JP2006511551A - Mitogen-activated protein kinase activated protein kinase-2 tricyclic aminocyanopyridine inhibitor - Google Patents

Abstract

An aminocyanopyridine compound capable of inhibiting mitogen-activated protein kinase activated protein kinase-2 is described. Also described are pharmaceutical compositions and kits containing aminocyanopyridine MK-2 inhibitory compounds.

Description

Detailed Description of the Invention

CROSS REFERENCE TO RELATED PATENTS AND PATENT APPLICATIONS This application claims the benefit of US Provisional Patent Application No. 60 / 432,844 (filed December 12, 2002), which is incorporated herein by reference in its entirety. This application is entitled “Method of using aminocyanopyridine compound as an inhibitor of mitogen-activated protein kinase-activated protein kinase-2”, both of which were filed on the same day as the present application (and provisional patent application number). Having a 60 / 432,807) and "method for making a tricyclic aminocyanopyridine compound" (and having a provisional patent application number 60 / 432,783) Related.

BACKGROUND ART (1) Field of Invention:
The present invention relates to aminocyanopyridine compounds, in particular, tricyclic aminocyanopyridine compounds that inhibit mitogen-activated protein kinase activated protein kinase-2 (MAPKAP kinase-2 or MK-2), and aminocyanopyridine compounds thereof. It relates to the composition containing this.

(2) Description of Related Art Mitogen-activated protein kinase (MAPK) is a member of a conserved signal transduction pathway that activates transcription factors, translation factors and other target molecules in response to various extracellular signals. is there. MAPK is activated by phosphorylation at the binary phosphorylation motif of the sequence: Thr-X-Tyr by mitogen-activated protein kinase kinase (MAPKK). In higher eukaryotes, the physiological role of MAPK signaling is associated with cellular events such as proliferation, carcinogenesis, development, and differentiation. Thus, the ability to modulate signaling through these pathways may lead to the development of therapeutic and prophylactic therapies for human diseases associated with MAPK signaling, such as inflammatory diseases, autoimmune diseases, and cancer. is there.

  In mammalian cells, three parallel MAPK pathways have been described. The best characterized pathway results in the activation of extracellular signal-regulated kinase (ERK). Less well understood are signaling pathways that result in activation of cJun N-terminal kinase (JNK) and p38 MAPK. See, for example, Davis, Trends Biochem. Sci. 19: 470-473 (1994); Cano, et al., Trends Biochem. Sci. 20: 117-122 (1995).

  The p38 MAPK pathway is potentially activated by a wide variety of stresses and cytotoxicity. These stresses and cytotoxicity include heat shock, UV irradiation, inflammatory cytokines (such as TNF and IL-1), tunicamycin, chemotherapeutic drugs (ie cisplatin), anisomycin, sorbitol / hyperosmotic pressure, γ Includes irradiation, sodium arsenite, and ischemia. See Ono, K., et al, Cellular Signaling 12, 1-13 (2000). In the activation of the p38 pathway, (1) production of pro-inflammatory cytokines such as TNF-α; (2) induction of enzymes such as Cox-2; (3) plays an important role in the regulation of oxidation, Expression of intracellular enzymes such as iNOS; (4) Induction of adhesion proteins such as VCAM-1 and many other inflammation-related molecules. Furthermore, the p38 pathway functions as a regulator in the growth and differentiation of cells of the immune system. See Ono, K., et al., Ibid, page 7.

  p38 kinase is an upstream kinase of mitogen-activated protein kinase activated protein kinase-2 (MAPKAP kinase-2 or MK-2) (Freshney, NW, et al., J. Cell, 78: 1039-1049 (1994) ) checking). MK-2 is a protein that appears to be exclusively regulated by p38 in cells. In fact, MK-2 was the first identified substrate of p38α. For example, in vitro phosphorylation of MK-2 by p38α activates MK-2. Substrates on which MK-2 acts include heat shock protein 27, lymphocyte specific protein 1 (LAP1), cAMP response element binding protein (CREB), ATF1, serum response factor (SRF), and tyrosine hydroxylase It is. The best characterized substrate to date is the small heat shock protein 27 (hsp27).

  The role of the p38 pathway in inflammation-related diseases has been studied in several animal models. The pyridinyl imidazole compound, SB203580, has been shown to be a specific inhibitor of p38 in vivo, and has been shown to be MK-2 (Rouse, J., et al, Cell, 78: 1027-1037 (1994) Cuenda, A., et al, Biochem. J., 333: 11-15 (1998)), as well as inhibiting the activation of a MAP kinase homolog called reactivation kinase (RK). (See Cuenda, A., et al., FEBS Lett., 364 (2): 229-233 (1995)). Inhibition of p38 by SB203580 can reduce mortality in a mouse model of endotoxin-induced shock and inhibit the development of mouse collagen-induced arthritis and rat adjuvant arthritis. See, for example, Badger, A.M., et al., J. Pharmacol Exp. Ther., 279: 1453-1461 (1996). Another p38 inhibitor utilized in animal models and considered to be more potent than SB203580 in its inhibitory effect on p38 is SB220025. Recent animal studies have demonstrated that SB220025 causes a significant dose-dependent decrease in vascular density of granulomas in experimental rats (Jackson, JR, et al, J. Pharmacol. Exp. Ther., 284 : 687-692 (1998)). The results of these animal studies have shown that p38, or a component of the p38 pathway, can be a useful therapeutic target for the prevention or treatment of inflammatory diseases.

  Due to its essential role in the p38 signaling pathway, MK-2 has been used as a monitor to measure the level of activation in this pathway. Because it is located downstream of this pathway compared to p38, MK-2 has been measured as an indirect but simpler method to assess p38 activation. However, so far, research efforts to explore therapeutic strategies associated with modulation of this pathway have focused primarily on the inhibition of p38 kinase.

  Several compounds that inhibit the activity of p38 kinase are described in US Pat. Nos. 6,046,208, 6,251,914, and 6,335,340. These compounds have been suggested to be useful in the treatment of CSBP / RK / p38 kinase mediated diseases. Practical efforts to apply p38 inhibitors have largely focused on two p38 inhibitors, the pyridinyl imidazole inhibitor SKF86002 and the 2,4,5-triarylimidazole inhibitor SB203580. See Lee, J. C., et al, Immunopharmacology 47, 185-192 (2000). Compounds possessing similar structures are also being investigated as potential p38 inhibitors. Indeed, the role of p38 MSP kinase in various disease states has been elucidated through the use of inhibitors.

Kotlyarov, A. et al, introduced a targeted mutation into the mouse MK-2 gene in Nat. Cell Biol., 1 (2): 94-97 (1999) to obtain MK-2 deficient mice. It was. Mice lacking MK-2 possess increased stress resistance and have been shown to survive more LPS-induced endotoxin shock than MK-2 ⁺ mice. The authors concluded that MK-2 is an essential factor in the inflammatory response that regulates TNFα biosynthesis at a post-transcriptional level. More recently, Lehner, MD, et al, in J. Immunol., 168 (9): 4667-4673 (2002), showed that MK-2 deficient mice have increased susceptibility to Listeria monocytogenes infection. MK-2 plays an essential role in host defense against intracellular bacteria, possibly through the regulation of TNF and IFN-γ production, which is required for activation of antimicrobial effector mechanisms. We concluded that we have.

  In the p38 signaling pathway, the location of MK-2 at a point downstream of p38 affects as much substrate as the regulation of further upstream enzymes (such as p38 MAP kinase) in this signaling cascade. Offers the potential that MK-2 may act as a focal point for modulating this pathway without.

  It would therefore be useful to provide compounds that can serve to modulate the activity of MK-2, in particular to act as inhibitors of MK-2 activity. Such compounds would be useful in providing benefits similar to p38 MAP kinase inhibitors, including benefits and prevention and treatment of diseases and disorders mediated by TNFα. It would be even more useful to provide MK-2 inhibitors that have increased potency and reduced unwanted side effects compared to p38 inhibitors.

SUMMARY OF THE INVENTION Briefly, therefore, the present invention has the structure:

[Where:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each:
Hydrogen, hydroxy, amino, halo, nitro,
Branched or unbranched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenoxy,
Branched or unbranched amino C ₁ -C ₆ alkyl, diamino C ₂ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, di (C _1- C ₆ alkyl) amino, C ₁ -C ₄ alkoxyarylamino, C ₁ -C ₄ alkoxyalkylamino, amino C ₁ -C ₆ alkoxy, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₆ alkoxy, Di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, dihalo C ₁ -C ₆ alkoxy, trihalo C ₁ -C ₆ alkoxy, cyano _C 1 -C ₆ alkyl, dicyano _C 1 -C ₆ alkyl, cyano _C 1 -C ₆ alkoxy, dicyano _C 1 -C ₆ alkoxy, Rubamiru _C 1 -C ₄ alkoxy, heterocyclyl _C 1 -C ₄ alkoxy, heteroaryl _C 1 -C ₄ alkoxy, sulfo, _sulfamyl, C 1 -C ₄ alkylaminosulfonyl, hydroxy _C 1 -C ₄ alkylaminosulfonyl, di ( C ₁ -C ₄ alkyl) _{aminosulfonyl,} C 1 -C _{4 alkylthio,} C 1 -C _{4 alkylsulfonyl,} C 1 -C ₄ alkylsulfinyl,
Aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, heteroaryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkoxy, heteroaryl C ₁ -C ₆ alkoxy, aryl C ₁ -C ₆ Alkoxy (wherein the aryl ring may be substituted or unsubstituted, and if substituted, the substituent is a group of C ₁ -C ₆ alkyl, halo, amino, and C ₁ -C ₆ alkoxy; Selected from one or more),
Substituted or unsubstituted C ₃ -C ₆ cyclyl, C ₃ -C ₆ heterocyclyl (and, if substituted, the substituent consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, amino) is selected from one or more of the group, and _C 3 -C ₆ heterocyclyl ring here, O, containing S, or N),
Branched or unbranched _C 1 -C ₆ alkoxycarbonyl _C 1 -C ₆ alkoxy, and carboxy, carboxy _C 1 -C ₆ alkoxy, carboxy _C 1 -C ₆ alkyl, hydroxy _C 1 -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl,
Independently selected from the group consisting of
Where R ⁶ and R ⁷ are as described above, optionally combined:

Forming a ring system of a more selected type;
G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
When G is nitrogen, R ⁴ is —H, R ⁹ is absent, and R ¹⁰ is C ₁ -C ₄ alkyl].

  The present invention also includes a pharmaceutically acceptable carrier and a structure:

[Where:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each:
Hydrogen, hydroxy, amino, halo, nitro,
Branched or unbranched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenoxy,
Branched or unbranched amino C ₁ -C ₆ alkyl, diamino C ₂ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, di (C _1- C ₆ alkyl) amino, C ₁ -C ₄ alkoxyarylamino, C ₁ -C ₄ alkoxyalkylamino, amino C ₁ -C ₆ alkoxy, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₆ alkoxy, Di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, dihalo C ₁ -C ₆ alkoxy, trihalo C ₁ -C ₆ alkoxy, cyano _C 1 -C ₆ alkyl, dicyano _C 1 -C ₆ alkyl, cyano _C 1 -C ₆ alkoxy, dicyano _C 1 -C ₆ alkoxy, Rubamiru _C 1 -C ₄ alkoxy, heterocyclyl _C 1 -C ₄ alkoxy, heteroaryl _C 1 -C ₄ alkoxy, sulfo, _sulfamyl, C 1 -C ₄ alkylaminosulfonyl, hydroxy _C 1 -C ₄ alkylaminosulfonyl, di ( C ₁ -C ₄ alkyl) _{aminosulfonyl,} C 1 -C _{4 alkylthio,} C 1 -C _{4 alkylsulfonyl,} C 1 -C ₄ alkylsulfinyl,
Aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, heteroaryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkoxy, heteroaryl C ₁ -C ₆ alkoxy, aryl C ₁ -C ₆ Alkoxy (wherein the aryl ring may be substituted or unsubstituted, and if substituted, the substituent is a group of C ₁ -C ₆ alkyl, halo, amino, and C ₁ -C ₆ alkoxy; Selected from one or more),
Substituted or unsubstituted C ₃ -C ₆ cyclyl, C ₃ -C ₆ heterocyclyl (and, if substituted, the substituent consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, amino) is selected from one or more of the group, and _C 3 -C ₆ heterocyclyl ring here, O, containing S, or N),
Branched or unbranched _C 1 -C ₆ alkoxycarbonyl _C 1 -C ₆ alkoxy, and carboxy, carboxy _C 1 -C ₆ alkoxy, carboxy _C 1 -C ₆ alkyl, hydroxy _C 1 -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl,
Independently selected from the group consisting of
Where R ⁶ and R ⁷ are as described above, optionally combined:

Forming a ring system of a more selected type;
G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
When G is nitrogen, R ⁹ is absent and R ¹⁰ is C ₁ -C ₄ alkyl] is directed to a novel pharmaceutical composition comprising an aminocyanopyridine MK-2 inhibitor compound having.

  The present invention also includes a structure:

[Where:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each:
Hydrogen, hydroxy, amino, halo, nitro,
Branched or unbranched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenoxy,
Branched or unbranched amino C ₁ -C ₆ alkyl, diamino C ₂ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, di (C _1- C ₆ alkyl) amino, C ₁ -C ₄ alkoxyarylamino, C ₁ -C ₄ alkoxyalkylamino, amino C ₁ -C ₆ alkoxy, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₆ alkoxy, Di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, dihalo C ₁ -C ₆ alkoxy, trihalo C ₁ -C ₆ alkoxy, cyano _C 1 -C ₆ alkyl, dicyano _C 1 -C ₆ alkyl, cyano _C 1 -C ₆ alkoxy, dicyano _C 1 -C ₆ alkoxy, Rubamiru _C 1 -C ₄ alkoxy, heterocyclyl _C 1 -C ₄ alkoxy, heteroaryl _C 1 -C ₄ alkoxy, sulfo, _sulfamyl, C 1 -C ₄ alkylaminosulfonyl, hydroxy _C 1 -C ₄ alkylaminosulfonyl, di ( C ₁ -C ₄ alkyl) _{aminosulfonyl,} C 1 -C _{4 alkylthio,} C 1 -C _{4 alkylsulfonyl,} C 1 -C ₄ alkylsulfinyl,
Aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, heteroaryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkoxy, heteroaryl C ₁ -C ₆ alkoxy, aryl C ₁ -C ₆ Alkoxy (wherein the aryl ring may be substituted or unsubstituted, and if substituted, the substituent is a group of C ₁ -C ₆ alkyl, halo, amino, and C ₁ -C ₆ alkoxy; Selected from one or more),
Substituted or unsubstituted C ₃ -C ₆ cyclyl, C ₃ -C ₆ heterocyclyl (and, if substituted, the substituent consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, amino) is selected from one or more of the group, and _C 3 -C ₆ heterocyclyl ring here, O, containing S, or N),
Branched or unbranched _C 1 -C ₆ alkoxycarbonyl _C 1 -C ₆ alkoxy, and carboxy, carboxy _C 1 -C ₆ alkoxy, carboxy _C 1 -C ₆ alkyl, hydroxy _C 1 -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl,
Independently selected from the group consisting of
Where R ⁶ and R ⁷ are as described above, optionally combined:

Forming a ring system of a more selected type;
G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
To a new kit comprising a dosage form containing an aminocyanopyridine MK-2 inhibitor compound having G ⁹ is nitrogen and R ⁹ is absent and R ¹⁰ is C ₁ -C ₄ alkyl] Directed.

  Thus, several advantages that have been found to be achieved by the present invention include the provision of compounds that can modulate the activity of MK-2, in particular, can inhibit MK-2 activity, and diseases mediated by TNFα and Attention may be given to the provision of compounds that are useful in the prevention and treatment of disorders.

Detailed Description of the Preferred Embodiments According to the present invention, it has been discovered that certain aminocyanopyridine compounds can inhibit the activity of MAPKAP kinase-2. Many of these compounds demonstrate their inhibitory effects at low concentrations, have in vitro MK-2 inhibition IC ₅₀ values of less than 1 μM, some of which are less than about 0.5 μM, and even about 0.2 μM. Have low IC ₅₀ values. Thus, these compounds may be potent and effective drugs for use in methods of preventing or treating diseases and disorders mediated by TNFα. For example, they can be used for the prevention or treatment of arthritis.

  Aminocyanopyridine compounds useful in the present methods include those of formula I:

[Where:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each:
Hydrogen, hydroxy, amino, halo, nitro,
Branched or unbranched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenoxy,
Branched or unbranched amino C ₁ -C ₆ alkyl, diamino C ₂ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, di (C _1- C ₆ alkyl) amino, C ₁ -C ₄ alkoxyarylamino, C ₁ -C ₄ alkoxyalkylamino, amino C ₁ -C ₆ alkoxy, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₆ alkoxy, Di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, dihalo C ₁ -C ₆ alkoxy, trihalo C ₁ -C ₆ alkoxy, cyano _C 1 -C ₆ alkyl, dicyano _C 1 -C ₆ alkyl, cyano _C 1 -C ₆ alkoxy, dicyano _C 1 -C ₆ alkoxy, Rubamiru _C 1 -C ₄ alkoxy, heterocyclyl _C 1 -C ₄ alkoxy, heteroaryl _C 1 -C ₄ alkoxy, sulfo, _sulfamyl, C 1 -C ₄ alkylaminosulfonyl, hydroxy _C 1 -C ₄ alkylaminosulfonyl, di ( C ₁ -C ₄ alkyl) _{aminosulfonyl,} C 1 -C _{4 alkylthio,} C 1 -C _{4 alkylsulfonyl,} C 1 -C ₄ alkylsulfinyl,
Aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, heteroaryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkoxy, heteroaryl C ₁ -C ₆ alkoxy, aryl C ₁ -C ₆ Alkoxy (wherein the aryl ring may be substituted or unsubstituted, and if substituted, the substituent is a group of C ₁ -C ₆ alkyl, halo, amino, and C ₁ -C ₆ alkoxy; Selected from one or more),
Substituted or unsubstituted C ₃ -C ₆ cyclyl, C ₃ -C ₆ heterocyclyl (and, if substituted, the substituent consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, amino) is selected from one or more of the group, and _C 3 -C ₆ heterocyclyl ring here, O, containing S, or N),
Branched or unbranched _C 1 -C ₆ alkoxycarbonyl _C 1 -C ₆ alkoxy, and carboxy, carboxy _C 1 -C ₆ alkoxy, carboxy _C 1 -C ₆ alkyl, hydroxy _C 1 -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl,
Independently selected from the group consisting of
Where R ⁶ and R ⁷ are as described above, optionally combined:

An aminocyanopyridine compound having the structure shown in [Forming a ring system of a more selected type].
As indicated above, ring substituents that join to form an additional ring structure adjacent to the ring to be substituted may be described in terms of a chemical formula that shows a dashed line to indicate that a partial molecule is shown. . In the above formula, the dashed line breaks the ring to which the substituent is attached (in this case, the phenyl ring of formula I) without traversing the bond connecting the substituent to the ring. Thus, the partial ring shown is a ring shown as having a substituent attached in the general formula.

G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
When G is nitrogen, R ⁴ is —H, R ⁹ is absent, and R ¹⁰ is C ₁ -C ₄ alkyl.

In a preferred embodiment, R ⁶ is other than cyano.
The term “alkyl” as used herein, alone or in combination, means a linear or branched acyclic alkyl group, preferably containing from 1 to about 10 carbon atoms, unless otherwise stated. And more preferably contains from 1 to about 6 carbon atoms. “Alkyl” also includes cyclic alkyl groups containing from 3 to about 7 carbon atoms, preferably from 3 to 5 carbon atoms. The alkyl group may be optionally substituted with a group as defined below. Examples of such alkyl groups include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, isoamyl, hexyl, Octyl, etc. are included.

  The term “alkenyl” means a linear or branched unsaturated acyclic hydrocarbon group so long as it contains at least one double bond. Unless otherwise stated, such residues preferably contain from 2 to about 6 carbon atoms, preferably from 2 to about 4 carbon atoms, more preferably from 2 to about 3 carbon atoms. An alkenyl group may be optionally substituted with groups as defined below. Examples of suitable alkenyl groups include propenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexene- 1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like are included.

  The term “alkynyl” means a straight or branched unsaturated acyclic hydrocarbon group as long as it contains one or more triple bonds, such residues preferably having from 2 to about 6 carbons. Contains atoms, more preferably from 2 to about 3 carbon atoms. Alkynyl groups may be optionally substituted with groups as described below. Examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl groups, and the like are included.

  The term “alkoxy” includes straight or branched chain oxy-containing groups, each of which, unless stated otherwise, such as 1 to 1, such as methoxy, ethoxy, propoxy, isopropoxy, isobutoxy groups, and the like. It has an alkyl moiety of about 6 carbon atoms, preferably 1 to about 4 carbon atoms.

  The term “alkoxyalkyl” also includes alkyl groups in which one or more alkoxy groups are attached to an alkyl group, ie, form monoalkoxyalkyl and dialkoxyalkyl groups. Examples of such residues include methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, tert-butoxyalkyl, and the like. An “alkoxy” group may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide a “haloalkoxy” group. Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, fluoropropoxy, and the like.

The term “alkylthio” includes residues that contain a straight or branched alkyl group, preferably of 1 to about 6 carbon atoms, attached to a divalent sulfur atom, unless otherwise stated. An example of “lower alkylthio” is methylthio (CH ₃ —S—).

The term “alkylthioalkyl” includes an alkylthio group attached to an alkyl group. An example of such a residue is methylthiomethyl.
The term “halo” means a residue comprising a halogen such as fluorine, chlorine, bromine, or iodine.

  The term “heterocyclyl” means a saturated or unsaturated mono- or polycyclic carbocycle in which one or more carbon atoms are replaced by N, S, P, or O. This includes, for example:

[Wherein Z, Z ¹ , Z ² , or Z ³ is C, S, P, O, or N. However, one of Z, Z ¹ , Z ² or Z ³ is other than carbon, but when attached to another Z by a double bond, or attached to another O or S atom, either O or S Absent. Furthermore, it is understood that optional substituents can be attached to Z, Z ¹ , Z ² , or Z ³ only when each is C]. The term “heterocycle” also includes fully saturated ring structures such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and the like.

  The term “heteroaryl” refers to a fully unsaturated heterocycle and may include, but is not limited to, furyl, thienyl, pyryl, imidazolyl, pyrazolyl, pyridyl, thiazolyl, quinolinyl, isoquinolinyl, benzothienyl, and indolyl.

In either “heterocyclyl” or “heteroaryl”, the point of attachment to the molecule of interest can be a heteroatom in the ring or anywhere else.
The term “cycloalkyl” refers to monocyclic or polycyclic, each ring containing from 3 to about 7 carbon atoms, preferably from 3 to about 6 carbon atoms, and more preferably from 3 to about 5 carbon atoms. Means carbocycle. Examples include residues such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term “cycloalkyl” additionally includes spiro systems in which the cycloalkyl ring shares a carbon ring atom with the 7-membered heterocyclic ring of benzothiepine.

The term “oxo” means a double bonded oxygen.
The term “aryl” means a fully unsaturated monocyclic or polycyclic carbocycle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl.

The aminocyanopyridine compound inhibits the activity of the MK-2 enzyme. When the subject compound is said to inhibit MK-2, it indicates that the enzyme activity of MK-2 is lower in the presence of the compound than in the absence of the compound under the same conditions. means. One way to express the efficacy of a compound as an MK-2 inhibitor is to measure the “IC ₅₀ ” value of the compound. The IC ₅₀ value of an MK-2 inhibitor is the concentration of compound required to reduce MK-2 enzyme activity by half. Thus, compounds with lower IC ₅₀ values are considered to be more potent inhibitors than compounds with higher IC ₅₀ values. As used herein, an aminocyanopyridine compound that inhibits MK-2 may be referred to as an aminocyanopyridine MK-2 inhibitor, or an aminocyanopyridine MK-2 inhibitor compound, or an MK-2 inhibitor. is there.

Tricyclic aminocyanopyridine compounds useful in the present invention include benzonaphthyridine, pyridochroman, and pyridothiochroman.
Examples of tricyclic aminocyanopyridine compounds useful as MK-2 inhibitors in this method are shown in Table I.

  Table I: Aminocyanopyridine MK-2 inhibitors

In another embodiment, the aminocyanopyridine compound has the formula I [where:
R ¹ is hydrogen, branched or unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy, carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl, alkylamino, halo, Selected from the group consisting of alkylaminoalkyl, alkoxy, alkoxyalkyl, monocyclyl, bicyclyl, polycyclyl, and heterocyclyl;
R ² is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl Selected;
R ³ is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituent, if any, includes a halo moiety;
R ⁴ is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituent, if any, includes a halo moiety;
R ⁵ is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkynyl, arylalkyl, or alkylaryl;
R ⁶ is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, aryl Selected from the group consisting of alkyl, alkylaryl, or arylamino;
R ⁷ is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy,
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is from hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl And G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
When G is nitrogen, R ⁹ is absent and R ¹⁰ is C ₁ -C ₄ alkyl].

In another embodiment, the aminocyanopyridine compound has the formula I [where:
R ¹ is selected from the group consisting of hydrogen, ethyl, dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl;
R ² is hydrogen, hydroxyethyl, propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl, phenylmethyl, dimethylaminoethyl, phthaloaminoethyl, butyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl Selected from the group consisting of:
R ³ is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
R ⁴ is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
R ⁵ is selected from the group consisting of hydrogen, hydroxy, methoxy, bromo, and 2-pyridomethyl;
R ⁶ is selected from the group consisting of hydrogen, hydroxy, methoxy, amino, carboxy, diaminoethoxy, bromo, propoxy, isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro, pyridylmethyl, and fluoro;
R ⁷ consists of hydrogen, hydroxy, methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy, morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy, dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and isobutylcarboxymethoxy Selected from the group,
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is hydrogen, hydroxy, fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl, hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy, dimethylaminoethoxy, carboxy, bromo, and Selected from the group consisting of pyridylmethyl; and G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
When G is nitrogen, R ⁹ is absent and R ¹⁰ is —CH ₃ ].

In another embodiment, the aminocyanopyridine compound may provide an IC ₅₀ of less than about 200 μM in an in vitro assay for MK-2 inhibitory activity. Examples of such compounds are those of formula I [where:
R ¹ is selected from the group consisting of hydrogen and C ₁ -C ₂ alkyl;
R ² is hydrogen, C ₁ -C ₃ alkyl, hydroxy C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxyphenyl, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkyl, amino C ₁ -C ₂ alkyl, Selected from the group consisting of phenyl C ₁ -C ₂ alkyl and diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, dicyano C ₁ -C ₂ alkyl, and halophenyl;
R ⁵ is selected from the group consisting of hydrogen and hydroxy;
R ⁶ is hydrogen, hydroxy, C ₁ -C ₃ alkoxy, amino, nitro, carboxy, diamino C ₁ -C ₂ alkoxy, halo, propenoxy, isoC ₃ -C ₄ alkylcarboxy C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino, and are selected from the group consisting of phenyl;
R ⁷ is hydrogen, hydroxy, C ₁ -C ₃ alkoxy, hydroxy C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkoxy, amino C ₁ -C ₂ alkoxy, morpholino C ₁ -C ₂ Alkoxy, carboxyl C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkyl, isoC ₃ -C ₄ alkyl carboxy C Selected from the group consisting of ₁ -C ₂ alkoxy, and 2-propenoxy;
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is hydrogen, hydroxy, halo, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, nitro, amino, pyrrolidyl C ₁ -C ₂ alkoxy, carboxy C ₁ -C ₂ alkoxy, hydroxy C ₁ -C ₂ Selected from the group consisting of alkoxy and amino C ₁ -C ₂ alkoxy; and G is selected from the group consisting of oxygen and sulfur;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
R ⁹ and R ¹⁰ are absent when G is oxygen].

In another embodiment, the aminocyanopyridine compound may provide an IC ₅₀ of less than about 100 μM in an in vitro assay for MK-2 inhibitory activity. Examples of such compounds are those of formula I [where:
R ¹ is hydrogen;
R ² is hydrogen, C ₁ -C ₃ alkyl, hydroxy C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxyphenyl, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkyl, amino C ₁ -C ₂ alkyl, Selected from the group consisting of phenyl C ₁ -C ₂ alkyl and diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and dicyano C ₁ -C ₂ alkyl;
R ⁵ is selected from the group consisting of hydrogen and hydroxy;
R ⁶ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, amino, carboxy, nitro, diamino C ₁ -C ₂ alkoxy, halo, 2-propenoxy, isoC ₃ -C ₄ alkylcarboxy C ₁ -C ₂ alkoxy, Selected from the group consisting of diC ₁ -C ₂ alkylamino and phenyl;
R ⁷ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, hydroxy C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkoxy, amino C ₁ -C ₂ alkoxy, morpholino C ₁ -C ₂ Alkoxy, carboxyl C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkyl, isoC ₃ -C ₄ alkyl carboxy C ₁ -C ₂ alkoxy, and is selected from the group consisting of 2-propenoxy;
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, hydroxy, halo, C ₁ -C ₂ alkoxy, nitro, amino, pyrrolidyl C ₁ -C ₂ alkoxy, and carboxy C ₁ -C ₂ alkoxy; and G is oxygen and Selected from the group consisting of sulfur;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
R ⁹ and R ¹⁰ are absent when G is oxygen].

In another embodiment, the aminocyanopyridine compound may provide an IC ₅₀ of less than about 50 μM in an in vitro assay for MK-2 inhibitory activity. Examples of such compounds are those of formula I [where:
R ¹ is hydrogen;
R ² is hydrogen, C ₁ -C ₃ alkyl, hydroxy C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxyphenyl, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkyl, amino C ₁ -C ₂ alkyl, And selected from the group consisting of phenyl C ₁ -C ₂ alkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and dicyano C ₁ -C ₂ alkyl;
R ⁵ is selected from the group consisting of hydrogen and hydroxy;
R ⁶ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, amino, carboxy, diamino C ₁ -C ₂ alkoxy, halo, 2-propenoxy, isoC ₃ -C ₄ alkylcarboxy C ₁ -C ₂ alkoxy, and di Selected from the group consisting of C ₁ -C ₂ alkylamino;
R ⁷ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, hydroxy C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkoxy, amino C ₁ -C ₂ alkoxy, morpholino C ₁ -C ₂ Alkoxy, carboxyl C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkyl, isoC ₃ -C ₄ alkyl carboxy C Selected from the group consisting of ₁ -C ₂ alkoxy, and 2-propenoxy;
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, hydroxy, halo, C ₁ -C ₂ alkoxy, nitro, amino, and pyrrolidyl C ₁ -C ₂ alkoxy; and G is selected from the group consisting of oxygen and sulfur;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
R ⁹ and R ¹⁰ are absent when G is oxygen].

In another embodiment, the aminocyanopyridine compound may provide an IC ₅₀ of less than about 20 μM in an in vitro assay for MK-2 inhibitory activity. Examples of such compounds are those of formula I [where:
R ¹ is hydrogen;
R ² is hydrogen, C ₁ -C ₃ alkyl, hydroxy C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxyphenyl, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkyl, and amino C ₁ -C ₂ alkyl Selected from the group consisting of:
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and dicyanoethyl;
R ⁵ is selected from the group consisting of hydrogen and hydroxy;
R ⁶ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, amino, carboxy, diamino C ₁ -C ₂ alkoxy, halo, 2-propenoxy, isoC ₃ -C ₄ alkylcarboxy C ₁ -C ₂ alkoxy, and di Selected from the group consisting of C ₁ -C ₂ alkylamino;
R ⁷ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, hydroxy C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkoxy, amino C ₁ -C ₂ alkoxy, morpholino C ₁ -C ₂ Alkoxy, carboxyl C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkyl, isoC ₃ -C ₄ alkyl carboxy C Selected from the group consisting of ₁ -C ₂ alkoxy, and 2-propenoxy;
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, hydroxy, halo, methoxy, nitro, and amino; and G is selected from the group consisting of oxygen and sulfur;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
R ⁹ and R ¹⁰ are absent when G is oxygen].

Examples of aminocyanopyridine MK-2 inhibitory compounds of the present invention include, without limitation, the following:
2,4-diamino-7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
8,10-diamino-2,3-dihydro-11H- [1,4] dioxino [2 ′, 3 ′: 6,7] chromeno [2,3-b] pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile 2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-morpholin-4-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-8-yl) oxy] acetic acid,
2,4-diamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4- (methylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- [2- (dimethylamino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-8-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-diamino-7,8-di [2- (amino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-hydroxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2- (2,4-diamino-3-cyano-7-bromo-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2-amino-8-ethoxy-4- (ethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,9-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-diamino-9-hydroxy-8- (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-bis (allyloxy) -2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-8- (2-ethoxyethoxy) -4-[(2-ethoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
{[2,4-diamino-7- (2-tert-butoxy-2-oxoethoxy) -3-cyano-5H-chromeno [2,3-b] pyridin-8-yl] oxy} tert-butyl acetate,
2-amino-4-[(2-aminoethyl) amino] -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-8-hydroxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-bromo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7- (dimethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-9-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2-amino-4- (benzylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
8- (allyloxy) -2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-9-yl) oxy] acetic acid,
2-amino-4-{[2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-phenyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-chloro-9-methyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
8-ethoxy-2,4-bis (ethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5- (2-fluoro-phenyl) -8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-chloro-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-bis {[2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-Amino-4-{[2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3 -B] pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-bromo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (pyridin-4-ylmethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-chloro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-tert-butyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
Ethyl 2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-9-carboxylate,
2,4-diamino-9- [2- (dimethylamino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-bis (butylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (butylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-bis (ethylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (ethylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7- (trifluoromethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-bromo-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-methoxy-7-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,9-diamino-10H- [1,3] dioxolo [6,7] chromeno [2,3-b] pyridine-8-carbonitrile,
7,9-diamino-10H- [1,3] dioxolo [6,7] chromeno [2,3-b] pyridine-8-carbonitrile,
2,4-diamino-8-methyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis [(2-methoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(2-methoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(2-pyrrolidin-1-ylethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis [(2-pyrrolidin-1-ylethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-bis (glycinyl) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
N- (2-amino-3-cyano-7,8-dimethoxy-5H-chromeno [2,3-b] pyridin-4-yl) glycine,
2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-9-carboxylic acid,
2,4-diamino-6-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-bromo-7-chloro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-bis (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6-bromo-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-7,9-bis (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5-phenyl-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5- (3-fluoro-phenyl) -8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-6,8-bis (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-bromo-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5-phenyl-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,9-dimethyl-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-isopropyl-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-ethyl-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-methyl-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-chloro-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-bromo-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-Amino-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile and 3-amino-5H-pyrido [3,4-b] [1,4] benzothiazine-4-carbo Nitrile.

  The salts and prodrugs of the aminocyanopyridine compounds described herein, as well as isomeric forms, tautomers, racemic mixtures, etc. of the compounds having the same or similar activity as the compounds described It should be understood that it is considered included in the description.

Aminocyanopyridine MK-2 inhibitor compounds of the type shown in Formula I above include tricyclic aminocyanopyridine MK-2 inhibitor compounds such as benzonaphthyridine, pyridochroman, and pyridothiochroman. A general method for the synthesis of these tricyclic aminocyanopyridines is shown in Scheme 1 below:
Scheme 1:

  In this method, the substituted benzaldehyde is reacted with tricarbonitrile, preferably 2-amino-1-propene-1,1,3-tricarbonitrile. This reaction can be carried out by heating the reactants to reflux in a solution of acetic acid and ethanol. The reaction product may be concentrated in vacuo and dissolved in trifluoroacetic acid. Triethylsilane is added and the mixture is stirred. In a preferred method, the mixture is stirred at 0 ° C. for about 1 hour. Dichloromethane is then added and the solid is collected. The solid may be collected by filtration and washed with dichloromethane and ether. This solid contains the desired tricyclic aminocyanopyridine MK-2 inhibitor compound of the type including benzonaphthyridine, pyridochroman, and pyridothiochroman.

With respect to the reactants and products shown above in Scheme I:
Z may be OH, SH, or NR ^a Y, where Y is a nitrogen protecting group. The Y group may be benzyl, allyl, alkyl carbamate, or benzyl carbamate. Other nitrogen protecting groups are known to those skilled in the art of organic synthesis. A preferred protecting group is tert-butyl carbamate. R ^a may be an alkyl group, an aryl group, or a heteroaryl group. The benzene ring of the benzaldehyde may be further substituted with 1, 2, 3, or 4 additional R groups at carbon 3, 4, 5, or 6. Each R is independently hydrogen; alkyl; aryl; _hydrogen, C 1 -C _{6 alkyl,} C 1 -C ₆ branched-chain alkyl, aryl, heteroaryl (wherein the heteroaryl include, but are not limited to, It may be a heteroatom such as O, N, or S, substituted with pyrazolyl, inidizolyl, pyryl, pyridyl, thiophyll, furyl, and pyrimidyl), esters, and amides.

  The advantages of this method include that it is a general method that can be used to produce various types of tricyclic compounds of Formula I, depending on the type of reactants used. This is also a simple and direct synthesis method that can be performed in a single vessel.

  In this synthetic embodiment, the tricyclic aminocyanopyridine MK-2 inhibitor compound has the structure:

A substituted benzaldehyde having the structure:

Produced by reacting with tricarbonitrile having the structure:

An aminocyanopyridine compound having the following formula can be obtained:
Z is selected from the group consisting of —OH, —SH, and —NR ^a Y;
R ^a is selected from the group consisting of alkyl, aryl, and heteroaryl;
Y is a protecting group for nitrogen. Examples of such nitrogen protecting groups include benzyl, allyl, alkyl carbamate and benzyl carbamate.

G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, it has no substituents;
When G is sulfur, it is unsubstituted or substituted with one or two oxo groups;
When G is nitrogen, it is substituted with _C 1 -C ₄ alkyl;
R ^b is selected from the group consisting of furyl and —NH—R ² ;
R ² is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl Selected;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituent, if any, includes a halo moiety;
R ⁵ , R ⁶ , R ⁷ , and R ⁸ are hydrogen, hydroxy, alkoxy, halo, alkyl, alkenyl, alkynyl, arylalkyl, alkylaryl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy Alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylamino, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, alkylcarboxyalkoxy, pyrrolidylethoxy, hydroxyalkoxy, and are each independently selected from the group consisting of alkyl carboxylate, wherein, R ⁶ and R ⁷ are those mentioned above, optionally Combine to form a 6-membered heterocyclic ring.

In the general law embodiments described above,
R ² is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl Selected;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituent, if any, includes a halo moiety;
R ⁵ is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkynyl, arylalkyl, or alkylaryl;
R ⁶ is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, aryl Selected from the group consisting of alkyl, alkylaryl, or arylamino;
R ⁷ is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy,
Wherein R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring; and R ⁸ is hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxy Selected from the group consisting of alkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl.

  In a preferred embodiment of the method, the substituted benzaldehyde comprises salicaldehyde and the tricarbonitrile comprises 2-amino-1-propene-1,1,3-tricarbonitrile. It is also preferred that the nitrogen protecting group “Y” comprises tert-butyl carbamate.

In an embodiment of the method,
Z is selected from the group consisting of —OH, —SH, and —NR ^a Y;
R ^a is selected from the group consisting of alkyl, aryl, and heteroaryl;
Y is a protecting group for nitrogen selected from the group consisting of benzyl, allyl, alkyl carbamate, and benzyl carbamate;
G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, it has no substituents;
When G is sulfur, it is unsubstituted or substituted with one or two oxo groups;
When G is nitrogen, it is substituted with _C 1 -C ₄ alkyl;
R ^b is selected from the group consisting of furyl and —NH—R ² ;
R ² is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl Selected;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituent, if any, includes a halo moiety;
R ⁵ , R ⁶ , R ⁷ , and R ⁸ are:
Hydrogen, hydroxy, amino, halo, nitro,
Branched or unbranched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenoxy,
Branched or unbranched amino C ₁ -C ₆ alkyl, diamino C ₂ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, di (C _1- C ₆ alkyl) amino, C ₁ -C ₄ alkoxyarylamino, C ₁ -C ₄ alkoxyalkylamino, amino C ₁ -C ₆ alkoxy, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₆ alkoxy, Di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, dihalo C ₁ -C ₆ alkoxy, trihalo C ₁ -C ₆ alkoxy, cyano _C 1 -C ₆ alkyl, dicyano _C 1 -C ₆ alkyl, cyano _C 1 -C ₆ alkoxy, dicyano _C 1 -C ₆ alkoxy, Rubamiru _C 1 -C ₄ alkoxy, heterocyclyl _C 1 -C ₄ alkoxy, heteroaryl _C 1 -C ₄ alkoxy, sulfo, _sulfamyl, C 1 -C ₄ alkylaminosulfonyl, hydroxy _C 1 -C ₄ alkylaminosulfonyl, di ( C ₁ -C ₄ alkyl) _{aminosulfonyl,} C 1 -C _{4 alkylthio,} C 1 -C _{4 alkylsulfonyl,} C 1 -C ₄ alkylsulfinyl,
Aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, heteroaryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkoxy, heteroaryl C ₁ -C ₆ alkoxy, aryl C ₁ -C ₆ Alkoxy (wherein the aryl ring may be substituted or unsubstituted, and if substituted, the substituent is a group of C ₁ -C ₆ alkyl, halo, amino, and C ₁ -C ₆ alkoxy; Selected from one or more),
Substituted or unsubstituted C ₃ -C ₆ cyclyl, C ₃ -C ₆ heterocyclyl (and, if substituted, the substituent consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, amino) is selected from one or more of the group, and _C 3 -C ₆ heterocyclyl ring here, O, containing S, or N),
Branched or unbranched _C 1 -C ₆ alkoxycarbonyl _C 1 -C ₆ alkoxy, and carboxy, carboxy _C 1 -C ₆ alkoxy, carboxy _C 1 -C ₆ alkyl, hydroxy _C 1 -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl,
Are independently selected from the group consisting of

  And here, the terms “alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkoxy, halo, alkylthio, alkylthioalkyl, heterocyclyl, cyclyl, aryl, heteroaryl, cycloaryl, and oxo” have the same meaning as above. .

Further details of the synthesis of aminocyanopyridine are provided in the examples.
The MK-2 inhibitory activity of an aminocyanopyridine compound may be determined by any of several methods well known to those skilled in the art of enzyme activity testing. One such method is described in detail in the General Methods section of this example. Furthermore, the effect of aminocyanopyridine MK-2 inhibitory compounds in therapeutic applications may be determined by testing inhibition of TNFα production in cell culture and animal model assays. In general, the aminocyanopyridine MK-2 inhibitory compounds of the present invention are preferably capable of inhibiting the production and / or inhibition of TNFα in cell cultures and animal models.

  In another aspect of the invention, a pharmaceutical composition can be provided. The pharmaceutical composition contains one or more tricyclic aminocyanopyridine MK-2 inhibitors described herein and a pharmaceutically acceptable carrier.

  In another embodiment, a kit can be produced that includes a dosage form comprising a tricyclic aminocyanopyridine MK-2 inhibitor in an amount that includes a therapeutically effective amount. If desired, the kit may also contain one or more other materials well known for use in pharmaceuticals.

  As used herein, an “effective amount” can be administered to a patient, readily determined by one of ordinary skill in the art, by using known techniques, and by observing the results obtained in a similar environment. Mean dose or effective amount and frequency of administration to a subject. The dose or effective amount that can be administered to a patient and the frequency of administration to a subject is readily determined by those skilled in the art, by using known techniques, and by observing the results obtained in a similar environment. can do. When determining an effective amount or dose, but not limited to, the efficacy and duration of action of the compound used, the nature and severity of the disease being treated, and the sex, age, weight, general health and individual responsiveness of the patient being treated Several factors are considered by the attending diagnostician, including other relevant situations.

  The phrase “therapeutically effective” refers to the ability of the drug to prevent or improve its severity while avoiding the adverse side effects typically associated with alternative therapies. The phrase “therapeutically effective” should be understood to be equivalent to the phrase “effective for treatment, prevention, or inhibition”, both of which avoid the harmful side effects typically associated with alternative therapies. It is contemplated to qualify each amount of the compound used in therapy to achieve the goal of improving the severity and frequency of onset of pain and inflammation.

  The person skilled in the art may determine the dose according to the guidance from “Goodman & Goldman's The Pharmacological Basis of Therapeutics”, 9th edition (1996), Appendix II, pages 1707-1711. I want you to understand.

  The frequency of dosing will depend on the half-life of the active ingredient in the composition. If the active molecule has a short half-life (eg, about 2-10 hours), it may be necessary to administer more than once a day. Alternatively, if the active molecule has a long half-life (eg, about 2 to about 15 days), it is sufficient to give a single dose once a day, once a week, or every 1-2 months. might exist. A preferred dose ratio is to administer the above dose once a day to the subject.

  For purposes of calculating and expressing the dose ratio, all doses expressed herein are calculated based on the average amount per day regardless of the dose ratio. For example, a 100 mg dose of aminocyanopyridine MK-2 inhibitor taken once every two days would be expressed as a dose ratio of 50 mg / day. Similarly, the dose ratio of components at which 50 mg is taken twice a day will be expressed as the 100 mg / day dose ratio.

For purposes of dose calculation, it is assumed that the normal adult body weight is 70 kg.
When the aminocyanopyridine MK-2 inhibitor is provided together with a pharmaceutically acceptable carrier, the pharmaceutical composition described above can be formed. Pharmaceutically acceptable carriers include, but are not limited to, saline, Ringer's phosphate solution or buffer, buffered saline, and other carriers known in the art. The pharmaceutical composition may also include stabilizers, antioxidants, colorants, and diluents. Pharmaceutically acceptable carriers and additives are selected so that the side effects from the pharmaceutical compound are minimized and the performance of the compound is not lost or inhibited to the extent that treatment is ineffective.

  The term “pharmacologically effective amount” means the amount of a drug or pharmaceutical agent that elicits a biological or medical response of a tissue, system, animal, or human that is being sought by a researcher or clinician. . This amount can be a therapeutically effective amount.

  The term “pharmaceutically acceptable” means herein that the modified noun is suitable for use in medicine. Pharmaceutically acceptable cations include metal ions and organic ions. More preferred metal ions include, but are not limited to, suitable alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc at their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, some of which are trimethylamine, diethylamine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N -Methylglucamine), and procaine. Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid. Acids, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxaloacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like are included.

  Also included in the present invention are isomeric and tautomeric forms of aminocyanopyridine MK-2 inhibitors and pharmaceutically acceptable salts. Exemplary pharmaceutically acceptable salts are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvin Acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfone It is prepared from acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid, β-hydroxybutyric acid, galactaric acid, and galacturonic acid.

  Suitable pharmaceutically acceptable base addition salts of the compounds of this invention include metal ion salts and organic ion salts. More preferred metal ion salts include, but are not limited to, suitable alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts, and other physiologically acceptable metal ions. Such salts can be made from ions of aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, some of which are trifluoroacetate, trimethylamine, diethylamine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine. , Ethylenediamine, meglumine (N-methylglucamine), and procaine. One of ordinary skill in the art can prepare any of the above salts from the corresponding compounds of the present invention by conventional means.

  The tricyclic aminocyanopyridine compounds of the present invention are useful for the prevention and treatment of diseases and disorders mediated by, but not limited to, TNFα. For example, the aminocyanopyridine MK-2 inhibitors of the present invention treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthritis, gout arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis Would be useful to do. Such aminocyanopyridine MK-2 inhibitor compounds of the present invention are useful for asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue damage or injury, and skin such as psoriasis, eczema, burns and dermatitis. It may be useful for the treatment of related conditions.

  Tricyclic aminocyanopyridine MK-2 inhibitory compounds useful in the methods of the present invention are such as inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis It may also be useful for treating gastrointestinal conditions and preventing or treating cancers such as colorectal cancer. Such aminocyanopyridine MK-2 inhibitory compounds include herpes simplex infection, HIV, pulmonary edema, kidney stones, mild injury, wound healing, vaginitis, candidiasis, lumbar spondyloarthritis, vascular disease, migraine, sinus Headache, tension headache, toothache, nodular arteritis, thyroiditis, irreproducible anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome It may be useful for treating inflammation in diseases and conditions such as Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, post-injury swelling, myocardial ischemia, and the like.

  Tricyclic aminocyanopyridine MK-2 inhibitors are also useful for the treatment of ophthalmic diseases such as retinitis, retinopathy, conjunctivitis, uveitis, and eye irritation and acute damage to ocular tissues. I will. These compounds may also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds may also be useful in the treatment of certain central nervous system disorders such as cortical dementias, including Alzheimer's disease.

The term “TNFα-mediated disease or disorder” as used herein is meant to include, without limitation, any of the symptoms or diseases described above.
The term “treating” or “treating” means alleviating symptoms, clearing the cause on either a temporary or permanent basis, or preventing or delaying the appearance of symptoms. The term “treatment” includes, but is not limited to, alleviation of pain and / or inflammation associated with any of the diseases or disorders described herein, elimination of its cause, or prevention. Besides being useful for human therapy, the compounds are also useful for the treatment of mammals including horses, dogs, cats, rats, mice, sheep, pigs, and the like.

  The term “subject” for therapeutic purposes includes any human or animal subject in need of prevention or treatment of any TNFα-mediated disease or disorder. The subject is typically a mammal. As used herein, the term “mammal” means any animal classified as a mammal, including humans, livestock and dairy animals such as dogs, horses, cats, cows, etc., zoos, Includes competition or pet animals. Preferably the mammal is a human.

  In the prevention method, the subject is any human or animal subject, preferably a subject in need of prevention and / or treatment of a TNFα-mediated disease or disorder. The subject may be a human subject at risk for acquiring a TNFα-mediated disease or disorder, as described above. The subject may be at risk due to genetic predisposition, sedentary lifestyle, diet, exposure to causative agents, exposure to pathogens, and the like.

  The pharmaceutical composition may be administered enterally and parenterally. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous administration, and other methods of administration known in the art. Enteral administration includes solutions, tablets, sustained release capsules, enteric shell capsules, and syrups. When administered, the pharmaceutical composition may be at or near body temperature.

  In particular, the pharmaceutical composition of the present invention is, for example, a tablet, coated tablet, dragee, troche, sweetened tablet, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule. Or orally as a syrup or elixir. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions are pharmaceutically refined and palatable preparations. In order to provide a product, it may contain one or more agents selected from the group consisting of sweeteners, fragrances, colorants, and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin Or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

  Formulations for oral use may be prepared as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or the active ingredient is presented as is, or water or oily It may be prepared as a soft gelatin capsule mixed with a medium such as peanut oil, liquid paraffin, or olive oil.

  An aqueous suspension containing an aminocyanopyridine MK-2 inhibitor mixed with excipients suitable for the preparation of an aqueous suspension can be prepared. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, and dispersing or wetting agents are naturally occurring phosphatides, For example, lecithin, or a concentrated product of fatty acid and alkene oxide, such as polyoxyethylene stearate, or a concentrated product of long chain fatty alcohol and ethylene oxide, such as hexadecaethyleneoxysetanol, or polyoxyethylene sorbitol monooleate. Concentrated products of partial esters and ethylene oxide derived from fatty acids and hexitol, or concentrated products of partial esters and ethylene oxide derived from fatty acids and anhydrous hexitol, such as If it may be polyoxyethylene sorbitan monooleate.

  Aqueous suspensions also contain one or more preservatives, such as ethyl or n-hydroxybenzoate, one or more colorants, one or more fragrances, or one or more sweetness such as sucrose or saccharin. An agent may be contained.

  Oily suspensions may be formulated in omega-3 fatty acids, vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or by suspending the active ingredient in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

  Sweetening agents such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

  Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring, and coloring agents may also be present.

  Syrups and elixirs containing novel MK-2 inhibitors can be formulated with sweetening agents such as glycerol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

  The composition may be administered parenterally in the form of a sterile injectable aqueous or oily suspension, either subcutaneously, intravenously, or intramuscularly, intrasternally, or by infusion techniques. . Such suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above, or other acceptable agents. A sterile injectable preparation is a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Also good. Among the acceptable carriers and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fatty oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fatty oil may be employed including synthetic mono- or diglycerides. In addition, n-3 polyunsaturated fatty acids may also find use in preparing injectable formulations.

  The composition is also suitable for administration by inhalation in the form of an aerosol or solution for nebulizers which is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. It may be administered rectally in the form of a suppository prepared by mixing the drug with an irritating excipient. Such materials are cocoa butter and polyethylene glycol.

The novel composition may also be administered topically in the form of a cream, ointment, jelly, eye wash, solution or suspension.
Daily doses will vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, for administration to adults, appropriate daily doses have been described above, but the limits established as preferred may be exceeded if convenient. The daily dose may be administered as a single dose or in divided doses.

Various delivery systems include, for example, capsules, tablets, and gelatin capsules.
The following examples describe preferred embodiments of the invention. Other embodiments within the scope of the claims herein will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. Since the scope and spirit of the invention is indicated by the claims following the examples, this specification is to be regarded as illustrative only, together with the examples. In the examples, all ratios are given on a weight basis unless otherwise stated.

General information about the production method:
Unless otherwise stated, reagents and solvents were used as received from commercial suppliers.

NMR analysis :
Proton nuclear magnetic resonance spectra were obtained with a Varian Unity Innova 400, Varian Unity Innova 300, Varian Unity 300, Bruker AMX 500, or Bruker AV-300 spectrometer. Chemical shifts are reported in ppm (δ), coupling constants, and J is reported in hertz. Tetramethylsilane was used as an internal standard for the proton spectrum, and a solvent peak was used as the reference peak for the carbon spectrum. Mass spectra were obtained from Perkin Elmer Sciex 100 atmospheric pressure ionization (APCI) mass spectrometer, Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) mass spectrometer, PerSeptive Biosystems Mariner TOF HPLC-MS (ESI) or WSI. Obtained in total (ESI).

Determination of MK-2 IC ₅₀ Recombinant MAPKAPK2 was obtained at 30 ° C. with 0.23 μM active p38α, 0.1 mM EDTA, 10 mM magnesium acetate, and 0.25 mM ATP (pH 7.5) in 50 mM HEPES at a concentration of 42-78 μM. And phosphorylated by incubation for 1 hour.

An anion exchange resin capture assay was used to measure phosphorylation of HSP-peptide (KKKALSRQLSVAA) by MAPKAPK2. This reaction was performed in the presence of HSP-peptide with 50 mM β-glycerophosphate, 0.04% BSA, 10 mM magnesium acetate, 2% DMSO and 0.8 mM with 0.2 μCi [γ ³³ P] ATP and 0.03 mM ATP. Dithiothreitol (pH 7.5) was used. The reaction was initiated by the addition of 15 nM MAPKAPK2 and incubated at 30 ° C. for 30 minutes. The reaction was stopped and [γ ³³ P] ATP was removed from the solution by addition of 150 μl of AG1 × 8 ion exchange resin in 900 mM sodium formate (pH 3.0). A 50 μl aliquot of the head volume was removed from this inactivated reaction mixture and added to a 96-well plate, 150 μl of Microscint-40 (Packard) was added, and the amount of phosphorylated peptide was determined. Prior to counting, the Microscint is left in the plate for 60 minutes.

Compounds are evaluated as potential inhibitors of MK2 kinase by measuring the effect of peptide substrates on MK2 phosphorylation. Compounds may be initially screened at two concentrations prior to determination of IC ₅₀ values. Screening results are expressed as percent inhibition at the concentration of the compound being tested. For determination of IC ₅₀ values, compounds are tested at 6 concentrations in 10-fold serial dilutions and tested in the same 3 specimens for each concentration. It represents the results as _{IC 50} values in the micromolar concentrations. The assay is performed at a final concentration of 2% DMSO.

Preferred aminocyanopyridine MK-2 inhibitor compounds of the present invention provide IC ₅₀ values of less than 200 μM for MK-2 inhibition. One method that can be used to determine MK-2 inhibition IC ₅₀ values is the one just described. More preferred aminocyanopyridine MK-2 inhibitory compounds are less than 100 μM, even more preferred are less than 50 μM, even more preferred are less than 20 μM, even more preferred are less than 10 μM, and even more preferred are less than 1 μM MK- Has the ability to provide 2 inhibition IC ₅₀ values.

U937 cells TNFα release assay A human monocytic cell line, U937 (ATCC # CRL-1593.2), in RPMI 1640 medium with 10% heat-inactivated fetal calf serum (GIBCO), glutamine, and penicillin / streptomycin. Incubate at 37 ° C. and 5% CO ₂ . Phorbol-12-myristate-13-acetate (Sigma) was added to a culture of U937 cells (approximately 500,000 cells / ml) at a final concentration of 20 ng / ml to convert U937 to monocyte / macrophage-like cells. Differentiation is induced and incubated for 24 hours. The cells are centrifuged, washed with PBS, resuspended in fresh medium without PMA and incubated for 24 hours. The cells adhering to the culture flask are rubbed and collected by centrifugation, resuspended in fresh medium to 2 million cells / ml, and 0.2 ml is dispensed into each of 96 wells of a flat bottom plate. The cells are then incubated for an additional 24 hours to allow recovery. The medium is removed from the cells and 0.1 ml of fresh medium is added to each well. Add 0.05 ml serially diluted compound or control carrier (medium with DMSO) to the cells. The final DMSO concentration does not exceed 1%. After 1 hour incubation, 0.05 ml of 400 ng / ml LPS (E. coli serotype 0111: B4, Sigma) is added to a final concentration of 100 ng / ml. Cells are incubated for 4 hours at 37 ° C. After 4 hours of incubation, the supernatant is collected and assayed for the presence of TNFα by ELISA.

U937 cell TNFα ELISA
ELISA plate (NUNC-Immuno ^™ Plate Maxisorb ^™ Surface) is coated with purified mouse monoclonal IgG1 anti-human TNFα antibody (R & D Systems # MAB610; 1.25 μg / ml in sodium bicarbonate (pH 8.0), 0.1 ml / well) And incubated at 4 ° C. The next day, the coating solution was aspirated and the wells were sealed for 2 days at 4 ° C. with 1 mg / ml gelatin in PBS (+ 1 × Timazole). Prior to use, the wells were washed 3 times with wash buffer (PBS with 0.05% Tween). The cultured medium sample was diluted in EIA buffer (bovine γ-globulin 5 mg / ml in PBS, gelatin 1 mg / ml, Tween-20 1 ml / l, thimerazol 1 mg / ml) and added to the wells in the same 3 samples (0. 1 ml / well) and incubated for 1.5 hours at 37 ° C. in a humidified chamber. The plate was washed again and a mixture of 0.1 ml / well rabbit anti-human TNFα polyclonal antibody in EIA buffer (1: 400 dilution of Sigma # T8300 and 1: 400 dilution of Calbiochem # 654250) at 37 ° C. Added for 1 hour. Plates were washed as before and peroxidase-conjugated goat anti-rabbit IgG (H + L) antibody (Jackson ImmunoResearch # 111-035-144, 1 μg / ml in EIA buffer, 0.1 ml / well) was added for 45 minutes. After the final wash, the plates were developed with peroxidase-ABTS solution (Kirkegaard / Perry # 50-66-01, 0.1 ml / well). Enzymatic conversion of ABTS to colored products was measured after 5-30 minutes using a SpectroMax 340 spectrophotometer (Molecular Device) at 405 nm. TNF levels were quantified from a recombinant human TNFα (R & D Systems # 210-TA-010) standard curve using quadratic variable fitting, generated by SoftMaxPro software. The sensitivity of the ELISA was approximately 30 pg TNF / ml. BioAssay Solver was used to obtain IC ₅₀ values for the compounds.

Preferred aminocyanopyridine MK-2 inhibitor compounds of the present invention provide TNFα release IC ₅₀ values of less than 200 μM in an in vitro cell assay. One method that can be used to determine the TNFα release IC ₅₀ in an in vitro cellular assay is that described immediately above. More preferred aminocyanopyridine MK-2 inhibitory compounds have the ability to provide a TNFα release IC ₅₀ value of less than about 50 μM, even more preferably less than 10 μM, and even more preferably less than 1.0 μM.

Lipopolysaccharide (LPS) induced TNFα production adult male 225~250g Lewis rats (Harlan, Sprague - Dawley) were used. Prior to oral dosing, rats were fasted for 18 hours, allowing free access to water throughout the experiment. Each treatment group consisted of 5 animals.

  The compound was prepared as a suspension in a carrier consisting of 0.5% methylcellulose, 0.025% Tween-20 in PBS. The compound or carrier was orally administered in a volume of 1 ml using an 18 gauge gavage needle. 1-4 hours later, LPS (E. coli serotype 0111: B4, lot number 39H4103, catalog number L-2630, Sigma) was administered by injection into the penile vein at a dose of 1 mg / kg in 0.5 ml of sterile saline. did. 1.5 hours after LPS injection, blood was collected into the serum separator tube by cardiac puncture at the time corresponding to maximum TNFα production. Serum was collected after clotting and stored at −20 ° C. until assayed by ELISA (described below).

Rat LPS TNFα ELISA
Protein G purified fraction of 2.5 μg / ml hamster anti-mouse / rat TNFα monoclonal antibody TN19.12 (2.5 μg / ml in PBS, 0.1 ml / well) with ELISA plate (NUNC-Immuno ^™ Plate Maxisorb ^™ Surface) The fractions were coated with 0.1 ml / well. This hybridoma cell line was kindly provided by Dr. Robert Schneider (University of Washington). The next day, the wells were sealed with 1 mg / ml gelatin in PBS. A serum sample is diluted in a buffer solution of bovine γ-globulin 5 mg / ml in PBS, gelatin 1 mg / ml, Tween-20 1 ml / l, and thimerazol 1 mg / ml. In addition, it was incubated at 37 ° C. for 2 hours. Plates were washed with PBS-Tween and 0.1 ml / well of rabbit anti-mouse / rat TNFα antibody 1: 300 dilution (BioSource International, Cat. No. AMC3012) was added at 37 ° C. for 1.5 hours. The plate was washed and a 1000-fold dilution of peroxidase-conjugated donkey anti-rabbit IgG antibody (Jackson ImmunoResearch catalog number 711-035-152) was added for 45 minutes. After washing, the plates were developed with 0.1 ml ABTS-peroxidase solution (Kirkegaard / Perry catalog number 50-66-01, 0.1 ml / well). About 30 minutes later, the enzymatic conversion of ABTS to a colored product was measured using a SpectroMax 340 spectrophotometer (Molecular Device) at 405 nm. TNF levels in serum were quantified from a recombinant rat TNFα (BioSource International, Cat. No. PRC3014) standard curve using quadratic variable fitting, generated by SoftMaxPro software. The sensitivity of the ELISA was approximately 30 pg TNF / ml. Results are expressed as percent inhibition of TNFα production compared to blood collected from control animals dosed with carrier alone.

  Preferred aminocyanopyridine MK-2 inhibitory compounds of the present invention are capable of providing a degree of inhibition of TNFα in animals. That is, the degree of inhibition of TNFα in animals exceeds 0%. One method for determining the degree of inhibition of TNFα is the rat LPS assay described immediately above. More preferred aminocyanopyridine MK-2 inhibitory compounds have rat LPS TNFα inhibition values of at least about 25%, even more preferably greater than 50%, even more preferably greater than 70%, and even more preferably greater than 80%. Has the ability to bring.

Example 1
This illustrates the formation of 2-amino-4- (2-furyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

3- (2-Furyl) -3-oxopropanenitrile (10 mmol, 1.0 eq, 1.35 g) and malononitrile (10 mmol, 1.0 eq, 600 μL) were combined in pyridine (10 mL). The mixture was heated to 100 ° C. for 1 hour. The reaction mixture was diluted with 150 mL dichloromethane and washed with 1M hydrochloric acid (HCl) (3 × 50 mL). The organic layer was dried and evaporated to give a dark oil. This oil was dissolved in ethyl alcohol (EtOH) (30 mL) and treated with salicaldehyde (10 mmol, 1.0 eq, 1.0 mL) and acetic acid (AcOH) (10 mL). The resulting mixture was heated to reflux for 2 hours. The solvent was evaporated in vacuo and the residue was dissolved in trifluoroacetic acid (15 mL). Triethylsilane (10 mL) was added and the solution was stirred overnight. The solvent was evaporated and the residue was purified by reverse phase chromatography. The product (370 mg, 13%) was isolated as a solid. ¹ H NMR (400 MHz, DMSO) δ 7.99 (s, 1H), 7.24-7.20 (m, 2H), 7.08-7.04 (m, 3H), 6.94 (bs, 2H), 6.76 (s, 1H), 3.96 (s, 2H): m / z 290 (M + H).

Example 2
This illustrates the formation of 2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile trifluoroacetate.

Step A: (Synthesis of t-butyl 2-bromophenyl (methyl) carbamate) 2-Bromoaniline (25 mmol, 1.0 equivalent, 4.3 g) was dissolved in tetrahydrofuran (THF) (150 mL). Sodium hydride (60% in mineral oil, 1.1 g) was added and the mixture was heated to reflux for 1 hour. After cooling to room temperature, di-t-butyl dicarbonate in THF (1.0 M, 30 mmol, 1.2 eq, 30 mL) was added followed by sodium hydride (1.1 g). The resulting mixture was heated to reflux for 14 hours. After cooling to room temperature, iodomethane (28 mmol, 1.12 eq, 1.75 mL) was added and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the reaction was quenched with water and diluted with ether. The organic layer was washed with a saturated aqueous ammonium chloride solution (sat. Aq. NH ₄ Cl), a saturated aqueous sodium bicarbonate solution (sat. Aq. NaHCO ₃ ), and a saturated aqueous sodium chloride solution (sat. Aq. NaCl). The organic layer was dried over magnesium sulfate (MgSO ₄ ), filtered and evaporated to give a yellow oil. Purification by silica gel chromatography gave the product (5.9 g, 82%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (d, 1H), 7.29 (t, 1H), 7.21 (d, 1H), 7.12 (t, 1H), 3.13 (s, 3H), 1.33 (s, 9H): m / z 271 (M + H).

Step B: (Synthesis of 2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile trifluoroacetate) 2-bromophenyl (methyl) carbamine T-Butyl acid (2.65 mmol, 1.0 eq, 759 mg) was dissolved in THF (20 mL). This solution was cooled in a dry ice acetone bath, and a hexane solution of n-BuLi (1.6 M, 1.1 equivalents, 1.8 mL) was added dropwise. After 15 minutes, dimethylformamide (DMF) (1 mL) was added and the reaction was allowed to warm to room temperature. The reaction mixture is washed with sat. aq. Quenched with NH ₄ Cl and partitioned between ether and water. The organic layer was washed with water, dried over MgSO ₄ , filtered and evaporated to give 820 mg of a yellow oil. This oil was carried over immediately without purification or characterization. The resulting oil is treated with 2-amino-1-propene-1,1,3-tricarbonitrile (2 mmol, 265 mg), acetic acid (2.0 mL), and ethanol (10 mL) and the resulting solution is heated to Refluxed overnight. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (TFA) (7 mL) at 0 ° C. Triethylsilane (5.0 mL) was added from a syringe. After stirring the reaction for 2 hours, the solvent was evaporated to give a brown solid. The solid was washed with dichloromethane and dried to give the product (90 mg, 9%) as a light brown solid. ¹ H NMR (400 MHz, DMSO) δ 7.16 (t, 1H), 7.03 (d, 1H), 6.97-6.91 (m, 2H), 3.70 (s, 2H), 3.34 (s, 3H): m / z 252 (M + H).

Example 3
This illustrates the formation of 2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile (400 mg, 1.0 mmol) and sodium hydroxide (NaOH) (166 mg, 4.2 mmol) ) Was suspended in dimethyl sulfoxide (DMSO) (5 mL) and warmed until dissolved. Ethyl bromide was added to the reaction mixture and heated to 85 ° C. until disappearance of starting material (HPCL monitoring). After neutralization with NH ₄ Cl, the crude reaction mixture was purified by reverse phase column chromatography (acetonitrile, H ₂ O, 0.05% TFA gradient). Evaporation of the solvent in the lyophilizer gave an orange solid as the TFA salt of 2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile. This was confirmed by 2D NMR analysis. ¹ H NMR (300 MHz, CD ₃ OD): δ 1.47 (t, 3H), 3.63 (s, 2H), 4.12 (quartet, 2H), 6.59-6.81 (m, 2H). Calculated _{HRMS C 15 H 14 N 4 O} 3 (M + H): 299.11. Found: 299.1132.

Example 4
This illustrates the formation of 2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile was prepared in the same manner as described above in Example 3. Prepared from 2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile using 2-bromoethyl-ethyl ether instead of 2-bromoethyl-ethyl ether . ¹ H NMR (300 MHz, CD3OD): δ 1.28 (t, 3H), 3.60 (s, 2H), 3.67 (quartet, 2H), 3.86 (s, 2H), 4.19 (s, 2H), 6.58- 6.82 (m, 2H). _{HRMS C 17 H 18 N 4 O} 4 Calculated (M + H): 343.13. Found: 343.1418.

Examples 5-6
This illustrates the production of the aminocyanopyridine compound of the present invention.
The aminocyanopyridine compounds shown in the table below were prepared according to the general method described in Example 3. NMR analysis is performed according to the method described above and the data obtained for each of the compounds is provided in a table.

Example 7
This illustrates the formation of 2,4-diamino-7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

A cooled (0 ° C.) solution of 2,4-diamino-7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile (1.34 mmol, 400 mg) and dichloromethane (4.0 mL) Boron tribromide (1M, dichloromethane, 8.04 mmol, 8.04 mL) was added slowly. The suspension was stirred at 0 ° C. for 15 minutes, then the ice bath was removed and the reaction was warmed to 23 ° C. overnight. After 16 hours at 23 ° C., the reaction was cooled to 0 ° C. and carefully neutralized to pH = 7 with 2.5 N sodium hydroxide. The product was collected by filtration, dissolved in dimethyl sulfoxide (1.0 mL) and purified by reverse phase chromatography. The product (62 mg, 17% yield) was isolated as a light orange solid. ¹ H NMR (400 MHz, DMSO) δ 9.071 (s, 1H), 8.795 (s, 1H), 6.520 (s, 1H), 6.410 (bs, 2H), 6.405 (s, 1H), 6.244 (bs, 2H ), 3.48 (s, 2H) : m / z 271 (M +); HRMS (M + H) calcd for _{C 13 H 11 N 4 O 3} : 271.0753. Found: 271.0721.

Example 8
This illustrates the formation of 2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2,4-dihydroxy-benzaldehyde (43.4 mmol, 6.0 g), 2-amino-1-propene-1,1,3-tricarbonitrile (43.4 mmol, 5.74 g), acetic acid (13. 0 mL) and ethanol (125.0 mL) were combined and heated to reflux for 2 hours. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (160.0 mL) at 0 ° C. Triethylsilane (0.28 mol, 32.76 g, 45.0 mL) was added via syringe. The reaction was stirred at 0 ° C. for 1 hour. To the reaction was added 300 mL of dichloromethane and the solid was collected by filtration and washed with dichloromethane and ether (2 × 75 mL). The product (13.10 g, 63% yield) was isolated as a light orange solid. ¹ H NMR (400 MHz, DMSO) δ 6.958 (d, 1H), 6.537 (dd, 1H), 6.390 (d, 1H), 3.510 (s, 2H): m / z 255 (M +); HRMS (M + H) C ₁₃ H ₁₁ N ₄ O ₂ calculated: 255.0804. Found: 255.0894.

Example 9
This is the formation of 8,10-diamino-2,3-dihydro-11H- [1,4] dioxino [2 ′, 3 ′: 6,7] chromeno [2,3-b] pyridine-9-carbonitrile. Is illustrated.

2,4-Diamino-7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile (0.56 mmol, 150 mg) was dissolved in DMSO (3.0 mL) and sodium hydroxide ( 2.24 mmol, 90 mg) was added followed by dibromoethane (0.56 mmol, 105.20 mg, 48.26 μL). This dark homogeneous solution was heated to 70 ° C. for 16 hours. The crude reaction mixture was cooled to 23 ° C., neutralized with trifluoroacetic acid, and directly purified by reverse phase chromatography. The product (30 mg, 18% yield) was isolated as a light orange solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 6.715 (s, 1H), 6.553 (s, 1H), 4.215 (bs, 4H), 3.575 (s, 2H): m / z 298 (M + H).

Example 10
This illustrates the formation of 2,4-diamino-8- (2-ethoxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile (0.62 mmol, 300 mg) was dissolved in DMSO (4.0 mL) and solid sodium hydroxide (2 .79 mmol, 111.6 mg) followed by 2-bromoethyl-ethyl ether (0.62 mmol, 69.9 μL). The reaction was heated to 80 ° C. with stirring for 9 hours. The crude reaction was filtered, diluted with DMSO (4.0 mL) and purified by reverse phase chromatography. The product (80 mg, 40% yield) was isolated as a tan solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.180 (d, 1H), 6.795 (d, 1H), 6.46 (d, 1H), 4.090 (t, 2H), 3.766 (t, 2H), 3.607 (s , 2H), 3.572 (t, 2H), 1.200 (t, 2H); m / z 327 (M + H).

Example 11
This illustrates the formation of 2,4-diamino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile is replaced by 1- (2- Prepared from 2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile in the same manner as described in Example 10 using chloroethyl) pyridine. The product (100 mg, 46% yield) was isolated as a tan solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.199 (d, 1H), 6.680 (d, 1H), 6.668 (d, 1H), 4.290 (t, 2H), 3.618 (s, 2H), 3.562 (t , 2H), 3.375 (bs, 4H), 2.077 (bs, 4H); m / z 352 (M + H). TNFα release assay IC ₅₀ : 2.9 μM; rat LPS assay: 60% inhibition at 20 mpk (IP).

Example 12
This illustrates the formation of 2,4-diamino-8- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-8- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile uses 2-bromoethylamine instead of 2-bromoethyl-ethyl ether Prepared from 2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile in the same manner as described in Example 10. The product (167 mg, 51% yield) was isolated as a tan solid. ¹ H NMR (400 MHz, DMSO) δ 8.180 (bs, 2H), 7.100 (d, 1H), 6.762 (d, 1H), 6.646 (bs, 1H), 4.154 (t, 2H), 3.573 (s, 2H ), 3.155 (t, 2H); m / z 398 (M + H). TNFα release assay IC ₅₀ : 6.9 μM; rat LPS assay: 88% inhibition at 20 mpk (IP).

Example 13
This illustrates the formation of [(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-8-yl) oxy] acetic acid.

[(2,4-Diamino-3-cyano-5H-chromeno [2,3-b] pyridin-8-yl) oxy] acetic acid was performed using bromoacetic acid instead of 2-bromoethyl-ethyl ether. Prepared from 2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile in the same manner as described in Example 10. The product (110.6 mg, 31% yield) was isolated as a tan solid. ¹ H NMR (400 MHz, DMSO) δ 7.030 (d, 1H), 6.640 (d, 1H), 6.516 (d, 1H), 6.474 (bs, 2H), 6.278 (bs, 2H), 4.633 (s, 2H ), 3.543 (s, 2H); m / z 427 (M + H).

Example 14
This illustrates the formation of 2,4-diamino-8- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-8- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile uses 2-bromoethanol instead of 2-bromoethyl-ethyl ether Prepared from 2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile in the same manner as described in Example 10. The product (120 mg, 35% yield) was isolated as a tan solid. ¹ H NMR (400 MHz, DMSO) δ 7.025 (d, 1H), 6.670 (d, 1H), 6.550 (d, 1H), 3.931 (t, 2H), 3.662 (t, 2H), 3.546 (s, 2H ); m / z 413 (M + H).

Example 15
This illustrates the formation of 2,4-diamino-8- (2-morpholin-4-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-8- (2-morpholin-4-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile is 1- (2- Prepared from 2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile in the same manner as described in Example 10 using chloroethyl) morpholine. The product (80 mg, 17% yield) was isolated as a tan solid. ¹ H NMR (400 MHz, DMSO) δ 7.071 (d, 1H), 6.714 (d, 1H), 6.654 (d, 1H), 6.527 (bs, 2H), 6.323 (bs, 2H), 4.311 (t, 2H ), 3.938 (m, 2H), 3.664 (t, 2H), 3.558 (s, 2H), 3.534 (m, 2H), 3.451 (m, 2H), 3.158 (m, 2H); m / z 482 (M + H).

Examples 16-22
This illustrates the production of the aminocyanopyridine compound of the present invention.
The aminocyanopyridine compounds shown in the following table were prepared according to the general method described in Example 10. NMR analysis is performed according to the method described above and the data obtained for each of the compounds is provided in a table.

Example 23
This illustrates the formation of 2,4-diamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile bis (trifluoroacetate).

3-methoxysalicylaldehyde (10 mmol, 1.52 g), 2-amino-1-propene-1,1,3-tricarbonitrile (10 mmol, 1.32 g), acetic acid (2.5 mL), and ethanol ( 40 mL) and heated to reflux overnight. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (15 mL) at 0 ° C. Triethylsilane (62 mmol, 7.2 g, 10 mL) was added via syringe. The reaction was stirred at room temperature for 1 hour. Dichloromethane (100 mL) was added to the reaction and the resulting solid was collected by filtration and washed with dichloromethane (2 ×). The product (2.5 g, 50% yield) was isolated as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.08 (t, J = 8 Hz, 1H), 7.00-6.80 (m, 2H), 6.73 (d, J = 7.4Hz, 2H), 3.83 (s , 3H), 3.68 (s, 2H); m / z 269 (M + H); elemental analysis _{C 14 H 12 N 4 O 2} -2CF 3 CO 2 H calculated: C, 43.56; H, 2 .84; N, 11.29. Found: C, 43.40; H, 2.98; N, 11.32.

Example 24
This illustrates the formation of 2,4-diamino-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile trifluoroacetate.

2,4-Diamino-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile is the same as that of Example 23 except that 5-hydroxysalicylaldehyde is used instead of methoxysalicylaldehyde. Prepared in the same manner as described. The product (951 mg, 30% yield) was isolated as a pink solid. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.88 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 6.55 (s, 1H), 3.6 (s, 2H ): m / z 255 (M + H); elemental analysis _{C 13 H 10 N 4 O 2} -1.5CF 3 CO 2 H-0.5H 2 O calculated: C, 44.25; H, 2 . 90; N, 12.90. Found: C, 44.04; H, 3.05; N, 12.84.

Example 25
This illustrates the formation of 2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile bis (trifluoroacetate).

2,4-Diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile was prepared in the same manner as described in Example 23, except that salicylaldehyde was used in place of methoxysalicylaldehyde. . The product (1.26 g, 33% yield) was isolated as a light brown solid. ¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.30-6.90 (m, 6H), 3.7 (s, 2H); m / z 239 (M + H); elemental analysis C ₁₃ H ₁₀ N ₄ O— _{2CF 3 CO 2 H-0.25H 2} O calculated: C, 43.37; H, 2.68 ; N, 11.90. Found: C, 43.07; H, 2.81; N, 11.79.

Example 26
This illustrates the formation of 2,4-diamino-8,9-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile trifluoroacetate.

2,4-diamino-8,9-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile, except that 2,3,4-trihydroxybenzaldehyde is used instead of methoxysalicylaldehyde Was prepared in the same manner as described in Example 23. The product (3.6 g, 82% yield) was isolated as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.1 (bs, 3H), 6.58 (d, J = 8 Hz, 1H), 6.47 (d, J = 8 Hz, 1H), 3.75 (s, 2H ); m / z 271 (M + H).

Example 27
This illustrates the formation of 2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile trifluoroacetate.

2,3-dihydroxy-4-methoxybenzaldehyde (3 mmol, 506 mg), 2-amino-1-propene-1,1,3-tricarbonitrile (3 mmol, 398 mg), acetic acid (1 mL), and ethanol (15 mL) ) And heated to reflux overnight. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (10 mL) at 0 ° C. Triethylsilane (25 mmol, 2.88 g, 4 mL) was added via syringe. The reaction was stirred at room temperature overnight to give a yellow slurry. Dichloromethane (50 mL) was added to the reaction and the resulting solid was collected by filtration and washed with dichloromethane (2 ×). The product (482 mg, 35% yield) was isolated as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.73 (d, J = 8.5 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 3.77 (s, 3H), 3.57 (s, 2H ); m / z 285 (M + H); elemental analysis _{C 14 H 12 N 4 O 3} -1.25CF 3 CO 2 H-1.5H 2 O calculated: C, 43.58; H, 3 . 62; N, 12.32. Found: C, 43.80; H, 3.22; N, 12.65.

Example 28
This illustrates the formation of 2,4-diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile trifluoroacetate.

2,3-dihydroxybenzaldehyde (5 mmol, 691 mg), 2-amino-1-propene-1,1,3-tricarbonitrile (5 mmol, 661 mg), acetic acid (1.2 mL), and ethanol (20 mL). Combined and heated to reflux overnight. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (20 mL) at 0 ° C. Triethylsilane (62 mmol, 7.2 g, 10 mL) was added via syringe. The reaction was stirred at room temperature for 2.5 days to give a solution that was concentrated in vacuo. The residue was stirred in methanol and the slurry was filtered. The filtrate was concentrated to give the product (167 mg, 9% yield) as a brown solid. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.91 (t, J = 7.7 Hz, 1H), 6.86-6.70 (m, 2H), 6.59 (d, J = 7.3 Hz 1H), 3.61 (s, 2H); m / z 255 (M + H).

Example 29
This illustrates the formation of 2,4,7-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

Step A : Preparation of 2,4-diamino-7-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile: 5-nitrosalicylaldehyde (132 mmol, 22.00 g), 2-amino- 1-propene-1,1,3-tricarbonitrile (132 mmol, 17.39 g), acetic acid (31 mL), and ethanol (500 mL) were combined and heated to reflux overnight. The resulting slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (350 mL) at 0 ° C. Triethylsilane (1.40 mol, 162 g, 225 mL) was added. The mixture was heated at 66 ° C. overnight. The mixture was cooled and concentrated in vacuo. Trituration with methanol gave 2,4-diamino-7-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile (22.48 g, 60% yield) as a yellow solid. Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.13 (d, J = 9.0 Hz, 1H), 8.00 (s, 1H), 7.25 (d, J = 9.0 Hz, 1H), 6.70 (br s, 2H), 6.50 (bs, 2H ), 3.82 (s, 2H); m / z 284 (M + H); elemental analysis _{C 13 H 9 N 5 O 3} -0.5H 2 O calculated: C, 53 .43; H, 3.45; N, 23.96. Found: C, 53.41; H, 3.17; N, 23.71.

Step B : 2,4-Diamino-7-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile (0.55 mmol, 155 mg) and palladium on carbon (Pd / C) A mixture of (35 mg, 10% on activated carbon) in dimethylformamide (DMF) (15 mL) was stirred under an atmosphere of hydrogen (balloon) for 3.5 hours. The catalyst was removed by filtration using a plug of celite. The filtrate was concentrated in vacuo and the residue was triturated with methanol to give 2,4,7-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile (109 mg, 79% yield). Was obtained as a gray solid. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.72 (d, J = 8.0 Hz, 1H), 6.39-6.5 (m, 4H), 6.25 (s, 2H), 3.52 (s, 2H); m / z 254 (M + H).

Example 30
This illustrates the formation of 2,4-diamino-9-fluoro-5H-chromeno [2,3-b] pyridine-3-carbonitrile trifluoroacetate.

3-fluoro-2-hydroxybenzaldehyde (3.45 mmol, 484 mg), 2-amino-1-propene-1,1,3-tricarbonitrile (3.50 mmol, 463 mg), acetic acid (0.9 mL), And ethanol (27 mL) were combined and heated to reflux for 14 hours. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (10.5 mL). Triethylsilane (43 mmol, 4.97 g, 6.9 mL) was added via syringe. The reaction was heated to reflux for 5 hours. Dichloromethane (50 mL) was added to the reaction, and the resulting solid was collected by filtration, washed with methanol and washed. The product (377 mg, 30% yield) was isolated as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.25-7.19 (m, 1H), 7.15-7.08 (m, 1H), 7.00-6.96 (m, 1H), 6.70 (bs, 2H), 6.51 ( bs, 2H), 3.75 (S, 2H); m / z 257 (M + H).

Example 31
This illustrates the formation of 2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-7-carboxylic acid bis (trifluoroacetate).

5-Carboxysalicylaldehyde (3 mmol, 500 mg), 2-amino-1-propene-1,1,3-tricarbonitrile (3 mmol, 396 mg), acetic acid (1.2 mL), and ethanol (15 mL) are combined. And heated to reflux for 2.5 days. The reaction slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (10 mL). Triethylsilane (62 mmol, 7.2 g, 10 mL) was added via syringe. The reaction was stirred at 50 ° C. for 4 hours and then at room temperature overnight. Dichloromethane (20 mL) was added to the reaction and the resulting solid was collected by filtration and washed with dichloromethane (2 ×). The product (560 mg, 36% yield) was isolated as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.86 (d, J = 7.4 Hz, 1H), 7.85 (s, 1H), 7.31 (d, J = 7.4 Hz, 1H), 6.80 (br s, 2H), 3.85 (s, 2H ); m / z 283 (M + H); elemental analysis _{C 14 H 10 N 4 O 3} -2CF 3 CO 2 H-0.25H 2 O calculated: C, 42. 00; H, 2.45; N, 10.88. Found: C, 42.30; H, 2.31; N, 10.51.

Example 32
This illustrates the formation of 2,4-diamino-6,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile trifluoroacetate.

2,4-Diamino-6,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile uses 2,4,6-trihydroxybenzaldehyde instead of 5-carboxysalicylaldehyde Except for this, it was prepared in the same manner as described in Example 31. The product (106 mg, 9% yield) was isolated as an orange solid. ¹ H NMR (free base, 300 MHz, DMSO-d ₆ ): δ 9.65 (s, 1H), 9.40 (s, 1H), 6.41 (s, 2H), 6.35 (s, 2H), 6.10 (s, 1H ), 5.85 (s, 1H), 3.31 (s, 2H); m / z 271 (M + H).

Examples 33-51
This illustrates the production of the aminocyanopyridine compound of the present invention.
The aminocyanopyridine compounds shown in the table below were prepared according to the general method described in Example 29. NMR analysis is performed according to the method described above and the data obtained for each of the compounds is provided in a table.

Example 52
This illustrates the formation of 2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile.

Step 1: Formation of 5-nitrothiosalicylaldehyde: A mixture of 2-chloro-5-nitrobenzaldehyde (2 g, 11 mmol) and lithium sulfide (0.54 g, 11.7 mmol) in 30 mL anhydrous DMSO under nitrogen. Stir at room temperature overnight. The solution was then added to an ice-water mixture, acidified with 2N HCl and extracted three times with ether. The combined ether layers were washed with water, brine, dried, filtered and concentrated to give crude 5-nitro-2-thiosalicylaldehyde (1.3 g, 65% yield) as an orange solid. It was.

Step 2: Crude 5-nitro-2-thiosalicylaldehyde (1.3 g, 7.1 mmol), 2-amino-1-propene-1,1,3-tricarbonitrile (7.6 in 70 mL ethanol) A solution of mmol, 1 g), acetic acid (2.5 mL) was heated at 76 ° C. overnight under nitrogen. The reaction mixture was cooled to room temperature and filtered. This solid was washed with ethanol to give the desired tricyclic intermediate (1.5 g, 71.4% yield) as a light brown solid.

Step 3: A reaction mixture of the above tricyclic intermediate (1.2 g, 4 mmol) and triethylsilane (15 mL) in 100 mL trifluoroacetic acid was heated between 60-65 ° C. under nitrogen for 2 hours. The solution was then cooled to room temperature and concentrated in vacuo. Ether was added to the residue. The solid was filtered and washed with additional ether to give 2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile (0.9 g, 75% yield). ) Was obtained as an orange powder. ¹ H NMR (400 MHz, CD ₃ CN + D ₂ O) δ 8.089 (d, 1H), 8.046 (dd, 1H), 7.609 (d, 1H), 3.898 (s, 2H); m / z 300 (M + H).

Example 53
This illustrates the formation of 2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile trifluoroacetate.

2,4-Diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile in 9 mL of 50% (wt) ethanol-water (produced as described in Example 52 above; 0 Iron powder (0.55 g, 10 mmol) was added to .8 g, 2.7 mmol). The mixture was heated to 60 ° C. before 0.5 mL HCl / ethanol (prepared from 5.2 mL concentrated HCl and 25 mL 50% ethanol-water) was added. The resulting mixture was heated at 76 ° C. for 2.5 hours and filtered hot. This solid was washed with 50% ethanol-water. The filtrates were combined and concentrated in vacuo to give a brownish yellow solid. The solid was then dissolved in acetonitrile and filtered to remove a small amount of insoluble solid and concentrated in vacuo. The resulting solid was then washed with methanol and trifluoroacetic acid. The trifluoroacetic acid filtrate was concentrated in vacuo to give an amber oil. Ether is added, the solid is filtered, washed with ether, air dried overnight and then dried in a vacuum oven at 44 ° C. for 2 hours to give the product (0.53 g, 71% yield) as grayish. As a solid. ¹ H NMR (400 MHz, CD ₃ CN + D ₂ O) δ 7.153 (d, 1H), 6.792 (s, 1H), 6.698 (d, 1H), 3.628 (s, 2H); m / z 270 (M + H).

Example 54
This illustrates the formation of 2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide.

2,4-Diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile (3 g) produced as described in Example 52 in 125 mL of trifluoroacetic acid cooled in a water bath. , 10 mmol), 30% aqueous hydrogen peroxide (8 g) was added dropwise. After the addition was complete, the water bath was removed. After 4 hours, additional 30% aqueous hydrogen peroxide (2 g) was added and stirring at room temperature was continued for another 2 hours. Water (20 mL) was then added and the resulting solution was concentrated to about 70 mL. Then more water was added and the yellow suspension was stirred overnight at room temperature. The suspension was filtered and washed with water to give the desired product (2 g, 60.4% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO + D ₂ O) δ 8.350 (dd, 1H), 8.265 (d, 1H), 8.220 (d, 1H), 4.160 (s, 2H); m / z 332 (M + H) .

Example 55
This illustrates the formation of 2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide.

2,4-Diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide (0.8 g, 2.4 mmol) formed as described in Example 54. ) And iron powder (0.58 g, 10 mmol) in 50% ethanol-water (10 mL) was heated to 70 ° C., then 1 mL HCl / ethanol (5.2 mL concentrated HCl and 25 mL 50% Ethanol-prepared from water) was added. The resulting mixture was heated at 76 ° C. for 3 hours and filtered hot. This solid was washed with methanol and trifluoroacetic acid. The trifluoroacetic acid filtrate was concentrated in vacuo and ether was added to the viscous oil. The solid was filtered and washed with ether to give the desired product (0.42 g, 57.5% yield) as a beige solid. ¹ H NMR (400 MHz, DMSO + D ₂ O) δ 7.521 (d, 1H), 6.60 (dd, 1H), 6.529 (s, 1H), 3.753 (s, 2H); m / z 302 (M + H ).

Example 56
This illustrates the formation of 2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile uses 2,5-difluorobenzaldehyde as a starting material instead of 2-chloro-5-nitrobenzaldehyde The bis-trifluoroacetate salt was prepared in the same manner as described in Example 52, except that The product (0.35 g, 35% yield) was isolated as a beige solid. ¹ H NMR (400 MHz, CD ₃ CN + D ₂ O), δ 7.425 (dd, 1H), 7.153 (dd, 1 H), 7.088 (dt, 1H) 3.743 (s, 2H); m / z 273 ( M + H).

Example 57
This illustrates the formation of 2,4-diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile bis (trifluoroacetate).

2,4-Diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile was performed except that 2-fluorobenzaldehyde was used as the starting material instead of 2-chloro-5-nitrobenzaldehyde. Prepared in the same manner as described in Example 52. The product (1.8 g, 47.4% yield) was isolated as a beige solid. ¹ H NMR (400 MHz, CD ₃ CN + D ₂ O) δ 7.271-7.435 (m, 4H), 3.785 (s, 2 H); m / z 255 (M + H).

Example 58
This illustrates the formation of 2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile is the same as that of Example 52 except that 2-fluoro-5-methoxybenzaldehyde is used as the starting material. Prepared in the same manner as described. The product (0.5 g, 49% yield) was isolated as a beige solid. ¹ H NMR (400 MHz, CD ₃ CN + D ₂ O) δ 7.329 (d, 1H), 6.938 (d, 1H), 6.885 (dd, 1H), 3.795 (s, 3H), 3.710 (s, 2H) m / z 285 (M + H).

Example 59
This illustrates the formation of 2,4-diamino-7-hydroxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile.

2,4-Diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile (0.3 g, 0.59 mmol) and 0.6 mL prepared as described in Example 58. Of boron tribromide (6.4 mmol) in 30 mL of methylene chloride was stirred at room temperature for 18 hours. The solid was then filtered and washed with methylene chloride, water, and methanol. The methanol filtrate was concentrated to give a solid that was washed with water, acetonitrile, and ether to give the desired product (54 mg, 33.6% yield) as a red solid. ¹ H NMR (400 MHz, DMSO + D ₂ O) δ 9.520 (s, 1H), 8.111 (d, 1H), 7.561 (d, 1H), 7.522 (s, 2H); m / z 271 (M + H ).

Example 60
This illustrates the formation of 2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide (alternative procedure).

2,4,7-Triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile (0.1 g, 0.26 mmol) and 30% water peroxide formed as described in Example 55 A mixture of (1.5 mL) in 3 mL trifluoroacetic acid was stirred overnight at room temperature. Water (30 mL) was then added and the resulting suspension was stirred at ambient temperature for 2 hours. This solid was filtered to give the desired product (18 mg, 8.6% yield) as a yellow solid: ¹ HNMR (400 MHz, DMSO + D ₂ O) δ 8.353 (dd, 1H) , 8.263 (d, 1H), 8.228 (d, 1H), 4.163 (s, 2H); m / z 332 (M + H).

Example 61
This illustrates the formation of 2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide.

2,4-Diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide was prepared as described in Example 60, using 2,4-diamino-7- Prepared in the same manner as nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide. The product (51 mg, 32.7% yield) was isolated as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ 8.028 (q, 1H), 7.433 (dt, 1H), 7.253 (d, 1H), 7.162 (bs, 1H), 6.917 (bs, 1H), 4.024 (s, 2H ); m / z 305 (M + H).

Example 62
This illustrates the formation of 2,4-diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide.

2,4-Diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide was prepared as described in Example 60, with 2,4-diamino-7-nitro-5H- Prepared in the same manner as thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide. The product (73 mg, 42.9% yield) was isolated as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ 7.945 (dd, 1H), 7.762 (dt, 1H), 7.568 (t, 1H), 7.467 (d, 2H), 7.179 (bs, 2H), 6.886 (bs, 1H ), 4.009 (s, 2H); m / z 287 (M + H).

Example 63
This illustrates the formation of 2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide.

2,4-Diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide was prepared as described in Example 60, using 2,4-diamino-7- Prepared in the same manner as nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide. The product (110 mg, 34.2% yield) was isolated as a light brown solid. ¹ H NMR (400 MHz, DMSO + D ₂ O) δ 7.858 (d, 1H), 7.107 (dd, 1H), 6.972 (d, 1H), 3.942 (2, 2H), 3.833 (s, 3H); m / z 316 (M + H).

Examples 64-65
This illustrates the production of the aminocyanopyridine compound of the present invention.
The aminocyanopyridine compounds shown in the table below were prepared according to the general method described in Example 60. NMR analysis is performed according to the method described above and the data obtained for each of the compounds is provided in a table.

Examples 66-81
This illustrates the production of several aminocyanopyridine compounds of the present invention.
General procedure for N-alkylation 2,4-diamino-7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile (1.34 mmol) and the corresponding halide (2.01 Mmol) in dimethylformamide (5 mL) is added sodium hydride (80 mg, 2.01 mmol). The reaction mixture is stirred at room temperature or heated to 40 ° C. to complete. The mixture is quenched with saturated aqueous ammonium chloride and purified directly by reverse phase chromatography. Both monoalkylated and dialkylated products were isolated.

The following compounds were prepared using the procedure described above:
Example 66: 2-amino-4-{[2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 67: 2,4-bis {[2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 68 2-amino-4-[(2-aminoethyl) amino] -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 69: 2-amino-4-{[2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
Example 70 2-amino-7,8-dimethoxy-4-[(2-pyrrolidin-1-ylethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 71: 7,8-dimethoxy-2,4-bis [(2-pyrrolidin-1-ylethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
Example 72: 2,4-bis (glycinyl) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile trifluoroacetate
Example 73: N- (2-amino-3-cyano-7,8-dimethoxy-5H-chromeno [2,3-b] pyridin-4-yl) glycine,
Example 74: 7,8-dimethoxy-2,4-bis [(2-methoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 75 2-amino-7,8-dimethoxy-4-[(2-methoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 76: 2,4-bis (butylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 77: 2-amino-4- (butylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
Example 78: 7,8-dimethoxy-2,4-bis (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
Example 79: 2-amino-7,8-dimethoxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 80: 2,4-bis (ethylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile, and Example 81: 2-amino-4- (ethyl) Amino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

General procedure for demethylation:
Boron tribromide (1M, dichloromethane, 3.38 mmol, 3.38 mL) is slowly added to a solution of the corresponding dimethoxyaryl analog (0.68 mmol) in dichloromethane (2 mL). The reaction mixture is stirred at room temperature for 4 hours, quenched with 5% aqueous sodium hydroxide and then neutralized with 5% aqueous HCl. The resulting solid is collected and the aqueous layer is extracted with dichloromethane. The organic layer is concentrated in vacuo and combined with the previous solid. The residue is purified by reverse phase chromatography.

Example 82
This illustrates the formation of 2-amino-4- (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2-Amino-4- (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile is 2-amino-4- (ethylamino) -7,8- Prepared using the demethylation procedure described above starting from dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile. ¹ H NMR (400 MHz, DMSO) δ 6.5 (s, 1H), 6.4 (s, 1H), 3.65 (q, 2H), 2.5 (s, 2H), 1.25 (t, 3H); m / z 299.15 ( _{M + H); HRMS (M} + H) calcd for _{C 15 H 15 N 4 O 3} : 299.1139. Actual value: 299.1113.

Example 83
This illustrates the formation of 2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile is 2-amino-7,8-dimethoxy-4- (propylamino) ) Prepared using the demethylation procedure described above for Examples 66-81 starting from -5H-chromeno [2,3-b] pyridine-3-carbonitrile. ¹ H NMR (400 MHz, DMSO) δ 6.5 (s, 1H), 6.4 (s, 1H), 3.55 (m, 2H), 2.5 (s, 2H), 1.6 (m, 2H), 1.35 (t, 3H ); m / z 313.16 (M + H); HRMS (M + H) calcd for _{C 16 H 17 N 4 O 3} : 313.1295. Found: 313.1325.

Example 84
This illustrates the formation of 2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

2-Amino-7,8-dihydroxy-4-[(2-hydroxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile is 2-amino-7,8-dimethoxy- Using the demethylation procedure described above for Examples 66-81 starting from 4-[(2-methoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile. Manufactured. ¹ H NMR (400 MHz, DMSO) δ 6.5 (s, 1H), 6.4 (s, 1H), 3.65 (m, 2H), 3.55 (m, 2H), 2.5 (s, 2H); m / z 315.13 ( M + H).

Example 85
This illustrates the formation of 2,4-bis (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

  2,4-Bis (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile was prepared by using the procedure described in Examples 66-81. .

Examples 86-91
This illustrates the production of several aminocyanopyridine compounds of the present invention.
General procedure for O-alkylation of phenol 2,4-diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile:
2,4-Diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile (0.73 mmol) and powdered sodium hydroxide (117 mg, 2.93 mmol) in dimethyl sulfoxide (4 mL) ) Heat the solution to 50 ° C. for 5 minutes. The corresponding halide is added and the reaction mixture is stirred at 50 ° C. or 75 ° C. until completion. The mixture is quenched with saturated aqueous ammonium chloride and purified directly by reverse phase chromatography.

The following compounds were prepared using the above procedure:
Example 86: 2,4-diamino-9- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 87: (2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-9-yl) oxy] acetic acid,
Example 88: 2,4-diamino-9- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile
Example 89: 2,4-diamino-9- [2- (dimethylamino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
Example 90: 2,4-Diamino-9- (pyridin-4-ylmethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile, and Example 91: 2,4-diamino-9- (2-Pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile.

Examples 92-120
This illustrates the production of several aminocyanopyridine compounds of the present invention.
General procedure for Mannich condensation:
Formic acid (37% solution, 76 μL, 1.01 mmol) and piperidine (100 μL, 1.01 mmol) are added to the corresponding phenol (0.92 mmol) in ethanol (5 mL). The reaction mixture is stirred at 75 ° C. until complete. The mixture is quenched with saturated aqueous ammonium chloride and purified directly by reverse phase chromatography to isolate each regioisomer.

The following compounds were prepared using the above procedure:
Example 92: 2,4-Diamino-9-hydroxy-6,8-bis (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile, and Example 93: 2 , 4-Diamino-9-hydroxy-8- (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile is produced as described in Examples 66-81. Prepared starting from 2,4-diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile and Example 94: 2,4-diamino-8-hydroxy-7, 9-bis (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile is formed as described in Example 8, 2,4-diamino-8-hydroxy. 5H- chromeno [2,3-b] starting from pyridine-3-carbonitrile, it was produced.

  Other aminocyanopyridine compounds of the present invention can be produced by the same general method and are shown in the table below with the NMR variables determined as described above.

Example 121
This illustrates the formation of 2,4-diamino-7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile.

Formaldehyde (37%, water, 39.5 mmol, 3.2 g) to a stirred solution of 3,4-dimethoxyphenol (35.7 mmol, 5.5 g) and piperidine (40 mmol, 3.4 g) in ethanol (50 mL) Was added slowly. The mixture was stirred at room temperature for 4 hours, then evaporated in vacuo and the resulting residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water, dried (MgSO ₄ ) and evaporated to give a colorless oily residue. To the above oily product acetone solution was added methyl iodide (100 mmol, 14.2 g) and the mixture was stirred at room temperature overnight. The resulting white precipitate was collected by filtration, washed with ether and air dried to give 8.14 g of a white solid.

Triethylamine (0.5 mL) was added to an ethanol (10 mL) slurry of the above solid (1 mmol, 390 mg) and 2-amino-1-propene-1,1,3-tricarbonitrile (1 mmol, 132 mg), The resulting solution was heated at reflux for 30 minutes. After cooling to room temperature, the precipitate was collected by filtration, washed with ether and air dried to give the product (178 mg, 60% yield) as a white solid. ¹ H NMR (400 MHZ, DMSO) δ 6.582 (s, 1H), 6.574 (s, 1H), 6.406 (s, 2H), 6.241 (s, 2H), 3.686 (s, 3H), 3.671 (s, 3H ), 3.524 (s, 2H); m / z 299 (M + H).

Example 122
This illustrates the formation of 2- (2,4-diamino-3-cyano-8-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile.

To a solution of 2-hydroxy-4-methoxybenzaldehyde (10 mmol, 1.52 g) and malononitrile (40 mmol, 2.64 g) in ethanol (250 mL) was added 6 drops of piperidine. The mixture was heated at 50 ° C. for 10 minutes and then stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration and recrystallized from methanol to give the product (1.19 g, 36% yield) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO) δ 7.274 (d, 1H), 6.999 (s, 2H), 6.817 (dd, 1H), 6.733 (d, 1H), 6.619 (s, 2H), 4.804 (d, 1H ), 4.734 (d, 1H), 3.757 (s, 3H); m / z 333 (M + H).

Example 123
This illustrates the formation of 2- (2,4-diamino-3-cyano-7-bromo-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile.

To a solution of 5-bromo-2-hydroxybenzaldehyde (10 mmol, 2 g) and malononitrile (35 mmol, 2.31 g) in ethanol (200 mL) was added 6 drops of piperidine and the mixture was stirred at room temperature for 30 hours. The resulting precipitate was collected by filtration and recrystallized from methanol to give the product (1.68 g, 44% yield) as a white solid. ¹ H NMR (400 MHz, DMSO) δ 7.489 (dd, 1H), 7.344 (d, 1H), 7.230 (d, 1H), 7.063 (s, 2H), 6.686 (s, 2H), 4.876 (d, 1H ), 4.850 (d, 1H); m / z 381, 383 (M + H).

Example 124
This illustrates the formation of 2- (2,4-diamino-3-cyano-7-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile.

To a solution of 2-hydroxy-5-methoxybenzaldehyde (10 mmol, 1.52 g) and malononitrile (40 mmol, 2.64 g) in ethanol (350 mL) was added 6 drops of piperidine and the mixture was stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed successively with ethanol and ether and air dried to give the product (1.42 g, 43% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO) δ 7.107 (d, 1H), 6.990 (m, 3H), 6.865 (d, 1H), 6.603 (s, 2H), 4.850 (d, 1H), 4.794 (d, 1H ), 3.724 (s, 3H); m / z 333 (M + H).

Example 125
This illustrates the formation of 2- (2,4-diamino-3-cyano-8-hydroxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile.

To a solution of 2,4-dihydroxybenzaldehyde (10 mmol, 1.38 g) and malononitrile (40 mmol, 2.64 g) in ethanol (350 mL) was added 6 drops of piperidine and the mixture was stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration, washed successively with ethanol and ether and air dried to give the product (1.62 g, 51% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ 9.887 (s, 1H), 7.162 (d, 1H), 6.971 (s, 2H), 6.613 (dd, 1H), 6.597 (s, 2H), 6.497 (d, 1H ), 4.743 (d, 1H), 4.687 (d, 1H); m / z 319 (M + H).

Examples 126-135
This illustrates the production of several aminocyanopyridine compounds of the present invention.
The aminocyanopyridine compounds listed in the table below were produced according to the general method described in Example 123. According to the method described above, each material was subjected to NMR analysis. The name and NMR data for each compound are provided in the table.

  All cited in this specification, including without limitation, all articles, publications, patents, patent applications, announcements, texts, reports, drafts, abstracts, books, Internet postings, journal articles, periodicals, etc. The references are incorporated herein by reference in their entirety. The discussion of the references in this document only summarizes the author's claims, and no reference is allowed to constitute prior art. Applicants have the right to challenge the accuracy and appropriateness of the cited references.

In light of the above, it will be seen that the several advantages of the invention are achieved and other advantageous results attained.
Since various changes can be made in the above methods and compositions without departing from the scope of the invention, all content contained in the above description is to be interpreted as illustrative and not restrictive. It is contemplated that it should.

Claims (20)

Construction:

[Where:
Each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is:
Hydrogen, hydroxy, amino, halo, nitro,
Branched or unbranched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenoxy,
Branched or unbranched amino C ₁ -C ₆ alkyl, diamino C ₂ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, di (C _1- C ₆ alkyl) amino, C ₁ -C ₄ alkoxyarylamino, C ₁ -C ₄ alkoxyalkylamino, amino C ₁ -C ₆ alkoxy, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₆ alkoxy, Di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, dihalo C ₁ -C ₆ alkoxy, trihalo C ₁ -C ₆ alkoxy, cyano _C 1 -C ₆ alkyl, dicyano _C 1 -C ₆ alkyl, cyano _C 1 -C ₆ alkoxy, dicyano _C 1 -C ₆ alkoxy, Rubamiru _C 1 -C ₄ alkoxy, heterocyclyl _C 1 -C ₄ alkoxy, heteroaryl _C 1 -C ₄ alkoxy, sulfo, _sulfamyl, C 1 -C ₄ alkylaminosulfonyl, hydroxy _C 1 -C ₄ alkylaminosulfonyl, di ( C ₁ -C ₄ alkyl) _{aminosulfonyl,} C 1 -C _{4 alkylthio,} C 1 -C _{4 alkylsulfonyl,} C 1 -C ₄ alkylsulfinyl,
Aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, heteroaryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkoxy, heteroaryl C ₁ -C ₆ alkoxy, aryl C ₁ -C ₆ Alkoxy (wherein the aryl ring may be substituted or unsubstituted, and if substituted, the substituent is a group of C ₁ -C ₆ alkyl, halo, amino, and C ₁ -C ₆ alkoxy; Selected from one or more),
Substituted or unsubstituted C ₃ -C ₆ cyclyl, C ₃ -C ₆ heterocyclyl (and, if substituted, the substituent consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, amino) is selected from one or more of the group, and _C 3 -C ₆ heterocyclyl ring here, O, containing S, or N),
Branched or unbranched _C 1 -C ₆ alkoxycarbonyl _C 1 -C ₆ alkoxy, and carboxy, carboxy _C 1 -C ₆ alkoxy, carboxy _C 1 -C ₆ alkyl, hydroxy _C 1 -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl,
Independently selected from the group consisting of
Where R ⁶ and R ⁷ are as described above, optionally combined:

Forming a ring system of a more selected type;
G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
When G is nitrogen, R ⁴ is hydrogen, R ⁹ is absent, and R ¹⁰ is C ₁ -C ₄ alkyl]. The structure of claim 1 [where:
R ¹ is hydrogen, branched or unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy, carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl, alkylamino, halo, Selected from the group consisting of alkylaminoalkyl, alkoxy, alkoxyalkyl, monocyclyl, bicyclyl, polycyclyl, and heterocyclyl;
R ² is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl Selected;
R ³ is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituent, if any, includes a halo moiety;
R ⁴ is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituent, if any, includes a halo moiety;
R ⁵ is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkynyl, arylalkyl, and alkylaryl;
R ⁶ is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, aryl Selected from the group consisting of alkyl, alkylaryl, and arylamino;
R ⁷ is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy,
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is from hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl And G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
When G is nitrogen, R ⁹ is absent and R ¹⁰ is C ₁ -C ₄ alkyl]. The structure of claim 1 [where:
R ¹ is selected from the group consisting of hydrogen, ethyl, dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl;
R ² is hydrogen, hydroxyethyl, propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl, phenylmethyl, dimethylaminoethyl, phthaloaminoethyl, butyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl Selected from the group consisting of:
R ³ is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
R ⁴ is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
R ⁵ is selected from the group consisting of hydrogen, hydroxy, methoxy, bromo, and 2-pyridomethyl;
R ⁶ is selected from the group consisting of hydrogen, hydroxy, methoxy, amino, carboxy, diaminoethoxy, bromo, propoxy, isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro, pyridylmethyl, and fluoro;
R ⁷ consists of hydrogen, hydroxy, methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy, morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy, dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and isobutylcarboxymethoxy Selected from the group,
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is hydrogen, hydroxy, fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl, hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy, dimethylaminoethoxy, carboxy, bromo, and Selected from the group consisting of pyridylmethyl; and G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
When G is nitrogen, R ⁹ is absent and R ¹⁰ is —CH ₃ ]. The structure of claim 1 [where:
R ¹ is selected from the group consisting of hydrogen and C ₁ -C ₂ alkyl;
R ² is hydrogen, C ₁ -C ₃ alkyl, hydroxy C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxyphenyl, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkyl, amino C ₁ -C ₂ alkyl, Selected from the group consisting of phenyl C ₁ -C ₂ alkyl and diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, dicyano C ₁ -C ₂ alkyl, and halophenyl;
R ⁵ is selected from the group consisting of hydrogen and hydroxy;
R ⁶ is hydrogen, hydroxy, C ₁ -C ₃ alkoxy, amino, nitro, carboxy, diamino C ₁ -C ₂ alkoxy, halo, propenoxy, isoC ₃ -C ₄ alkylcarboxy C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino, and are selected from the group consisting of phenyl;
R ⁷ is hydrogen, hydroxy, C ₁ -C ₃ alkoxy, hydroxy C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkoxy, amino C ₁ -C ₂ alkoxy, morpholino C ₁ -C ₂ Alkoxy, carboxyl C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkyl, isoC ₃ -C ₄ alkyl carboxy C Selected from the group consisting of ₁ -C ₂ alkoxy, and 2-propenoxy;
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is hydrogen, hydroxy, halo, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, nitro, amino, pyrrolidyl C ₁ -C ₂ alkoxy, carboxy C ₁ -C ₂ alkoxy, hydroxy C ₁ -C ₂ Selected from the group consisting of alkoxy and amino C ₁ -C ₂ alkoxy; and G is selected from the group consisting of oxygen and sulfur;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
R ⁹ and R ¹⁰ are absent when G is oxygen]. The structure of claim 1 [where:
R ¹ is hydrogen;
R ² is hydrogen, C ₁ -C ₃ alkyl, hydroxy C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxyphenyl, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkyl, amino C ₁ -C ₂ alkyl, Selected from the group consisting of phenyl C ₁ -C ₂ alkyl and diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and dicyano C ₁ -C ₂ alkyl;
R ⁵ is selected from the group consisting of hydrogen and hydroxy;
R ⁶ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, amino, carboxy, nitro, diamino C ₁ -C ₂ alkoxy, halo, 2-propenoxy, isoC ₃ -C ₄ alkylcarboxy C ₁ -C ₂ alkoxy, Selected from the group consisting of diC ₁ -C ₂ alkylamino and phenyl;
R ⁷ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, hydroxy C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkoxy, amino C ₁ -C ₂ alkoxy, morpholino C ₁ -C ₂ Alkoxy, carboxyl C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkyl, isoC ₃ -C ₄ alkyl carboxy C ₁ -C ₂ alkoxy, and is selected from the group consisting of 2-propenoxy;
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, hydroxy, halo, C ₁ -C ₂ alkoxy, nitro, amino, pyrrolidyl C ₁ -C ₂ alkoxy, and carboxy C ₁ -C ₂ alkoxy; and G is oxygen and Selected from the group consisting of sulfur;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
R ⁹ and R ¹⁰ are absent when G is oxygen]. The structure of claim 1 [where:
R ¹ is hydrogen;
R ² is hydrogen, C ₁ -C ₃ alkyl, hydroxy C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxyphenyl, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkyl, amino C ₁ -C ₂ alkyl, And selected from the group consisting of phenyl C ₁ -C ₂ alkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and dicyano C ₁ -C ₂ alkyl;
R ⁵ is selected from the group consisting of hydrogen and hydroxy;
R ⁶ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, amino, carboxy, diamino C ₁ -C ₂ alkoxy, halo, 2-propenoxy, isoC ₃ -C ₄ alkylcarboxy C ₁ -C ₂ alkoxy, and di Selected from the group consisting of C ₁ -C ₂ alkylamino;
R ⁷ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, hydroxy C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkoxy, amino C ₁ -C ₂ alkoxy, morpholino C ₁ -C ₂ Alkoxy, carboxyl C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkyl, isoC ₃ -C ₄ alkyl carboxy C Selected from the group consisting of ₁ -C ₂ alkoxy, and 2-propenoxy;
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, hydroxy, halo, C ₁ -C ₂ alkoxy, nitro, amino, and pyrrolidyl C ₁ -C ₂ alkoxy; and G is selected from the group consisting of oxygen and sulfur;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
R ⁹ and R ¹⁰ are absent when G is oxygen]. The structure of claim 1 [where:
R ¹ is hydrogen;
R ² is hydrogen, C ₁ -C ₃ alkyl, hydroxy C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxyphenyl, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkyl, and amino C ₁ -C ₂ alkyl Selected from the group consisting of:
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and dicyanoethyl;
R ⁵ is selected from the group consisting of hydrogen and hydroxy;
R ⁶ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, amino, carboxy, diamino C ₁ -C ₂ alkoxy, halo, 2-propenoxy, isoC ₃ -C ₄ alkylcarboxy C ₁ -C ₂ alkoxy, and di Selected from the group consisting of C ₁ -C ₂ alkylamino;
R ⁷ is hydrogen, hydroxy, C ₁ -C ₂ alkoxy, hydroxy C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkoxy C ₁ -C ₂ alkoxy, amino C ₁ -C ₂ alkoxy, morpholino C ₁ -C ₂ Alkoxy, carboxyl C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkoxy, diC ₁ -C ₂ alkylamino C ₁ -C ₂ alkoxy, pyrrolidyl C ₁ -C ₂ alkyl, isoC ₃ -C ₄ alkyl carboxy C Selected from the group consisting of ₁ -C ₂ alkoxy, and 2-propenoxy;
Wherein the R ⁶ and R ⁷ groups are optionally joined to form a 6-membered heterocyclic ring;
R ⁸ is selected from the group consisting of hydrogen, hydroxy, halo, methoxy, nitro, and amino; and G is selected from the group consisting of oxygen and sulfur;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
R ⁹ and R ¹⁰ are absent when G is oxygen]. 2,4-diamino-7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
8,10-diamino-2,3-dihydro-11H- [1,4] dioxino [2 ′, 3 ′: 6,7] chromeno [2,3-b] pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile 2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-morpholin-4-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-8-yl) oxy] acetic acid,
2,4-diamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4- (methylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- [2- (dimethylamino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-8-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-diamino-7,8-di [2- (amino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-hydroxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2- (2,4-diamino-3-cyano-7-bromo-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2-amino-8-ethoxy-4- (ethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,9-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-diamino-9-hydroxy-8- (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-bis (allyloxy) -2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-8- (2-ethoxyethoxy) -4-[(2-ethoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
{[2,4-diamino-7- (2-tert-butoxy-2-oxoethoxy) -3-cyano-5H-chromeno [2,3-b] pyridin-8-yl] oxy} tert-butyl acetate,
2-amino-4-[(2-aminoethyl) amino] -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-8-hydroxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-bromo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7- (dimethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-9-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2-amino-4- (benzylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
8- (allyloxy) -2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-9-yl) oxy] acetic acid,
2-amino-4-{[2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-phenyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-chloro-9-methyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
8-ethoxy-2,4-bis (ethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5- (2-fluoro-phenyl) -8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-chloro-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-bis {[2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-Amino-4-{[2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3 -B] pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-bromo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (pyridin-4-ylmethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-chloro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-tert-butyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
Ethyl 2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-9-carboxylate,
2,4-diamino-9- [2- (dimethylamino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-bis (butylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (butylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-bis (ethylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (ethylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7- (trifluoromethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-bromo-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-methoxy-7-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,9-diamino-10H- [1,3] dioxolo [6,7] chromeno [2,3-b] pyridine-8-carbonitrile,
7,9-diamino-10H- [1,3] dioxolo [6,7] chromeno [2,3-b] pyridine-8-carbonitrile,
2,4-diamino-8-methyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis [(2-methoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(2-methoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(2-pyrrolidin-1-ylethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis [(2-pyrrolidin-1-ylethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-bis (glycinyl) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
N- (2-amino-3-cyano-7,8-dimethoxy-5H-chromeno [2,3-b] pyridin-4-yl) glycine,
2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-9-carboxylic acid,
2,4-diamino-6-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-bromo-7-chloro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-bis (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6-bromo-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-7,9-bis (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5-phenyl-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5- (3-fluoro-phenyl) -8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-6,8-bis (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-bromo-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5-phenyl-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,9-dimethyl-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-isopropyl-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-ethyl-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-methyl-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-chloro-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7-bromo-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-Amino-5-oxo-5H-chromeno [2,3-b] pyridine-3-carbonitrile and 3-amino-5H-pyrido [3,4-b] [1,4] benzothiazine-4-carbo An aminocyanopyridine compound selected from the group consisting of nitriles. 2,4-diamino-7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
8,10-diamino-2,3-dihydro-11H- [1,4] dioxino [2 ′, 3 ′: 6,7] chromeno [2,3-b] pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-morpholin-4-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-8-yl) oxy] acetic acid,
2,4-diamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4- (methylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- [2- (dimethylamino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-8-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-diamino-7,8-di [2- (amino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-hydroxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2- (2,4-diamino-3-cyano-7-bromo-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2-amino-8-ethoxy-4- (ethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,9-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-diamino-9-hydroxy-8- (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-bis (allyloxy) -2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-8- (2-ethoxyethoxy) -4-[(2-ethoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
{[2,4-diamino-7- (2-tert-butoxy-2-oxoethoxy) -3-cyano-5H-chromeno [2,3-b] pyridin-8-yl] oxy} tert-butyl acetate,
2-amino-4-[(2-aminoethyl) amino] -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-8-hydroxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-7-bromo-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7- (dimethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-9-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2-amino-4- (benzylamino) -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
8- (allyloxy) -2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-9-yl) oxy] acetic acid,
2-amino-4-{[2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide,
9. An aminocyanopyridine compound according to claim 8, selected from the group consisting of 2,4-diamino-7-phenyl-5H-chromeno [2,3-b] pyridine-3-carbonitrile, and prodrugs thereof. Salts, tautomers, and combinations. 2,4-diamino-7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
8,10-diamino-2,3-dihydro-11H- [1,4] dioxino [2 ′, 3 ′: 6,7] chromeno [2,3-b] pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile 2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-morpholin-4-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-8-yl) oxy] acetic acid,
2,4-diamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4- (methylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- [2- (dimethylamino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-8-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-diamino-7,8-di [2- (amino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-nitro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-hydroxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2- (2,4-diamino-3-cyano-7-bromo-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2-amino-8-ethoxy-4- (ethylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,9-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2- (2,4-diamino-3-cyano-7-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile,
2,4-diamino-9-hydroxy-8- (piperidin-1-ylmethyl) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
7,8-bis (allyloxy) -2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
Selected from the group consisting of 2-amino-8- (2-ethoxyethoxy) -4-[(2-ethoxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile. Item 11. The aminocyanopyridine compound according to Item 8, and prodrugs, salts, tautomers, and combinations thereof. 2,4-diamino-7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl) amino] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-4- (ethylamino) -7,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-hydroxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
8,10-diamino-2,3-dihydro-11H- [1,4] dioxino [2 ′, 3 ′: 6,7] chromeno [2,3-b] pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-ethoxyethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-aminoethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-morpholin-4-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno [2,3-b] pyridin-8-yl) oxy] acetic acid,
2,4-diamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4- (methylamino) -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4-diamino-8- [2- (dimethylamino) ethoxy] -5H-chromeno [2,3-b] pyridine-3-carbonitrile,
2,4,7-triamino-9-methoxy-5H-chromeno [2,3-b] pyridine-3-carbonitrile,
9. The aminocyano of claim 8, selected from the group consisting of 2- (2,4-diamino-3-cyano-8-methoxy-5H-chromeno [2,3-b] pyridin-5-yl) malononitrile. Pyridine compounds and their prodrugs, salts, tautomers, and combinations.   The aminocyanopyridine compound according to claim 1, which is capable of inhibiting the activity of MK-2. To provide an _{IC 50} value less than 100μM in the MK-2 activity inhibition assay amino cyanopyridine compound of claim 1. The aminocyanopyridine compound of claim 1, which provides an MK-2 IC ₅₀ value of less than 1 μM in an MK-2 activity inhibition assay. The aminocyanopyridine compound of claim 1, which provides a TNFα release IC ₅₀ value of less than 200 μM in an in vitro cell assay. The aminocyanopyridine compound of claim 1, which provides a TNFα release IC ₅₀ value of less than 1 μM in an in vitro cell assay.   The aminocyanopyridine compound of claim 1, which provides a degree of inhibition of TNFα of at least about 25% in a rat LPS assay.   2. The aminocyanopyridine MK-2 inhibitor compound of claim 1, which provides a degree of inhibition of TNFα greater than 80% in a rat LPS assay. Pharmaceutically acceptable carriers and structures:

[Where:
Each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is:
Hydrogen, hydroxy, amino, halo, nitro,
Branched or unbranched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenoxy,
Branched or unbranched amino C ₁ -C ₆ alkyl, diamino C ₂ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, di (C _1- C ₆ alkyl) amino, C ₁ -C ₄ alkoxyarylamino, C ₁ -C ₄ alkoxyalkylamino, amino C ₁ -C ₆ alkoxy, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₆ alkoxy, Di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, dihalo C ₁ -C ₆ alkoxy, trihalo C ₁ -C ₆ alkoxy, cyano _C 1 -C ₆ alkyl, dicyano _C 1 -C ₆ alkyl, cyano _C 1 -C ₆ alkoxy, dicyano _C 1 -C ₆ alkoxy, Rubamiru _C 1 -C ₄ alkoxy, heterocyclyl _C 1 -C ₄ alkoxy, heteroaryl _C 1 -C ₄ alkoxy, sulfo, _sulfamyl, C 1 -C ₄ alkylaminosulfonyl, hydroxy _C 1 -C ₄ alkylaminosulfonyl, di ( C ₁ -C ₄ alkyl) _{aminosulfonyl,} C 1 -C _{4 alkylthio,} C 1 -C _{4 alkylsulfonyl,} C 1 -C ₄ alkylsulfinyl,
Aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, heteroaryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkoxy, heteroaryl C ₁ -C ₆ alkoxy, aryl C ₁ -C ₆ Alkoxy (wherein the aryl ring may be substituted or unsubstituted, and if substituted, the substituent is a group of C ₁ -C ₆ alkyl, halo, amino, and C ₁ -C ₆ alkoxy; Selected from one or more),
Substituted or unsubstituted C ₃ -C ₆ cyclyl, C ₃ -C ₆ heterocyclyl (and, if substituted, the substituent consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, amino) is selected from one or more of the group, and _C 3 -C ₆ heterocyclyl ring here, O, containing S, or N),
Branched or unbranched _C 1 -C ₆ alkoxycarbonyl _C 1 -C ₆ alkoxy, and carboxy, carboxy _C 1 -C ₆ alkoxy, carboxy _C 1 -C ₆ alkyl, hydroxy _C 1 -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl,
Independently selected from the group consisting of
Where R ⁶ and R ⁷ are as described above, optionally combined:

Forming a ring system of a more selected type;
G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
A pharmaceutical composition comprising an aminocyanopyridine MK-2 inhibitory compound having R ⁹ is absent and R ¹⁰ is C ₁ -C ₄ alkyl when G is nitrogen. Construction:

[Where:
Each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is:
Hydrogen, hydroxy, amino, halo, nitro,
Branched or unbranched C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenoxy,
Branched or unbranched amino C ₁ -C ₆ alkyl, diamino C ₂ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, di (C _1- C ₆ alkyl) amino, C ₁ -C ₄ alkoxyarylamino, C ₁ -C ₄ alkoxyalkylamino, amino C ₁ -C ₆ alkoxy, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₆ alkoxy, Di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, dihalo C ₁ -C ₆ alkoxy, trihalo C ₁ -C ₆ alkoxy, cyano _C 1 -C ₆ alkyl, dicyano _C 1 -C ₆ alkyl, cyano _C 1 -C ₆ alkoxy, dicyano _C 1 -C ₆ alkoxy, Rubamiru _C 1 -C ₄ alkoxy, heterocyclyl _C 1 -C ₄ alkoxy, heteroaryl _C 1 -C ₄ alkoxy, sulfo, _sulfamyl, C 1 -C ₄ alkylaminosulfonyl, hydroxy _C 1 -C ₄ alkylaminosulfonyl, di ( C ₁ -C ₄ alkyl) _{aminosulfonyl,} C 1 -C _{4 alkylthio,} C 1 -C _{4 alkylsulfonyl,} C 1 -C ₄ alkylsulfinyl,
Aryl, aryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, heteroaryl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkoxy, heteroaryl C ₁ -C ₆ alkoxy, aryl C ₁ -C ₆ Alkoxy (wherein the aryl ring may be substituted or unsubstituted, and if substituted, the substituent is a group of C ₁ -C ₆ alkyl, halo, amino, and C ₁ -C ₆ alkoxy; Selected from one or more),
Substituted or unsubstituted C ₃ -C ₆ cyclyl, C ₃ -C ₆ heterocyclyl (and, if substituted, the substituent consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, amino) is selected from one or more of the group, and _C 3 -C ₆ heterocyclyl ring here, O, containing S, or N),
Branched or unbranched _C 1 -C ₆ alkoxycarbonyl _C 1 -C ₆ alkoxy, and carboxy, carboxy _C 1 -C ₆ alkoxy, carboxy _C 1 -C ₆ alkyl, hydroxy _C 1 -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl,
Independently selected from the group consisting of
Where R ⁶ and R ⁷ are as described above, optionally combined:

Forming a ring system of a more selected type;
G is selected from the group consisting of oxygen, sulfur, and nitrogen;
When G is oxygen, R ⁹ and R ¹⁰ are absent;
When G is sulfur, each of R ⁹ and R ¹⁰ is optionally absent or oxo;
A kit comprising an aminocyanopyridine MK-2 inhibitory compound having an aminocyanopyridine MK-2 inhibitor compound having R ⁹ absent and R ¹⁰ is C ₁ -C ₄ alkyl when G is nitrogen.