhalation, such as intranasally. Additionally, the compound of formula I can be administered transdermally, topically, via implantation, or transdermally. In certain embodiments, the compound of formula I can be delivered orally. The compound can also be delivered rectally, buccally, intravaginally, ocularly, anally, or by insufflation. The disorders and diseases mediated by bromodomains can be treated prophylactically, acutely, and chronically using the compound of formula I, depending on the nature of the disorder or disease. Typically, the host or patient in each of these methods is human, although other mammals can also benefit from the administration of the compound of formula I.

A "bromodomain-mediated disease or disorder" is characterized by the involvement of one or more bromodomains (e.g., BRD4) in the onset, manifestation, severity, or progression of one or more symptoms or disease markers of the disorder or disease.

Therefore, the compounds of formula I can be used to treat cancers including, but not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, Colorectal cancer, craniopharyngeal cancer, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's carcinoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, Leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma (lympagiendotheliosarcoma), lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant diseases and proliferative lesions of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, malignant lymphoproliferative diseases of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, N UT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (cell carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, benign synovioma, sweat gland carcinoma, radiation-induced thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

In addition, the compounds of Formula I can be used to treat inflammatory diseases, inflammatory conditions, and autoimmune diseases, including but not limited to: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, cardiomyopathy, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, heart failure, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

The compound of formula I or a pharmaceutically acceptable salt thereof can be used to treat AIDS.

The compounds of Formula I can be co-administered to a patient. The term "co-administered" refers to the co-administration of two or more different pharmaceutical agents or treatments (e.g., radiotherapy) to a patient, either in the same pharmaceutical composition or in different pharmaceutical compositions. Thus, co-administration involves the simultaneous administration of a single pharmaceutical composition containing two or more pharmaceutical agents, or the simultaneous or different administration of two or more different compositions to the same patient.

The compounds of the present invention can be administered in combination with a therapeutically effective amount of one or more agents for treating cancer, examples of which include, for example, radiation agents, alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (e.g., Bcl-xL, Bcl-w, and Bfl-1) inhibitors, activators of death receptor pathways, Bcr-Abl kinase inhibitors, BiTE (bispecific T cell bridge) antibodies, antibody drug conjugates, biological response modifiers, cell cycle kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (bivariate domain antibodies), leukemia virus oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock proteins (HSPs), and cytotoxic T cells. )-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormone therapy therapeutics, immunotherapies, inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, mRNA, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum-based chemotherapy drugs, Paul-like kinase (PLK) inhibitors, phosphatidylinositol-3-kinase (bromodomain) inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, small RNA inhibitors (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, etc., or one or more of the above agents are used in combination.

BiTE antibodies are bispecific antibodies that guide T-cells to attack cancer cells by simultaneously binding to T-cells and cancer cells. T cells then attack target cancer cells. Examples of BiTE antibodies include adetumomab (Micromet MT201), blinatumomab (Micromet MT103), etc. Without being limited by theory, one of the mechanisms by which T cells cause apoptosis of target cancer cells is the exocytosis of cytolytic granule components (including perforin and granzyme B). In this regard, Bcl-2 has been shown to reduce apoptosis induced by perforin and granzyme B. These data suggest that inhibiting Bcl-2 can enhance the cytotoxic effect caused by T cells when targeting cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules with endogenous RNA bases or chemically modified nucleotides. The modification does not eliminate cellular activity, but rather imparts improved stability and/or enhanced cellular efficacy. Examples of chemical modifications include thiophosphate groups, 2'-deoxynucleotides, ribonucleotides containing 2'-OCH ₃ , 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides, their combinations, etc. siRNA can have variable lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, protrusions, gaps/clefts, mispairings), and are processed in cells to provide active gene silencing. Double-stranded siRNA (dsRNA) can have the same number of nucleotides on each chain (flat end) or asymmetric end (overhang). The overhang of 1-2 nucleotides can be present on the sense strand and/or antisense strand, and be present at the 5'-end and/or 3'-end of a given chain.

Multivalent binding proteins are binding proteins containing two or more antigen binding sites. Multivalent binding proteins are designed to have three or more antigen binding sites and are generally non-naturally occurring antibodies. The term "multispecific binding protein" refers to a binding protein that can bind to two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins containing two or more antigen binding sites. Such DVDs can be monospecific (i.e., capable of binding to one antigen) or multispecific (i.e., capable of binding to two or more antigens). DVD binding proteins containing two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Igs. Each half of a DVD Ig contains a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site contains a heavy chain variable domain and a light chain variable domain, and each antigen binding site has a total of 6 CDRs involved in antigen binding. Multispecific DVDs include DVD binding proteins that bind to DLL4 and VEGF, or C-met and EFGR, or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquinone, carmustine (BCUN), chlorambucil, ^{CLORETAZINE®} (laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, dibromomannitol, dibromodulcitol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, ^TREANDA® (bendamustine), treosulfan, rofosfamide, and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors, and the like.

Antimetabolites include ^ALIMTA® (pemetrexed disodium, LY 231514, MTA), 5-azacitidine, ^XELODA® (capecitabine), carmofur, ^LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine sodium octadecanoate phosphate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1-β-D-ribofuranosyl imidazole-4-carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, ^GEMZAR® (gemcitabine), hydroxyurea, ^ALKERAN® (phenylalanine nitrogen mustard), mercaptopurine, 6-mercaptopurine nucleoside, methotrexate, mycophenolic acid, nelarabine, lolatrexed, sodium octadecanoate (ocfosfate), pilitrexol, pentostatin, raltitrexed, ribavirin, triapine, trimetrexate, S-1, thiazofurine, tegafur, TS-1, vidarabine, UFT, etc.

Antiviral drugs include ritonavir, hydroxychloroquine, etc.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, aurora A-specific kinase inhibitors, aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors, etc.

Bcl-2 protein inhibitors include AT-101 ((-)gossypol), ^GENASENSE® (G3139 or oblimersen (antisense oligonucleotides targeting Bcl-2)), IPI 194, IPI-565, N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (ABT-263), GX-070 (obatoclax), ABT-199, and the like.

Bcr-Abl kinase inhibitors include ^DASATINIB® (BMS-354825), ^GLEEVEC® (imatinib), and others.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT 2584, flavopyridol, GPC-286199, MCS 5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-cyclin B kinase inhibitor), ZK-304709, and the like.

COX-2 inhibitors include ABT-963, ^ARCOXIA® (etoricoxib), ^BEXTRA® (valdecoxib), BMS347070, ^CELEBREX® (celecoxib), COX 189 (lumiracoxib), CT-3, ^DERAMAXX® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC 58125, SD-8381, SVT 2016, S-2474, T-614, ^VIOXX® (rofecoxib), and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFR immunoliposomes, EGF vaccine, EMD-7200, ^ERBITUX® (cetuximab), HR3, IgA antibodies, ^IRESSA® (gefitinib), ^TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusion proteins, ^TYKERB® (lapatinib), and others.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), ^HERCEPTIN® (trastuzumab), ^TYKERB® (lapatinib), ^OMNITARG® (2C4, pertuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecific antibody, mAB AR-209, mAB2B-1, etc.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid, and the like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF 2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, ^MYCOGRAB® (human recombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009, and the like.

Inhibitors of apoptosis protein inhibitors include HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242, and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75, etc.

Activators of death receptor pathways include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5), such as apo- omab, conatumumab, ETR2-ST01, GDC0145, (lexalimumab), HGS-1029, LBY-135, PRO-1762, and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors, such as AZD4877 and ARRY-520; CENPE inhibitors, such as GSK923295A, and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019, and INCB018424, among others.

MEK inhibitors include ARRY-142886, ARRY-438162, PD-325901, PD-98059, and the like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors including PI-103, PP242, PP30, Torin 1, and the like.

NSAIDs include ^AMIGESIC® (salsalate), DOLOBID® (diflunisal), ^MOTRIN® (ibuprofen), ^ORUDIS® (ketoprofen), ^RELAFEN® (nabumetone), ^FELDENE® (piroxicam), ibuprofen cream, ^ALEVE® (naproxen) and ^NAPROSYN® (naproxen), ^VOLTAREN® (diclofenac), ^INDOCIN® (indomethacin), ^CLINORIL® (sulindac), TOLECTIN® (tolmetin), ^{LODINE® (} etodolac), ^TORADOL® (ketorolac), ^DAYPRO® ( ^oxaprozin ), and many others.

PDGFR inhibitors include C-451, CP-673, CP-868596, and the like.

Platinum chemotherapy drugs include cisplatin, ELOXATIN ^® (oxaliplatin), epazote, lobaplatin, nedaplatin, PARAPLATIN ^® (carboplatin), satraplatin, picoplatin, etc.

Paul-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765, and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1, and the like.

VEGFR inhibitors include ^AVASTIN® (bevacizumab), ABT-869, AEE-788, ANGIOZYME ^™ (ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron (Emeryville, CA)), axitinib (AG-13736), AZD-2171, CP-547, 632, IM-862, MACUGEN (pegaptamib), NEXAVAR® (sorafenib ^, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), ^SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA ^™ (vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3-specific antibody, BSG2-specific antibody, DLL4-specific antibody and C-met-specific antibody, etc.

Antibiotics include the embedded antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, doxorubicin, ^BLENOXANE® (bleomycin), daunorubicin, ^CAELYX® or ^MYOCET® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ^ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, piridomycin, stimalamer, streptozotocin, ^VALSTAR® (valrubicin), zenastatin, and others.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, aminafide, amsacrine, becatecarin, belotecan, BN-80915, ^CAMPTOSAR® (irinotecan hydrochloride), camptothecin, ^CARDIOXANE® (dexrazoxine), diflomotecan, edotecarin, ^ELLENCE® or ^{PHARMORUBICIN®} (epirubicin), itoposide, isatecan, 10-hydroxycamptothecin, gimatecan, lertotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan, and the like.

Antibodies include ^AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT-1/ ^B , denizumab, ERBITUX® (cetuximab), HUMAX ^CD4® (zatumumab), IGF1R-specific antibodies, lintuzumab, ^PANOREX® (edrecolomab), ^RENCAREX® (WX G250), ^RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20 antibodies type I and II, and others.

Hormonal therapies include ^ARIMIDEX® (anastrozole), ^AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutamide), ^CETROTIDE® (cetrorelix), degarelix, deslorelin, ^DESOPAN® (trilostane), dexamethasone, ^DROGENIL® (flutamide), ^EVISTA® (raloxifene), AFEMA ^{™ (} fadrozole), ^FARESTON® (toremifene), FASLODEX® (fulvestrant), ^FEMARA® (letrozole), formestane, adrenal glucocorticoids, ^HECTOROL® (doxercalciferol), ^RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate, ^MEGACE® (megesterol), ^MIFEPREX® (mifepristone), ^{NILANDRON™ (} nilutamide), ^NOLVADEX® (tamoxifen citrate), PLENAXISTM (abarelix), prednisone, PROPECIA ^® (finasteride), rilostane, SUPREFACT ^® (buserelin), TRELSTAR ^® (gonadotropin-releasing hormone (LHRH)), VANTAS ^® (histrelin implant), VETORYL ^® (trilostane or modrastane), ZOLADEX ^® (fosrelin, goserelin), and others.

Deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PANRETIN ^® (aliretinoin), ATRAGEN ^® (liposomal tretinoin), TARGRETIN ^® (bexarotene), LGD-1550, and others.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231, and others.

Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine, and the like.

Proteasome inhibitors include VELCADE ^® (bortezomib), MG132, NPI-0052, PR-171, and others.

Examples of immunotherapy drugs include interferons and other immunopotentiators. Interferons include interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-1a, ^ACTIMMUNE® (interferon γ-1b), or interferon γ-1, combinations thereof, and the like. Other agents include ^ALFAFERONE® (IFN-α), BAM-002 (oxidized glutathione), ^BEROMUN® (tasonermin), BEXXAR® (tositumomab), ^CAMPATH® (alemtuzumab), ^CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, ^GRANOCYTE® (lenograstim), lentinan, interferon α, imiquimod, MDX 010 (anti-CTLA-4), melanoma vaccine, mitumomab, molaspomandib, MYLOTARG ^™ (gemtuzumab ozogamicin), ^NEUPOGEN® (filgrastim), OncoVAC-CL, ^OVAREX® (oregovomab), pemtumomab (Y muHMFG1), ^PROVENGE® (sipuleucel-T), sargaramostim, sizoran, tesileukin, THERACYS ^® (BCG), ubenimex, VIRULIZIN ^® (immunotherapy drug, Lorus Pharmaceuticals), Z-100 (Maruyama's specific substance (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN ^® (aldesleukin), ZADAXIN ^® (thymalfasin), ZENAPAX ^® (daclizumab), ZEVALIN ^® (90Y-ibritumomab tiuxetan), etc.

Biological response modifiers are agents that regulate the defense mechanisms or biological responses of living organisms (such as the survival, growth or differentiation of tissue cells) to induce them to have anti-tumor activity, including Yunzhi polysaccharide, Lentinan, Sizosan, Streptozotocin PF-3512676 (CpG-8954), Ubenimex, etc.

Pyrimidine analogs include cytarabine (ara C or cytarabine C), cytosine arabinoside, doxifluridine, ^FLUDARA® (fludarabine), 5-FU (5-fluorouracil), floxuridine, ^GEMZAR® (gemcitabine), ^TOMUDEX® (ratitrexed), TROXATYL ^™ (triacetyluridine olecitabine), and the like.

Purine analogs include LANVIS ^® (thioguanine) and PURI-NETHOL ^® (mercaptopurine).

Antimitotic drugs include batabulin, epothilone D (KOS-862), N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, ^TAXOTERE® (docetaxel), PNU100940 (109881), patupirone, XRP-9881 (lortaxel), vinflunine, ZK-EPO (synthetic epothilone), and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors such as nutlins, NEDD8 inhibitors such as MLN4924, and the like.

The compounds of the present invention can also be used as radiosensitizers for enhancing the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy, closed source radiotherapy, and non-closed source radiotherapy.

In addition, the compounds of formula (I) can be combined with other chemotherapeutic agents, such as ABRAXANE ^™ (ABI-007), ABT-100 (farnesyl transferase inhibitor), ^ADVEXIN® (Ad5CMV-p53 vaccine), ^ALTOCOR® or ^MEVACOR® (lovastatin), ^AMPLIGEN® (poly I:poly C12U, synthetic RNA), ^APTOSYN® (exilamide), ^AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane (1-methyl-3,17-dione-androst-1,4-diene), ^AVAGE® (tazarotene), AVE-8062 (combreastatin derivative), BEC2 (mitomab), cachexin or cachexin (tumor necrosis factor), Conversen (vaccine), ^CEAVAC® (cancer vaccine), ^CELEUK® (simoleukin), ^CEPLENE® (histamine dihydrochloride), ^CERVARIX® (human papillomavirus vaccine), ^CHOP® (C: ^CYTOXAN® (cyclophosphamide); H: ^ADRIAMYCIN® (hydroxydoxorubicin); O: vincristine ( ^ONCOVIN® ); P: prednisone), CYPAT ^™ (cyproterone acetate), carbetatin A4P, DAB(389)EGF (catalytic and transport domains of diphtheria toxin fused to human epidermal growth factor via a His-Ala linkage) or TransMID 107R ^™ (diphtheria toxin), dacarbazine, actinomycin D, 5,6-dimethylxanthone-4-acetic acid (DMXAA), uracil, EVIZON ^™ (squalamine lactate), ^DIMERICINE® (T4N5 liposomal lotion), discodermolide, DX-8951f (isotecan mesylate), enzastaurin, EPO906 (epithilone B), GARDASIL ^® (quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine), GASTRIMMUNE ^® , GENASENSE ^® , GMK (ganglioside conjugate vaccine), GVAX ^® (prostate cancer vaccine), piperaquantel, histerelin, hydroxyurea, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-Pseudomonas exotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifatide), lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine (cetylphosphocholine), NEOVASTAT ^® (AE-941), NEUTREXIN ^® (trimetrexate glucuronide), NIPENT ^® (pentostatin), ONCONASE ^® (ribonuclease), ONCOPHAGE ^® (melanoma vaccine therapy), ONCOVAX ^® (IL-2 vaccine), ORATHECIN™ (rubitecan), OSIDEM ^® (antibody-based cellular medicine), OVAREX ^® MAb (mouse monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponins from Panax ginseng containing 20(S)-protopanaxadiol (aPPD) and 20(S)-protopanaxatriol (aPPT)), panitumumab, PANVAC ^® -VF (investigational cancer vaccine), pegaspargase, PEG interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB ^® (catumaxomab), REVLIMID ^® (lenalidomide), RSR13 (eprexirol), SOMATULINE® LA (lanreotide), SORIATANE® (etretinoic acid), staurosporine (Streptomyces asteroides), talabostat (PT100), TARGRETIN® (bexarotene), ^TAXOPREXIN® (DHA-paclitaxel), ^TELCYTA® (canfosfamide, TLK286), temilifene, ^{TEMODAR® (} temozolomide), tesmilifene, thalidomide, ^THERATOPE® (STn-KLH), noradrenaline (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline dihydrochloride), TNFERADE™ (adenoviral vector: a DNA vector containing the gene for tumor necrosis factor-alpha), ^TRACLEER® , or ZAVESCA ^® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX ^® (arsenic trioxide), VIRULIZIN ^® , ukrain (alkaloid derivative from the celandine plant), integrin antagonist (vitaxin) (anti-αvβ3 antibody), XCYTRIN ^® (motesafam gadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel polyglutamic acid), YONDELIS ^® (trabectedin), ZD-6126, ZINECARD ^® (dextromethorphan), ZOMETA ^® (zolendronic acid), zorubicin, etc.

The compounds of the present invention may also be administered with a therapeutically effective amount of one or more agents to treat inflammatory diseases or conditions, or autoimmune diseases, examples of which include, for example, methotrexate, 6-mercaptopurines, azathioprine, sulfasalazine, mesalazine, olsalazine chloroquine/hydroxychloroquine, penicillamine, gold thiomalate (intramuscular and oral), azathioprine, colchicine, corticosteroids (oral, inhaled and local injection), beta2 adrenergic receptor agonists (salbutamol, terbutaline, salmeterol), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium bromide, cyclosporine, FK506, Rapamycin, mycophenolate mofetil, leflunomide, nonsteroidal anti-inflammatory drugs such as ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, anticoagulants, complement inhibitors, adrenergic drugs, agents that interfere with signaling through proinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors, T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and their derivatives (e.g., soluble p55 or p75 TNF receptors and derivatives p75TNFRIgG (etanercept) and p55TNFRIgG (lenercept), sIL-1RI, sIL-1RII, sIL-6R), anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, and TGFβ), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspartame Aspirin, triamcinolone acetonide, propoxyphene napsylate/paracetamol, folic acid, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone hydrochloride, hydrocodone bitartrate/paracetamol, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol hydrochloride, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, paracetamol, alendronate sodium, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulfate sulf)/chondroitin, amitriptyline hydrochloride, sulfadiazine, oxycodone hydrochloride/paracetamol, olopatadine hydrochloride, misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, roflumilast, IC-485, CDC-801, S1P1 agonists (e.g., FTY720), PKC family inhibitors (e.g., rubustadine or AEB-071), and mesopram. In certain embodiments, the combination includes methotrexate or leflunomide, and in the case of moderate or severe rheumatoid arthritis, the combination includes the above-mentioned cyclosporine and anti-TNF antibodies.

Non-limiting examples of therapeutic agents for inflammatory bowel disease that can be co-administered with the compounds of formula (I) of the present invention include the following: budesonide; epidermal growth factor; corticosteroids; cyclosporine, sulfasalazine; aminosalicylates; 6-mercaptopurines; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridyl-imidazole compounds; antibodies or other antagonists of human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP -II, GM-CSF, FGF and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; nonsteroidal anti-inflammatory drugs, for example, ibuprofen, corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; tonics agents that interfere with signaling by proinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors; TNFα converting enzyme inhibitors; T-cell signaling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin-converting enzyme inhibitors; soluble cytokine receptors and their derivatives (e.g., soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R), and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, and TGFβ). Preferred examples of Crohn's disease therapeutic agents that can be combined with compounds of formula (I) include the following: TNF antagonists, e.g., anti-TNF antibodies, D2E7 (adalimumab), CA2 (infliximab), CDP571, TNFR-Ig constructs, p75 TNFR IgG (etanercept) and p55 TNFR IgG (Lenercept ^™ ) inhibitors, and PDE4 inhibitors. The compounds of formula (I) can be combined with corticosteroids, such as budesonide and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents that interfere with the synthesis and action of proinflammatory cytokines such as IL-1, for example, IL-1β converting enzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors; 6-mercaptopurines; IL-11; mesalazine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atropine sulfate; loperamide hydrochloride; methotrexate; omeprazole; leaflet hydrochloride; ciprofloxacin/dextrose water; hydrocodone bitartrate/acetaminophen; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; scopolamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone hydrochloride/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium; codeine phosphate/acetaminophen; colesevelam hydrochloride; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab, and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis that can be co-administered with a compound of formula (I) include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-beta 1a ( ^Avonex® ; Biogen); interferon-beta 1b ( ^Betaseron® ; Chiron/Berlex); interferon alpha-n3 (Interferon Sciences/Fujimoto), interferon-alpha (Alfa Wassermann/J&J), interferon beta 1A-IF (Serono/Inhale Therapeutics), pegylated interferon alpha 2B (Enzon/Schering-Plough), copolymer 1 (Cop-1; ^Copaxone® , Teva Pharmaceutical Industries, Ltd. Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; antibodies or antagonists to other human cytokines or growth factors and their receptors (e.g., TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF). The compounds of formula (I) can be combined with antibodies to cell surface molecules (e.g., CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90) or their ligands. The compounds of formula (I) may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, S1P1 agonists, nonsteroidal anti-inflammatory drugs such as ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with signaling by proinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and their derivatives (e.g., soluble p55 or p75 TNF receptor, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (such as IL-4, IL-10, IL-13 and TGFβ).

The compound of formula (I) can also be co-administered with the following agents: alemtuzumab, dronabinol, daclizumab, mitoxantrone, zaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposomally encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrapol 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-β2, tiplimotide, VLA-4 antagonists (e.g., TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma antagonists, and IL-4 agonists.

Non-limiting examples of ankylosing spondylitis therapeutic agents that can be co-administered with a compound of Formula (I) include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocycline, prednisone, and the anti-TNF antibodies, D2E7 ( ^HUMIRA® ), CA2 (infliximab), CDP571, TNFR-Ig constructs, (p75TNFRIgG ( ^ENBREL® ) and p55TNFRIgG ( ^LENERCEPT® ).

Non-limiting examples of asthma therapeutic agents that can be co-administered with the compounds of formula (I) include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol hydrochloride, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, sodium cromoglycate, fexofenadine hydrochloride, flunisolide aconite/menthol, amoxicillin/clavulanic acid, levofloxacin, inhaler assist device, guaifenesin, dexamethasone sodium phosphate, moxifloxacin hydrochloride, doxycycline hydrochloride, guaifenesin/d-methorphan, p-ephedrine/COD/chlorpheniramine, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol nabenate, benzonatate, cephalexin, PE/hydrocodone/chlorpheniramine, cetirizine hydrochloride/pseudoephedrine, phenylephrine/COD/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenol sulfate.

Non-limiting examples of COPD therapeutic agents that can be co-administered with the compounds of formula (I) include the following: albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate , levalbuterol hydrochloride, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanic acid, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorpheniramine, pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast, and roflumilast.

Non-limiting examples of psoriasis therapeutic agents that can be co-administered with the compounds of formula (I) include the following: calcipotriol, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinolone acetonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone acetonide, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, HC/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollients, fluocinonide/emollients, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alecept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874, and ustekinamab.

Non-limiting examples of psoriatic arthritis therapeutic agents that can be co-administered with the compounds of formula (I) include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone dipropionate, acetaminophen, dapoxetine ... augmented, infliximab, methotrexate, folic acid, triamcinolone acetonide, diclofenac, dimethyl sulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, naproxenone, tolmetin sodium, calcipotriol, cyclosporine, diclofenac sodium/misoprostol, fluocinolone acetonide, glucosamine sulfate, aurothiobutane sodium, hydrocodone bitartrate/acetaminophen, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alecept, D2E7 (adalimumab), and efalizumab.

Preferred examples of SLE (lupus) therapeutic agents that can be co-administered with the compounds of formula (I) include the following: nonsteroidal anti-inflammatory drugs, such as diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, such as celecoxib, rofecoxib, valdecoxib; antimalarials, such as hydroxychloroquine; steroids, such as prednisone, prednisolone, budesonide, dexamethasone; cytotoxic drugs, such as azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; PDE4 inhibitors or purine synthesis inhibitors, such as CellCept®. The compounds of formula (I ⁾ can also be used in combination with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, ^Imuran® , and agents that interfere with the synthesis, production, or action of proinflammatory cytokines such as IL-1, such as caspase inhibitors such as IL-1β converting enzyme inhibitors and IL-1ra. The compound of formula (I) can also be used together with a T cell signaling inhibitor, for example, a tyrosine kinase inhibitor; or a molecule targeting a T cell activation molecule, for example, CTLA-4-IgG or an anti-B7 family antibody, an anti-PD-1 family antibody. The compound of formula (I) can be used together with IL-11 or an anti-cytokine antibody, for example, fonotolizumab (anti-IFNg antibody), or an anti-receptor receptor antibody, for example, an anti-IL-6 receptor antibody and a B cell surface molecule antibody. The compound of formula (I) can also be used together with LJP394 (Abetimus), an agent that depletes or inactivates B cells, for example, rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), a TNF antagonist, for example, an anti-TNF antibody, D2E7 (adalimumab), CA2 (infliximab), CDP571, a TNFR-Ig construct, (p75TNFRIgG (etanercept) and p55TNFRIgG (Lenercept ^™ ).

The compounds of the present invention may also be co-administered with a therapeutically effective amount of one or more agents for the prevention or treatment of AIDS, examples of which include HIV reverse transcriptase inhibitors, HIV protease inhibitors, immunomodulators, and other retroviral drugs. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir, adefovir, didanosine, adefovir dipivoxil, delavirdine, efavirenz, lamivudine, nevirapine, stavudine zalcitabine, and zidovudine. Examples of protease inhibitors include, but are not limited to, amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir.

The compound of formula (I) can also be administered together with insulin for the treatment of type I diabetes.

The compounds of the present invention may also be co-administered with one or more therapeutically effective amounts of agents used in the prevention or treatment of AIDS, examples of which include HIV reverse transcriptase inhibitors, HIV protease inhibitors, immunomodulators, and other retroviral drugs. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir, adefovir, didanosine, adefovir dipivoxil, delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine, and zidovudine. Examples of protease inhibitors include, but are not limited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Examples of other retroviral drugs include, but are not limited to, elvitegravir, enfuvirtide, maraviroc, and raltegravir.

The compounds of the present invention may also be co-administered with a therapeutically effective amount of one or more agents used in the treatment of obesity, examples of which include orlistat.

The compounds of the present invention may also be co-administered with a therapeutically effective amount of one or more agents used in the treatment of type II diabetes, examples of which include α-glucosidase inhibitors, insulin, metformin, sulfonylureas (e.g., amobutamide, acetohexamide, chlorpropamide, glibenclamide, glibenclamide, glibourea, gliclazide, glimepiride, glipizide, gliquidone, glisipide, glyclopyrimide, tolbutamide, and tolazamide), non-sulfonylureas (e.g., nateglinide and repaglinide), and thiazolidinediones (e.g., pioglitazone).

The compounds of the present invention may also be co-administered with a therapeutically effective amount of one or more agents for preventing or treating type II diabetes, hepatic steatosis, insulin resistance, metabolic syndrome and related conditions, examples of which include, but are not limited to, insulin and insulin modified to improve the duration of action in the body; agents that stimulate insulin secretion, such as acetohexamide, chlorpropamide, glyburide, glimepiride, glipizide, glicazide, glycopyramide, gliquidone, rapaglinide, natag agents that inhibit dipeptidyl peptidase IV, such as vildagliptin, sitagliptin, saxagliptin, linagliptin, alloliptin, and septagliptin; agents that bind to peroxisome proliferator-activated receptor gamma, such as rosiglitazone and pioglitazone; agents that reduce insulin resistance, such as metformin; and agents that reduce glucose absorption in the small intestine, such as acarbose, miglitol, and voglibose.

The compounds of the present invention can also be co-administered with a therapeutically effective amount of one or more agents for preventing or treating acute renal dysfunction and chronic kidney disease, examples of which include, but are not limited to, dopamine, diuretics such as furosemide, bumetanide, thiazide, etc., mannitol, calcium gluconate, sodium bicarbonate, salbutamol, paricalcitol, doxorcalciferol, and cinacalcet.

The following examples may be used for illustrative purposes and should not be considered to limit the scope of the present invention.

Example

Example 1

4-(Cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 1a

(E)-2-(5-Bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethyleneamine

5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) was dissolved in dimethylformamide (300 mL), and lithium methoxide (6.07 mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated at 100°C. 1,1-Dimethoxy-N,N-dimethylmethanamine (64.5 mL, 486 mmol) was added to the mixture over 10 minutes. The reaction mixture was stirred at 95°C for 16 hours. The reaction mixture was cooled to ambient temperature and water (300 mL, exothermic) was carefully added. The resulting precipitate was collected by vacuum filtration, washed with water, and dried to give the title compound (13.9 g, 45.9 mmol, 76% yield).

Example 1b

4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

Example 1a (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added to a Ra-Ni 2800 (pre-washed with ethanol) aqueous slurry (6.9 g, 118 mmol) in a stainless steel pressure bottle and stirred at 30 psi and ambient temperature for 30 minutes. The reaction mixture was filtered and concentrated. The residue was triturated with dichloromethane, and the solid was filtered to obtain the title compound (5.82 g). The mother liquor was concentrated, and the residue was triturated with dichloromethane and filtered to obtain another 1.63 g of the title compound. Total yield = 7.45 g, 72% yield.

Example 1c

4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

A solution of Example 1b (7.42 g, 32.7 mmol) in dimethylformamide was stirred at ambient temperature. To this solution was added sodium hydride (1.18 g, 1.96 g of 60% dispersion in oil, 49.0 mmol) and the reaction mixture was stirred for 10 minutes. Then p-toluenesulfonyl chloride (9.35 g, 49.0 mmol) was added portionwise and the mixture was stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was carefully quenched with water, and the resulting beige solid was collected by vacuum filtration through a Buchner funnel and washed with water. The solid was collected and dried in a vacuum oven at 50 ° C to obtain 12.4 g (100%) of the title compound.

Example 1d

4-Bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A solution of Example 1c (12.4 g, 32.6 mmol) in dioxane (140 mL) was stirred at ambient temperature. To this solution was added 4M HCl/dioxane (140 mL). The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated. The residue was triturated with diethyl ether, filtered, washed with additional diethyl ether, and dried to afford the title compound (11.23 g, 30.6 mmol, 94% yield) as a beige solid.

Example 1e

4-Bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Under a nitrogen atmosphere and with stirring, sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% dispersion in oil) was added to a solution of Example 1d (11.2 g, 30.4 mmol) in dimethylformamide (217 mL). After 30 minutes, iodomethane (2.27 mL, 36.5 mmol) was added and the solution was stirred at ambient temperature for 3 hours. After adding water (250 mL), a precipitate formed. The precipitate was collected by vacuum filtration, washed with water (50 mL), and dried in a vacuum oven at 55°C overnight to give 11.2 g of the title compound (96%).

Example 1f

6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 1e (6.55 g, 17.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (8.73 g, 34.4 mmol), potassium acetate (3.71 g, 37.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.393 g, 0.430 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS, 0.819 g, 1.72 mmol) were combined and stirred with argon sparge for 1 hour. Dioxane (86 mL) was sparged with nitrogen for 1 hour, transferred to the solid component via cannula under nitrogen, and the mixture was heated at 80° C. under argon for 5 hours. The reaction mixture is cooled to environment temperature, distributed between ethyl acetate and water, and filtered through diatomite.Ethyl acetate layer is washed twice with saturated sodium chloride aqueous solution, dried (anhydrous sodium sulfate), filtered and concentrated.Residue is purified by chromatography (silica gel, 25-80% ethyl acetate/hexane).From the material gained by chromatography, triturate with minimum hexane (30mL) and collect particle solid by filtration, wash with minimum hexane and be dried to constant weight to obtain title compound (5.4 g, 73%).

Example 1g

(3-Bromo-4-fluorophenyl)(isopropyl)sulfane

3-Bromo-4-fluorothiophenol (3.89 g, 18.79 mmol), sodium hydroxide (3.95 mL, 19.73 mmol), and methanol were added to a 250 mL round-bottom flask. The reaction mixture was stirred at 0°C for 10 minutes. 2-Iodopropane (3.83 g, 22.54 mmol) was added to the solution. The reaction mixture was stirred at ambient temperature for 6 hours. The solvent was removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with additional ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound.

Example 1h

2-Bromo-1-fluoro-4-(isopropylsulfonyl)benzene

To a 500 mL round-bottom flask was added Example 1g (4.0 g, 16.06 mmol) and dichloromethane (200 mL). mCPBA (8.71 g, 35.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was filtered and the solid was washed with additional dichloromethane. The filtrate was washed with 10% NaOH (50 mL, twice) and then with saturated sodium bicarbonate. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel (15% ethyl acetate/heptane) to give the title compound.

Example 1i

2-Bromo-N-(cyclopropylmethyl)-4-(isopropylsulfonyl)aniline

A mixture of Example 1h (0.562 g, 2 mmol) and cyclopropylmethylamine (0.427 g, 6.00 mmol) in dioxane (10 mL) was heated overnight at 100° C. The solvent was removed and the residue was purified by flash chromatography (50% ethyl acetate/heptane) to provide the title compound.

Example 1j

4-(2-((Cyclopropylmethyl)amino)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 1f (0.086 g, 0.2 mmol), Example 1i (0.066 g, 0.2 mmol), cesium fluoride (0.091 g, 0.600 mmol), and tetrakistriphenylphosphine palladium (0.012 g, 10.00 μmol) in dimethoxyethane (2 mL) and methanol (1 mL) was heated under microwave conditions (120°C, 40 min). The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to provide the title compound.

Example 1k

4-(Cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 4 mL vial was added Example 1j (0.0106 g, 0.027 mmol), paraformaldehyde (3.98 mg, 0.133 mmol), and methanol (0.265 mL) to give a white suspension. Hydrochloric acid (4N in dioxane, 0.133 mL, 0.531 mmol) was added. The vial was sealed and the reaction mixture was heated at 90°C for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with diethyl ether. The resulting suspension was filtered, and the solid was washed with diethyl ether, collected, and dried in a vacuum oven at 60°C overnight to give a white solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 8.04 (d, J = 2.04 Hz, 1H), 7.65 (m, 2H), 7.41 (d, J = 8.82 Hz, 1H), 7.18 (d, J = 2.03 Hz, 1H), 4.26 (s,2H), 3.64 (s, 3H), 3.49 (m, 1H), 3.03 (d, J = 6.1 Hz, 2H), 1.20 (d, J = 6.78Hz, 6H), 0.90 (m, 1H), 0.41 (m, 2H), 0.09 (q, J = 4.63 Hz, 2H). MS (ESI+) m/z412.1 (M+H) ⁺ .

Example 2

4-(Cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 2a

(3-Bromo-4-fluorophenyl)(ethyl)sulfane

A mixture of 3-bromo-4-fluorothiophenol (3.89 g, 18.79 mmol) and sodium hydroxide (3.95 mL, 19.73 mmol) in methanol was stirred at 0°C for 10 minutes. To this solution was added iodoethane (1.803 mL, 22.54 mmol). The reaction mixture was stirred at ambient temperature for 6 hours. The solvent was removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (4.35 g, 18.50 mmol, 98% yield).

Example 2b

2-Bromo-4-(ethylsulfonyl)-1-fluorobenzene

Example 2a (4.4 g, 18.71 mmol) in dichloromethane (250 mL) was cooled to 0°C. To this solution was added mCPBA (10.15 g, 41.2 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 6 hours. The solids in the reaction mixture were removed by filtration. The filtrate was washed several times with saturated aqueous sodium bicarbonate solution. The aqueous layer was then extracted three times with additional dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane to provide the title compound (4.4 g, 16.47 mmol, 88% yield).

Example 2c

2-Bromo-N-(cyclopropylmethyl)-4-(ethylsulfonyl)aniline

Example 2c was prepared according to the procedure used to prepare Example 1i, substituting Example 2b for Example 1h to provide the title compound.

Example 2d

4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 2d was prepared according to the procedure used to prepare Example 1j, substituting Example 2c for Example 1i to provide the title compound.

Example 2e

4-(Cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 2d (0.03 g, 0.078 mmol) and paraformaldehyde (0.012 g, 0.389 mmol) in methanol (0.778 mL) was treated with 4M hydrochloric acid (0.389 mL, 1.557 mmol). The mixture was heated at 90°C for 1 hour, cooled, and concentrated. Purification by chromatography (silica gel, 1-5% methanol/dichloromethane) afforded the title compound (0.022 g, 71%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.51 (s, 1H), 8.08 (d, J = 2.14 Hz, 1H), 7.66 (dd, J = 8.54, 2.14 Hz, 1H), 7.58 (s, 1H), 7.44 (d, J = 8.54 Hz, 1H), 7.12(d, J = 2.75 Hz, 1H), 4.27 (s, 2H), 3.64 (s, 3H), 3.28 (d, J = 7.32 Hz, 2H), 3.03 (d, J = 6.10 Hz, 2H), 1.18 (t, J = 7.32 Hz, 3H), 0.83-0.98 (m, 1H), 0.33-0.43 (m, 2H), 0.04-0.11 (m, 2H). MS (ESI+) m/z 398 (M+H) ⁺ .

Example 3

4-(Cyclopropylmethyl)-3-ethyl-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 2d (0.045 g, 0.117 mmol) and propionaldehyde (0.136 g, 2.335 mmol) in methanol (1.167 mL) was treated with 4M hydrochloric acid (0.584 mL, 2.34 mmol). The mixture was heated at 90°C for 3 hours, cooled, and concentrated. The residue was dissolved in ethyl acetate, washed with 5% aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried (anhydrous _Na2SO4 ), filtered, and concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) gave a solid, which was triturated in a minimum of 30% ethyl acetate/heptane _to yield the title compound (0.017 g, 34%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 8.05 (s, 1H), 7.70 (s, 1H), 7.65 (dd, J = 8.31,2.20 Hz, 1H), 7.41 (d, J = 8.48 Hz, 1H), 7.14 (d, J = 2.37 Hz, 1H), 4.37 (s,1H), 3.64 (s, 3H), 3.37 (q, J = 7.29 Hz, 2H), 3.13 (s, 1H), 2.93 (s, 1H),1.41-1.59 (m, 1H), 1.14 (t, J = 7.29 Hz, 3H), 1.03-1.09 (m, 1H), 0.86 (t, J =6.78 Hz, 3 H), 0.77-0.88 (m, 1H), 0.36 (d, J = 8.14 Hz, 2H), 0.03-0.10 (m, 2H). MS (ESI+) m/z 426 (M+H) ⁺ .

Example 4

10-Methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 4a

4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Combine 2-bromo-4-(methylsulfonyl)aniline (1.0 g, 4.00 mmol), Example 1f (1.712 g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.110 g, 0.120 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.117 g, 0.400 mmol), and sodium carbonate (1.483 g, 13.99 mmol) and sparge with argon for 15 minutes. Simultaneously, sparge a 4:1 dioxane/water solution (26 mL) with nitrogen for 15 minutes and transfer to the reaction vessel via syringe under argon. The mixture was stirred at 60°C for 3 hours, cooled and diluted into 100 mL of water. The resulting solid was collected by filtration, washed with water and dried to constant weight to give the title compound (2.05 g, 100%).

Example 4b

4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 4b was prepared according to the procedure used to prepare Example 5e, substituting Example 4a for Example 5d. Purification by trituration in dichloromethane afforded the title compound (0.55 g, 82%).

Example 4c

10-Methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 4c was prepared according to the procedure used for Example 1k, substituting Example 4b for Example 1j, to provide the title compound as its HCl salt (0.046 g, 98%). ^H NMR (400 MHz, DMSO- d ₆ ) δ 11.53 (s, 1H), 8.14 (d, J = 2.14 Hz, 1H), 7.63 (s, 1H), 7.56 (dd, J = 8.39, 2.29 Hz, 1H), 7.23 (d, J = 8.54 Hz, 1H), 7.13 (d, J = 2.44 Hz, 1H), 4.23 (s, 2H), 3.65 (s, 3H), 3.17 (s, 3H). MS (ESI+) m/z 330 (M+H) ⁺ .

Example 5

10-Methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 5a

1-((Methylsulfonyl)methyl)-4-nitrobenzene

To a solution of 4-nitrobenzyl bromide (10.02 g, 46.4 mmol) in N,N-dimethylformamide (25 mL) was added sodium methanesulfinate (7.10 g, 69.6 mmol). The reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with water. The resulting suspension was stirred for 10 minutes and filtered through a medium-sized glass fritted funnel to provide the title compound.

Example 5b

4-((Methylsulfonyl)methyl)aniline

Example 5a (8.2 g, 38.1 mmol) and tetrahydrofuran (200 mL) were added to a 50 mL pressure bottle containing wet 5% Pd/C (1.6 g, 0.376 mmol). Stir at 30 psi and 50°C for 2 hours. The mixture was filtered through a nylon membrane and washed with small amounts of tetrahydrofuran and methanol. The solvent was removed to yield the title compound.

Example 5c

2-iodo-4-((methylsulfonyl)methyl)aniline

To a solution of Example 5b (3.80 g, 20.51 mmol) in N,N-dimethylformamide (103 mL) was added N-iodosuccinimide (5.08 g, 22.56 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with 150 mL of 10% sodium thiosulfate and 100 mL of saturated sodium bicarbonate. The reaction mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and concentrated. Water was added and the resulting suspension was stirred at ambient temperature for 10 minutes. The suspension was filtered and dried overnight to obtain the title compound.

Example 5d

4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 100 mL round-bottom flask were added Example 5c (0.160 g, 0.514 mmol), Example 1f (0.200 g, 0.467 mmol), potassium phosphate (0.446 g, 2.101 mmol), tris(dibenzylideneacetone)dipalladium(II) (0.021 g, 0.023 mmol) and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.023 g, 0.079 mmol). The solid was purged with a stream of nitrogen for 30 minutes. Degassed dioxane (3.74 mL) and water (0.934 mL) were added. The reaction mixture was heated at 60 ° C for 3 hours. The reaction mixture was cooled to ambient temperature and diluted with water. The resulting suspension was filtered and a brown solid was collected.

Example 5e

4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 250 mL round-bottom flask was added Example 5d (0.230 g, 0.474 mmol), potassium hydroxide (0.691 g, 12.32 mmol), N,N,N-trimethylhexadecyl-1-ammonium bromide (8.63 mg, 0.024 mmol), dioxane (3.55 mL), and water (1.18 mL) to give a light yellow solution. The reaction mixture was heated at 90°C overnight. The reaction mixture was cooled to ambient temperature and treated with 1N hydrochloric acid to a pH of 1. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (0%-10% methanol/dichloromethane) to provide the title compound.

Example 5f

10-Methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 20 mL microwave tube was added Example 5e (0.0397 g, 0.120 mmol), paraformaldehyde (0.018 g, 0.599 mmol), and methanol (1.198 mL) to give a white suspension. Hydrochloric acid (4N in dioxane, 0.599 mL, 2.396 mmol) was added. The reaction mixture was heated at 90°C for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with ether and ethyl acetate. The reaction mixture was washed with saturated sodium bicarbonate and saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (0%-10% methanol/dichloromethane) to give the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.75 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.50 (s, 1H), 7.07-7.15 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 4.37 (s, 2H), 4.11 (d, J = 3.2Hz, 2H), 3.61 (s, 3H), 2.90 (s, 3H). MS (ESI+) m/z 344.4 (M+H) ⁺ .

Example 6

4-(Cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 6a

N-(Cyclopropylmethyl)-2-iodo-4-((methylsulfonyl)methyl)aniline

Example 5c (0.200 g, 0.643 mmol) and cyclopropanecarboxaldehyde (0.062 mL, 0.836 mmol) were suspended in dichloromethane (3.21 mL) and methanol (3.21 mL). Acetic acid (0.368 mL, 6.43 mmol) was added. The reaction mixture was heated at 50 ° C for 30 minutes and then cooled to ambient temperature. Polymer-supported cyanoborohydride (0.817 g, 1.928 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. Cyclopropanecarboxaldehyde (0.062 mL, 0.836 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered, washed thoroughly with dichloromethane, and concentrated. The title compound was obtained by purifying the residue by flash chromatography (20-100% ethyl acetate/heptane).

Example 6b

4-(2-((Cyclopropylmethyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 250 mL round-bottom flask were added Example 6a (0.1546 g, 0.423 mmol), Example 1f (0.404 g, 1.905 mmol), tris(dibenzylideneacetone)dipalladium(II) (0.019 g, 0.021 mmol), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.021 g, 0.072 mmol). The solid was purged with nitrogen for 30 minutes. Degassed dioxane (3.40 mL) and water (0.850 mL) were added. The reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (0-5% methanol/dichloromethane) to provide the title compound (0.211 g, 92% yield).

Example 6c

4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a 250 mL round-bottom flask was added Example 6b (0.211 g, 0.391 mmol), potassium hydroxide (0.570 g, 10.17 mmol), N,N,N-trimethylhexadecyl-1-ammonium bromide (7.12 mg, 0.020 mmol), dioxane (2.93 mL), and water (0.977 mL). The reaction mixture was heated at 90°C for 2.5 hours. The reaction mixture was cooled to ambient temperature and treated with 1N HCl to a pH of approximately 7. The reaction mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound (0.0886 g, 59% yield).

Example 6d

4-(Cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5 mL microwave tube was added Example 6c (0.027 g, 0.070 mmol), paraformaldehyde (0.032 g, 0.350 mmol), and methanol (0.700 mL) to give a white suspension. 4N HCl/dioxane (0.350 mL, 1.401 mmol) was added. The tube was sealed and heated at 90°C for 1 hour. The reaction was cooled to room temperature and diluted with diethyl ether. The resulting suspension was filtered, and the solid was washed with diethyl ether, collected, and dried in a vacuum oven at 60°C overnight to give the title compound. ¹ H NMR (400MHz, DMSO- d ₆ 90 ℃) δ 11.64 (m, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.39-7.52(m, 1H), 7.32 (d, J = 7.1 Hz, 1H), 7.19 (s, 1H), 4.44 (s, 2H), 4.40 (s, 2H), 3.55 (s, 1H), 2.84-2.92 (m, 5H), 0.85 (s, 1H), 0.35 (dd, J = 7.9, 1.1 Hz,2H), -0.02-0.04 (m, 2H). MS (ESI+) m/z 398.0 (M+H) ⁺ .

Example 7

4-(Cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester

Example 6c (0.027 g, 0.070 mmol), ethyl glyoxylate (0.069 mL, 0.350 mmol) and ethanol (0.700 mL) were added to a 5 mL microwave tube to obtain a white suspension. Hydrochloric acid (4N in dioxane, 0.350 mL, 1.401 mmol) was added to convert the suspension into a colorless solution. The vial was sealed and the reaction mixture was heated at 90°C for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with ether to form a white precipitate. The resulting suspension was filtered, washed with ether, and the resulting solid was collected and dried in a 60°C vacuum oven overnight. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1%TFA), 0-100% gradient) to obtain the title compound (0.0090 g, 27%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.91 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.21 (dd, J = 13.0, 5.3Hz, 4H), 5.39 (s, 1H), 4.42 (m, 2H), 3.83 (s, 2H), 3.83 (s, 2H), 3.63 (s,3H), 2.86 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H), 0.83 (m, 1H), 0.29-0.46 (m, 2H), 0.07 (m, 2H). MS (ESI+) m/z 470.0 (M+H) ⁺ .

Example 8

4-(4-Fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 8a

4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Combine Example 1f (1.71 g, 4.00 mmol), 2-bromo-4-(methylsulfonyl)aniline (1.00 g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium (0.110 g, 0.120 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.117 g, 0.400 mmol), and sodium carbonate (1.48 g, 14.0 mmol) and purge with argon for 15 minutes. A mixture of dioxane (21.3 mL) and water (5.3 mL) was purged with nitrogen for 15 minutes and transferred to a reaction vessel. The reaction mixture was heated at 60°C for 3 hours, cooled to ambient temperature, and diluted with water. The resulting solid was filtered, washed with water, and dried to afford the title compound (2.06 g, quantitative yield).

Example 8b

4-(2-((4-fluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 8a (47.2 mg, 0.100 mmol), 1-bromo-4-fluorobenzene (17.5 mg, 0.100 mmol), palladium acetate (0.9 mg, 4 μmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (3.8 mg, 8.0 μmol), and cesium carbonate (45.6 mg, 0.140 mmol) were combined in a mixture of toluene (1.6 mL) and tert-butanol (0.4 mL). The reaction mixture was heated at 150°C in a microwave reactor for 15 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl-functionalized silica gel, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to provide the title compound (30 mg, 53%).

Example 8c

4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 8b (28 mg, 0.050 mmol), potassium hydroxide (41.7 mg, 0.743 mmol), and hexadecyltrimethylammonium bromide (0.90 mg, 2.5 μmol) were combined in a mixture of tetrahydrofuran (2 mL) and water (1 mL). The reaction mixture was heated at 100°C for 20 hours and then cooled to ambient temperature. Water was added to the mixture, and the pH was adjusted to pH 7 with 1M HCl. The mixture was extracted with ethyl acetate, and the organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to provide the title compound (13 mg, 64%).

Example 8d

4-(4-Fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 8c (8.0 mg, 0.019 mmol), paraformaldehyde (5.8 mg, 0.19 mmol) and methanol (0.5 mL) were added to a 2 mL vial. 4M HCl/dioxane (0.097 mL, 0.39 mmol) was added to the suspension. The vial was sealed and stirred at 90 ° C for 4 hours. The reaction mixture was cooled to ambient temperature and concentrated. Water was added to the residue, and the pH was adjusted to pH 7 by adding saturated sodium bicarbonate aqueous solution. The residue was sonicated for 5 minutes and filtered to obtain the title compound (7.0 mg, 85%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.88 (d, J=1.70 Hz, 1 H) 8.37 (d, J=2.37 Hz, 1 H) 7.88 (dd, J=8.14, 2.37 Hz, 1 H) 7.85 (s, 1 H) 7.53 (d, J=8.14 Hz, 1 H) 7.35 (d, J=2.37 Hz, 1 H) 6.75-6.91 (m, 2 H) 6.43-6.51 (m, 2 H)4.80 (s, 2 H) 3.59 (s, 3 H) 3.36 (s, 3 H). MS (ESI+) m/z 424 (M+H) ⁺ .

Example 9

4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 9a

1-Bromo-4-((methylsulfonyl)methyl)benzene

To a 250 mL round-bottom flask was added 4-bromobenzyl bromide (5.000 g, 20.01 mmol) and N,N-dimethylformamide (10.81 mL) to give a colorless solution. Sodium methanesulfinate (3.06 g, 30.0 mmol) was added, and the reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with water. The resulting suspension was stirred for 10 minutes and filtered. The solid was washed with water and dried under house vacuum for two days to give the title compound (4.75 g, 95% yield).

Example 9b

4-Fluoro-N-(4-((methylsulfonyl)methyl)phenyl)aniline

To a 100 mL microwave tube was added 4-fluoroaniline (0.388 mL, 4.04 mmol), Example 9a (1.0065 g, 4.04 mmol), palladium acetate (0.036 g, 0.162 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.154 g, 0.323 mmol), cesium carbonate (1.843 g, 5.66 mmol), toluene (20.20 mL), and tert-butanol (4.04 mL) to yield a yellow suspension. The tube was sealed, and the reaction mixture was heated to 150°C in a Milestone Ethos microwave reactor for a fixed time of 15 minutes. The reaction mixture was filtered through a 10 g Celite SPE cartridge and washed with ethyl acetate. The filtrate was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated onto silica gel. The crude product was purified by flash chromatography (20-100% ethyl acetate/heptane) to provide the title compound as an off-white solid.

Example 9c

2-Bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline

Example 9b (1.32 g, 4.73 mmol) and acetic acid (47.3 mL) were added to a 250 mL round-bottom flask to give a white suspension. The reaction mixture was cooled in a water bath. N-bromosuccinimide (0.807 g, 4.54 mmol) was added in two portions 10 minutes apart. The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was quenched with 10% sodium thiosulfate (40 mL) and diluted with 2N sodium hydroxide and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated onto silica gel. The crude product was purified by flash chromatography (20-70% ethyl acetate/heptane) to obtain the title compound as a white solid.

Example 9d

4-(2-((4-Fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 250 mL round-bottom flask were added Example 9c (1.9175 g, 5.35 mmol), Example 1f (2.084 g, 4.87 mmol), sodium carbonate (1.805 g, 17.03 mmol), tris(dibenzylideneacetone)dipalladium(II) (0.223 g, 0.243 mmol), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.242 g, 0.827 mmol). The solid was purged with nitrogen for 30 minutes. Degassed dioxane (38.9 mL) and water (9.73 mL) were added. The reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and mercaptopropyl silica gel, filtered, and concentrated. The residue was taken up in dichloromethane, triturated with ether, and filtered to afford the title compound (2.13 g, 75% yield).

Example 9e

4-(2-((4-Fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 250 mL round-bottom flask was added Example 9d (2.1251 g, 3.67 mmol), potassium hydroxide (5.35 g, 95 mmol), N,N,N-trimethylhexadecyl-1-ammonium bromide (0.067 g, 0.183 mmol), dioxane (55.0 mL), and water (18.33 mL). The reaction mixture was heated at 90°C for 2.5 hours. The reaction mixture was cooled to room temperature and diluted to 500 mL (total volume) with water. The resulting suspension was filtered, and the solid was washed with water and dried on a glass frit funnel for 1.5 hours. The solid was collected and dried in a vacuum oven at 60°C overnight to give the title compound (1.24 g, 80% yield).

Example 9f

4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 20 mL microwave tube was added Example 9e (0.5195 g, 1.221 mmol), paraformaldehyde (0.550 g, 6.10 mmol), and methanol (12.21 mL) to give a white suspension. Hydrochloric acid (4N in dioxane, 6.10 mL, 24.42 mmol) was added. The vial was sealed and the reaction mixture was heated at 90°C for 1 hour. The reaction mixture was cooled to ambient temperature. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dispersed in dichloromethane and triturated with diethyl ether. The resulting slurry was stirred for 10 minutes and filtered. The white solid was washed with diethyl ether, collected, and dried in a vacuum oven at 60°C overnight to give the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.90-11.84 (m, 1H),7.91 (d, J = 1.9 Hz, 1H), 7.61 (s, 1H), 7.44 (dd, J = 8.0, 1.9 Hz, 1H), 7.33(d, J = 4.9 Hz, 2H), 6.80 (t, J = 8.8 Hz, 2H), 6.35-6.46 (m, 2H), 4.56 (m,2H), 3.55 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z 438.2 (M+H) ⁺ .

Example 10

4-(Cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-7-sulfonamide

Example 10a

5-Bromo-6-((cyclopropylmethyl)amino)pyridine-3-sulfonamide

A mixture of 5-bromo-6-chloropyridine-3-sulfonamide (0.272 g, 1 mmol) and cyclopropylmethylamine (0.213 g, 3.00 mmol) in dioxane (5 mL) was heated at 100°C overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 60% ethyl acetate/hexane to yield 0.298 g (97%) of the title compound.

Example 10b

6-[(Cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 10b was prepared according to the procedure used to prepare Example 1j, substituting Example 10a for Example 1i to provide the title compound.

Example 10c

4-(Cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-7-sulfonamide

Example 10c was prepared according to the procedure used to prepare Example 1k, substituting Example 10b for Example 1j to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.90 (s, 1H), 8.46 (d, J = 2.44 Hz,1H), 8.31 (d, J = 2.44 Hz, 1H), 7.51 (s, 1H), 7.31 (s, 2H), 7.22 (d, J = 2.44Hz, 1H), 4.39 (s, 2H), 3.63 (s, 3H), 3.48 (d, J = 6.41 Hz, 2H), 0.45 (dd, J =8.09, 1.68 Hz, 2H), 0.25 (dd, J = 4.88 Hz, 2H). MS (ESI+) m/z 386.1 (M+H) ⁺ .

Example 11

4-(4-Fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazatribenzo[cd,f]azulene-11(10H)-one

Example 11a

3-Bromo-N-(4-fluorophenyl)-5-methylpyridin-2-amine

Combine 2-amino-3-bromo-5-methylpyridine (0.468 g, 2.5 mmol), 4-fluoroiodobenzene (0.555 g, 2.500 mmol), palladium acetate (0.017 g, 0.075 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.043 g, 0.075 mmol), and sodium 2-methylpropan-2-ol (0.336 g, 3.50 mmol) in tert-butanol (10.00 mL) and sparge with argon for 10 minutes. Heat the mixture at 85°C for 60 minutes, cool, dilute with 50 mL of ethanol, and filter through Celite to remove solids. The concentrated filtrate is diluted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), treated with 3-mercaptopropyl-functionalized silica, filtered, and concentrated. Purification by chromatography (silica gel, 0-25% ethyl acetate/heptane) provided the title compound (0.317 g, 45%).

Example 11b

4-(2-((4-Fluorophenyl)amino)-5-methylpyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Combine Example 11a (0.3 g, 1.067 mmol), Example 1f (0.457 g, 1.067 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.032 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.031 g, 0.107 mmol), and sodium carbonate (0.396 g, 3.74 mmol) and purge with argon for 15 minutes. A 4:1 dioxane/water solution (12 mL) was bubbled with nitrogen for 15 minutes and transferred to the reaction vessel via syringe under argon. The mixture was stirred at 60°C for 1 hour, cooled, and partitioned between 100 mL of water and 120 mL of dichloromethane. The organic layer was washed with water, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), treated with 3-mercaptopropyl-functionalized silica, filtered, and concentrated. Purification by trituration with 9:1 heptane/ethyl acetate afforded the title compound (0.46 g, 86%).

Example 11c

4-(2-((4-Fluorophenyl)amino)-5-methylpyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 11c was prepared according to the procedure used to prepare Example 5e, substituting Example 11b for Example 5d. Purification by trituration in dichloromethane afforded the title compound (0.20 g, 63%).

Example 11d

4-(4-Fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 11c (0.05 g, 0.144 mmol), paraformaldehyde (0.043 g, 1.435 mmol) and 4M hydrochloric acid (1.076 mL, 4.31 mmol) in methanol (1.435 mL) in a sealed microwave tube was heated at 130 ° C for 2 hours. The mixture was concentrated and the residue was distributed between ethyl acetate and 5% sodium bicarbonate aqueous solution. The organic layer was washed with saturated sodium chloride solution, dried (anhydrous sodium sulfate), filtered and concentrated. The title compound (0.008 g, 14%) was obtained by purification by chromatography (silica gel, 1-4% methanol/dichloromethane). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.48(s, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.63 (s, 1H), 7.27 (s, 1H), 6.78 (t, J =9.00 Hz, 2H), 6.49-6.55 (m, 2H), 4.74 (s, 2H), 3.57 (s, 3H), 2.39 (s, 3H). MS(ESI+) m/z 361 (M+H) ⁺ .

Example 12

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 12a

2,4-Difluoro-N-(4-((methylsulfonyl)methyl)phenyl)aniline

To a 100 mL microwave tube was added 2,4-difluoroaniline (1.235 mL, 12.26 mmol), Example 9a (3.0539 g, 12.26 mmol), palladium acetate (0.055 g, 0.245 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.234 g, 0.490 mmol), cesium carbonate (5.59 g, 17.16 mmol), toluene (40.9 mL), and tert-butanol (8.17 mL). The tube was sealed, and the reaction mixture was heated in a Milestone Ethos microwave, gradually increasing to 150°C over 5 minutes and then holding for a fixed time of 10 minutes. The reaction mixture was filtered through a 10 g Celite SPE cartridge and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (20-100% ethyl acetate/heptane) to provide the title compound (3.44 g, 94% yield).

Example 12b

2-Bromo-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline

To a 500 mL round-bottom flask was added Example 12a (3.4409 g, 11.57 mmol) and acetic acid (116 mL). The reaction mixture was placed in a water bath. N-bromosuccinimide (2.060 g, 11.57 mmol) was added in two portions 10 minutes apart. The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was quenched with 200 mL of 10% sodium thiosulfate and diluted with water. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with 2N NaOH (until the pH of the aqueous layer was >7) and once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dispersed in ethyl acetate and then treated with heptane. The resulting slurry was stirred for 30 minutes and filtered to yield the title compound (3.82 g, 88% yield).

Example 12c

4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 250 mL round-bottom flask was added Example 12b (1.9813 g, 5.27 mmol), Example 1f (2.051 g, 4.79 mmol), sodium carbonate (1.776 g, 16.76 mmol), tris(dibenzylideneacetone)dipalladium(II) (0.219 g, 0.239 mmol), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.238 g, 0.814 mmol). The solid was purged with nitrogen for 30 minutes. Degassed dioxane (38.3 mL) and water (9.58 mL) were added. The reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The residue was taken up in dichloromethane, triturated with ether, and filtered to afford the title compound (2.30 g, 80% yield).

Example 12d

4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 20 mL microwave tube was added Example 12c (1.9830 g, 3.32 mmol), lithium hydroxide monohydrate (1.392 g, 33.2 mmol), dioxane (16 mL), and water (5.33 mL) to give a white suspension. The reaction mixture was heated at 50°C for 72 hours. The reaction mixture was cooled to ambient temperature and diluted with water. The resulting suspension was filtered, and the solid was washed with water and dried under vacuum overnight (1.25 g, 85% yield).

Example 12e

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5 mL microwave tube was added Example 12d (0.0504 g, 0.114 mmol), paraformaldehyde (0.051 g, 0.568 mmol) and methanol (1.137 mL). 4N HCl/dioxane (0.568 mL, 2.273 mmol) was added. The tube was sealed and the reaction mixture was heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with ether. The resulting suspension was filtered, and the solid was washed with ether and collected. The solid and filtrate were combined and purified by flash chromatography (0-5% methanol/dichloromethane) to give the title compound (0.0234 g, 45% yield). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.26 (d, J = 10.2 Hz, 1H), 6.99-7.19(m, 3H), 6.81 (s, 1H), 4.72-4.78 (m, 2H), 4.49 (d, J = 1.1 Hz, 3H), 4.01 (m,1H), 3.62 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 456.3 (M+H) ⁺ .

Example 13

4-(Cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 13a

2-Bromo-N-(cyclopropylmethyl)aniline

To a 100 mL flask was added 2-bromoaniline (1.72 g, 10.0 mmol), cyclopropanecarboxaldehyde (0.374 mL, 5.00 mmol), acetic acid (2.86 mL, 50.0 mmol), and dichloromethane (50 mL). The resulting solution was heated at 50°C for 1 hour. The solution was cooled in an ice bath, and sodium triacetoxyborohydride (2.119 g, 10.0 mmol) was added portionwise over several minutes. After 15 minutes, the ice bath was removed, and the solution was stirred for 2 hours while warming to ambient temperature. The reaction mixture was quenched with 2.5 M sodium hydroxide (approximately 15 mL) and partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-10% ethyl acetate/heptane) to yield the title compound (1.05 g, 93%).

Example 13b

4-(2-((Cyclopropylmethyl)amino)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 25 mL vial was added Example 1f (244 mg, 0.570 mmol), tris(dibenzylideneacetone)dipalladium(0) (15.66 mg, 0.017 mmol), Example 13a (132.1 mg, 0.584 mmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (18.33 mg, 0.063 mmol) and potassium phosphate (363 mg, 1.710 mmol). The mixture was purged with argon for 30 minutes. A mixture of dioxane (4 mL) and water (1 mL) was added to the vial [which had been degassed with argon for 30 minutes]. The mixture was heated at 75° C. for 2.5 hours. After cooling, the reaction mixture was partitioned between ethyl acetate (75 mL) and 50% saturated aqueous sodium chloride solution (100 mL). The layers were separated and the organic layer was treated with 3-mercaptopropyl functionalized silica gel (Aldrich), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-3% methanol/dichloromethane) to provide the title compound (266 mg, 100%).

Example 13c

4-(2-((Cyclopropylmethyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 25 mL flask was added Example 13b (255 mg, 0.570 mmol), hexadecyltrimethylammonium bromide (10.38 mg, 0.028 mmol), potassium hydroxide (615 mg, 10.96 mmol), dioxane (9 mL), and water (3 mL). The mixture was heated at 90°C for 2.5 hours. After cooling, the mixture was neutralized with 1M aqueous hydrochloric acid and partitioned between ethyl acetate (80 mL) and 50% saturated aqueous sodium chloride solution (75 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to give the title compound (120 mg, 72%).

Example 13d

4-(Cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5 mL microwave vial was added Example 13c (60 mg, 0.205 mmol), paraformaldehyde (92 mg, 1.023 mmol), methanol (2 mL) and hydrochloric acid (4M / dioxane, 1.023 mL, 4.09 mmol). The vial was sealed and the reaction mixture was heated at 90 ° C for 1 hour. After cooling, the reaction mixture was partitioned between 50% saturated bicarbonate solution (100 mL) and ethyl acetate (75 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to give the title compound (52 mg, 83%). 1H NMR (400 MHz, DMSO- d ₆ ) δ 11.74 (s, 1H), 7.63-7.67 (m, 1H), 7.59 (s,1H), 7.10-7.25 (m, 4H), 4.19 (s, 2H), 3.60 (s, 3H), 2.68 (d, J=6.41 Hz, 2H), 0.74-0.87 (m, 1H), 0.45-0.36 (m, 2H), -0.07 (q, J=4.78 Hz, 2H). MS (ESI+) m/z306.0 (M+H) ⁺ .

Example 14

Methyl 3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

The stock solution of Example 6c (0.086 M in methanol, 455 μL, 0.040 mmol, 1.0 equiv), HCl (4.0 M/dioxane, 195 μL, 0.78 mmol, 20 equiv) and methyl 4-oxobutanoate (0.40 M in methanol, 243 μL, 0.19 mmol, 5 equiv) were combined and heated at 90° C. under microwave conditions for 99 minutes. The reaction mixture was concentrated and purified by reverse phase HPLC (C8 column, CH ₃ CN/water (0.1% ammonium acetate), 5-100% gradient) to give the title compound (5.1 mg, 27% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.70 (s, 1H), 7.52 (s, 1H), 7.22-7.33(m, 2H), 7.12 (s, 1H), 4.43 (bs, 1H), 3.63 (s, 2H), 3.55 (m, 4H), 2.89 (s,3H), 1.71 (m, 2H), 0.74 (s, 1H), 0.02-0.37 (m, 2H), -0.13 (s, 2H). MS (APCI)m/z 484.1 (M+H) ⁺ .

Example 15

4-(Cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Combine the stock solution of Example 6c (0.086 M in methanol, 455 μL, 0.040 mmol, 1.0 equiv), HCl (4.0 M/dioxane, 195 μL, 0.78 mmol, 20 equiv) and 3-methoxypropanal (0.40 M in methanol, 243 μL, 0.19 mmol, 5 equiv) and heat under microwave conditions at 90° C. for 99 minutes. The reaction mixture was concentrated and purified by reverse phase HPLC (C8 column, CH ₃ CN/water (0.1% ammonium acetate), 5-100% gradient) to give the title compound. ¹ H NMR (400MHz, DMSO- d ₆ -D ₂ O) δ 7.69 (bs, 1H), 7.51 (s, 1H), 7.19-7.32 (m, 2H), 7.10 (s,1H), 4.42 (bs, 2H), 3.63 (s, 3H), 2.74-2.93 (m, 5H), 1.77 (s, 2H), 1.08-1.43 (m, 1H), 0.70-0.83 (m, 1H), 0.02-0.40 (m, 2H), -0.11 (s, 2H). MS (APCI) m/z456.1 (M+H) ⁺ .

Example 16

3-Benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The stock solution of Example 5e (0.11 M in methanol, 417 μL, 0.045 mmol, 1.0 equiv), HCl (4.0 M/dioxane, 226 μL, 0.90 mmol, 20 equiv) and 2-phenylacetaldehyde (0.40 M in methanol, 189 μL, 0.225 mmol, 5 equiv) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm ID), and loaded into the injection loop. The reaction portion was injected into a continuous reactor (Hastelloy coil, 0.75 mm ID, 1.8 mL internal volume) set at 100° C. and passed through the reactor at 180 μL/min (10 minute residence time). After exiting the reactor, the reaction mixture was directly loaded into an injection loop and purified by reverse phase HPLC (C8 column, CH ₃ CN/water (0.1% ammonium acetate), 5-100% gradient) to afford the title compound (3.4 mg, 17% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.70 (d, J = 2.0 Hz, 1H), 7.51 (s, 1H), 7.27 (t, J = 7.2 Hz, 2H), 7.21 (dd, J = 8.3, 6.1 Hz, 1H), 7.10 (dd, J = 10.1,4.3 Hz, 3H), 6.78 (d, J = 0.4 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.54 (t, J =7.2 Hz, 1H), 4.36 (bs, 2H), 3.64 (s, 3H), 2.91-3.01 (m, 2H), 2.88 (s, 3H). MS(APCI) m/z 434.0 (M+H) ⁺ .

Example 17

Methyl 3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

Example 17 was prepared according to the procedure used to prepare Example 16, substituting methyl 4-oxobutanoate for 2-phenylacetaldehyde to give the title compound (8.7 mg, 45% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.68 (d, J =2.0 Hz, 1H), 7.49 (s, 1H), 7.14 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (s, 1H), 7.03(d, J = 8.0 Hz, 1H), 4.36 (bs, 2H), 4.27 (t, J = 6.8 Hz, 1H), 3.63 (s, 3H), 3.55 (s, 3H), 2.87 (s, 3H), 2.26-2.46 (m, 2H), 1.75-1.97 (m, 2H). MS (APCI) m/z 430.0 (M+H) ⁺ .

Example 18

10-Methyl-7-((methylsulfonyl)methyl)-3-phenylethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 18 was prepared according to the procedure used in Example 16, using 3-phenylpropanal instead of 2-phenylacetaldehyde, to give the title compound (5.1 mg, 25% yield). ^1H NMR (400 MHz, DMSO -d6 _{- D2O} ) δ 7.67 (d, J = 2.0 Hz, 1H), 7.49 (s, 1H), 7.21 (t, J = 7.4 Hz, 2H), 7.01-7.19 (m, 6H), 4.36 (bs, 2H), 4.23-4.30 (m, 1H), 3.63 (s, 3H), 2.86 (s, 3H), 2.72-2.84 (m, 1H), 2.58-2.71 (m, 1H), 1.65-1.98 (m, 2H). MS (APCI) m/z 448.1 (M+H) ⁺ .

Example 19

3-Isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 19 was prepared according to the procedure used to prepare Example 16, substituting 3-methylbutanal for 2-phenylacetaldehyde to give the title compound (4.4 mg, 24% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.67 (d, J = 2.0Hz, 1H), 7.48 (s, 1H), 7.13 (dd, J = 8.1, 2.0 Hz, 1H), 7.09 (s, 1H), 7.00 (d,J = 8.0 Hz, 1H), 4.35 (bs, 2H), 4.27 (t, J = 7.0 Hz, 1H), 3.63 (s, 3H), 2.87(s, 3H), 1.63-1.79 (m, 1H), 1.54 (ddd, J = 13.6, 7.7, 6.0 Hz, 1H), 1.33-1.48(m, 1H), 0.89 (t, J = 6.6 Hz, 6H). MS (APCI) m/z 400.0 (M+H) ⁺ .

Example 20

(E)-3-(4-Fluorophenylvinyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 20 was prepared according to the procedure used to prepare Example 16, substituting (E)-3-(4-fluorophenyl)propenal for 2-phenylacetaldehyde to provide the title compound (4.8 mg, 23% yield). ¹ H NMR (400 MHz, DMSO-D ₂ O) δ 7.67 (s,1H), 7.52 (s, 1H), 7.31 (dd, J = 8.7, 5.6 Hz, 2H), 7.11-7.17 (m, 1H), 7.01-7.11 (m, 4H), 6.45 (d, J = 15.8 Hz, 1H), 6.29 (dd, J = 15.9, 6.9 Hz, 1H), 5.00 (d, J = 6.7 Hz, 1H), 4.35 (s, 2H), 3.65 (s, 3H), 2.82 (s, 3H). MS (APCI)m/z 464.0 (M+H) ⁺ .

Example 21

7-Amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

Example 21a

Combine 3-bromo-2-chloro-5-nitropyridine (3.936 g, 16.58 mmol), 4-fluoroaniline (5.53 g, 49.7 mmol), and dimethyl sulfoxide (DMSO) (33.2 mL) and stir at 120°C for 1 hour. The reaction mixture is cooled to ambient temperature, resulting in the formation of a solid. Further precipitation is induced by the addition of 150 mL of water. The solid is collected by filtration and washed with 600 mL of water. The solid is purified by flash chromatography (silica gel, 0-20% ethyl acetate/heptane) and then triturated with 15% ethyl acetate/heptane to yield 4.2 g (81%) of the title compound.

Example 21b

4-(2-((4-Fluorophenyl)amino)-5-nitropyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 21b was prepared according to the procedure used to prepare Example 1j, substituting Example 21a for Example 1i to provide the title compound.

Example 21c

4-(4-Fluorophenyl)-10-methyl-7-nitro-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

Example 21c was prepared according to the procedure used to prepare Example 1k, substituting Example 21b for Example 1j to provide the title compound.

Example 21d

7-Amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 21c (0.06 g, 0.153 mmol) and Pd/C (0.033 g, 0.031 mmol) in ethyl acetate (10 mL) was treated with a hydrogen balloon. The reaction mixture was stirred overnight. The solvent was removed, and the residue was purified by reverse-phase HPLC (C18 _CH3CN /water (0.1% TFA), 0-100% gradient) to afford the title compound as its bis-TFA salt (0.0351 g, 63%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.92 (s, 1H), 7.85 (d, J = 2.44Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.36 (d, J = 2.44 Hz, 1H), 6.84 (t, J =8.85 Hz, 1H), 6.44-6.47 (m, 2H), 4.81 (s, 2H), 3.56 (s, 3H). MS (ESI+) m/z362.1 (M+H) ⁺ .

Example 22

N-(4-(4-Fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide

A mixture of Example 21d (0.025 g, 0.069 mmol), ethanesulfonyl chloride (0.027 g, 0.208 mmol), and triethylamine (0.042 g, 0.415 mmol) in dichloromethane (2 mL) was stirred at ambient temperature for 2 hours. The solvent was removed, and the residue was treated with dioxane (2 mL) and 2.0 N NaOH (1 mL). The reaction mixture was heated at 85°C for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated. The aqueous layer was neutralized to pH = 7 and extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to give the title compound as the mono-TFA salt (0.022 g, 0.049 mmol, 70.1% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ11.89 (s, 1H), 10.12 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.59 (s, 1H), 7.35(s, 1H), 6.83 (t, J = 8.39 Hz, 1H), 6.49-6.50 (m, 2H), 4.76 (s, 2H), 3.57 (s,3H), 3.27 (q, J = 7.17 Hz, 2H), 1.29 (t, J = 7.17 Hz, 3H). MS (ESI+) m/z 451.1(M+H) ⁺ .

Example 23

N-(4-(2,4-Difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide

Example 23a

3-Bromo-N-(2,4-difluorophenyl)-5-nitropyridin-2-amine

A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10 mmol) and 2,4-difluoroaniline (2.58 g, 20 mmol) in DMSO (20 mL) was heated at 100°C for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:20 ethyl acetate/heptane to give the title compound (1.75 g, 5.30 mmol, 53.0% yield) as yellow crystals.

Example 23b

4-(2-((2,4-difluorophenyl)amino)-5-nitropyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 23a (0.330 g, 1 mmol), Example 1f (0.471 g, 1.100 mmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.034 g, 0.117 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.027 g, 0.030 mmol), and potassium phosphate (0.531 g, 2.500 mmol) in dioxane (4 mL) and water (1 mL) was degassed and backfilled with nitrogen several times. The reaction mixture was heated at 60°C overnight. Dioxane (5 mL) and 2.0 N NaOH (5 mL) were added to the reaction mixture. The reaction mixture was heated at 90°C for 2 hours. After cooling, the reaction mixture was partitioned between 0.1 N HCl and ethyl acetate. The pH of the aqueous layer was approximately 5. The organic layer was separated, and the aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was triturated with 3:7 ethyl acetate/heptane to afford the title compound (0.365 g, 0.919 mmol, 92% yield).

Example 23c

4-(2,4-Difluorophenyl)-10-methyl-7-nitro-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 23b (0.17 g, 0.428 mmol), 4N hydrochloric acid/dioxane (3.21 mL, 12.84 mmol) and formaldehyde (0.128 g, 4.28 mmol) in methanol (2) was heated at 130°C under microwave conditions for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted three times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was used in the next reaction without further purification.

Example 23d

7-Amino-4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

A mixture of 23c (0.18 g, 0.440 mmol), iron (0.123 g, 2.199 mmol), and ammonium hydrochloride (0.047 g, 0.879 mmol) in tetrahydrofuran (5 mL), water (1 mL), and ethanol (5 mL) was heated at 90°C for 2 hours. The solid was filtered and washed several times with ethyl acetate. It was then poured into water. The organic layer was separated, and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to give 0.05 g (23.1%) of the title compound as the bis-TFA salt.

Example 23e

N-(4-(2,4-Difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide

A mixture of Example 23d (0.05 g, 0.132 mmol), ethanesulfonyl chloride (0.017 g, 0.132 mmol) and triethylamine (0.013 g, 0.132 mmol) in dichloromethane (5 mL) was stirred at ambient temperature for 2 hours. The solvent was removed and the residue was treated with dioxane (2 mL) and 2.0 N NaOH (1 mL). The reaction mixture was heated at 85°C for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated. The aqueous layer was neutralized to pH = 7 and extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to give the title compound as a mono-TFA salt (0.048 g, 0.77 mmol, 58.3% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.92(s, 1H), 9.76 (s, 1H), 7.91-7.93 (m, 2H), 7.62 (s, 1H), 7.29-7.35 (m, 1H),7.20 (d, J = 2.75 Hz, 1H), 7.07-7.13 (m, 1H), 7.00-7.06 (m, 1H), , 4.76 (s,2H), 3.65 (s, 3H), 3.14 (q, J = 7.32 Hz, 2H), 1.25 (t, J = 7.32 Hz, 3H). MS(ESI+) m/z 472.2 (M+H) ⁺ .

Example 24

4-Butyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5 mL vial was added Example 5f (75 mg, 0.218 mmol), butyraldehyde (0.039 mL, 0.437 mmol), acetic acid (0.125 mL, 2.184 mmol) and dichloromethane (2.5 mL). The vial was sealed and the mixture was heated at 60 ° C for 1 hour. The reaction mixture was cooled in an ice bath and sodium triacetoxyborohydride (93 mg, 0.437 mmol) was added portionwise over a few minutes. Stirring was continued overnight while warming to ambient temperature. The reaction mixture was quenched with 1 M sodium hydroxide (2 mL) and distributed between a saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-10% methanol/dichloromethane) to obtain the title compound (74 mg, 85%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.76 (s, 1H), 7.68 (d, J=1.83 Hz, 1H), 7.50 (s, 1H), 7.23-7.29 (m,1H), 7.17-7.21 (m, 1H), 7.14 (d, J=2.14 Hz, 1H), 4.44 (s, 2H), 4.08 (s, 2H), 3.62 (s, 3H), 2.90-2.98 (m, 5H), 1.32-1.43 (m, 2H), 1.14-1.25 (m, 2H), 0.77(t, J=7.32 Hz, 3H). MS (ESI+) m/z 400.1 (M+H) ⁺ .

Example 25

tert-Butyl 3-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)methyl)pyrrolidine-1-carboxylate

Example 25 was prepared according to the procedure used to prepare Example 24, substituting tert-butyl 3-formylpyrrolidine-1-carboxylate for butyraldehyde to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.79 (d, J=2.14 Hz, 1H), 7.70 (d, J=1.83 Hz, 1H), 7.53 (s, 1H), 7.24-7.29 (m, 1H), 7.18-7.24 (m, 1H),7.14 (d, J=2.44 Hz, 1H), 4.44 (s, 2H), 4.12 (s, 2H), 3.62 (s, 3H), 3.13-3.24(m, 2H), 3.03-3.12 (m, 1H), 2.75-2.97 (m, 6H), 2.18-2.30 (m, 1H), 1.73 (d, J=6.71 Hz, 1H), 1.26-1.49 (m, 10H). MS (ESI+) m/z 526.9 (M+H) ⁺ .

Example 26

10-Methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5mL vial was added Example 5f (75 mg, 0.218 mmol), tetrahydrofuran-3-carbaldehyde (50 wt % in water, 131 mg, 0.655 mmol), acetic acid (0.125 mL, 2.184 mmol) and dichloromethane (2.5 mL). The vial was sealed and the mixture was heated at 60°C for 1 hour. The reaction mixture was cooled in an ice bath and sodium triacetoxyborohydride (93 mg, 0.437 mmol) was added portionwise over a few minutes. Stirring was continued overnight while warming to ambient temperature. The reaction mixture was quenched with 1M sodium hydroxide (2mL) and distributed between a saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-10% methanol/dichloromethane) to provide the title compound (79.6 mg, 85%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.79 (s, 1H), 7.70 (d, J=1.83 Hz, 1H), 7.54 (s, 1H), 7.24-7.30 (m, 1H), 7.18-7.23 (m, 1H), 7.15 (d, J=2.44 Hz, 1H), 4.45 (s,2H), 4.13 (s, 2H), 3.45-3.66 (m, H), 3.25-3.30 (m, 1H), 2.94 (s, 3H), 2.84-2.92 (m, 1H), 2.77 (dd, J=12.36, 8.70 Hz, 1H), 2.20-2.35 (m, 1H), 1.65-1.85 (m, 1H), 1.33-1.46 (m, 1H). MS (ESI+) m/z 428.1 (M+H) ⁺ .

Example 27

4-((4,4-difluorocyclohexyl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 27 was prepared according to the procedure used to prepare Example 24, substituting 4,4-difluorocyclohexanecarboxaldehyde for butyraldehyde to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.77 (d, J=1.83 Hz, 1H), 7.69 (d,J=1.83 Hz, 1H), 7.51 (s, 1H), 7.24-7.29 (m, 1H), 7.19-7.23 (m, 1H), 7.13 (d,J=2.44 Hz, 1H), 4.44 (s, 2H), 4.08 (s, 2H), 3.62 (s, 3H), 2.94 (s, 3H), 2.82(d, J=7.02 Hz, 2H), 1.82-1.96 (m, 2H), 1.48-1.76 (m, 5H), 0.94-1.10 (m, 2H). MS (ESI+) m/z 428.1 (M+H) ⁺ .

Example 28

tert-Butyl 4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)methyl)piperidine-1-carboxylate

Example 28 was prepared according to the procedure used to prepare Example 24, substituting tert-butyl 4-formylpiperidine-1-carboxylate for butyraldehyde to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.77 (d, J=2.44 Hz, 1H), 7.68 (d, J=1.83 Hz, 1H), 7.51 (s, 1H), 7.23-7.28 (m, 1H), 7.18-7.23 (m, 1H),7.13 (d, J=2.44 Hz, 1H), 4.44 (s, 2H), 4.08 (s, 2H), 3.81 (d, J=11.90 Hz,2H), 3.62 (s, 3H), 2.94 (s, 3H), 2.80 (d, J=6.10 Hz, 2H), 2.51 (s, 2H), 1.56(d, J=10.68 Hz, 3H), 1.34 (s, 9H), 0.76-0.92 (m, 2H). MS (ESI+) m/z 540.9 (M+H) ⁺ .

Example 29

10-Methyl-7-((methylsulfonyl)methyl)-4-((tetrahydro-2H-pyran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 29 was prepared according to the procedure used to prepare Example 24, substituting tetrahydro-2H-pyran-3-carbaldehyde for butyraldehyde to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.77 (d, J=1.83 Hz, 1H), 7.68 (d,J=2.14 Hz, 1H), 7.51 (s, 1H), 7.23-7.29 (m, 1H), 7.18-7.23 (m, 1H), 7.15 (d,J=2.75 Hz, 1H), 4.44 (s, 2H), 4.00-4.13 (m, 2H), 3.56-3.70 (m, 5H), 3.16-3.25(m, 1H), 2.91-3.00 (m, 4H), 2.83-2.91 (m, 1H), 2.73-2.81 (m, 1H), 1.57-1.72(m, 2H), 1.28-1.50 (m, 2H), 1.07 (t, J=9.61 Hz, 1H). MS (ESI+) m/z 540.9 (M+H) ⁺ .

Example 30

4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 30 was prepared according to the procedure used in Example 24, using 4,4-difluorocyclohexanone instead of butanal, to provide the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.84 (d, J = 1.70 Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.25 (s, 2H), 7.19 (d, J = 2.71 Hz, 1H), 4.46 (s, 2H), 4.08 (s, 2H), 3.62 (s, 3H), 2.94 (s, 3H), 2.88 (s, 1H), 1.96 (d, J = 12.55 Hz, 2H), 1.19-1.86 (m, 6H). MS (ESI+) m/z 462.1 (M+H) ⁺ .

Example 31

4-(4-Fluorophenyl)-(3,3- ² H ₂ )-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 20 mL microwave tube was added Example 9e (0.0506 g, 0.119 mmol), formaldehyde- _d2 (0.095 mL, 0.595 mmol) and methanol (1.189 mL). 4N HCl / dioxane (0.595 mL, 2.379 mmol) was added. The tube was sealed and the reaction mixture was heated at 90°C for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dispersed in dichloromethane and triturated with ether. The resulting slurry was stirred for 10 minutes and filtered. The white solid was washed with ether, collected, and dried in a vacuum oven at 60°C to give the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.80-11.85 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.60 (s, 1H), 7.40-7.51 (m, 1H), 7.33 (d, J = 4.5 Hz, 2H), 6.72-6.85 (m,2H), 6.36-6.46 (m, 2H), 4.53-4.59 (m, 2H), 3.56 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z 440.1 (M+H) ⁺ .

Example 32

7-Fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

Example 32a

4-(2-Amino-5-fluoropyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Combine 3-bromo-5-fluoropyridin-2-amine (0.3 g, 1.571 mmol), Example 1f (0.673 g, 1.571 mmol), tris(dibenzylideneacetone)dipalladium (0.043 g, 0.047 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.046 g, 0.157 mmol), and potassium phosphate (1.167 g, 5.50 mmol) and purge with argon for 15 minutes. Simultaneously, a 4:1 dioxane/water solution (8 mL) was bubbled with nitrogen for 15 minutes and then transferred to the reaction vessel via syringe under argon. The mixture was stirred at 60°C for 2 hours, cooled, diluted with 50 mL of water, and the crude solid was collected by filtration, washed with additional water, and dried to yield the title compound (0.648 g, 100%).

Example 32b

4-(5-Fluoro-2-((4-fluorophenyl)amino)pyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

1-Bromo-4-fluorobenzene (0.424 g, 2.425 mmol), Example 32a (0.5 g, 1.212 mmol), palladium acetate (10.89 mg, 0.048 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.046 g, 0.097 mmol), and cesium carbonate (0.790 g, 2.425 mmol) were combined in a mixture of tert-butanol (2.021 mL) and toluene (10.10 mL) and heated in a microwave at 150°C for 2 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), treated with 3-mercaptopropyl-functionalized silica, filtered, and concentrated. Purification by chromatography (silica gel, 1-5% methanol/dichloromethane) provided the title compound (0.065 g, 15%).

Example 32c

7-Fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

In a sealed tube, Example 32b (0.055 g, 0.156 mmol), paraformaldehyde (0.141 g, 4.68 mmol) and hydrochloric acid (4M in 1,4-dioxane, 1 mL, 4.00 mmol) were combined in methanol (1 mL) and heated at 130°C by microwave for 2 hours, cooled and concentrated. Purification by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) gave the title compound as a TFA salt (0.009 g, 12%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.91 (s,1H), 8.43 (d, J = 2.75 Hz, 1H), 8.27 (dd, J = 9.92, 2.90 Hz, 1H), 7.85 (s,1H), 7.36 (d, J = 2.44 Hz, 1H), 6.78-6.92 (m, 2H), 6.43-6.53 (m, 2H), 4.78(s, 2H), 3.56 (s, 3H). MS (ESI+) m/z 365 (M+H) ⁺ .

Example 33

4-(4-Fluorophenyl)-7,10-dimethyl-3-phenyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

In a sealed tube, a mixture of Example 11c and benzaldehyde (0.116 mL, 1.148 mmol) in acetic acid (1 mL) was heated at 110°C for 15 hours, cooled, and concentrated. Purification by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) afforded the title compound (0.016 g, 25%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.75(s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.68 (s, 1H), 7.38 (d, J = 2.75 Hz, 1H), 6.98-7.12 (m, 5H), 6.81-6.88 (m, 2H), 6.71-6.78 (m, 2H), 6.68 (s, 1H), 3.60 (s, 3H), 2.25 (s, 3H). MS (ESI+) m/z 437 (M+H) ⁺ .

Example 34

4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester

Example 34 was prepared according to the procedure used to prepare Example 7, substituting Example 9e for Example 6c to provide the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.95-12.00 (m, 1H), 7.85 (d, J = 2.0 Hz,1H), 7.62 (s, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.87(t, J = 8.7 Hz, 2H), 6.46-6.61 (m, 2H), 6.18-6.29 (m, 1H), 4.44-4.62 (m, 2H), 3.70-4.03 (m, 2H), 3.58 (s, 3H), 2.93 (s, 3H), 0.87-1.03 (m, 3H). MS (ESI+) m/z 510.1 (M+H) ⁺ .

Example 35

tert-Butyl 4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)piperazine-1-carboxylate

Example 35a

4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid

To a 100 mL round-bottom flask was added Example 34 (0.453 g, 0.888 mmol), dioxane (6.66 mL) and water (2.22 mL) to give a yellow solution. Lithium hydroxide hydrate (0.186 g, 4.44 mmol) was added. The reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was quenched with 1N hydrochloric acid. The resulting slurry was stirred for 10 minutes and filtered. The solid was washed with water, dried overnight on a glass frit funnel and collected to give the title compound (0.3664 g, 86% yield).

Example 35b

tert-Butyl 4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)piperazine-1-carboxylate

To a 2 mL microwave tube was added Example 35a (0.0498 g, 0.103 mmol), tert-butyl piperazine-1-carboxylate (0.019 g, 0.103 mmol), polymer-supported carbodiimide (0.248 g, 0.310 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.014 g, 0.103 mmol), N-ethyl-N-isopropylpropan-2-amine (0.036 mL, 0.207 mmol), and dimethylacetamide (1.034 mL). The tube was sealed, and the reaction mixture was heated in a Biotage Creator at 110°C for a fixed time of 10 minutes. The reaction mixture was filtered, and the resin was washed thoroughly with ethyl acetate. The filtrate was washed twice with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-10% methanol/dichloromethane) to provide the title compound (0.0133 g, 20% yield). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.78-11.89 (m, 1H), 7.77-7.89 (m, 1H), 7.50-7.61 (m, 1H), 7.35-7.45 (m, 1H), 7.20-7.34 (m, 2H), 6.76-6.90 (m, 2H), 6.43-6.57 (m, 2H), 6.33-6.43 (m, 1H), 4.42-4.66 (m, 2H), 3.66-3.81 (m, 2H), 3.40-3.61 (m, 5H), 2.98-3.22 (m, 2H), 2.92 (s, 3H), 2.66-2.85 (m, 2H), 1.47-1.29 (m, 9H). MS (ESI+) m/z 549.8 (M+H) ⁺ .

Example 36

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyrrolidin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Into a 4mL vial, add Example 25 (98 mg, 0.186 mmol) and dichloromethane (2mL). In an ice bath, cool the mixture and add 2,2,2-trifluoroacetic acid (1 mL, 12.98 mmol). Continue stirring for 2 hours while the reaction mixture is warmed to ambient temperature. Under a stream of hot nitrogen, concentrate the reaction mixture and distribute the residue between a saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). Separate the layers and extract the aqueous layer with 10% methanol/dichloromethane (16 x 100 mL). The combined organic layer is also dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by reversed-phase HPLC (C18, CH ₃ CN/water (0.1% TFA), 0-100% gradient) yields the title compound as trifluoroacetate (56.6 mg, 56%). ¹ H NMR (400MHz, pyridine- d ₅ ) δ 13.48 (s, 1H), 11.08-11.34 (m, 1H), 8.06 (d, J=1.83 Hz, 1H), 7.56 (s, 2H), 7.38-7.42 (m, 1H), 7.36 (d, J=8.24 Hz, 1H), 4.76 (s, 2H), 4.25-4.40 (m, 2H), 3.63 (s, 3H), 3.58 (dd, J=11.29, 7.63 Hz, 1H), 3.42-3.52 (m,1H), 3.30-3.42 (m, 2H), 3.14-3.21 (m, 1H), 3.14 (s, 3H), 3.02 (dd, J=12.51,9.16 Hz, 1H), 2.59-2.72 (m, 1H), 1.90-2.04 (m, 1H), 1.59-1.73 (m, 1H). MS (ESI+) m/z 427.1 (M+H) ⁺ .

Example 37

10-Methyl-7-((methylsulfonyl)methyl)-4-(piperidin-4-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Into a 4mL bottle, add Example 28 (81.5 mg, 0.151 mmol) and dichloromethane (2mL). Cool the mixture in an ice bath and add 2,2,2-trifluoroacetic acid (1 mL, 13 mmol). Continue stirring for 2 hours while warming to ambient temperature. The reaction mixture is concentrated under a stream of hot nitrogen and purified by reversed-phase HPLC (C18, CH ₃ CN/water (0.1% TFA), 0-100% gradient) to obtain the title compound as trifluoroacetate (76.9 mg, 92%). ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.45 (d, J=1.53 Hz, 1H), 10.89 (d, 1H), 8.08 (d, J=2.14 Hz, 1H), 7.61 (dd, J=8.24, 1.83 Hz, 2H), 7.41 3.00 (d, J=6.41 Hz, 2H), 2.88-2.98 (m, 2H), 1.80-1.99 (m, 3H), 1.55 (d,J=12.82 Hz, 2H). MS (ESI+) m/z 441.1 (M+H) ⁺ .

Example 38

7-Fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

Example 38a

4-(2-Amino-5-fluoropyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 38a was prepared according to the procedure used to prepare Example 8a, using 3-bromo-5-fluoropyridin-2-amine in place of 2-bromo-4-(methylsulfonyl)aniline and a reaction time of 4 hours instead of 3 hours to give the title compound in quantitative yield.

Example 38b

4-(2-Amino-5-fluoropyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 38a (825 mg, 2.00 mmol), potassium hydroxide (1.68 g, 30.0 mmol), and cetyltrimethylammonium bromide (36.4 mg, 0.100 mmol) were combined in a mixture of dioxane (20 mL) and water (10 mL). The reaction mixture was heated at 100°C for 3 hours and then cooled to ambient temperature. Water was added to the mixture, and the pH was adjusted to pH 7 by adding 1M HCl. The mixture was extracted with ethyl acetate, and the organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl-functionalized silica gel, filtered, and concentrated. The residue was triturated with dichloromethane to provide the title compound (460 mg, 89%).

Example 38c

7-Fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

To a 5mL vial was added Example 38b (25.8 mg, 0.100 mmol), paraformaldehyde (30 mg, 1.0 mmol) and methanol (2 mL). To the suspension was added 4M HCl/ dioxane (0.50 mL, 2.0 mmol). The vial was sealed and heated at 120 ° C for 2 hours in a microwave reactor. The reaction mixture was cooled to ambient temperature and concentrated. Water was added to the residue, and the pH was adjusted to pH 7 by adding saturated sodium bicarbonate aqueous solution. The residue was sonicated for 5 minutes and filtered to obtain the title compound (23 mg, 85%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.84 (s, 1 H) 7.96-8.06 (m, 2 H) 7.79 (s, 1 H) 7.18 (d, J=2.71 Hz, 1 H) 6.16 (t, J=3.05 Hz, 1 H)4.15 (d, J=3.05 Hz, 2 H) 3.61 (s, 3 H). MS (ESI+) m/z 271 (M+H) ⁺ .

Example 39

7-Fluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester

To a 5 mL vial was added Example 38b (25.8 mg, 0.100 mmol), 50% ethyl 2-oxoacetate/toluene (0.198 mL, 1.00 mmol) and ethanol (2 mL). To this suspension was added 4M HCl/dioxane (0.50 mL, 2.0 mmol). The vial was sealed and heated at 120° C. for 2 hours in a microwave reactor. The reaction mixture was cooled to ambient temperature and concentrated. The title compound (17 mg, 50%) was obtained by flash chromatography (silica gel, 2-4% methanol/dichloromethane) purification of the residue. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.10 (s, 1 H) 7.96-8.06 (m, 2 H) 7.87 (s, 1H) 7.34 (d, J=2.71 Hz, 1 H) 6.50 (d, J=5.43 Hz, 1 H) 5.11 (d, J=5.43 Hz, 1 H)3.91 (q, J=7.12 Hz, 2 H) 3.61 (s, 3 H) 0.98 (t, J=7.12 Hz, 3 H). MS (ESI+) m/z343 (M+H) ⁺ .

Example 40

4-(4-Fluorophenyl)-3-(4-methoxypiperidine-1-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 40 was prepared according to the procedure used to prepare Example 35b, substituting 4-methoxypiperidine for tert-butyl piperazine-1-carboxylate to provide the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.78-11.83 (m, 1H), 7.81-7.86 (m, 1H), 7.55 (s, 1H), 7.33-7.43 (m, 1H), 7.24-7.33 (m, 1H), 7.21 (d, J= 7.7 Hz, 1H), 6.79-6.89 (m, 2H), 6.43-6.53 (m, 2H), 6.28-6.40 (m, 1H), 4.46-4.61 (m, 2H), 4.01 (d, J = 1.1 Hz, 1H), 3.53-3.41 (m, 1H), 3.56 (s, 3H), 3.41-3.53 (m, 1H), 3.25-3.29 (m, 5H), 2.92 (s, 3H), 1.89-2.14 (m, 1H), 1.69-1.89 (m, 1H), 1.32-1.69 (m, 2H). MS (ESI+) m/z 579.0 (M+H) ⁺ .

Example 41

4-(4-Fluorophenyl)-10-methyl-3-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 41 was prepared according to the procedure used to prepare Example 35b, substituting 1-methylpiperazine for tert-butyl piperazine-1-carboxylate to provide the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.79-11.85 (m, 1H), 7.84 (d,J = 1.7 Hz, 1H), 7.55 (s, 1H), 7.40 (dd, J = 8.0, 1.9 Hz, 1H), 7.18-7.32 (m,2H), 6.78-6.89 (m, 2H), 6.45-6.54 (m, 2H), 6.32-6.40 (m, 1H), 4.47-4.61 (m,2H), 3.44-3.61 (m, 5H), 2.74-3.04 (m, 5H), 2.15-2.38 (m, 5H). MS (ESI+) m/z564.1 (M+H) ⁺ .

Example 42

5,7-Difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 42a

4-(2-Amino-3,5-difluorophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Combine 2-bromo-4,6-difluoroaniline (1.0 g, 4.81 mmol), Example 1f (2.059 g, 4.81 mmol), tris(dibenzylideneacetone)dipalladium(0), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.141 g, 0.481 mmol), and potassium phosphate (3.57 g, 16.83 mmol) and purge with argon for 15 minutes. Simultaneously, a 4:1 dioxane/water solution (8 mL) was bubbled with nitrogen for 15 minutes and transferred to the reaction vessel via syringe under argon. The mixture was stirred at 60°C for 2 hours, cooled to ambient temperature, and diluted with 100 mL of water. The resulting solid was collected by filtration, washed with additional water, and dried to afford the title compound (1.6 g, 77%).

Example 42b

4-(2-Amino-3,5-difluorophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 42a (1.6 g, 3.73 mmol), potassium hydroxide (6.27 g, 112 mmol), and N,N,N-trimethylhexadecyl-1-ammonium bromide (0.068 g, 0.186 mmol) were combined in dioxane (33.1 mL)/water (16.6 mL) and heated at 100°C for 3 hours. Cool, dilute with ethyl acetate and water, and adjust the pH to pH 8 by carefully adding 12 M HCl. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. Purification by chromatography (silica gel, 0.5-4% methanol/dichloromethane) gave the title compound (0.80 g, 78%).

Example 42c

5,7-Difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 42b (0.25 g, 0.908 mmol) and paraformaldehyde (0.273 g, 9.08 mmol) in methanol (9.08 mL) was treated with hydrochloric acid (4 M in 1,4-dioxane, 6.81 mL, 27.2 mmol). The mixture was heated at 90°C in a sealed tube for 3 hours, cooled, and filtered to collect the solid, which was repeatedly washed with diethyl ether. The solid was sonicated in 2 mL of methanol and 20 mL of 5% aqueous sodium bicarbonate solution for 5 minutes and collected by filtration to yield the title compound (0.2 g, 77%).

Example 42d

5,7-Difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of tetrahydrofuran-3-carbaldehyde (0.131 g, 0.654 mmol) and Example 42c (0.063 g, 0.218 mmol) in dichloromethane (2.5 mL) in a sealed tube was treated with acetic acid (0.125 mL, 2.180 mmol) and heated at 60°C for 1 hour. The mixture was cooled to 0°C and treated portionwise with sodium triacetoxyborohydride (0.092 g, 0.436 mmol). The reaction mixture was stirred for 18 hours and allowed to warm to ambient temperature. The mixture was partitioned between dichloromethane and 5% aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. The title compound was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to afford the title compound as a TFA salt (0.04 g, 38%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.91 (s, 1H), 7.83 (d, J = 2.03 Hz, 1H), 7.41-7.46 (m, 1H), 7.06-7.22 (m, 2H), 4.19-4.30 (m, 1H), 4.00-4.10 (m, 1H), 3.61 (s, 3H), 3.25-3.63 (m, 5H), 1.66-2.70 (m, 4H). MS (ESI+) m/z 372 (M+H) ⁺ .

Example 43

4-(4-Fluorophenyl)-7,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester

A mixture of ethyl glyoxylate (0.586 g, 2.87 mmol) and Example 11c (0.1 g, 0.287 mmol) in ethanol (2 mL) was treated with hydrochloric acid (4 M in 1,4-dioxane, 2.153 mL, 8.61 mmol). The mixture was heated at 120°C in a sealed tube for 18 hours, cooled, and concentrated. The title compound was purified by reverse-phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to afford the title compound as the TFA salt (0.01 g, 6%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ12.06 (d, J = 1.70 Hz, 1H), 8.16 (s, 2H), 7.83 (s, 1H), 7.39 (d, J = 2.71 Hz,1H), 6.92-7.00 (m, 2H), 6.74-6.81 (m, 2H), 6.18 (s, 1H), 3.91 (d, J = 7.12Hz, 2H), 3.61 (s, 3H), 2.36 (s, 3H), 0.92 (t, J = 7.12 Hz, 3H). MS (ESI+) m/z433 (M+H) ⁺ .

Example 44

N-Cyclopentyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

To a 5 mL vial was added Example 5f (72.5 mg, 0.211 mmol), isocyanatocyclopentane (0.036 mL, 0.317 mmol), N-ethyl-N-isopropylpropan-2-amine (0.110 mL, 0.633 mmol), dichloromethane (2 mL), and N,N-dimethylformamide (2 mL). The reaction mixture was stirred at ambient temperature for 18 hours and then heated at 90°C for 72 hours. After cooling, the reaction mixture was partitioned between 50% saturated aqueous sodium chloride solution (60 mL) and dichloromethane (60 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-10% methanol/dichloromethane) to provide the title compound (59.1 mg, 62%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.85 (d, J=2.37 Hz, 1H), 7.83 (d, J=2.03 Hz, 1H), 7.63 (s, 1H), 7.33-7.40 (m, 1H), 7.25-7.31 (m, 1H), 7.20 (d, J=2.03 Hz,1H), 5.36 (d, J=15.94 Hz, 1H), 5.24 (d, J=6.78 Hz, 1H), 4.52-4.62 (m, 1H),4.40-4.51 (m, 1H), 3.96 (d, J=15.60 Hz, 1H), 3.69-3.83 (m, 1H), 3.62 (s, 3H), 2.96 (s, 3H), 1.54-1.72 (m, 2H), 1.31-1.52 (m, 4H), 1.09-1.27 (m, 2H). MS (ESI+) m/z 455.1 (M+H) ⁺ .

Example 45

N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 45 was prepared according to the procedure used to prepare Example 44, substituting isocyanatoethane for isocyanatocyclopentane to provide the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.85 (d, J=1.36 Hz, 1H), 7.83 (d, J=1.70 Hz, 1H), 7.62 (s, 1H), 7.34-7.40 (m, 1H), 7.26-7.32 (m, 1H),7.19 (d, J=2.37 Hz, 1H), 5.59 (s, 1H), 5.35 (d, J=15.94 Hz, 1H), 4.42-4.62(m, 2H), 3.94 (d, J=15.60 Hz, 1H), 3.59-3.66 (m, 3H), 2.97 (s, 3H), 2.75-2.96 (m, 2H), 0.85 (t, J=7.12 Hz, 3H). MS (ESI+) m/z 415.1 (M+H) ⁺ .

Example 46

N-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 46 was prepared according to the procedure used to prepare Example 44, substituting 1-fluoro-4-isocyanatobenzene for isocyanatocyclopentane to provide the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.91 (d, J=2.37 Hz,1H), 7.87 (s, 2H), 7.66 (s, 1H), 7.38 (s, 2H), 7.28-7.34 (m, 2H), 7.25 (d, J=2.37 Hz, 1H), 6.95-7.02 (m, 2H), 5.52 (d, J=15.60 Hz, 1H), 4.45-4.63 (m, 2H), 4.07 (d, J=16.62 Hz, 1H), 3.63 (s, 3H), 2.98 (s, 3H). MS (ESI+) m/z 481.1 (M+H) ⁺ .

Example 47

4-Butyl-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of butyraldehyde (0.079 g, 1.097 mmol) and Example 42c (0.063 g, 0.219 mmol) in dichloroethane (1.0 mL) in a sealed tube was treated with acetic acid (0.126 mL, 2.193 mmol) and heated at 60°C for 2 hours. The mixture was cooled to 0°C and treated portionwise with sodium triacetoxyborohydride (0.139 g, 0.658 mmol). The reaction mixture was stirred for 18 hours and the mixture was allowed to warm to ambient temperature. The mixture was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate solution. The organic layer was washed with saturated sodium chloride solution, dried (anhydrous sodium sulfate), filtered, and concentrated. The solid generated was purified by chromatography (silica gel, 0.5-3% methanol/dichloromethane) and then triturated in 9:1 hexane/ethyl acetate to give the title compound (0.057 g, 76%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.89 (s, 1H), 7.81 (s, 1H), 7.40-7.45 (m, 1H), 7.19 (d, J = 2.14 Hz, 1H), 7.05-7.14 (m, 1H), 4.19-4.24(m, 2H), 4.01-4.06 (m, 2H), 3.61 (s, 3H), 1.13-1.33 (m, 4H), 0.76 (t, J =7.02 Hz, 3H). MS (ESI+) m/z 344 (M+H) ⁺ .

Example 48

5,7-Difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of propanaldehyde (0.064 g, 1.097 mmol) and Example 42c (0.063 g, 0.219 mmol) in 1,2-dichloroethane (1.0 mL) in a sealed tube was treated with acetic acid (0.126 mL, 2.193 mmol) and heated at 60°C for 2 hours. The mixture was cooled to 0°C and treated portionwise with sodium triacetoxyborohydride (0.139 g, 0.658 mmol). The reaction mixture was stirred for 18 hours and allowed to warm to ambient temperature. The mixture was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous _Na₂SO₄ ), filtered, and concentrated. The resulting solid was purified by flash chromatography (silica gel, 0.5-3% methanol/dichloromethane) _and triturated in 9:1 hexane/ethyl acetate to provide the title compound (0.044 g, 60%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.89 (s, 1H), 7.81 (s, 1H), 7.43 (d, J = 10.68 Hz, 1H), 7.18 (s, 1H), 7.05-7.13 (m, 1H), 4.17-4.25 (m,1H), 3.99-4.08 (m, 1H), 3.61 (s, 3H), 2.39-2.64 (m, 2H), 1.07-1.43 (m, 2H), 0.74 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 330 (M+H) ⁺ .

Example 49

4-(Cyclopropylmethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 49 was prepared according to the procedure used to prepare Example 47, substituting cyclopropanecarboxaldehyde for butyraldehyde to provide the title compound (0.054 g, 72%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.90 (s, 1H), 7.80 (s, 1H), 7.38-7.45 (m, 1H), 7.18 (d, J = 1.83 Hz, 1H), 7.08-7.13 (m, 1H), 4.35 (d, J =15.87 Hz, 1H), 4.08 (d, J = 15.87 Hz, 1H), 3.60 (s, 3H), 2.61 (dd, J = 12.51,6.41 Hz, 1H), 2.25 (dd, J = 12.51, 7.02 Hz, 1H), 0.73-0.82 (m, 1H), 0.23-0.36 (m, 1H), 0.10-0.20 (m, 1H), -0.18--0.08 (m, 1H), -0.42--0.30 (m, 1H). MS (ESI+) m/z 342 (M+H) ⁺ .

Example 50

Methyl 4-(5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)butanoate

Example 50 was prepared according to the procedure used to prepare Example 47, substituting methyl 4-oxobutyrate for butyraldehyde to provide the title compound (0.064 g, 74%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.90 (s, 1H), 7.82 (s,1H), 7.43 (d, J = 9.77 Hz, 1H), 7.19 (s, 1H), 7.07-7.14 (m, 1H), 4.17-4.23(m, 1H), 4.01-4.07 (m, 1H), 3.61 (s, 3H), 3.52 (s, 3H), 2.59-2.68 (m, 2H), 2.30 (t, J = 7.32 Hz, 2H), 1.46-1.56 (m, 2H). MS (ESI+) m/z 388 (M+H) ⁺ .

Example 51

5,7-Difluoro-10-methyl-4-(3-phenylpropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 51 was prepared according to the procedure used for Example 47, using 3-phenylpropanal in place of butanal, to provide the title compound (0.062 g, 69%). ^H NMR (400 MHz, DMSO- d ₆ ) δ 11.89 (s, 1H), 7.81 (s, 1H), 7.43 (dd, J = 10.83, 1.37 Hz, 1H), 7.01-7.24 (m, 7H), 4.22-4.27 (m, 1H), 4.04-4.10 (m, 1H), 3.61 (s, 3H), 2.49-2.69 (m, 4H), 1.44-1.67 (m, 2H). MS (ESI+) m/z 406 (M+H) ⁺ .

Example 52

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(o-tolyl)-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

To a 4 mL vial was added Example 5f (25 mg, 0.073 mmol), 1-isocyanato-2-methylbenzene (13.39 mg, 0.091 mmol), diisopropylethylamine (38.4 μL, 0.220 mmol), and N,N-dimethylformamide (1 mL). The reaction mixture was heated at 80°C for 18 hours. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to afford the title compound (5.6 mg, 16%). ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.90 (d, J = 1.8 Hz, 1H), 7.67 (s, 1H), 7.45-7.53 (m, 2H), 7.31-7.39 (m, 1H), 7.26 (s, 1H), 7.02 (t, J = 7.2 Hz, 2H), 6.86-6.94 (m, 1H), 5.40-5.48 (m, 1H), 4.51-4.56 (m, 2H), 4.10-4.19 (m, 1H), 3.64 (s, 3H), 2.96(s, 3H), 1.76 (s, 3H). MS (ESI+) m/z 477.1 (M+H) ⁺ .

Example 53

2-Ethylhexyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

To a 4 mL vial was added Example 5f (15 mg, 0.044 mmol), 2-ethylhexyl chloroformate (10.10 mg, 0.05 mmol), diisopropylethylamine (50 μL, 0.287 mmol), and N,N-dimethylacetamide (2 mL). The reaction mixture was heated at 80°C for 18 hours. To this mixture was added O- (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19.93 mg, 0.05 mmol), and heating was continued for 18 hours. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to afford the title compound (4.4 mg, 20.2%). ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.78-7.81 (m, 1H), 7.59-7.60 (m, 1H), 7.35-7.39 (m, 1H), 7.27-7.31 (m, 1H), 7.20-7.22 (m, 1H), 5.17-5.23 (m, 1H),4.44-4.54 (m, 1H), 4.12-4.19 (m, 1H), 3.77 (bs, 2H), 3.61-3.64 (m, 3H), 2.90-2.94 (m, 3H), 1.21-1.35 (m, 1H), 0.95-1.18 (m, 9H), 0.65-0.79 (m, 6H). MS (ESI+) m/z 500.1 (M+H) ⁺ .

Example 54

4-Isobutyryl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 4 mL vial was added Example 5f (15 mg, 0.044 mmol), isobutyryl chloride (4.65 mg, 0.044 mmol), diisopropylethylamine (50 μL, 0.287 mmol), and N,N-dimethylacetamide (2 mL). The reaction mixture was heated at 80°C for 18 hours. To this mixture was added O- (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19.93 mg, 0.05 mmol), and heating was continued for 18 hours. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to afford the title compound (1.3 mg, 7.2%). ¹ HNMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.83-7.87 (m, 1H), 7.65-7.69 (m, 1H), 7.42-7.45(m, 1H), 7.33-7.41 (m, 1H), 7.20-7.26 (m, 1H), 5.45-5.60 (m, 1H), 4.47-4.58(m, 2H), 3.89-4.01 (m, 1H), 3.63 (s, 3H), 2.95 (s, 4H), 1.96 (s, 1H), 0.91-1.01 (m, 3H), 0.44-0.55 (m, 2H). MS (ESI+) m/z 414.1 (M+H) ⁺ .

Example 55

5,7-Difluoro-10-methyl-4-phenylethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 55 was prepared following the procedure used to prepare Example 47, substituting 2-phenylacetaldehyde for butyraldehyde. Purification by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) afforded the title compound (0.034 g, 40%). ¹ HNMR (400 MHz, DMSO- d ₆ ) δ 11.91 (d, J = 1.22 Hz, 1H), 7.82 (s, 1H), 7.44 (dd,J = 10.38, 2.14 Hz, 1H), 7.08-7.21 (m, 5H), 7.02 (d, J = 6.71 Hz, 2H), 4.28-4.33 (m, 1H), 4.05-4.10 (m, 1H), 3.60 (s, 3H), 2.67-2.78 (m, 2H), 2.45-2.53(m, 2H). MS (ESI+) m/z 392 (M+H) ⁺ .

Example 56

4-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 56 was prepared according to the procedure used for Example 47, substituting 2-(benzo[d][1,3]dioxol-5-yl)acetaldehyde for butyraldehyde. Purification by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) gave impure product, which was purified again (silica gel, 0.5-3% methanol/dichloromethane) to afford the title compound (0.033 g, 32%). ¹ HNMR (400 MHz, DMSO- d ₆ ) δ 11.90 (s, 1H), 7.80 (s, 1H), 7.43 (dd, J = 8.70,2.59 Hz, 1H), 7.19 (d, J = 2.14 Hz, 1H), 7.08-7.16 (m, 1H), 6.68 (d, J = 7.93Hz, 1H), 6.60 (s, 1H), 6.39-6.49 (m, 1H), 5.89 (s, 2H), 4.28 (d, J = 15.87Hz, 1H), 4.05 (d, J = 15.87 Hz, 1H), 3.60 (s, 3H), 2.33-2.88 (m, 4H). MS (ESI+) m/z 436 (M+H) ⁺ .

Example 57

4-((1Z,3E)-2,4-diphenylbuta-1,3-dien-1-yl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 57 was prepared following the procedure used to prepare Example 47, substituting 2-phenylacetaldehyde for butyraldehyde. The crude material was triturated in 1 mL of 50/50 DMSO/methanol and filtered to collect a yellow solid (0.013 g, 12%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.62 (s, 1H), 7.60 (s, 1H), 6.95-7.16 (m, 10H), 6.87 (d, J = 15.87 Hz, 1H), 6.67 (dd, J = 6.56, 2.59 Hz, 2H), 6.59 (s, 1H), 6.50-6.56 (m, 1H), 5.42 (d, J = 15.56 Hz, 1H), 4.68 (d, J = 15.56 Hz, 1H), 4.26(d, J = 14.95 Hz, 1H), 3.66 (s, 3H). MS (ESI+) m/z 492 (M+H) ⁺ .

Example 58

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 58a

(Z)-3-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-2-hydroxyethyl acrylate

To a solution of ethanol (15 mL) and diethyl ether (150 mL) was added 5-bromo-2-methoxy-4-methyl-3-nitropyridine (14.82 g, 60 mmol), diethyl oxalate (13.15 g, 90 mmol), and potassium ethoxide (6.06 g, 72 mmol). The reaction mixture was heated at 45°C for 24 hours. During the reaction, the flask was shaken several times by hand. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 10-20% ethyl acetate/hexane to give 9.5 g of the title compound (46% yield).

Example 58b

4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

A mixture of Example 58a (9.5 g, 27.4 mmol) and iron powder (7.64 g, 137 mmol) in ethanol (60 mL) and acetic acid (60 mL) was heated at 100°C for 1 hour. The solid was filtered off and then washed with additional ethyl acetate. The solvent was removed under reduced pressure to 20% of the original volume, and the mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted several times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-40% ethyl acetate/hexane to give 6.05 g of the title compound.

Example 58c

1-Benzyl-4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

Example 58b (0.88 g, 2.94 mmol) in dimethylformamide (15 mL) was treated with 60% sodium hydride (0.106 g, 4.41 mmol, 0.117 g, 60% dispersion in oil). The solution was stirred at ambient temperature for 10 minutes. Benzyl bromide (0.59 g, 3.45 mmol) was added to the solution. The reaction mixture was stirred for an additional 2 hours and then distributed between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 20-40% ethyl acetate/hexane to obtain 1.07 g of the title compound.

Example 58d

1-Benzyl-4-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

A mixture of Example 58c (2, 5.14 mmol) in dioxane (20 mL) was treated with 4.0 M HCl in dioxane (20 mL, 80 mmol). The reaction mixture was stirred at 45°C for 18 hours. The mixture was concentrated to remove the dioxane. The residue was slurried in petroleum ether to afford the title compound (1.8 g, 4.80 mmol, 93% yield) as a gray solid.

Example 58e

1-Benzyl-4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

To the suspension of dimethylformamide (100 mL) of embodiment 58d (5.16 g, 13.75 mmol) was added NaH (0.660 g, 16.50 mmol) at ambient temperature, and the mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture, iodomethane (1.032 mL, 16.50 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours, then distributed between water and ethyl acetate. The aqueous layer was extracted twice with other ethyl acetate. The combined organic layer was washed with saturated sodium chloride water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel, eluted with 20-40% ethyl acetate/hexane to obtain the title compound (4.23 g, 8.91 mmol, 64.8% yield).

Example 58f

1-Benzyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

A mixture of Example 58e (2 g, 5.14 mmol), pinacol diboronate (2.61 g, 10.3 mmol), potassium acetate (1.11 g, 11.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.235 g, 0.257 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.245 g, 0.514 mmol) in dioxane (50 mL) was stirred at 90° C. under argon for 16 hours. The mixture was filtered through celite, washed several times with ethyl acetate, and concentrated. The residue was purified by flash chromatography (silica gel, 50-75% ethyl acetate/petroleum ether gradient) to provide the title compound (1.15 g, 40% yield).

Example 58g

2-Bromo-4-((methylsulfonyl)methyl)aniline

To a solution of Example 5b (2 g, 10.80 mmol) in DMF (60 mL) was added 1-bromopyrrolidine-2,5-dione (1.922 g, 10.80 mmol), and the reaction mixture was stirred at 15 ° C for 1 hour. The reaction mixture was quenched with 150 mL of 10% sodium thiosulfate and 100 mL of saturated sodium bicarbonate. The reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution and concentrated to a semi-solid. Water was added, and the resulting suspension was stirred at ambient temperature for 10 minutes. The solid was collected by filtration and dried on a glass frit funnel overnight to obtain the title compound (2.1 g, 7.85 mmol, 72.7% yield) as a tan solid.

Example 58h

2-Bromo-N-(4-chlorophenyl)-4-((methylsulfonyl)methyl)aniline

Under argon atmosphere and ambient temperature, to a 500 mL flask was added Example 58g (10 g, 37.9 mmol), 1-chloro-4-iodobenzene (18.06 g, 76 mmol), PdOAc ₂ (0.425 g, 1.893 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (1.75 g, 3.03 mmol), Cs ₂ CO ₃ (24.67 g, 76 mmol) and anhydrous dioxane (350 mL). The mixture was heated at 110° C. for 18 hours. The reaction mixture was filtered through celite and washed with ethyl acetate (100 mL). The filtrate was concentrated to remove the solvent, and the residue was treated with ethyl acetate (50 mL) and petroleum ether (20 mL) and stirred at ambient temperature for 15 minutes. The resulting solid was collected by filtration, washed with a small amount of petroleum ether and dried under reduced pressure to give the title compound (9.6 g, 24.85 mmol, 65.6% yield) as a yellow solid.

Example 58i

1-Benzyl-4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

Example 58i was prepared according to the procedures used to prepare Example 5d, substituting Example 58h for Example 5c and Example 58f for Example 1f, respectively, to provide the title compound.

Example 58j

4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

A mixture of Example 58i (0.5 g, 0.828 mmol), anisole (0.181 mL, 1.655 mmol), and _H2SO4 ( _0.5 mL, 9.38 mmol) in TFA (20 mL, 260 mmol) was heated at 90°C for 10 hours. Excess TFA was removed under reduced pressure, and the residue was partitioned between water (10 mL) and ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted twice with additional ethyl acetate (20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (10 mL), then with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound (0.38 g, 0.355 mmol, 42.9% yield) as a light solid.

Example 58k

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid ethyl ester

A mixture of Example 58j (0.200 g, 0.389 mmol), HCl (4M in dioxane) (4 mL, 16.00 mmol), and paraformaldehyde (0.234 g, 7.78 mmol) in methanol (2 mL) was heated at 130°C under microwave for 1.5 hours. The solvent was removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (0.14 g, 0.130 mmol, 33.5% yield).

Example 581

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid

A mixture of Example 58k and LiOH (0.646 mL, 1.293 mmol) in dioxane (3 mL) was heated at 65°C for 18 hours. The solvent was removed and water (20 mL) was added. The aqueous layer was adjusted to pH 3 with 1N HCl. The solid was filtered and dried to afford the title compound (0.25 g, 0.487 mmol, 75% yield) as a light-colored solid.

Example 58m

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

To a solution of Example 581 (0.1 g, 0.201 mmol) in anhydrous dichloromethane (5 mL) was added oxalyl chloride (0.035 mL, 0.402 mmol) and DMF (0.777 μL, 10.04 μmol), and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to dryness. The residue was redissolved in dichloromethane (5 mL) and treated with ammonium hydroxide (25% wt /wt in water) (2 mL, 92 mmol), and the reaction mixture was stirred at ambient temperature overnight. The resulting solid was filtered, treated twice with methanol, and filtered again to give the title compound (30 mg, 0.057 mmol, 28.3% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.23 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.68 (s,2H), 7.47 (d, J = 7.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 8.6 Hz, 2H), 5.89 (m, 1H), 4.68-4.35 (m, 3H), 3.59 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 497.1 (M+H) ⁺ .

Example 59

4-(4-Chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 59 was prepared according to the procedure used to prepare Example 58m, substituting ethylamine for ammonium hydroxide (25% wt/wt in water) to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ -MeOD): δ 8.33 (t, J = 5.0Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.67 (s, 1H), 7.47 (dd, J = 8.1, 1.8 Hz,1H), 7.38 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 9.1 Hz, 2H), 6.36 (d, J = 9.1 Hz,2H), 6.13-5.82 (m, 2H), 4.50 (dd, J = 56.8, 24.0 Hz, 3H), 3.58 (s, 3H), 3.01(s, 3H), 1.25-1.14 (m, 3H). MS (ESI+) m/z 525.0 (M+H) ⁺ .

Example 60

4-(4-Chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 60 was prepared according to the procedure used to prepare Example 58m, substituting 1-methylpiperazine for ammonium hydroxide (25% wt/wt in water) to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.34 (s, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.66 (s, 1H), 7.47 (dd, J = 8.1, 1.8 Hz, 1H), 7.37(d, J = 8.0 Hz, 1H), 6.97 (d, J = 9.1 Hz, 2H), 6.45 (d, J = 9.1 Hz, 2H), 5.10 (d, J = 16.8 Hz, 1H), 4.68-4.40 (m, 3H), 3.69-3.40 (m, 7H), 3.00 (s, 3H),2.36 (s, 4H), 2.21 (s, 3H). MS (ESI+) m/z 580.2 (M+H) ⁺ .

Example 61

N-(2,6-Dimethylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 61 was prepared according to the procedure used in Example 52, using 2-isocyanato-1,3-dimethylbenzene instead of 1-isocyanato-2-methylbenzene, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 //} D ₂ O) δ 7.85 (s, 1H), 7.62 (s, 1H), 7.44 (s, 2H), 7.23 (s, 1H), 6.86-6.96 (m, 3H), 5.31-5.40 (m, 1H), 4.48-4.53 (m, 2H), 4.11-4.21 (m, 1H), 3.65 (s, 3H), 2.95 (s, 3H), 1.82 (s, 6H). MS (ESI+) m/z 491.1 (M+H) ⁺ .

Example 62

N-(4-Methoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 62 was prepared according to the procedure used to prepare Example 52, substituting 1-isocyanato-4-methoxybenzene for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ 7.86 (d,J = 1.9 Hz, 1H), 7.63 (s, 1H), 7.43 (dd, J = 8.0, 1.9 Hz, 1H), 7.39 (d, J =8.0 Hz, 1H), 7.25 (s, 1H), 7.08-7.15 (m, 1H), 6.70-6.76 (m, 1H), 5.43-5.54(m, 1H), 4.52 (bs, 2H), 4.02-4.16 (m, 1H), 3.65 (d, J = 10.2 Hz, 2H), 2.97(s, 3H). MS (ESI+) m/z 493.0 (M+H) ⁺ .

Example 63

N-(4-Ethylphenethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 63 was prepared according to the procedure used to prepare Example 52, substituting 1-ethyl-4-(2-isocyanatoethyl)benzene for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ7.81 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 7.34 (dd, J = 8.1, 2.0 Hz, 1H), 7.16-7.20 (m, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 5.27-5.41(m, 1H), 4.49 (s, 2H), 3.93-4.01 (m, 1H), 3.64 (s, 3H), 3.02-3.20 (m, 2H),2.95 (s, 3H), 2.53-2.58 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H). MS (ESI+) m/z 519.1(M+H) ⁺ .

Example 64

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 64 was prepared according to the procedure used to prepare Example 52, substituting 1-isocyanatopropane for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ 7.82 (d, J =1.9 Hz, 1H), 7.59 (s, 1H), 7.40 (dd, J = 8.1, 2.0 Hz, 1H), 7.30 (d, J = 8.0Hz, 1H), 7.19 (s, 1H), 5.33 (s, 1H), 4.50 (s, 2H), 3.94-4.05 (m, 1H), 3.63(s, 3H), 2.95 (s, 3H), 2.71-2.92 (m, 2H), 1.25 (h, J = 7.3 Hz, 2H), 0.66 (t,J = 7.4 Hz, 3H). MS (ESI+) m/z 429.1 (M+H) ⁺ .

Example 65

N-(3-Methoxybenzyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 65 was prepared according to the procedure used to prepare Example 52, substituting 1-(isocyanatomethyl)-3-methoxybenzene for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ7.82 (d, J = 1.9 Hz, 1H), 7.59 (s, 1H), 7.40 (dd, J = 8.1, 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 5.33 (s, 1H), 4.50 (s, 2H), 3.94-4.05 (m,1H), 3.63 (s, 3H), 2.95 (s, 3H), 2.71-2.92 (m, 2H), 1.25 (h, J = 7.3 Hz, 2H),0.66 (t, J = 7.4 Hz, 3H). MS (ESI+) m/z 507.0 (M+H) ⁺ .

Example 66

N-(2-Chloroethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 66 was prepared according to the procedure used to prepare Example 52, substituting 1-chloro-2-isocyanatoethane for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ 7.95 (d, J= 0.4 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 8.2, 1.9Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 4.37 (s, 2H), 4.13 (s, 2H), 3.79 (t, J =6.1 Hz, 2H), 3.73 (s, 3H), 3.69 (dt, J = 6.4, 3.5 Hz, 2H), 2.89 (s, 3H). MS(ESI+) m/z 449.2 (M+H) ⁺ .

Example 67

N-(Cyclohexylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 67 was prepared according to the procedure used to prepare Example 52, substituting (isocyanatomethyl)cyclohexane for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ 7.83 (d,J = 2.0 Hz, 1H), 7.59 (s, 1H), 7.40 (dd, J = 8.0, 2.0 Hz, 1H), 7.30 (d, J =7.9 Hz, 1H), 7.19 (s, 1H), 5.24-5.37 (m, 1H), 4.50 (s, 1H), 3.96-4.08 (m,1H), 3.63 (s, 3H), 2.95 (s, 3H), 2.65-2.83 (m, 1H), 1.45-1.58 (m, 3H), 1.34(dd, J = 13.7, 1.1 Hz, 1H), 1.09-1.27 (m, 1H), 0.95-1.10 (m, 3H), 0.56-0.70 (m, 2H). MS (ESI+) m/z 483.1 (M+H) ⁺ .

Example 68

N-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 68 was prepared according to the procedure used to prepare Example 52, substituting 2,4-difluoro-1-isocyanatobenzene for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.90-11.98(m, 1H), 7.90 (bs, 1H), 7.70 (s, 1H), 7.33-7.52 (m, 4H), 7.26 (d, J = 1.0 Hz,1H), 7.11-7.21 (m, 1H), 6.88-6.97 (m, 1H), 5.46 (d, J = 15.6 Hz, 1H), 4.60 (d, J = 13.5 Hz, 1H), 4.50 (d, J = 13.5 Hz, 1H), 4.10 (d, J = 15.1 Hz, 1H), 3.64 (s, 3H), 2.98 (s, 3H). MS (ESI+) m/z 499.1 (M+H) ⁺ .

Example 69

N-(4-Isopropylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 69 was prepared according to the procedure used to prepare Example 52, substituting 1-isocyanato-4-isopropylbenzene for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ 7.86 (d,J = 1.8 Hz, 1H), 7.63 (s, 1H), 7.43 (dd, J = 8.1, 2.0 Hz, 1H), 7.38 (d, J =8.1 Hz, 1H), 7.25 (s, 1H), 7.12 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.5 Hz,2H), 5.43-5.57 (m, 1H), 4.52 (s, 2H), 4.04-4.14 (m, 1H), 3.64 (s, 3H), 2.97(s, 3H), 2.77 (dt, J = 14.1, 7.0 Hz, 1H), 1.17-1.20 (m, 1H), 1.13 (d, J = 6.9Hz, 6H). MS (ESI+) m/z 505.2 (M+H) ⁺ .

Example 70

N-(2,6-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 70 was prepared according to the procedure used to prepare Example 52, substituting 1,3-difluoro-2-isocyanatobenzene for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ 7.85 (d,J = 1.7 Hz, 1H), 7.64 (s, 1H), 7.40-7.45 (m, 2H), 7.15-7.25 (m, 2H), 6.94 (t,J = 8.0 Hz, 2H), 5.45 (d, J = 15.2 Hz, 1H), 4.50 (d, J = 4.0 Hz, 2H), 4.08-4.16 (m, 1H), 3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 499.1 (M+H) ⁺ .

Example 71

N-(4-Fluoro-3-(trifluoromethyl)phenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 71 was prepared according to the procedure used to prepare Example 52, substituting 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ7.87 (d, J = 1.7 Hz, 1H), 7.73 (dd, J = 6.5, 2.7 Hz, 1H), 7.64 (s, 1H), 7.58(ddd, J = 8.9, 5.6, 2.4 Hz, 1H), 7.43 (dd, J = 8.1, 1.8 Hz, 1H), 7.39 (d, J =8.1 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J = 9.6 Hz, 1H), 5.49-5.56 (m, 1H), 4.53(d, J = 3.5 Hz, 2H), 4.08-4.14 (m, 1H), 3.64 (s, 3H), 2.97 (s, 3H). MS (ESI+)m/z 549.0 (M+H) ⁺ .

Example 72

Ethyl 4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4-carboxamido)methyl)cyclohexanecarboxylate

Example 72 was prepared according to the procedure used for Example 52, substituting ethyl 4-(isocyanatomethyl)cyclohexanecarboxylate for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ7.83 (d, J = 1.9 Hz, 1H), 7.59 (s, 1H), 7.41 (dd, J = 8.1, 2.0 Hz, 1H), 7.31(d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 5.26-5.36 (m, 1H), 4.50 (d, J = 1.2 Hz,2H), 3.95-4.08 (m, 3H), 3.63 (s, 3H), 2.95 (s, 3H), 2.68-2.83 (m, 2H), 2.03(tt, J = 12.2, 3.7 Hz, 1H), 1.75 (dd, J = 12.8, 2.2 Hz, 2H), 1.36-1.46 (m, 2H), 1.06-1.19 (m, 6H), 0.60-0.71 (m, 2H). MS (ESI+) m/z 555.1 (M+H) ⁺ .

Example 73

N-(3-Methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 73 was prepared according to the procedure used to prepare Example 52, substituting 1-isocyanato-3-methoxypropane for 1-isocyanato-2-methylbenzene to provide the title compound. ¹ H NMR (400 MHz, DMSO- d _{6 /} /D ₂ O) δ 7.83(d, J = 1.9 Hz, 1H), 7.60 (s, 1H), 7.41 (dd, J = 8.1, 2.0 Hz, 1H), 7.30 (d, J= 8.1 Hz, 1H), 7.19 (s, 1H), 5.29-5.38 (m, 1H), 4.50 (d, J = 2.0 Hz, 2H), 3.94-4.04 (m, 1H), 3.63 (s, 3H), 3.15 (t, J = 5.9 Hz, 2H), 3.06 (s, 3H),2.98-3.04 (m, 1H), 2.95 (s, 3H), 2.86-2.93 (m, 1H), 1.47 (p, J = 6.4 Hz, 2H). MS (ESI+) m/z 555.1 (M+H) ⁺ .

Example 74

10-Methyl-7-((methylsulfonyl)methyl)-4-toluenesulfonyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 4 mL vial was added Example 5f (15 mg, 0.04 mmol), 4-methylbenzene-1-sulfonyl chloride (19 mg, 0.1 mmol), diisopropylethylamine (15 μL, 0.08 mmol), and N,N-dimethylacetamide (0.75 mL). The reaction mixture was heated at 50°C for 18 hours. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to afford the title compound (1.4 mg, 6%). ¹ H NMR (500 MHz, DMSO- d ₆ /D ₂ O) δ7.66 (d, J=1.83 Hz, 1H), 7.47-7.49 (m, 1H), 7.41 (dd, J=8.24, 1.83 Hz, 1H), 7.25 (s, 1H), 7.22 (s, 1H), 6.77-6.80 (m, 2H), 6.72-6.75 (m, 2H), 5.21 (d, J=16.48 Hz, 1H), 4.58-4.62 (m, 1H), 4.52 (d, J=4.88 Hz, 1H), 4.49 (s, 1H), 3.51(s, 3H), 2.98(s, 3H), 2.15 (s, 3H). MS (APCI+) m/z 498 (M+H) ⁺ .

Example 75

4-([1,1'-biphenyl]-4-ylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 75 was prepared according to the procedure used to prepare Example 74, substituting biphenyl-4-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ /D ₂ O) δ 7.66 (d, J=2.14 Hz, 1H)7.52-7.55 (m, 3H) 7.48 (t, J=7.32 Hz, 2H) 7.42-7.45 (m, 2H) 7.29 (s, 1H)7.20-7.23 (m, 3H) 6.93 (d, J=8.54 Hz, 2H) 5.29 (d, J=16.48 Hz, 1H) 4.48-4.63(m, 3H) 3.18 (s, 3H) 2.98 (s, 3H). MS (APCI+) m/z 560 (M+H) ⁺ .

Example 76

4-((4-Methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 76 was prepared according to the procedure used to prepare Example 74, substituting 4-methoxybenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ /D ₂ O) δ 7.65 (d, J=2.14Hz, 1H) 7.47-7.50 (m, 1H) 7.39-7.43 (m, 1H) 7.24 (s, 2H) 6.78 (d, J=9.16 Hz, 2H) 6.44 (d, J=8.85 Hz, 2H) 5.21 (d, J=16.48 Hz, 1H) 4.57-4.62 (m, 1H) 4.50 (s, 1H) 4.46-4.48 (m, J=2.75 Hz, 1H) 3.69 (s, 3H) 3.49 (s, 3H) 2.97 (s, 3H). MS (APCI+) m/z 514 (M+H) ⁺ .

Example 77

10-Methyl-7-((methylsulfonyl)methyl)-4-(phenylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 77 was prepared according to the procedure used to prepare Example 74, substituting benzenesulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ /D ₂ O) δ 7.65 (d, J=1.83 Hz, 1H)7.47-7.51 (m, 1H) 7.41 (dd, J=8.09, 1.98 Hz, 1H) 7.22-7.26 (m, 2H) 7.21 (s,1H) 6.93-6.98 (m, 2H) 6.88-6.91 (m, 2H) 5.24 (d, J=16.48 Hz, 1H) 4.58-4.62(m, 1H) 4.48-4.54 (m, 2H) 3.47 (s, 3H) 2.97 (s, 3H). MS (APCI+) m/z 484 (M+H) ⁺ .

Example 78

4-((2-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 78 was prepared according to the procedure used to prepare Example 74, substituting 2-methoxybenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ /D ₂ O) δ 7.74 (d, J=1.83Hz, 1H) 7.50 (s, 1H) 7.33-7.39 (m, 1H) 7.26-7.30 (m, 2H) 7.12-7.16 (m, 2H)6.81 (d, J=8.24 Hz, 1H) 6.72 (t, J=7.48 Hz, 1H) 5.25 (d, J=16.48 Hz, 1H)4.54-4.59 (m, 1H) 4.41-4.52 (m, 2H) 3.58 (s, 3H) 3.44 (s, 3H) 2.99 (s, 3H). MS (APCI+) m/z 514 (M+H) ⁺ .

Example 79

10-Methyl-7-((methylsulfonyl)methyl)-4-((4-phenoxyphenyl)sulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 79 was prepared according to the procedure used to prepare Example 74, substituting 4-phenoxybenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ /D ₂ O) δ 7.70 (d, J=1.83Hz, 1H) 7.47-7.52 (m, 3H) 7.41 (dd, J=8.24, 1.83 Hz, 1H) 7.38 (s, 1H) 7.28(t, J=7.48 Hz, 1H) 7.21 (s, 1H) 7.08 (d, J=7.63 Hz, 2H) 6.91-6.94 (m, 2H)6.39-6.44 (m, 2H) 5.22 (d, J=16.48 Hz, 1H) 4.58-4.63 (m, 1H) 4.47-4.56 (m,2H) 3.57 (s, 3H) 2.98 (s, 3H). MS (APCI+) m/z 576 (M+H) ⁺ .

Example 80

4-((4-Fluorophenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 80 was prepared according to the procedure used to prepare Example 74, substituting 4-fluorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ /D ₂ O) δ 7.67 (d, J=1.83 Hz,1H) 7.48-7.51 (m, 1H) 7.42 (dd, J=8.09, 1.68 Hz, 1H) 7.29 (s, 1H) 7.25 (s,1H) 6.96 (dd, J=8.85, 5.19 Hz, 2H) 6.76 (t, J=8.85 Hz, 2H) 5.23 (d, J=16.48Hz, 1H) 4.57-4.63 (m, 1H) 4.47-4.56 (m, 2H) 3.51 (s, 3H) 2.98 (s, 3H). MS (APCI+) m/z 502 (M+H) ⁺ .

Example 81

4-(2-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 81 was prepared according to the procedure used to prepare Example 54, substituting 2-naphthoyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.96-7.99 (m, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.80 (d, J=7.02 Hz, 1H), 7.71-7.76 (m, 1H), 7.63-7.67 (m, 2H),7.57-7.61 (m, 1H), 7.46-7.53 (m, 2H), 7.42 (s, 1H), 7.08 (dd, J=8.39, 1.37Hz, 1H), 5.93 (d, J=14.95 Hz, 1H), 4.39-4.45 (m, 1H), 4.31-4.38 (m, 1H), 4.20 (d, J=14.65 Hz, 1H), 3.73 (s, 3H), 2.77 (s, 3H). MS (ESI+) m/z 498.1 (M+H) ⁺ .

Example 82

Methyl 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

In tetrahydrofuran (1 mL), embodiment 12d (44.3 mg, 0.100 mmol) and methyl 4-oxobutanoate (58.1 mg, 0.500 mmol) were combined. 1M titanium (IV) chloride/dichloromethane (0.200 mL, 0.200 mmol) was added to the suspension. The reaction mixture was stirred at ambient temperature for 20 hours and distributed between ethyl acetate and water. The organic layer was washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound (38 mg, 70%) was obtained by flash chromatography (silica gel, 2-4% methanol/dichloromethane) purification of the residue. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.91(d, J=2.14 Hz, 1 H) 7.85 (d, J=1.83 Hz, 1 H) 7.69 (s, 1 H) 7.24 (dd, J=8.24,1.83 Hz, 1 H) 7.04-7.13 (m, 2 H) 6.81-7.02 (m, 3 H) 5.03 (t, J=7.63 Hz, 1 H)4.38-4.63 (m, 2 H) 3.64 (s, 3 H) 3.55 (s, 3 H) 2.93 (s, 3 H) 2.35-2.46 (m, 2H) 1.82-2.03 (m, 1H) 1.34-1.61 (m, 1H). MS (ESI+) m/z 542 (M+H) ⁺ .

Example 83

4-(2,4-Difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo[cd,f]azulene-11(10H)-one

Example 83a

5-Chloro-N-(2,4-difluorophenyl)pyrimidin-4-amine

Combine 2,4-difluoroaniline (0.433 g, 3.36 mmol), 4,5-dichloropyrimidine (0.5 g, 3.36 mmol), cesium carbonate (2.187 g, 6.71 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.097 g, 0.168 mmol), and palladium acetate (0.038 g, 0.168 mmol) in toluene (4 mL), seal, sparge with argon for 15 minutes, and heat at 110°C for 18 hours. Partition the reaction mixture between ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), treated with 3-mercaptopropyl-functionalized silica, filtered, and concentrated. Purification by chromatography (silica gel, 10-50% ethyl acetate/heptane) affords the title compound (0.66 g, 81%).

Example 83b

4-(4-((2,4-difluorophenyl)amino)pyrimidin-5-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Combine Example 83a (0.2 g, 0.828 mmol), Example 1f (0.355 g, 0.828 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.038 g, 0.041 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.041 g, 0.141 mmol), and sodium carbonate (0.307 g, 2.90 mmol) and purge with argon for 15 minutes. Simultaneously, a 4:1 dioxane/water solution (4 mL) was bubbled with nitrogen for 15 minutes and transferred to the reaction vessel via syringe under argon. The mixture was stirred at 80°C for 18 hours, cooled, diluted with 100 mL of ethyl acetate and 20 mL of water, and filtered through celite to remove elemental palladium. The filtrate layers were separated. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), treated with 3-mercaptopropyl-functionalized silica gel, filtered, and concentrated. Purification by chromatography (silica gel, 0.5-4% methanol/dichloromethane) afforded the title compound (0.272 g, 65%).

Example 83c

4-(4-((2,4-difluorophenyl)amino)pyrimidin-5-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 83b (0.26 g, 0.512 mmol) and lithium hydroxide monohydrate (0.215 g, 5.12 mmol) were combined in dioxane (4 mL) and water (1.333 mL) and heated at 50°C for 18 hours. The mixture was cooled, diluted with water, and the pH was adjusted to pH 9 with 1 M HCl. The resulting solid was collected by filtration, washed with water, and dried to constant weight to afford the title compound (0.171 g, 94%).

Example 83d

4-(2,4-Difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo[cd,f]azulene-11(10H)-one

Example 83c (0.03 g, 0.085 mmol) and paraformaldehyde (0.025 g, 0.849 mmol) were combined in methanol (1.0 mL) and treated with hydrochloric acid (4 M in 1,4-dioxane, 1.0 mL, 4.00 mmol). The mixture was sealed and heated in a microwave at 130°C for 2 hours. The mixture was cooled, diluted with diethyl ether, and filtered to collect the title compound as the HCl salt (0.0025 g, 7%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.75 (d, J = 2.44 Hz, 1H), 10.45(s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 7.77 (d, J = 2.75 Hz, 1H), 7.40-7.52 (m,3H), 7.17 (t, J = 8.39 Hz, 1H), 5.58 (d, J = 14.95 Hz, 1H), 4.81 (d, J =15.26 Hz, 1H), 3.58 (s, 3H). MS (ESI+) m/z 366 (M+H) ⁺ .

Example 84

(R)-4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester

Example 34 (13.4 mg, 0.026 mmol) was purified by SFC using a modified Berger Instruments PrepSFC ^™ system. The manual Berger system incorporates a Gilson 232 autosampler for sample injection and a Cavro MiniPrep ^™ pipette for fraction collection at atmospheric pressure (Olson, J.; Pan, J.; Hochlowski, J.; Searle, P.; Blanchard, D. JALA 2002, 7, 69-74). Custom-designed collection shoes allow collection into 18×150 mm tubes, and a methanol wash system washes the shoe between fractions to maximize recovery and avoid cross-contamination of fractions. The system was controlled using SFC ProNTo ^™ software (version 1.5.305.15) and a Visual Basic application developed by Abbott for autosampler and fraction collector control. The outlet pressure was 100 bar, the oven temperature was 35°C, and the mobile phase flow rate on a ChiralPak OD-H column (21 x 250 mm, 5 microns) was 40 mL/min. The sample solution was injected in 1.5 mL of methanol. The preparative SFC system was controlled using SFC ProNTo ^™ software (version 1.5.305.15) and custom software for autosampler and fraction collector control. Fractions were collected based on UV signal thresholds, and molecular weight confirmation was performed using an online Thermo MSQ mass spectrometer (using positive ion mode ESI ionization). Mass spectra were acquired using Navigator 4.0 software and a Visual Basic interface developed by Abbott that communicated with the SFC control software to obtain two white solids (Example 84, 6.5 mg, 48% yield) and Example 85 (6.0 mg, 44% yield). The first eluting enantiomer was arbitrarily designated as the R-isomer (Example 84), and the second eluting enantiomer was designated as the S-isomer (Example 85). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.95-12.00 (m, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.62 (s, 1H), 7.37(d, J = 1.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.87 (t, J = 8.7 Hz, 2H), 6.46-6.61 (m, 2H), 6.18-6.29 (m, 1H), 4.44-4.62 (m, 2H), 3.70-4.03 (m, 2H), 3.58 (s, 3H), 2.93 (s, 3H), 0.87-1.03 (m, 3H). MS (ESI+) m/z 510.1 (M+H) ⁺ .

Example 85

(S)-4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.95-12.00 (m, 1H), 7.85 (d, J = 2.0 Hz,1H), 7.62 (s, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.87(t, J = 8.7 Hz, 2H), 6.46-6.61 (m, 2H), 6.18-6.29 (m, 1H), 4.44-4.62 (m, 2H), 3.70-4.03 (m, 2H), 3.58 (s, 3H), 2.93 (s, 3H), 0.87-1.03 (m, 3H). MS (ESI+) m/z 510.1 (M+H) ⁺ .

Example 86

2-Methoxyethyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 86 was prepared according to the procedure used for Example 53, using 2-methoxyethyl chloroformate instead of 2-ethylhexyl chloroformate, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.78-7.80 (m, 1H), 7.61 (s, 1H), 7.35-7.39 (m, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 5.20-5.30 (m, 1H), 4.49 (d, J = 6.8 Hz, 2H), 3.88-4.20 (m, 2H), 3.63 (s, 3H), 3.33-3.39 (m, 1H), 3.12 (s, 2H), 2.94 (s, 3H). MS (ESI+) m/z 446.0 (M+H) ⁺ .

Example 87

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid ethyl ester

Example 87 was prepared according to the procedure used for Example 53, using ethyl chloroformate instead of 2-ethylhexyl chloroformate, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.78-7.80 (m, 1H), 7.61 (s, 1H), 7.35-7.39 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 5.21-5.27 (m, 1H), 4.49 (d, J = 6.8 Hz, 2H), 4.12-4.17 (m, 1H), 3.85-3.99 (m, 2H), 3.63 (s, 3H), 2.95 (s, 3H), 1.00-1.08 (m, 3H). MS (ESI+) m/z 416.1 (M+H) ⁺ .

Example 88

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid pentyl ester

Example 88 was prepared according to the procedure used to prepare Example 53, substituting amyl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.79 (d, J = 1.9 Hz, 1H), 7.60 (s, 1H), 7.37 (dd, J = 8.1, 1.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.22(s, 1H), 5.22 (d, J = 15.5 Hz, 1H), 4.44-4.54 (m, 2H), 4.14 (d, J = 15.6 Hz, 1H), 3.91 (dd, J = 11.9, 5.4 Hz, 1H), 3.80-3.87 (m, 1H), 3.63 (s, 3H), 2.94(s, 3H), 1.33-1.41 (m, 2H), 1.03-1.18 (m, 4H), 0.75 (t, J = 7.1 Hz, 3H). MS(ESI+) m/z 458.1 (M+H) ⁺ .

Example 89

4-Chlorobutyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 89 was prepared according to the procedure used to prepare Example 53, substituting 4-chlorobutyl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.80 (d, J = 1.9 Hz, 1H), 7.61 (s, 1H), 7.36-7.39 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.23 (s, 1H), 5.23 (d, J = 15.7 Hz, 1H), 4.45-4.54 (m, 2H), 4.15 (d, J = 15.8 Hz, 1H), 3.93-3.99 (m, 1H), 3.83-3.92 (m, 1H), 3.63 (s, 3H), 3.40-3.47 (m, 2H), 2.94(s, 3H), 1.47-1.58 (m, 4H). MS (ESI+) m/z 478.0 (M+H) ⁺ .

Example 90

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid naphthalen-2-yl ester

Example 90 was prepared according to the procedure used for Example 53, substituting naphthyl 2-yl chloroformate for 2-ethylhexyl chloroformate, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.76-7.88 (m, 4H), 7.71 (s, 1H), 7.55-7.63 (m, 1H), 7.39-7.50 (m, 4H), 7.29-7.33 (m, 1H), 7.07 (d, J = 8.9 Hz, 1H), 5.33-5.46 (m, 1H), 4.46-4.57 (m, 2H), 4.27-4.38 (m, 1H), 3.67 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 513.9 (M+H) ⁺ .

Example 91

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid p-tolyl ester

Example 91 was prepared according to the procedure used to prepare Example 53, substituting p-tolyl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.84 (d, J = 1.9 Hz, 1H), 7.68 (s, 1H), 7.47-7.54 (m, 1H), 7.42 (dd, J = 8.0, 1.8 Hz, 1H), 7.29(s, 1H), 7.08 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 5.30-5.37 (m,1H), 4.46-4.56 (m, 2H), 4.22-4.32 (m, 1H), 3.66 (s, 3H), 2.95 (s, 3H), 2.23 (s, 3H). MS (ESI+) m/z 478.2 (M+H) ⁺ .

Example 92

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid neopentyl ester

Example 92 was prepared according to the procedure used to prepare Example 53, substituting neopentyl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.81 (d, J = 1.8 Hz, 1H), 7.62 (s, 1H), 7.38 (dd, J = 8.1, 1.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.23 (s, 1H), 5.23 (d, J = 15.5 Hz, 1H), 4.44-4.54 (m, 2H), 4.18 (d, J = 15.6Hz, 1H), 3.63 (s, 3H), 3.27-3.29 (m, 2H), 2.91 (s, 3H), 0.62-0.79 (m, 9H). MS(ESI+) m/z 458.1 (M+H) ⁺ .

Example 93

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid phenyl ester

Example 93 was prepared according to the procedure used to prepare Example 53, substituting phenyl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.85 (d, J = 1.9 Hz, 1H), 7.69 (s, 1H), 7.50-7.55 (m, 1H), 7.42 (dd, J = 8.0, 2.0 Hz, 1H), 7.29 (t, J =7.8 Hz, 3H), 7.14 (t, J = 7.3 Hz, 1H), 6.89 (dd, J = 8.6, 1.1 Hz, 2H), 5.30-5.39 (m, 1H), 4.46-4.57 (m, 2H), 4.26-4.34 (m, 1H), 3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 464.1 (M+H) ⁺ .

Example 94

4-Fluorophenyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 94 was prepared according to the procedure used to prepare Example 53, substituting 4-fluorophenyl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.85 (d, J = 1.7 Hz, 1H), 7.68 (s, 1H), 7.50-7.57 (m, 1H), 7.42 (dd, J = 8.2, 2.0 Hz, 1H), 7.29(s, 1H), 7.07 (t, J = 8.8 Hz, 2H), 6.91-6.96 (m, 2H), 5.31-5.38 (m, 1H), 4.46-4.56 (m, 2H), 4.25-4.34 (m, 1H), 3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 482.0 (M+H) ⁺ .

Example 95

2-Methoxyphenyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 95 was prepared according to the procedure used to prepare Example 53, substituting 2-methoxyphenyl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.84 (d, J = 1.8Hz, 1H), 7.68 (s, 1H), 7.49-7.55 (m, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.27 (s, 1H), 7.08-7.14 (m, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.83-6.86 (m, 2H), 5.29-5.36 (m, 1H), 4.45-4.56 (m, 2H), 4.23-4.33 (m, 1H), 3.67 (s, 3H), 3.54 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 494.1 (M+H) ⁺ .

Example 96

2-Fluoroethyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 96 was prepared according to the procedure used to prepare Example 53, substituting 2-fluoroethyl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.80 (d, J = 1.5 Hz, 1H), 7.62 (s, 1H), 7.38 (dd, J = 8.3, 1.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 0.6 Hz, 1H), 5.27 (d, J = 15.6 Hz, 1H), 4.45-4.55 (m, 3H), 4.34-4.39 (m, 1H), 3.99-4.28 (m, 3H), 3.63 (s, 3H), 2.94 (s, 3H). MS (ESI+) m/z434.0 (M+H) ⁺ .

Example 97

4-Methoxyphenyl 10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 97 was prepared according to the procedure used for Example 53, using 4-methoxyphenyl chloroformate instead of 2-ethylhexyl chloroformate, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.84 (d, J = 1.8 Hz, 1H), 7.68 (s, 1H), 7.46-7.56 (m, 1H), 7.39-7.44 (m, 1H), 7.25-7.32 (m, 1H), 6.82 (s, 4H), 5.30-5.39 (m, 1H), 4.45-4.56 (m, 2H), 4.21-4.34 (m, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 494.0 (M+H) ⁺ .

Example 98

10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid but-2-yn-1-yl ester

Example 98 was prepared according to the procedure used to prepare Example 53, substituting but-2-yn-1-yl chloroformate for 2-ethylhexyl chloroformate to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.80 (d, J = 1.9Hz, 1H), 7.62 (s, 1H), 7.39 (dd, J = 8.3, 1.9 Hz, 1H), 7.31 (d, J = 8.1 Hz,1H), 7.25 (s, 1H), 5.21-5.27 (m, 1H), 4.44-4.55 (m, 4H), 4.13-4.19 (m, 1H), 3.63 (s, 3H), 2.95 (s, 3H), 1.72 (t, J = 2.3 Hz, 3H). MS (ESI+) m/z 440.1 (M+H) ⁺ .

Example 99

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide

Example 99a

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoic acid

In a mixture of dioxane (6 mL) and water (2 mL), embodiment 82 (375 mg, 0.692 mmol) and lithium hydroxide (83 mg, 3.5 mmol) were combined. The reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with water, the pH was adjusted to 4 by adding 1M HCl, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (365 mg, 100%).

Example 99b

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide

Example 99a (31.7 mg, 0.060 mmol), 2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (49.6 mg, 0.120 mmol), and diisopropylethylamine (0.042 mL, 0.240 mmol) were combined in dimethylformamide (1 mL). To this solution was added 0.5 M ammonia in dioxane (0.240 mL, 0.120 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 10-100%) to give the title compound (18 mg, 57%). ¹ HNMR (400 MHz, DMSO- d ₆ ) δ 11.91 (s, 1 H) 7.82 (d, J=1.83 Hz, 1 H) 7.68 (s, 1H) 7.34 (s, 1 H) 7.22 (dd, J=8.24, 1.83 Hz, 1 H) 7.01-7.17 (m, 3 H) 6.86-6.99 (m, 2 H) 6.77 (s, 1 H) 5.01 (dd, J=9.00, 5.95 Hz, 1 H) 4.38-4.55 (m, 2 H)3.64 (s, 3 H) 2.93 (s, 3 H) 2.10-2.20 (m, 2 H) 1.87-1.98 (m, 1 H) 1.31-1.45 (m, 1 H). MS (ESI+) m/z 549 (M+Na) ⁺ .

Example 100

4-(4-Fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 100 was prepared according to the procedure used for Example 54, substituting 4-fluorobenzoyl chloride for isobutyryl chloride, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.83 (d, J = 1.9 Hz, 1H), 7.75 (s, 1H), 7.25-7.33 (m, 1H), 7.10 (ddd, J = 13.0, 8.5, 5.9 Hz, 3H), 6.90-7.03 (m, 3H), 5.66-5.88 (m, 1H), 4.33-4.50 (m, 2H), 4.16 (d, J = 16.2 Hz, 1H), 3.69 (s, 3H), 2.84 (s, 3H). MS (ESI+) m/z 466.1 (M+H) ⁺ .

Example 101

4-(3-methoxypropionyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 101 was prepared according to the procedure used to prepare Example 54, substituting 3-methoxypropanoyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.86 (s, 1H), 7.67 (s, 1H), 7.38-7.46 (m, 2H), 7.22-7.25 (m, 1H), 5.48-5.61 (m, 1H), 4.52 (q, J = 14.0Hz, 2H), 3.93-4.01 (m, 1H), 3.64 (s, 3H), 3.29-3.43 (m, 3H), 3.00 (s, 2H), 2.95 (s, 3H), 2.33-2.43 (m, 1H), 1.93-2.02 (m, 1H). MS (ESI+) m/z 430.2 (M+H) ⁺ .

Example 102

4-([1,1'-biphenyl]-4-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 102 was prepared according to the procedure used to prepare Example 54, substituting [1,1'-biphenyl]-4-carbonyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.85 (d, J = 1.8 Hz, 1H), 7.78 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.39-7.46 (m, 4H), 7.29-7.37 (m, 2H),7.14 (d, J = 8.4 Hz, 3H), 6.99-7.06 (m, 1H), 5.70-5.94 (m, 1H), 4.42 (d, J =5.2 Hz, 2H), 4.14-4.22 (m, 1H), 3.70 (s, 3H), 2.81 (s, 3H). MS (ESI+) m/z424.0 (M+H) ⁺ .

Example 103

4-(3-cyclopentylpropionyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 103 was prepared according to the procedure used to prepare Example 54, substituting 3-cyclopentylpropionyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.86 (s, 1H), 7.65 (s, 1H), 7.41 (dd, J = 22.9, 9.0 Hz, 2H), 7.23 (s, 1H), 5.51-5.59 (m, 1H), 4.52 (q, J= 13.6 Hz, 2H), 3.89-3.99 (m, 1H), 3.63 (s, 3H), 2.94 (s, 3H), 1.83-2.10 (m,2H), 1.19-1.40 (m, 9H), 0.66-0.80 (m, 2H). MS (ESI+) m/z 468.2 (M+H) ⁺ .

Example 104

4-(2-(3-methoxyphenyl)acetyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 104 was prepared according to the procedure used for Example 54, using 2-(3-methoxyphenyl)acetyl chloride instead of isobutyryl chloride, to provide the title compound. ^H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.65-7.74 (m, 1H), 7.39-7.49 (m, 2H), 7.16-7.30 (m, 2H), 6.52-6.94 (m, 2H), 6.04-6.18 (m, 1H), 5.49-5.61 (m, 1H), 4.45-4.56 (m, 2H), 3.58 (s, 3H), 3.47 (s, 2H), 2.95 (s, 4H). MS (ESI+) m/z 492.1 (M+H) ⁺ .

Example 105

10-Methyl-7-((methylsulfonyl)methyl)-4-propionyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 105 was prepared according to the procedure used to prepare Example 54, substituting propionyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.81-7.88 (m, 1H), 7.63-7.69 (m, 1H), 7.37-7.45 (m, 2H), 7.22-7.26 (m, 1H), 5.51-5.61 (m, 1H), 4.52 (q, J = 13.8Hz, 2H), 3.91-3.99 (m, 1H), 3.63 (s, 3H), 2.95 (s, 3H), 2.13 (dq, J = 14.8,7.3 Hz, 1H), 1.64-1.81 (m, 1H), 0.72-0.87 (m, 3H). MS (ESI+) m/z 400.1 (M+H) ⁺ .

Example 106

10-Methyl-4-(3-methylbutyryl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 106 was prepared according to the procedure used to prepare Example 54, substituting 3-methylbutyryl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.81-7.88 (m, 1H), 7.63-7.69 (m, 1H), 7.32-7.47 (m, 2H), 7.22-7.25 (m, 1H), 5.49-5.62 (m, 1H), 4.47-4.59 (m,2H), 3.91-3.99 (m, 1H), 3.63 (s, 3H), 2.95 (s, 3H), 1.90-2.01 (m, 1H), 1.66-1.81 (m, 1H), 0.63-0.69 (m, 3H), 0.43-0.51 (m, 4H). MS (ESI+) m/z 428.1 (M+H) ⁺ .

Example 107

4-(3,3-Dimethylbutyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 107 was prepared according to the procedure used for Example 54, using 3,3-dimethylbutyryl chloride instead of isobutyryl chloride, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.85 (s, 1H), 7.65 (s, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 5.57-5.64 (m, 1H), 3.87-3.97 (m, 1H), 4.52 (q, J = 13.7 Hz, 2H), 3.63 (s, 3H), 2.94 (s, 3H), 1.84-2.01 (m, 2H), 0.69 (s, 9H). MS (ESI+) m/z 442.2 (M+H) ⁺ .

Example 108

10-Methyl-7-((methylsulfonyl)methyl)-4-(2-phenylacetyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 108 was prepared according to the procedure used in Example 54, using 2-phenylacetyl chloride instead of isobutyryl chloride, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.69-7.74 (m, 1H), 7.44 (s, 2H), 7.24-7.28 (m, 2H), 7.19-7.23 (m, 2H), 6.93-7.01 (m, 2H), 6.54-6.62 (m, 1H), 5.49-5.57 (m, 1H), 4.46-4.57 (m, 2H), 3.95-4.01 (m, 1H), 3.58 (s, 3H), 2.96 (s, 5H). MS (ESI+) m/z 462.1 (M+H) ⁺ .

Example 109

4-Benzoyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 109 was prepared according to the procedure used to prepare Example 54, substituting benzoyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.90-7.96 (m, 1H), 7.82 (d, J = 2.0Hz, 1H), 7.75 (s, 1H), 7.20-7.34 (m, 2H), 7.09-7.18 (m, 2H), 7.04 (d, J = 7.4Hz, 2H), 6.92-7.01 (m, 1H), 5.65-5.87 (m, 1H), 4.41 (d, J = 5.0 Hz, 2H), 4.11-4.21 (m, 1H), 3.69 (s, 3H), 2.82 (s, 3H). MS (ESI+) m/z 448.0 (M+H) ⁺ .

Example 110

4-(4-Methoxybenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 110 was prepared according to the procedure used to prepare Example 54, substituting 4-methoxybenzoyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.83 (d, J = 1.8 Hz, 1H), 7.75 (s, 1H), 7.27 (s, 1H), 7.14 (dd, J = 8.0, 2.1 Hz, 1H), 7.01 (d, J = 8.8Hz, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 5.72-5.92 (m,1H), 4.36-4.49 (m, 2H), 4.12 (d, J = 14.4 Hz, 1H), 3.68 (d, J = 5.3 Hz, 6H),2.85 (s, 3H). MS (ESI+) m/z 478.1 (M+H) ⁺ .

Example 111

Methyl 4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)-4-oxobutanoate

Example 111 was prepared according to the procedure used to prepare Example 54, substituting methyl 4-chloro-4-oxobutanoate for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.85-7.89 (m, 1H), 7.66-7.71 (m, 1H), 7.42-7.47 (m, 2H), 7.21-7.25 (m, 1H), 5.49-5.58 (m, 1H), 4.47-4.58 (m, 2H), 3.93-4.01 (m, 1H), 3.64 (s, 3H), 3.40-3.44 (m, 2H), 2.95 (s,3H), 2.28-2.49 (m, 2H), 1.84-2.00 (m, 1H). MS (ESI+) m/z 458.1 (M+H) ⁺ .

Example 112

4-(2,4-Difluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 112 was prepared according to the procedure used for Example 54, using 2,4-difluorobenzoyl chloride instead of isobutyryl chloride, to provide the title compound. ^1H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.79 (s, 1H), 7.70 (s, 1H), 7.29-7.38 (m, 1H), 7.00-7.17 (m, 3H), 6.78-6.95 (m, 2H), 5.74-5.85 (m, 1H), 4.33-4.47 (m, 2H), 4.14-4.24 (m, 1H), 3.67 (s, 3H), 2.81 (s, 3H). MS (ESI+) m/z 484.1 (M+H) ⁺ .

Example 113

4-(2-Fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 113 was prepared according to the procedure used in Example 54, using 2-fluorobenzoyl chloride instead of isobutyryl chloride, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.80-7.86 (m, 1H), 7.70 (s, 1H), 7.58-7.64 (m, 1H), 7.30-7.40 (m, 1H), 7.17-7.28 (m, 1H), 6.99-7.14 (m, 2H), 6.83-6.99 (m, 2H), 5.72-5.88 (m, 1H), 4.26-4.49 (m, 2H), 4.12-4.25 (m, 1H), 3.68 (s, 3H), 2.77 (s, 3H). MS (ESI+) m/z 466.0 (M+H) ⁺ .

Example 114

4-(1-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 114 was prepared according to the procedure used to prepare Example 54, substituting 1-naphthoyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.74-7.81 (m, 1H), 7.66-7.73 (m, 1H), 7.60-7.67 (m, 1H), 7.52-7.60 (m, 2H), 7.38-7.49 (m, 2H), 7.16-7.32 (m,2H), 6.94-7.07 (m, 2H), 6.84-6.92 (m, 1H), 5.89-6.00 (m, 1H), 4.33-4.61 (m,1H), 4.20-4.30 (m, 2H), 3.69 (s, 3H), 2.59-2.76 (m, 3H). MS (ESI+) m/z 498.1(M+H) ⁺ .

Example 115

4-(Cyclopropylcarbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 115 was prepared according to the procedure used to prepare Example 54, substituting cyclopropylcarbonyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.83-7.91 (m, 1H), 7.63-7.71 (m, 1H), 7.39-7.47 (m, 2H), 7.18-7.27 (m, 1H), 5.53-5.66 (m, 1H), 4.44-4.61 (m,2H), 3.89-4.05 (m, 1H), 3.64 (s, 3H), 2.96 (s, 3H), 1.91-1.98 (m, 1H), 1.18-1.32 (m, 1H), 1.04-1.15 (m, 2H), 0.55-0.66 (m, 1H). MS (ESI+) m/z 412.1 (M+H) ⁺ .

Example 116

10-Methyl-7-((methylsulfonyl)methyl)-4-(3-phenylpropionyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 116 was prepared according to the procedure used to prepare Example 54, substituting 3-phenylpropionyl chloride for isobutyryl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ 7.83 (d, J = 0.6 Hz, 1H), 7.59(s, 1H), 7.40 (d, J = 9.5 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H), 6.97-7.06 (m, 3H), 6.76-6.84 (m, 2H), 5.51-5.63 (m, 1H), 4.51 (q, J = 13.9Hz, 2H), 3.89-4.01 (m, 1H), 3.63 (s, 3H), 2.93 (s, 3H), 2.61 (t, J = 7.8 Hz,2H), 2.33-2.43 (m, 1H), 2.02-2.14 (m, 1H). MS (ESI+) m/z 476.2 (M+H) ⁺ .

Example 117

2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione

Example 12d (0.4 g, 0.902 mmol) and 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (0.683 g, 3.61 mmol) were combined in tetrahydrofuran (9.02 mL) under nitrogen, cooled to 0°C, and treated dropwise with 1M titanium(IV) chloride/dichloromethane (3.61 mL, 3.61 mmol) to yield an opaque red solution. The solution was stirred at ambient temperature for 72 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 0.5-5% methanol/dichloromethane) provided the title compound as a yellow powder (0.45 g, 81%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.78 (d, J = 1.83 Hz, 1H), 7.93 (d, J = 1.53 Hz, 1H), 7.81-7.86 (m, 4H), 7.76 (s, 1H), 7.24-7.30 (m, 1H),7.21 (dd, J = 8.24, 1.83 Hz, 1H), 7.09-7.15 (m, 1H) 6.99-7.05 (m, 1H), 6.96(d, J = 2.44 Hz, 1H), 6.92 (d, J = 8.24 Hz, 1H), 5.44 (dd, J = 9.92, 5.34Hz, 1H), 4.51-4.56 (m, 1H), 4.44-4.48 (m, 1H), 3.87 (dd, J = 13.28, 5.34 Hz, 1H), 3.66 (s, 3H), 3.52 (dd, J = 13.28, 10.22 Hz, 1H), 2.98 (s, 3H). MS (ESI+)m/z 615 (M+H) ⁺ .

Example 118

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-methylpropionamide

Example 118 was prepared following the procedure used to prepare Example 99b, substituting methylamine for ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 20-100%) afforded the title compound (22 mg, 68%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.90 (d, J=1.22 Hz, 1 H) 7.82 (d, J=1.83 Hz, 1 H) 7.77 (q, J=4.48 Hz, 1 H) 7.68 (s, 1 H) 7.22 (dd, J=8.24, 1.83 Hz, 1 H) 7.02-7.12 (m, 3H) 6.87-7.00 (m, 2 H) 5.00 (dd, J=9.00, 5.95 Hz, 1 H) 4.33-4.58 (m, 2 H) 3.64(s, 3 H) 2.93 (s, 3 H) 2.55 (d, J=4.58 Hz, 3 H) 2.07-2.22 (m, 2 H) 1.83-2.00 (m, 1 H) 1.31-1.48 (m, 1 H). MS (ESI+) m/z 563 (M+Na) ⁺ .

Example 119

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylpropionamide

Example 119 was prepared following the procedure used to prepare Example 99b, using dimethylamine in place of ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 20-100%) afforded the title compound (24 mg, 72%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.89 (s, 1 H) 7.83 (d, J=1.83 Hz, 1 H) 7.68 (s, 1 H) 7.22 (dd, J=8.24, 2.14 Hz, 1 H) 7.13-7.20 (m, 1 H) 7.11 (s, 1 H) 7.02-7.10 (m, 1H) 6.97 (d, J=8.24 Hz, 1 H) 6.88-6.96 (m, 1 H) 5.03-5.12 (m, 1 H) 4.37-4.57(m, 2 H) 3.64 (s, 3 H) 2.94 (s, 3 H) 2.87 (s, 3 H) 2.80 (s, 3 H) 2.28-2.46 (m, 2 H) 1.85-1.95 (m, 1 H) 1.37-1.52 (m, 1 H). MS (ESI+) m/z 577 (M+Na) ⁺ .

Example 120

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-morpholino-3-oxopropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 120 was prepared following the procedure used to prepare Example 99b, substituting morpholine for ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 20-100%) afforded the title compound (28 mg, 78%). ¹ H NMR (500MHz, DMSO- d ₆ ) δ 11.89 (s, 1 H) 7.83 (d, J=1.83 Hz, 1 H) 7.68 (s, 1 H) 7.22 (dd, J=8.24, 1.83 Hz, 1 H) 7.03-7.16 (m, 3 H) 6.99 (d, J=8.24 Hz, 1 H) 6.88-6.94 (m, 1 H) 5.08 (t, J=7.63 Hz, 1 H) 4.39-4.57 (m, 2 H) 3.64 (s, 3 H) 3.37-3.55 (m, 8 H) 2.94 (s, 3 H) 2.40-2.48 (m, 1 H) 2.29-2.39 (m, 1 H) 1.84-1.94 (m, 1 H) 1.38-1.55 (m, 1 H). MS (ESI+) m/z 619 (M+Na) ⁺ .

Example 121

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(tetrahydro-2H-pyran-4-yl)propanamide

Example 121 was prepared following the procedure used to prepare Example 99b, substituting tetrahydro-2H-pyran-4-amine for ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 20-100%) afforded the title compound (28 mg, 76%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.90 (s, 1 H) 7.86 (d, J=7.63 Hz, 1 H) 7.82 (d, J=1.83 Hz, 1 H) 7.68 (s, 1 H) 7.22 (dd, J=8.24, 1.83 Hz, 1 H) 7.02-7.13 (m, 3H) 6.87-6.98 (m, 2 H) 5.00 (dd, J=9.16, 5.80 Hz, 1 H) 4.36-4.57 (m, 2 H)3.70-3.85 (m, 3 H) 3.64 (s, 3 H) 2.93 (s, 3 H) 2.16 (t, J=7.17 Hz, 2 H) 1.89-2.00 (m, 1 H) 1.58-1.73 (m, 2 H) 1.27-1.45 (m, 3 H). MS (ESI+) m/z 633 (M+Na) ⁺ .

Example 122

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N'-methyl-N'-phenylpropionylhydrazide

Example 122 was prepared following the procedure used to prepare Example 99b, substituting 1-methyl-1-phenylhydrazine for ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 30-100%) afforded the title compound (20 mg, 53%). ¹ HNMR (500 MHz, DMSO- d ₆ ) δ 11.95 (d, J=1.83 Hz, 1 H) 9.95 (s, 1 H) 7.85 (d, J=1.83 Hz, 1 H) 7.70 (s, 1 H) 7.25 (dd, J=8.24, 1.83 Hz, 1 H) 7.13-7.19 (m, 3H) 6.97-7.12 (m, 3 H) 6.83-6.92 (m, 1 H) 6.64-6.75 (m, 3 H) 5.05 (dd, J=8.85,6.10 Hz, 1 H) 4.39-4.56 (m, 2 H) 3.65 (s, 3 H) 3.05 (s, 3 H) 2.93 (s, 3 H)2.22-2.32 (m, 2 H) 1.92-2.01 (m, 1 H) 1.43-1.54 (m, 1 H). MS (ESI+) m/z 654 (M+Na) ⁺ .

Example 123

N-Benzyl-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide

Example 123 was prepared following the procedure used to prepare Example 99b, substituting phenylmethylamine for ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 30-100%) afforded the title compound (26 mg, 70%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.91 (d, J=2.14 Hz, 1 H) 8.39 (t, J=5.95 Hz, 1 H) 7.83 (d, J=1.83 Hz, 1 H) 7.68 (s, 1 H) 7.27-7.33 (m, 2 H) 7.19-7.25 (m, 4 H) 7.02-7.11 (m, 3 H) 6.97 (d, J=7.93 Hz, 1 H) 6.81-6.92 (m, 1 H) 5.02 (dd, J=9.00,5.95 Hz, 1 H) 4.38-4.57 (m, 2 H) 4.25 (d, J=5.80 Hz, 2 H) 3.64 (s, 3 H) 2.93 (s, 3 H) 2.25 (t, J=7.48 Hz, 2 H) 1.91-2.02 (m, 1 H) 1.35-1.56 (m, 1 H). MS(ESI+) m/z 639 (M+Na) ⁺ .

Example 124

3-(4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-yl)-N-(1,1-dioxotetrahydrothiophen-3-yl)propanamide

Example 124 was prepared following the procedure used to prepare Example 99b, substituting 3-aminotetrahydrothiophene 1,1-dioxide for ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 20-100%) afforded the title compound (27 mg, 70%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.92 (s, 1 H) 8.31 (dd, J=6.71, 3.66Hz, 1 H) 7.83 (s, 1 H) 7.68 (s, 1 H) 7.22 (dd, J=8.24, 1.83 Hz, 1 H) 7.01-7.13 (m, 3 H) 6.88-6.98 (m, 2 H) 4.95-5.05 (m, 1 H) 4.38-4.55 (m, 3 H) 3.64 (s, 3 H) 3.36-3.44 (m, 1 H) 3.23-3.29 (m, 1 H) 3.06-3.18 (m, 1H) 2.93 (s, 3H) 2.78-2.92 (m, 1 H) 2.27-2.40 (m, 1 H) 2.14-2.24 (m, 2 H) 1.87-2.05 (m, 2H) 1.37-1.51 (m, 1 H). MS (ESI+) m/z 667 (M+Na) ⁺ .

Example 125

tert-Butyl 4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoyl)piperazine-1-carboxylate

Example 125 was prepared following the procedure used to prepare Example 99b, substituting tert-butyl piperazine-1-carboxylate for ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 30-100%) afforded the title compound (46 mg, 74%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.89 (d, J=1.53 Hz, 1 H) 7.83 (d, J=1.83 Hz, 1 H)7.68 (s, 1 H) 7.23 (dd, J=8.24, 1.53 Hz, 1 H) 7.11-7.19 (m, 2 H) 7.03-7.11(m, 1 H) 6.98 (d, J=8.24 Hz, 1 H) 6.87-6.95 (m, 1 H) 5.08 (t, J=7.63 Hz, 1 H)4.39-4.56 (m, 2 H) 3.64 (s, 3 H) 3.38-3.44 (m, 2 H) 3.24-3.30 (m, 6 H) 2.93 (s, 3 H) 2.32-2.46 (m, 2 H) 1.84-1.98 (m, 1 H) 1.43-1.52 (m, 1 H) 1.40 (s, 9H). MS (ESI+) m/z 696 (M+H) ⁺ .

Example 126

tert-Butyl 4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propionamido)piperidine-1-carboxylate

Example 126 was prepared following the procedure used to prepare Example 99b, substituting tert-butyl 4-aminopiperidine-1-carboxylate for ammonia. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 30-100%) afforded the title compound (48 mg, 75%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.91 (d, J=2.44 Hz, 1 H) 7.80-7.85 (m, 2 H)7.68 (s, 1 H) 7.22 (dd, J=8.24, 1.83 Hz, 1 H) 7.02-7.13 (m, 3 H) 6.88-6.98(m, 2 H) 5.00 (dd, J=9.16, 6.10 Hz, 1 H) 4.34-4.55 (m, 2 H) 3.76-3.86 (m, 2H) 3.68-3.75 (m, 1 H) 3.64 (s, 3 H) 2.93 (s, 3 H) 2.73-2.88 (m, 2 H) 2.15 (t,J=7.02 Hz, 2 H) 1.88-1.99 (m, 1 H) 1.61-1.73 (m, 2 H) 1.34-1.48 (m, 10 H)1.11-1.27 (m, 2 H). MS (ESI+) m/z 732 (M+Na) ⁺ .

Example 127

4-(4-Chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 127a

2-Bromo-N-(4-chlorophenyl)aniline

Example 127a was prepared according to the procedure used for Example 58h, substituting 2-bromoaniline for Example 58g to provide the title compound.

Example 127b

1-Benzyl-4-(2-((4-chlorophenyl)amino)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

Example 127b was prepared according to the procedures used to prepare Example 5d, substituting Example 127a for Example 5c and Example 58f for Example 1f, respectively, to provide the title compound.

Example 127c

4-(2-((4-chlorophenyl)amino)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

Example 127c was prepared according to the procedure used to prepare Example 58j, substituting Example 127b for Example 58i to provide the title compound.

Example 127d

4-(4-Chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid ethyl ester

Example 127d was prepared according to the procedure used to prepare Example 58k, substituting Example 127c for Example 58j to provide the title compound.

Example 127e

4-(4-Chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 127d (150 mg, 0.346 mmol) and ethylamine (25% wt/wt in ethanol) (5 mL, 0.832 mmol) was sealed and heated at 78°C for 2 days. The reaction mixture was cooled to ambient temperature and concentrated. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to give the title compound (18 mg, 0.042 mmol, 12.03% yield) as a light solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 12.37 (s, 1H), 8.50 (s, 1H), 7.69 (d, J = 4.2 Hz, 1H), 7.43 (m, 3H), 7.27 (m, 1H), 6.92 (d,J = 8.8 Hz, 2H), 6.46 (d, J = 8.3 Hz, 2H), 6.13 (d, J = 15.3 Hz, 1H), 4.53 (m, 1H), 3.76 (s, 3H), 3.58 (m, 2H), 1.32 (m, 3H). MS (ESI+) m/z 433.0 (M+H) ⁺ .

Example 128

6-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)hexyl acetate

Under nitrogen, 7-oxoheptyl acetate (0.155 g, 0.902 mmol) and Example 12d (0.1 g, 0.225 mmol) were combined in tetrahydrofuran (2.255 mL) at 5 ° C, and 1M titanium (IV) chloride / dichloromethane (0.676 mL, 0.676 mmol) was added dropwise to give a dark red reaction mixture. The reaction mixture was stirred at ambient temperature for 18 hours and distributed between ethyl acetate and water. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound (0.108 g, 80%) was obtained by purification by chromatography (silica gel, 0.5-4% methanol / dichloromethane). ¹ HNMR (500 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.23 (d,J = 7.93 Hz, 1H), 7.13 (s, 1H), 7.04-7.10 (m, 1H), 6.98 (d, J = 7.93 Hz, 1H), 6.84 (d, J = 5.49 Hz, 2H), 5.00 (t, J = 6.56 Hz, 1H), 4.40-4.56 (m, 2H), 3.92 (t, J = 6.56 Hz, 2H) 3.64 (s, 3H), 2.92 (s, 3H), 1.96 (s, 3H), 1.09-1.67 (m, 10H). MS (ESI+) m/z 598 (M+H) ⁺ .

Example 129

3-(Aminomethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 117 (0.45 g, 0.732 mmol) and hydrazine hydrate (0.733 g, 14.64 mmol) were combined in ethanol (14.64 mL) and stirred at reflux for 2 hours. The solution was cooled to ambient temperature and filtered to remove the resulting white solid. The filtrate was concentrated to obtain a residue. The residue was purified by reverse-phase HPLC (C18, _CH3CN /10mM ammonium acetate/water, 10-100% gradient) to afford the title compound (0.280 mg, 80%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.84 (s,1H), 7.82 (d, J = 1.83 Hz, 1H), 7.67 (s, 1H), 7.24-7.30 (m, 1H), 7.22 (dd, J= 8.09, 1.98 Hz, 1H), 7.15 (s, 1H), 7.00-7.06 (m, 2H), 6.89-6.95 (m, 1H), 5.02 (dd, J = 8.24, 6.41 Hz, 1H), 4.41-4.55 (m, 2H), 3.64 (s, 3H), 3.57 (s,1H), 2.94 (s, 3H), 2.69 (dd, J = 12.97, 8.70 Hz, 1H), 2.45 (dd, J = 12.97, 6.26 Hz, 1H). MS (ESI+) m/z 485 (M+H) ⁺ .

Example 130

N-((((4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)(dimethylamino)methylene)-N-methylmethanamine

Example 129 (0.03 g, 0.062 mmol), N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)(dimethylamino)methylene)-N-methylmethanaminium (HCTU, 0.033 g, 0.080 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.032 mL, 0.186 mmol) were combined in DMF (0.619 mL). To the mixture was added acetic acid (10.63 μL, 0.186 mmol), stirred for 1 hour, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by reverse phase HPLC (C18, _CH3CN /water with 0.1% TFA, 10-100% gradient) gave the title compound as a trifluoroacetic acid salt (0.03 g, 78%). ¹ H NMR (500MHz, pyridine- d ₆ ) δ 13.11 (s, 1H), 9.84 (s, 1H), 8.08 (d, J = 1.47 Hz, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.43-7.49 (m, 2H), 7.20 (d, J = 8.07 Hz, 1H), 6.82-6.89 (m, 1H), 6.74-6.79 (m, 1H), 5.95-6.00 (m, 1H), 4.65 (s, 2H), 3.73 (dd, J= 13.48, 8.71 Hz, 1H), 3.61 (s, 3H), 3.57 (dd, J = 13.48, 6.33 Hz, 1H), 3.08 (s, 3H), 2.77 (s, 12H). MS (ESI+) m/z 583 (M) ⁺ .

Example 131

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-oxo-3-(piperazin-1-yl)propyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a mixture of Example 125 (40 mg, 0.057 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.50 mL, 6.5 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated. Water was added to the residue, and the pH was adjusted to 7 by adding saturated aqueous sodium bicarbonate. The mixture was sonicated for 5 minutes, filtered, washed with water, and dried to afford the title compound (18 mg, 53%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.89 (s, 1 H) 7.83 (d, J=1.83 Hz, 1 H) 7.68 (s, 1 H) 7.22 (dd, J=8.24, 1.83 Hz, 1 H) 7.03-7.18 (m, 3 H) 6.97 (d, J=7.93 Hz, 1 H) 6.87-6.94 (m, 1 H) 5.08 (t, J=7.63 Hz, 1 H)4.39-4.60 (m, 2 H) 3.64 (s, 3 H) 3.18-3.25 (m, 2 H) 2.94 (s, 3 H) 2.55-2.61(m, 4 H) 2.27-2.46 (m, 3 H) 1.83-1.94 (m, 1 H) 1.38-1.57 (m, 1 H). MS (ESI+)m/z 596 (M+H) ⁺ .

Example 132

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(piperidin-4-yl)propanamide

To a mixture of Example 126 (42 mg, 0.059 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.50 mL, 6.5 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated. Purification by reverse phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 20-100% gradient) afforded the title compound (15 mg, 42%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.77-7.86 (m, 2 H) 7.68 (s, 1 H) 7.22 (dd, J=8.24, 1.83Hz, 1 H) 7.01-7.13 (m, 3 H) 6.85-6.99 (m, 2 H) 5.00 (dd, J=9.16, 6.10 Hz, 1H) 4.38-4.56 (m, 2 H) 3.57-3.67 (m, 4 H) 3.39-3.52 (m, 1 H) 2.90-2.99 (m, 5H) 2.51-2.58 (m, 2 H) 2.15 (t, J=7.17 Hz, 2H) 1.89-1.97 (m, 1 H) 1.62-1.72 (m, 2 H) 1.36-1.46 (m, 1 H) 1.20-1.35 (m, 2 H). MS (ESI+) m/z 610 (M+H) ⁺ .

Example 133

4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)butane-1,2-diyl diacetate

Under nitrogen at 5°C, 5-oxopentane-1,2-diyl diacetate (0.182 g, 0.902 mmol) and Example 12d (0.1 g, 0.225 mmol) were combined in tetrahydrofuran (2.2 mL) and treated dropwise with 1M titanium(IV) chloride/toluene (0.676 mL, 0.676 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by reverse-phase HPLC (C18, _CH3CN /0.1% TFA/water, 10-100% gradient) afforded the title compound (0.038 g, 26%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87 (s, 1H), 7.83-7.87 (m, 1H), 7.69 (s, 1H), 7.22-7.28 (m, 1H), 6.96-7.18 (m, 3H), 6.69-6.87 (m, 2H), 5.01 (t, J = 6.71 Hz,1H), 4.78-4.92 (m, 1H), 4.40-4.56 (m, 2H), 3.85-4.08 (m, 2H), 3.64 (s, 3H), 2.92 (s, 3H), 1.95 (s, 3H), 1.88 (s, 3H), 1.30-1.79 (m, 4H). MS (ESI ⁺ ) m/z 628(M+H) ⁺ .

Example 134

Methyl 5-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pentanoate

Under nitrogen at 5°C, methyl 6-oxohexanoate (0.130 g, 0.902 mmol) and Example 12d (0.1 g, 0.225 mmol) were combined in tetrahydrofuran (2.3 mL) and treated dropwise with 1M titanium(IV) chloride (0.676 mL, 0.676 mmol)/dichloromethane. The reaction mixture was stirred at ambient temperature for 18 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The title compound (0.069 g, 54%) was purified by reverse-phase HPLC (C18, _CH3CN /0.1% TFA/water, 10-100% gradient). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.84 (d, J = 1.83 Hz, 1H), 7.85 (d, J = 1.53 Hz, 1H), 7.68(s, 1H), 7.24 (dd, J = 8.24, 1.83 Hz, 1H), 7.13 (d, J = 2.44 Hz, 1H), 7.03-7.11 (m, 1H), 6.98 (d, J = 8.24 Hz, 1H), 6.76-6.88 (m, 2H), 4.99 (t, J = 7.32Hz, 1H), 4.42-4.55 (m, 2H), 3.64 (s, 3H), 3.54 (s, 3H), 2.92 (s, 3H), 2.19 (t, J = 6.71 Hz, 2H), 1.21-1.66 (m, 6H). MS (ESI ⁺ ) m/z 570 (M+H) ⁺ .

Example 135

tert-Butyl (2-(((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)-2-oxoethyl)carbamate

2-(tert-Butoxycarbonyl)amino)acetic acid (0.022 g, 0.124 mmol), N-ethyl-N-isopropylpropan-2-amine (0.032 mL, 0.186 mmol), and 2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HCTU, 0.028 g, 0.068 mmol) were combined in N,N-dimethylformamide (0.619 mL) and stirred at ambient temperature for 15 minutes. To this solution was added dropwise a solution of Example 129 (0.03 g, 0.062 mmol) in N,N-dimethylformamide (0.619 mL). The reaction mixture was stirred at ambient temperature for 2 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by reverse phase HPLC (C18, CH ₃ CN/10 mM ammonium acetate/water, 10-100% gradient) afforded the title compound (0.02 g, 50%). ¹ HNMR (400 MHz, DMSO- d ₆ ) δ 11.93 (s, 1H), 7.82 (m, 1H), 7.81 (d, J = 1.83 Hz,1H), 7.69 (s, 1H), 7.33-7.46 (m, 1H), 7.20 (dd, J = 8.24, 1.83 Hz, 1H), 7.12(s, 1H), 6.93-7.09 (m, 4H), 5.20 (dd, J = 8.39, 6.26 Hz, 1H), 4.39-4.53 (m,2H), 3.65 (s, 3H), 3.53 (d, J = 6.10 Hz, 2H), 2.92 (s, 3H), 2.82-2.91 (m,2H), 2.48-2.51 (m,9H). MS (ESI ⁺ ) m/z 640 (M+H) ⁺ .

Example 136

4-(2,4-Difluorophenyl)-3-(6-hydroxyhexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 128 (0.08 g, 0.134 mmol) and lithium hydroxide monohydrate (0.056 g, 1.339 mmol) were combined in tetrahydrofuran (1.785 mL)/water (0.892 mL) and stirred at 50°C for 2 hours. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate and water, and the pH was adjusted to 7 by careful addition of 1 M aqueous HCl. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by reverse-phase HPLC (C18, _CH3CN /0.1% TFA/water, 10-100% gradient) afforded the title compound (0.05 g, 67%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 7.84 (d, J = 1.83 Hz, 1H), 7.67 (s, 1H), 7.23 (dd, J = 8.09, 1.98 Hz, 1H), 7.12 (d, J = 2.44 Hz, 1H), 7.03-7.10 (m, 1H), 6.98 (d, J = 8.24 Hz, 1H), 6.78-6.89 (m, 2H), 5.00 (t, J = 7.17 Hz, 1H), 4.41-4.54 (m, 2H), 4.32 (t, J = 6.56 Hz, 1H), 3.64 (s, 3H), 3.31 (t, J = 6.56Hz, 2H), 2.92 (s, 3H), 1.20-1.67 (m, 10H). MS (ESI+) m/z 556 (M+H) ⁺ .

Example 137

N-((4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)benzamide

The product from Example 129 (0.03 g, 0.062 mmol), N-ethyl-N-isopropylpropan-2-amine (0.216 mL, 1.238 mmol), and benzoyl chloride (0.036 mL, 0.310 mmol) were combined in N,N-dimethylformamide (1.238 mL) and heated at 50°C for 2 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by reverse-phase HPLC (C18, _CH3CN /0.1% TFA/water, 10-100% gradient) afforded the title compound (0.023 g, 63%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (d, J = 2.44 Hz, 1H), 8.55 (t, J = 5.49 Hz, 1H), 7.84 (d, J= 1.83 Hz, 1H), 7.81 (s, 1H), 7.79 (d, J = 1.53 Hz, 1H), 7.72 (s, 1H), 7.44-7.56 (m, 4H), 7.21 (dd, J = 8.24, 1.83 Hz, 1H), 7.02-7.12 (m, 2H), 6.99 (d, J= 2.75 Hz, 1H), 6.94 (d, J = 8.24 Hz, 1H), 5.42 (dd, J = 9.61, 5.34 Hz, 1H), 4.40-4.55 (m, 2H), 3.66 (s, 3H), 2.96-3.06 (m, 2H), 2.94 (s, 3H). MS (ESI+) m/z 589 (M+H) ⁺ .

Example 138

1-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)-3-phenylurea

The product of Example 129 (0.03 g, 0.062 mmol), N-ethyl-N-isopropylpropan-2-amine (0.054 mL, 0.310 mmol), and phenyl isocyanate (6.77 μL, 0.062 mmol) were combined in tetrahydrofuran (1.238 mL) and stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated and purified by reverse phase HPLC (C18, CH ₃ CN/0.1% TFA/water, 10-100% gradient) to provide the title compound (0.021 g, 56%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.96 (d, J =2.44 Hz, 1H), 8.71 (s, 1H), 7.85 (d, J = 1.83 Hz, 1H), 7.72 (s, 1H), 7.41 (d,J = 7.63 Hz, 2H), 7.17-7.28 (m, 4H), 7.15 (d, J = 2.75 Hz, 1H), 7.03-7.11 (m,2H), 6.88-6.98 (m, 2H), 6.12 (t, J = 5.65 Hz, 1H), 5.25 (t, J = 7.48 Hz, 1H),4.42-4.56 (m, 2H), 3.65 (s, 3H), 3.22-3.31 (m, 1H), 3.00-3.08 (m, 1H), 2.94 (s, 3H). MS (ESI+) m/z 602 (M+H) ⁺ .

Example 139

2-Amino-N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)acetamide

A mixture of the product of Example 135 (0.01 g, 0.016 mmol) in dichloromethane (2 mL)/TFA (1.0 mL) was stirred at ambient temperature for 1 hour, concentrated and azeotroped three times with toluene to afford the title compound as a TFA salt (0.01 g, 98%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.03 (d, J = 2.44 Hz, 1H), 8.45 (t, J = 5.80Hz, 1H), 8.00 (s, 2H), 8.00 (s, 1H), 7.83 (d, J = 1.83 Hz, 1H), 7.72 (s, 1H),6.92-7.40 (m, 5H) 5.18 (dd, J = 9.16, 5.49 Hz, 1H), 4.40-4.55 (m, 2H), 3.65(s, 3H), 3.43-3.67 (m, 4H), 2.94 (s, 3H). MS (ESI+) m/z 542 (M+H) ⁺ .

Example 140

4-(2,4-Difluorophenyl)-3-(3,4-dihydroxybutyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 133 (0.038 g, 0.061 mmol) and lithium hydroxide (0.029 g, 1.211 mmol) were combined in tetrahydrofuran (1.614 mL)/water (0.807 mL) and stirred at 50°C for 2 hours. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate and water, and the pH was adjusted to 7 by careful addition of 1 M aqueous HCl. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (0.028 g, 85%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 7.83 (d, J = 1.83 Hz, 1H), 7.67 (s,1H), 7.19-7.25 (m, 1H), 7.11 (dd, J = 5.04, 2.59 Hz, 1H), 7.03-7.09 (m, 1H), 6.84-6.99 (m, 3H), 4.97-5.04 (m, 1H), 4.43-4.53 (m, 2H), 4.34-4.41 (m, J =13.28, 1.98 Hz, 2H), 3.64 (s, 3H), 3.10-3.30 (m, 3H), 2.92 (s, 3H), 1.19-1.86 (m, 4H). MS (ESI+) m/z 544 (M+H) ⁺ .

Example 141

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 141a

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester

Example 141a was prepared according to the procedure used to prepare Example 82, substituting ethyl glyoxylate for methyl 4-oxobutanoate to provide the title compound as a white solid.

Example 141b

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid

To a 250 mL round-bottom flask was added Example 141a (0.6446 g, 1.222 mmol), dioxane (9.16 mL), and water (3.05 mL) to give a yellow solution. Lithium hydroxide hydrate (0.256 g, 6.11 mmol) was added. The reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was quenched with 1N HCl. The resulting suspension was stirred for 15 minutes and filtered. The solid was washed with water, dried at ambient temperature overnight, and then dried in a vacuum oven at 60°C for 72 hours to give the title compound (0.5521 g, 90% yield) as a yellow solid.

Example 141c

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

To a 250 mL round-bottom flask was added Example 141b (0.0473 g, 0.095 mmol) and dichloromethane (1.894 mL) to give a yellow-brown solution. Oxalyl chloride (0.021 mL, 0.237 mmol) and N,N-dimethylformamide (0.733 μL, 9.47 μmol) were added. The reaction mixture was stirred at ambient temperature for 2 hours and then cooled to 0°C. Ammonium hydroxide (0.186 mL, 4.73 mmol) was added. The reaction mixture was stirred at 0°C for 15 minutes and stirred overnight at ambient temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The reaction mixture was purified by HPLC (Phenomenex Luna C8 (2) 5 μm 100Å AXIA column (30 mm × 75 mm). Gradient elution was performed using acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A). Sample was injected in 1.5 mL of DMSO:methanol (1:1)) to afford the title compound (7.0 mg, 15% yield) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.96-12.01 (m, 1H), 7.75 (d, J =2.0 Hz, 1H), 7.66 (s, 1H), 7.49-7.59 (m, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.10-7.16 (m, 2H), 6.93-7.11 (m, 3H), 6.89 (d, J = 8.2 Hz, 1H), 6.68 (bs, 1H), 5.75 (s, 1H), 4.36-4.50 (m, 2H), 2.91 (s, 3H). MS (ESI+) m/z 499.1 (M+H) ⁺ .

Example 142

4-(2,4-Difluorophenyl)-3-(3-hydroxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a solution of Example 82 (542 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was added 1.0 M lithium aluminum hydride/tetrahydrofuran (1.00 mL, 1.00 mmol) dropwise at 0°C. The reaction mixture was stirred at ambient temperature for 2 hours and quenched by adding water (0.04 mL), 15% aqueous sodium hydroxide solution (0.04 mL), and water (0.12 mL). The resulting mixture was stirred for 20 minutes, diluted with ethyl acetate, filtered through celite, and concentrated. The residue was triturated with dichloromethane to give the title compound (413 mg, 80%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 7.83 (d, J =1.9 Hz, 1H), 7.67 (s, 1H), 7.22 (dd, J = 8.2, 1.9 Hz, 1H), 7.13 (s, 1H),7.11-7.05 (m, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.93-6.84 (m, 2H), 5.05-4.98 (m,1H), 4.53-4.42 (m, 2H), 4.36 (s, br, 1H), 3.64 (s, 3H), 2.93 (s, 3H), 1.71-1.62 (m, 1H), 1.61-1.54 (m, 1H), 1.50-1.42 (m, 1H), 1.34-1.25 (m, 1H). MS (ESI+) m/z 514 (M+H) ⁺ .

Example 143

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 142 (31 mg, 0.060 mmol), phenol (8.5 mg, 0.090 mmol), and triphenylphosphine (23.6 mg, 0.0900 mmol) were combined in tetrahydrofuran (0.1 mL) and sonicated for 5 minutes. Diisopropyl azodicarboxylate (0.017 mL, 0.090 mmol) was added to the reaction mixture, and the mixture was sonicated for 6 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane). The product obtained by flash chromatography was triturated with 10% dichloromethane/heptane to obtain the title compound (18 mg, 51%). ¹ H NMR (500MHz, DMSO- d ₆ ) δ 11.89 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.30-7.15 (m, 4H), 7.12-7.04 (m, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.93-6.77 (m, 5H), 5.13-5.05 (m,1H), 4.54-4.42 (m, 2H), 3.89 (s, br, 2H), 3.64 (s, 3H), 2.92 (s, 3H), 1.95-1.85 (m, 1H), 1.84-1.71 (m, 2H), 1.49-1.40 (m, 1H). MS (ESI+) m/z 590 (M+H) ⁺ .

Example 144

(S)-4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 143 was purified by chiral chromatography using a Chiralpak IB column eluting with a 4:6 methanol/carbon dioxide mixture. The fractions containing the first eluting enantiomer were collected and concentrated. This compound was arbitrarily designated as the (S)-enantiomer. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.88 (s, 1H), 7.86 (d, J = 1.7Hz, 1H), 7.69 (s, 1H), 7.28-7.20 (m, 3H), 7.17 (s, 1H), 7.11-7.04 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.92-6.82 (m, 5H), 5.09 (t, J = 7.1 Hz, 1H), 4.55-4.42 (m, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.65 (s, 3H), 2.92 (s, 3H), 1.97-1.85(m, 1H), 1.83-1.72(m, 2H), 1.49-1.38(m, 1H). MS (ESI+) m/z 590 (M+H) ⁺ .

Example 145

(R)-4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 143 was purified by chiral chromatography using a Chiralpak IB column eluting with a 4:6 methanol/carbon dioxide mixture. Fractions containing the second eluting enantiomer were collected and concentrated. This compound was arbitrarily designated as the (R)-enantiomer. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.88 (s, 1H), 7.86 (d, J = 1.5 Hz,1H), 7.69 (s, 1H), 7.28-7.20 (m, 3H), 7.17 (s, 1H), 7.11-7.04 (m, 1H), 6.99(d, J = 8.1 Hz, 1H), 6.92-6.80 (m, 5H), 5.09 (t, J = 7.1 Hz, 1H), 4.55-4.42(m, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.64 (s, 3H), 2.92 (s, 3H), 1.95-1.84 (m,1H), 1.84-1.72 (m, 2H), 1.49-1.39 (m, 1H). MS (ESI+) m/z 590 (M+H) ⁺ .

Example 146

4-(4-Chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 146a

4-(4-Chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid

Example 146a was prepared according to the procedure used for Example 581, substituting Example 127d for Example 58k to provide the title compound.

Example 146b

4-(4-Chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a solution of Example 146a (0.12 g, 0.296 mmol) in anhydrous dichloromethane (5 mL) were added oxalyl chloride (0.052 mL, 0.591 mmol) and dimethylformamide (1.1 µl, 0.015 mmol), and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to dryness and then dried under vacuum for 2 hours. The residue was redissolved in dichloromethane (5 mL) and treated with 1-methylpiperazine (0.118 g, 1.183 mmol), and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to give the crude title compound, which was used in the next reaction without further purification.

Example 146c

4-(4-Chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a solution of Example 146b (100 mg, 0.133 mmol) in anhydrous tetrahydrofuran (5 mL) was added BH ₃ ^{.tetrahydrofuran} (1.332 mL, 1.332 mmol), and the reaction mixture was stirred at 65 ° C for 3 hours. After cooling, the reaction mixture was quenched with ethanol (1 mL) and then concentrated. 3N HCl (2 mL) was added, and the mixture was heated at 78 ° C for 4 hours. The reaction mixture was cooled to ambient temperature and 5 N NaOH (2 mL) was added. The mixture was then extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC (C18, CH ₃ CN / water (0.01N ammonium carbonate), 25-55% gradient) to give the title compound (22 mg, 0.044 mmol, 33% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.37 (s, 1H), 8.50 (s, 1H), 7.69 (d, J =4.2 Hz, 1H), 7.43 (m, 3H), 7.27 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.46 (d, J = 8.3 Hz, 2H), 6.13 (d, J = 15.3 Hz, 1H), 4.53 (m, 1H), 3.76 (s, 3H), 3.58 (m, 2H), 1.32 (m, 3H). MS (ESI ⁺ ) m/z 433.0 (M+H) ⁺ .

Example 147

4-(2,4-Difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 147a

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propyl methanesulfonate

Example 142 (103 mg, 0.200 mmol), methanesulfonyl chloride (0.023 mL, 0.30 mmol) and triethylamine (0.056 mL, 0.40 mmol) were combined in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at ambient temperature for 20 hours. Methanesulfonyl chloride (0.023 mL, 0.30 mmol) and triethylamine (0.056 mL, 0.40 mmol) were added to the reaction mixture, and the mixture was stirred at ambient temperature for another 20 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound in quantitative yield.

Example 147b

4-(2,4-Difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Combine Example 147a (35.5 mg, 0.0600 mmol) and 25% sodium methoxide in methanol (0.027 mL, 0.12 mmol) in tetrahydrofuran (1 mL). Heat the reaction mixture at 60°C for 2 hours, cool, and concentrate. The residue is purified by flash chromatography (silica gel, 2-4% methanol in dichloromethane) to provide the title compound (10 mg, 32%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.91 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.74 (s,1H), 7.29 (dd, J = 8.2, 1.8 Hz, 1H), 7.20 (d, J = 2.6 Hz, 1H), 7.17-7.10 (m,1H), 7.03 (d, J = 8.1 Hz, 1H), 6.97-6.89 (m, 2H), 5.07 (t, J = 7.3 Hz, 1H), 4.59-4.48 (m, 2H), 3.70 (s, 3H), 3.29 (t, J = 6.1 Hz, 2H), 3.19 (s, 3H), 2.99 (s, 3H), 1.82-1.67 (m, 2H), 1.65-1.54 (m, 1H), 1.43-1.32 (m, 1H). MS (ESI+) m/z 528 (M+H) ⁺ .

Example 148

4-(2,4-Difluorophenyl)-3-(3-ethoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 148 was prepared according to the procedure used to prepare Example 147b, using 21% sodium ethoxide in ethanol instead of 25% sodium methoxide in methanol to provide the title compound (16 mg, 49%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (d, J =2.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.23 (dd, J = 8.2, 2.0Hz, 1H), 7.14 (d, J = 2.7 Hz, 1H), 7.11-7.04 (m, 1H), 6.97 (d, J = 8.2 Hz,1H), 6.90-6.84 (m, 2H), 5.08-4.97 (m, 1H), 4.55-4.43 (m, 2H), 3.64 (s, 3H),3.34-3.25 (m, 4H), 2.93 (s, 3H), 1.72-1.60 (m, 2H), 1.58-1.48 (m, 1H), 1.38-1.25 (m, 1H), 1.03 (t, J = 7.0 Hz, 3H). MS (ESI+) m/z 542 (M+H) ⁺ .

Example 149

4-Isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 4 mL vial was added Example 5f (20 mg, 0.058 mmol), isobutyraldehyde (8.36 mg, 0.116 mmol), acetic acid (0.100 mL, 1.747 mmol) and dichloroethane (2.0 mL). The vial was sealed and the mixture was heated at 80 ° C for 1 hour. To this mixture was added silica gel-supported sodium cyanoborohydride (200 mg, 0.89 mmol/g, 0.178 mmol), and the mixture was heated at 80 ° C for 4 hours. After cooling, the reaction mixture was filtered and concentrated. The residue was purified by reverse phase HPLC (C18, CH ₃ CN/water (0.1% TFA), 0-100% gradient) to give the title compound (16.4 mg, 71%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.80 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.25 (p, J = 8.4 Hz, 2H), 7.18 (s, 1H), 4.43 (s, 2H), 4.15 (s, 2H), 3.59 (s, 3H), 2.91 (s, 3H), 2.76 (d, J = 7.1 Hz, 2H), 1.62 (dt, J = 13.4, 6.8 Hz, 1H), 0.69 (d, J = 6.6 Hz, 6H). MS (ESI+) m/z 400.1 (M+H) ⁺ .

Example 150

4-((1-ethylpiperidin-3-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 150 was prepared according to the procedure used to prepare Example 149, substituting 1-ethylpiperidine-3-carbaldehyde for isobutyraldehyde to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 7.66 (d, J = 1.7Hz, 1H), 7.53 (s, 1H), 7.24 (dt, J = 17.1, 5.0 Hz, 2H), 7.15 (s, 1H), 4.43(s, 2H), 4.08 (t, J = 15.9 Hz, 2H), 3.59 (s, 3H), 3.19 (d, J = 54.0 Hz, 2H), 3.06-2.66 (m, 7H), 2.63 (s, 1H), 2.35 (s, 1H), 1.95-1.35 (m, 4H), 0.93 (s, 4H). MS (ESI+) m/z 469.1 (M+H) ⁺ .

Example 151

10-Methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 151 was prepared according to the procedure used to prepare Example 149, substituting dihydro-2H-pyran-4(3H)-one for isobutyraldehyde to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.88 (s, 1H), 7.67 (d, J =1.9 Hz, 1H), 7.58 (s, 1H), 7.27-7.17 (m, 3H), 4.48-4.39 (s, 2H), 3.75-4.3 (m,2H) 3.73-3.64 (m, 2H), 3.59 (s, 3H), 3.00 (dd, J = 11.7, 2.3 Hz, 2H), 2.90(s, 3H), 2.85-2.77 (m, 1H), 1.80-1.55 (m, 2H), 1.45-1.25 (m, 2H). MS (ESI+) m/z 469.1 (M+H) ⁺ . MS (ESI+) m/z 428.1 (M+H) ⁺ .

Example 152

4-((2,2-Dimethyltetrahydro-2H-pyran-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 152 was prepared according to the procedure used to prepare Example 149, substituting 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde for isobutyraldehyde to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.76 (s, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.52 (s, 1H), 7.28-7.13 (m, 3H), 4.41 (s, 2H), 4.07 (s, 2H), 3.57 (d, J = 16.4 Hz, 3H), 3.45 (dd, J = 11.3, 4.4 Hz, 1H), 3.36 (t, J =11.2 Hz, 1H), 2.90 (s, 3H), 2.83-2.66 (m, 2H), 1.78 (s, 1H), 1.39 (dd, J =26.2, 11.8 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H), 0.91-0.47 (m, 2H). MS (ESI+) m/z470.1 (M+H) ⁺ .

Example 153

4-(4-Ethoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 153 was prepared according to the procedure used for Example 149, using 4-ethoxybutan-2-one instead of isobutyraldehyde, to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.65 (s, 1H), 7.49 (s, 1H), 7.20 (d, J = 18.5 Hz, 3H), 4.41 (s, 2H), 4.37-4.14 (m, 3H), 3.58 (s, 3H), 3.54-2.95 (m, 4H), 2.90 (s, 3H), 1.63 (dd, J = 13.6, 6.7 Hz, 1H), 1.51-1.41 (m, 1H), 1.06 (s, 3H), 0.84 (s, 3H). MS (ESI+) m/z 444.1 (M+H) ⁺ .

Example 154

N-(2-Cyanoethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Stock solutions of Example 141b and diisopropylethylamine (0.13 M and 0.38 M in N,N-dimethylacetamide, 224 μL, respectively), 0.03 mmol 3-aminopropionitrile (1.0 equiv), and 0.09 mmol diisopropylethylamine (3.0 equiv), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (0.2 M in N,N-dimethylacetamide, 224 μL, 0.045 mmol, 1.5 equiv), and 3-aminopropionitrile (0.40 M in N,N-dimethylacetamide, 113 μL, 0.045 mmol, 1.5 equiv) were aspirated from their respective source vials and passed through a perfluoroalkoxy mixing tube (0.2 The reaction mixture was mixed and fed into an injection loop. The reaction mixture was injected into a continuous reactor (Hastard coil, 0.75 mm ID, 1.8 mL internal volume) set at 100°C and passed through the reactor at a rate of 180 μL min ^-1 (10 min residence time). After leaving the reactor, the reaction mixture was directly introduced into the injection loop and purified by preparative HPLC (Phenomenex Luna C8(2) 5 μm 100Å AXIA column (30 mm × 75 mm), gradient elution with acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A), injecting 1.5 mL of sample in DMSO:methanol (1:1)) to afford the title compound (12.6 mg, 76% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.72 (d, J = 2.0 Hz, 1H), 7.71 (s, 1H), 7.51-7.67 (m, 1H), 7.33 (s, 1H), 7.16 (dd, J = 8.2, 2.0 Hz, 1H), 6.98-7.08(m, 2H), 6.86 (d, J = 8.1 Hz, 1H), 5.86 (s, 1H), 4.38-4.51 (m, 2H), 3.67 (s,3H), 3.14 (ddd, J = 13.3, 7.3, 6.0 Hz, 1H), 2.94-3.05 (m, 1H), 2.93 (s, 3H), 1.96-2.16 (m, 2H). MS (ESI+) m/z 551.7 (M+H) ⁺ .

Example 155

Methyl 2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamido)acetate

Example 155 was prepared according to the procedure used to prepare Example 154, substituting methyl 2-aminoacetate for 3-aminopropionitrile to provide the title compound (12.7 mg, 74% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.75 (d,J = 2.1 Hz, 1H), 7.71 (s, 1H), 7.51-7.61 (m, 1H), 7.36 (s, 1H), 7.13 (dd, J =8.3, 2.0 Hz, 1H), 6.99-7.09 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 5.88 (s, 1H), 4.38-4.49 (m, 1H), 3.67 (s, 3H), 3.60 (s, 1H), 3.48 (s, 2H), 2.90 (s, 2H). MS(ESI+) m/z 571.0 (M+H) ⁺ .

Example 156

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-phenethyl-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 156 was prepared according to the procedure used to prepare Example 154, substituting 2-phenylethylamine for 3-aminopropionitrile to provide the title compound (15.4 mg, 85% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.75 (d, J =2.1 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 6.4 Hz, 1H), 7.29 (s, 1H), 7.09-7.22(m, 4H), 6.98-7.10 (m, 2H), 6.97 (d, J = 1.7 Hz, 2H), 6.93-6.97 (m, 2H), 6.83(d, J = 8.2 Hz, 1H), 5.81 (s, 1H), 4.47 (d, J = 13.7 Hz, 1H), 4.40 (d, J =13.6 Hz, 1H), 3.68 (s, 3H), 3.12 (ddd, J = 12.8, 8.8, 5.8 Hz, 1H), 2.87-2.99(m, 1H), 2.81 (s, 3H), 2.32 (ddd, J = 13.6, 8.2, 5.6 Hz, 1H), 2.15-2.26 (m,1H). MS (ESI+) m/z 603.0 (M+H) ⁺ .

Example 157

N-Butyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 157 was prepared according to the procedure used to prepare Example 154, substituting butan-1-amine for 3-aminopropionitrile to provide the title compound (13.8 mg, 83% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.73 (d, J = 2.0Hz, 1H), 7.69 (s, 1H), 7.59-7.68 (m, 1H), 7.32 (s, 1H), 7.18-7.12 (m, 2H),6.98-7.08 (m, 2H), 6.85 (d, J = 8.1 Hz, 1H), 5.79 (s, 1H), 4.36-4.50 (m, 1H),3.67 (s, 3H), 2.90-3.00 (m, 2H), 2.90 (s, 3H), 2.72 (dd, J = 11.6, 4.9 Hz, 1H), 0.81-1.02 (m, 4H), 0.66 (t, J = 7.1 Hz, 3H). MS (ESI+) m/z 555.1 (M+H) ⁺ .

Example 158

N-cyclohexyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 158 was prepared according to the procedure used to prepare Example 154, substituting cyclohexylamine for 3-aminopropionitrile to provide the title compound (13.1 mg, 75% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.74 (d, J = 2.0Hz, 1H), 7.71 (s, 1H), 7.48-7.58 (m, 1H), 7.32 (s, 1H), 7.16 (dd, J = 8.2,2.0 Hz, 1H), 6.97 -7.09 (m, 2H), 6.82 (dd, J = 25.9, 8.2 Hz, 2H), 5.78 (s,1H), 4.36-4.51 (m, 2H), 3.67 (s, 3H), 3.24-3.36 (m, 1H), 2.87 (s, 3H), 1.85(s, 1H), 1.34-1.55 (m, 4H), 0.86-1.19 (m, 5H), 0.70-0.85 (m, 1H). MS (ESI+) m/z 581.0 (M+H) ⁺ .

Example 159

N-Benzyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 159 was prepared according to the procedure used to prepare Example 154, substituting phenylmethylamine for 3-aminopropionitrile to provide the title compound (13.2 mg, 75% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.66-7.80 (m,3H), 7.36 (s, 1H), 7.13-7.17 (m, 1H), 7.11 (m, 3H), 7.09-6.99 (m, 2H), 6.87(d, J = 8.2 Hz, 1H), 6.67-6.73 (m, 2H), 5.94 (s, 1H), 4.44-4.57 (m, 2H), 4.27(d, J = 15.3 Hz, 1H), 3.90 (d, J = 15.2 Hz, 1H), 3.65 (s, 3H), 2.94 (s, 3H). MS (ESI+) m/z 589.0 (M+H) ⁺ .

Example 160

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(3-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 160 was prepared according to the procedure used to prepare Example 154, substituting 3-phenylpropan-1-amine for 3-aminopropionitrile to provide the title compound (10.77 mg, 58% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.61-7.73 (m, 3H), 7.32 (s, 1H), 7.17-7.26 (m, 3H), 7.09-7.17 (m, 2H), 6.97-7.07(m, 4H), 6.85 (d, J = 8.2 Hz, 1H), 5.81 (s, 1H), 4.32 (d, J = 13.7 Hz, 1H), 4.18-4.26 (m, 1H), 3.67 (s, 3H), 2.85-3.03 (m, 1H), 2.79 (s, 3H), 2.65-2.76(m, 1H), 2.20 (t, J = 7.6 Hz, 2H), 1.20-1.34 (m, 2H). MS (ESI+) m/z 617.0 (M+H) ⁺ .

Example 161

4-(2,4-Difluorophenyl)-N-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 161 was prepared according to the procedure used to prepare Example 154, substituting 2-methylpropan-1-amine for 3-aminopropionitrile to provide the title compound (12.7 mg, 76% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.72-7.76(m, 1H), 7.71 (s, 1H), 7.66 (dd, J = 15.1, 9.1 Hz, 1H), 7.33 (s, 1H), 7.14(dd, J = 8.2, 2.3 Hz, 2H), 6.98-7.09 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 5.82(s, 1H), 4.34-4.42 (m, 2H), 3.67 (s, 3H), 2.89 (s, 3H), 2.83 (dd, J = 12.8,7.7 Hz, 1H), 1.84 (s, 2H), 1.27 (dt, J = 13.4, 6.8 Hz, 1H), 0.47 (dd, J =6.6, 1.8 Hz, 6H). MS (ESI+) m/z 555.1 (M+H) ⁺ .

Example 162

4-(2,4-Difluorophenyl)-N-(2-hydroxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 162 was prepared according to the procedure used to prepare Example 154, substituting 2-aminoethanol for 3-aminopropionitrile to provide the title compound (11.7 mg, 72% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.74 (d, J =2.1 Hz, 1H), 7.70 (s, 1H), 7.54-7.65 (m, 1H), 7.34 (s, 1H), 7.16 (dd, J =8.2, 2.0 Hz, 1H), 6.98-7.08 (m, 2H), 6.85 (d, J = 8.2 Hz, 1H), 5.84 (s, 1H), 4.37-4.52 (m, 2H), 3.67 (s, 3H), 2.86-3.08 (m, 7H). MS (ESI+) m/z 543.0 (M+H) ⁺ .

Example 163

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-N-(oxazol-4-ylmethyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 163 was prepared according to the procedure used to prepare Example 154, substituting oxazol-4-ylmethylamine for 3-aminopropionitrile to provide the title compound (7.2 mg, 41% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 8.14 (d, J= 0.9 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.57-7.67 (m, 1H), 7.36 (s, 1H), 7.14 (dd, J = 8.2, 2.0 Hz, 1H), 6.96-7.10 (m, 3H), 6.85 (d, J =8.2 Hz, 1H), 5.90 (s, 1H), 4.38-4.52 (m, 2H), 3.84-4.07 (m, 2H), 3.67 (s,3H), 2.92 (s,3H). MS (ESI+) m/z 580.0 (M+H) ⁺ .

Example 164

N-(Cyclopropylmethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 164 was prepared according to the procedure used to prepare Example 154, substituting cyclopropylmethylamine for 3-aminopropionitrile to provide the title compound (13.8 mg, 83% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.74 (d, J =2.1 Hz, 1H), 7.71 (s, 1H), 7.54-7.64 (m, 1H), 7.33 (s, 1H), 7.15 (dd, J =8.2, 2.0 Hz, 1H), 6.97-7.08 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 5.82 (s, 1H), 4.37-4.50 (m, 2H), 3.67 (s, 3H), 2.89 (s, 3H), 2.78-2.87 (m, 1H), 2.60-2.73(m, 1H), 0.42-0.52 (m, 1H), 0.05-0.18 (m, 2H), -0.21--0.14 (m, 2H). MS (ESI+)m/z 553.0 (M+H) ⁺ .

Example 165

4-(2,4-Difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 165 was prepared according to the procedure used to prepare Example 154, substituting 1-amino-2-methylpropan-2-ol for 3-aminopropionitrile to provide the title compound (12.2 mg, 71% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ7.73-7.77 (m, 1H), 7.72 (s, 1H), 7.67 (dd, J = 12.7, 6.5 Hz, 1H), 7.38 (s,1H), 7.13 (dd, J = 8.2, 2.0 Hz, 1H), 6.98-7.10 (m, 2H), 6.83 (d, J = 8.2 Hz,1H), 5.90 (s, 1H), 4.35-4.48 (m, 2H), 3.67 (s, 3H), 2.96 (dd, J = 13.2, 5.1Hz, 1H), 2.88 (s, 3H), 2.74 (d, J = 13.1 Hz, 1H), 0.79 (s, 3H), 0.60 (s, 3H). MS (ESI+) m/z 571.0 (M+H) ⁺ .

Example 166

4-(2,4-Difluorophenyl)-N-(1-(hydroxymethyl)cyclopropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 166 was prepared according to the procedure used to prepare Example 154, substituting (1-aminocyclopropyl)methanol for 3-aminopropionitrile to provide the title compound (11.5 mg, 68% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.75(d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.43-7.53 (m, 1H), 7.30 (s, 1H), 7.18 (dd,J = 8.2, 2.0 Hz, 1H), 6.94-7.08 (m, 2H), 6.87 (d, J = 8.1 Hz, 1H), 5.77 (s,1H), 4.36-4.53 (m, 2H), 3.66 (s, 3H), 3.26 (d, J = 11.1 Hz, 1H), 3.08 (d, J =11.1 Hz, 1H), 2.90 (s, 3H), 0.40-0.53 (m, 2H), -0.03-0.13 (m, 2H). MS (ESI+)m/z 569.0 (M+H) ⁺ .

Example 167

4-(2,4-Difluorophenyl)-10-methyl-N-(1-methylcyclopropyl)-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 167 was prepared according to the procedure used to prepare Example 154, substituting 1-methylcyclopropylamine for 3-aminopropionitrile to provide the title compound (10.8 mg, 65% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.75 (d,J = 2.1 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.28 (s, 1H), 7.18(dd, J = 8.2, 2.0 Hz, 1H), 6.94-7.08 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 5.73(s, 1H), 4.36-4.52 (m, 2H), 3.66 (s, 3H), 2.88 (s, 3H), 0.93 (s, 3H), 0.23-0.34 (m, 2H), 0.13-0.18 (m, 2H). MS (ESI+) m/z 553.0 (M+H) ⁺ .

Example 168

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(4-phenylbutyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 168 was prepared according to the procedure used to prepare Example 154, substituting 4-phenylbutan-1-amine for 3-aminopropionitrile to provide the title compound (14.7 mg, 77% yield). ¹ H NMR (400 MHz, DMSO- d ₆ -D ₂ O) δ 7.70-7.72(m, 1H), 7.69 (s, 1H), 7.57-7.67 (m, 1H), 7.32 (s, 1H), 7.20-7.27 (m, 2H),6.98-7.19 (m, 6H), 6.84 (d, J = 8.2 Hz, 1H), 5.80 (s, 1H), 4.32-4.44 (m, 2H), 3.67 (s, 3H), 2.97 (dt, J = 13.2, 6.6 Hz, 1H), 2.87 (s, 3H), 2.68-2.81 (m,1H), 2.37 (t, J = 7.5 Hz, 2H), 1.11-1.25 (m, 2H), 0.96-1.11 (m, 2H). MS (ESI+)m/z 630.9 (M+H) ⁺ .

Example 169

4-(3,3-Dimethylbutyryl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 42c (0.05 g, 0.174 mmol), tert-butylacetyl chloride (0.028 g, 0.209 mmol), N,N-dimethylpyridin-4-amine (2.126 mg, 0.017 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.152 mL, 0.870 mmol) were combined in dimethylacetamide (0.870 mL) and stirred at 50°C for 18 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by reverse phase HPLC (C18, _CH3CN /0.1% TFA/water, 10-100% gradient) afforded the title compound (0.012 g, 18%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.60 (s, 1H), 7.83 (s,1H), 7.53 (d, J = 10.38 Hz, 1H), 7.18-7.26 (m, 2H), 5.59 (d, J = 14.65 Hz,1H), 3.87 (d, J = 14.95 Hz, 1H), 3.60 (s, 3H), 1.79-1.92 (m, 2H), 0.70 (s, 9H). MS (ESI+) m/z 386 (M+H) ⁺ .

Example 170

tert-Butyl ((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

Example 170a

tert-Butyl (trans-4-((2-bromo-4-(methylsulfonyl)phenyl)amino)cyclohexyl)carbamate

A mixture of 2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.403 g, 1.592 mmol) and tert-butyl (trans-4-aminocyclohexyl)carbamate (0.352 g, 1.592 mmol) in dimethyl sulfoxide (12 mL) and N,N-diisopropylethylamine (0.32 mL, 1.831 mmol) was heated at 100°C for 4 hours. The reaction mixture was cooled to ambient temperature and partitioned between aqueous ammonium chloride and diethyl ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 25% ethyl acetate/hexane to provide the title compound (0.390 g, 0.872 mmol, 55% yield).

Example 170b

tert-Butyl ((trans)-4-((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl)amino)cyclohexyl)carbamate

A mixture of Example 170a (0.380 g, 0.849 mmol), Example 1f (0.382 g, 0.892 mmol), cesium fluoride (0.387 g, 2.550 mmol), and tetrakis(triphenylphosphine)palladium (0.098 g, 0.085 mmol) in dimethoxyethane (20 mL) and methanol (10 mL) was stirred at 80°C for 2 hours under an argon atmosphere. The reaction mixture was cooled to ambient temperature, and an excess of 5N sodium hydroxide solution (8 mL) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then partitioned between aqueous ammonium chloride and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 2% methanol/dichloromethane to provide the title compound (0.279 g, 0.543 mmol, 64% yield).

Example 170c

tert-Butyl ((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

To a stirred mixture of Example 170b (0.048 g, 0.093 mmol) and paraformaldehyde (0.048 g, 1.599 mmol) in tetrahydrofuran (1.0 mL) was added a 1M titanium tetrachloride/toluene solution (0.187 mL, 0.187 mmol) at ambient temperature. The reaction mixture suspension was stirred at ambient temperature for 1 hour and then partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) to give the title compound (0.0043 g, 9% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.83 (s,1H), 8.13 (s, 1H), 7.73-7.62 (m, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.20-7.14 (m,1H), 6.62 (d, J = 7.7 Hz, 1H), 4.18 (s, 2H), 3.64 (s, 3H), 3.26 (s, 3H), 3.22-3.14 (m, 1H), 3.02-2.93 (m, 1H), 1.83-1.55 (m, 4H), 1.52-1.25 (m, 11H),1.16-0.95 (m, 2H). MS (ESI+) m/z 527.1 (M+H) ⁺ .

Example 171

4-((trans)-4-aminocyclohexyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 170c (0.0114 g, 0.022 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (0.20 mL) and stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and dried under vacuum to afford the title compound as a trifluoroacetate salt (0.0113 g, 97% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 8.5, 2.3 Hz, 4H), 7.37 (d, J = 8.5Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 4.12 (bs, 2H), 3.64 (s, 3H), 3.26 (s, 3H), 3.09-2.90 (m, 2H), 1.87 (d, J = 10.6 Hz, 2H), 1.72 (d, J = 12.6 Hz, 2H), 1.47(dd, J = 23.8, 11.1 Hz, 2H), 1.29-1.18 (m, 2H). MS (ESI+) m/z 427.1 (M+H) ⁺ .

Example 172

4-(Cyclopropylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 172 was prepared according to the procedure used to prepare Example 74, substituting cyclopropanesulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ 0) δ 7.84 (d, J = 2.0 Hz,1H), 7.75 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.40-7.35 (m, 1H), 7.32 (s, 1H), 5.12 (d, J = 16.7 Hz, 1H), 4.54 (dt, J = 30.5, 15.1 Hz, 3H), 3.64 (s, 3H), 2.99 (s, 3H), 1.76-1.64 (m, 1H), 0.49 (d, J = 5.1 Hz, 3H), 0.35-0.24 (m, 1H). MS (APCI+) m/z 448.0 (M+H) ⁺ .

Example 173

5,7-Difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid ethyl ester

Example 173a

tert-Butyl 5,7-difluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-1-carboxylate

The product of Example 42c (0.86 g, 2.99 mmol), di-tert-butyl dicarbonate (0.98 g, 4.49 mmol), N,N-dimethylpyridin-4-amine (0.018 g, 0.150 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.569 mL, 8.98 mmol) were combined in dimethylacetamide (11.98 mL) and stirred at 50°C for 1 hour. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (1.0 g, 86%).

Example 173b

5,7-Difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-1,4(3H)-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

The product of Example 173a (0.7 g, 1.807 mmol), ethyl chloroformate (0.7 g, 6.45 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (1.0 g, 2.63 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.6 mL, 9.16 mmol) were combined in dimethylacetamide (9 mL) and stirred at 50°C for 2 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 0-60% ethyl acetate/heptane) afforded the title compound (0.57 g, 69%).

Example 173c

5,7-Difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylic acid ethyl ester

The product of Example 173b (0.57 g, 1.241 mmol) in dichloromethane (5 mL) in TFA (5 mL) was stirred at ambient temperature for 1 hour, concentrated, and azeotroped three times with dichloromethane. Purification by trituration in a minimum amount of 9:1 dichloromethane/methanol afforded the title compound (0.427 g, 96%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.00 (s,1H), 7.90 (s, 1H), 7.53 (dd, J = 10.68, 1.53 Hz, 1H), 7.25-7.33 (m, 2H), 5.25(d, J = 15.56 Hz, 1H), 4.13 (d, J = 15.56 Hz, 1H), 3.99-4.06 (m, 1H), 3.74-3.84 (m, 1H), 3.61 (s, 3H), 0.99 (t, J = 7.17 Hz, 3H). MS (ESI+) m/z 360 (M+H) ⁺ .

Example 174

4-(2,4-Difluorophenyl)-10-methyl-3-(3-(methylamino)propyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 147a (35.5 mg, 0.0600 mmol), 2.0 M methylamine/tetrahydrofuran (0.150 mL, 0.300 mmol), and potassium carbonate (24.9 mg, 0.180 mmol) were combined in tetrahydrofuran (1 mL). The reaction mixture was heated at 60°C for 2 hours, cooled, and concentrated. The residue was purified by reverse-phase HPLC (C18, _CH3CN /water (10 mM ammonium acetate), 20-100% gradient) to provide the title compound (19 mg, 60%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.84 (d, J =1.8 Hz, 1H), 7.68 (s, 1H), 7.23 (dd, J = 8.2, 1.8 Hz, 1H), 7.14 (s, 1H),7.13-7.04 (m, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.93-6.82 (m, 2H), 5.05-4.97 (m,1H), 4.56-4.42 (m, 2H), 3.64 (s, 3H), 2.92 (s, 3H), 2.45 (t, J = 6.1 Hz, 2H),2.22 (s, 3H), 1.72-1.58 (m, 2H), 1.54-1.42 (m, 1H), 1.36-1.24 (m, 1H). MS (ESI+) m/z 527 (M+H) ⁺ .

Example 175

4-(2,4-Difluorophenyl)-3-(3-(dimethylamino)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 175 was prepared according to the procedure used to prepare Example 174, substituting 2.0 M dimethylamine/tetrahydrofuran for 2.0 M methylamine/tetrahydrofuran, to provide the title compound (20 mg, 62%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84(s, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.67 (s, 1H), 7.22 (dd, J = 8.2, 1.7 Hz,1H), 7.14 (s, 1H), 7.10-7.05 (m, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.93-6.83 (m,2H), 5.01 (t, J = 7.4 Hz, 1H), 4.53-4.42 (m, 2H), 3.64 (s, 3H), 2.92 (s, 3H),2.21-2.03 (m, 2H), 2.01 (s, 6H), 1.72-1.60 (m, 1H), 1.59-1.53 (m, 1H), 1.51-1.41 (m, 1H), 1.32-1.22 (m, 1H). MS (ESI+) m/z 541 (M+H) ⁺ .

Example 176

4-(4-Chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a solution of Example 60 (110 mg, 0.190 mmol) in anhydrous tetrahydrofuran (5 mL) was added BH ₃ ·THF (1.896 mL, 1.896 mmol), and the reaction mixture was stirred at 65°C for 18 hours. The reaction mixture was quenched with ethanol (1 mL), followed by the addition of HCl (3 M, 2 mL). The mixture was stirred at 70°C for an additional 4 hours. The solvent was evaporated, the residue was treated with 5N NaOH (2 mL), and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were concentrated, and the residue was purified by HPLC (C18, 30%-40% acetonitrile/0.1% aqueous ammonium hydroxide) to afford the title compound (15 mg, 0.026 mmol, 14% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.9Hz, 2H), 6.43 (d, J = 8.9 Hz, 2H), 5.22-5.18 (m, 1H), 4.66-4.34 (m, 3H), 3.79-3.73 (m, 1H), 3.66-3.60 (m, 1H), 3.54 (s, 3H), 3.00 (s, 3H), 2.47-2.27(m, 8H), 2.17(s, 3H). MS (ESI+) m/z 566.2 (M+H) ⁺ .

Example 177

2-(4-(4-Fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-7-yl)acetonitrile

Example 177a

2-(4-Amino-3-bromophenyl)acetonitrile

To a solution of 2-(4-aminophenyl)acetonitrile (3.0 g, 22.70 mmol) in 40 mL of dimethylformamide cooled in an ice bath was added portionwise N-bromosuccinimide (4.04 g, 22.70 mmol). The mixture was stirred at 0°C for 30 minutes, then at ambient temperature for 1 hour. Water was added. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven at 40°C to give the title compound (3.56 g, 16.9 mmol, 74.4% yield).

Example 177b

2-(4-amino-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetonitrile

A mixture of Example 177a (0.739 g, 3.50 mmol), Example 1f (1.5 g, 3.50 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.080 g, 0.088 mmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.051 g, 0.175 mmol), and potassium phosphate (2.230 g, 10.51 mmol) in 30 mL of dioxane and 10 mL of water was heated at 80° C. under nitrogen for 2 hours. Water was added, and the mixture was extracted with ethyl acetate (3×), washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 0-40% ethyl acetate/heptane gradient) to provide the title compound (0.933 g, 2.157 mmol, 61.6% yield).

Example 177c

{4-[(4-Fluorophenyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}acetonitrile

A mixture of Example 177b (120 mg, 0.277 mmol), 1-bromo-4-fluorobenzene (48.6 mg, 0.277 mmol), cesium carbonate (226 mg, 0.694 mmol) and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-phos) (13.23 mg, 0.028 mmol) in 4 mL of toluene and 1 mL of tert-butanol was heated at 150°C in a Biotage Initiator microwave oven for 40 minutes. The reaction mixture was then concentrated. The residue was treated with 1 mL of 4N aqueous NaOH and 3 mL of dioxane. The resulting mixture was heated at 80°C in a microwave oven for 20 minutes. Water was added, and the mixture was extracted with ethyl acetate (3X), washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 0-10% methanol/dichloromethane gradient) to provide the title compound (43 mg, 0.115 mmol, 41.6% yield).

Example 177d

2-(4-(4-Fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-7-yl)acetonitrile

To a mixture of Example 177c (36 mg, 0.097 mmol) and paraformaldehyde (43.5 mg, 1.450 mmol) in 2 mL of tetrahydrofuran was added titanium (IV) chloride (193 µL, 0.193 mmol, 1.0 M solution in toluene). The dark red mixture was stirred at ambient temperature for 3 hours. The mixture was cooled with an ice bath and quenched with water, extracted with ethyl acetate (2X), washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, 0-10% methanol/dichloromethane gradient) to give the title compound (12 mg, 0.031 mmol, 32% yield). ¹ H NMR(400 MHz, DMSO- d ₆ ) δ 11.62-11.28 (m, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.58 (s,1H), 7.36 (dd, J = 8.0, 1.9 Hz, 1H), 7.32-7.26 (m, 2H), 6.79-6.71 (m, 2H), 6.47-6.34 (m, 2H), 4.85-4.62 (m, 2H), 4.05 (s, 2H), 3.56 (s, 3H). MS (ESI+) m/z 385.2 (M+H) ⁺ .

Example 178

4-(2,2-Dimethyl-3-(pyrrolidin-1-yl)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 178 was prepared according to the procedure used to prepare Example 149, substituting 2,2-dimethyl-3-(pyrrolidin-1-yl)propanal for isobutyraldehyde to provide the title compound as a trifluoroacetate salt. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.69-12.65 (m, 1H), 8.08 (dd, J = 10.0, 2.0 Hz, 1H), 7.57 (d, J = 3.6 Hz, 2H), 7.42-7.31 (m, 2H), 4.78 0.99 (s,6H). MS (ESI+) m/z 483.1 (M+H) ⁺ .

Example 179

2-(3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)pyrrolidin-1-yl)acetic acid

Example 179 was prepared according to the procedure used to prepare Example 149, substituting 2-(3-oxopyrrolidin-1-yl)acetic acid for isobutyraldehyde to provide the title compound as a trifluoroacetate salt. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.47-13.38(m, 1H), 8.10-8.01 (m, 1H), 7.57-7.48 (m, 2H), 7.47-7.29 (m, 2H), 4.73 (s,2H), 4.39-3.77 (m, 4H), 3.64 (s, 3H), 3.58-3.16 (m, 4H), 3.12 (d, J = 6.6 Hz,3H), 2.50 (s, 1H), 2.22-2.03 (m, 2H), 1.37-1.22 (m, 1H). MS (APCI+) m/z 471.1(M+H) ⁺ .

Example 180

10-Methyl-7-((methylsulfonyl)methyl)-4-(2-methyltetrahydrofuran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 180 was prepared according to the procedure used to prepare Example 149, substituting 2-methyldihydrofuran-3(2H)-one for isobutyraldehyde to provide the title compound. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.49-13.40 (m, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.4, 1.9 Hz, 1H), 7.54 (d, J = 7.7 Hz,1H), 7.45-7.27 (m, 2H), 4.82-4.68 (m, 2H), 4.68-3.92 (m, 5H), 3.86-3.40 (m,4H), 3.12 (s, 3H), 2.25-1.85 (m, 2H), 1.36-1.14 (m, 3H). MS (APCI+) m/z 428.1(M+H) ⁺ .

Example 181

10-Methyl-4-(1-methylpiperidin-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 181 was prepared according to the procedure used to prepare Example 149, substituting 1-methylpiperidin-4-one for isobutyraldehyde to provide the title compound as a trifluoroacetate salt. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 14.00-13.44 (m, 1H), 8.17-7.99 (m, 1H), 7.58-7.42 (m, 2H), 7.42-7.28 (m, 2H), 4.89-4.71 (m, 2H),4.67-4.11 (m, 3H), 3.65 (s, 3H), 3.53-3.30 (m, 2H), 3.18-3.10 (m, 3H), 2.90-2.6 (m, 2H), 2.69 (s, 3H), 2.27-1.52 (m, 4H). MS (APCI+) m/z 441.1 (M+H) ⁺ .

Example 182

10-Methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 182 was prepared according to the procedure used to prepare Example 149, substituting dihydro-2H-pyran-3(4H)-one for isobutyraldehyde to provide the title compound. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.52-13.29 (m, 1H), 8.09-8.01(m, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.52-7.28 (m, 2H), 4.84-4.69 (m, 2H), 4.60-3.66 (m, 4H), 3.65-3.56 (m, 3H), 3.53-3.16 (m, 2H), 3.16-3.03 (m, 2H), 2.72-2.56 (m, 1H), 2.21-1.19 (m, 5H). MS (APCI+) m/z 428.1 (M+H) ⁺ .

Example 183

4-((1-Isopropylpiperidin-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 183 was prepared according to the procedure used to prepare Example 149, substituting 1-isopropylpiperidine-4-carbaldehyde for isobutyraldehyde to provide the title compound as a trifluoroacetate salt. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.69-12.65 (m,1H), 8.08 (dd, J = 10.0, 2.0 Hz, 1H), 7.57 (d, J = 3.6 Hz, 2H), 7.42-7.31 (m,2H), 4.81-4.71 (m, 2H), 4.30-4.19 (m, 2H), 3.64 (d, J = 6.9 Hz, 3H), 3.54-3.19 (m, 4H), 3.21 (s, 3H), 3.06-2.88 (m, 2H), 2.78-2.53 (m, 2H), 1.97 (dddd, J = 9.6, 8.6, 5.4, 2.1 Hz, 2H), 1.84-1.75 (m, 2H), 1.18-1.02 (m, 6H). MS (APCI+) m/z 483.1 (M+H) ⁺ .

Example 184

10-Methyl-7-((methylsulfonyl)methyl)-4-(1-(2-oxotetrahydrofuran-3-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 184 was prepared according to the procedure used for Example 149, using 3-acetyldihydrofuran-2(3H)-one instead of isobutyraldehyde, to provide the title compound. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.48-13.34 (m, 1H), 8.10-8.01 (m, J = 2.1 Hz, 1H), 7.61-7.53 (m, 2H), 7.50-7.31 (m, 2H), 4.80-4.67 (m, 2H), 4.40-3.98 (m, 4H), 3.62 (s, 3H), 3.10 (s, 3H), 2.80-2.60 (m, 1H), 2.46 (s, 3H), 2.18-1.77 (m, 3H). MS (APCI+) m/z 456.1 (M+H) ⁺ .

Example 185

4-(1-methoxypropan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 185 was prepared according to the procedure used to prepare Example 149, substituting 1-methoxypropan-2-one for isobutyraldehyde to provide the title compound. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.89-12.95 (m, 1H), 8.05 (d, J =1.3 Hz, 1H), 7.56-7.44 (m, 3H), 7.44-7.34 (m, 1H), 4.71 (d, J = 12.4 Hz, 2H),4.63-4.06 (m, 2H), 3.73-3.64 (m, 1H), 3.64-3.56 (m, 3H), 3.56-3.42 (m, 1H),3.40-3.27 (m, 1H), 3.17 (s, 3H), 3.09 (d, J = 5.1 Hz, 3H), 1.27-1.12 (m, 3H). MS (APCI+) m/z 416.0 (M+H) ⁺ .

Example 186

4-(4-Methoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 186 was prepared according to the procedure used to prepare Example 149, substituting 4-methoxybutan-2-one for isobutyraldehyde to provide the title compound. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.63-13.11 (m, 1H), 8.04 (d, J =2.0 Hz, 1H), 7.57-7.36 (m, 4H), 4.88-4.51 (m, 2H), 4.51-3.96 (m, 2H), 3.86-3.72 (m, 1H), 3.62 (s, 3H), 3.47-3.34 (m, 1H), 3.33-3.20 (m, 1H), 3.17-2.99(m, 6H), 2.06-1.87 (m, 1H), 1.80-1.62 (m, 1H), 1.31-1.05 (m, 3H). MS (APCI+)m/z 430.0 (M+H) ⁺ .

Example 187

10-Methyl-4-(1-methylpyrrolidin-3-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 187 was prepared according to the procedure used to prepare Example 149, substituting 1-methylpyrrolidin-3-one for isobutyraldehyde to provide the title compound as a trifluoroacetate salt. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.57-13.33 (m,1H), 8.05 (d, J = 1.9 Hz, 1H), 7.57-7.52 (m, 2H), 7.51-7.29 (m, 2H), 4.81-4.69 (m, 2H), 4.69-4.06 (m, 3H), 3.67 (s, 3H), 3.62-3.16 (m, 4H), 3.13 (s,3H), 2.92-2.74 (m, 3H), 2.35-1.91 (m, 2H).MS (APCI+) m/z 427.1 (M+H) ⁺ .

Example 188

10-Methyl-7-((methylsulfonyl)methyl)-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 188 was prepared according to the procedure used to prepare Example 149, substituting (tetrahydro-2H-pyran-4-yl)ethanone for isobutyraldehyde to provide the title compound. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.48-13.34 (m, 1H), 8.11-8.02 (m, 1H), 7.67-7.59 (m, 1H), 7.51-7.40 (m, 2H), 7.39-7.29 (m, 1H), 4.90-4.63 (m, 2H), 4.54-3.64 (m, 4H), 3.61 (s, 3H), 3.51-3.15 (m, 3H), 3.11 (s,3H), 1.83-1.44 (m, 4H), 1.38-1.01 (m, 4H). MS (APCI+) m/z 456.1 (M+H) ⁺ .

Example 189

10-Methyl-4-(1-methylazepan-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 189 was prepared according to the procedure used to prepare Example 149, substituting 1-methylazepan-4-one for isobutyraldehyde to provide the title compound as a trifluoroacetic acid salt. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.83-13.26 (m,1H), 8.07 (dd, J = 18.6, 1.9 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.50-7.27 (m,3H), 4.82-4.73 (m, 1H), 4.66 (s, 2H), 4.54-4.45 (m, 2H), 3.62 (s, 3H), 3.59-3.20 (m, 4H), 3.06 (s, 3H), 2.80 (s, 3H), 2.39-1.46 (m, 6H). MS (APCI+) m/z455.2 (M+H) ⁺ .

Example 190

4-(1-ethylpiperidin-3-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 190 was prepared according to the procedure used to prepare Example 149, substituting 1-ethylpiperidin-3-one for isobutyraldehyde to provide the title compound as a trifluoroacetate salt. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.83-12.95 (m, 1H), 8.08-8.00 (m, 1H), 7.75-7.69 (m, 1H), 7.56 (s, 1H), 7.49-7.35 (m, 2H), 4.84-4.58 (m, 2H), 4.65-3.76 (m, 3H), 3.69 (s, 3H), 3.47-3.19 (s, 2H), 3.20-3.14(m, 3H), 3.11-2.55 (m, 4H), 2.40-1.58 (m, 4H), 1.16-1.02 (m, 3H). MS (APCI+)m/z 455.0 (M+H) ⁺ .

Example 191

10-Methyl-7-((methylsulfonyl)methyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 191 was prepared according to the procedure used to prepare Example 149, substituting 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde for isobutyraldehyde to provide the title compound. ¹ H NMR (400 MHz, pyridine- d ₅ ) δ 13.45-13.38 (m, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.66-7.60 (m, 1H), 7.56 (s, 1H), 7.50-7.37 (m, 2H), 4.74 (s, 2H), 4.33 (s, 2H), 3.91-3.78 (m, 2H), 3.63 (s, 3H), 3.29-3.13 (m, 4H),3.11 (s, 3H), 1.56-1.28 (m, 5H), 1.26-1.07 (m, 2H). MS (APCI+) m/z 456.1 (M+H) ⁺ .

Example 192

4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)benzonitrile

Example 192a

4-((4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile

To a 20 mL microwave vial was added 4-aminobenzonitrile (0.121 g, 1.023 mmol), Example 9a (0.2549 g, 1.023 mmol), palladium acetate (9.19 mg, 0.041 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.039 g, 0.082 mmol), cesium carbonate (0.467 g, 1.432 mmol), toluene (8.5 mL), and tert-butanol (1.7 mL) to yield a yellow suspension. The vial was sealed, and the reaction mixture was heated in a Biotage Creator at 150°C for a fixed time of 15 minutes. The reaction mixture was filtered through a 2 g Celite SPE cartridge and washed with ethyl acetate. The filtrate was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (20-100% ethyl acetate/heptane) to provide the title compound (0.100 g, 34% yield).

Example 192b

4-((2-Bromo-4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile

To a 250 mL round-bottom flask was added Example 192a (0.100 g, 0.349 mmol) in acetic acid (3.49 mL) to yield a white suspension. N-bromosuccinimide (0.062 g, 0.349 mmol) was added in two portions 10 minutes apart. After the first portion of N-bromosuccinimide was added, 3 mL of dimethylformamide was added. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was quenched with 30 mL of 10% sodium thiosulfate and diluted with water. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with 2N NaOH (until the pH of the aqueous layer was >7) and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (50-100% ethyl acetate/heptane) to afford the title compound (0.1007 g, 79% yield) as a white solid.

Example 192c

4-((2-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile

Example 192c was prepared according to the procedure used to prepare Example 6b, substituting Example 192b for Example 6a, to provide the title compound (0.115 g, 78% yield) as a white solid.

Example 192d

4-((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile

Example 192d was prepared according to the procedure used to prepare Example 12d, substituting Example 192c for Example 12c to provide the title compound (0.0575 g, 68% yield).

Example 192e

4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)benzonitrile

Example 192e was prepared according to the procedure used to prepare Example 82, substituting Example 192d for Example 12d and paraformaldehyde for methyl 4-oxobutyrate to provide the title compound (0.0277 g, 47% yield). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.88-11.93 (m, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.64 (s, 1H), 7.48 (dd, J = 8.0, 1.9 Hz, 1H), 7.34-7.46 (m, 4H), 6.48-6.58 (m, 2H), 5.28(d, J = 16.3 Hz, 1H), 4.71-4.42 (m, 3H), 3.56 (s, 3H), 3.01 (s, 3H). MS (ESI+)m/z 445.2 (M+H) ⁺ .

Example 193

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 193a

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholine-4-carbonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 193a was prepared according to the procedure used to prepare Example 58m, substituting morpholine for ammonium hydroxide (25% wt/wt aqueous solution) to provide the title compound.

Example 193b

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 193b was prepared according to the procedure used to prepare Example 146c, substituting Example 193a for Example 146b to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.90 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.49-7.41 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 9.0Hz, 2H), 6.42 (d, J = 9.0 Hz, 2H), 5.24-5.20 (m, 1H), 4.61-4.38 (m, 3H), 3.80-3.71 (m, 1H), 3.69-3.57 (m, 5H), 3.54(s, 3H), 3.00 (s, 3H), 2.46-2.36 (m, 4H). MS (ESI+) m/z 553.2 (M+H) ⁺ .

Example 194

N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 194a

2-Bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline

To a 100 mL flask at room temperature under argon atmosphere was added Example 58g (2 g, 7.57 mmol), 1-fluoro-4-iodobenzene (3.36 g, 15.14 mmol), palladium(II) acetate (0.085 g, 0.379 mmol), xantphos (0.219 g, 0.379 mmol), _Cs2CO3 (2.52 g, 7.72 mmol), and anhydrous _dioxane (40 mL). The mixture was heated at 110°C for 18 hours. After cooling, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The solvent was removed, and the residue was purified by silica gel chromatography using a 10/1 to 2/1 petroleum ether/ethyl acetate gradient to afford the title compound (1.1 g, 2.9 mmol, 39% yield) as a yellow solid.

Example 194b

1-Benzyl-4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

Combine a mixture of Example 58f (0.8 g, 1.192 mmol), Example 194a (0.498 g, 1.251 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.035 g, 0.119 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.055 g, 0.060 mmol), and K ₃ PO ₄ (0.632 g, 2.98 mmol) and purge with argon for 30 minutes. A solution of 1,4-dioxane (10 mL) and water (2.500 mL) was bubbled with nitrogen for 30 minutes and transferred to the reaction vessel via syringe under argon. The reaction mixture was stirred at 60° C. for 4 hours. The mixture was treated with ethyl acetate (150 mL) and water (50 mL), and the undissolved solid was filtered off and washed several times with ethyl acetate. The resulting solid was dried under vacuum to afford the title compound (0.58 g, 0.711 mmol, 59.6% yield).

Example 194c

4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

A mixture of Example 194b (0.58 g, 0.987 mmol), anisole (0.216 mL, 1.974 mmol), and concentrated _H₂SO₄ (0.5 mL, 9.38 mmol) in TFA (10 mL, 130 mmol) was heated at ₉₀ °C for 6 hours. Excess TFA was removed under reduced pressure, and the residue was partitioned between water (10 mL) and ethyl acetate (50 mL). The organic layer was separated, and the aqueous layer was extracted twice with additional ethyl acetate (20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (10 mL), then saturated aqueous sodium chloride (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound (0.24 g, 0.241 mmol, 24.4% yield).

Example 194d

4-(4-Fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid ethyl ester

A mixture of Example 194c (0.31 g, 0.623 mmol), HCl (4 M in dioxane) (4 mL, 16.00 mmol) and paraformaldehyde (0.374 g, 12.46 mmol) in methanol (2.5 mL) was heated in a microwave at 130° C. for 1.5 h. The solvent was removed under reduced pressure to provide the title compound.

Example 194e

N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 194f (150 mg, 0.294 mmol) and ethylamine (25% wt/wt in ethanol) (5 mL, 0.832 mmol) was sealed and heated at 78°C for 2 days. The reaction mixture was cooled to ambient temperature and concentrated. The residue was purified by reverse phase preparative HPLC (C18, 30-60% acetonitrile/ _0.01 N _NH4CO3 /water) to afford the title compound (25 mg, 0.049 mmol, 16.7% yield). ¹ H NMR(400 MHz, DMSO- d ₆ ) δ 12.15 (brs, 1H), 8.30(t, J = 5.1 Hz, 1H), 7.94 (t, J = 8.2Hz, 1H), 7.69-7.61 (m, 1H), 7.48-7.46(m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 6.88-6.77(m, 2H), 6.39-6.29 (m, 2H), 6.33-5.88 (m, 1H), 4.81-4.14 (m, 3H), 3.58 (s, 3H), 3.34-3.32 (m, 2H), 3.01 (s,3H), 1.24-1.15 (m, 3H). MS (ESI+) m/z 509.2 (M+H) ⁺ .

Example 195

5-Cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 195a

2-Cyclopropyl-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline

To a 5 mL microwave vial was added Example 12b (0.2287 g, 0.608 mmol), cyclopropylboronic acid (0.209 g, 2.432 mmol), cesium carbonate (0.990 g, 3.04 mmol), and bistriphenylphosphine palladium (II) dichloride (0.021 g, 0.030 mmol). The tube was sealed and the mixture was purged with nitrogen for 30 minutes. Degassed dioxane (2.53 mL) and water (0.507 mL) were added. The reaction mixture was heated at 100°C overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The reaction mixture was purified by flash chromatography (10-70% ethyl acetate/heptane) to give the title compound (0.143 g, 70% yield).

Example 195b

2-Bromo-6-cyclopropyl-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline

To a 250 mL round-bottom flask was added Example 195a and acetic acid (1.41 mL) to give a tan solution. N-bromosuccinimide (0.079 g, 0.445 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with sodium thiosulfate (10 mL 10%) and neutralized with saturated aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous sodium chloride and concentrated. The residue was purified by flash chromatography (silica gel, 10-70% ethyl acetate/heptane) to give the title compound (0.111 g, 63% yield).

Example 195c

4-(3-cyclopropyl-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 250 mL round-bottom flask was added Example 195b (0.111 g, 0.268 mmol), Example 1f (0.104 g, 0.243 mmol), sodium carbonate (0.090 g, 0.851 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.011 g, 0.012 mmol), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.012 g, 0.041 mmol). The solid was purged with nitrogen for 30 minutes. Degassed dioxane (1.946 mL) and water (0.487 mL) were added. The reaction mixture was heated at 60°C for 3 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to provide the title compound (0.155 g, 100% yield).

Example 195d

4-(3-cyclopropyl-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 100 mL round-bottom flask was added Example 195c (0.1553 g, 0.244 mmol), lithium hydroxide hydrate (0.102 g, 2.435 mmol), dioxane (1.826 mL), and water (0.609 mL). The reaction mixture was heated at 50°C overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to provide the title compound (0.0792 g, 67% yield).

Example 195e

5-Cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 250 mL round-bottom flask was added Example 195d (0.0792 g, 0.164 mmol), paraformaldehyde (0.074 g, 0.819 mmol), and tetrahydrofuran (1.638 mL). Titanium (IV) chloride (0.328 mL, 0.328 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate and mercaptopropyl silica gel for 1 hour. The slurry was filtered through a 10 g Celite SPE column and concentrated. The residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to provide the title compound (0.0609 g, 75% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.79-11.84 (m, 1H), 7.67 (d, J= 2.0 Hz, 1H), 7.63 (s, 1H), 7.21 (d, J = 2.5 Hz, 1H), 6.96-7.05 (m, 1H),6.95 (d, J = 1.8 Hz, 1H), 6.59-6.68 (m, 1H), 6.24-6.34 (m, 1H), 5.76 (s, 2H),5.19 (d, J = 16.3 Hz, 1H), 4.35-4.56 (m, 3H), 3.59 (s, 3H), 2.95 (s, 3H), 2.07-2.18 (m, 1H), 0.83-0.94 (m, 1H), 0.62-0.72 (m, 2H), 0.28-0.37 (m, 1H). MS(ESI+) m/z 496.1 (M+H) ⁺ .

Example 196

tert-Butyl (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

A mixture of Example 5f (0.262 g, 0.763 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (0.332 g, 1.526 mmol) in dichloromethane (17 mL) was treated with acetic acid (0.437 mL, 7.630 mmol). The reaction mixture was stirred at 60°C for 1.5 hours, then cooled to 0°C and treated with sodium triacetoxyborohydride (0.340 g, 1.526 mmol). The reaction mixture was removed from the 0°C ice bath and stirred at ambient temperature for 18 hours. Saturated sodium bicarbonate solution was slowly added to quench the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 1% methanol in dichloromethane to afford the title compound as a mixture of cis and trans isomers (0.304 g, 0.543 mmol, 74% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87-11.77 (m, 2H), 7.73-7.66 (m, 2H), 7.59-7.52 (m, 2H), 7.31-7.12 (m, 6H), 6.81-6.70 (m, 1H), 6.53-6.48 (m, 1H), 4.54-4.30 (m, 6H), 4.10-3.90 (m, 2H), 3.67-3.57 (m, 6H), 3.30-3.23 (m, 1H), 3.16-3.06 (m, 1H), 2.94 (s, 6H), 2.78-2.68 (m, 1H), 2.62-2.55 (m, 1H), 1.96-1.47(m, 8H), 1.39-1.32 (m, 18H), 1.26-1.13 (m, 6H), 0.95-0.85 (m, 2H). ). MS (ESI+) m/z 541.2 (M+H) ⁺ .

Example 197

tert-Butyl ((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

Example 196 (0.025 mg, 0.046 mmol) (mixture of cis and trans isomers) was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% TFA), 5-70% gradient). The first eluting isomer fractions were collected, concentrated, and maintained under vacuum to remove residual trifluoroacetic acid to give the title compound (0.008 g, 0.015 mmol). ¹ HNMR(500 MHz, DMSO- d ₆ ) δ 11.81 (s, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.24-7.21(m, 1H), 7.18-7.12 (m, 2H), 6.51 (d, J = 8.0 Hz, 1H), 4.45 (bs, 4H), 3.62 (s,3H), 3.15-3.06 (m, 1H), 2.94 (s, 3H), 2.58 (t, J = 10.9 Hz, 1H), 1.81-1.55(m, 4H), 1.33 (s, 9H), 1.20-1.16 (m, 2H), 0.94-0.87 (m, 2H). MS (ESI+) m/z541.0 (M+H) ⁺ .

Example 198

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 198a

4-Chloro-N-(4-((methylsulfonyl)methyl)phenyl)aniline

To a 20 mL microwave vial was added 4-chloroaniline (0.129 g, 1.012 mmol), Example 9a (0.2522 g, 1.012 mmol), palladium acetate (9.09 mg, 0.040 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.039 g, 0.081 mmol), cesium carbonate (0.462 g, 1.417 mmol), toluene (8.44 mL), and tert-butanol (1.687 mL). The vial was sealed and the reaction mixture was heated at 150°C under a Biotage Creator microwave for a fixed time of 15 minutes. The reaction mixture was filtered through a Celite SPE column (2 g) and washed with ethyl acetate. The reaction mixture was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20-100% ethyl acetate/heptane) to provide the title compound (0.255 g, 85% yield).

Example 198b

2-Bromo-N-(4-chlorophenyl)-4-((methylsulfonyl)methyl)aniline

To a 250 mL round-bottom flask was added Example 198a (0.2553 g, 0.863 mmol) and acetic acid (8.63 mL). N-bromosuccinimide (0.154 g, 0.863 mmol) was added in two portions 10 minutes apart. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with sodium thiosulfate (30 mL, 10%) and diluted with water. The reaction mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with 2N sodium hydroxide until the pH of the aqueous layer was >7, followed by washing with saturated sodium chloride solution, drying over anhydrous magnesium sulfate, filtering, and concentrating. The residue was purified by flash chromatography (silica gel, 50-100% ethyl acetate/heptane) to afford the title compound (0.198 g, 61% yield).

Example 198c

4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 250 mL round-bottom flask was added Example 198b (0.1981 g, 0.529 mmol), Example 1f (0.206 g, 0.481 mmol), sodium carbonate (0.178 g, 1.682 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.022 g, 0.024 mmol), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.024 g, 0.082 mmol). The solids were purged with a stream of nitrogen for 1 hour, and degassed dioxane (4.0 mL) and water (1.0 mL) were added. The reaction mixture was heated at 60°C for 3 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (0-5% methanol/dichloromethane) to afford a tan solid. The solid was triturated with dichloromethane and heptane and filtered to afford the title compound (0.167 g, 58% yield).

Example 198d

4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 4 mL vial was added Example 198c (0.1673 g, 0.281 mmol), lithium hydroxide hydrate (0.118 g, 2.81 mmol), dioxane (1.40 mL), and water (0.47 mL). The reaction mixture was heated at 50°C overnight. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to provide the title compound (0.0795 g, 64% yield).

Example 198e

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 250 mL round-bottom flask was added Example 198d (0.0794 g, 0.180 mmol), paraformaldehyde (0.081 g, 0.898 mmol), and tetrahydrofuran (1.797 mL). Titanium (IV) chloride (0.359 mL, 0.359 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to provide the title compound (0.0596 g, 73% yield). ¹ H NMR (400 MHz, DMSO- d ₆ )δ 11.86 (bs, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.45 (dd, J = 7.9,1.9 Hz, 1H), 7.34 (d, J = 5.5 Hz, 2H), 6.98 (d, J = 9.1 Hz, 2H), 6.42 (d, J =9.0 Hz, 2H), 5.13 (s, 1H), 4.37-4.66 (m, 3H), 3.56 (s, 3H), 3.00 (s, 3H). MS(ESI+) m/z 454.1 (M+H) ⁺ .

Example 199

4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile

To a suspension of Example 58m (50 mg, 0.101 mmol) and triethylamine (0.028 mL, 0.201 mmol) in tetrahydrofuran (1 mL) at 0°C was added trifluoroacetic anhydride (0.043 mL, 0.302 mmol) dropwise and the reaction mixture was stirred at ambient temperature for an additional 60 minutes. The solvent was removed, and the residue was purified by reverse phase HPLC (C8 column, CH ₃ CN/water (0.01N ammonium carbonate, 25%-55%) to give the title compound (5 mg, 10.44 μmol, 10% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.36 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.50 (d, J = 9.5 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.35 (d, J = 9.0 Hz, 2H), 5.23-5.13 (m, 1H), 4.70-4.47 (m, 3H), 3.58 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 479.0 (M+H) ⁺ .

Example 200

4-(2,4-Difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 200a

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic acid ethyl ester

Combine Example 12d (89 mg, 0.20 mmol) and ethyl 2-oxoacetate (0.119 mL, 0.600 mmol) in tetrahydrofuran (2 mL). To this suspension is added 1M titanium (IV) chloride/dichloromethane (0.400 mL, 0.400 mmol). The reaction mixture is stirred at ambient temperature for 20 hours and partitioned between ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to give the title compound (78 mg, 74%).

Example 200b

4-(2,4-Difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a solution of Example 200a (76.0 mg, 0.144 mmol) in tetrahydrofuran (2 mL) was added 1.0 M lithium aluminum hydride in tetrahydrofuran (0.144 mL, 0.144 mmol) dropwise at 0°C. The reaction mixture was stirred at ambient temperature for 2 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2-5% methanol in dichloromethane) to provide the title compound (45 mg, 64%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.90 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.60-7.49 (m, 1H), 7.21-7.14 (m, 2H), 7.06-6.96 (m,2H), 6.90 (d, J = 8.8 Hz, 1H), 5.18 (dd, J = 9.2, 5.4 Hz, 1H), 4.99 (t, J =4.6 Hz, 1H), 4.52-4.39 (m, 2H), 3.64 (s, 3H), 3.48-3.34 (m, 2H), 2.93 (s, 3H). MS (ESI+) m/z 486 (M+H) ⁺ .

Example 201

4-(4-Chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile

Example 201a

4-(4-Chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid

Example 201a was prepared according to the procedure used for Example 581, substituting Example 127d for Example 58k to provide the title compound.

Example 201b

4-(4-Chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 201b was prepared according to the procedure used to prepare Example 58m, substituting Example 201a for Example 581 to provide the title compound.

Example 201c

4-(4-Chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile

Example 201c was prepared according to the procedure used for Example 199, substituting Example 201b for Example 58m, to provide the title compound. ^H NMR (400 MHz, DMSO- d ₆ ) δ 7.92 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.52-7.47 (m, 2H), 7.36 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 9.1 Hz, 2H), 6.33 (d, J = 9.1 Hz, 2H), 5.20-5.15 (m, 1H), 4.66-4.63 (m, 1H), 3.57 (s, 3H). MS (ESI+) m/z 387.1 (M+H) ⁺ .

Example 202

4-(2,4-Difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 208i (250 mg, 0.289 mmol) and ethylamine (25% wt/wt in ethanol) (5 mL, 1.386 mmol) was sealed and heated at 78°C for 2 days. The mixture was cooled to ambient temperature, the resulting solid was collected by filtration, and washed several times with methanol. The solid was then purified by reverse-phase preparative HPLC (C18, 30-60% acetonitrile/ _0.01 N _NH₄CO₃ /water) to afford the title compound (30 mg, 0.057 mmol, 19.71% yield) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (s, 1H), 8.26 (d, J = 4.8 Hz, 1H), 7.82 (d, J =1.7 Hz, 1H), 7.71 (s, 1H), 7.29-7.22 (m, 1H), 7.21-7.07 (m, 1H), 7.02-6.89(m, 3H), 5.15 (brs, 1H), 4.49 (s, 2H), 3.66 (s, 3H), 3.29-3.26 (m, 3H), 2.96(s, 3H), 1.14 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 527.2 (M+H) ⁺ .

Example 203

4-(4-Cyanophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 59 (100 mg, 0.190 mmol), potassium hexacyanoferrate(II) trihydrate (17.70 mg, 0.042 mmol), _Pd2 (dba) ₃ (8.72 mg, 9.52 μmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (X-Phos) (9.08 mg, 0.019 mmol), palladium(II) acetate (4.28 mg, 0.019 mmol), and _Cs2CO3 (93 _mg , 0.286 mmol) in dioxane (6 mL) and water (1.5 mL) was sealed and heated in a microwave at 130°C for 3 hours. The reaction mixture was filtered through celite, washed with ethyl acetate, and then concentrated. The residue was purified by reverse phase HPLC (C18, CH ₃ CN/water (0.01 N ammonium carbonate), 25-55% gradient) to afford the title compound (8.4 mg, 0.016 mmol, 8.55% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.28 (s, 1H), 8.35 (t, J = 5.0 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.71 (s, 1H), 7.52-7.49(m, 1H), 7.45-7.37 (m, 3H), 6.47 (d, J = 7.6 Hz, 2H), 5.98 (d, J = 17.0 Hz,1H), 4.67-4.63 (m, 1H), 4.54 (d, J = 2.3 Hz, 1H), 4.51-4.50 (m, 1H), 3.59 (s,3H), 3.42-3.36 (m, 2H), 3.02 (s, 3H), 1.20 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z516.2 (M+H) ⁺ .

Example 204

(S)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione

The product of Example 117 (0.019 g) was subjected to preparative chiral SFC separation on a (S,S) WHELK-O1 column (21 mm x 250 mm, 5 microns) eluted with a 4:6 mixture of 0.1% diethylamine/methanol and carbon dioxide to afford the title compound. The stereochemistry of the first eluting peak (5.004 minutes, 98% ee, 5.1 mg, 64% recovery) was randomly assigned. ¹ HNMR (500 MHz, DMSO- d ₆ ) δ 11.78 (d, J = 1.83 Hz, 1H), 7.93 (d, J = 1.53 Hz, 1H), 7.81-7.86 (m, 4H), 7.76 (s, 1H), 7.24-7.30 (m, 1H), 7.21 (dd, J = 8.24,1.83 Hz, 1H), 7.09-7.15 (m, 1H) 6.99-7.05 (m, 1H), 6.96 (d, J = 2.44 Hz, 1H), 6.92 (d, J = 8.24 Hz, 1H), 5.44 (dd, J = 9.92, 5.34 Hz, 1H), 4.51-4.56(m, 1H), 4.44-4.48 (m, 1H), 3.87 (dd, J = 13.28, 5.34 Hz, 1H), 3.66 (s, 3H), 3.52 (dd, J = 13.28, 10.22 Hz, 1H), 2.98 (s, 3H). MS (ESI+) m/z 615 (M+H) ⁺ .

Example 205

(R)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione

The product of Example 117 (0.019 g) was subjected to preparative chiral SFC separation on a (S,S) WHELK-O1 column (21 mm x 250 mm, 5 microns) eluted with a 4:6 mixture of 0.1% diethylamine/methanol and carbon dioxide to afford the title compound. The stereochemistry of the second eluting peak (5.732 minutes, >99% ee, 5.6 mg, 70% recovery) was randomly assigned. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.78 (d, J = 1.83 Hz, 1H), 7.93 (d, J = 1.53 Hz, 1H), 7.81-7.86 (m, 4H), 7.76 (s, 1H), 7.24-7.30 (m, 1H), 7.21 (dd, J = 8.24,1.83 Hz, 1H), 7.09-7.15 (m, 1H) 6.99-7.05 (m, 1H), 6.96 (d, J = 2.44 Hz, 1H), 6.92 (d, J = 8.24 Hz, 1H), 5.44 (dd, J = 9.92, 5.34 Hz, 1H), 4.51-4.56(m, 1H), 4.44-4.48 (m, 1H), 3.87 (dd, J = 13.28, 5.34 Hz, 1H), 3.66 (s, 3H), 3.52 (dd, J = 13.28, 10.22 Hz, 1H), 2.98 (s, 3H). MS (ESI+) m/z 615 (M+H) ⁺ .

Example 206

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile

Example 206a

2,6-Dibromo-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline

To a 500 mL round-bottom flask was added Example 12a (3.000 g, 7.97 mmol) and trifluoroacetic acid (80 mL) to give a colorless solution. The reaction mixture was cooled to 0°C. N-bromosuccinimide (1.419 g, 7.97 mmol) was added in two portions 10 minutes apart. The cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed, and 200 mL of 2N sodium hydroxide, 50 mL of 10% sodium thiosulfate, and 200 mL of ethyl acetate were added. The reaction mixture was stirred for 30 minutes. The layers were separated, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated onto silica gel. The reaction mixture was purified by flash chromatography (20-100% ethyl acetate:heptane) to yield a white solid (2.48 g, 68%).

Example 206b

4-(3-Bromo-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 206b was prepared according to the procedures used to prepare Example 6b, substituting Example 206a for Example 6a to provide the title compound (0.0872 g, 50% yield) as a yellow solid.

Example 206c

4-(3-Bromo-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 206c was prepared according to the procedure used to prepare Example 12d, substituting Example 206b for Example 12c, to provide the title compound (0.0552 g, 44% yield) as a red oil.

Example 206d

5-Bromo-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 206d was prepared according to the procedure used to prepare Example 82, substituting Example 206c for Example 12d, to provide the title compound (0.0352 g, 62% yield) as a yellow solid.

Example 206e

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile

To a 2 mL microwave tube was added zinc(II) cyanide (0.012 g, 0.099 mmol) and dichlorobis(triphenylphosphine)palladium(II) (4.62 mg, 6.59 µmol). Example 206d (0.0352 g, 0.066 mmol) and N,N-dimethylformamide (0.659 mL) were added. The tube was sealed and the reaction mixture was heated in a Biotage Creator at 200°C for a fixed time of 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and mercaptopropyl silica gel, filtered, and concentrated. The reaction mixture was purified by flash chromatography (0-5% methanol:dichloromethane) to afford a white solid (0.0209 g, 66% yield). ¹ H NMR(500 MHz, DMSO- d ₆ ) δ 11.95 (bs,1H), 8.24 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.24(s, 1H), 6.99-7.20 (m, 1H), 6.73 (td, J = 8.5, 2.8 Hz, 1H), 6.45 (td, J =9.5, 5.8 Hz, 1H), 5.05-5.14 (m, 1H), 4.43-4.80 (m, 3H), 3.62 (s, 3H), 3.02(s, 3H). MS (ESI+) m/z 481.0 (M+H) ⁺ .

Example 207

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 207a

4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Combine Example 1f (2.0 g, 4.67 mmol), Example 5c (1.6 g, 5.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.128 g, 0.14 mmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.136 g, 0.467 mmol), and sodium carbonate (2.13 g, 20.1 mmol) and purge with nitrogen for 30 minutes. To this mixture was added nitrogen-bubbled 1,4-dioxane (24 mL) and water (6 mL) via syringe. The reaction mixture was stirred at 60°C for 5 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, treated with 3-mercaptopropyl-functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, filtered through a plug of celite, and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/dichloromethane). The product was further purified by trituration with diethyl ether and then dried in a vacuum oven at 70°C to give 2.06 g (91%) of the title compound.

Example 207b

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 207a (0.4 g, 0.824 mmol), 2-bromopyridine (0.325 g, 2.06 mmol), palladium acetate (0.046 g, 0.206 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.196 g, 0.412 mmol), and cesium carbonate (0.537 g, 1.65 mmol) were combined in a 20-mL microwave vial equipped with a magnetic stir bar. Toluene (6.6 mL) and tert-butanol (1.65 mL) were added, and the mixture was reacted at 160°C in a Biotage microwave reactor for 1 hour. The reaction step was repeated, and the two reaction mixtures were combined and filtered through a fritted glass funnel to remove the Pd solids. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, treated with 3-mercaptopropyl-functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, filtered through a plug of celite, and concentrated. The residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate/dichloromethane, then 5-7% methanol/dichloromethane) to provide 0.211 g (23%) of the title compound.

Example 207c

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 207b (0.21 g, 0.373 mmol) in 1,4-dioxane (5 mL) and water (1.7 mL) was treated with lithium hydroxide•H ₂ O (0.157 g, 3.73 mmol) and N,N,N-trimethylhexadecyl-1-ammonium bromide (0.0041 g, 0.011 mmol) and heated at 63°C for 3.5 hours, stirred overnight at ambient temperature, and then heated at 75°C for an additional 1.5 hours. The reaction mixture was cooled to ambient temperature and neutralized with hydrochloric acid solution (2 N aqueous solution). The resulting mixture was then partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-25% methanol/dichloromethane) to provide 0.15 g (99%) of the title compound.

Example 207d

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stir bar, Example 207c (0.15 g, 0.367 mmol), paraformaldehyde (0.033 g, 1.1 mmol) and acetic acid (7.3 mL) were added. The vial was sealed and heated at 75°C for 55 minutes. The second reaction mixture was operated as follows. To a 5-mL microwave vial equipped with a magnetic stir bar, Example 207c (0.082 g, 0.2mmol), paraformaldehyde (0.018 g, 0.6 mmol) and acetic acid (4 mL) were added. The vial was sealed and heated at 75°C for 45 minutes. The reaction mixtures were combined and concentrated. To the residue were added 1,4-dioxane (5.7 mL) and sodium hydroxide solution (4 N aqueous solution) (1.4 mL, 5.67 mmol). The reaction mixture was heated at 60°C for 1 hour, cooled to ambient temperature, and neutralized with hydrochloric acid solution (2 N aqueous solution). The resulting mixture was then distributed between ethyl acetate and water and washed with a saturated sodium chloride solution. The combined aqueous layer was extracted with ethyl acetate until no product was detected. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reversed-phase HPLC (C18, acetonitrile/water (0.1% TFA), 10-60%) to obtain 0.271 g (89%) of the title compound as a TFA salt. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.84 (d, J=1.53 Hz, 1H), 7.98 (dd, J=4.88, 1.22 Hz, 1 H), 7.91 (d, J=1.83 Hz, 1 H), 7.63 (s, 1 H), 7.43 (m, 1 H), 7.36 (d, J=7.93 Hz, 1 H), 7.29 (m, 2 H), 6.51 (ddd, J=7.02,4.88, 0.61 Hz, 1 H), 6.16 (d, J=8.24 Hz, 1 H), 5.79 (d, J=15.56 Hz, 1 H),4.62 (d, 1 H), 4.52 (d, 1 H), 4.24 (d, J=15.56 Hz, 1 H), 3.57 (s, 3 H), 3.01 (s, 3 H). MS (ESI+) m/z 421.1 (M+H) ⁺ .

Example 208

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid ethyl ester

Example 208a

4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

To a solution of 5-bromo-2-methoxy-3-nitropyridine (50 g, 215 mmol) in tetrahydrofuran (2000 mL) at -70°C was added vinylmagnesium bromide (800 mL, 644 mmol) dropwise, and the mixture was stirred at -70 to -60°C for 2 hours. The reaction mixture was quenched with 20% aqueous _NH₄Cl solution, extracted with ethyl acetate, dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under reduced pressure to yield a brown residue. This material was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the crude product, which was triturated with dichloromethane and dried under vacuum to afford the title compound (20 g, 41.1% yield) as a light yellow solid.

Example 208b

4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

At 0 ° C, sodium hydride (6.98 g, 290 mmol) was added portionwise to a solution of Example 208a (44 g, 194 mmol) in tetrahydrofuran (600 mL). The mixture was stirred for 1 hour. Then, 4-methylbenzene-1-sulfonyl chloride (55.4 g, 290 mmol) was added portionwise to the mixture at 0 ° C. After stirring for 2 hours at ambient temperature, the reaction mixture was quenched with 20% aqueous sodium chloride solution. The mixture was extracted three times with ethyl acetate and distributed. The combined organic layers were dried (anhydrous sodium sulfate) and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was recrystallized from ethyl acetate and petroleum ether to obtain the title compound (52 g, 70.4% yield) as a light yellow solid.

Example 208c

4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

To a solution of Example 208b (10.5 g, 27.5 mmol) in tetrahydrofuran (170 mL) was added lithium diisopropylamide (20.7 mL, 41.40 mmol) dropwise at -70°C, and the reaction mixture was stirred at -70°C to -50°C for 45 minutes. To the stirred mixture was added ethyl chloroformate (4.48 g, 41.3 mmol) dropwise at -70°C. The reaction mixture was stirred at -70°C for 1.5 hours, quenched with 20% aqueous ammonium chloride solution, and extracted with ethyl acetate (150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was washed with dichloromethane to afford the title compound (10 g, 80%) as a white solid.

Example 208d

4-Bromo-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

To a mixture of Example 208c (32.5 g, 71.7 mmol) and sodium iodide (16.12 g, 108 mmol) in acetonitrile (554 mL) was added chlorotrimethylsilane (11.68 g, 108 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 hour. Water (0.685 g, 38.0 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at 65 ° C for 3 hours. The reaction mixture was cooled to ambient temperature and filtered. The precipitate was dissolved in dichloromethane. The mixture was filtered again, and the combined filtrate was concentrated under reduced pressure to obtain a brown solid, which was washed with petroleum ether and dichloromethane to obtain the title compound (23 g, 52.4 mmol, 73.0% yield) as a light yellow solid.

Example 208e

4-Bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

To a solution of Example 208d (7.5 g, 17.07 mmol) in tetrahydrofuran (100 mL) at 0°C was added sodium hydride (0.520 g, 21.68 mmol) in portions, and the reaction mixture was stirred for 30 minutes. Methyl iodide (3.64 g, 25.6 mmol) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at ambient temperature for 3 hours, and additional methyl iodide (3.64 g, 25.6 mmol) was added at 0°C. The reaction mixture was stirred at ambient temperature for 12 hours, quenched with 20% aqueous ammonium chloride, and extracted three times with ethyl acetate. The combined mixture was dried over _{anhydrous Na₂SO₄} , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography, eluting with 1:1 ethyl acetate/hexane to afford a yellow crude product, which was then washed with methanol to afford the title compound (15.3 g, 80% yield).

Example 208f

6-Methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

Example 208f was prepared according to the procedure used to prepare Example 1f, substituting Example 208e for Example 1e to provide the title compound.

Example 208g

4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

Example 208g was prepared according to the procedures used to prepare Example 5d, substituting Example 12b for Example 5c and Example 208f for Example 1f, respectively, to provide the title compound.

Example 208h

4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester

A mixture of Example 208g (0.2 g, 0.299 mmol) in dioxane (2 mL) and ethanol (0.5 mL) was treated with sodium hydroxide (0.747 mL, 1.493 mmol) at ambient temperature. The reaction mixture was heated at 60°C for 2 minutes. After cooling to ambient temperature, the reaction mixture was partitioned between 1.0 N HCl and ethyl acetate. The organic layer was separated and the aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (0.15 g, 0.291 mmol, 97% yield).

Example 208i

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid ethyl ester

Example 208i was prepared according to the procedure used to prepare Example 58k, substituting Example 208h for Example 58j to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.67 (s, 1H), 7.84 (d, J = 2.14 Hz, 1H), 7.72 (s, 1H), 7.29 (dd, J = 8.24, 1.83 Hz, 1H), 7.09-7.13 (m, 1H), 7.03(d, J = 7.93 Hz, 1H), 6.84-6.89 (m, 1H), 6.75-6.81 (m, 1H), 5.09 (s, 2H), 4.49 (s, 2H), 4.29 (q, J = 7.02 Hz, 1H), 3.64 (s, 3H), 2.96 (s, 3H), 1.34 (t,J = 7.02 Hz, 3H). MS (ESI+) m/z 528.1 (M+H) ⁺ .

Example 209

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 209a

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid

Example 209a was prepared according to the procedure used for Example 581, substituting Example 208i for Example 58k to provide the title compound.

Example 209b

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 209b was prepared according to the procedure used to prepare Example 58m, substituting Example 209a for Example 581 to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.19 (s, 1H), 7.82 (d, J = 2.14Hz, 1H), 7.72 (s, 2H), 7.70 (s, 1H), 7.53 (s, 1H), 7.26 (dd, J = 8.09, 1.98Hz, 1H), 7.05-7.11 (m, 1H), 6.98 (d, J = 7.93 Hz, 1H), 6.90-6.93 (m, 2H), 6.75-6.81 (m, 1H), 5.14 (s, 2H), 4.48 (s, 2H), 3.66 (s, 3H), 2.95 (s, 3H). MS(ESI+) m/z 499.1 (M+H) ⁺ .

Example 210

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile

Example 210 was prepared according to the procedure used to prepare Example 199, substituting Example 209b for Example 58m to provide the title compound. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.32 (s, 1H), 7.89 (d, J = 1.83 Hz, 1H), 7.82 (s, 1H), 7.32 (dd, J = 8.24, 1.83 Hz, 1H), 7.12-7.15 (m, 1H), 7.08(d, J = 8.24 Hz, 1H), 6.83-6.88 (m, 1H), 6.71-6.77 (m, 1H), 4.86 (s, 2H), 4.51 (s, 2H), 3.65 (s, 3H), 2.97 (s, 3H). MS (ESI+) m/z 481.1 (M+H) ⁺ .

Example 211

10-Methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 211a

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-((3,4,5-trimethoxyphenyl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Under argon, a mixture of Example 5d (0.075 g, 0.154 mmol), 5-bromo-1,2,3-trimethoxybenzene (0.114 g, 0.463 mmol), cesium carbonate (0.101 g, 0.309 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (XPhos) (0.0368 g, 0.077 mmol), and palladium(II) acetate (0.0087 g, 0.039 mmol) in toluene (3 mL) and tert-butanol (0.75 mL) was heated in a sealed tube in a microwave reactor at 160°C for 2 hours. The reaction mixture was cooled to ambient temperature and filtered through filter paper. The filtrate was concentrated to near dryness and mixed with ethanol (2 mL), tetrahydrofuran (4 mL), and excess 5N sodium hydroxide solution (2 mL). The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated to 5 mL and partitioned between aqueous ammonium chloride and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel flash column chromatography, eluting with 3% methanol/dichloromethane to provide the title compound (0.020 g, 0.040 mmol, 26% yield).

Example 211b

10-Methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 211a (0.020 g, 0.040 mmol) and paraformaldehyde (0.006 g, 0.201 mmol) in tetrahydrofuran (2 mL) was treated with 1 M titanium tetrachloride solution (0.080 mL, 0.080 mmol) at ambient temperature under argon. The reaction mixture suspension was stirred at ambient temperature for 1 hour and then partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was triturated with methanol to give the title compound (0.0026 g, 13% yield). ¹ H NMR (500MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 7.92 (s, 1H), 7.64 (s, 1H), 7.46-7.29 (m, 3H), 5.71 (s, 2H), 5.49-4.66 (m, 2H), 4.56 (s, 2H), 3.57 (s, 3H), 3.51 (s, 6H), 3.45 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 510.3 (M+H) ⁺ .

Example 212

4-(4-Aminocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 196 (0.240 g, 0.444 mmol) in dichloromethane (10 mL) was treated with an excess of trifluoroacetic acid (1 mL) and stirred at ambient temperature for 6 hours. The reaction mixture was concentrated and dried under vacuum to give a solid residue, which was partitioned between a saturated sodium carbonate solution and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was triturated with ethyl acetate and filtered to give the title compound (0.0066 g, 0.015 mmol, 45% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ 11.80(bs, 1H), 7.68 (s, 1H), 7.51-7.45 (m, 1H), 7.27-7.09 (m, 3H), 4.44-4.39 (m,2H), 4.18 (s, 2H), 3.10 (bs, 2H), 3.61 (s, 3H), 2.90 (s, 3H), 2.82-2.42 (m,2H), 1.68-1.45 (m, 4H), 1.36-1.17 (m, 3H), 0.88-0.81 (m, 1H). MS (ESI+) m/z440.8 (M+H) ⁺ .

Example 213

4-(3,5-Difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 213a

4-(2-((3,5-difluoropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

In a 20-mL microwave vial equipped with a magnetic stir bar, Example 207a, 2-bromo-3,5-difluoropyridine (0.245 g, 1.263 mmol), palladium acetate (0.032 g, 0.143 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.137 g, 0.287 mmol), and cesium carbonate (0.374 g, 1.148 mmol) were combined. Toluene (4.4 mL) and tert-butanol (1.1 mL) were added, and the reaction mixture was reacted in a Biotage microwave reactor at 160°C for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and water, and filtered through a plastic fritted funnel to remove Pd solids. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-70% ethyl acetate/dichloromethane) to provide 0.229 g (71%) of the title compound.

Example 213b

4-(2-((3,5-difluoropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To Example 213a (0.2129 g, 0.356 mmol) in tetrahydrofuran (8 mL) was added tetrabutylammonium fluoride (0.28 g, 1.07 mmol). The reaction mixture was heated at 60°C for 45 minutes, cooled to ambient temperature, partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-8% methanol/dichloromethane) to afford the title compound as a mixture. This was further purified by flash chromatography (silica gel, 40-75% ethyl acetate/dichloromethane (containing 2-4% methanol as an additive)) to afford 0.116 g (73%) of the title compound.

Example 213c

4-(3,5-Difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stir bar was added Example 213b (0.116 g, 0.261 mmol), paraformaldehyde (0.024 g, 0.783 mmol) and acetic acid (4.5 mL). The vial was sealed and heated at 75 ° C for 50 minutes. The reaction mixture was cooled to ambient temperature, concentrated in vacuo, diluted with 1,4-dioxane (6 mL), treated with sodium hydroxide solution (4 M aqueous solution, 1.3 mL, 5.22 mmol), and heated at 75 ° C for 1 hour. The reaction mixture was cooled to ambient temperature, concentrated in vacuo, slurried in water and neutralized with hydrochloric acid solution (2 N aqueous solution). The solid was collected by filtration and washed with additional water (20 mL). The solid was purified by reverse phase HPLC (C18, acetonitrile/water (0.1% TFA), 10-70%) to give 0.09 g (61%) of the title compound as a TFA salt. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.87 (s, 1 H), 8.06 (d, J=1.83 Hz, 1 H), 7.83 (s, 1 H), 7.67 (s, 1 H), 7.59 (m, 1 H), 7.29 (d, J=7.93Hz, 1 H), 7.25 (d, J=1.53 Hz, 1 H), 7.13 (d, J=8.24 Hz, 1 H), 5.95 (s, 1 H), 4.52 (s, 2 H), 4.20 (s, 1 H), 3.62 (s, 3 H), 2.96 (s, 3 H). MS (ESI+) m/z457.1 (M+H) ⁺ .

Example 214

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Combine Example 12d (66.5 mg, 0.150 mmol) and benzaldehyde (0.076 mL, 0.75 mmol) in tetrahydrofuran (2 mL). To this suspension is added 1M titanium (IV) chloride/toluene (0.300 mL, 0.300 mmol). The reaction mixture is stirred at ambient temperature for 72 hours and partitioned between ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to provide the title compound (65 mg, 82%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.04 (d, J =2.0 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.68 (s, 1H), 7.28 (d, J = 2.6 Hz,1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H), 6.47 (s, 1H), 4.39-4.29 (m, 2H), 3.66 (s, 3H), 2.70 (s, 3H). MS (ESI+) m/z 532 (M+H) ⁺ .

Example 215

(R)-4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 214 was purified by chiral chromatography on a (S,S) WHELK-O1 column (21 x 250 mm, 5 microns) eluting with a 4:6 mixture of 0.1% diethylamine/methanol and carbon dioxide. The first enantiomer fraction was collected and concentrated. The isolated compound was arbitrarily designated as the (R) enantiomer. ¹ H NMR (500 MHz, DMSO- d ₆ )δ 12.04 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.68 (s, 1H), 7.28 (d,J = 2.6 Hz, 1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H), 6.47 (s, 1H), 4.39-4.29 (m, 2H), 3.66 (s, 3H), 2.70 (s, 3H). MS (ESI+) m/z 532 (M+H) ⁺ .

Example 216

(S)-4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 214 was purified by chiral chromatography on a (S,S) WHELK-O1 column (21 x 250 mm, 5 microns) eluting with a 4:6 mixture of 0.1% diethylamine/methanol and carbon dioxide. The second enantiomer fraction was collected and concentrated. The isolated compound was arbitrarily designated as the (S) enantiomer. ¹ H NMR (500 MHz, DMSO- d ₆ )δ 12.04 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.68 (s, 1H), 7.28 (d,J = 2.6 Hz, 1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H), 6.47 (s, 1H), 4.39-4.29 (m, 2H), 3.66 (s, 3H), 2.70 (s, 3H). MS (ESI+) m/z 532 (M+H) ⁺ .

Example 217

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(naphthalen-1-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Under nitrogen, Example 12d (0.06 g, 0.135 mmol) and 1-naphthaldehyde (0.148 mL, 1.082 mmol) were combined in tetrahydrofuran (1.353 mL) and treated with 1M titanium(IV) chloride/toluene (1.082 mL, 1.082 mmol). The reaction mixture was heated at 70°C for 24 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 1-5% methanol/dichloromethane) afforded the title compound (0.015 g, 19%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.07(s, 1H), 8.75 (d, J = 8.85 Hz, 1H), 7.86 (d, J = 7.93 Hz, 1H), 7.69-7.75 (m,3H), 7.61 (d, J = 8.54 Hz, 1H), 7.55 (t, J = 7.32 Hz, 1H), 7.38 (d, J = 1.53Hz, 1H), 7.24 (d, J = 2.44 Hz, 1H), 7.11-7.19 (m, 1H), 6.98 (t, J = 7.63 Hz, 1H), 6.65-6.73 (m, 2H), 6.60 (d, J = 7.02 Hz, 1H), 6.37-6.45 (m, 1H), 6.30 (d, J = 7.93 Hz, 1H), 4.20-4.34 (m, 2H), 3.66 (s, 3H), 2.59 (s, 3H). MS (ESI+)m/z 582 (M+H) ⁺ .

Example 218

4-(2,4-Difluorophenyl)-(3,3- ² H ₂ )-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 218 was prepared according to the procedure used to prepare Example 82, substituting formaldehyde- _d2 for methyl 4-oxobutanoate to afford the title compound (0.0352 g, 62% yield) as a yellow solid. ¹ H NMR(500 MHz, DMSO- d ₆ ) δ 11.85(s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.27 (dd, J = 8.1, 2.0 Hz,1H), 7.18 (d, J = 2.5 Hz, 1H), 7.08 (ddd, J = 12.4, 9.0, 3.1 Hz, 1H), 7.03(d, J = 8.1 Hz, 1H), 6.80-6.88 (m, 1H), 6.76 (td, J = 9.4, 5.9 Hz, 1H), 4.50(bs, 2H), 3.63 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 458.1 (M+H) ⁺ .

Example 219

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-neopentyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Under nitrogen, Example 12d (0.06 g, 0.135 mmol) and 3,3-dimethylbutanal (0.081 g, 0.812 mmol) were combined in tetrahydrofuran (1.353 mL) and treated dropwise with 1M titanium(IV) chloride/toluene (0.812 mL, 0.812 mmol). The reaction mixture was stirred at 60°C for 2 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 30-60% 3:1 ethyl acetate and ethanol/heptane) afforded the title compound (0.010 g, 14%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.81 (s, 1H), 7.91 (d, J = 1.53 Hz, 1H), 7.68 (s, 1H), 7.25 (dd, J = 8.09, 1.68 Hz, 1H), 7.16 (d, J = 2.44 Hz, 1H), 7.06-7.13 (m, 1H), 6.98 (d, J = 7.93 Hz, 1H), 6.73-6.80 (m, 1H), 6.53-6.60 (m, 1H), 5.19 (dd, J= 7.32, 4.88 Hz, 1H), 4.45-4.56 (m, 2H), 3.63 (s, 3H), 2.94 (s, 3H), 1.67(dd, J = 13.73, 4.88 Hz, 1H), 1.20 (dd, J = 13.73, 7.63 Hz, 1H), 0.89 (s,9H). MS (ESI+) m/z 526 (M+H) ⁺ .

Example 220

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoindolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 220a

2-(2,2-Dimethoxyethyl)isoindolin-1-one

To a 5 mL microwave tube, isoindolin-1-one (0.2544 g, 1.911 mmol), cesium carbonate (1.245 g, 3.82 mmol), and N-methyl-2-pyrrolidone (9.55 mL) were added to yield a colorless solution. Bromoacetaldehyde dimethyl acetal (1.125 mL, 9.55 mmol) was added. The tube was sealed, and the reaction mixture was heated in a Biotage Creator at 160°C for a fixed time of 60 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The reaction mixture was purified by flash chromatography (20-70% ethyl acetate:heptane) to yield a brown oil (0.179 g, 42% yield).

Example 220b

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoindolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 220b was prepared according to the procedure used to prepare Example 82, substituting Example 220a for methyl 4-oxobutanoate to provide the title compound (0.0169 g, 29% yield) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ11.84 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.51-7.66 (m, 3H), 7.47 (t, J = 6.7 Hz, 1H), 4.53 (d, J = 15.7 Hz, 2H), 4.46 (d, J = 13.7 Hz, 1H), 4.17-4.26 (m, 1H), 3.89 (dd, J = 13.4, 5.7 Hz, 1H), 3.66 (s, 3H), 3.34-3.44 (m, 1H), 2.97 (s, 3H). MS (ESI-) m/z 599.2 (MH) ⁺ .

Example 221

4-(2,4-Difluorophenyl)-3-(2,6-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Combine Example 12d (53.2 mg, 0.120 mmol) and 2,6-dimethoxybenzaldehyde (100 mg, 0.600 mmol) in tetrahydrofuran (1 mL). To this suspension is added 1M titanium(IV) chloride/toluene (0.240 mL, 0.240 mmol). Heat the reaction mixture at 60°C for 24 hours, cool to ambient temperature, and partition between ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to provide the title compound (8 mg, 11% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.62 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.69 (s, 1H), 7.16-6.73 (m, 7H), 6.60-6.34 (m, 3H), 4.52-4.30 (m, 2H), 3.65 (s, 3H), 3.32 (s, 6H), 2.85 (s, 3H). MS (ESI+) m/z 592 (M+H) ⁺ .

Example 222

4-(2,4-Difluorophenyl)-3-(3,5-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 222 was prepared according to the procedure used to prepare Example 221, substituting 3,5-dimethoxybenzaldehyde for 2,6-dimethoxybenzaldehyde to provide the title compound (39 mg, 55%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.02(s, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.69 (s, 1H), 7.26 (d, J = 1.7 Hz, 1H),7.19-7.04 (m, 2H), 6.96-6.81 (m, 3H), 6.34 (s, 1H), 6.27-6.18 (m, 3H), 4.46-4.31 (m, 2H), 3.66 (s, 3H), 3.56 (s, 6H), 2.75 (s, 3H). MS (ESI+) m/z 592 (M+H) ⁺ .

Example 223

3-(3,5-di-tert-butylphenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 223 was prepared according to the procedure used to prepare Example 221, substituting 3,5-di-tert-butylbenzaldehyde for 2,6-dimethoxybenzaldehyde to provide the title compound (60 mg, 78%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.99(d, J = 1.8 Hz, 1H), 7.70-7.64 (m, 2H), 7.29 (d, J = 2.4 Hz, 1H), 7.18-7.09(m, 1H), 7.07-6.99 (m, 2H), 6.96 (s, 2H), 6.92-6.82 (m, 2H), 6.75 (d, J = 8.1Hz, 1H), 6.44 (s, 1H), 4.41-4.22 (m, 2H), 3.66 (s, 3H), 2.64 (s, 3H), 1.08(s, 18H). MS (ESI+) m/z 644 (M+H) ⁺ .

Example 224

Methyl (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

To a mixture of Example 212 (0.065 g, 0.148 mmol) and N,N-diisopropylethylamine (0.103 mL, 0.590 mmol) in dimethylformamide (5 mL) was treated dropwise with methyl chloroformate (0.012 mL, 0.148 mmol) under argon at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours and then partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound (0.050 g, 0.100 mmol, 68% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.43 (s,1H), 7.70-7.65 (m, 1H), 7.49-7.43 (m, 1H), 7.28-7.14 (m, 2H), 7.09 (s, 1H), 6.60 (s, 0.5H), 6.37 (d, J = 7.0 Hz, 0.5H), 4.43-4.37 (m, 2H), 4.19 (s, 2H), 3.61 (s, 3H), 3.54-3.44 (m, 3H), 3.42-3.10 (m, 1H), 2.89 (s, 3H), 2.85-2.66(m, 1H), 1.74-1.45 (m, 4H), 1.39-1.18 (m, 3H), 1.04-0.94 (m, 1H). MS (ESI+) m/z 499.1 (M+H) ⁺ .

Example 225

Methyl ((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

The geometric isomers of Example 224 were separated using reverse phase HPLC (C18, CH ₃ CN/water (0.1% TFA), 5-40% gradient). The first eluting isomer fractions were collected and concentrated to afford the title compound (0.008 g, 0.016 mmol, 11% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.49 (s, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.49 (s, 1H), 7.28-7.18 (m, 2H), 7.13 (d, J = 2.5 Hz, 1H), 6.38 (s, 1H), 4.41(s, 2H), 4.25 (s, 2H), 3.61 (s, 3H), 3.47 (s, 3H), 3.21-3.11 (m, 1H), 2.89(s, 3H), 2.79-2.71 (m, 1H), 1.75-1.58 (m, 4H), 1.39-1.25 (m, 3H), 1.02-0.94(m, 1H). MS (ESI+) m/z 499.1 (M+H) ⁺ .

Example 226

Methyl ((cis)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

The geometric isomers of Example 224 were separated using reverse phase HPLC (C18, CH ₃ CN/water (0.1% TFA), 5-40% gradient). The second eluting isomer fractions were collected and concentrated to afford the title compound (0.0046 g, 0.009 mmol, 6% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.47 (s, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.49 (s, 1H), 7.30-7.23 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.60 (s, 1H), 4.42(s, 2H), 4.23 (s, 2H), 3.61 (s, 3H), 3.51 (s, 3H), 2.89 (s, 3H), 2.87-2.79(m, 2H), 1.72-1.26 (m, 8H). MS (ESI+) m/z 499.1 (M+H) ⁺ .

Example 227

2-(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)isoindoline-1,3-dione

Under nitrogen, Example 12d (0.06 g, 0.135 mmol) and 3-(1,3-dioxoisoindolin-2-yl)propanal (0.082 g, 0.406 mmol) were combined in tetrahydrofuran (1.353 mL) and treated dropwise with 1M titanium(IV) chloride/toluene (0.406 mL, 0.406 mmol). The reaction mixture was stirred at 60°C for 18 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by reverse-phase HPLC (C18, _CH3CN /water (0.1% TFA), 0-100% gradient) afforded the title compound (0.018 g, 21%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.94 (d, J = 2.14 Hz, 1H), 7.88 (d, J =1.53 Hz, 1H), 7.80-7.86 (m, 4H), 7.72 (s, 1H), 7.31 (d, J = 2.75 Hz, 1H),7.28 (dd, J = 8.09, 1.98 Hz, 1H), 7.02-7.10 (m, 2H), 6.77-6.83 (m, 1H), 6.65-6.72 (m, 1H), 5.06-5.11 (m, 1H), 4.40-4.57 (m, 2H), 3.70-3.79 (m, 1H), 3.65(s, 3H), 3.54-3.63 (m, 1H), 2.95 (s, 3H), 1.97-2.07 (m, 1H), 1.62 (dd, J =13.12, 5.19 Hz, 1H). MS (ESI+) m/z 629 (M+H) ⁺ .

Example 228

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Under nitrogen, Example 12d (0.05 g, 0.113 mmol) and tetrahydropyran-4-carbaldehyde (0.064 g, 0.564 mmol) were combined in tetrahydrofuran (1.127 mL) and treated dropwise with 1M titanium(IV) chloride/toluene (0.248 mL, 0.248 mmol). The reaction mixture was stirred at 60°C for 24 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 30-60% 3:1 ethyl acetate/(ethanol/heptane)) afforded the title compound (0.028 g, 45%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.88 (d, J = 1.22 Hz, 1H), 7.89 (d, J = 1.83 Hz, 1H), 7.68 (s, 1H), 7.25 (dd, J = 8.24, 1.83 Hz, 1H), 7.02-7.12 (m, 3H), 6.72-6.85(m, 2H), 4.68 (d, J = 9.46 Hz, 1H), 4.49 (q, J = 13.73 Hz, 2H), 3.83 (d, J =11.60 Hz, 1H), 3.72 (d, J = 9.77 Hz, 1H), 3.64 (s, 3H), 2.91 (s, 3H), 2.81-2.98 (m, 2H), 1.97-2.02 (m, 1H), 1.48-1.60 (m, 1H), 1.32 (t, J = 8.70 Hz, 2H), 1.03 (d, J = 9.16 Hz, 1H). MS (ESI+) m/z 540 (M+H) ⁺ .

Example 229

Benzyl (2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)carbamate

Under nitrogen, Example 12d (0.05 g, 0.113 mmol) and 3-[(benzyloxycarbonyl)amino]-1-propanal (0.070 g, 0.338 mmol) were combined in tetrahydrofuran (1.127 mL) and treated dropwise with 1M titanium(IV) chloride/toluene (0.248 mL, 0.248 mmol). The reaction mixture was stirred at 60°C for 24 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 30-60% 3:1 ethyl acetate/(ethanol/heptane)) afforded the title compound (0.012 g, 17%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.88 (s, 1H), 7.83 (d, J = 1.83 Hz, 1H), 7.68 (s, 1H), 7.28-7.42 (m, 6H), 7.23 (d, J = 7.93 Hz, 1H), 7.21 (d, J = 2.44Hz, 1H), 7.08 (dd, J = 12.66, 9.61 Hz, 1H), 6.95 (d, J = 7.93 Hz, 1H), 6.81 (d, J = 7.02 Hz, 2H), 5.06 (dd, J = 9.16, 5.49 Hz, 1H), 5.03 (s, 2H) 4.40-4.54 (m, 2H), 3.64 (s, 3H), 3.03-3.09 (m, 2H), 2.93 (s, 3H), 1.80-1.92 (m,1H), 1.30-1.39 (m, 1H). MS (ESI+) m/z 633 (M+H) ⁺ .

Example 230

3-([1,1'-biphenyl]-2-yl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 230 was prepared according to the procedure used to prepare Example 221, substituting [1,1'-biphenyl]-2-carbaldehyde for 2,6-dimethoxybenzaldehyde and a reaction time of 48 hours instead of 24 hours to provide the title compound (11 mg, 15%). ¹ HNMR (500 MHz, DMSO- d ₆ ) δ 12.00 (d, J = 2.3 Hz, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.72 (s, 1H), 7.64 (d, J = 7.1 Hz, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.46 (d, J= 7.3 Hz, 1H), 7.30 (s, 1H), 7.15-7.04 (m, 3H), 6.81-6.58 (m, 5H), 6.53-6.45(m, 1H), 6.00-5.85 (m, 1H), 4.48-4.34 (m, 2H), 3.64 (s, 3H), 2.73 (s, 3H). MS(ESI+) m/z 608 (M+H) ⁺ .

Example 231

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(quinolin-8-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Combine Example 12d (53.2 mg, 0.120 mmol) and quinoline-8-carbaldehyde (94.0 mg, 0.600 mmol) in tetrahydrofuran (1 mL). To this suspension is added 1M titanium(IV) chloride/toluene (0.240 mL, 0.240 mmol). The reaction mixture is heated at 60°C for 48 hours, cooled, diluted with water, the pH adjusted to 7 by adding saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to provide the title compound (14 mg, 20%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.02 (s, 1H), 9.14 (dd, J = 4.2, 1.7 Hz, 1H), 8.34 (dd, J = 8.3, 1.7 Hz, 1H), 8.21 (td, J = 9.6, 6.2 Hz, 1H), 7.77-7.68 (m, 4H), 7.62 (dd, J = 8.3, 4.2 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.08(t, J = 7.7 Hz, 1H), 7.00 (td, J = 8.1, 2.0 Hz, 1H), 6.93-6.84 (m, 2H), 6.71(dd, J = 8.1, 1.8 Hz, 1H), 6.09 (d, J = 8.1 Hz, 1H), 4.37-4.23 (m, 2H), 3.69(s, 3H), 2.64 (s, 3H). MS (ESI+) m/z 583 (M+H) ⁺ .

Example 232

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Combine Example 12d (53.2 mg, 0.12 mmol) and 2-pyridinecarboxaldehyde (0.057 mL, 0.60 mmol) in tetrahydrofuran (1 mL). To this suspension is added 1M titanium(IV) chloride/toluene (0.240 mL, 0.240 mmol). Heat the mixture at 70°C for 66 hours, cool, dilute with water, adjust the pH to 7 by adding saturated aqueous sodium bicarbonate, and extract with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to provide the title compound (14 mg, 22%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.04 (d, J = 1.8 Hz, 1H), 8.54-8.49 (m, 1H), 8.13 (td, J = 9.4, 6.1 Hz, 1H), 7.68 (s, 2H), 7.40 (td, J = 7.7, 1.8 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.15-6.99 (m, 3H), 6.91 (dd, J = 8.3, 1.9 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 6.61 (s, 1H), 6.50 (d, J = 8.2 Hz, 1H), 4.41-4.23 (m, 2H), 3.68 (s, 3H), 2.69 (s, 3H). MS (ESI+) m/z 533 (M+H) ⁺ .

Example 233

10-Methyl-7-((methylsulfonyl)methyl)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 233a

5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

A mixture of 5-iodo-1H-indazole (1.02 g, 4.18 mmol) in tetrahydrofuran (20 mL) was treated with sodium hydride (60% oil dispersion, 0.192 g, 4.81 mmol) at 0°C under argon. The reaction mixture was stirred at 0°C for 15 minutes. (2-(Chloromethoxy)ethyl)trimethylsilane (0.767 g, 4.60 mmol) was added dropwise, and the reaction mixture was stirred at ambient temperature for 17 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 10% ethyl acetate/heptane to provide the title compound (0.933 g, 2.49 mmol, 60% yield).

Example 233b

N-(2-Bromo-4-((methylsulfonyl)methyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-amine

Under argon, a mixture of Example 233a (0.520 g, 1.389 mmol), Example 58g (0.367 g, 1.389 mmol), cesium carbonate (0.905 g, 2.780 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (0.161 g, 0.278 mmol), and palladium(II) acetate (0.031 g, 0.139 mmol) in dioxane (20 mL) was heated in a sealed tube in a microwave reactor at 130° C. for 4 hours. The reaction mixture was cooled to ambient temperature and partitioned between saturated sodium chloride solution and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 33% ethyl acetate/heptane to provide the title compound (0.170 g, 0.333 mmol, 24% yield).

Example 233c

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Under argon, a mixture of Example 233b (0.320 g, 0.627 mmol) and Example 1f (0.282 g, 0.658 mmol) in dimethoxyethane (20 mL) and methanol (10 mL) was treated with cesium fluoride (0.286 g, 1.880 mmol) and tetrakis(triphenylphosphine)palladium (0.72 g, 0.063 mmol). The reaction mixture was stirred at 75 ° C for 2 hours. The reaction mixture was cooled to ambient temperature and an excess of 5N sodium hydroxide solution (8 mL) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then distributed between aqueous ammonium chloride solution and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 1% methanol/dichloromethane to afford the title compound (0.221 g, 0.381 mmol, 61% yield).

Example 233d

10-Methyl-7-((methylsulfonyl)methyl)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Under argon, a mixture of Example 233c (0.221 g, 0.383 mmol) and paraformaldehyde (0.057 g, 1.913 mmol) in tetrahydrofuran (10 mL) was treated with a 1M solution of titanium tetrachloride in toluene (0.765 mL, 0.765 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was quenched by slowly adding an excess of saturated sodium bicarbonate solution and partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate and then with dichloromethane. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 2% methanol/dichloromethane to give the title compound (0.120 g, 0.203 mmol, 53% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.79 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 0.5 Hz, 1H), 7.58 (s, 1H), 7.44 (dd, J =8.0, 1.9 Hz, 1H), 7.34 (dd, J = 8.8, 4.0 Hz, 3H), 6.79 (dd, J = 9.2, 2.2 Hz,1H), 6.57 (d, J = 2.0 Hz, 1H), 5.52 (s, 2H), 4.67 (bs, 2H), 4.57 (s, 2H),3.51 (s, 3H), 3.41-3.36 (m, 2H), 3.00 (s, 3H), 0.74-0.68 (m, 2H), -0.15--0.21(m, 9H). MS (ESI-) m/z 588.2 (MH) ^- .

Example 234

3-(4-(1H-imidazol-1-yl)phenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 234 was prepared according to the procedure used to prepare Example 232, substituting 4-(1H-imidazol-1-yl)benzaldehyde for 2-pyridinecarboxaldehyde and a reaction time of 48 hours instead of 66 hours to provide the title compound (8 mg, 11 %). ¹ HNMR (500 MHz, DMSO- d ₆ ) δ 12.09 (s, 1H), 8.11 (t, J = 1.1 Hz, 1H), 7.73 (d, J= 1.8 Hz, 1H), 7.70 (s, 1H), 7.59 (t, J = 1.3 Hz, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 1.7 Hz, 1H), 7.24-7.14 (m, 3H), 7.07-7.02 (m, 2H), 6.91-6.80 (m, 3H), 6.50 (s, 1H), 4.44-4.27 (m, 2H), 3.67 (s, 3H), 2.70 (s, 3H). MS(ESI+) m/z 598 (M+H) ⁺ .

Example 235

4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile

Example 235 was prepared according to the procedure used to prepare Example 232, substituting 4-formylbenzonitrile for 2-pyridinecarboxaldehyde and a reaction time of 48 hours instead of 66 hours to provide the title compound (27 mg, 40 %). ¹ H NMR (500MHz, DMSO- d ₆ ) δ 12.13 (s, 1H), 7.71 (d, J = 9.8 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.37-7.26 (m, 3H), 7.23-7.15 (m, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.90-6.78 (m, 3H), 6.54 (s, 1H), 4.45-4.26 (m, 2H), 3.66 (s, 3H), 2.73 (s, 3H). MS(ESI+) m/z 557 (M+H) ⁺ .

Example 236

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-(pyridin-2-yl)phenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 236 was prepared according to the procedure used to prepare Example 232, substituting 3-(pyridin-2-yl)benzaldehyde for 2-pyridinecarboxaldehyde and a reaction time of 48 hours instead of 66 hours to provide the title compound (32 mg, 44 %). ¹ H NMR(500 MHz, DMSO- d ₆ ) δ 12.07 (d, J = 2.3 Hz, 1H), 8.61-8.56 (m, 1H), 7.85-7.79(m, 2H), 7.76-7.64 (m, 4H), 7.34 (d, J = 2.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.24(t, J = 7.7 Hz, 1H), 7.21-7.13 (m, 2H), 7.03 (dd, J = 8.2, 1.9 Hz, 1H), 6.94-6.81 (m, 3H), 6.57 (s, 1H), 4.42-4.25 (m, 2H), 3.67 (s, 3H), 2.64 (s, 3H). MS(ESI+) m/z 609 (M+H) ⁺ .

Example 237

3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile

Example 237 was prepared according to the procedure used to prepare Example 232, substituting 3-formylbenzonitrile for 2-pyridinecarboxaldehyde and a reaction time of 48 hours instead of 66 hours to provide the title compound (20 mg, 30 %). ¹ H NMR (500MHz, DMSO- d ₆ ) δ 12.13 (s, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.71 (s, 1H), 7.55(d, J = 7.6 Hz, 1H), 7.47-7.40 (m, 2H), 7.39-7.31 (m, 2H), 7.22-7.13 (m, 1H), 7.06 (dd, J = 8.2, 1.9 Hz, 1H), 6.93-6.80 (m, 3H), 6.53 (s, 1H), 4.46-4.27(m, 2H), 3.66 (s, 3H), 2.72 (s, 3H). MS (ESI+) m/z 557 (M+H) ⁺ .

Example 238

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 238a

1-(2,2-Dimethoxyethyl)pyridin-2(1H)-one

2-Hydroxypyridine (0.220 g, 2.313 mmol), cesium carbonate (1.507 g, 4.63 mmol) and acetonitrile (11.57 mL) were added to a 20 mL microwave tube to give a white suspension. Bromoacetaldehyde dimethyl acetal (1.362 mL, 11.57 mmol) was added. The tube was sealed and the reaction mixture was heated at 120 ° C in a Biotage Creator for a fixed retention time of 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The reaction mixture was purified by flash chromatography (0-5% methanol: dichloromethane) to give the title compound (0.210 g, 50% yield).

Example 238b

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 238b was prepared according to the procedure used to prepare Example 82, substituting Example 238a for methyl 4-oxobutanoate to provide the title compound (0.0884 g, 55 % yield) as a white solid. ¹ H NMR (500 MHz, DMSO- d ₆ )δ 11.88-11.93 (m, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.72-7.63 (m,1H), 7.43 (ddd, J = 8.9, 6.7, 2.1 Hz, 1H), 7.21 (dd, J = 8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H), 6.82-6.89 (m, 2H), 6.67 (d, J = 2.6 Hz, 1H), 6.46 (d, J =9.1 Hz, 1H), 6.00 (td, J = 6.6, 1.4 Hz, 1H), 5.50 (dd, J = 9.1, 5.6 Hz, 1H), 4.54-4.36 (m, 3H), 3.66 (s, 3H), 3.54-3.44 (m, 1H), 2.95 (s, 3H). MS (ESI+) m/z 563.0 (M+H) ⁺ .

Example 239

Ethyl 4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

Example 239a

4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

A suspension of Example 208g (450 mg, 0.672 mmol) in 6 mL of tetrahydrofuran was treated with 2N aqueous sodium hydroxide solution (2016 µL, 4.03 mmol) and heated at 70°C for 2 hours. Additional 2N sodium hydroxide (2016 µL, 4.03 mmol) and 3 mL of ethanol were added. The mixture was heated at 70°C for an additional 4 hours. The reaction mixture was concentrated, and the residue was taken up in water (10 mL) and adjusted to pH 2. The precipitate was collected by filtration to provide the title compound, which was used without further purification.

Example 239b

4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A solution of Example 239a (270 mg, 0.554 mmol) in 4 mL of dichloromethane was treated with 2 drops of dimethylformamide and oxalyl chloride (242 µL, 2.77 mmol) at 0°C. The mixture was stirred at ambient temperature for 3 hours and then concentrated. The residue was dissolved in 2 mL of tetrahydrofuran and treated with ethylamine (2769 µL, 5.54 mmol, 2.0 M in tetrahydrofuran) at 0°C. The mixture was then stirred overnight. Water was added, and the mixture was extracted with ethyl acetate (3x) and partitioned. The combined organic layers were washed with water (2x) and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0-8% methanol/dichloromethane gradient elution) to provide the title compound (86 mg, 0.167 mmol, 30% yield).

Example 239c

Ethyl 4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

To a suspension of Example 239b (77 mg, 0.150 mmol) and ethyl 2-oxoacetate (148 µL, 0.748 mmol, 50% in toluene) in tetrahydrofuran (2 mL) at ambient temperature was added titanium (IV) chloride (1048 µL, 1.048 mmol, 1.0 M in toluene). The mixture was stirred at ambient temperature under nitrogen for 40 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, 0-8% methanol/dichloromethane gradient) to give the title compound (46 mg, 0.077 mmol, 51% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.33 (s, 1H), 8.41-8.21 (m, 1H), 7.76 (d, J= 1.9 Hz, 1H), 7.74 (s, 1H), 7.64 (td, J = 9.4, 5.9 Hz, 1H), 7.20 (dd, J =8.3, 1.9 Hz, 1H), 7.17-7.04 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 4.49 (d, J = 13.7 Hz, 1H), 4.39 (d, J = 13.7 Hz, 1H), 3.94 (ddd, J = 14.3,9.0, 5.4 Hz, 1H), 3.85 (dq, J = 10.9, 7.1 Hz, 1H), 3.69 (s, 3H), 3.26 (td, J= 7.2, 3.7 Hz, 2H), 2.87 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H). MS (ESI+) m/z 599.0 (M+H) ⁺ .

Example 240

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide

Example 240a

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxylic acid methyl ester

Example 206d (20 mg, 0.037 mmol) in methanol (20 mL) was added to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.369 mg, 1.871 µmol) and triethylamine (10.43 µL, 0.075 mmol) in a 50 mL pressure bottle. The mixture was pressurized with carbon dioxide (60 psi) and stirred at 100°C for 32 hours. The solvent was removed. The reaction mixture was purified by flash chromatography (0-5% methanol:dichloromethane) to yield a white solid.

Example 240b

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxylic acid

To a 250 mL round-bottom flask was added Example 240a (0.108 g, 0.210 mmol), lithium hydroxide (0.050 g, 2.103 mmol), tetrahydrofuran (3.00 mL), methanol (1.00 mL), and water (1.00 mL) to give a colorless solution. The reaction mixture was stirred at ambient temperature for 120 hours. The reaction mixture was quenched with 1N HCl. The reaction mixture was filtered, and the solid was washed with water and dried in a vacuum oven at 60°C overnight to afford the title compound (0.0695 g, 66% yield) as a tan solid.

Example 240c

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonyl chloride

To a 25 mL round-bottom flask was added Example 204b (0.0695 g, 0.139 mmol) and dichloromethane (1.391 mL) to yield a tan suspension. Oxalyl chloride (0.018 mL, 0.209 mmol) and N,N-dimethylformamide (1.077 µL, 0.014 mmol) were added. The reaction mixture was stirred at ambient temperature for 45 minutes. The solvent was removed, dichloromethane and toluene were added, and the solvent was evaporated. This reaction was repeated three times to yield a tan solid.

Example 240d

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide

To a 25 mL round-bottom flask was added Example 240c (0.024 g, 0.046 mmol) and dichloromethane (0.463 mL) to give a tan solution. Ammonium hydroxide (0.027 mL, 0.695 mmol) was added, and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse phase HPLC (Phenomenex Luna C8(2) 5 μm 100Å AXIA column (30 mm × 75 mm) using a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/min (0-0.5 min 10 % A, 0.5-7.0 min linear gradient 10-95 % A, 7.0-10.0 min 95 % A, 10.0-12.0 min linear gradient 95-10 % A). Samples were injected in 1.5 mL of DMSO:methanol (1:1)) to give a white solid (0.0010 g, 4 % yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 7.91 (m, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.40 (m, 1H), 7.36 (s, 1H), 7.20 (m, 1H), 6.92 (m, 1H), 6.61 (t, J = 7.4 Hz, 1H), 6.30 (dd, J = 15.9, 9.4 Hz, 1H), 5.09(d, J = 16.7 Hz, 1H), 4.56 (m, 3H), 3.60 (s, 6H), 3.01 (s, 6H). MS (ESI+) m/z499.1 (M+H) ⁺ .

Example 241

4-(2,4-Difluorophenyl)-N,10-dimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide

Example 241 was prepared according to the procedure used to prepare Example 240d, substituting methylamine for ammonium hydroxide to provide the title compound (0.0091 g, 38 % yield) as a white solid. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.83 (m,1H), 7.96 (q, J = 4.6 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.73 (s, 1H), 7.31(d, J = 2.0 Hz, 1H), 7.18 (d, J = 2.6 Hz, 1H), 6.93 (m, 1H), 6.64 (td, J =8.6, 3.0 Hz, 1H), 6.38 (td, J = 9.6, 5.8 Hz, 1H), 5.01(m, 1H), 4.55 (m, 3H),3.61 (s, 3H), 2.99 (s, 3H), 2.62 (d, J = 4.6 Hz, 3H). MS (ESI+) m/z 513.1 (M+H) ⁺ .

Example 242

4-(2,4-Difluorophenyl)-N,N,10-trimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide

Example 242 was prepared according to the procedure used to prepare Example 240d, using N,N-dimethylamine instead of ammonium hydroxide to provide the title compound (0.0076 g, 31% yield) as a white solid. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ11.82 (s, 1H), 7.93 (d, J = 5.9 Hz, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.18 (t,J = 3.5 Hz, 1H), 7.21-7.11 (m, 2H), 7.11-6.92 (m, 1H), 6.72 (s, 1H), 6.58 (s,1H), 6.31 (s, 1H), 4.93 (dd, J = 16.1, 10.8 Hz, 1H), 4.66-4.42 (m, 2H), 4.34(d, J = 16.5 Hz, 1H), 3.63 (s, 4H), 2.98 (s, 3H), 2.88 (s, 3H), 2.72 (s, 2H), 2.22 (s, 2H). MS (ESI+) m/z 527.0 (M+H) ⁺ .

Example 243

N-(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)acetamide

A mixture of Example 212 (0.062 g, 0.079 mmol) in dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine (0.062 mL, 0.356 mmol) and acetyl chloride (0.0062 g, 0.079 mmol) at ambient temperature under argon. The reaction mixture was stirred at ambient temperature for 2 hours and then partitioned between aqueous ammonium chloride and ethyl acetate. The aqueous layer was extracted four times with additional ethyl acetate and then three times with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound (0.017 g, 0.035 mmol, 45% yield). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.48 (s, 1H), 7.70 (s, 1H), 7.52-7.46 (m, 1H), 7.40-7.15 (m, 3H), 7.12 (s, 1H), 4.45-4.38 (m, 2H), 4.22 (s, 2H), 3.68-3.54 (m, 3.5H), 3.44-3.35 (m, 0.5H), 3.17-3.09 (m, 0.5H), 2.90-2.88 (m, 3H), 2.83-2.79 (m, 0.5H), 1.81-1.44 (m, 5H), 1.30 (m, 4H), 1.06-0.86 (m, 2H). MS (ESI+) m/z 483.1(M+H) ⁺ .

Example 244

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 244a

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-3-ylamino)phenyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A suspension of Example 5d (200 mg, 0.412 mmol), 3-bromopyridine (65.1 mg, 0.412 mmol), cesium carbonate (335 mg, 1.030 mmol) and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-phos) (39.3 mg, 0.082 mmol) in toluene (4 mL) and tert-butanol (1 mL) was purged with nitrogen and then heated at 150 ° C in a Biotage Initiator microwave for 45 minutes. Water was added. The mixture was extracted with ethyl acetate (3X). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, 0-8% methanol/dichloromethane gradient) to give the title compound (74 mg, 0.132 mmol, 31.9% yield).

Example 244b

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-3-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 244a (55 mg, 0.098 mmol) and lithium hydroxide monohydrate (20.51 mg, 0.489 mmol) were stirred in dioxane (1.5 mL) and water (0.5 mL) at 60 ° C for 6 hours. The mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3X). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0-8% methanol/dichloromethane gradient) to give the title compound (33 mg, 0.081 mmol, 83% yield) as an off-white solid.

Example 244c

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A suspension of Example 244b (27 mg, 0.066 mmol) and paraformaldehyde (19.85 mg, 0.661 mmol) in acetic acid (1 mL) was stirred at 75°C for 1.5 hours. The acetic acid was evaporated under reduced pressure, and the residue was dissolved in dichloromethane and washed with 1N NaOH solution. The aqueous layer was back-extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, 0-8% methanol/dichloromethane gradient) to give the title compound (15 mg, 0.036 mmol, 54.0% yield) as a white solid. 1H NMR (500 MHz, DMSO- d ₆ ) δ 11.88 (s, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.73 (dd, J = 4.5, 1.1Hz, 1H), 7.63 (s, 1H), 7.47 (dd, J = 8.0, 1.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 6.97 (dd, J = 8.5, 4.5 Hz, 1H), 6.82-6.76 (m, 1H), 5.24 (d, J = 14.3 Hz,1H), 4.52 (dd, J = 60.4, 26.1 Hz, 3H), 3.55 (s, 3H), 3.01 (s, 3H). MS ESI (+)421.1 (M+H) ⁺ .

Example 245

4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 245a

4-(2-((5-chloropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 245a was prepared according to the procedure used to prepare Example 244a, substituting 2-bromo-5-chloropyridine for 3-bromopyridine to provide the title compound.

Example 245b

4-(2-((5-chloropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 245b was prepared according to the procedure used for Example 244b, substituting Example 245a for Example 244a to provide the title compound.

Example 245c

4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 245c was prepared according to the procedure used for Example 244c, substituting Example 245b for Example 244b to provide the title compound. 1H NMR (400 MHz, DMSO- d ₆ ) δ 16.38-16.29 (m, 1H), 11.86 (s, 1H), 7.95 (d, J = 25.9 Hz, 2H), 7.64 (s, 1H), 7.49-7.27 (m, 4H), 6.19 (d,J = 8.3 Hz, 1H), 5.69 (d, J = 15.8 Hz, 1H), 4.62 (d, J = 13.5 Hz, 1H), 4.51(d, J = 13.5 Hz, 1H), 4.29 (d, J = 15.6 Hz, 1H), 3.58 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 455.1.

Example 246

4-(1H-indazol-5-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

At ambient temperature, under argon, a mixture of Example 233d (0.058 g, 0.098 mmol) in dioxane (2 mL) was treated with an excess of 4N HCl/dioxane (7 mL). The reaction mixture was stirred at ambient temperature for 16 hours, and then the anti-mixture was quenched by slowly adding saturated sodium bicarbonate solution until pH = 8. The mixture was distributed between sodium bicarbonate aqueous solution and ethyl acetate. The water layer was extracted with additional ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC (C18, CH ₃ CN/water (0.1% TFA), 0-100% gradient) to give the title compound as trifluoroacetate (0.024 g, 0.042 mmol, 43% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.79 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.39 (dd, J = 40.3, 7.9 Hz, 3H), 7.18 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 9.1Hz, 1H), 6.62 (s, 1H), 4.72 (s, 2H), 4.57 (s, 2H), 3.53 (s, 3H), 3.50 (bs,1H), 3.01 (s, 3H). MS (ESI+) m/z 460.1 (M+H) ⁺ .

Example 247

4-Benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 5f (0.0515 g, 0.150 mmol) and benzaldehyde (0.0318 g, 0.300 mmol) in dichloromethane (6 mL) was treated with acetic acid (0.086 mL, 1.500 mmol). The reaction mixture was stirred at 60°C for 1 hour, then cooled to 0°C (ice bath) and treated with sodium triacetoxyborohydride (0.0669 g, 0.300 mmol). The reaction mixture was removed from the 0°C ice bath and stirred at ambient temperature for 16 hours. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution and then extracted twice with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by recrystallization from methanol and dimethyl sulfoxide to afford the title compound (0.0145 g, 0.033 mmol, 22% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.80 (s, 1H), 7.71 (d, J = 1.3 Hz, 1H), 7.56 (s, 1H), 7.27-7.16 (m, 7H), 6.99 (d, J = 2.2Hz, 1H), 4.43 (s, 2H), 4.25 (s, 2H), 4.05 (s, 2H), 3.65 (s, 3H), 2.93 (s, 3H). MS (ESI+) m/z 434.1 (M+H) ⁺ .

Example 248

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 248a

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-5-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Under argon, a mixture of Example 5d (0.300 g, 0.618 mmol), 5-iodopyrimidine (0.382 g, 1.853 mmol), cesium carbonate (0.403 g, 1.236 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (XPhos) (0.147 g, 0.309 mmol), and palladium(II) acetate (0.035 g, 0.154 mmol) in toluene (12 mL) and tert-butanol (3 mL) was heated in a sealed tube in a microplate reactor at 160°C for 1 hour. The reaction mixture was cooled to ambient temperature and filtered through filter paper. The filtrate was concentrated to near dryness and mixed with ethanol (10 mL), dioxane (20 mL), and excess 5N sodium hydroxide solution (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated to 5 mL and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 5% methanol/dichloromethane to provide the title compound (0.066 g, 0.161 mmol, 26% yield).

Example 248b

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 248a (0.040 g, 0.098 mmol) and paraformaldehyde (0.015 g, 0.488 mmol) in acetic acid (10 mL) was stirred at 75° C. under argon for 2 hours. The reaction mixture was concentrated to a semisolid and purified by reverse phase HPLC (C18, CH ₃ CN/water (0.1% TFA), 0-100% gradient) and dried under vacuum to give the title compound (0.0065 g, 0.015 mmol, 15% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.59 (s, 1H), 8.31 (s, 1H), 7.95 (s, 3H), 7.59 (s, 1H), 7.51-7.46 (m, 1H), 7.40-7.35 (m, 2H), 4.87 (s, 2H), 4.54 (s, 2H), 3.56 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z422.1 (M+H) ⁺ .

Example 249

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 5f (208 mg, 0.606 mmol), 2-pyridinecarboxaldehyde (0.116 mL, 1.211 mmol) and acetic acid (0.347 mL, 6.06 mmol) in dichloromethane (12 mL) was heated under reflux for 2 hours. The reaction mixture was cooled to ice/water bath temperature for 15 minutes, then sodium triacetoxyborohydride (297 mg, 1.333 mmol) was added to the reaction mixture under argon. The mixture was stirred at 0°C for 15 minutes, allowed to slowly warm to ambient temperature over 2 hours, and then stirred at ambient temperature for 16 hours. The pH of the mixture was adjusted to pH = 6-7 by adding saturated aqueous bicarbonate solution, and the mixture was then extracted with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated with methanol and dimethyl sulfoxide, and the resulting solid was collected and dried to give the title compound (108 mg, 41% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.80 (bs, 1H), 8.46 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.64 (td, J = 7.6, 1.8 Hz, 1H), 7.56 (s, 1H), 7.29-7.15 (m, 4H), 7.03 (d, J = 2.5 Hz, 1H), 4.45-4.39 (m, 4H), 4.13 (s, 2H), 3.65 (s, 3H), 2.92 (s, 3H). (ESI+) m/z 435.1 (M+H) ⁺ .

Example 250

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridazin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 250 was prepared according to the procedure used for Example 249, substituting pyridazine-3-carboxaldehyde for 2-pyridinecarboxaldehyde, to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.82 (bs, 1H), 9.08 (dd, J = 4.7,1.8 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.62-7.51 (m, 3H), 7.30-7.19 (m, 2H), 7.03 (d, J = 2.6 Hz, 1H), 4.56 (s, 2H), 4.43 (s, 2H), 4.15 (s, 2H), 3.65 (s, 3H), 2.92 (s, 3H). (ESI+) m/z 436.4 (M+H) ⁺ .

Example 251

(S)-4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 238 (0.0204 g) was subjected to preparative chiral SFC separation using a WHELK-O SS column (21 x 250 mm, 5-micron column, eluted with 30% methanol/critical _CO₂ at 70 mL/min for 20 minutes) to afford the title compound as the first eluting peak. The stereochemistry of this first eluting peak was randomly assigned (8.6 mg, 84% recovery). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.90 (bs, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.64-7.72 (m, 1H), 7.43 (ddd, J = 8.9, 6.7, 2.1 Hz, 1H), 7.21 (dd, J = 8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H), 6.82-6.89 (m, 2H), 6.67 (s, 1H), 6.46 (dd, J= 9.1, 1.3 Hz, 1H), 6.00 (td, J = 6.6, 1.4 Hz, 1H), 5.50 (dd, J = 9.1, 5.6Hz, 1H), 4.37-4.55 (m, 3H), 3.66 (s, 3H), 3.44-3.54 (m, 1H), 2.95 (s, 3H). MS(ESI+) m/z 563.1 (M+H) ⁺ .

Example 252

(R)-4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

The product of Example 238 (0.0204 g) was subjected to preparative chiral SFC separation using a WHELK-O SS column (21 x 250 mm, 5-micron column, eluted with 30% methanol/critical _CO₂ at 70 mL/min for 20 minutes) to afford the title compound as the second eluting peak. The stereochemistry of this second eluting peak was randomly assigned (7.9 mg, 77% recovery). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.90 (bs, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J = 6.3 Hz, 1H), 7.43 (ddd, J = 8.9, 6.7, 2.1 Hz, 1H), 7.21 (dd, J =8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H), 6.82-6.89 (m, 2H), 6.67 (s, 1H), 6.46(d, J = 9.1 Hz, 1H), 6.00 (td, J = 6.6, 1.3 Hz, 1H), 5.50 (dd, J = 9.1, 5.6Hz, 1H), 4.36-4.55 (m, 3H), 3.66 (s, 3H), 3.44-3.51 (m, 1H), 2.95 (s, 3H). MS(ESI+) m/z 563.1 (M+H) ⁺ .

Example 253

10-Methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 253a

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 207a (0.16 g, 0.33 mmol), 2-bromo-5-(trifluoromethyl)pyridine (0.112 g, 0.495 mmol), palladium acetate (0.019 g, 0.083 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.079 g, 0.165 mmol), and cesium carbonate (0.215 g, 0.66 mmol) were combined in a 20-mL microwave vial and purged with nitrogen for 30 minutes. Nitrogen-sparged anhydrous toluene (2.4 mL) and tert-butanol (0.6 mL) were added. The reaction mixture was heated at 105°C overnight, then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, treated with 3-mercaptopropyl-functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, filtered through a plug of celite, and concentrated. The residue was purified by flash chromatography (silica gel, 25-100% ethyl acetate/dichloromethane, then 5-15% methanol/dichloromethane) to afford 0.077 g (37%) of the title compound and 0.0245 g (16%) of Example 253b.

Example 253b

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 253a (0.077 g, 0.122 mmol) in tetrahydrofuran (1.5 mL) was treated with tetrabutylammonium fluoride (0.028 g, 0.107 mmol) and heated at 50°C for 50 minutes, then at 60°C for 1 hour. The mixture was stirred at ambient temperature overnight. Additional tetrabutylammonium fluoride (0.028 g, 0.107 mmol) was added, and heating at 60°C was continued for 3 hours. The reaction mixture was concentrated to dryness, triturated with ethyl acetate, and then dried in a vacuum oven at 70°C to afford 0.054 g (93%) of the title compound.

Example 253c

10-Methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stir bar was added Example 253b (0.025 g, 0.052 mmol), paraformaldehyde (0.006 g, 0.207 mmol), and acetic acid (1.2 mL). The vial was sealed and heated at 75°C for 45 minutes. Additional paraformaldehyde (0.006 g, 0.207 mmol) was added and heating at 75°C continued for 1 hour. The reaction mixture was then concentrated. The residue was dissolved in acetonitrile (3 mL) and water (0.75 mL), treated with sodium acetate (0.043 g, 0.518 mmol), and heated at 50°C for 1 hour. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate and water, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-8% methanol/dichloromethane) to afford 0.026 g (103%) of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.91 (s, 1 H), 8.33 (s, 1 H), 7.95 (s, 1 H), 7.67 (s, 1 H), 7.62 (d, J=7.63 Hz, 1 H), 7.44 (m, 2H), 7.34 (s, 1 H), 6.29 (s, 1 H), 5.83 (s, 1 H), 4.64 (m, 1 H), 4.53 (m, 1H), 4.35 (d, J=14.95 Hz, 1 H), 3.58 (s, 3 H), 3.02 (s, 3 H). MS (ESI+) m/z489.1 (M+H) ⁺ .

Example 254

4-(2-Fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 254a

A mixture of Example 207a (0.146 g, 0.3 mmol), 4-bromo-2-fluoropyridine (0.069 g, 0.390 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.072 g, 0.150 mmol), palladium(II) acetate (0.017 g, 0.075 mmol), and cesium carbonate (0.244 g, 0.750 mmol) in toluene (3 mL) and tert-butanol (0.750 mL) was heated at 160°C for 1 hour. The same procedure was repeated two more times, and the combined reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted several times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 100:10:1 ethyl acetate/methanol/ _NH4OH to provide 0.14 g (36%) of the title compound.

Example 254b

4-(2-Fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 254a (0.13 g, 0.305 mmol) and paraformaldehyde (0.027 g, 0.914 mmol) in acetic acid (6 mL) was heated at 75° C. for 4 hours. The solvent was evaporated and the residue was purified by reverse phase preparative HPLC (C18, CH ₃ CN/water (0.1% trifluoroacetic acid), 0-100% gradient) to give the title compound as a trifluoroacetate salt (0.085 g, 0.154 mmol, 50.5% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.94 (s, 1H), 7.96 (d, J =1.9 Hz, 1H), 7.65 (d, J = 17.7 Hz, 2H), 7.55-7.34 (m, 4H), 5.27 (d, J = 16.3Hz, 1H), 4.64 (d, J = 13.6 Hz, 1H), 4.60-4.46 (m, 2H), 3.57 (s, 3H), 3.01 (s,3H). MS (ESI+) m/z 438.9 [M + H] ⁺ .

Example 255

10-Methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 255 was prepared according to the procedure used to prepare Example 249, substituting 1-methyl-1H-pyrazole-3-carbaldehyde for 2-pyridinecarbaldehyde, and the residue was recrystallized from dichloromethane to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ11.75 (bs, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.54-7.48 (m, 2H), 7.29 (d, J = 8.2Hz, 1H), 7.23 (dd, J = 8.2, 2.0 Hz, 1H), 7.15-6.97 (m, 1H), 5.96 (d, J = 2.1Hz, 1H), 4.43 (bs, 2H), 4.23-4.04 (m, 4H), 3.75 (s, 2H), 3.63 (s, 3H), 2.92(s, 3H). (ESI+) m/z 438.1 (M+H) ⁺ .

Example 256

4-(6-Methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 256a

4-(2-((6-methoxypyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

In a 5-mL microwave vial, Example 207a (0.243 g, 0.5 mmol), 2-bromo-6-methoxypyridine (0.188 g, 1 mmol), palladium acetate (0.028 g, 0.125 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.12 g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were combined. Anhydrous toluene (4 mL) and tert-butanol (1 mL) were added. The vial was sealed and the mixture was heated at 160°C in a Biotage microwave reactor for 1 hour. The reaction mixture was filtered through a fritted funnel to remove the palladium solids. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, treated with 3-mercaptopropyl-functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, filtered through a plug of celite, and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/dichloromethane, then 5-10% methanol/ethyl acetate) to provide 0.15 g (51%) of the title compound and 0.08 g (37%) of Example 256b.

Example 256b

4-(2-((6-methoxypyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 256a (0.122 g, 0.206 mmol) and tetrabutylammonium fluoride (0.108 g, 0.412 mmol) in tetrahydrofuran (3.5 mL) was heated at 60°C for 50 minutes and then concentrated. The residue was purified by flash chromatography (silica gel, 0-20% methanol/dichloromethane) and triturated in dichloromethane to afford 0.077 g (71%) of the title compound. A portion of this material was then combined with a portion of the deprotected material obtained in Example 256a (0.133 g total) and purified by reverse-phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid), 5-70%) to afford 0.071 g (43% recovery) of the title compound as a trifluoroacetate salt.

Example 256c

4-(6-Methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 256b (0.043 g, 0.077 mmol) and paraformaldehyde (0.005 g, 0.155 mmol) was combined in a 5-mL microwave vial. The vial was sealed and the mixture was purged with nitrogen for 30 minutes. Acetic acid (3 mL) bubbled with nitrogen was added thereto. The resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was then quenched with methanol and concentrated to dryness (keeping the water bath temperature below 30°C). The residue was purified by reverse phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid), 5-75%) to give 0.019 g (43%) of the title compound as a trifluoroacetate salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ11.85 (d, J=1.83 Hz, 1 H), 7.93 (d, J=1.53 Hz, 1 H), 7.64 (s, 1 H), 7.44 (m,1 H), 7.39 (m, 1 H), 7.31 (d, , 4.52 (m, 1 H), 4.22 (d, J=15.26 Hz, 1 H), 3.74 (s, 3 H), 3.58 (s, 3 H), 2.99 (m, 3 H). MS (ESI+) m/z 451.1 (M+H) ⁺ .

Example 257

4-(2,2-Dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 257a

4-(2-((2,2-dimethyl-3-morpholinopropyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 5d (77 mg, 0.159 mmol) and 2,2-dimethyl-3-morpholinopropanal (0.056 mL, 0.317 mmol) was stirred in dichloromethane (5 mL). Acetic acid (0.045 mL, 0.793 mmol) was added to the mixture. The resulting partial suspension was heated under reflux for 1.5 hours. The reaction mixture was cooled in an ice/water bath for 15 minutes, and then sodium triacetoxyborohydride (106 mg, 0.476 mmol) was added to the mixture under argon. The mixture was stirred at 0°C for 15 minutes and then allowed to slowly warm to ambient temperature over 1 hour. The mixture was then stirred at ambient temperature for 16 hours. Saturated aqueous sodium bicarbonate solution was added, followed by saturated aqueous ammonium chloride solution and water. The mixture was extracted with dichloromethane and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound.

Example 257b

4-(2-((2,2-dimethyl-3-morpholinopropyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 257a (130 mg, 0.203 mmol) was dissolved in dioxane (8 mL) and ethanol (4 mL). To this mixture was added 5N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at ambient temperature for 4 hours. The mixture was concentrated to approximately 1/3 of its volume and then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was triturated with a mixture of ether and ethyl acetate, filtered, and dried to give the title compound.

Example 257c

4-(2,2-Dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 257b (38 mg, 0.077 mmol) and paraformaldehyde (12.5 mg, 0.411 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature. To the resulting suspension was added a 1M titanium tetrachloride solution (0.82 mL). The reaction mixture was stirred at ambient temperature for 24 hours and then added to a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2% methanol/dichloromethane) to provide the title compound (10.8 mg, 28% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.75 (bs, 1H), 7.63 (d, J = 2.1 Hz,1H), 7.51 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.24 (dd, J = 8.2, 2.0 Hz, 1H),7.10 (d, J = 2.5 Hz, 1H), 4.42 (s, 2H), 4.13 (s, 2H), 3.63 (s, 3H), 3.37 (m,4H), 2.91 (s, 3H), 2.13 (bs, 4H), 1.88 (bs, 2H), 0.63 (s, 6H). (ESI+) m/z 499.2 (M+H) ⁺ .

Example 258

4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 258a

4-(2-((5-fluoropyrimidin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

In a 5-mL microwave vial, Example 207a (0.243 g, 0.5 mmol), 2-bromo-5-fluoropyrimidine (0.177 g, 1 mmol), palladium acetate (0.028 g, 0.125 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.12 g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were combined and purged with nitrogen for 30 minutes. A nitrogen-sparged solution of anhydrous toluene (3.2 mL) and tert-butanol (0.8 mL) was added. The reaction mixture was heated at 110°C for 3 hours, cooled to ambient temperature, and filtered through a fritted funnel to remove the palladium solids. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, treated with 3-mercaptopropyl functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, filtered through a plug of celite and concentrated. The residue was triturated with methanol, filtered and dried in a vacuum oven at 70°C to give 0.215 g (74%) of the title compound.

Example 258b

4-(2-((5-fluoropyrimidin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 258a (0.215 g, 0.37 mmol) in tetrahydrofuran (15 mL) was treated with tetrabutylammonium fluoride (0.145 g, 0.554 mmol) and stirred at 60°C for 1 hour and 40 minutes. The reaction mixture was cooled to ambient temperature and concentrated. The concentrate was slurried in dichloromethane, and the solid was collected by filtration and dried in a vacuum oven at 70°C to afford 0.068 g (43%) of the title compound.

Example 258c

4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 258b (0.059 g, 0.137 mmol) and paraformaldehyde (0.016 g, 0.548 mmol) was combined in a 5-mL microwave vial. The vial was sealed and purged with nitrogen for 30 minutes. Nitrogen-bubbled acetic acid (5 mL) was added, and the mixture was heated at 75 ° C for 3 hours and 40 minutes. The reaction mixture was concentrated to dryness, slurried in water and treated with sodium acetate until basic. The resulting mixture was heated at 50 ° C for 2 hours and then cooled to ambient temperature. The solid was collected by filtration, washed with 300 mL of water, and dried in a vacuum oven at 70 ° C overnight. The solid was then slurried in ethyl acetate, stirred for 1 hour and filtered. To this solid (0.04 g, 0.091 mmol) / methanol (0.25 mL) was added hydrochloric acid solution (4 M in 1,4-dioxane) (0.3 mL, 1 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes. The solid was collected by filtration and dried in a vacuum oven at 70 °C to afford 0.0354 g (54%) of the title compound as the HCl salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87 (d, J=2.14 Hz, 1 H), 8.31 (s, 2 H), 7.83 (d, J=1.53 Hz, 1H), 7.60 (s, 1 H), 7.37 (m, 2 H), 7.30 (d, J=2.44 Hz, 1 H), 5.70 (d, J=15.56Hz, 1 H), 4.60 (m, 1 H), 4.49 (m, 1 H), 4.34 (d, J=15.56 Hz, 1 H), 3.58 (s, 3H), 3.01 (s, 3 H). MS (ESI+) m/z 440.1 (M+H) ⁺ .

Example 259

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 259a

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-4-ylamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

In a 5-mL microwave vial, Example 207a (0.243 g, 0.5 mmol), 4-bromopyrimidine (0.159 g, 1 mmol), palladium acetate (0.028 g, 0.125 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.12 g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were combined and purged with nitrogen for 30 minutes. A nitrogen-sparged solution of anhydrous toluene (3.2 mL) and tert-butanol (0.8 mL) was added. The reaction mixture was heated at 110°C for 16.5 hours, cooled to ambient temperature, and filtered through a fritted funnel to remove the palladium solids. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, treated with 3-mercaptopropyl-functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, filtered through a plug of celite, and concentrated. The residue was purified by flash chromatography (silica gel, 20-100% ethyl acetate/(ethanol/heptane) in a 3:1 ratio) to yield an impure mixture. This material was purified by a second flash chromatography (silica gel, 45-50% ethyl acetate/(ethanol/heptane) in a 3:1 ratio) to yield 0.042 g (15%) of the title compound.

Example 259b

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-4-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 259a (0.042 g, 0.075 mmol) in tetrahydrofuran (2 mL) was treated with tetrabutylammonium fluoride (0.02 g, 0.075 mmol) and heated at 60 ° C for 45 minutes. Additional tetrabutylammonium fluoride (0.02 g, 0.075 mmol) was added and heating continued for another 1.25 hours. The reaction mixture was cooled to ambient temperature, concentrated and slurried in ethyl acetate. The solid was collected by filtration and then purified by reverse phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid), 5-70%) to give 0.039 g (99%) of the title compound.

Example 259c

10-Methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stir bar was added Example 259b (0.039 g, 0.075 mmol), paraformaldehyde (0.011 g, 0.375 mmol), and acetic acid (1.3 mL). The vial was sealed and heated at 75°C for 40 minutes. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (3 mL) and water (0.75 mL) and treated with sodium acetate until basic. The resulting mixture was heated at 50°C for 1 hour and then cooled to ambient temperature. The reaction mixture was partitioned between ethyl acetate and water. Washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid), 10-60%) to give 0.004 g (9%) of the title compound as a trifluoroacetate salt. ¹ HNMR (500 MHz, DMSO- d ₆ ) δ 11.87 (d, J=0.61 Hz, 1 H), 8.24 (m, 2 H), 7.82 (s, 1H), 7.60 (s, 1 H), 7.35 (m, 3 H), 6.60 (t, J=4.73 Hz, 1 H), 5.79 (d, J=15.56Hz, 1 H), 4.60 (m, 1 H), 4.49 (d, J=13.43 Hz, 1 H), 4.30 (d, J=15.26 Hz, 1H), 3.58 (s, 3 H), 3.01 (s, 3 H). MS (ESI+) m/z 422.1 (M+H) ⁺ .

Example 260

4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 260a

4-(2-((2-(3-(dimethylamino)propoxy)benzyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 5d (106 mg, 0.218 mmol) and 2-(3-(dimethylamino)propoxy)benzaldehyde (0.067 mL, 0.314 mmol) was stirred in dichloroethane (5 mL). To this mixture was added acetic acid (0.062 mL, 1.091 mmol). The resulting partial suspension was heated at reflux for 1.5 hours. The reaction mixture was cooled in an ice/water bath for 15 minutes, then sodium triacetoxyborohydride (146 mg, 0.655 mmol) was added to the mixture under argon. The mixture was stirred at 0°C for 15 minutes, then allowed to slowly warm to ambient temperature over 1 hour. The mixture was then stirred at ambient temperature for 16 hours. Saturated aqueous sodium bicarbonate solution was added, followed by saturated aqueous sodium carbonate solution and water. The mixture was extracted with dichloromethane and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 4-10% methanol/dichloromethane) to provide the title compound.

Example 260b

4-(2-((2-(3-(dimethylamino)propoxy)benzyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 260a (101 mg, 0.149 mmol) was dissolved in dioxane (5 mL). 5N aqueous sodium hydroxide solution (5 mL) was added to the mixture, and the mixture was stirred at 80°C for 4 hours. The mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 10% methanol/dichloromethane) to provide the title compound.

Example 260c

4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 260b (43 mg, 0.082 mmol) and paraformaldehyde (10 mg, 0.329 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature. A 1M titanium tetrachloride solution (0.66 mL) was added to the resulting suspension. The reaction mixture was stirred at ambient temperature for 24 hours and then added to a mixture of saturated sodium bicarbonate aqueous solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% trifluoroacetic acid), 0-100% gradient) to give the title compound as the trifluoroacetate salt (16.5 mg, 38%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 9.41 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.25-7.15 (m, 3H), 7.11 (d, J = 7.3Hz, 1H), 7.06 (d, J = 2.7 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.83 (t, J = 7.4Hz, 1H), 4.44 (s, 2H), 4.25 (s, 2H), 4.12 (s, 2H), 4.00 (t, J = 5.9 Hz, 2H),3.57 (s, 3H), 3.16 (dt, J = 9.7, 5.3 Hz, 2H), 2.94 (s, 3H), 2.77 (d, J = 4.5Hz, 6H), 2.05 (dq, J = 11.6, 5.9 Hz, 2H). (ESI+) m/z 535.1 (M+H) ⁺ .

Example 261

2-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)-2-phenylacetonitrile

A mixture of Example 5f (57.7 mg, 0.168 mmol), benzaldehyde (19.6 mg, 0.185 mmol), and sodium cyanide (9.3 mg, 0.185 mmol) in methanol (8 mL) was heated at 60°C for 30 minutes. Acetic acid (0.481 mL, 8.40 mmol) was added, and a portion of the suspension was heated at 60°C for 18 hours. Water (10 mL) was added to the cooled reaction mixture, and the resulting precipitate was collected by filtration. The precipitate was purified by reverse-phase HPLC (C18, _CH3CN /water (0.1% trifluoroacetic acid), 0-100% gradient) to afford the title compound (20 mg, 26%). ¹ H NMR (400 MHz, 90℃, DMSO- d ₆ ) δ 11.53 (s,1H), 7.76 (d, J = 2.0 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J = 12.7 Hz, 7H), 6.93(d, J = 2.7 Hz, 1H), 5.64 (s, 1H), 4.43 (d, J = 1.6 Hz, 2H), 4.19 (s, 2H), 3.64 (s, 3H), 2.88 (s, 3H). (ESI+) m/z 459.1 (M+H) ⁺ .

Example 262

2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)methyl)phenoxy)acetamide

Example 262a

2-(2-(((2-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methylsulfonyl)methyl)phenyl)amino)methyl)phenoxy)acetamide

A mixture of Example 5d (260 mg, 0.536 mmol) and 2-(2-formylphenoxy)acetamide (80 mg, 0.446 mmol) was stirred in dichloroethane (7 mL). To this mixture was added acetic acid (0.128 mL, 2.232 mmol). The resulting partial suspension was heated at 80°C for 2.5 hours. The reaction mixture was cooled in an ice/water bath for 15 minutes, then sodium triacetoxyborohydride (299 mg, 1.34 mmol) was added to the mixture under argon. The mixture was stirred at 0°C for 15 minutes, then allowed to slowly warm to ambient temperature over 1 hour. The mixture was then stirred at ambient temperature for 16 hours. Saturated aqueous sodium bicarbonate solution was added, followed by water. The mixture was extracted with dichloromethane and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-3% methanol/dichloromethane) to provide the title compound.

Example 262b

2-(2-(((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methylsulfonyl)methyl)phenyl)amino)methyl)phenoxy)acetamide

Example 262a (170 mg, 0.262 mmol) was dissolved in dioxane (10 mL). 5N aqueous sodium hydroxide solution (3 mL) was added to the mixture, and the mixture was stirred at 80°C for 6 hours. The mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the title compound.

Example 262c

2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-yl)methyl)phenoxy)acetamide

A mixture of Example 262b (49 mg, 0.099 mmol) and paraformaldehyde (12 mg, 0.396 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature. A 1M titanium tetrachloride solution (0.79 mL) was added to the resulting suspension. The reaction mixture was stirred at ambient temperature for 16 hours and then added to a mixture of saturated sodium bicarbonate aqueous solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% trifluoroacetic acid), 0-70% gradient) to give the title compound (3.4 mg, 7%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.51 (s, 1H), 7.73 (s, 1H), 7.52 (s, 1H), 7.21 (s, 2H), 7.16 (t, J = 7.9 Hz, 1H), 7.12-6.96 (m, 4H), 6.89(d, J = 8.3 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 4.41 (d, J = 5.6 Hz, 4H), 4.28(s, 2H), 4.17 (s, 2H), 3.65 (s, 3H), 2.89 (s, 3H). (ESI+) m/z 507.2 (M+H) ⁺ .

Example 263

4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic acid

Example 263 was prepared as described in Example 209a. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.21 (s,1 H), 12.44 (s, 1 H), 7.83 (d, J=1.22 Hz, 1 H), 7.71 (s, 1 H), 7.28 (dd, J=8.24, 1.53 Hz, 1 H), 7.10 (m, 1 H), 7.01 (d, J=7.93 Hz, 1 H), 6.88 (td, J=8.54, 2.44 Hz, 1 H), 6.82 (td, J=9.23, 5.95 Hz, 1 H), 5.09 (s, 2 H), 4.49 (s, 2 H), 3.63 (s, 3 H), 2.96 (s, 3 H). MS (ESI+) m/z 500.1 (M+H) ⁺ .

Example 264

10-Methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 264a

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-((2-(pyridin-2-ylmethoxy)benzyl)amino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 5d (72.4 mg, 0.149 mmol) and 2-(pyridin-2-ylmethoxy)benzaldehyde (0.027 mL, 0.124 mmol) was stirred in dichloroethane (5 mL). To this mixture was added acetic acid (0.036 mL, 0.621 mmol). The resulting partial suspension was heated at 80°C for 2.5 hours. The reaction mixture was cooled in an ice/water bath for 15 minutes, then sodium triacetoxyborohydride (83 mg, 0.373 mmol) was added to the mixture under argon. The mixture was stirred at 0°C for 15 minutes, then allowed to slowly warm to ambient temperature over 1 hour. The mixture was then stirred at ambient temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added, followed by water. The mixture was extracted with dichloromethane and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-2% methanol/dichloromethane) to provide the title compound.

Example 264b

6-Methyl-4-(5-((methylsulfonyl)methyl)-2-((2-(pyridin-2-ylmethoxy)benzyl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 264a (90 mg, 0.132 mmol) was dissolved in dioxane (8 mL). 5N aqueous sodium hydroxide solution (2 mL) was added to the mixture, and the mixture was stirred at 85°C for 4 hours. The mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the title compound.

Example 264c

10-Methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 264b (44 mg, 0.083 mmol) and paraformaldehyde (10 mg, 0.333 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature. A 1M titanium tetrachloride solution (0.67 mL) was added to the resulting suspension. The reaction mixture was stirred at ambient temperature for 7 hours and then added to a mixture of saturated sodium bicarbonate aqueous solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, _CH3CN /water (0.1% trifluoroacetic acid), 0-100% gradient) to give the title compound (19.7 mg, 44%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.97 (d, J = 2.9 Hz, 1H), 8.63 (dd, J = 5.0, 1.6 Hz, 1H), 7.88 (td, J = 7.7, 1.7 Hz, 1H), 7.77 (d, J =2.0 Hz, 1H), 7.59 (s, 1H), 7.50-7.37 (m, 2H), 7.28-7.12 (m, 5H), 7.01 (d, J =8.2 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 5.20 (s, 2H), 4.46 (s, 2H), 4.34 (s,2H), 4.31 (s, 2H), 3.62 (s, 3H), 2.94 (s, 3H). (ESI+) m/z 541.1 (M+H) ⁺ .

Example 265

(R)-7-(Ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 265a

(R)-2-Bromo-4-(ethylsulfonyl)-N-(1-phenylethyl)aniline

A mixture of Example 2b (661 mg, 2.476 mmol), (R)-1-phenylethylamine (526 mg, 4.340 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.12 mL, 6.420 mmol) in dimethyl sulfoxide (12 mL) was heated at 100°C for 16 hours. The mixture was cooled to ambient temperature and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2% ethanol and 6% ethyl acetate/heptane) to provide the title compound.

Example 265b

(R)-4-(5-(ethylsulfonyl)-2-((1-phenylethyl)amino)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 265a (320 mg, 0.869 mmol), Example 1f (558 mg, 1.30 mmol), cesium fluoride (528 mg, 3.480 mmol), and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) was purged with argon for 15 minutes, followed by the addition of a mixture of degassed dimethoxyethane (20 mL) and methanol (10 mL). The reaction mixture was heated at 85°C for 2.5 hours. The mixture was cooled to ambient temperature and partitioned between saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound.

Example 265c

(R)-4-(5-(ethylsulfonyl)-2-((1-phenylethyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 265b (170 mg, 0.262 mmol) was dissolved in dioxane (20 mL). 5N aqueous sodium hydroxide solution (5 mL) was added to the mixture, and the mixture was stirred at 85°C for 4 hours. The mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-2% methanol/dichloromethane) to provide the title compound.

Example 265d

(R)-7-(Ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

A mixture of Example 265c (140 mg, 0.321 mmol) and paraformaldehyde (39 mg, 1.286 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature. 1M titanium tetrachloride solution (2.57 mL) was added to the resulting suspension. The reaction mixture was stirred at ambient temperature for 4 hours and then added to a mixture of saturated sodium bicarbonate aqueous solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by recrystallization from methanol and dimethyl sulfoxide to give the title compound (109 mg, 76%). ¹ H NMR (400MHz, 90℃, DMSO- d ₆ ) δ 11.50 (s, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.64 (s, 1H), 7.60 (dd, J = 8.3, 2.2 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.29-7.12 (m, 5H), 6.91 (s, 1H), 4.38 (q, J = 6.7 Hz, 1H), 4.23-4.01 (m, 2H), 3.67 (s, 3H), 3.28(q, J = 7.4 Hz, 2H), 1.22 (d, J = 6.6 Hz, 3H), 1.16 (t, J = 7.3 Hz, 3H). (ESI+) m/z 448.0 (M+H) ⁺ .

Example 266

10-Methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

Example 266a

3-Bromo-2-chloro-5-(pyrrolidin-1-ylsulfonyl)pyridine

5-Bromo-6-chloropyridine-3-sulfonyl chloride (4.7 g, 16.2 mmol) in dichloromethane (60 mL) was treated dropwise with pyrrolidine (2.7 mL, 32.3 mmol) at 0°C and stirred at 0°C for 20 minutes. The ice bath was removed and stirring continued at ambient temperature for 45 minutes. The reaction mixture was concentrated, slurried in water, and filtered. The solid was then slurried in diethyl ether and filtered to yield 4.66 g (88%) of the title compound.

Example 266b

To a mixture of Example 266a (1 g, 3.1 mmol) and pyridine-2-amine (0.36 g, 3.8 mmol) in dimethyl sulfoxide (10 mL) was added sodium hydride (0.25 g, 6.2 mmol). The mixture was stirred at ambient temperature for 1.5 hours and then at 50°C for 1 hour. The reaction mixture was cooled to ambient temperature and water was added to induce precipitation. The solid was collected by filtration, washed with additional water, and air-dried. The solid was then slurried in diethyl ether, stirred for 1 hour, and filtered. The diethyl ether filtrate was concentrated. The solid and the residue obtained by concentration were each purified by flash chromatography (silica gel, 5-60% ethyl acetate/heptane) and then combined to give 0.785 g (67%) of the title compound.

Example 266c

6-Methyl-4-(2-(pyridin-2-ylamino)-5-(pyrrolidin-1-ylsulfonyl)pyridin-3-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Combine Example 266b (0.066 g, 0.173 mmol), Example 1f (0.064 g, 0.15 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.004 g, 4.5 µmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.004 g, 0.015 mmol), and sodium carbonate (0.068 g, 0.645 mmol) and purge with nitrogen for 30 minutes. Nitrogen-bubbled 1,4-dioxane (0.8 mL) and water (0.2 mL) were added. The reaction mixture was stirred at 60°C for 4 hours and then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, treated with 3-mercaptopropyl-functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, filtered through a plug of celite, and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to provide 0.049 g (54%) of the title compound.

Example 266d

6-Methyl-4-(2-(pyridin-2-ylamino)-5-(pyrrolidin-1-ylsulfonyl)pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 266c (0.047 g, 0.078 mmol) in 1,4-dioxane (0.75 mL) and ethanol (0.25 mL) was treated with sodium hydroxide solution (4 M aqueous solution, 0.1 mL, 0.4 mmol) and heated at 60°C for 30 minutes. The reaction mixture was cooled to ambient temperature and neutralized with hydrochloric acid solution (2 M aqueous solution). The resulting mixture was partitioned between ethyl acetate and water, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid), 20-90%) to give 0.04 g (92%) of the title compound as a trifluoroacetate salt.

Example 266e

10-Methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stir bar was added Example 266d (0.031 g, 0.055 mmol), paraformaldehyde (0.008 g, 0.275 mmol) and acetic acid (1 mL). The vial was sealed and heated at 70°C for 45 minutes. Additional paraformaldehyde (0.008 g, 0.275 mmol) was added and heating was continued at 80°C for 90 minutes. Additional paraformaldehyde (0.016 g, 0.55 mmol) was added again and heating was continued at 80°C overnight. The reaction mixture was concentrated and then dissolved in acetonitrile (3 mL). Saturated sodium bicarbonate solution was added to reach pH = 10. Water (0.5 mL) was added to obtain a homogeneous solution. The mixture was heated at 50°C overnight. The reaction mixture was cooled to ambient temperature, diluted with water (5 mL) and neutralized with hydrochloric acid solution (2 M). The layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated. The residue was purified by reverse phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid), 15-90%) to give 0.007 g (21%) of the title compound as a trifluoroacetic acid salt. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.97 (d, J=1.83 Hz, 1 H), 8.75 (d, J=2.14 Hz, 1 H), 8.62 (d, J=2.14 Hz, 1 H), 8.09 (dd, J=5.04, 1.07 Hz, 1 H), 7.92 (s, 1 H), 7.46 (m, 1 H), 7.34 (d, J=2.75 Hz, 1 H), 6.73 (dd, J=6.71, 5.49 Hz, 1 H), 6.57 (d, J=8.54 Hz, 1 H), 5.15 (s, 2 H), 3.64 (s, 3 H), 3.31 (m, 4 H), 1.74(m, 4H). LCMS m/z 463.21.

Example 267

(S)-7-(Ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 267 was prepared according to the procedure used to prepare Example 265, substituting (S)-1-phenylethylamine for (R)-1-phenylethylamine to provide the title compound. ¹ H NMR (400 MHz, 90℃, DMSO- d ₆ ) δ 11.52 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.65 (s, 1H), 7.60 (dd, J = 8.4, 2.2 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.29-7.12 (m, 5H), 6.91 (d, J = 2.6 Hz, 1H), 4.38 (q, J = 6.6Hz, 1H), 4.22-4.01 (m, 2H), 3.67 (s, 3H), 3.29 (q, J = 7.4 Hz, 2H), 3.19 (s,2H), 1.22 (d, J = 6.6 Hz, 3H), 1.16 (t, J = 7.3 Hz, 3H). (ESI+) m/z 448.0 (M+H) ⁺ .

Example 268

(R)-methyl 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

The product of Example 82 was purified by chiral chromatography using a Chiralpak OJ-H column (21 x 250 mm, 5 microns) eluting with a 7:13 mixture of methanol/carbon dioxide. The first enantiomer fractions were collected and concentrated. The isolated compound was arbitrarily designated as the (R) enantiomer. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.91 (s,1H), 7.85 (d, J = 1.5 Hz, 1H), 7.70 (s, 1H), 7.24 (dd, J = 8.2, 1.7 Hz, 1H), 7.13 (s, 1H), 7.11-7.06 (m, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.97-6.85 (m, 2H), 5.04 (t, J = 7.6 Hz, 1H), 4.57-4.42 (m, 2H), 3.64 (s, 3H), 3.55 (s, 3H), 2.93(s, 3H), 2.46-2.36 (m, 2H), 1.96-1.85 (m, 1H), 1.59-1.48 (m, 1H). (ESI+) m/z542 (M+H) ⁺ .

Example 269

(S)-methyl 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

The product of Example 82 was purified by chiral chromatography using a Chiralpak OJ-H column (21 x 250 mm, 5 microns) eluting with a 7:13 mixture of methanol/carbon dioxide. The second eluting enantiomer fractions were collected and concentrated. The isolated compound was arbitrarily designated as the (S) enantiomer. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.89 (s,1H), 7.85 (d, J = 1.6 Hz, 1H), 7.69 (s, 1H), 7.24 (dd, J = 8.2, 1.7 Hz, 1H), 7.12 (s, 1H), 7.11-7.04 (m, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.96-6.84 (m, 2H), 5.03 (t, J = 7.6 Hz, 1H), 4.57-4.40 (m, 2H), 3.64 (s, 3H), 3.55 (s, 3H), 2.93(s, 3H), 2.46-2.37 (m, 2H), 1.97-1.84 (m, 1H), 1.60-1.47 (m, 1H). (ESI+) m/z542 (M+H) ⁺ .

Example 270

4-(2,4-Difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 270a

4-Bromo-2-iodo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

To a solution of n-butyllithium (2.5 M, 36 mL, 90 mmol in tetrahydrofuran) in anhydrous tetrahydrofuran (200 mL) at -70°C, diisopropylamine (7.33 g, 72.4 mmol) was added dropwise, and the reaction mixture was stirred at -70°C to -50°C for 45 minutes. To a solution of Example 1c (23.0 g, 60.3 mmol) in anhydrous tetrahydrofuran (400 mL) at -70°C, the above lithium diisopropylamide solution was added dropwise and stirred for 1.5 hours. A solution of iodine (35.2 g, 139 mmol) in anhydrous tetrahydrofuran (300 mL) was then added dropwise to the mixture at -70°C. The reaction mixture was stirred at -70°C for an additional 3 _hours and poured into an _{aqueous Na₂S₂O₃} solution. The suspension was filtered and the filter cake was washed with dichloromethane and then dried to give the title compound (20 g, 39.4 mmol, 65.4% yield) as a white solid.

Example 270b

4-Bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To the reaction mixture of Example 270a (15 g, 29.6 mmol) and sodium iodide (7.09 g, 47.3 mmol) in acetonitrile (300 mL) was added chlorotrimethylsilane (5.88 mL, 46.0 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Water (0.266 mL, 14.79 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at 65 ° C for 4 hours. After cooling to room temperature, the reaction mixture was filtered to obtain the crude product, which was then dissolved in dichloromethane. The solid was filtered off and the filtrate was concentrated under reduced pressure to obtain the title compound (11 g, 22.31 mmol, 75% yield) as a white solid.

Example 270c

4-Bromo-2-iodo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of Example 270b in dimethylformamide (51.7 mL) was added sodium hydride (0.538 g, 13.45 mmol) portionwise at 0°C, and the mixture was stirred for 30 minutes, followed by dropwise addition of iodomethane (0.839 mL, 13.45 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride. The resulting suspension was filtered, and the filter cake was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with ethyl acetate and then dried to give the title compound (5 g, 9.86 mmol, 95% yield).

Example 270d

4-Bromo-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 270c (0.431 g, 0.85 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.177 g, 0.850 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.021 mmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.025 g, 0.085 mmol), and sodium carbonate (0.135 g, 1.275 mmol) in dioxane (5 mL) and water (1.25 mL) was stirred at 50° C. for 3 hours. The mixture was concentrated to dryness and extracted with ethyl acetate (20 mL). The filtrate was concentrated and the residue was purified by silica gel flash chromatography (petroleum ether/ethyl acetate 1:1 to 0:1) to give the title compound (0.353 g, 0.697 mmol, 82% yield).

Example 270e

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 270d (0.5 g, 1.084 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (0.330 g, 1.301 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.079 g, 0.108 mmol), and potassium acetate (0.160 g, 1.626 mmol) in 1,4-dioxane (5 mL) was stirred at 100°C for 16 hours. The mixture was filtered and concentrated. The residue was purified by silica gel flash chromatography (petroleum ether/ethyl acetate 1:1 to 0:1) to provide the title compound (0.3 g, 0.395 mmol, 36.5% yield).

Example 270f

2-Bromo-N-(2,4-difluorophenyl)-4-(methylsulfonyl)aniline

A mixture of 2-bromo-4-(methylsulfonyl)aniline (0.8 g, 3.20 mmol), 2,4-difluoro-1-iodobenzene (0.768 g, 3.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.146 g, 0.160 mmol), X-phos (2.78 g, 4.80 mmol), and cesium carbonate (0.104 g, 0.320 mmol) in 1,4-dioxane (10 mL) was stirred at 100°C for 16 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was washed with petroleum ether/ethyl acetate (1:1) to give the title compound (0.9 g, 2.485 mmol, 78% yield).

Example 270g

4-(2-((2,4-difluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 270e (150 mg, 0.295 mmol), Example 270f (107 mg, 0.295 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.75 mg, 7.38 µmol), dipotassium hydrogen phosphate (77 mg, 0.443 mmol), and 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (8.62 mg, 0.030 mmol) in 1,4-dioxane (12 mL) and water (3.00 mL) was stirred at 60°C for 3 hours. The mixture was concentrated to dryness and extracted with ethyl acetate (20 mL). The filtrate was concentrated, and the residue was purified by flash chromatography (silica gel, petroleum ether/ethyl acetate 1:1 to 0:1) to provide the title compound (150 mg, 0.158 mmol, 53.6% yield).

Example 270h

4-(2-((2,4-difluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of Example 270g (50 mg, 0.075 mmol) in 1,4-dioxane (10 mL) was added sodium hydroxide (50 mg, 1.250 mmol) and water (2 mL). The mixture was stirred at 80°C for 5 hours. The mixture was adjusted to pH 5 with 1N HCl and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (50 mg, 0.041 mmol, 54.7% yield) as a yellow solid, which was used in the next step without further purification.

Example 270i

4-(2,4-Difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a solution of Example 270h (100 mg, 0.196 mmol) in tetrahydrofuran (5 mL) was added paraformaldehyde (5.89 mg, 0.196 mmol) and _TiCl₄ (0.022 mL, 0.196 mmol) at 0°C, and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with water (10 mL) and ethyl acetate (10 mL), then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by reverse-phase preparative HPLC (C₁₈, _CH₃CN /water (0.1% trifluoroacetic acid), 0-100% gradient) to afford the title compound (25 mg, 0.047 mmol, 23.94% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.91 (d, J = 14.6 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.35-6.91 (m, 4H), 4.85 (s, 2H), 3.90 (s, 3H), 3.68 (s, 3H), 3.31 (s, 3H). MS (ESI+) m/z 522.0 [M + H] ⁺ .

Example 271

4-(4-Chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 271a

2-Bromo-N-(4-chlorophenyl)-4-(methylsulfonyl)aniline

A mixture of 2-bromo-4-(methylsulfonyl)aniline (0.8 g, 3.20 mmol), 1-chloro-4-iodobenzene (0.763 g, 3.20 mmol), tris(dibenzylideneacetone)dipalladium (0.293 g, 0.320 mmol), cesium carbonate (0.052 g, 0.160 mmol), and Xantphos (2.78 g, 4.80 mmol) was stirred at 90°C under nitrogen for 16 hours. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated. The residue was washed with petroleum ether/ethyl acetate (3:1) to obtain the title compound (0.8 g, 1.996 mmol, 62.4% yield).

Example 271b

4-(2-((4-chlorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 270e (150 mg, 0.295 mmol), Example 271a (106 mg, 0.295 mmol), tris(dibenzylideneacetone)dipalladium (6.75 mg, 7.38 µmol), dipotassium hydrogen phosphate (77 mg, 0.443 mmol), and 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (8.62 mg, 0.030 mmol) in dioxane (12 mL) and water (3 mL) was stirred at 50°C for 3 hours. The mixture was concentrated and extracted with ethyl acetate (20 mL). The filtrate was concentrated, and the solid was washed with petroleum ether/ethyl acetate (1:1) to give the title compound (0.15 g, 0.161 mmol, 54.5% yield).

Example 271c

4-(2-((4-chlorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of Example 271b (150 mg, 0.227 mmol) in 1,4-dioxane (10 mL) was added sodium hydroxide (80 mg, 2.000 mmol) and water (2 mL). The reaction mixture was stirred at 60°C for 3 hours. The mixture was cooled to ambient temperature, and the pH was adjusted to pH 5 by adding 1N HCl. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (80 mg, 0.079 mmol, 34.8% yield).

Example 271d

4-(4-Chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stir bar was added Example 271c (70 mg, 0.134 mmol), paraformaldehyde (12.08 mg, 0.402 mmol) and acetic acid (2 mL). The vial was sealed and heated at 75 ° C for 1 hour. The mixture was concentrated in vacuo. The residue was suspended in methanol (10 mL) and acetic acid (1 mL) and heated at 85 ° C for 20 minutes, then allowed to cool to ambient temperature. The resulting solid was collected by filtration and washed with methanol to give the title compound as an off-white solid. ¹ H NMR(300 MHz, DMSO- d ₆ ) δ 12.12 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H),7.97-7.82 (m, 2H), 7.58 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.18 (d, J = 8.6 Hz, 2H), 5.12 (s, 1H), 4.61 (s, 1H), 3.94 (s, 3H), 3.60 (s, 3H), 3.34-3.09 (m, 3H). MS (ESI+) m/z 518.0 [M + H] ⁺ .

Example 272

(R)-N-Ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 272a

4-Bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

Example 208e (7.25 g, 24.2 mmol) was heated in tetrahydrofuran/ethanol (1:2, 210 mL) at 75°C to dissolve the solid. The mixture was then cooled to 35°C. To this solution was added 1M aqueous lithium hydroxide solution (97 mL). The mixture was heated at 75°C for 2 hours and then cooled to ambient temperature. The reaction mixture was then mixed with 1N HCl (100 mL) and water (300 mL) and stirred at ambient temperature overnight. The resulting precipitate was collected by filtration, washed with water, and dried to afford the title compound (6.41 gm, 98%).

Example 272b

4-Bromo-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of embodiment 272a (5.4 g, 19.9 mmol) in dimethyl sulfoxide (100 mL) was treated with 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (8.33 g, 21.91 mmol) and N-ethyl-N-isopropylpropan-2-amine (10.5 mL, 60.1 mmol) and stirred for 5 minutes. Ethylamine solution (2 M in tetrahydrofuran) (11 mL, 22.00 mmol) was added and stirring was continued at ambient temperature for 7 hours. The reaction mixture was then diluted with 600 mL of water and stirred overnight at ambient temperature. The resulting solid was collected by filtration and washed with 1 L of water, and the dried solid gave the title compound (5.54 g, 93%).

Example 272c

N-ethyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 272b (5.4 g, 18.11 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (13.80 g, 54.3 mmol), X-Phos (0.363 g, 0.761 mmol), tris(dibenzylideneacetone)dipalladium (0.166 g, 0.181 mmol), and oven-dried potassium acetate (5.33 g, 54.3 mmol) was degassed by purging the flask with a stream of nitrogen gas into and across the solid for 1 hour. Degassed anhydrous dioxane (60 mL) was then added to the mixture via cannula, and the mixture was heated at 75°C overnight. The reaction mixture was cooled to ambient temperature, then diluted with water and ethyl acetate and stirred for 30 minutes. The mixture was further diluted with ethyl acetate and methanol was added to aid in dissolution of the solid. The mixture was partitioned. The gained organic layer is washed with saturated sodium chloride aqueous solution, and the aqueous washing solution merged is stripped with 10% methanol/ethyl acetate. 10 g SiliaMetS® Thiol palladium scavenger (Silicycle) is added to the organic extract merged, and stirred for 1 hour. Anhydrous sodium sulfate is directly added to the mixture and stirring is continued for another 30 minutes. The whole mixture is then filtered through a Buchner funnel, washed with ethyl acetate, and the obtained filtrate is concentrated under reduced pressure. The gained residue is mixed with 10% ether/heptane of 200 mL, and sonicated for 30 minutes. The gained solid is collected by vacuum filtration, washed with 10% ether/heptane of 100 mL, then washed with 200 mL heptane, and dried to give title compound (5.1 g, 82% yield).

Example 272d

(R)-2-Bromo-4-(ethylsulfonyl)-N-(1-phenylpropyl)aniline

A mixture of Example 2b (522 mg, 1.954 mmol), (R)-1-phenylpropan-1-amine (801 mg, 5.860 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.683 mL, 3.910 mmol) in dimethyl sulfoxide (10 mL) was heated at 120°C for 18 hours. The mixture was cooled to ambient temperature and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2% ethanol and 6% ethyl acetate/heptane) to provide the title compound.

Example 272e

(R)-N-Ethyl-4-(5-(ethylsulfonyl)-2-((1-phenylpropyl)amino)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 272d (288 mg, 0.753 mmol), Example 272c (200 mg, 0.579 mmol), potassium phosphate (369 mg, 1.738 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (20.3 mg, 0.070 mmol), and tris(dibenzylideneacetone)dipalladium(0) (21.2 mg, 0.023 mmol) was purged with argon for 15 minutes, followed by the addition of a mixture of degassed tetrahydrofuran (6 mL) and water (1.5 mL). The reaction mixture was heated at 60°C for 3 hours. The mixture was cooled to ambient temperature and partitioned between saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 8% ethanol and 25% ethyl acetate/heptane) to provide the title compound.

Example 272f

(R)-N-Ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 272e (100 mg, 0.192 mmol) and paraformaldehyde (23 mg, 0.768 mmol) in tetrahydrofuran (6 mL) was stirred at ambient temperature. To the resulting suspension was added a 1M titanium tetrachloride solution (0.39 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then at 60°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between a saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by recrystallization from methanol to give the title compound (87 mg, 85%). ¹ H NMR (400 MHz, 90℃, DMSO- d ₆ ) δ 11.79 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.94 (t, J = 5.4 Hz, 1H), 7.64-7.54 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.27-7.12 (m, 5H), 4.76 (d, J =16.5 Hz, 1H), 4.48 (d, J = 16.5 Hz, 1H), 4.27 (t, J = 7.1 Hz, 1H), 3.68 (s,3H), 3.21-3.32 (m, 4H), 1.76 (p, J = 7.2 Hz, 2H), 1.15 (dt, J = 16.7, 7.3 Hz, 6H), 0.52 (t, J = 7.2 Hz, 3H). (ESI+) m/z 532.9 (M+H) ⁺ .

Example 273

10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 273a

N-(2-Bromo-4-((methylsulfonyl)methyl)phenyl)pyridin-2-amine

Example 273a was prepared according to the procedure used to prepare Example 58h, substituting 2-iodopyridine for 1-chloro-4-iodobenzene to provide the title compound.

Example 273b

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 273b was prepared according to the procedure used to prepare Example 270g, substituting Example 273a for Example 270f to provide the title compound.

Example 273c

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 273c was prepared according to the procedure used to prepare Example 270h, substituting Example 273b for Example 270g to provide the title compound.

Example 273d

10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 273d was prepared according to the procedure used to prepare Example 270i, substituting Example 273c for Example 270h to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.99 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.92 (m, 2H), 7.63 (s, 1H), 7.46 (dd, J = 8.0, 1.6 Hz, 1H),7.37 (d, J = 8.0 Hz, 1H), 7.28-7.24 (m, 1H), 6.47 (dd, J = 6.7, 5.2 Hz, 1H),6.01 (d, J = 8.4 Hz, 1H), 5.94 (d, J = 15.6 Hz, 1H), 4.63(d, J = 13.6Hz, 1H),4.52(d, J = 13.6Hz, 1H), 4.33 (d, J = 15.7 Hz, 1H), 3.94 (s, 3H), 3.59 (s,3H), 3.01 (s, 3H). MS (ESI+) m/z 501.0 [M + H] ⁺ .

Example 274

10-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 274a

2-Bromo-4-(methylsulfonyl)-N-phenylaniline

Example 274a was prepared according to the procedure used to prepare Example 270f, substituting iodobenzene for 2,4-difluoro-1-iodobenzene to provide the title compound.

Example 274b

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(phenylamino)phenyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 274b was prepared according to the procedure used to prepare Example 270g, substituting Example 274a for Example 270f to provide the title compound.

Example 274c

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(phenylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 274c was prepared according to the procedure used to prepare Example 270h, substituting Example 274b for Example 270g to provide the title compound.

Example 274d

10-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 274d was prepared according to the procedure used to prepare Example 270i, substituting Example 274c for Example 270h to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.06 (s, 1H), 8.37 (d, J =2.1 Hz, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.92 (dd, J = 8.2, 2.2 Hz, 1H), 7.85 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 6.98-6.90 (m, 2H), 6.51 (s, 1H), 6.23 (d, J = 8.0 Hz, 2H), 3.95 (s, 3H), 3.59 (s, 3H), 3.38 (s, 3H). MS (ESI+) m/z 486.0 [M+ H] ⁺ .

Example 275

10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 275a

N-(2-Bromo-4-(methylsulfonyl)phenyl)pyridin-2-amine

Example 275a was prepared according to the procedure used to prepare Example 270f, substituting 2-iodopyridine for 2,4-difluoro-1-iodobenzene to provide the title compound.

Example 275b

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(pyridin-2-ylamino)phenyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 275b was prepared according to the procedure used to prepare Example 270g, substituting Example 275a for Example 270f to provide the title compound.

Example 275c

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(pyridin-2-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 275c was prepared according to the procedure used to prepare Example 270h, substituting Example 275b for Example 270g to provide the title compound.

Example 275d

10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 275d was prepared according to the procedure used to prepare Example 270i, substituting Example 275c for Example 270h to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.06 (s, 1H), 8.37 (d, J = 2.0Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.97- 7.85 (m, 3H),7.61 (d, J = 8.3 Hz,1H), 7.35 (s,1H), 6.56 (d, J = 6.1 Hz, 1H), 6.13 (d, J = 8.5 Hz,1H), 5.88 (d,J = 16.1 Hz, 1H), 4.37 (s, 1H), 3.95(s, 3H), 3.61 (s, 3H), 3.37 (s, 3H). MS(ESI+) m/z 487.0 [M + H]+.

Example 276

4-(4-Fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 276a

2-Bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline

Example 276a was prepared according to the procedure used to prepare Example 58h, substituting 1-fluoro-4-iodobenzene for 1-chloro-4-iodobenzene to provide the title compound.

Example 276b

4-(2-((4-Fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 276b was prepared according to the procedure used to prepare Example 270g, substituting Example 276a for Example 270f to provide the title compound.

Example 276c

4-(2-((4-Fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 276c was prepared according to the procedure used to prepare Example 270h, substituting Example 276b for Example 270g to provide the title compound.

Example 276d

4-(4-Fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-11(10H)-one

Example 276d was prepared according to the procedure used to prepare Example 270i, substituting Example 276c for Example 270h to provide the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.02(s, 1H), 8.29 (s, 1H),8.05 (s, 1H), 7.90(s, 1H), 7.60 (s,1H), 7.47 (d, J = 8.0Hz, 1H), 7.35 (d, J =7.9 Hz, 1H), 6.75(t, J = 8.9 Hz, 2H), 6.13 (dd, J = 9.2,4.4 Hz, 2H), 4.57 (s,2H), 3.94 (s, 3H),3.57 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z 518.0 [M + H] ⁺ .

Biological Examples

Bromodomain binding assay

The affinity of the example compounds described in Table 1 for each bromodomain of BRD4 was determined using time-resolved fluorescence resonance energy transfer (TR-FRET) analysis. The first (BD1: amino acids K57-E168) and second (BD2: amino acids E352-E168) bromodomains of His-tagged BRD4 were expressed and purified. In this test, an Alexa647-labeled BET inhibitor was used as a fluorescent probe.

Synthesis of Alexa647-labeled bromodomain inhibitor compounds

2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid. Methyl 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (WO2006129623) (100.95 mg, 0.243 mmol) was suspended in 1 mL of methanol, and freshly prepared lithium hydroxide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) was added and shaken at ambient temperature for 3 hours. The methanol was evaporated, and the pH was adjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol). The mixture was extracted four times with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and evaporated to yield 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (85.3 mg, 87.0%); ESI-MS m/z = 401.1 [(M+H) ⁺ ], which was used directly in the next reaction.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide bis(2,2,2-trifluoroacetate). Combine 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (85.3 mg, 0.213 mmol) and 2,2'-(ethane-1,2-diylbis(oxy))diethylamine (Sigma-Aldrich, 0.315 mg, 2.13 mmol) in 5 mL of anhydrous dimethylformamide. Add (1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate (V) (PyBOB, CSBio, Menlo Park, CA; 332 mg, 0.638 mmol) and shake at ambient temperature for 16 hours. The reaction was diluted to 6 mL with dimethyl sulfoxide:water (9:1, v:v) and injected twice. The product was purified using a Waters Deltapak C18 200 x 25 mm column with time acquisition and a gradient elution using water and acetonitrile containing 0.1% trifluoroacetic acid (v/v). The fractions containing the two purified products were lyophilized to give N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide bis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS m/z = 531.1 [(M+H) ⁺ ]; 529.1 [(MH) ^- ] and (S,Z)-N,N'-(2,2'-(ethane-1,2-diylbis(oxy)bis(ethane-2,1-diyl))bis(2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)bis(2,2,2-trifluoroacetate) (3.0 mg, 1.5%); ESI-MS m/z = 913.2 [(M+H) ⁺ ]; 911.0 [(MH) ^- ].

N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (2,2,2-trifluoroacetate). N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide bis(2,2,2-trifluoroacetate) (5.4 mg, 0.0071 mmol) and Alexa ^Fluor® 647 carboxylic acid succinimidyl ester (Life Technologies, Grand Island, NY; 3 mg, 0.0024 mmol) were combined in 1 mL of anhydrous dimethyl sulfoxide containing diisopropylethylamine (1% v/v) and shaken at room temperature for 16 hours. The reaction was diluted to 3 mL with dimethyl sulfoxide:water (9:1, v:v) and purified using a single injection using a time-acquisition Waters Deltapak C18 200 x 25 mm column, eluting with a gradient of water and acetonitrile containing 0.1% trifluoroacetic acid (v/v). Fractions containing the purified product were lyophilized to afford N-(2-(2-(2-amido(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (2,2,2-trifluoroacetate salt) (1.8 mg) as a dark blue powder. MALDI-MS m/z = 1371.1, 1373.1 [(M+H) ⁺ ].

Determination

Serial dilutions of compound solutions in DMSO were prepared via approximately 3-fold serial dilutions from one of the following:

Assay C: 1250 μM-21 nM

Assay D: 500 μM-8.5 nM

Assay E: 0.47 mM to 7.8 nM

Assay F: 250 μM-4.2 nM

Assay G: 0.047 mM to 0.78 nM

Alternatively, prepare serial dilutions of the compound in DMSO from a 5-fold serial dilution of one of the following:

Assay A: 2.5 mM-800 nM

Assay B: 2.5 mM-797 nM

For assay methods A, C, D, and F: The compound was then diluted in a 6:100 ratio with assay buffer (20 mM sodium phosphate, pH 6.0, 50 mM sodium chloride, 1 mM ethylenediaminetetraacetic acid, 0.01% Triton X-100, 1 mM DL-dithiothreitol) to obtain a 3X working solution. 6 microliters (μL) of the working solution was then transferred to a white, small-volume assay plate (Costar #3673). A 1.5X assay mixture containing a His-tagged bromodomain, a Europium-conjugated anti-His antibody (Invitrogen PV5596), and an Alexa-647-conjugated probe molecule was also prepared. 12 μL of this solution was added to the assay plate to reach a final volume of 18 μL.

For assays B, E, and G: Using Labcyte Echo in combination with Labcyte Access and ThermoMultidrop CombinL robotics, diluted solutions of compounds were added directly to white, small-volume assay plates (Perkin Elmer Proxiplate 384 Plus # 6008280). The compounds were then suspended in 8 microliters (μL) of assay buffer (20 mM sodium phosphate, pH 6.0, 50 mM NaCl, 1 mM ethylenediaminetetraacetic acid disodium salt dihydrate, 0.01% Triton X-100, 1 mM DL-dithiothreitol) containing His-tagged bromodomains, Europium-labeled anti-His antibodies (Invitrogen PV5596), and Alexa-647-conjugated probes.

The final concentration of the 1X assay mixture for assay methods A, B, C, D, E, F, and G contained 2% DMSO, 8 nM His-labeled bromodomain, 1 nM Europium-labeled anti-His-tag antibody, and 100 nM or 30 nM probe (for BDI or BDII, respectively) and the following range of compound concentrations: 50 μM-16 nM for method A, 49.02 μM-15.63 nM for method B, 25 μM-423 pM for method C, 10 μM-169 pM for method D, 9.19 μM - 150 pM for method E, 5 μM- 85 pM for method F, and 0.92 μM - 15 pM for method G.

After equilibration for one hour at room temperature, the TR-FRET ratio was determined using an Envision multilabel plate reader (Ex 340, Em 495/520).

TR-FRET data were normalized to the mean of 24 no-compound controls ("high") and the mean of 8 controls containing 1 μM unlabeled probe ("low"). Percent inhibition was plotted as a function of compound concentration, and the data were fitted with a 4-parameter logistic formula to obtain _IC50 . Inhibition constants ( _Ki ) were calculated from _IC50 , probe _Kd , and probe concentration. Typical Z' values were between 0.65 and 0.75. The lowest significance ratio was determined to evaluate the reproducibility of the assay (Eastwood et al., (2006) J Biomol Screen, 11: 253-261). For BDI, the measured value of the MSR was 2.03, for BDII, the measured value of the MSR was 1.93, and the mobile MSR (last six run MSR overtime) for BDI and BDII was generally <3. _Ki values are listed in Table 1.

MX-1 cell line proliferation assay

The effects of the example compounds on cancer cell proliferation were determined in a 3-day proliferation assay using the breast cancer cell line MX-1 (ATCC). The data are listed in Table 1. MX-1 cells were cultured in RPMI 1640 medium (Sigma) containing 10% FBS at 37°C in a 5% _CO₂ atmosphere. For compound testing, MX-1 cells were seeded at a density of 5,000 cells/well in a 96-well black-bottom plate containing 90 µL of medium per well and incubated overnight at 37°C to allow cell adhesion and spreading. A DMSO dilution series of compound solutions was prepared by three-fold serial dilution from 3 mM to 0.1 µM. These DMSO dilutions were then diluted 1:100 with phosphate buffered saline, and 10 µL of the resulting solution was added to the corresponding wells of the MX-1 cell plate. The final compound concentrations in the wells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, and 0.0001 μM or 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, and 0.00003 μM. After compound addition, cells were incubated for an additional 72 hours, and the amount of viable cells was determined using the Cell Titer Glo assay kit (Promega) according to the manufacturer's recommended protocol.

Luminescence readings from the Cell Titer Glo assay were normalized to those from DMSO-treated cells and analyzed using GraphPad Prism software. _EC50 values were calculated using a sigmoidal curve fit. The minimal significance ratio (MSR) was determined to assess the reproducibility of the assay (Eastwood et al., (2006) J Biomol Screen, 11: 253-261). The total MSR was 2.1, and the moving MSR (last six run MSR overtime) was <2.

Table 1

Example Compound# TR-FRET assay protocol TR-FRET binding Ki:BRD4(BDI_K57-E168) (μM) TR-FRET binding Ki:BRD4(BDII_E352-M457) (μM) 1 E 0.0327 0.0105 0.0272 2 E 0.0246 0.00836 0.0192 3 E 0.046 0.00891 0.0487 4 E 2 3.09 ND 5 E 0.765 0.758 ND 6 E 0.00108 0.00171 0.00201 7 B 0.0511 0.0267 0.0145 8 E 0.000646 0.00377 0.00568 9 G 0.000453 0.00111 0.000721 10 E 0.00694 0.00599 0.0608 11 G 0.00161 0.00257 0.00164 12 G 0.00134 0.000472 0.0040 13 G 0.00484 0.00768 0.00726 14 E 0.0069 0.000882 0.0146 15 E 0.00522 0.000631 0.00875 16 E 0.0926 0.0189 0.337 17 E 0.165 0.0539 ND 18 E 0.145 0.0241 0.343 19 E 0.246 0.0438 0.37 20 E 0.158 0.0245 0.544 twenty one G 0.00443 0.003 0.00105 twenty two G 0.000875 0.00095 0.00171 twenty three E 0.0017 0.000783 0.0070 twenty four E 0.000963 0.000801 0.00107 25 E 0.00174 0.000847 0.0087 26 G 0.000701 0.000719 0.00103 27 E 0.00119 0.00101 0.00127 28 E 0.0011 0.00117 0.0137 29 E 0.00695 0.00274 0.00103 30 E 0.00498 0.00136 0.00139 31 G 0.00167 0.00118 0.000752 32 G 0.00101 0.00114 0.00138 33 G 0.0383 0.0228 0.495 34 G 0.00245 0.00389 0.0147 35 G 0.0355 0.0951 0.331 36 G 0.00505 0.00625 >1 37 G 0.00336 0.0024 >1 38 G > 0.238 > 0.408 ND 39 G > 0.238 > 0.408 ND 40 G 0.0294 0.136 0.398 41 G 0.0495 0.0578 >1 42 G 0.00156 0.00203 0.00544 43 G 0.00729 0.0247 ND 44 G 0.00261 0.00247 0.0487 45 G 0.00392 0.00375 0.141 46 G 0.0137 0.00748 0.152 47 G 0.00137 0.00127 0.00833 48 G 0.00112 0.000855 0.00441 49 G 0.00199 0.00221 0.00863 50 G 0.00344 0.00551 0.0422 51 G 0.00443 0.0132 0.174 52 G 0.0174 0.00499 0.247 53 G 0.00478 0.0219 ND 54 G 0.00585 0.00145 ND 55 G 0.00896 0.0159 0.146 56 G 0.0144 0.0353 0.197 57 G 0.0647 0.0906 ND 58 G 0.00202 0.000617 0.00538 59 G 0.0031 0.000972 0.0038 60 G 0.00255 0.0331 0.115 61 G 0.0211 0.00374 > 1 62 G 0.00723 0.00473 0.91 63 G 0.0822 0.0736 ND 64 G 0.00269 0.00285 0.0846 65 G > 0.238 0.238 ND 66 G > 0.238 > 0.408 ND 67 G > 0.238 > 0.408 ND 68 G 0.0127 0.00422 0.0401 69 G 0.00325 0.00324 0.0431 70 G 0.00741 0.00188 0.131 71 G 0.0304 0.0267 ND 72 G 0.0262 0.037 ND 73 G 0.0165 0.0194 ND 74 G > 0.238 0.369 ND 75 G > 0.238 > 0.408 ND 76 G > 0.238 > 0.408 ND 77 G > 0.238 0.275 ND 78 G 0.216 0.126 ND 79 G > 0.238 > 0.408 ND 80 G > 0.238 > 0.408 ND 81 G 0.0517 0.0323 ND 82 G 0.0133 0.00112 0.979 83 G > 0.238 > 0.408 ND 84 G 0.00224 0.00386 0.0177 85 G 0.0108 0.0111 0.0489 86 G 0.0103 0.0139 ND 87 G 0.00254 0.0021 0.00469 88 G 0.00346 0.00176 ND 89 G 0.00577 0.00453 ND 90 G 0.00132 0.00201 0.0306 91 G 0.00327 0.00115 0.00181 92 G 0.00374 0.00558 ND 93 G 0.00284 0.00163 0.00259 94 G 0.00603 0.00349 0.00602 95 G 0.00218 0.00253 0.0141 96 G 0.00346 0.00161 ND 97 G 0.00321 0.00135 ND 98 G 0.00234 0.00315 0.00441 99 G 0.0155 0.00166 0.165 100 G 0.0298 0.00741 ND 101 G 0.00483 0.00277 ND 102 G 0.00941 0.0269 0.151 103 G 0.00812 0.00471 ND 104 G 0.0347 0.0262 ND 105 G 0.00549 0.00268 0.0162 106 G 0.00589 0.00191 0.0192 107 G 0.00642 0.00379 0.00704 108 G 0.0139 0.00211 0.165 109 G 0.0641 0.0156 ND 110 G 0.0417 0.0199 ND 111 G 0.0077 0.00331 0.084 112 G 0.0532 0.0152 ND 113 G 0.0856 0.0109 ND 114 G 0.112 0.0255 ND 115 G 0.0087 0.00271 0.00783 116 G 0.016 0.0112 ND 117 G 0.0723 0.00127 >1 118 G 0.0126 0.00138 0.174 119 G 0.0119 0.000602 0.134 120 G 0.00928 0.00159 >1 121 G 0.00665 0.000799 >1 122 G 0.0108 0.000922 >1 123 G 0.00995 0.000983 >1 124 G 0.00884 0.00278 0.944 125 G 0.00926 0.00236 0.342 126 G 0.0536 0.08 ND 127 G 0.00268 0.00135 0.0417 128 G 0.0291 0.002 0.0729 129 G 0.0162 0.0025 0.25 130 G 0.215 0.0146 ND 131 G 0.0107 0.00235 >1 132 G 0.0113 0.00314 >1 133 G 0.00929 0.0014 0.204 134 G 0.0144 0.00111 0.182 135 G 0.0114 0.00214 0.51 136 G 0.0132 0.00133 0.0492 137 G 0.0517 0.00387 0.24 138 G 0.0225 0.00194 0.256 139 G 0.0175 0.00233 0.627 140 G 0.00999 0.00224 0.936 141 G 0.0208 0.0109 0.319 142 G 0.00861 0.00060 0.0518 143 G 0.0549 0.00306 0.175 144 G > 0.238 0.0188 0.318 145 G 0.0551 0.00138 0.0806 146 G 0.00142 0.017 0.124 147 G 0.00702 0.00097 0.0203 148 G 0.00677 0.00054 0.0319 149 G 0.00178 0.00082 0.00193 150 G 0.00405 0.0108 ND 151 G 0.00114 0.0023 0.00426 152 G 0.00718 0.011 ND 153 G 0.00372 0.00918 ND 154 G 0.0507 0.0531 ND 155 G 0.0427 0.0478 0.349 156 G 0.0468 0.0421 0.214 157 G 0.0396 0.0239 0.0774 158 G 0.0603 0.0773 ND 159 G 0.0386 0.0198 0.0578 160 G 0.125 0.118 ND 161 G 0.0321 0.0214 0.0416 162 G 0.0471 0.0604 ND 163 G 0.0574 0.0454 ND 164 G 0.0417 0.030 0.0725 165 G 0.0814 0.0796 ND 166 G 0.060 0.0733 ND 167 G 0.0692 0.0763 ND 168 G 0.0932 0.124 ND 169 G 0.0124 0.00467 0.0699 170 G 0.00707 0.0252 0.0576 171 G 0.0164 0.0292 ND 172 G 0.0578 0.0128 0.551 173 G 0.00672 0.00314 0.0199 174 G 0.0126 0.00153 0.239 175 G 0.015 0.0019 0.0999 176 G 0.00101 0.00355 0.0142 177 G 0.00202 0.00127 0.00372 178 G 0.00436 0.00438 0.123 179 G 0.0201 0.0807 ND 180 G 0.00151 0.0027 ND 181 G 0.00333 0.0171 ND 182 G 0.00131 0.0020 0.00108 183 G 0.00384 0.0155 ND 184 G 0.00434 0.00682 ND 185 G 0.00419 0.0102 0.0283 186 G 0.00421 0.0092 ND 187 G 0.00574 0.050 ND 188 G 0.00364 0.00462 ND 189 G 0.00582 0.0223 ND 190 G 0.0267 0.0309 ND 191 G 0.00100 0.00338 0.0107 192 G 0.00165 0.00108 0.00125 193 G 0.00185 0.0124 0.0317 194 G 0.00133 0.00038 0.00147 195 G 0.00266 0.00062 0.00377 196 G 0.00114 0.00172 0.00382 197 G 0.00152 0.00265 0.00266 198 G 0.00159 0.00063 0.00069 199 G 0.00081 0.00121 0.0108 200 G 0.00818 0.00205 0.0342 201 G 0.00085 0.0032 0.0278 202 G 0.00079 0.00035 0.0043 203 G 0.00099 0.00071 0.00543 204 G 0.0461 0.00122 > 1 205 G 0.20 0.0291 > 1 206 G 0.00096 0.00051 0.00141 207 G 0.00092 0.00209 0.00133 208 G 0.00341 0.00115 0.0107 209 G 0.0012 0.00086 0.00654 210 G 0.00172 0.00080 0.0133 211 G 0.00567 0.00747 0.118 212 G 0.00239 0.0050 0.155 213 G 0.00065 0.00042 0.0014 214 G 0.0408 0.00325 0.431 215 G 0.0657 0.00587 0.454 216 G 0.0573 0.0658 0.603 217 G 0.193 0.0426 > 1 218 G 0.00064 0.00064 0.00136 219 G 0.0399 0.00476 0.301 220 G 0.0516 0.00261 0.285 221 G 0.0316 0.0123 0.033 222 G 0.17 0.0294 0.16 223 G > 0.238 > 0.408 ND 224 G 0.00164 0.0014 0.00584 225 G 0.00325 0.00239 0.0122 226 G 0.00384 0.00186 0.00782 227 G 0.00794 0.00118 0.134 228 G 0.0245 0.00222 0.0849 229 G 0.00411 0.00196 0.0412 230 G > 0.238 0.0581 0.528 231 G 0.039 0.00542 0.149 232 G 0.108 0.00848 0.363 233 G 0.00615 0.00377 ND 234 G 0.0103 0.0094 > 1 235 G 0.0161 0.00651 0.162 236 G 0.0859 0.030 > 1 237 G 0.0218 0.0121 0.313 238 G 0.0621 0.0046 0.275 239 G 0.0319 0.00212 0.294 240 G 0.00314 0.00193 0.0859 241 G 0.00307 0.00176 0.0515 242 G 0.0126 0.00378 > 1 243 G 0.00185 0.00347 0.153 244 G 0.00043 0.00102 0.00213 245 G 0.00054 0.00094 0.00109 246 G 0.00432 0.0036 0.0117 247 G 0.00222 0.00242 0.00494 248 G 0.00339 0.00329 0.0256 249 G 0.0061 0.0191 0.0177 250 G 0.0088 0.0225 0.845 251 G > 0.238 0.142 ND 252 G 0.0161 0.00224 0.108 253 G 0.00070 0.00118 0.0013 254 G 0.00112 0.00071 0.0039 255 G 0.00453 0.00733 0.0343 256 G 0.00059 0.00054 0.00035 257 G 0.00234 0.00919 0.0211 258 G 0.00092 0.00239 0.00443 259 G 0.0034 0.00305 0.019 260 G 0.00726 0.0034 0.219 261 G 0.00932 0.00778 > 1.0 262 G 0.00937 0.0132 ND 263 G 0.00704 0.00807 >1.0 264 G 0.00697 0.00153 0.899 265 G 0.0256 0.00421 0.17 266 G 0.0178 0.00815 0.0427 267 G 0.0727 0.0947 ND 268 G 0.0828 0.0164 ND 269 G 0.00569 0.00092 ND 270 G 0.011 0.00335 0.0807 271 G 0.00391 0.00164 0.0852 272 G 0.0589 0.00635 ND 273 G 0.00112 0.00088 ND 274 G 0.00283 0.00156 ND 275 G 0.00209 0.00085 ND 276 G 0.00119 0.00118 ND

ND = not determined.

Mouse assay for LPS (lipopolysaccharide)-induced IL-6 production

The ability of the example compounds listed in Table 2 to inhibit LPS (lipopolysaccharide)-induced IL-6 (interleukin-6) production in mice was determined. One hour after oral administration of the compounds, Fox Chase ^SCID® female mice (Charles Rivers Labs, 5 mice per group) or CD1 female mice (5 mice per group) were injected intraperitoneally with lipopolysaccharide (2.5 mg/kg, L2630 E. coli 0111:B4). Two hours after the LPS injection, the mice were euthanized, blood was collected by cardiac puncture, and serum collected from the blood samples was frozen at -80°C. On the day of the assay, serum samples were brought to room temperature and then diluted 1:20 with phosphate buffered saline containing 2% bovine serum albumin. Using the cytokine assay kit from Meso Scale Discovery (Gaithersburg, Maryland), mouse serum was assayed for interleukin-6 according to the manufacturer's protocol and read on a SECTOR Imager 6000 (Meso Scale Discovery, Gaithersburg, Maryland) instrument. Statistical analysis was performed using Prism software (version 5.0) including Dunnett's one-way analysis of variance. The mean and standard deviation of IL-6 in the vehicle-treated animal group were compared with the mean and standard deviation of IL-6 in the drug-treated group. P value < 0.05 means that the probability that the mean value is equal in the two groups is less than 5%. Table 2 shows a p value less than 0.05 for % inhibition.

Table 2

Inhibition of LPS-induced IL-6 production

Example Compound# %inhibition Mouse strains 6 64 SCID 7 53 SCID 8 53 SCID 9 79 SCID 12 90 SCID 15 68 SCID twenty three 54 SCID twenty four 78 SCID 26 88 SCID 27 79 SCID 29 76 SCID 30 81 SCID 31 83 SCID 42 86 CD1 58 39 CD1 59 68 CD1 60 44 CD1 149 86 CD1 151 57 CD1 173 87 CD1 182 77 CD1 191 60 CD1 192 73 CD1 194 53 CD1 195 85 CD1 196 79 CD1 198 86 CD1 199 90 CD1 202 47 CD1 206 76 CD1 207 65 CD1

Xenograft tumor growth inhibition assay

The effect of the embodiment compounds on the growth of OPM-2 xenograft tumors implanted in mice was evaluated. A suspension of cancer cells (5 x10 ⁶ / 0.1 mL) prepared in RPMI culture medium (Invitrogen, Carlsbad, CA) was diluted with Matrigel™ solution (BD Biosciences, Franklin Lakes, NJ) 1:1 and subcutaneously inoculated into the right posterior flank of female SCID-beige (Charles River Labs) mice. When the average tumor volume reached approximately 250 mm ³ , random groups were assigned to treatment and vehicle control groups (8-10 per group). Compounds were formulated in 2.5% DMSO, 10% ethanol, 27.5% PEG400, and 60% Phosol 53 MCT. Compounds or vehicles were administered starting the day after randomization and continued for 21 days. Tumors were measured twice a week using calipers during the treatment period, and tumor volume was calculated according to the formula V = L×W ² /2 (V: volume, mm ³ ; L: length, mm. W: width, mm). Tumor growth inhibition was calculated based on the average tumor volume measured on the first day when the average volume of the vehicle group exceeded 2000 mm ³ according to the following formula:

%TGI = 100 - (100 x (mean tumor volume of the treated group/mean tumor volume of the control group))

The results are shown in Table 3.

Table 3

OPM-2 human multiple myeloma xenograft cancer model

Example Compound # Dosage mg/kg Pathway, plan 9 1.85 PO, QD x21 87*** 56 9 3.75 PO, QD x21 100 12 1.5 IP, QD x21 82** 11 12 1.5 IP, QD x21 91*** twenty two 12 3 IP, QD x21 89** 11 12 3 IP, QD x21 100 12 3 PO, 3 on 4 off x3 weeks 81*** 0 12 3 PO, QD x11 72*** 0 12 1.5 PO, QD x21 87*** twenty two 12 3 PO, QD x21 94*** 56 173 1.25 PO, QD x21 49** 0 173 2.5 PO, QD x21 67 196 2.5 PO, QD x21 84*** 0 196 5 PO, QD x21 92*** 44 199 1.25 PO, QD x21 91*** 38 199 2.5 PO, QD x21 50 199 5 PO, QD x21 50 207 0.25 PO, QD x21 60*** 0 207 0.5 PO, QD x21 93*** 11 207 0.5 PO, QD x21 94*** 13 207 1.0 PO, QD x21 97*** 44 213 0.5 PO, QD x21 82*** 13 213 1 PO, QD x21 96*** 25 213 1 PO, QD x21 95*** 13 213 2 PO, QD x21 63

a. p values (indicated by asterisks) were derived from Student's T-test comparisons of the treated group versus the control group. *** p<0.001, ** p<0.01, * p<0.05.

b. Percentage of treatment groups removed from the study due to death or weight loss greater than 20%.

c. Not determined.

It should be understood that the above detailed description and the accompanying examples are merely illustrative and should not be considered as limiting the scope of the present invention, which is limited only by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. These changes and modifications (including, but not limited to, those relating to chemical structures, substituents, derivatives, intermediates, synthesized, compositions and/or methods of use of the present invention) can be made without departing from its spirit and scope. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all aspects.

Claims (51)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, in ^Y1 is CH; ^R1 is a methyl group; ^R2 is H; ^Y3 is ^CR3 ; ^R3 is H, _C1 - _C6 alkyl, -CN, -C(O) ^R3a , -C(O) ^OR3a , -C(O) ^NR3b , ^R3c , or ^G1 ; wherein the _C1 - _C6 alkyl is unsubstituted or substituted by one or two substituents independently selected from ^G1 ; ^Y2 is ^{CR4R5 ; R4} is H, deuterium, or _C1 - _C6 alkyl; R ⁵ is H, deuterium, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^{5bR 5c} , or G ¹ ; wherein the _C1 - _C6 alkyl and C2 _{- C6} alkenyl are each independently unsubstituted or substituted by one or two independently selected substituents from the following: G ¹ , -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR 5bR 5c, -C(O)N(R ^5b )NR ^{5bR 5c} , -OR ^5a , -OC(O)R ^5d , -NR ^{5bR 5c} , N(R 5b)C(O)R ^5d , N(R ^5b )C(O)OR ^5d , N(R ^5b )C(O)OR ^5d , N(R ^{5b )} )C(O)NR ^5b R ^5c , N(R ^5b )SO ₂ NR ^5b R ^5c and N(R ^5b )C(NR ^5b R ^5c )=NR ^5b R ^5c ; ^R3a , ^R3b , ^R3c , ^R5a , and ^R5b each appear independently as H, _C1 - _C6 alkyl, _C2 - _C6 alkynyl, ^G1 , or -( _C1 - _C6 alkylene) ^-G1 ; R ^5c is independently H, _C1 - _C6 alkyl, _C2 - _C6 ynyl, ^G1 , -( _C1 - _C6 alkylene) ^-G1 , -(C1- _C6 alkylene) ^-ORa or -( _C1 - _C6 alkylene)-C(O) ^ORa each time _it appears; R ^5d is independently _C1 - _C6 alkyl, ^G1 , -( _C1 - _C6 alkylene) ^-G1 , -( _C1 - _C6 alkylene) ^-NRcRd or -( _C1 - _C6 alkylene)-N( ^{Re )} C(O)O( ^Rb ) each time it appears; Each ^G1 is independently an aryl, heteroaryl, heterocyclic, or cycloalkyl group; and each ^G1 is optionally substituted by 1, 2, 3, 4, or 5 ^R1g groups; ^R6 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, -C(O) ^R6a , -C(O) ^OR6a , -C(O) ^NR6bR6c , -S(O) _2R6a or ^G2 ; wherein the _C1 - _C6 ^alkyl and _C2 - ^C6 _alkenyl are each independently unsubstituted or substituted by one or two substituents independently selected from the following: ^G2 , -CN, -C(O) ^OR6a and ^-OR6a ; ^R6a , ^R6b , and ^R6c each appear independently as H, _C1 - _C6 alkyl, _C2 - _C6 ynyl, _C1 - _C6 haloalkyl, ^G2 , -( _C1 - _C6 alkylene) ^-G2 , -( _C1 - _C6 alkylene) ^-ORa , or -( _C1 - _C6 alkylene)-C(O) ^ORa ; Each time ^G2 appears, it is independently aryl, heteroaryl, heterocyclic, or cycloalkyl; and each ^G2 is optionally substituted by 1, 2, 3, 4, or 5 ^R2g groups; ^A1 is C(R ⁷ ) or N; ^A2 is C(R ⁸ ); ^A3 is C(R ⁹ ) or N; and ^A4 is C(R ¹⁰ ); where zero, one, or both of ^A1 or ^A3 are N; ^R7 and ^R9 are each independently H, _C1 - _C6 alkyl, halogen, -CN, -S( ^O ) _2Ry1 , -C(O) ^NRy3Ry4 , ^-NRy3Ry4 , ^{G3 , -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O)2Ry1 or} _- ⁽ _{C1 -} ^C6 _{alkylene ) -S (} O) _2NRy3Ry4 ^; R ⁸ is H; ^Ry1 , ^Ry3 , and ^Ry4 each appear independently as H, _C1 - _C6 alkyl, or ^G3 ; ^G3 is independently cycloalkyl or heterocyclic each time it appears; R ¹⁰ is H; ^R1g and ^R2g are each independently selected from oxo, _C1 - _C6 alkyl, halogen, _C1 - _C6 haloalkyl, -CN, ^G2a , ^-ORa , -C(O) ^ORa , -NRcRd, -N( ^Re )C(O) ^Rb , ^-N (Re)C(O) ^O ( ^Rb ), -( _C1 - _C6 alkylene) ^-ORa or ^- ( _C1 - _C6 alkylene)-C(O) ^ORa ; ^Ra , ^Rc , ^Rd , and ^Re each appear independently as H, _C1 - _C6 alkyl, ^G2a , - ⁽ _C1 - _C6 alkylene) ^-NRz3Rz4 , -( _C1 - _C6 alkylene)-C(O) ^{NRz3Rz4 ,} or -( _C1 - _C6 alkylene) ^-G2a ; ^Rb is independently a _C1 - _C6 alkyl group each time it appears; Each occurrence of G ^2a is independently either aryl or heteroaryl; and R ^z3 and R ^z4 are each independently H or _C1 - _C6 alkyl groups each time they appear; The cycloalkyl group referred to therein refers to a monocyclic cycloalkyl group, a bicyclic cycloalkyl group, or a spirocycloalkyl group. The monocyclic cycloalkyl group is a carbon-ring system containing 3-8 carbon atoms, zero heteroatoms, and zero double bonds. The bicyclic cycloalkyl group is a monocyclic cycloalkyl group fused to a monocyclic cycloalkyl ring. The spirocycloalkyl group is a monocyclic cycloalkyl group in which two substituents on the same carbon atom of the monocyclic cycloalkyl ring, together with the carbon atom, form a second monocyclic cycloalkyl ring. The cycloalkenyl group refers to a monocyclic or bicyclic hydrocarbon cyclic group, wherein the monocyclic cycloalkenyl group has four, five, six, seven or eight carbon atoms and zero heteroatoms; the bicyclic cycloalkenyl group is a monocyclic cycloalkenyl group fused to a monocyclic cycloalkyl group or a monocyclic cycloalkenyl group fused to a monocyclic cycloalkenyl group. The heterocyclic group refers to a monocyclic heterocyclic group, a bicyclic heterocyclic group, and a spirocyclic heterocyclic group, wherein the monocyclic heterocyclic group is a three-, four-, five-, six-, seven-, or eight-membered carbon ring, and further contains at least one heteroatom independently selected from O, N, and S; the bicyclic heterocyclic group is a monocyclic heterocyclic group fused to a phenyl group, or a monocyclic heterocyclic group fused to a monocyclic cycloalkyl group, or a monocyclic heterocyclic group fused to a monocyclic cycloalkenyl group, or a monocyclic heterocyclic group fused to a monocyclic heterocyclic group; the spirocyclic heterocyclic group is a monocyclic heterocyclic group, wherein two substituents on the same carbon atom of the monocyclic heterocyclic group ring, together with the carbon atom, form a second ring system selected from monocyclic cycloalkyl, bicyclic cycloalkyl, monocyclic heterocyclic group, or bicyclic heterocyclic group; The aryl group refers to phenyl or naphthyl, or phenyl fused to a monocyclic cycloalkyl group, or phenyl fused to a monocyclic cycloalkenyl group; and The heteroaryl group refers to a monocyclic heteroaryl group and a bicyclic heteroaryl group containing at least one heteroatom selected from O, N and S, wherein the monocyclic heteroaryl group is a five- or six-membered monocyclic ring; the bicyclic heteroaryl group is composed of a monocyclic heteroaryl group fused to a phenyl group, or a monocyclic heteroaryl group fused to a monocyclic cycloalkyl group, or a monocyclic heteroaryl group fused to a monocyclic cycloalkenyl group, or a monocyclic heteroaryl group fused to a monocyclic heteroaryl group, or a monocyclic heteroaryl group fused to a monocyclic heterocyclic group. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R3 is H, -CN, -C(O) ^R3a , -C(O) ^OR3a , -C(O) ^NR3b , ^R3c , or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally substituted with a substituent selected from ^G1 . 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R4 is H or deuterium; and R ⁵ is H, deuterium, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, -C(O)R ^5a , -C(O)OR ^5a , or ^G1 ; wherein the _C1 - _C6 alkyl and _C2 - _C6 alkenyl are each independently unsubstituted or substituted by one or two substituents independently selected from the following: ^G1 , -C(O)R ^5a , -C(O)OR ^5a , -C(O)NR ^{5bR 5c} , -C(O)N(R ^5b )NR ^{5bR 5c} , -OR ^5a , -OC(O)R ^5d , -NR ^{5bR 5c} , N(R ^5b )C(O)R ^5d , N(R ^5b )SO _2R ^5d , N(R ^5b )C(O)OR ^5d , and N(R ^5b )C(O)NR ^5b R ^5c . 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R6 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, -C(O) ^R6a , -C(O) ^OR6a , -C(O) ^NR6bR6c , -S(O) _2R6a or ^G2 ; wherein the _C1 - _C6 ^alkyl and _C2 - ^C6 _alkenyl are each independently unsubstituted or substituted by one or two substituents independently selected from the following: ^G2 , -CN and -C(O) ^OR6a . 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ), and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ), and ^A4 is C( ^R10 ); or ^A1 is N, ^A2 is C(R ⁸ ), ^A3 is N and ^A4 is C(R ¹⁰ ). 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R9 is H, _C1 - _C6 alkyl, halogen, -CN, -S(O) _2Ry1 , -C( ^O ) ^NRy3Ry4 , ^-NRy3Ry4 , ^- ( _C1 - _C6 ^alkylene )-S( _O ^{)2Ry1 or -} ( _C1 - _C6 alkylene)-S(O) _2NRy3Ry4 . 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R4 is H or deuterium; and ^R5 is a _C2 - _C6 alkenyl group optionally substituted with a ^G1 group, or ^R5 is H, deuterium, _C1 - _C6 alkyl, -C(O) ^R5a , -C(O) ^OR5a or ^G1 ; wherein the _C1 - _C6 alkyl group is unsubstituted or substituted with a substituent selected from the following: ^G1 , -C(O) ^R5a , -C(O) ^OR5a , ^-C (O) ^NR5bR5c , -C(O)N( ^R5b ) ^NR5bR5c , ^-OR5a , -OC( ^O ) ^{R5d , -NR5bR5c and N(R5b )} C ^{( NR5bR5c} )= ^NR5bR5c . 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R3 is H, -C(O) ^R3a , or -C(O) ^{NR3b R3c} . 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R6 is H, _C1 - _C6 alkyl, -C(O) ^R6a , -C(O) ^OR6a , -C(O) ^NR6bR6c , -S(O) _2R6a or ^{G2 ;} wherein the _C1 - _C6 alkyl is ^{unsubstituted} or substituted with a substituent selected from the following: ^G2 and -C(O) ^OR6a . 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R9 is H, _C1 - _C6 alkyl, halogen, -S(O) _2Ry1 ^{, -NRy3Ry4} or - ⁽ _C1 - _C6 alkylene) ^-S(O)2Ry1 _. 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R4 is H or deuterium; ^R7 is H, halogen, _C1 - _C3 alkyl, or cyclopropyl; R ⁸ is H; and R ¹⁰ is H. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein... ^R3 is H or -C(O)NR ^3b R ^3c . 13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein... ^R5 is a _C1 - _C6 alkyl group substituted with H, deuterium, or optionally with a substituent selected from the following: -C(O) ^OR5a and ^OR5a . 14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein... ^R6 is -C(O) ^R6a , -C(O) ^OR6a , -C(O) ^NR6bR6c , ^G2 or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is unsubstituted or substituted ^with a ^G2 group. 15. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein... ^R9 is a halogen, -NR ^y3 R ^y4 or -(C ₁ -C ₆ alkylene)-S(O) ₂ R ^y1 . 16. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein... ^R7 is H or a halogen; and R ⁸ is H. 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein... ^R9 is a halogen or -( _C1 - _C6 alkylene)-S(O) _2Ry1 ^. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein ^R6 is -C(O) ^R6a , -C(O) ^OR6a , -C(O) ^NR6bR6c , ^G2 or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is unsubstituted or substituted ^with a ^G2 group. 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein ^R5 is a _C1 - _C6 alkyl group substituted with H, deuterium, or optionally with a substituent selected from the following: -C(O) ^OR5a and ^OR5a . 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein... ^R3 is H or -C(O)NR ^3b R ^3c . 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein... ^R3b and ^R3c are each independently H or _C1 - _C6 alkyl; R ^5a is a _C1 - _C6 alkyl group; R ^y1 is a _C1 - _C6 alkyl group; and R ^y3 is H. 22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^A1 is C( ^R7 ), ^A2 is C( ^R8 ), ^A3 is C( ^R9 ), and ^A4 is C( ^R10 ). 23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^A1 is N, ^A2 is C( ^R8 ), ^A3 is C( ^R9 ) and ^A4 is C( ^R10 ). 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^A1 is N, ^A2 is C(R ⁸ ), ^A3 is N and ^A4 is C(R ¹⁰ ). 25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R3 is H, -C(O) ^{NR3b R3c} , -CN, or a _C1 - _C6 alkyl group substituted with ^G1 ; wherein ^G1 is a _C4 - _C6 heterocyclic group optionally substituted with _C1 - _C6 alkyl. ^R4 is H or deuterium; ^R7 is H, halogen, -CN, _C1 - _C3 alkyl, or cyclopropyl; R ⁸ is H; and ^R9 is a halogen or -( _C1 - _C6 alkylene)-S(O) _2Ry1 ^. 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein... R ⁵ is H; and ^R6 is phenyl, pyridyl, or cyclohexyl; each of which is optionally substituted with a halogen, -CN, -OC1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _-NH2 , -NHC1 _{- C6} alkyl, -N( _C1 - _C6 alkyl) ₂ , -C(O) _OC1 - _C6 alkyl, -NHC(O) _C1 - _C6 alkyl, or -NHC(O) _OC1 - _C6 alkyl; or ^R6 is -C(O)O( _C1 - _C6 alkyl); or ^R6 is _-CH2- (tetrahydropyranyl, optionally substituted with _C1 - _C6 alkyl). 27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R3 is ^G1 ; ^R4 is H or deuterium; ^R7 is H, halogen, -CN, _C1 - _C3 alkyl, or cyclopropyl; R ⁸ is H; and ^R9 is either -S ^(O)2Ry1 _or -( _C1 - _C6 alkylene)-S ^(O)2Ry1 _. 28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R3 is ^G1 ; where ^G1 is a heteroaryl group that is optionally substituted; ^R4 is H or deuterium; ^R7 is H, halogen, -CN, _C1 - _C3 alkyl, or cyclopropyl; R ⁸ is H; ^R9 is -S ⁽ O) _₂Ry₁ or -( _C₁ - _C₆ alkylene)-S(O) _₂Ry₁ ; ^and R ⁵ is H. 29. The mixture of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 4-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylmethyl)-3-ethyl-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-(methanesulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxylic acid ethyl ester; 4-(4-fluorophenyl)-10-methyl-7-(methanesulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-7-sulfonamide; 4-(4-fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)propionate; 4-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-Benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)propionate; 10-Methyl-7-((methylsulfonyl)methyl)-3-phenylethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-Isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (E)-3-(4-fluorostyryl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 7-Amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-11(10H)-one; N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azon-7-yl)ethanesulfonamide; N-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azon-7-yl)ethanesulfonamide; 4-Butyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((4,4-difluorocyclohexyl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-4-((tetrahydro-2H-pyran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-fluorophenyl)-( ^3,3-2H2 ₎ -10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 7-Fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-11(10H)-one; 4-(4-fluorophenyl)-7,10-dimethyl-3-phenyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-11(10H)-one; 4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxylic acid ethyl ester; 4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carbonyl)piperazine-1-carboxylic acid tert-butyl ester; 10-Methyl-7-((methanesulfonyl)methyl)-4-(pyrrolidone-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(piperidin-4-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 7-Fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-11(10H)-one; 7-Fluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-3-carboxylic acid ethyl ester; 4-(4-fluorophenyl)-3-(4-methoxypiperidin-1-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-fluorophenyl)-10-methyl-3-(4-methylpiperazin-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 5,7-Difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-fluorophenyl)-7,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-3-carboxylic acid ethyl ester; N-Cyclopentyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-Ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(4-Fluorophenyl)-10-methyl-7-((methanesulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; 4-Butyl-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 5,7-Difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylmethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)methyl butyrate; 5,7-Difluoro-10-methyl-4-(3-phenylpropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(o-tolyl)-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-carboxylic acid 2-ethylhexyl ester; 4-Isobutyryl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 5,7-Difluoro-10-methyl-4-phenylethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2-(benzo[d][1,3]dioxacyclopenten-5-yl)ethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((1Z,3E)-2,4-diphenylbut-1,3-dien-1-yl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 4-(4-Chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 4-(4-Chlorophenyl)-10-methyl-2-(4-methylpiperazin-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; N-(2,6-dimethylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(4-methoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(4-Ethylphenethyl)-10-methyl-7-((methanesulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(3-methoxybenzyl)-10-methyl-7-((methanesulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(2-chloroethyl)-10-methyl-7-((methanesulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(cyclohexylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(4-Isopropylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(2,6-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; 4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-4-formylamino)methyl)cyclohexanecarboxylic acid ethyl ester; N-(3-methoxypropyl)-10-methyl-7-((methanesulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; 10-Methyl-7-((methylsulfonyl)methyl)-4-toluenesulfonyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-([1,1'-biphenyl]-4-ylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((4-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(phenylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((2-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-((4-phenoxyphenyl)sulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((4-fluorophenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2-Naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)propionate; 4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentazadibenzo[cd,f]azine-11(10H)-one; (R)-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxylic acid ethyl ester; (S)-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxylic acid ethyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formic acid 2-methoxyethyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formate ethyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-pentyl formate; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-carboxylic acid 4-chlorobutyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-carboxylic acid naphthalene-2-yl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-carboxylic acid p-toluene ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formate neopentyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-carboxylic acid phenyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formic acid 4-fluorophenyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formic acid 2-methoxyphenyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formic acid 2-fluoroethyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formic acid 4-methoxyphenyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formic acid butyl-2-yn-1-yl ester 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)propionamide; 4-(4-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(3-methoxypropionyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-([1,1'-biphenyl]-4-carbonyl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(3-Cyclopentylpropionyl)-10-methyl-7-((Methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2-(3-methoxyphenyl)acetyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-propionyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-4-(3-methylbutyryl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(3,3-dimethylbutyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(2-phenylacetyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-Benzoyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-methoxybenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(10-methyl-7-((methanesulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)-4-oxobutyrate methyl ester; 4-(2,4-Difluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(1-Naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylcarbonyl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(3-phenylpropionyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)methyl)isoindoline-1,3-dione; 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)-N-methylpropionamide; 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)-N,N-dimethylpropionamide; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-morpholino-3-oxopropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)-N-(tetrahydro-2H-pyran-4-yl)propionamide; 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)-N'-methyl-N'-phenylpropionylhydrazine; N-Benzyl-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)propionamide; 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)-N-(1,1-dioxotetrahydrothiophen-3-yl)propionamide; 4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)propionyl)piperazine-1-carboxylic acid tert-butyl ester; 4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)propionylamino)piperidine-1-carboxylic acid tert-butyl ester; 4-(4-Chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; Acetic acid 6-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)hexyl ester; 3-(aminomethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)methyl)amino)(dimethylamino)methylene)-N-methylmethylammonium; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-oxo-3-(piperazin-1-yl)propyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)-N-(piperidin-4-yl)propionamide; 4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)butane-1,2-diyl ester; 5-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)valerate methyl ester; (2-(((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azu-3-yl)methyl)amino)-2-oxoethyl)tert-butyl carbamate; 4-(2,4-Difluorophenyl)-3-(6-hydroxyhexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)methyl)benzamide; 1-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)methyl)-3-phenylurea; 2-Amino-N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)methyl)acetamide; 4-(2,4-difluorophenyl)-3-(3,4-dihydroxybutyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-Difluorophenyl)-3-(3-hydroxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-Chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-Difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-Difluorophenyl)-3-(3-ethoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-Isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((1-ethylpiperidin-3-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-ethoxybut-2-yl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; N-(2-Cyanoethyl)-4-(2,4-Difluorophenyl)-10-methyl-7-((Methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxyamino)methyl acetate; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-phenethyl-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; N-Butyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; N-Cyclohexyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; N-Benzyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(3-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-Difluorophenyl)-N-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-Difluorophenyl)-N-(2-hydroxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-N-(oxazol-4-ylmethyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; N-(cyclopropylmethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-Difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-Difluorophenyl)-N-(1-(hydroxymethyl)cyclopropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-Difluorophenyl)-10-methyl-N-(1-methylcyclopropyl)-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(4-phenylbutyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxamide; 4-(3,3-dimethylbutyryl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; ((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)cyclohexyl)tert-butyl carbamate; 4-((trans)-4-aminocyclohexyl)-10-methyl-7-(methanesulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(cyclopropylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 5,7-Difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formate ethyl ester; 4-(2,4-difluorophenyl)-10-methyl-3-(3-(methylamino)propyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-Difluorophenyl)-3-(3-(dimethylamino)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-Chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 2-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-7-yl)acetonitrile; 4-(2,2-dimethyl-3-(pyrrolidone-1-yl)propyl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 2-(3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)pyrrolidine-1-yl)acetic acid; 10-Methyl-7-((methylsulfonyl)methyl)-4-(2-methyltetrahydrofuran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-4-(1-methylpiperidin-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-((1-isopropylpiperidin-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(1-(2-oxotetrahydrofuran-3-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(1-Methoxypropyl-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-methoxybut-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-4-(1-methylpyrrolidone-3-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-4-(1-methylazacycloheptane-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(1-Ethylpiperidin-3-yl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)benzylnitrile; 4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; N-Ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 5-Cyclopropyl-4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)cyclohexyl)tert-butyl carbamate; (trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)cyclohexyl)tert-butyl carbamate; 4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-2-carboxynitrile; 4-(2,4-Difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-Chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-2-carboxynitrile; 4-(2,4-Difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 4-(4-cyanophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; (S)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)methyl)isoindoline-1,3-dione; (R)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)methyl)isoindoline-1,3-dione; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-5-carboxynitrile; 10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxylic acid ethyl ester; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-2-carboxynitrile; 10-Methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-aminocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(3,5-Difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(naphth-1-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-( ^3,3-2H2 ) _-10 -methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-neopentyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methanesulfonyl)methyl)-3-((1-oxoisoindoline-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-3-(2,6-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-3-(3,5-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(3,5-di-tert-butylphenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)cyclohexyl)methyl formate; ((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)cyclohexyl)methyl formate; Methyl ((cis)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)cyclohexyl)formate; 2-(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)ethyl)isoindoline-1,3-dione; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)ethyl)carbamate; 3-([1,1'-biphenyl]-2-yl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(quinolin-8-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(4-(1H-imidazol-1-yl)phenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)benzylnitrile; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-(pyridin-2-yl)phenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)benzylnitrile; 4-(2,4-difluorophenyl)-10-methyl-7-((methanesulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-Difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-carboxylic acid ethyl ester; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-5-carboxamide; 4-(2,4-difluorophenyl)-N,10-dimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-5-carboxamide; 4-(2,4-difluorophenyl)-N,N,10-trimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-5-carboxamide; N-(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)cyclohexyl)acetamide; 10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(5-chloropyridin-2-yl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(1H-indazol-5-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-Benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methanesulfonyl)methyl)-4-(pyridazin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (S)-4-(2,4-difluorophenyl)-10-methyl-7-((methanesulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (R)-4-(2,4-difluorophenyl)-10-methyl-7-((methanesulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2-Fluoropyridin-4-yl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(6-methoxypyridin-2-yl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(5-Fluoropyrimidin-2-yl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 2-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)-2-phenylacetonitrile; 2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)methyl)phenoxy)acetamide; 4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxylic acid; 10-Methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-4-(pyridin-2-yl)-7-(pyrrolidine-1-ylsulfonyl)-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-11(10H)-one; (S)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (R)-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)propionate; Methyl (S)-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-3-yl)propionate; 4-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-Chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methanesulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (R)-N-ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 10-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methanesulfonyl)-4-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-2-(1-Methyl-1H-pyrazol-4-yl)-7-(methanesulfonyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azon-11(10H)-one; and 4-(4-fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azon-11(10H)-one. 30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-3-yl)propionate; 4-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azon-7-yl)ethanesulfonamide; N-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azon-7-yl)ethanesulfonamide; 10-Methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-fluorophenyl)-( ^3,3-2H2 ₎ -10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 7-Fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azine-11(10H)-one; 5,7-Difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 5,7-Difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 4-(4-Chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formamide; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formate ethyl ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-carboxylic acid p-toluene ester; 10-Methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formic acid 4-fluorophenyl ester; and 4-(3,3-dimethylbutyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one. 31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azon-7-yl)ethanesulfonamide; 10-Methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 5,7-Difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-formate ethyl ester; 4-(4-Chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; N-Ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 5-Cyclopropyl-4-(2,4-Difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-4(3H)-yl)cyclohexyl)tert-butyl carbamate; 4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(4-Chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-2-carboxynitrile; 4-(2,4-Difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azine-2-carboxamide; 4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azon-5-carboxynitrile; 10-Methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(3,5-Difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 10-Methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; 4-(6-methoxypyridin-2-yl)-10-methyl-7-((methanesulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one; and 4-(4-Chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azine-11(10H)-one. 32. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 33. Use of a therapeutically effective amount of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient with cancer. 34. The use of claim 33, wherein the cancer is selected from: acoustic neuroma, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, craniopharynx carcinoma, cystadenocarcinoma, dysplastic changes, embryonal carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, primary thrombocytosis, germ cell testicular carcinoma, glioma, malignant glioma, heavy chain disease, angioblastoma, liver tumor, leukemia, lung cancer, lymphoma. Medullary carcinoma, myeloid cyst, melanoma, meningioma, mesothelioma, myeloma, neuroblastoma, NUT midline carcinoma, oral cancer, ovarian cancer, pancreatic cancer, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, gastric cancer, squamous cell carcinoma, synovoma, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor. 35. The use of claim 34, wherein the leukemia is selected from acute lymphoblastic leukemia, acute myeloid leukemia, acute T-cell leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, erythroleukemia, lymphoblastic leukemia, and myeloid leukemia. 36. The use of claim 34, wherein the sarcoma is selected from: chondrosarcoma, endothelial sarcoma, Ewing sarcoma, fibrosarcoma, glioma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, myxosarcoma, osteosarcoma, and rhabdomyosarcoma. 37. The use of claim 34, wherein the lymphoma is selected from Hodgkin lymphoma and non-Hodgkin lymphoma. 38. The use of claim 34, wherein the breast cancer is estrogen receptor-positive breast cancer. 39. The use of claim 34, wherein the liver tumor is hepatocellular carcinoma. 40. The use of claim 34, wherein the prostate cancer is hormone-insensitive prostate cancer. 41. The use of claim 34, wherein the glioma is a oligodendroglioma. 42. The use of claim 34, wherein the myeloma is multiple myeloma. 43. The use of claim 34, wherein the lung cancer is selected from non-small cell lung cancer and small cell lung cancer. 44. Use of a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient’s disease or condition, wherein the disease or condition is selected from: Addison’s disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Bechtel’s disease, bullous dermatitis, cardiomyopathy, cardiac hypertrophy, chronic obstructive pulmonary disease (COPD), dermatitis, eczema, giant cell arteritis, heart failure, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Goran’s arteritis, toxic shock, thyroiditis, type I diabetes, uveitis, vitiligo, vasculitis, and Wegener’s granulomatosis. 45. The use of claim 44, wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis. 46. ​​Use of a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient with chronic kidney disease or condition, wherein said disease or condition is selected from: diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change glomerulonephritis, polycystic kidney disease, and tubulointerstitial nephritis. 47. Use of a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating acute kidney disease or condition in a patient, wherein the acute kidney disease or condition is selected from: kidney disease caused by ischemia-reperfusion, kidney disease caused by cardiac and major surgery, kidney disease caused by percutaneous coronary intervention, nephropathy caused by radiocontrast agents, kidney disease caused by sepsis, kidney disease caused by pneumonia, and kidney disease caused by drug toxicity. 48. Use of a therapeutically effective amount of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating patients with acquired immunodeficiency syndrome (AIDS). 49. Use of a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient’s disease or condition, wherein the disease or condition is selected from: obesity, dyslipidemia, Alzheimer’s disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy and diabetic neuropathy. 50. The use of claim 49, wherein the dyslipidemia is hypercholesterolemia. 51. Use of a therapeutically effective amount of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for contraception in male patients.