RU2444524C2 - Azabenzothiophenyl compounds and methods of use - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to azabenzothiophenyl compounds of formula I

and salts thereof, where: Z¹ denotes CR¹; Z² denotes N; Z³ denotes CR³; Z⁴ denotes CR⁴; R¹, R³ and R⁴ are independently selected from H or halogen; W denotes

, R⁵ and R⁶ denote H; X¹ denotes -OR¹¹; X² denotes phenyl which is optionally substituted with one or two groups selected from halogen or (C₁-C₃)alkylsulphanyl; R¹¹ denotes (C₁-C₁₂) alkyl, substituted by one or two groups independently selected from - (CR¹⁹R²⁰)_nOR¹⁶; n equals 0; R¹⁶ denotes H, (C₁-C₁₂) alkyl or (C₂-C₈) alkenyl. The invention also relates to a pharmaceutical composition based on said compounds, which can be used in medicine for treating hyperproliferative disorders.

EFFECT: high efficiency of using said compounds.

11 cl, 12 ex

Description

Related Applications

This application is an international patent application claiming the priority of provisional application for US patent No. 60/839163, filed August 21, 2006, provisional application for US patent No. 60/871600, filed December 22, 2006, and provisional patent application US No. 60/917624, filed May 11, 2007, incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to azabenzothiophenyl compounds with anti-cancer and / or anti-inflammatory activity, and more particularly, to azabenzothiophenyl compounds that inhibit MEK kinase activity. The invention also relates to methods of using the compounds for in vitro, in situ and in vivo diagnostics or treatment of mammalian cells or treatment of associated pathological conditions.

BACKGROUND OF THE INVENTION

In search of an understanding of how Ras transmits extracellular growth signals, the metabolic pathway of MAP (mitogen-activated protein) kinase (MAPK) is identified as a critical path between membrane-bound Ras and nuclei. The metabolic pathway of MAPK covers a cascade of phosphorylation events that includes three key kinases, namely Raf, MEK (MAP kinase kinase) and ERK (MAP kinase). Active GTP-bound Ras leads to the activation and indirect phosphorylation of Raf kinase. Raf then phosphorylates MEK1 and 2 at two serine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (Ahn et al., Methods in Enzymology, 2001, 332, 417-431). Then, activated MEK phosphorylates only its known substrates — MAP, ERK1 and 2 kinases. Phosphorylation of ERK MEK occurs in Y204 and T202 in the case of ERK1 and Y185 and T183 in the case of ERK2 (Ahn et al., Methods in Enzymology, 2001, 332, 417- 431). Phosphorylated ERK dimerizes and then moves into the nucleus, where it accumulates (Khokhlatchev et al., Cell, 1998, 93, 605-615). In the nucleus, ERK is involved in several important cellular functions, including but not limited to nuclear transfer, signal transduction, DNA repair, nucleosome assembly and translocation, and mRNA processing and translation (Ahn et al., Molecular Cell, 2000, 6, 1343 -1354). In general, treatment of cells with growth factors leads to activation of ERK1 and 2, which leads to proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res., 1998, 74, 49-139).

There is strong evidence that genetic mutations and / or overexpression of protein kinases involved in the cascade of MAP kinase reactions leads to unregulated cell proliferation and, obviously, tumor formation in proliferative diseases. For example, some carcinomas contain mutations that result in the continuous activation of such a cascade due to the continuous production of growth factors. Other mutations can lead to impaired deactivation of the activated GTP-linked Ras complex, and again lead to activation of the MAP kinase reaction cascade. Mutated oncogenic forms of Ras are found in 50% of colon cancers and more than 90% of pancreatic cancers, as well as in many other types of cancers (Kohl et al., Science, 1993, 260, 1834-1837). Recently, bRaf mutations have been identified in more than 60% of cases of malignant melanoma (Davies H. et al., Nature, 2002, 417, 949-954). Such bRaf mutations result in a constitutively active MAP kinase cascade. Studies of primary tumor samples and cell lines also show constitutive or overactivation of the MAP kinase exchange pathway for cancer of the pancreas, colon, lungs, ovaries, and kidneys (Hoshino R. et al., Oncogene, 1999, 18, 813-822).

MEK has been identified as an attractive therapeutic target for the exchange of MAP kinase. MEK along the Ras and Raf signaling pathways is highly specific for the phosphorylation of MAP kinase; indeed, the only known MEK phosphorylation substrates are MAP ERK1 and 2 kinases. Some studies have shown that inhibition of MEK has a potentially beneficial therapeutic effect. For example, low molecular weight MEK inhibitors have been shown to inhibit the growth of human tumors in xenografts in nude mice (Sebolt-Leopold et al., Nature-Medicine, 1999, 5 (7), 810-816); Trachet et al., AACR Apr., 6-10, 2002, Poster # 5426; Tecle H., IBC, 2.sup.nd International Conference of Protein Kinases, Sep., 9-10, 2002), block static allodynia in animals (WO 01/053090, published January 25, 2001) and inhibit cell growth acute myeloid leukemia (Milella et al., J. Clin. Invest., 2001, 108 (6), 851-859).

Some low molecular weight MEK inhibitors are also discussed in, for example, WO 02/06213, WO 03/077855 and WO 03/077914. There is still a need for new MEK inhibitors as effective and safe therapeutic agents for the treatment of various proliferative diseases, such as conditions associated with MEK hyperactivity, as well as diseases modulated by the MEK cascade.

SUMMARY OF THE INVENTION

The invention relates, in general, to azabenzothiophenyl compounds of formula I (and / or their solvates and salts) having anti-cancer and / or anti-inflammatory activity and, more specifically, MEK kinase inhibition activity. Some hyperproliferative and inflammatory disorders are characterized by modulation of the MEK kinase function, for example, due to mutations or overexpression of proteins. Accordingly, the compounds of this invention and their compositions are useful in the treatment of hyperproliferative disorders, such as cancer, and / or inflammatory diseases, such as rheumatoid arthritis.

where Z ¹ represents CR ¹ or N;

Z ² represents CR ² or N;

Z ³ represents CR ³ or N;

Z ⁴ represents CR ⁴ or N;

where one or two of Z ¹ , Z ² , Z ³ and Z ⁴ represent N;

R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, halogen, CN,

CF ₃ , -OCF ₃ , -NO ₂ , - (CR ¹⁴ R ¹⁵ ) _n C (= Y) R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n C (= Y) OR ¹¹ ,

- (CR ¹⁴ R ¹⁵ ) _n C (= Y) NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n OR ¹¹ ,

- (CR ¹⁴ R ¹⁵ ) _n SR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² C (= Y) R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² C (= Y) OR ¹¹ ,

- (CR ¹⁴ R ¹⁵ ) _n NR ¹³ C (= Y) NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n NR ¹² SO ₂ R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n OC (= Y) R ¹¹ ,

- (CR ¹⁴ R ¹⁵ ) _n OC (= Y) OR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n OC (= Y) NR ¹¹ R ¹² ,

- (CR ¹⁴ R ¹⁵ ) _n OS (O) ₂ (OR ¹¹ ), - (CR ¹⁴ R ¹⁵ ) _n OP (= Y) (OR ¹¹ ) (OR ¹² ),

- (CR ¹⁴ R ¹⁵ ) _n OP (OR ¹¹ ) (OR ¹² ), - (CR ¹⁴ R ¹⁵ ) _n S (O) R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n S (O) ₂ R ¹¹ ,

- (CR ¹⁴ R ¹⁵ ) _n S (O) ₂ NR ¹¹ R ¹² , - (CR ¹⁴ R ¹⁵ ) _n S (O) (OR ¹¹ ), - (CR ¹⁴ R ¹⁵ ) _n S (O) ₂ (OR ¹¹ )

- (CR ¹⁴ R ¹⁵ ) _n SC (= Y) R ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n SC (= Y) OR ¹¹ , - (CR ¹⁴ R ¹⁵ ) _n SC (= Y) NR ¹¹ R ¹² ,

(C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, carbocyclyl,

heterocyclyl, aryl and heteroaryl;

W represents

R ⁵ and R ^{6 are} independently selected from H or (C ₁ -C ₁₂ ) alkyl;

X ^{1 is} selected from R ¹¹ , —OR ¹¹ , —NR ¹¹ R ¹² , —S (O) R ^11, and S (O) ₂ R ¹¹ ; when X ¹ is R ¹¹ or —OR ¹¹ , R ¹¹ or —OR ¹¹ from X ¹ and —R ⁵ , optionally taken together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or unsaturated ring, having 0-2 additional heteroatoms selected from O, S, and N atoms, wherein said ring is optionally substituted with one or more groups selected from halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, —Si (C ₁ -C ₆ alkyl), - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

(CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

(CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ;

X ^{2 is} selected from carbocyclyl, heterocyclyl, aryl and heteroaryl;

R ¹¹ , R ¹² and R ¹³ independently represent H, (C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl;

or R ¹¹ and R ^12, together with the nitrogen atom to which they are attached, form a 3-8 membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from O, S and N atoms, wherein said ring is optionally substituted with one or several groups selected from halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , (C ₁ –C ₆ ) alkyl, —OH, —SH, —O (C ₁ –C ₆ ) alkyl,

-S (C ₁ -C ₆ ) alkyl, -NH ₂ , -NH (C ₁ -C ₆ ) alkyl, -N (C ₁ -C ₆ alkyl) ₂ ,

-SO ₂ (C ₁ -C ₆ ) alkyl, -CO ₂ H, -CO ₂ (C ₁ -C ₆ ) alkyl, -C (O) NH ₂ ,

-C (O) NH (C ₁ -C ₆ ) alkyl, -C (O) N (C ₁ -C ₆ alkyl) ₂ ,

—N (C ₁ -C ₆ alkyl) CO (O) (C ₁ -C ₆ ) alkyl, —NHC (O) (C ₁ -C ₆ ) alkyl,

-NHSO ₂ (C ₁ -C ₆ ) alkyl), -N (C ₁ -C ₆ alkyl) SO ₂ (C ₁ -C ₆ ) alkyl, -SO ₂ NH ₂ ,

SO ₂ NH (C ₁ -C ₆ ) alkyl, -SO ₂ N (C ₁ -C ₆ alkyl) ₂ , -OC (O) NH ₂ ,

-OC (O) NH (C ₁ -C ₆ ) alkyl, -OC (O) N (C ₁ -C ₆ alkyl) ₂ , -OC (O) O (C ₁ -C ₆ ) alkyl,

-NHC (O) NH (C ₁ -C ₆ ) alkyl, -NHC (O) N (C ₁ -C ₆ alkyl) ₂ ,

-N (C ₁ -C ₆ alkyl) C (O) NH (C ₁ -C ₆ ) alkyl,

-N (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) O (C ₁ -C ₆ ) alkyl and

-N (C ₁ -C ₆ alkyl) C (O) O (C ₁ -C ₆ ) alkyl;

R ¹⁴ and R ^{15 are} independently selected from H, (C ₁ -C ₁₂ ) alkyl, aryl, carbocyclyl, heterocyclyl and heteroaryl;

m and n are independently selected from 0, 1, 2, 3, 4, 5, or 6;

Y independently represents O, NR ¹¹ or S;

where each specified alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl in R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X ¹ , X ² , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ^{15 are} optionally and independently substituted with one or more groups independently selected from halogen, CN,

CF ₃ , —OCF ₃ , —NO ₂ , oxo, —Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ′) R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ;

each R ¹⁶ , R ¹⁷ and R ¹⁸ independently represents H, (C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, CN, —OCF ₃ , CF ₃ , —NO ₂ , (C ₁ -C ₆ ) alkyl, —OH, -SH,

-O (C ₁ -C ₆ ) alkyl, -S (C ₁ -C ₆ ) alkyl, -NH ₂ , -NH (C ₁ -C ₆ ) alkyl,

-N (C ₁ -C ₆ alkyl) ₂ , -SO ₂ (C ₁ -C ₆ ) alkyl, -CO ₂ H, -CO ₂ (C ₁ -C ₆ ) alkyl,

-C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ ) alkyl, -C (O) N (C ₁ -C ₆ alkyl) ₂ ,

—N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ ) alkyl, —NHC (O) (C ₁ -C ₆ ) alkyl,

-NHSO ₂ (C ₁ -C ₆₎ alkyl, -N & (C _1- C ₆ alkyl) SO ₂ (C ₁ -C ₆₎ alkyl, -SO ₂ NH _2,

SO ₂ NH (C ₁ -C ₆ ) alkyl, -SO ₂ N (C ₁ -C ₆ alkyl) ₂ , -OC (O) NH ₂ ,

-OC (O) NH (C ₁ -C ₆ ) alkyl, -OC (O) N (C ₁ -C ₆ alkyl) ₂ , -OC (O) O (C ₁ -C ₆ ) alkyl,

-NHC (O) NH (C ₁ -C ₆ ) alkyl, -NHC (O) N (C ₁ -C ₆ alkyl) ₂ ,

-N (C ₁ -C ₆ alkyl) C (O) NH (C ₁ -C ₆ ) alkyl,

-N (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) O (C ₁ -C ₆ ) alkyl and

-N (C ₁ -C ₆ alkyl) C (O) O (C ₁ -C ₆ ) alkyl;

or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3-8 membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from O, S and N atoms, wherein said ring is optionally substituted with one or several groups selected from halogen, CN,

—OCF ₃ , CF ₃ , —NO ₂ , (C ₁ –C ₆ ) alkyl, —OH, —SH, —O (C ₁ –C ₆ ) alkyl,

-S (C ₁ -C ₆ ) alkyl, -NH ₂ , -NH (C ₁ -C ₆ ) alkyl, -N (C ₁ -C ₆ alkyl) ₂ ,

-SO ₂ (C ₁ -C ₆ ) alkyl, -CO ₂ H, -CO ₂ (C ₁ -C ₆ ) alkyl, -C (O) NH ₂ ,

-C (O) NH (C ₁ -C ₆ ) alkyl, -C (O) N (C ₁ -C ₆ alkyl) ₂ ,

—N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ ) alkyl, —NHC (O) (C ₁ -C ₆ ) alkyl,

-NHSO ₂ (C ₁ -C ₆ ) alkyl, -N (C ₁ -C ₆ alkyl) SO ₂ (C ₁ -C ₆ ) alkyl, -SO ₂ NH ₂ ,

SO ₂ NH (C ₁ -C ₆ ) alkyl, -SO ₂ N (C ₁ -C ₆ alkyl) ₂ , -OC (O) NH ₂ ,

-OC (O) NH (C ₁ -C ₆ ) alkyl, -OC (O) N (C ₁ -C ₆ alkyl) ₂ , -OC (O) O (C ₁ -C ₆ ) alkyl,

-NHC (O) NH (C ₁ -C ₆ ) alkyl, -NHC (O) N (C ₁ -C ₆ alkyl) ₂ ,

-N (C ₁ -C ₆ alkyl) C (O) NH (C ₁ -C ₆ ) alkyl,

-N (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₆ alkyl) ₂ , NHC (O) O (C ₁ -C ₆ ) alkyl, and

-N (C ₁ -C ₆ alkyl) C (O) O (C ₁ -C ₆ ) alkyl;

R ¹⁹ and R ^{20 are} independently selected from H, (C ₁ -C ₁₂ ) alkyl, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n- carbocyclyl, - (CH ₂ ) _n- heterocyclyl, and - (CH ₂ ) _n- heteroaryl;

R ²¹ represents (C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, where each R ²¹ substituent is optionally substituted with one or more groups selected from halogen, oxo, CN, —OCF ₃ ,

CF ₃ , —NO ₂ , (C ₁ –C ₆ ) alkyl, —OH, —SH, —O (C ₁ –C ₆ ) alkyl,

-S (C ₁ -C ₆ ) alkyl, -NH ₂ , -NH (C ₁ -C ₆ ) alkyl, -N (C ₁ -C ₆ alkyl) ₂ ,

-SO ₂ (C ₁ -C ₆ ) alkyl, -CO ₂ H, -CO ₂ (C ₁ -C ₆ ) alkyl, -C (O) NH ₂ ,

-C (O) NH (C ₁ -C ₆ ) alkyl, -C (O) N (C ₁ -C ₆ alkyl) ₂ ,

—N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ ) alkyl, —NHC (O) (C ₁ -C ₆ ) alkyl,

-NHSO ₂ (C ₁ -C ₆ ) alkyl, -N (C ₁ -C ₆ alkyl) SO ₂ (C ₁ -C ₆ ) alkyl, -SO ₂ NH ₂ ,

SO ₂ NH (C ₁ -C ₆ ) alkyl, -SO ₂ N (C ₁ -C ₆ alkyl) ₂ , -OC (O) NH ₂ ,

-OC (O) NH (C ₁ -C ₆ ) alkyl, -OC (O) N (C ₁ -C ₆ alkyl) ₂ , -OC (O) O (C ₁ -C ₆ ) alkyl,

-NHC (O) NH (C ₁ -C ₆ ) alkyl, -NHC (O) N (C ₁ -C ₆ alkyl) ₂ ,

-N (C ₁ -C ₆ alkyl) C (O) NH (C ₁ -C ₆ ) alkyl,

-N (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₆ alkyl) ₂ ,

-NHC (O) O (C ₁ -C ₆ ) alkyl; and -N (C ₁ -C ₆ alkyl) C (O) O (C ₁ -C ₆ ) alkyl;

each Y ′ independently represents O, NR ²² or S; and

R ²² represents H or (C ₁ -C ₁₂ ) alkyl.

The present invention relates to a composition (eg, a pharmaceutical composition) comprising a compound of formula I (and / or solvates and salts thereof) and a carrier (pharmaceutically acceptable carrier). The present invention also relates to a composition (eg, a pharmaceutical composition) comprising a compound of formula I (and / or solvates and salts thereof) and a carrier (pharmaceutically acceptable carrier), and further comprising a second chemotherapeutic agent and / or a second anti-inflammatory agent. The compositions of the present invention are useful for inhibiting abnormal cell growth or treating hyperproliferative disorder in a mammal (e.g., human). The compositions of the present invention are useful for treating inflammatory diseases in a mammal (eg, a human).

The present invention relates to a method for inhibiting abnormal cell growth or treating hyperproliferative disorder in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or its solvates and salts) or a composition containing said compound, as such or in combination with a second chemotherapeutic agent.

The present invention relates to a method for treating an inflammatory disease in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or its solvates and salts) or a composition containing said compound, as such or in combination with a second anti-inflammatory means.

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

Detailed Description of Exemplary Embodiments

Now will be described in detail some embodiments of the invention, examples of which are illustrated by the accompanying structures and formulas. Although the invention will be described in connection with the above options for implementation, it should be borne in mind that it is not intended to limit the invention to these options for implementation. On the contrary, it is intended that the invention covers all alternatives, modifications, and equivalents that may be included within the scope of the present invention as defined in the claims. One skilled in the art will be able to present many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the described methods and materials. In the event that one or more of the references, patents and similar materials included in the description differ or conflict with this description, including, but not limited to, certain terms, application of terms, described methods or the like, this governs this description.

Definitions

The term “alkyl”, as used herein, refers to a saturated linear or branched monovalent hydrocarbon radical with one to twelve carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, —CH ₃ ), ethyl (Et, —CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, —CH ₂ CH ₂ CH ₃ ) , 2-propyl (iso-Pr, isopropyl, -CH (CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (iso-Bu, isobutyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl (sec-Bu, sec-butyl, -CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl ( tert-Bu, tert-butyl, -C (CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH (CH ₂ CH ₂ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl ( -CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3 -hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2- pentyl (-CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ ) (CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl ( -C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ ) ₃ ), 1-heptyl, 1-octyl, etc. .

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical with two to twelve carbon atoms with at least one unsaturation site, i.e. a carbon-carbon double bond sp ² , where the alkenyl radical includes radicals having the "cis" and "trans" orientations, or, alternatively, the "E" and "Z" orientations. Examples include, but are not limited to, ethylenyl or vinyl (—CH = CH ₂ ), allyl (—CH ₂ CH = CH ₂ ), and the like.

The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with two to twelve carbon atoms with at least one unsaturation site, i.e. carbon-carbon triple bond sp. Examples include, but are not limited to, ethynyl (—CH≡CH), propynyl (propargyl, —CH ₂ CH≡CH), and the like.

The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and "cycloalkyl" refer to a monovalent non-aromatic saturated or partially unsaturated ring with 3-12 carbon atoms as a monocyclic ring and 7-12 carbon atoms as a bicyclic ring. Bicyclic carbocycles with 7-12 atoms can be represented, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles with 9 or 10 atoms in the ring can be represented as a bicyclo [5.6] or [6.6] system, or as bridging systems such as bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.

The term "aryl" means a monovalent aromatic hydrocarbon radical with 6-18 carbon atoms formed by the removal of one hydrogen atom from one carbon atom of the original aromatic ring system. Some aryl groups are represented in the examples of structures as “Ar”. Aryl includes bicyclic radicals including an aromatic ring fused to a saturated, partially unsaturated ring or an aromatic carbocyclic or heterocyclic ring. Typical aryl groups include, but are not limited to, radicals formed from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, formed from 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, etc. P.

The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., with one or more double and / or triple bonds within the ring) carbocyclic radical with 3- 18 atoms in the ring, in which at least one atom in the ring is a heteroatom selected from nitrogen, oxygen and sulfur atoms, the remaining atoms in the ring being C atoms, where one or more atoms in the ring may optionally be optionally substituted with one or more substituents described below. The heterocycle may be a monocycle with 3-7 atoms in the ring (2-6 carbon atoms and 1-4 heteroatoms, their selected atoms N, O, P and S) or a bicycle with 7-10 atoms in the ring (4-9 carbon atoms and 1-6 heteroatoms selected from their atoms N, O, P and S), for example a bicyclo [4,5], [5,5], [5,6] or [6,6] system. Heterocycles are described in Paquette Leo A, “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), in particular in chapters 1, 3, 4, 6, 7, and 9; in “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 and to date), in particular in volumes 13, 14, 16, 19 and 28; and in J. Am. Chem. Soc. (1960), 82: 5566. “Heterocyclyl” also includes radicals in which heterocyclic radicals are fused to a saturated, partially unsaturated ring or an aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thiazaniphenyl-azanediophenyl, homo-thiophenyl, di-homo-azanediophenyl, di-homo-azanediophenyl, diphenyl, nitropanil, diazepinyl, thiazepinyl, 2-pyrroinyl, 3-pyrroinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidi nilimidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl and azabicyclo [2.2.2] hexanyl. Spiro groups are also included in the scope of this definition. Examples of heterocyclic groups in which 2 atoms in the ring are substituted with oxo groups (= O) are pyrimidinonyl and 1,1-dioxothiomorpholinyl.

The term “heteroaryl” refers to a monovalent aromatic radical of 5- or 6-membered rings and includes fused ring systems (at least one of which is aromatic) with 5-18 atoms containing one or more heteroatoms independently selected from nitrogen atoms, oxygen and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolazole, thiazolazole pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolisinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl benzothiothirazothiolazothiraziozylazothiazothiolazothiazothiazothiazothiol l, benzooxazolyl, quinazolinyl, quinoxaline, naphthyridinyl and furopyridinyl.

Heterocyclic or heteroaryl groups can be attached at the carbon atom (carbon attachment) or nitrogen (nitrogen attachment), where possible. As an example, but not limitation, carbon-attached heterocycles or heteroaryls are attached at position 2, 3, 4, 5, or 6 of pyridine, position 3, 4, 5, or 6 of pyridazine, position 2, 4, 5, or 6 of pyrimidine, position 2 , 3, 5 or 6 of pyrazine, position 2, 3, 4 or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4 or 5 of oxazole, imidazole or thiazole, position 3, 4 or 5 of isoxazole, pyrazole or isothiazole, position 2 or 3 of aziridine, position 2, 3 or 4 of azetidine, position 2, 3, 4, 5, 6, 7 or 8 of quinoline or position 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

As an example, but not limitation, nitrogen-attached heterocycles or heteroaryls are attached at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of isoindole or isoindoline, position 4 of morpholine and position 9 of carbazole or β-carboline.

The term “halogen” refers to F, Cl, Br or I. Hetero atoms present in heteroaryl or heterocyclyl include oxidized forms such as N ⁺ → O ^- , S (O) and S (O) ₂ .

The terms “treat” and “treatment” refer to both therapeutic properties and preventive or preventative measures when an object needs to prevent or slow down (reduce) an undesirable physiological change or disorder, such as the development or spread of cancer. For the purposes of this invention, favorable or desirable clinical results include, but are not limited to, alleviating symptoms, reducing the degree of disease, stabilizing (i.e., not worsening) the condition of the disease, eliminating or slowing the progress of the disease, reducing the intensity or alleviating the disease state, and remission ( either partial or complete) that are detectable or not detectable. “Treatment” can also mean a longer lifespan than expected if treatment is not received. Those in need of treatment include individuals who already have a condition or disorder, as well as those prone to acquire a disease state or disorder, or individuals in whom the condition or disorder needs to be prevented.

The term “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents a particular disease, condition or disorder, (ii) alleviates, reduces the intensity or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e. weaken to some extent and preferably stop) cancer cell infiltration into distant organs; inhibit (i.e., weaken to some extent and preferably stop) tumor metastasis; inhibit to some extent tumor growth and / or weaken to some extent one or more symptoms associated with cancer. To the extent that the drug can prevent the growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. The effectiveness of cancer treatment can be measured, for example, by assessing the time to disease progression (TTP) and / or by determining the response rate (RR).

The terms “abnormal cell growth” and “hyperproliferative disease” are used interchangeably herein. The term "abnormal cell growth" as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (eg, lack of contact inhibition). The term includes, for example, abnormal growth of (1) tumor cells (tumors) that proliferate by expression of a mutated tyrosine kinase or overexpression of receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate due to receptor tyrosine kinases; (4) any tumors that proliferate due to aberrant activation of serine / threonine kinase; and (5) benign and malignant cells of other proliferative diseases in which aberrant activation of serine / threonine kinase occurs.

The terms “cancer” and “cancerous” refer to or describe a physiological condition in a mammal that is specifically characterized by unregulated cell growth. A “tumor” includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma), lung cancer including small cell lung cancer, non-small cell lung cancer (“NSCLC”), lung adenocarcinoma and squamous cell carcinoma, peritoneal cancer, hepatocellular cancer, gastric cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, acute leukemia, as well as head / brain cancer and neck cancer.

A “chemotherapeutic agent” is a chemical compound used in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (tarceva®, Genetech / OSI Pharm.), Bortezomib (velcade®, Millennium Pharm.), Fulvestrant (faslodex®, AstraZeneca), sutent (SU11248, Pfizer), letrozole (femara®, Novartis), mesylate imatinib (gleevec®, Novartis), PTK787 / ZK 222584 (Novartis), oxaliplatin (eloxatin®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, rapamune®, Wyeth), lapatinib (tuker GSK572016, Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs) and gefitinib (iressa®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as cytoxide cytoxide ®; alkyl sulfonates such as bisulfan, improsulfan and piposulfan; aziridines, such as benzodopa, carboxwon, meturedopa and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylene melamine, triethylene phosphoramide, triethylene thiophosphoramide and trimethylomelamine; acetoginins (in particular, bullatacin and bullatacinon); camptothecin (including the synthetic analogue of topotecan); bryostatin; callistatin; SS-1065 (including its synthetic analogs, adozelesin, carcelesin and biselezin) cryptophycin (in particular, cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including its synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pankratistatin; sarcodictin; spongistatin; mustard gas nitrogen analogues, such as chlorambucil, chlorofazine, chlorophosphamide, estramustine, ifosfamide, mechlortamine, mechlortamine oxide hydrochloride, melphalan, novembicin, phenesterol, prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorzotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics such as enedin antibiotics (e.g. calicheamicin, in particular calicheamicin-gamma-1I and calicheamicin-omega-I1 (Angew. Chem. Intl. Ed. Engl. (1994), 33: 183-186); dinemycin, including dinemycin A; bisphosphonates such as clodronate; esperamycin; as well as the neocarzinostatin chromophore and related chromophores of the chromoprotein enedin antibiotics), aclacinomisins, actinomycin, autramycin, azaserin, bleomycin, cactinomycin, carabicin, carminomycin, carzinomycinin, chromecinomycin, dichrominocinofinin, dichrominocinofinin, dichrominocinofinin, dichrominocinin, dichrominocidin, dichrominocinin, dichrominocinin, dichrominocinin, dichrominocinin, dichrominocinin, dichrominocinin, dichrominicin, dichrominocidin, d, oxo-L-norleucine, adriamycin® (doxor bicine, morfolinodoksorubitsin, tsianomorfolinodoksorubitsin, 2-pyrrolino and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, martsellomitsin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, redorubitsin, streptonigrin, streptozocin, tubercidin , ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimerexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, karmofur, cytarabine, dideoxyuridine, doxyfluridine, enocytabine, phloxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostan, testolactone; antiadrenergic agents such as aminoglutetimide, mitotan, trilostane; folic acid replenishment agent, such as frolinic acid; Aceglaton; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisanthrene; edatraxate; defofamine; demecolcin; diazikhon; elfonitin; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidanin; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pyrarubicin; losoxantrone; podophyllic acid; 2-ethyl hydrazide; procarbazine; PSK® polysaccharide complexes (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sisofiran; spiro germanium; tenuazonic acid; triazichone; 2,2 ', 2 ”trichlorotriethylamine; trichotecenes (in particular, T-2 toxin, verracurin A, roridin A and anguidin); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacitosin; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g. taxol® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), abraxane ™ (cremophor-free), nanocomposites of paclitaxel based on albumin (American Pharmaceutical Pertners, Schaumberg, Illinois) and taxotere® (doxetaxel; Rhfne- Poulenc Rorer, Antony, France); chloranambucil; gemzar® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; navelbine® (vinorelbine); novantron; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (xeloda®); ibandronate; SRT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

The definition of “chemotherapeutic agent” also includes (i) anti-hormonal agents that act on tumors as regulating or inhibiting the action of hormones, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including nolvadex®; tamoxifen citrate) , raloxifene, droloxifene, 4-hydroxy tamoxifen, trioxifene, keoxifen, LY117018, onapriston and fareston® (toremifine citrate); (ii) aromatase inhibitors that inhibit the aromatase enzyme that regulates the production of estrogen in the adrenal glands, such as, for example, 4 (5) -imidazoles, aminoglutethimide, megase® (megestrol acetate), aromazin® (exemestane; Pfizer), formestani, fadrozole, rivizor® (Vorozol), femara® (Letrozole, Novartis) and arimidex® (Anastrozole; AstraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; as well as troxacitabine (an analog of 1,3-dioxolannucleosidecytosine); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, in particular oligonucleotides that inhibit gene expression in signaling cascades involved in aberrant cell proliferation, such as, for example, PKC alpha, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g. angiozime®), and HER2 expression inhibitors; (viii) vaccines, such as vaccines for gene therapy, for example allovectin®, leuvectin® and vexid®; proleukin® rIL-2; topoisomerase 1 inhibitors such as lurtotecan®, abarelix® rmRH; (ix) anti-angiogenic agents such as bevacizumab (avastin®, Genetech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above. Other anti-angiogenic agents include MMP-2 inhibitors (matrix metalloprotein kinase 2), MMP-9 inhibitors (matrix metalloprotein kinase 9), COX-II inhibitors (cyclooxygenase II), and VEGF receptor tyrosine kinase inhibitors. Examples of such matrix metalloprotein kinase inhibitors that can be used in combination with the compounds / compositions of the present invention are described in WO 96/33172, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98 / 34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606046, EP 931788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864 , US patent No. 5863949, US patent No. 5861510 and EP 780386, all of which are incorporated into this description by reference. Examples of VEGF receptor tyrosine kinase inhibitors include 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpipridin-4-ylmethoxy) quinazoline (ZD6474; example 2 in WO 01/32651), 4- (4 -fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171; example 240 in WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and such compounds as disclosed in PCT Publication No. WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354).

Other examples of chemotherapeutic agents that can be used in combination with the compounds of the present invention include PI3K (phosphoinositide-3-kinase) inhibitors, such as those described by Yaguchi et al. (2006), in Jour. of the Nat. Cancer Inst., 98 (8): 545-556; US 7173029; US 7,037,915; US 6608056; US 6608053; US 6,838,457; US 6,770,641; US 6,633,320; US 6403588; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO 2004/006916; W) 2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; US 2003/158212; EP 141796; US 2004/053946; JP 2001247477; JP 0817990; JP 08176070; US 6703414 and WO 97/15658, all of which are incorporated herein by reference. Specific examples of such PI3K inhibitors include SF-116 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.).

The term “inflammatory diseases” as used herein includes, but is not limited to rheumatoid arthritis, atherosclerosis, congestive heart failure, inflammatory bowel disease (including Crohn’s disease and ulcerative colitis, and other diseases), chronic obstructive pulmonary disease, fibrotic liver and kidney disease, Crohn’s disease, skin diseases such as psoriasis, eczema and scleroderma, osteoarthritis, multiple sclerosis, asthma, diseases and disorders associated with complicated diabetes, fibrous insufficiency in organs such as the lungs, liver, kidneys, and complications due to inflammation of the cardiovascular system, such as acute coronary syndrome.

An “anti-inflammatory agent” is a compound useful in the treatment of inflammation. Examples of anti-inflammatory drugs include protein injectable drugs such as Enbrel®, Remicade®, Humira® and Kineret®. Other examples of anti-inflammatory drugs include non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or aspirin (which reduce swelling and ease pain); disease modifying antirheumatic drugs (DMARDs) such as methotrexate; 5-aminosalicylates (sulfazalazine and sulfur-free products); corticosteroids; immunomodulators such as 6-mercatoputin (“6-MR”), azathioprine (“AZA”), cyclosporins, and biological response modifiers such as remicad.RTM. (infliximab) and Enbrel.RTM. (etanercept); fibroblast growth factors; platelet growth factors; enzyme blockers such as Arava.RTM. (leflunomide); and / or an agent for protecting cartilage, such as hyaluronic acid, glucosamine and chondroitin.

The term “prodrug”, as used herein, refers to a precursor or derivative of a compound of this invention that is capable of being activated either enzymatically or hydrolytically, or converted to a more active parent form. See, for example, Wilman, “Prodrugs in Cancer Chemotherapy”, Biochemical Society Transactions, 14, pp. 375-382, 615 ^th Meeting Belfast (1986), and Stella et al., “Prodrugs: A Chemical Approach to Targeted Drug Delivery ”, Directed Drug Delivery, Borchardt et al. (ed.), pp. 247-267, Humana Press (1985). Prodrugs of this invention include, but are not limited to, prodrugs containing esters, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, modified D-amino acid prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, optionally prodrugs, phenoxyacetamides, prodrugs containing optionally substituted phenylacetamides, 5-fluorocytosine and other prodrugs on based on 5-fluoruridines, which can be converted into a more active cytotoxic free drug. Examples of cytotoxic drugs that can be converted to prodrugs for use in this invention include compounds of this invention and chemotherapeutic agents, such as those described above, and other drugs.

"Metabolite" is a product obtained by metabolism in the body of a particular compound or its salt. Metabolites of a compound can be identified using conventional methods known in the art, and their activity is determined using assays such as those described herein. Such products may result, for example, from oxidation, hydroxylation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like. the introduced compound. Accordingly, the invention includes metabolites of the compounds of this invention, including compounds obtained by a method comprising contacting a compound of this invention with a mammalian organism for a time sufficient to produce a product of its metabolism.

A “liposome” is a small vesicle composed of various types of lipids, phospholipids and / or surfactant that is useful for delivering a drug (such as the MEK inhibitors disclosed herein, and optionally a chemotherapeutic agent) into a mammalian body. Components of liposomes are usually arranged in two layers, similar to the arrangement of lipids in biological membranes.

The term “package insert” is used to refer to instructions usually included in commercial packages of therapeutic products that contain information about the indications, usefulness, dosage, administration, contraindications and / or warnings regarding the use of such therapeutic products.

The term “chiral” refers to molecules having the property of being impossible to align with the corresponding mirror image, while the term “achiral” refers to molecules that can combine with the corresponding mirror image.

The term “stereoisomer” refers to compounds that have identical chemical composition and bonds, but different orientations of their atoms in space, which cannot be mutually transformed by rotation around a simple bond.

The term “diastereomer” refers to a stereoisomer with two or more chirality centers whose molecules are not mirror images of each other. Diastereomers have various physical properties, for example, melting points, boiling points, spectral properties and reactivity. Mixtures of diastereomers can be separated by high resolution analytical methods such as crystallization, electrophoresis and chromatography.

The term "enantiomers" refers to two stereoisomers of a compound that are incompatible mirror images of each other.

The stereochemical definitions and rules used in this description correspond to the work of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel E. and Wilen S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers and, therefore, exist in various stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of this invention, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e. they have the ability to rotate plane-polarized light. When describing optically active compounds, the prefixes D and L, R and S are used to indicate the absolute configuration of a molecule relative to its chiral center (s). The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, and (-) or l means that the compound is levorotatory. A connection prefixed with (+) or d is dextrorotatory. For a given chemical structure, such stereoisomers are identical, except that they are mirror images of each other. A particular stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species lacking optical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers of various energies that can be mutually converted through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) through proton migration are involved in mutual transformations, such as keto-enol and imino-enamine isomerization. Valence tautomers are involved in mutual transformations by reorganization of some binding electrons.

The term “pharmaceutically acceptable salt” as used herein refers to pharmaceutically acceptable organic or inorganic salts of a compound of this invention. Examples of salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, hydrophosphates, isonicotinates, lactates, salicylates, hydrocyrates, tartrates, oleates, tannates, pantothenates, bitartrates, and , succinates, maleates, gentisinates, fumarates, gluconates, sugars, formates, benzoates, glutamates, methanesulfonates, "mesylates", ethanesulfonates, benzenesulfonates, p-toluenesulfonates, pamoates (i.e. 1,1'-methylenebis (2-hydroxy- 3-naphthoates), alkali metal salts (e.g. sodium and potassium), s alkali earth metal salts (eg magnesium) and ammonium salts. A pharmaceutically acceptable salt may include the inclusion of another molecule, such as an acetate ion, a succinate ion or other counterion. The counterion may be an organic or inorganic particle that stabilizes the charge on the parent compound. Moreover, a pharmaceutically acceptable salt may have several charged atoms in its structure. In cases where multiply charged atoms are part of a pharmaceutically acceptable salt, there may be several counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

If the compound of this invention is a base, the desired pharmaceutically acceptable salt can be obtained by any suitable method available in the art, for example, treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and etc., or with an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid ota, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or a similar compound.

If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Representative examples of suitable salts include, but are not limited to, organic salts obtained with amino acids such as glycine and arginine, ammonia, primary, secondary or tertiary amines and cyclic amines such as piperidine, morpholine and peperazine, and inorganic salts obtained with sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The expression “pharmaceutically acceptable” indicates that the substance or composition should be chemically and / or toxicologically compatible with the other ingredients that make up the composition and / or the mammalian body that is being treated.

The term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term "hydrate" refers to a complex in which the solvent molecule is water.

The term “protecting group” refers to a substituent that is typically used to block or protect a particular functional group while other groups of the compound are reacting. For example, an “amino protecting group” is a substituent attached to an amino group that blocks or protects the functional amino group of the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, the term “hydroxy protecting group” refers to a hydroxy substituent that blocks or protects the functional hydroxy group of the compound. Suitable protecting groups include acetyl and silyl. The term “carboxy protecting group” refers to a substituent of a carboxy group that blocks or protects the functional carboxy group of the compound. Common carboxy protecting groups include phenylsulfonylethyl, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) ethyl, nitro groups. For a general description of protective groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms “compound of this invention” and “compounds of the present invention” and “compounds of formula I”, unless otherwise indicated, include compounds of formula I and their stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts (for example, pharmaceutically acceptable salts) and prodrugs.

The present invention relates to the azabenzothiophenyl compounds of formula I described above, useful as kinase inhibitors, in particular as MEK kinase inhibitors. The present invention includes compounds of formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II-a, II-b, II-c, II-d, II-e, II-f, II-g , II-h, II-i, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h and III-i, and all other variables have the values indicated for formula I.

In an embodiment of the present invention, the compounds are compounds of formulas Ib, If, Ig, Ih, II-b, II-f, II-g, II-h, III-b, III-f, III-g and III-h, and all other variables have the meanings indicated for formula I.

In an embodiment of the present invention, the compounds are compounds of formula III-c, and all other variables are as defined for formula I.

In an embodiment of the present invention, R ¹ is H, halogen, CN, CF ₃ , —NR ¹¹ R ¹² , —OR ¹¹ , —SR ¹¹ , —C (= O) NR ¹¹ R ^12, or (C ₁ -C ₆ ) alkyl, and all other variables have the meanings given for formulas I, Ia, Ib, Id, If, Ig, II-a, II-b, II-d, II-f, II-g, III-a, III- b, III-d, III-f or III-g.

In another embodiment of the present invention, R ¹ is H, halogen, CN, CF ₃ , (C ₁ -C ₆ ) alkyl, —NR ¹¹ R ¹² , where R ¹¹ and R ^{12 are} independently H or (C ₁ -C ₆ ) alkyl, —OR ¹¹ where R ¹¹ represents H or (C ₁ -C ₆ ) alkyl, or —SR ¹¹ where R ¹¹ represents H or (C ₁ -C ₆ ) alkyl; and all other variables have the meanings given for formulas I, Ia, Ib, Id, If, Ig, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.

In another embodiment of the present invention, R ¹ is H, Cl, CN, CF ₃ , methyl, —NH ₂ , —NH (CH ₃ ), —N (CH ₃ ) ₂ , —OH, or —OCH ₃ ; and all other variables have the meanings given for formulas I, Ia, Ib, Id, If, Ig, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.

In yet another embodiment of the present invention, R ¹ is H; and all other variables have the meanings given for formulas I, Ia, Ib, Id, If, Ig, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.

In an embodiment of the present invention, R ² is H, halogen, CN, CF ₃ , -NR ¹¹ R ¹² , -OR ¹¹ , -SR ¹¹ , -C (= O) NR ¹¹ R ¹² or (C ₁ -C ₆ ) alkyl, and all other variables have the meanings given for formulas I, Ia, Ic, Id, Ie, Ii, II-a, II-c, II-d, II-e, II-i, III- a, III-c, III-d, III-e or III-i, or the above values.

In another embodiment of the present invention, R ² is H, halogen, CN, CF ₃ , (C ₁ -C ₆ ) alkyl, —NR ¹¹ R ¹² , where R ¹¹ and R ^{12 are} independently H or (C ₁ -C ₆ ) alkyl, —OR ¹¹ where R ¹¹ represents H or (C ₁ -C ₆ ) alkyl, or —SR ¹¹ where R ¹¹ represents H or (C ₁ -C ₆ ) alkyl; and all other variables have the meanings indicated for the formulas I, Ia, I-c, Id, I-e, Ii, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i, or the above values.

In another embodiment of the present invention, R ² is H, Cl, CN, CF ₃ , methyl, —NH ₂ , —NH (CH ₃ ), —N (CH ₃ ) ₂ , —OH, or —OCH ₃ ; and all other variables have the meanings indicated for the formulas I, Ia, I-c, Id, I-e, Ii, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i, or the above values.

In an embodiment of the present invention, R ³ is H, halogen, CN, CF ₃ , —NR ¹¹ R ¹² , —OR ¹¹ , —SR ¹¹ , —C (= O) NR ¹¹ R ^12, or (C ₁ -C ₆ ) alkyl, and all other variables have the meanings given for formulas I, Ia, Ic, Id, Ie, Ii, II-a, II-c, II-d, II-e, II-i, III- a, III-c, III-d, III-e or III-i, or the above values.

In another embodiment of the present invention, R ³ is H, halogen, CF ₃ , (C ₁ -C ₆ ) alkyl; and all other variables have the meanings indicated for the formulas I, Ia, I-c, Id, I-e, Ii, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i, or the above values.

In yet another embodiment of the present invention, R ³ is H, F, CF ₃ or methyl; and all other variables have the meanings indicated for the formulas I, Ia, I-c, Id, I-e, Ii, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i, or the above values.

In yet another embodiment of the present invention, R ³ is H, F, Cl, methyl or CN; and all other variables have the meanings indicated for the formulas I, Ia, I-c, Id, I-e, Ii, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i, or the above values.

In an embodiment of the present invention, R ⁴ is H, halogen, CN, CF ₃ , —NR ¹¹ R ¹² , —OR ¹¹ , —SR ¹¹ , —C (= O) NR ¹¹ R ^12, or (C ₁ -C ₆ ) alkyl, and all other variables have the meanings given for formulas I, Ia, Ib, Ic, Ie, Ig, Ih, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h, or the above values.

In another embodiment of the present invention, R ⁴ is H, halogen, CN, CF ₃ , —NR ¹¹ R ¹² or —C (═O) NR ¹¹ R ¹² , where R ¹¹ and R ^{12 are} independently H or (C ₁ —C ₆ ) alkyl, —OR ¹¹ where R ¹¹ is H or (C ₁ -C ₆ ) alkyl, or —SR ¹¹ where R ¹¹ is H or (C ₁ -C ₆ ) alkyl; and all other variables have the meanings given for formulas I, Ia, Ib, Ic, Ie, Ig, Ih, II-a, II-b, II-c, II-e, II-g, II- h, III-a, III-b, III-c, III-e, III-g or III-h, or the above values.

In another embodiment of the present invention, R ⁴ is H, Br, CN, CF ₃ , —NH ₂ , —NH (CH ₃ ), —N (CH ₃ ) ₂ , —C (O) NH ₂ , —C (O ) NH (CH ₃ ), C (O) N (CH ₃ ) ₂ , -OH or -OCH ₃ ; and all other variables have the meanings given for formulas I, Ia, Ib, Ic, Ie, Ig, Ih, II-a, II-b, II-c, II-e, II-g, II- h, III-a, III-b, III-c, III-e, III-g or III-h, or the above values.

In another embodiment of the present invention, R ⁴ is H, Br, Cl, CN, CF ₃ , —NH ₂ , —NH (CH ₃ ), —N (CH ₃ ) ₂ , —C (O) NH ₂ , —C (O) NH (CH ₃ ), -C (O) N (CH ₃ ) ₂ , -OH or -OCH ₃ ; and all other variables have the meanings given for formulas I, Ia, Ib, Ic, Ie, Ig, Ih, II-a, II-b, II-c, II-e, II-g, II- h, III-a, III-b, III-c, III-e, III-g or III-h, or the above values.

In another embodiment of the present invention, R ⁴ is halogen, —OH or (C ₁ –C ₆ ) alkyl optionally substituted with halogen, and all other variables are as defined for formulas I, Ia, Ib, Ic, I— e, Ig, Ih, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h, or the above values.

In another embodiment of the present invention, R ⁴ independently represents Cl, Br, Me, Et, F, CHF ₂ , CF ₃ or —OH; and all other variables have the meanings given for formulas I, Ia, Ib, Ic, Ie, Ig, Ih, II-a, II-b, II-c, II-e, II-g, II- h, III-a, III-b, III-c, III-e, III-g or III-h, or the above values.

In an embodiment of the present invention, R ⁵ is H or (C ₁ -C ₆ ) alkyl; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii) or (II-a) - (II-i), or the above values.

In another embodiment of the present invention, R ⁵ is H or methyl; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii) or (II-a) - (II-i), or the above values.

In another embodiment of the present invention, R ⁵ is H; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii) or (II-a) - (II-i), or the above values.

In another embodiment of the present invention, R ⁵ is methyl; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii) or (II-a) - (II-i), or the above values.

In an embodiment of the present invention, R ⁶ is H or (C ₁ -C ₆ ) alkyl; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, R ⁶ is H or methyl; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, R ⁶ is H; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, R ⁶ is methyl; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In an embodiment of the present invention, X ¹ is OR ¹¹ (i.e., formulas (II-a) - (II-i)); and all other variables have the meanings indicated for formulas I or (Ia) to (Ii), or the meanings indicated above.

In another embodiment of the present invention, X ¹ represents OR ¹¹ , where R ¹¹ represents H; and all other variables have the meanings indicated for formulas I or (Ia) to (Ii), or the meanings indicated above.

In another embodiment of the present invention, X ¹ is OR ¹¹ , where R ¹¹ is (C ₁ -C ₁₂ ) alkyl (e.g., (C ₁ -C ₆ ) alkyl) substituted with one or more groups independently selected from halogen, CN, CF ₃ , -OCF ₃ ,

-NO ₂ , oxo, -Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

(CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and all other variables have the meanings indicated for formulas I or (Ia) to (Ii), or the meanings indicated above.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I or (I-a) to (I-I), or the meanings indicated above.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I or (I-a) to (I-I), or the meanings indicated above.

In another embodiment of the present invention, X ¹ is OR ¹¹ , where R ¹¹ is heterocyclyl (e.g., a 4-6 membered heterocyclyl) optionally substituted with one or more groups independently selected from halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, —Si (C ₁ -C ₆ ) alkyl,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y ') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y') OR ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ;

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In another embodiment of the present invention, X ¹ is OR ¹¹ , where R ¹¹ is a 4-6 membered heterocyclyl with 1 nitrogen atom in the ring, wherein said heterocyclyl is optionally substituted with one or more groups independently selected from halogen, CN, CF ₃ , -OCF ₃ ,

-NO ₂ , oxo, -Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the values indicated above.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In an embodiment of the present invention, X ¹ is R ¹¹ , and X ¹ and R ⁵ taken together with the nitrogen atom to which they are attached form a 5-7 membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from O, S, and N atoms, wherein said ring is optionally substituted with one or more groups selected from halogen,

CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, —Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ′) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the values indicated above.

In another embodiment of the present invention, X ¹ represents R ¹¹ , and X ¹ and R ⁵ taken together with the nitrogen atom to which they are attached form a 5-6 membered saturated ring having 0-2 additional heteroatoms selected from atoms O, S, and N, wherein said ring is optionally substituted with one or more groups selected from halogen, CN, CF ₃ ,

-OCF ₃ , -NO ₂ , oxo, -Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the values indicated above.

In another embodiment of the present invention, W is

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In another embodiment of the present invention, W is

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In another embodiment of the present invention, W is

;

;

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In an embodiment of the present invention, X ¹ is R ¹¹ , and X ¹ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 4-membered saturated or unsaturated ring having 0-1 additional heteroatom selected from O atoms , S and N, wherein said ring is optionally substituted with one or more groups selected from halogen,

CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, —Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ′) R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the values indicated above.

In another embodiment of the present invention, W is

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In an embodiment of the present invention, X ¹ is —OR ¹¹ , and —OR ¹¹ from X ¹ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from O, S, and N atoms, wherein said ring is optionally substituted with one or more groups selected from halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, —Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y') OR ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the values indicated above.

In another embodiment of the present invention, X ¹ is —OR ¹¹ , and —OR ¹¹ from X ¹ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5-7 membered saturated or unsaturated ring having 0- 2 additional heteroatoms selected from O, S and N atoms, wherein said ring is optionally substituted with one or more groups selected from halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo,

-Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y') OR ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the values indicated above.

In another embodiment of the present invention, X ¹ is —OR ¹¹ , and —OR ¹¹ from X ¹ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring having 0-2 additional heteroatoms selected from O, S and N atoms, wherein said ring is optionally substituted with one or more groups selected from halogen,

CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, —Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ′) R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the values indicated above.

In another embodiment of the present invention, W is

and all other variables have the meanings indicated for formulas I or (I-a) - (I-i), or the meanings indicated above.

In an embodiment of the present invention, X ¹ represents R ¹¹ ; and all other variables have the meanings indicated for formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or the above values.

In another embodiment of the present invention, X ¹ represents R ¹¹ where R ¹¹ represents H; and all other variables have the meanings indicated for formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or the above values.

In another embodiment of the present invention, X ¹ is R ¹¹ , where R ¹¹ is (C ₁ -C ₁₂ ) alkyl (e.g., (C ₁ -C ₆ ) alkyl) substituted with one or more groups independently selected from halogen, CN, CF ₃ , -OCF ₃ ,

-NO ₂ , oxo, -Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and all

other variables have the meanings indicated for formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i, or the above values.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i, or the above values.

In another embodiment of the present invention, X ¹ represents

and all other variables have the meanings indicated for formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i, or the above values.

In another embodiment of the present invention, X ¹ is —S (O) ₂ R ¹¹ and all other variables are as defined for formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or the above values.

In another embodiment of the present invention, X ¹ is —S (O) ₂ R ¹¹ where R ¹¹ is H or methyl; and all other variables have the meanings indicated for formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or the above values.

In another embodiment of the present invention, W is —OR ¹¹ (i.e., the compound has the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III- h or III-i), where R ¹¹ W represents H or (C ₁ -C ₁₂ ) alkyl; and all other variables have the above meanings.

In another embodiment of the present invention, W is —OR ¹¹ (i.e., the compound has the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III- h or III-i), where R ¹¹ W represents H; and all other variables have the above meanings.

In another embodiment of the present invention, W is —OR ¹¹ (i.e., the compound has the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III- h or III-i), where R ¹¹ W represents (C ₁ -C ₆ ) alkyl; and all other variables have the above meanings.

In an embodiment of the present invention, X ² is aryl (e.g. phenyl), wherein said aryl is optionally substituted with one or more groups independently selected from halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo,

-Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y') OR ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings specified for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

и все другие переменные имеют значения, указанные для формул I, (I-a)-(I-i), (II-a)-(II-i) или (III-a)-(III-i), или указанные выше значения.In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (Ia) - (Ii), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² is (C ₆ -C ₁₀ ) aryl substituted with (C ₁ -C ₄ ) alkyl; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² is carbocyclyl (e.g., (C ₄ -C ₆ ) carbocyclyl) or heterocyclyl (e.g. 4-6 membered heterocyclyl), wherein said carbocyclyl or heterocyclyl is optionally substituted with one or more groups independently selected halogen, CN, CF ₃ ,

-OCF ₃ , -NO ₂ , oxo, -Si (C ₁ -C ₆ ) alkyl, - (CR ¹⁹ R ²⁰ ) _n C (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n C (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n C (= Y') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ C (= Y ') OR ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁸ C (= Y') NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n NR ¹⁷ SO ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y ') R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n OC (= Y') OR ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n OC (= Y ') NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OS (O) ₂ (OR ¹⁶ ),

- (CR ¹⁹ R ²⁰ ) _n OP (= Y ') (OR ¹⁶ ) (OR ¹⁷ ), - (CR ¹⁹ R ²⁰ ) _n OP (OR ¹⁶ ) (OR ¹⁷ ),

- (CR ¹⁹ R ²⁰ ) _n S (O) R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ R ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ NR ¹⁶ R ¹⁷ ,

- (CR ¹⁹ R ²⁰ ) _n S (O) (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n S (O) ₂ (OR ¹⁶ ), - (CR ¹⁹ R ²⁰ ) _n SC (= Y ') R ¹⁶ ,

- (CR ¹⁹ R ²⁰ ) _n SC (= Y ') OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SC (= Y') NR ¹⁶ R ¹⁷ and R ²¹ ; and

all other variables have the meanings specified for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² is (C ₄ -C ₆ ) carbocyclyl substituted with —C (= Y ′) R ¹⁶ ; and all other variables have the meanings indicated for formulas I, (Ia) - (Ii), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

In another embodiment of the present invention, X ² represents

and all other variables have the meanings indicated for formulas I, (I-a) - (I-i), (II-a) - (II-i) or (III-a) - (III-i), or the above values.

Another embodiment of the present invention includes the compounds described in examples 5-12, and the compounds indicated below:

The compounds of the present invention are prepared according to the procedures described below in the schemes and examples, or by methods known in the art. Starting materials and various intermediates can be obtained from commercial sources, obtained from commercially available compounds, or prepared using well known synthetic methods (for example, the methods described in WO 02/06213, WO 03/077855 and WO 03/077914).

For example, 5-azabenzothiophenes of the formula (I-b), (II-b) or (III-b) can be obtained using the synthesis pathways depicted in schemes 1, 2 and 3.

Scheme 1

Compounds of formula (IV) can be prepared using methods described in the literature. They can be reacted with methylthioglycolate or ethylthioglycolate in the presence of a base, such as sodium hydride, in a suitable solvent, such as N, N-dimethylformamide or 1,2-dimethoxyethane, at a temperature of from -50 ° C to room temperature, to give the compound formulas (VI).

Compounds of formula (VI) can be converted to compounds of formula (VII) by reacting with a halogenating agent such as phosphorus oxybromide, pure or in a suitable solvent, such as toluene, at a temperature from room temperature to 140 ° C. Alternatively, the compounds of formula (VI) can be reacted with nonafluorobutanesulfonyl fluoride in the presence of a base such as diisopropylethylamine and a catalyst such as N, N-dimethyl-4-aminopyridine in a solvent such as dichloromethane at room temperature with N-phenyl trifluoromethanesulfonimide in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as 1,2-dimethoxyethane, at a temperature from room temperature to the reflux temperature of the solvent. In addition, the compounds of formula (VI) can be treated with trifluoromethanesulfonic anhydride in the presence of a base such as pyridine in a solvent such as dichloromethane at a temperature of from -20 ° C to ambient temperature.

Compounds of formula (VIII) can be prepared from compounds of formula (VII) by reaction with aniline (including the corresponding substituents R1) in the presence of a catalyst such as tris (dibenzylideneacetone) dipalladium (0) or palladium acetate, a base such as potassium phosphate, tert-butoxide sodium, 1,8-diazabicyclo [5.4.1] undec-7-ene or cesium carbonate, a ligand such as 9,9'-dimethyl-4,5-bis (diphenylphosphino) xanthene, 2,2'-bis (diphenylphosphino ) -1,1'-binaphthyl, 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2', 6 '- (dimethoxy) biphenyl or tributyl osfin, in a suitable solvent such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at a temperature from room temperature to the reflux temperature of the solvent, or under microwave irradiation at a temperature of from 70 ° C to 150 ° C.

Alternatively, compounds of formula (VIII) can be prepared from compounds of formula (VI) by reaction with compounds of formula (IX) (prepared using methods described in the literature) in a suitable solvent, such as toluene or 1,2-dimethoxyethane, at a temperature of room temperature to the reflux temperature of the solvent or when exposed to microwave irradiation at a temperature of from 100 ° C to 180 ° C.

Compounds of formula (X) can be prepared from compounds of formula (VIII) by reaction with a base, such as sodium hydroxide, in a protic solvent, such as ethanol or methanol, at a temperature from room temperature to reflux temperature.

Compounds of formula (X) can be reacted with a functionalized hydroxylamine of formula (XII) (commercially available or prepared according to Scheme 6) or an amine and a suitable coupling agent such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide or N, N'-dicyclohexylcarbodiimide hydrochloride, in the presence of N-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base such as diisopropylethylamine or triethylamine, in an inert solvent such as tetrag drofuran, N, N-dimethylformamide or dichloromethane at about room temperature, to yield the formula (XI) compound. Alternatively, compounds of formula (XI) can be prepared directly from compounds of formula (VIII) by reacting with an amine or hydroxylamine DNHR in the presence of a Lewis acid such as trimethylaluminum in a solvent such as DCM at room temperature to reflux temperature.

Alternatively, compounds of formula (VIII) can be prepared from compounds of formula (XIII) according to Scheme 2.

Scheme 2

Compounds of formula (XIII) can be prepared using methods described in the literature. Compounds of general formula (XIV) can be prepared from compounds of formula (XIII) using the methods described above to prepare compounds of formula (VI) from compounds of formula (IV).

Compounds of formula (VIII) can be prepared from compounds of formula (XIV) by reaction with compounds of formula (XV) (including the corresponding substituents R1) using the methods described above to prepare compounds of formula (VIII) from compounds of formula (VI). Alternatively, compounds of formula (VIII) can be prepared from compounds of formula (XIV) by reaction with compounds of formula (XVI) (including the corresponding substituents R1) in the presence of a base such as sodium hydride or lithium hexamethyldisilazane, in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide, at a temperature of from room temperature to 150 ° C.

Alternatively, compounds of formula (X) can also be prepared from compounds of formula (VII) according to Scheme 3.

Scheme 3

Compounds of formula (VII) can be converted to compounds of formula (XVII) using the methods described above to prepare compounds of formula (X) from compounds of formula (VIII). Compounds of formula (XVII) may be coupled with amines, such as 2-amino-2-methyl-1-propanol, using the methods described above to prepare compounds of formula (XI) from compounds of formula (X), followed by reaction with an agent such as thionyl chloride or phosphorus oxychloride, pure or in a suitable solvent, such as dichloromethane, chloroform or diethyl ether, at a temperature from room temperature to the reflux temperature of the solvent, to obtain compounds of formula (XVIII).

Compounds of formula (XIX) can be prepared from compounds of formula (XVIII) by reaction with aniline (including the corresponding substituents R1) in the presence of a catalyst such as tris (dibenzylideneacetone) dipalladium (0) or palladium acetate, a base such as potassium phosphate, tert-butoxide sodium, 1,8-diazabicyclo [5.4.1] undec-7-ene or cesium carbonate, a ligand such as 9,9'-dimethyl-4,5-bis (diphenylphosphino) xanthene, 2,2'-bis (diphenylphosphino ) -1,1'-binaphthyl, 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2', 6 '- (dimethoxy) biphenyl or tributyl phosphine, in a suitable solvent, such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at a temperature of from room temperature to the reflux temperature of the solvent or when exposed to microwave irradiation at a temperature of from 70 ° C to 150 ° C.

Alternatively, compounds of formula (XIX) can be prepared from compounds of formula (XVIII) by reaction with anilines (including the corresponding R1 substituents) in the presence of a base such as sodium hydride or lithium hexamethyldisalazane in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide, at a temperature of from room temperature to 150 ° C. Compounds of formula (X) can be prepared from compounds of formula (XIX) by reaction with an acid, such as hydrogen chloride or acetic acid, in a suitable solvent, such as water, at a temperature from room temperature to the reflux temperature of the solvent.

6-Azabenzothiophenes of the formula I-c, II-c or III-c can be obtained using the synthesis pathways depicted in Scheme 4.

Scheme 4

Compounds of formula (XX) can be prepared using methods described in the literature. They can be reacted with methyl glycolate or ethyl glycolate in the presence of phosphine, such as triphenylphosphine, an alkyl carboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, in an aprotic solvent, such as tetrahydrofuran or diethyl ether, at a temperature from room temperature to a temperature of a temperature to warm the mixture. (Xxi).

The compounds of formula (XXI) can be reacted in the presence of a base, such as sodium hydride, in a suitable solvent, such as N, N-dimethylformamide or 1,2-dimethoxyethane, at a temperature of from -50 ° C to room temperature, to obtain compounds of the formula (Xxii).

Compounds of formula (XXII) can be converted to compounds of formula (XXIII) by reaction with a halogenating agent, such as phosphorus oxybromide, pure or in a suitable solvent, such as toluene, at a temperature from room temperature to 140 ° C. Alternatively, compounds of formula (XXII) may be reacted with nonafluorobutanesulfonyl fluoride in the presence of a base such as diisopropylethylamine and a catalyst such as N, N-dimethyl-4-aminopyridine in a solvent such as dichloromethane at room temperature with N-phenyl trifluoromethanesulfonimide in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as 1,2-dimethoxyethane, at a temperature from room temperature to the reflux temperature of the solvent. In addition, the compounds of formula (VI) can be treated with trifluoromethanesulfonic anhydride in the presence of a base such as pyridine in a solvent such as dichloromethane at a temperature of from -20 ° C to ambient temperature.

Compounds of formula (XXIV) can be prepared from compounds of formula (XXIII) by reacting with aniline (including the corresponding R1 substituents) in the presence of a catalyst such as tris (dibenzylideneacetone) dipalladium (0) or palladium acetate, a base such as potassium phosphate, tert-butoxide sodium, 1,8-diazabicyclo [5.4.1] undec-7-ene or cesium carbonate, a ligand such as 9,9'-dimethyl-4,5-bis (diphenylphosphino) xanthene, 2,2'-bis (diphenylphosphino ) -1,1'-binaphthyl, 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2', 6 '- (dimethoxy) biphenyl or tributi phosphine, in a suitable solvent such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at a temperature from room temperature to the reflux temperature of the solvent, or under microwave irradiation at a temperature of from 70 ° C to 150 ° C.

Alternatively, compounds of formula (XXIV) can be prepared from compounds of formula (XXII) by reaction with compounds of formula (IX) (prepared using methods described in the literature) in a suitable solvent, such as toluene or 1,2-dimethoxyethane, at a temperature of room temperature to the reflux temperature of the solvent or when exposed to microwave irradiation at a temperature of from 100 ° C to 180 ° C.

Compounds of formula (XXVI) can be prepared from compounds of formula (XXIV) by reaction with a base, such as sodium hydroxide, in a protic solvent, such as ethanol or methanol, at a temperature from room temperature to reflux temperature.

Compounds of formula (XXVI) can be reacted with a functionalized hydroxylamine of formula (XII) (commercially available or prepared according to Scheme 6) or an amine and a suitable coupling agent such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide or N, N'-dicyclohexylcarbodiimide hydrochloride, in the presence of N-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base such as diisopropylethylamine or triethylamine, in an inert solvent such as tetra idrofuran, N, N-dimethylformamide or dichloromethane at about room temperature, to give compounds of formula (XXVIII). Alternatively, compounds of formula (XXVI) can be prepared directly from compounds of formula (XXIV) by reacting with an amine or hydroxylamine DNHR in the presence of a Lewis acid such as trimethylaluminum in a solvent such as DCM at room temperature to reflux temperature.

Thieno [2,3-d] pyrimidines of the formula I-f, II-f or III-f can be obtained using the synthesis pathways depicted in Scheme 5.

Scheme 5

Compounds of formula (XXVIII) can be prepared according to the methods described in the literature. They can be reacted with a halogenating agent, such as phosphorus oxychloride, pure or in a suitable solvent, such as toluene, at a temperature from room temperature to reflux, to give compounds of formula (XXIX).

Compounds of formula (XXXVI) can be prepared from compounds of formula (XXXIX) using methods described for preparing compounds of formula (XI) from compounds of formula (IV), as shown in Scheme 5.

Hydroxylamines of formula (XII) can be obtained using the methods described in the literature, or synthetically, as shown in scheme 6.

Scheme 6

Primary or secondary alcohols of the general formula (XXXVII) can be prepared using methods described in the literature. They can be reacted with 1-hydroxyphthalimide using phosphine and coupling reagents such as diethyl azodicarboxylate to give compounds of general formula (XXXVIII). From the compounds of general formula (XXXVIII), the protecting group can be removed using hydrazine or methylhydrazine to give hydroxylamines of general formula (XII-a). Compounds of general formula (XII-a) can be further modified by reductive amination with aldehydes or ketones using a reducing agent, such as sodium triacetoxyborohydride, sodium cyanoborohydride or borane-pyridine, in a solvent, such as dichloroethane, at a temperature from ambient temperature to boiling point with reflux condenser. In addition, compounds of general formula (XII-a) can be further modified by alkylation with an alkyl halide in the presence of a base such as triethylamine in a solvent such as dichloromethane to give hydroxylamines of general formula (XII-b).

Anilines of the general formula (XXXIX) used in the cross-coupling reactions described above can be obtained using the methods described in the literature or according to Scheme 7.

Scheme 7

Substituted 4-chloronitrobenzene can be reacted with hexamethyldisilane in a solvent such as xylene using a catalyst such as tetrakis (triphenylphosphine) palladium at a temperature from room temperature to reflux temperature. The nitro group can be reduced using methods described in the literature, such as a reaction in a hydrogen atmosphere at a pressure of 1 to 5 atmospheres in the presence of a catalyst, such as palladium-carbon, and in a solvent, such as ethanol or ethyl acetate, at room temperature.

Trifluoromethanesulfonyl esters of the general formula (XL) used in the cross-coupling reactions described above can be prepared using methods described in the literature or according to Scheme 8.

Scheme 8

Halogen phenols of general formula (XLI) can be reacted with two equivalents of alkyl lithium reagents, such as n-butyl lithium, in a solvent such as THF, followed by quenching with a trialkylsilyl halide such as trimethylsilyl chloride to give trialkylsilyl phenols (XLII). Then, trialkylsilylphenols can be reacted using the procedures described in the literature to produce trifluoromethanesulfonates or nonaphthalates of the general formula (XL).

It should be borne in mind that when there are corresponding functional groups, compounds of formulas (I), (II), (III) or any intermediate compounds used in their preparation, it is possible to further derivatize one or more standard synthesis methods using substitution and oxidation reactions recovery or cleavage. Certain references to substitution reactions include conventional methods of alkylation, arylation, heteroarylation, acylation, sulfonylation, gelation, nitration, formylation and combinations.

For example, aryl bromide or chloride groups can be converted to aryl iodide groups using the Finkelstein reaction using iodine sources such as sodium iodide, a catalyst such as copper iodide, and a ligand such as trans-N, N'-dimethyl-1,2- cyclohexanediamine, in a solvent such as 1,4-dioxane, by heating the reaction mixture to reflux. Aryl trialkylsilanes can be converted to aryl iodides by treating the silane with an iodine source, such as iodine monochloride, in a solvent, such as dichloromethane, with or without Lewis acid, such as silver tetrafluoroborate, at a temperature from -40 ° C to reflux temperature.

In another example, primary amino groups (—NH ₂ ) can be alkylated using a reductive alkylation method using an aldehyde or ketone and borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, or alcohol , such as ethanol, if necessary, in the presence of an acid, such as acetic acid, at ambient temperature. Secondary amino groups (—NH—) can be alkylated in a similar manner using an aldehyde.

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

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

In another example, an amino group (—CH ₂ NH ₂ ) can be prepared by reducing nitriles (—CN), for example, by catalytic hydrogenation using, for example, hydrogen in the presence of a metal catalyst, for example palladium on a support such as coal, or Raney nickel, in a solvent such as an ether, for example, a cyclic ether, such as tetrahydrofuran, at a temperature of from -78 ° C to a reflux temperature of the solvent.

In another example, amino groups (—NH ₂ ) can be obtained from carboxyl groups (—CO ₂ H) by conversion to the corresponding acyl azide (—CON ₃ ), Kurtis rearrangement, and hydrolysis of the resulting isocyanate (—N = C = O).

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

In another example, aldehyde groups can be converted to alkenyl groups (-CH = CHR ') using the Wittig or Wadsworth-Emmons reaction using the appropriate phosphonate under standard conditions known to those skilled in the art.

Aldehyde groups can be prepared by reduction of ester groups (such as —CO ₂ Et) or nitriles (—CN) using diisobutylaluminum hydride in a suitable solvent such as toluene. Alternatively, aldehyde groups can be prepared by oxidizing alcohol groups using a suitable oxidizing agent known to those skilled in the art.

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

Carboxyl groups (—CO ₂ H) can be converted to amide groups (—CONHR ′ or —CONR′R ″) by reacting with the corresponding amine in the presence of a suitable coupling agent, such as HATU, in a suitable solvent, such as dichloromethane.

In another example, carboxylic acids can be homogenized to one carbon atom (i.e., from —CO ₂ H to —CH ₂ CO ₂ H) by conversion to the corresponding acid chloride (—COCl) followed by Arndt-Eystert synthesis.

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

Alcohol groups can be converted to leaving groups, such as halogen atoms, or sulfonyloxy groups, such as alkylsulfonyloxy, for example trifluoromethylsulfonyloxy, or arylsulfonyloxy, for example, p-toluenesulfonyloxy, using conditions known to those skilled in the art. For example, the alcohol can be reacted with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to give the corresponding chloride. In the reaction, a base (e.g. triethylamine) can also be used.

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

Aromatic halogen-containing substituents in the compounds can be exchanged for halogen to metal by treatment with a base, for example, a lithium base, such as n-butyl or tert-butyl lithium, optionally at a low temperature, for example, about -78 ° C, in a solvent, such as tetrahydrofuran, and then quench with an electrophilic compound to introduce the desired substituent. So, for example, you can enter the formyl group using N, N-dimethylformamide as the electrophile. Alternatively, aromatic halogen-containing substituents can be subjected to metal-catalyzed reactions (e.g., palladium or copper) to introduce, for example, acidic, ester, cyano-, amide, aryl, heteroaryl, alkenyl, alkynyl, thio or amino substituents. Suitable techniques that can be used include those described by Heck, Suzuki, Still, Buchwald or Hartwig.

Aromatic halogen-containing substituents can also be nucleophilic substituted by reaction with an appropriate nucleophile, such as an amine or an alcohol. Such an interaction can advantageously be carried out at elevated temperature in the presence of microwave irradiation.

The compounds of the present invention were tested for their ability to inhibit the activity and activation of MEK (primary assays) and for their biological effect on cell growth (secondary assays), as described below. Compounds having an IC _{50 of} less than 10 μM (more preferably less than 5 μM, even more preferably less than 1 μM, most preferably less than 0.5 μM) in an MEK activity assay in Example 1a or 1b, having an IC _{50 of} less than 5 μM (more preferably less than 0.1 μM, most preferably less than 0.01 μM) in the MEK activation analysis in Example 2, IC ₅₀ less than 10 μM (more preferably less than 5 μM, most preferably less than 0.5 μM) in MEK cell proliferation assay example 3, and / or IC ₅₀ less than 10 μm (preferably less than 1 μm, most preferably less than 0.1 μm) in the analysis ERK phosphorylation in Example 4 can be used as MEK inhibitors.

The present invention relates to a composition (eg, a pharmaceutical composition) comprising a compound of formula I (and / or solvates and salts thereof) and a carrier (pharmaceutically acceptable carrier). The present invention also relates to a composition (eg, a pharmaceutical composition) comprising a compound of formula I (and / or solvates and salts thereof) and a carrier (pharmaceutically acceptable carrier), and further comprising a second chemotherapeutic agent and / or a second anti-inflammatory agent, such as described in this description. The compositions of the present invention are useful for inhibiting abnormal cell growth or treating hyperproliferative disorder in a mammal (e.g., human). The compositions of the present invention are also useful for the treatment of inflammatory diseases in a mammal (eg, a human).

The compounds and compositions of the present invention are also useful for the treatment of autoimmune disease, destructive bone disorder, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (e.g., human). Examples of such diseases / disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retroletal fibroplasia, age-related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis and atopic dermatitis, kidney disease and renal failure, polycystic kidney disease congestive heart failure, neurofibromatosis, organ transplant rejection, cachexia, stroke, septic shock, heart failure, Alzheimer's disease, chronic and whether neuropathic pain and viral infections such as HIV, hepatitis B virus (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Chronic pain for the purposes of the present invention includes, but is not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, hypothyroidism, inflammation, arthritis, and postoperative pain. Neuropathic pain is associated with a number of conditions that include, but are not limited to, inflammation, postoperative pain, phantom pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crushing, squeezing damage, tissue damage, limb amputation, arthritic pain and nerve damage between the peripheral nervous system and the central nervous system.

The compounds and compositions of the present invention are also useful for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-caused kidney disease) in a mammal (e.g., a human).

The compounds and compositions of the present invention are also useful for preventing blastocyte implantation in a mammal (e.g., human).

The present invention relates to a method for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or its solvates and salts) or a composition thereof. The present invention also relates to a method for treating an inflammatory disease in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or its solvates and salts) or its composition.

The present invention relates to a method for inhibiting abnormal cell growth or treating hyperproliferative disorder in a mammal (e.g., a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or its solvates and salts) or a composition thereof in combination with a second chemotherapeutic agent, such as described in this description. The present invention also relates to a method of treating an inflammatory disease in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or its solvates and salts) or its composition in combination with a second anti-inflammatory agent, such as described in this description.

The present invention relates to a method for treating an autoimmune disease, destructive bone disorder, proliferative disorder, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or solvates and salts) or a composition thereof, as well as optionally a second therapeutic agent. Examples of such diseases / disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retroletal fibroplasia, age-related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis and atopic dermatitis, kidney disease and renal failure, polycystic kidney disease congestive heart failure, neurofibromatosis, organ transplant rejection, cachexia, stroke, septic shock, heart failure, Alzheimer's disease, chronic th or neuropathic pain, and viral infections such as HIV, hepatitis B virus (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV).

The present invention relates to a method for treating pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-caused kidney disease) in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or its solvates and salts) or its composition as well as optionally a second therapeutic agent.

The present invention relates to a method for preventing implantation of a blastocyte in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or its solvates and salts) or a composition thereof, and optionally comprising administering a second therapeutic agent.

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

It is also contemplated that the compounds of the present invention may confer abnormal cells greater sensitivity to radiation treatment for the purpose of killing and / or inhibiting the growth of such cells. Accordingly, the invention also relates to a method for sensitizing abnormal cells in a mammal (eg, a human) to radiation treatment, comprising administering to said mammal an amount of a compound of formula I (and / or its solvates and salts) or a composition thereof effective for sensitizing abnormal cells to treatment irradiation.

The administration of the compounds of the present invention (hereinafter “active (s) compound (s)”) can be carried out by any method that delivers the compounds to the site of action. Such methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion), local routes, inhalation and rectal administration.

The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, route of administration, placement of the compound, and choice and prescription of the attending physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in a single dose or in divided doses. For a person weighing 70 kg, this may represent an amount of about 0.05-7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, doses below the lower limit of the above interval may be adequate, while in other cases even higher doses can be used without any harmful side effects, provided that such higher doses are first divided into several small doses for introduction during the day.

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

The pharmaceutical composition may be, for example, in a form suitable for oral administration in the form of a tablet, capsule, pill, powder, sustained release composition, solution, suspension, for parenteral injection in the form of a sterile solution, suspension or emulsion, for external administration as ointments or creams or for rectal administration in the form of a suppository. The pharmaceutical composition may be in unit dosage forms suitable for a single administration of exact dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound of the present invention as an active ingredient. In addition, the composition may contain other drugs or pharmaceuticals, carriers, adjuvants, etc.

Examples of forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. Such dosage forms may be buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or excipients, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavoring agents, binders, excipients and the like. Thus, in the case of oral administration in tablets containing various excipients, such as citric acid, various disintegrants such as starch, alginic acid and certain complex silicates, and binders such as sucrose, gelatin and gum arabic can also be used. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used for tabletting purposes. Solid compositions of a similar type may also be used in soft and hard filled gelatin capsules. Therefore, preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active component therein may be combined with various sweetening or flavoring agents, coloring agents or coloring agents and, if desired, emulsifiers or suspending agents, along with diluents such as water, ethanol, propylene glycol, glycerin or a combination thereof.

Methods for preparing pharmaceutical compositions with a certain amount of active compound are known or will be apparent to those skilled in the art. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

Examples

Abbreviations

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DCM Dichloromethane Dipa Diisopropylethylamine DMAP 4-dimethylaminopyridine DMF Dimethylformamide EDCI 1-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide Hatu O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate Hcl Hydrochloric acid Hm-n Isolute® HM-N is a modified form of diatomaceous earth that can effectively absorb water samples Hobt 1-hydroxybenzotriazole Lda Lithium diisopropylamide Meoh Methanol NHCO ₃ Bicarbonate of soda

NaOH Sodium hydroxide Pd (PPh ₃ ) ₄ Tetrakis (triphenylphosphine) palladium (0) Pd ₂ dba ₃ Tris (dibenzylideneacetone) dipalladium (0) PdCl ₂ (PPh ₃ ) ₂ Dichlorobis (triphenylphosphine) palladium (II) Si-spe Isolute® Pre-Filled Silica Flash Cartridge THF Tetrahydrofuran Xanthos 9,9-Dimethyl-4,5-bis (diphenylphosphino) xanthene

General experimental conditions

¹ H NMR spectra were recorded at ambient temperature using a Varian Unity Inova spectrometer (400 MHz) with a 5 mm triple resonance probe. Chemical shifts are expressed in ppm. relative to tetramethylsilane. The following abbreviations are used: ush = broadened signal, s = singlet, d = doublet, dd = double doublet, t = triplet, k = quartet, m = multiplet.

High performance liquid chromatography-mass spectrometry (LCMS) experiments to determine the retention time (R _T ) and the mass of the associated ions are carried out using one of the following methods.

Method A. The experiments are carried out on a Waters Micromass ZQ quadrupole mass spectrometer connected to a Hewlett Packard HP1100 LC system with a diode array detector. A 100 × 3.0 mm column, Higgins Clipeus, C18, 5 μm, and a flow rate of 1 ml / min were used. The initial solvent system consists of 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute, followed by a gradient of up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system is kept constant for another 5 minutes.

Method B. The experiments are carried out on a Waters Platform LC quadrupole mass spectrometer connected to a Hewlett Packard HP1100 LC system with a diode array detector and a 100-position autosampler using a 30 × 4.6 mm column, Phenomena Luna, C18 (2), and a flow rate of 2 ml / min. The solvent system is 95% solvent A and 5% solvent B for the first 0.50 minutes, followed by a gradient of up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system is kept constant for another 0.50 minutes.

Microwave experiments are performed using the Personal Chemistry Emrys Initiator or Optimizer, which use a single-mode resonator and dynamic field tuning, both of which give reproducibility and adjustment. You can reach a temperature of 40-250 ° C and raise the pressure to 20 bar.

Example 1a

MEK analysis (MEK activity analysis)

Constitutively activated human mutant MEK1 expressed in insect cells is used as a source of enzymatic activity at a final concentration in the kinase analysis of 62.5 nM.

The analysis was carried out for 30 minutes in the presence of 50 μM ATP using recombinant GST-ERK1 produced in E. coli as a substrate. Phosphorylation of the substrate is detected and quantified using HTRF reagents supplied by Cisbio. The reagents consist of anti-GST antibodies conjugated with allophycocyanin (XL665) and anti-phospho (Thr202 / Tyr204) -ERK antibodies conjugated to europium cryptate. Antibodies against phospho recognize ERK1 diphosphorylated by Thr202 and Tyr204. When both types of antibodies bind to ERK1 (i.e., when the substrate is phosphorylated), energy is transferred from cryptate to allophycocyanin after excitation at 340 nm, resulting in fluorescence emission proportional to the amount of phosphorylated substrate obtained. Fluorescence is detected using a multi-well fluorimeter.

Compounds are diluted in DMSO before being added to the assay buffer, and the final concentration of DMSO in the assay is 1%.

IC _{50 is} defined as the concentration at which 50% inhibition of control is achieved with this compound. IC ₅₀ values are calculated using XLift software (version 2.0.5).

Example 1b

MEK analysis (MEK activity analysis)

Constitutively activated human mutant MEK1 expressed in insect cells is used as a source of enzymatic activity at a final concentration in a 15 nM kinase assay.

The analysis was carried out for 30 minutes in the presence of 50 μM ATP using recombinant GST-ERK1 produced in E. coli as a substrate. Phosphorylation of the substrate is detected and quantified using HTRF reagents supplied by Cisbio. The reagents consist of anti-GST antibodies conjugated with allophycocyanin (XL665) and anti-phospho (Thr202 / Tyr204) -ERK antibodies conjugated to europium cryptate. They are used at a final concentration of 4 μg / ml and 0.84 μg / ml, respectively. Antibodies against phospho recognize ERK1 diphosphorylated by Thr202 and Tyr204. When both types of antibodies bind to ERK1 (i.e., when the substrate is phosphorylated), energy is transferred from cryptate to allophycocyanin after excitation at 340 nm, resulting in fluorescence emission proportional to the amount of phosphorylated substrate obtained. Fluorescence is detected using a multi-well fluorimeter.

Compounds are diluted in DMSO before being added to the assay buffer, and the final concentration of DMSO in the assay is 1%.

IC _{50 is} defined as the concentration at which 50% inhibition of control is achieved with this compound. IC ₅₀ values are calculated using XLift software (version 2.0.5).

The compounds of examples 5-8 and 10-12 show an IC _{50 of} less than 10 μM in the assay described in example 1a or 1b, most of these compounds show an IC _{50 of} less than 5 μM.

Example 2

BRaf Assay (MEK Activation Assay)

A constitutively activated mutant bRaf expressed in insect cells is used as a source of enzymatic activity.

The analysis is carried out for 30 minutes in the presence of 200 μM ATP using recombinant GST-MEK1 produced in E. coli as a substrate. Phosphorylation of the substrate is detected and quantified using HTRF reagents supplied by Cisbio. The reagents consist of anti-GST antibodies conjugated with allophycocyanin (XL665) and anti-phospho antibodies (Ser217 / Ser221) -MEK conjugated to europium cryptate. Antibodies against phospho recognize MEK diphosphorylated at Ser217 and Ser221 or monophosphorylated at Ser217. When both types of antibodies bind to MEK (i.e. when the substrate is phosphorylated), energy is transferred from cryptate to allophycocyanine after excitation at 340 nm, resulting in fluorescence emission proportional to the amount of phosphorylated substrate obtained. Fluorescence is detected using a multi-well fluorimeter.

Compounds are diluted in DMSO before being added to the assay buffer, and the final concentration of DMSO in the assay is 1%.

IC _{50 is} defined as the concentration at which 50% inhibition of control is achieved with this compound. IC ₅₀ values are calculated using XLift software (version 2.0.5).

In this assay, the compounds of Examples 5-7 and 10 show an IC _{50 of} less than 5 μM.

Example 3

Cell Proliferation Assay

Compounds are tested in an analysis of cell proliferation using the following cell lines:

HCT116 - human colorectal carcinoma (ATCC);

A375 - malignant human melanoma (ATCC).

Both cell lines were retained in DMEM / F12 (1: 1) (Gibco) media supplemented with 10% FCS at 37 ° C in a humid chamber with 5% CO ₂ .

Cells are seeded in 96-well plates at 2000 cells / well and after 24 hours they are exposed to various concentrations of compounds in 0.83% DMSO. Cells were grown for another 72 hours and an equal volume of CellTiter reagent (Promega) was added to each well. This leads to cell lysis and generates a luminescent signal proportional to the amount of ATP released (and therefore proportional to the number of cells in the well), which can be detected using a multi-well lumenometer.

EC _{50 is} defined as the concentration at which 50% inhibition of control is achieved with this compound. EC ₅₀ values are calculated using XLift software (version 2.0.5).

In this assay, the compounds of Examples 5 and 10 show an EC _{50 of} less than 10 μM in any of the cell lines.

Example 4

Phospho-ERK Cell Based Assay

Compounds are tested in ELISA phospho-ERK cells using the following cell lines:

HCT116 - human colorectal carcinoma (ATCC);

A375 - malignant human melanoma (ATCC).

Both cell lines were retained in DMEM / F12 (1: 1) (Gibco) media supplemented with 10% FCS at 37 ° C in a humid chamber with 5% CO ₂ .

Cells are seeded in 96-well plates at 2000 cells / well and after 24 hours they are exposed to various concentrations of compounds in 0.83% DMSO. Cells are grown for another 2 hours or 24 hours, fixed with formaldehyde (final concentration of 2%) and impregnated with methanol. After blocking TBST-3% BSA, the fixed cells were incubated with primary antibodies (against rabbit phospho-ERK) overnight at 4 ° C. Cells are incubated with propidium iodide (DNA fluorescent dye) and cell p-ERK is detected using anti-rabbit secondary antibodies conjugated to Alexa Fluor 488 fluorescent dye (molecular probes). Fluorescence was analyzed using an Acumen Explorer microplate scanning laser cytometer (TTP Labtech), and the Alexa Fluor 488 signal was normalized to the PI signal (proportional to the number of cells).

The EC _{50 is} defined as the concentration at which the connection achieves half the signal between the baseline and the maximum response. EC ₅₀ values are calculated using XLift software (version 2.0.5).

In this assay, the compounds of Examples 5 and 10-12 show an EC _{50 of} less than 10 μM in any of the cell lines.

Example 5

4-chloronicotinic acid

According to the methodology in Guillier et al. (1995), J. Org. chem., 60 (2): 292-6, to a cooled (-78 ° C) solution of LDA (21 ml, 1.6 M in hexane, 33.3 mmol) in anhydrous THF (70 ml) in an argon atmosphere, 4- chloropyridine (5.0 g, 33.3 mmol). After keeping at -78 ° C for 1 hour, the solution was quickly poured onto a layer of solid CO ₂ contained in a 250 ml conical flask. After the reaction solution is warmed to room temperature, the solution is quenched with water (30 ml). Volatile organic solvents were removed in vacuo and the remaining aqueous suspension was extracted with diethyl ether (3 × 100 ml). The aqueous phase is cooled to 0 ° C and the pH is adjusted to 4 by adding concentrated hydrochloric acid. The resulting precipitate was incubated for 30 minutes and then separated by filtration. The solid was washed with cold diethyl ether (10 ml) to obtain the title compound as a white solid (3.2 g, 61%).

Ethyl 4-chloronicotinate

A suspension of 4-chloronicotinic acid (3.0 g, 19.0 mmol) in thionyl chloride (50 ml) was refluxed for 90 minutes. After cooling to ambient temperature, the solution was concentrated to dryness, then the residue was subjected to azeotropic distillation with toluene (2 × 50 ml) to obtain a solid. The resulting solid was added in portions to a chilled (0 ° C.) mixture of ethanol (25 ml) and DIPEA (15 ml). The reaction mixture was stirred at room temperature for 4 hours, then concentrated in vacuo and water (75 ml) was added. The solution was extracted with ethyl acetate (2 × 75 ml), then the combined organic phases were dried over sodium sulfate and then concentrated to obtain the title compound as a brown oil (3.3 g, 94%). ¹ H NMR (CDCl ₃ , 400 MHz) 9.03 (s, 1H), 7.58 (d, J = 5.4 Hz, 1H), 7.41 (dd, J = 5.4 Hz, 0, 5 Hz, 1H), 4.45 (q, J = 7.3 Hz, 2H), 1.43 (t, J = 7.3 Hz, 3H).

3-hydroxythieno [3,2-c] pyridine-2-carboxylic acid ethyl ester

To a chilled (5 ° C) solution of ethyl 4-chloronic nicotinate (1.55 g, 8.4 mmol) and ethyl mercaptoacetic acid (2.6 ml, 23.4 mmol) in anhydrous DMF (30 ml) with stirring under an argon atmosphere, sodium hydride (21.7 mmol, 60% dispersion in oil, 868 mg) was added in portions over 20 minutes. Stirring is continued at 5 ° C. for 10 minutes and then for 1.5 hours at room temperature. Then the reaction was quenched by adding water (5 ml), the reaction mixture was acidified by adding acetic acid (1 ml), then concentrated and a residue was obtained. The residue was taken up in ethyl acetate (150 ml) and water (100 ml). The layers were separated and the aqueous phase was extracted with DCM (100 ml). The combined organic phases are dried over sodium sulfate, filtered and evaporated to give a solid. The solid was triturated with diethyl ether: pentane (1: 1, 15 ml) to give the title compound as a yellow solid (1.5 g, 81%). LCMS (method B): R _T = 2.21 min, M + H ⁺ = 224.

3- (nonafluorobutane-1-sulfonyloxy) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester

To a solution of 3-hydroxythieno [3,2-c] pyridine-2-carboxylic acid ethyl ester (1.3 g, 5.82 mmol) and DMAP (35 mg, 0.29 mmol) in DCM (10 ml) with stirring at 0 ° C, DIPEA (2.5 ml, 14.0 mmol) and nonafluorobutyl sulfonyl chloride (1.36 ml, 7.56 mmol) are added. After 10 minutes, the reaction mixture was warmed to room temperature and stirred for another 20 hours. The reaction mixture was diluted with DCM (50 ml) and washed with water (30 ml). The organic phase was separated, dried over sodium sulfate, filtered and evaporated to give a brown oil. The oil was purified by flash chromatography (Si-SPE, pentane: diethyl ether, gradient from 100: 0 to 70:30) to give the title compound as a colorless oil, which crystallized upon standing (420 mg, 14%). LCMS (method B): R _T = 4.46 min, M + H ⁺ = 508.

3- (4-Bromo-2-fluorophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester

Degassed ethyl ester solution of 3- (nonafluorobutane-1-sulfonyloxy) thieno [3,2-c] pyridine-2-carboxylic acid (206 mg, 1.08 mmol), 4-bromo-2-fluoroaniline (206 mg, 1, 08 mmol), Pd ₂ dba ₃ (38 mg, 0.04 mmol), xanthos (48 mg, 0.08 mmol) and DBU (316 μl, 2.08 mmol) in toluene (1 ml) are subjected to microwave irradiation at 150 ° C for 10 minutes. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (30 ml). The resulting solution was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo to obtain a solid residue. The solid residue was purified by flash chromatography (Si-SPE, pentane: diethyl ether, gradient 90:10 to 70:30) to give the title compound as a white solid (210 mg, 64%). LCMS (method B): R _T = 3.78 min, M + H ⁺ = 395/397.

3- (2-Fluoro-4-iodophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid ethyl ester

Mixture of ethyl 3- (4-bromo-2-fluorophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (209 mg, 0.53 mmol), copper (I) iodide (5 mg, 0.026 mmol) , sodium iodide (159 mg, 1.06 mmol) and trans-N, N'-dimethyl-1,2-cyclohexanediamine (8.5 μl, 0.053 mmol) in 1,4-dioxane (1.0 ml) are heated at 105 ° C for 24 hours in an argon atmosphere. Copper (I) iodide (5 mg, 0.026 mmol) and trans-N, N'-dimethyl-1,2-cyclohexanediamine (8.5 μl, 0.053 mmol) were added and heating continued for another 24 hours. Once the reaction mixture has cooled to room temperature, it is treated with ethyl acetate (30 ml) and a mixture of 10% v / v ammonia 0.880 / water (20 ml). The layers were separated and the aqueous phase was extracted with DCM (30 ml). The combined organic layer was dried over sodium sulfate, filtered and evaporated, then the residue was purified by flash chromatography on Si-SPE (elution with pentane: diethyl ether mixtures, gradient from 90:10 to 70:30) to give the title compound as a yellow solid substances (174 mg, 74%). LCMS (method B): R _T = 3.97 min, M + H ⁺ = 443.

((R) -2,2-Dimethyl [1,3] dioxolan-4-ylmethoxy) amide 3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid

A mixture of ethyl ester of 3- (2-fluoro-4-iodophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid (50 mg, 0.11 mmol), 1N. an aqueous solution of NaOH (0.12 ml, 0.12 mmol) and ethanol (2 ml) are heated at 65 ° C for 45 minutes. The reaction mixture was concentrated and then subjected to azeotropic distillation with toluene (2 × 2 ml) to obtain a solid residue. The solid residue was dissolved in anhydrous THF (2 ml) and O - ((R) -2,2-dimethyl [1,3] dioxolan-4-ylmethyl) hydroxylamine (27 mg, 0.23 mmol) was added, EDCI (27 mg 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59 μl, 0.34 mmol). After stirring for 19 hours, the solvent was evaporated and the residue was taken up in ethyl acetate (30 ml) and water (20 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane: ethyl acetate, gradient 80:20 to 50:50) to give the title compound as a yellow solid (18 mg, 30%). LCMS (method B): R _T = 3.09 min, M + H ⁺ = 544.

((R) -2,3-dihydroxypropoxy) amide 3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid

((R) -2,2-Dimethyl [1,3] dioxolan-4-ylmethoxy) amide 3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (18 mg , 0.03 mmol) was dissolved in methanol (1 ml) and concentrated hydrochloric acid (1 drop) was added. The mixture was stirred for 2 hours and then evaporated to dryness to give a residue. The residue was treated with aqueous saturated NaHCO ₃ solution (10 ml), water (20 ml) and DCM (20 ml). The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give a yellow solid. The solid was purified by flash chromatography (Si-SPE, DCM: MeOH, gradient 98: 2 to 92: 8) to give the title compound as a yellow solid (8 mg, 50%). LCMS (method A): R _T = 6.32 min, M + H ⁺ = 504. ¹ H NMR (d ₄ -MeOH, 400 MHz) 8.56 (s, 1H), 8.34 (d, J = 5.7 Hz, 1H), 7.87 (d, J = 5.7 Hz, 1H), 7.45 (dd, J = 10.5 Hz, 1.8 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.61 (dd, J = 8, 5 Hz, 8.5 Hz), 3.89-3.94 (m, 1H), 3.76-3.85 (m, 2H), 3.45-3.54 (m, 2H).

Example 6

((R) -2,2-Dimethyl [1,3] dioxolan-4-ylmethoxy) amide 3- (4-bromo-2-fluorophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid

A mixture of ethyl 3- (4-bromo-2-fluorophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (36 mg, 0.09 mmol), 1N. aqueous NaOH (0.10 ml, 0.10 mmol) and methanol (2 ml) are heated at 65 ° C for 45 minutes. The reaction mixture was concentrated and then subjected to azeotropic distillation with toluene (2 × 2 ml) to obtain a solid residue. The solid residue was dissolved in anhydrous THF (2 ml) and O - ((R) -2,2-dimethyl [1,3] dioxolan-4-ylmethyl) hydroxylamine (22 mg, 0.18 mmol) was added, EDCI (22 mg , 0.12 mmol), HOBt (17 mg, 0.13 mmol) and DIPEA (48 μl, 0.28 mmol). After stirring overnight at ambient temperature, the reaction mixture was concentrated in vacuo to give a yellow residue. The resulting residue was dissolved in ethyl acetate (30 ml), the solution was washed with water (20 ml) and then with brine (10 ml), then the organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane: ethyl acetate, 90:10 to 50:50 gradient) to give the title compound as a yellow oil (18 mg, 41%). LCMS (method B): R _T = 3.03 min, M + H ⁺ = 496/498.

((R) -2,3-dihydroxypropoxy) amide 3- (4-bromo-2-fluorophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid

A solution of ((R) -2,2-dimethyl [1,3] dioxolan-4-ylmethoxy) amide 3- (4-bromo-2-fluorophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (18 mg, 0.036 mmol) in methanol (1 ml) was loaded into an isolute® SCX-2 cartridge (5 g). Then the cartridge is washed with methanol (15 ml), then the desired product is eluted using a 2M solution of ammonia in MeOH, then the collected eluent is concentrated and a residue is obtained. The residue was purified by flash chromatography (Si-SPE, DCM: MeOH, gradient from 100: 0 to 94: 6) to give the title compound as an off-white solid (9 mg, 53%). LCMS (method A): R _T = 5.59 min, M + H ⁺ = 456/458. ¹ H NMR (d _4- MeOH, 400 MHz) 8.60 (s, 1H), 8.40 (d, J = 5.7 Hz, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.39 (dd, J = 10.6 Hz, 2.2 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.80 (dd, J = 8, 5 Hz, 1H), 4.01-4.10 (m, 1H), 3.89-4.00 (m, 2H), 3.57-3.67 (m, 2H).

Example 7

3-Chloroisonicotinic Acid Ethyl Ester

A suspension of 3-chloroisonicotinic acid (1.0 g, 6.35 mmol) in thionyl chloride (10 ml) was refluxed for 2.5 hours. After cooling to ambient temperature, the solution was concentrated to dryness, then the residue was subjected to azeotropic distillation with toluene (10 ml) to obtain an oil. The resulting oil was added dropwise over 10 minutes to a chilled (0 ° C.) mixture of ethanol (15 ml) and DIPEA (5 ml). The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and water (20 ml) was added. The solution was extracted with ethyl acetate (30 ml), the organic phase was dried over sodium sulfate and then concentrated to obtain the title compound as an orange oil (1.1 g, 94%). ¹ H NMR (CDCl ₃ , 400 MHz) 8.72 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 7.63 (dd, J = 4.9 Hz, 0, 5 Hz, 1H), 4.44 (q, J = 7.3 Hz, 2H), 1.42 (t, J = 7.3 Hz, 3H).

3-hydroxythieno [2,3-c] pyridine-2-carboxylic acid ethyl ester

To a chilled (5 ° C) solution of 3-chloroisonicotinic acid ethyl ester (1.11 g, 6.0 mmol) and mercaptoacetic acid ethyl ester (1.8 ml, 16.7 mmol) in anhydrous DMF (20 ml) with stirring in an argon atmosphere, sodium hydride (15.6 mmol, 60% dispersion in oil, 622 mg) is added in portions over 20 minutes. Stirring is continued at 5 ° C for 20 minutes and then for 18 hours at room temperature. Then the reaction was quenched by adding water (5 ml), the reaction mixture was acidified by adding acetic acid (1 ml), then concentrated and a residue was obtained. The residue was taken up in ethyl acetate (150 ml) and water (50 ml). The organic phase is dried over sodium sulfate, filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane: ethyl acetate, gradient from 80:20 to 30:70) to give the title compound as a yellow solid (1.33 g, 99%). LCMS (method B): R _T = 2.57 min, M + H ⁺ = 224.

3- (nonafluorobutane-1-sulfonyloxy) thieno [2,3-c] pyridine-2-carboxylic acid ethyl ester

To a solution of 3-hydroxythieno [2,3-c] pyridine-2-carboxylic acid ethyl ester (950 mg, 4.26 mmol) and DMAP (26 mg, 0.21 mmol) in DCM (12 ml) with stirring at 0 ° C, DIPEA (1.8 ml, 10.2 mmol) and nonafluorobutylsulfonyl chloride (0.99 ml, 5.53 mmol) are added. After 10 minutes, the reaction mixture was warmed to room temperature and stirred for another 20 hours. The reaction mixture was diluted with DCM (30 ml) and washed with water (20 ml). The organic phase was dried over sodium sulfate, filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane: diethyl ether, gradient 90:10 to 65:35) to give the title compound as a colorless oil, which crystallized upon standing (678 mg, 31%). LCMS (method B): R _T = 4.49 min, M + H ⁺ = 508.

3- (4-Bromo-2-fluorophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid ethyl ester

Degassed solution of ethyl 3- (nonafluorobutane-1-sulfonyloxy) thieno [2,3-c] pyridine-2-carboxylic acid (678 mg, 1.33 mmol), 4-bromo-2-fluoroaniline (329 mg, 1, 73 mmol), Pd ₂ dba ₃ (61 mg, 0.07 mmol), xanthos (78 mg, 0.14 mmol) and DBU (509 μl, 3.35 mmol) in toluene (3 ml) are subjected to microwave irradiation at 150 ° C for 10 minutes. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (70 ml). The resulting solution was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo to give an orange oil. The oil was purified by flash chromatography (Si-SPE, pentane: diethyl ether, gradient 90:10 to 50:50), followed by crystallization from ethyl acetate: pentane to give the title compound as a white solid (353 mg, 67 %). LCMS (method B): R _T = 4.08 min, M + H ⁺ = 395/397.

3- (2-Fluoro-4-iodophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid ethyl ester

A mixture of 3- (4-bromo-2-fluorophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid ethyl ester (288 mg, 0.73 mmol), copper (I) iodide (7 mg, 0.036 mmol) , sodium iodide (219 mg, 1.46 mmol) and trans-N, N'-dimethyl-1,2-cyclohexanediamine (10.4 mg, 0.073 mmol) in 1,4-dioxane (1.0 ml) are heated at 105 ° C for 24 hours in an argon atmosphere. Copper (I) iodide (7 mg, 0.036 mmol) and trans-N, N'-dimethyl-1,2-cyclohexanediamine (10.4 mg, 0.073 mmol) are added and heating is continued for another 24 hours. The reaction mixture was cooled to room temperature and the mixture was treated with DCM (30 ml) with concentrated aqueous ammonia (2 ml) and water (13 ml). The organic layer was separated, dried over sodium sulfate, filtered and evaporated, then the residue was purified by flash chromatography (Si-SPE, DCM) to give the title compound as a yellow solid (275 mg, 85%). LCMS (method B): R _T = 4.23 min, M + H ⁺ = 443.

((R) -2,2-Dimethyl [1,3] dioxolan-4-ylmethoxy) amide 3- (2-fluoro-4-iodophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid

A mixture of ethyl ester of 3- (2-fluoro-4-iodophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid (50 mg, 0.11 mmol), 1N. an aqueous solution of NaOH (0.12 ml, 0.12 mmol) and ethanol (2 ml) are heated at 65 ° C for 45 minutes. The reaction mixture was concentrated and then subjected to azeotropic distillation with toluene (2 × 2 ml) and a solid residue was obtained. The solid residue was dissolved in anhydrous THF (4 ml) and O - ((R) -2,2-dimethyl [1,3] dioxolan-4-ylmethyl) hydroxylamine (27 mg, 0.23 mmol), EDCI (27 mg) were added. 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59 μl, 0.34 mmol). After stirring for 19 hours, the solvent was evaporated and the residue was taken up in ethyl acetate (20 ml) and water (15 ml). The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give a brown oil. The oil was purified by flash chromatography (Si-SPE, pentane: ethyl acetate, gradient 80:20 to 0: 100) to give the title compound as an orange oil (40 mg, 66%). LCMS (method B): R _T = 3.30 min, M + H ⁺ = 544.

((R) -2,3-dihydroxypropoxy) amide 3- (2-fluoro-4-iodophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid

((R) -2,2-Dimethyl [1,3] dioxolan-4-ylmethoxy) amide 3- (2-fluoro-4-iodophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid (40 mg , 0.07 mmol) was dissolved in methanol (1 ml) and concentrated hydrochloric acid (1 drop) was added. The mixture was stirred for 2 hours and then evaporated to dryness to give a residue. The residue was treated with aqueous saturated NaHCO ₃ solution (3 ml), water (20 ml) and DCM (20 ml). The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give a yellow solid. The solid was purified by flash chromatography (Si-SPE, DCM: MeOH, gradient 99: 1 to 92: 8) to give the title compound as a yellow solid (21 mg, 57%). LCMS (method A): R _T = 7.12 min, M + H ⁺ = 504. ¹ H NMR (d ₄ -MeOH, 400 MHz) 9.15 (s, 1H), 8.38 (d, J = 5.7 Hz, 1H), 7.52 (dd, J = 10.6 Hz, 2.0 Hz, 1H), 7.44 (dd, J = 5.7 Hz, 1.0 Hz, 1H), 7.32 (ddd, J = 8.5 Hz, 2.0 Hz, 1.0 Hz, 1H), 6.56 (dd, J = 8.5 Hz, 8.5 Hz, 1H), 4.00-4.13 (m, 1H), 3.85-3.95 (m, 2H ), 3.54-3.65 (m, 2H).

Example 8

((R) -2,2-Dimethyl [1,3] dioxolan-4-ylmethoxy) amide 3- (4-bromo-2-fluorophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid

A mixture of ethyl 3- (4-bromo-2-fluorophenylamino) thieno [2,3-c] pyridine-2-carboxylate (63 mg, 0.16 mmol), 1N aqueous NaOH solution (0.17 ml, 0.17 mmol) and ethanol (2 ml) are heated at 65 ° C for 45 minutes. The resulting reaction mixture was concentrated in vacuo, then the residue was subjected to azeotropic distillation with toluene (2 × 2 ml) and a solid residue was obtained. The resulting solid residue was suspended in anhydrous THF (2 ml) and then O - ((R) -2,2-dimethyl [1,3] dioxolan-4-ylmethyl) hydroxylamine (38 mg, 0.32 mmol) was added, EDCI ( 38 mg, 0.20 mmol), HOBt (30 mg, 0.22 mmol) and DIPEA (83 μl, 0.48 mmol). After stirring for 66 hours at ambient temperature, the reaction mixture was concentrated in vacuo to give a yellow residue. The resulting residue was dissolved in ethyl acetate (50 ml), the solution was washed with water (20 ml), then the organic layer was separated, dried over sodium sulfate, then concentrated in vacuo to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane: ethyl acetate, gradient from 60:40 to 0: 100) to give the title compound as a yellow foam (61 mg, 77%). LCMS (method B): R _T = 3.02 min, M + H ⁺ = 496/498.

((R) -2,3-dihydroxypropoxy) amide 3- (4-bromo-2-fluorophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid

A solution of ((R) -2,2-dimethyl [1,3] dioxolan-4-ylmethoxy) amide 3- (4-bromo-2-fluorophenylamino) thieno [2,3-c] pyridine-2-carboxylic acid (61 mg, 0.12 mmol) and 1 drop of concentrated HCl in methanol (2 ml) was stirred at ambient temperature for 2 hours. The solvent was evaporated in vacuo and the resulting residue was treated with dichloromethane (20 ml), water (10 ml) and saturated NaHCO ₃ solution (3 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The resulting yellow oil was purified by flash chromatography (Si-SPE, DCM: MeOH, gradient 99: 1 to 92: 8), followed by trituration in a methanol / acetonitrile mixture to afford the title compound as an off-white solid (15 mg , 26%). LCMS (method A): R _T = 6.01 min, M + H ⁺ = 456/458. ¹ H NMR (d ₄ -MeOH, 400 MHz) 9.16 (d, J = 0.8 Hz, 1H), 8.38 (d, J = 5.8 Hz, 1H), 7.37-7, 46 (m, 2H), 7.17 (ddd, J = 8.6 Hz, 2.3 Hz, 2.2 Hz, 1H), 6.72 (dd, J = 8.7 Hz, 8.7 Hz , 1H); 4.00-4.05 (m, 1H); 3.84-3.96 (m, 2H); 3.53-3.64 (m, 2H).

Example 9

3- (2-Fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (2-vinylethoxy) amide

A mixture of ethyl ester of 3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (124 mg, 0.28 mmol), 1N. aqueous NaOH (0.30 ml, 0.30 mmol) and ethanol (4 ml) are heated at 65 ° C. for 45 minutes. The reaction mixture was concentrated in vacuo, then the resulting residue was subjected to azeotropic distillation with toluene (2 × 2 ml) and a solid residue was obtained. The solid residue was dissolved in anhydrous THF (4 ml) and then O- (2-vinyloxyethyl) hydroxylamine (58 mg, 0.56 mmol), EDCI (67 mg, 0.35 mmol), HOBt (53 mg, 0.39) were added. mmol) and DIPEA (147 μl, 0.84 mmol). After stirring for 18 hours at ambient temperature, the solvent was evaporated, the resulting residue was diluted with water (20 ml), then extracted with ethyl acetate (30 ml) and then dichloromethane (30 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a yellow oil. The resulting yellow oil was purified by flash chromatography (Si-SPE, dichloromethane: methanol, gradient from 100: 0 to 98: 2) to give the title compound as a yellow solid (91 mg, 65%). LCMS (method B): R _T = 3.05 min, M + H ⁺ = 500.

Example 10

3- (2-Fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (2-hydroxyethoxy) amide

3- (2-Fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (2-vinylethoxy) amide (91 mg, 0.18 mmol) was dissolved in ethanol (2 ml) and 1M was added hydrochloric acid (0.5 ml). The mixture was stirred for 2 hours, then evaporated to dryness and a residue was obtained. The resulting residue was treated with aqueous saturated NaHCO ₃ solution (3 ml), water (20 ml) and DCM (20 ml). The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give a yellow solid. The resulting yellow solid was purified by flash chromatography (Si-SPE, DCM: MeOH, gradient 100: 0 to 98: 2) and then reverse phase HPLC (Phenomenex Luna 5 phenyl / hexyl, 0.1% TFA in water at a gradient with methanol from 95: 5 to 40:60) to give the title compound as a yellow solid (34 mg, 40%). LCMS (method A): R _T = 6.00 min, M + H ⁺ = 474. ¹ H NMR (d _4- MeOH, 400 MHz) 8.68 (d, J = 5.7 Hz, 1H), 7.98 (dd, J = 5.7 Hz, 0.8 Hz, 1H), 7 55 (dd, J = 10.5 Hz, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 6.7 (dd, J = 8.5 Hz, 8.5 Hz , 1H), 3.98 (t, J = Hz, 2H), 3.74 (t, J = Hz, 2H).

Example 11

3-amino-7-fluorothieno [3,2-c] pyridine-2-carboxylic acid ethyl ester

Ethyl thioglycolate (0.73) was added dropwise to a mixture of 4-chloro-5-fluoro-nicotinonitrile (1.0 g, 6.4 mmol) and potassium carbonate (4.4 g, 32 mmol) in DMF (15 ml) at 0 ° C. ml, 6.7 mmol). The reaction mixture was stirred at 0 ° C for 10 minutes, at room temperature for 20 minutes, and then at 40 ° C for 30 minutes. The reaction mixture was cooled to room temperature and treated with water and ethyl acetate. The organic layer was separated and washed with water, then with brine, dried over sodium sulfate and concentrated to give the title compound as a yellow solid (1.5 g, quantitative). LCMS (method B): R _T = 3.41 min, M + H ⁺ = 241.

7-fluoro-3- (2-fluoro-4-trimethylsilanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester

Mixture of 3-amino-7-fluorothieno [3,2-c] pyridine-2-carboxylic acid ethyl ester (360 mg, 1.5 mmol), 2-fluoro-4-trimethylsilanylphenyl trifluoromethanesulfonic acid ester (411 mg, 1.3 mmol), Pd ₂ dba ₃ (69 mg, 0.075 mmol), xanthos (86 mg, 0.15 mmol) and Cs ₂ CO ₃ (685 mg, 2.1 mmol) in toluene (6 ml) are subjected to microwave irradiation at 160 ° C for 20 minutes. The reaction mixture was filtered through a celite® pad. The filtrate was concentrated under reduced pressure to obtain a residue which was flash chromatographed (Si-SPE, pentane: diethyl ether, gradient from 100: 0 to 90:10) to give the title compound as a yellow solid (338 mg, 55 %). LCMS (method B): R _T = 5.20 min, M + H ⁺ = 407.

7-fluoro-3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester

To a chilled (0 ° C) solution of 7-fluoro-3- (2-fluoro-4-trimethylsilanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester (330 mg, 0.81 mmol) in DCM (10 ml) was added dropwise a 1M solution of iodine monochloride in DCM (1.6 ml, 1.6 mmol). Upon completion of the addition, the mixture was stirred at 0 ° C. for 1 hour, and then the reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 ml). The mixture was vigorously stirred for 10 minutes and treated with ethyl acetate and water. The organic layer was separated and washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (358 mg, 54%.). LCMS (method B): R _T = 4.72 min, M + H ⁺ = 461.

(2-Vinyloxyethoxy) amide 7-fluoro-3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid

To a solution of 7-fluoro-3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester (175 mg, 0.38 mmol) in IMS (4 ml) was added 1 , 0M aqueous sodium hydroxide solution (0.5 ml, 0.5 mmol). The reaction mixture was heated at 65 ° C for 1 hour, then cooled to room temperature and concentrated in vacuo. The resulting residue was subjected to azeotropic distillation with toluene (3 × 10 ml) and then the residue was suspended in THF (5 ml). Then, O- (2-vinyloxyethyl) hydroxylamine (78 mg, 0.76 mmol), N, N-diisopropylethylamine (0.26 ml, 1.52 mmol), EDCI (146 mg, 0.76 mmol) and HOBt are successively added. (103 mg, 0.76 mmol) and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was treated with water and ethyl acetate. The organic layer was separated and washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (Si-SPE, gradient 0-2% methanol in DCM) to obtain the title compound as a pale yellow solid (106 mg, 54%). LCMS (method B): R _T = 3.92 min, M + H ⁺ = 518.

(2-Hydroxyethoxy) amide 7-fluoro-3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid

Solution of (2-vinyloxyethoxy) amide 7-fluoro-3- (2-fluoro-4-iodophenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (100 mg, 0.19 mmol) in a mixture of methanol and DCM loaded into a cartridge with 5 g of SCX-2, which is eluted with methanol and then with a 2M solution of ammonia in methanol. The appropriate fractions are combined and concentrated under reduced pressure. The remaining solid was purified by column chromatography (Si-SPE, gradient 0-40% tert-butyl dimethyl ether in DCM, then a mixture of 10% methanol in DCM) to give the title compound as a yellow solid (50 mg, 53%). LCMS (method A): R _T = 9.60 min, M + H ⁺ = 492. ¹ H NMR (CD ₃ OD, 400 MHz) 3.58 (2H, t, J = 4.89 Hz), 3.84 (2H, t, J = 4.91 Hz), 6.89 (1H, t , J = 8.76 Hz), 6.98 (1H, dd, J = 8.41, 2.15 Hz), 7.21-7.26 (1H, m), 8.02 (1H, d, J = 5.61 Hz), 8.45 (1H, dd, J = 8.25, 5.61 Hz), 8.53-8.59 (1H, m).

Example 12

3- (2-Fluoro-4-methylsulfanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester

Degassed solution of 3- (nonafluorobutane-1-sulfonyloxy) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester (0.74 g, 1.5 mmol), 2-fluoro-4-methylsulfanylphenylamine (0.12 g, 0.76 mmol), Pd ₂ dba ₃ (0.035 g, 0.038 mmol), xanthos (0.044 g, 0.076 mmol) and K ₃ PO ₄ (0.32 g, 1.5 mmol) in toluene (10 ml) refluxed for 18 hours. The reaction mixture was cooled to ambient temperature and then filtered through a layer of guillo, washing with ethyl acetate. The filtrate was concentrated in vacuo, the resulting residue was flash chromatographed (Si-SPE, 0-10% ethyl acetate in dichloromethane gradient) to give the title compound as a yellow solid (0.16 g, 57%). LCMS (method B): R _T = 3.84 min, M + H ⁺ = 363.

3- (2-Fluoro-4-methylsulfanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid

A suspension of 3- (2-fluoro-4-methylsulfanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester (0.19 g, 0.52 mmol) in IMS (10 ml) is treated with sodium hydroxide (1M aqueous solution, 0.63 ml) and the reaction mixture is heated at 60 ° C for 3 hours. The resulting mixture was cooled and then concentrated in vacuo. The crude residue is treated with water and the mixture is adjusted to pH 5 with acetic acid. The resulting suspension was filtered, the residue was separated and dried in vacuo to give the title compound as a green solid (0.107 g, 56%), which was used in the next step without further purification.

(2-Vinyloxyethoxy) amide 3- (2-fluoro-4-methylsulfanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid

A suspension of 3- (2-fluoro-4-methylsulfanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (0.107 g, 0.32 mmol) in dry dichloromethane (5 ml) under nitrogen atmosphere is cooled to 0 ° C and treated with DMF (1 drop) and oxalyl chloride (0.081 ml, 0.96 mmol). The reaction mixture was stirred for 1 hour and then the solvent was removed in vacuo. The resulting residue was resuspended in dry dichloromethane (1 ml) and treated dropwise with a solution of O- (2-vinyloxyethyl) hydroxylamine (0.066 g, 0.64 mmol) and DIPEA (0.167 ml, 0.96 mmol) in dry dichloromethane ( 4 ml), and then stirred for 18 hours. The reaction mixture was washed (water, brine), dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting residue was flash chromatographed (Si-SPE, 0-30% ethyl acetate in dichloromethane gradient) to give the title compound as a yellow solid (0.024 g, 18%). LCMS (method B): R _T = 3.17 min, M + H ⁺ = 420.

3- (2-Fluoro-4-methylsulfanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (2-hydroxyethoxy) amide

(2-Vinyloxyethoxy) amide 3- (2-fluoro-4-methylsulfanylphenylamino) thieno [3,2-c] pyridine-2-carboxylic acid (20 mg, 0.048 mmol) was dissolved in methanol (1 ml), treated with concentrated hydrochloric acid (0.01 ml, 0.12 mmol) and then stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue was subjected to reverse phase HPLC (0.1% HCO ₂ N in water, in a gradient of acetonitrile). The appropriate fractions were combined and freeze dried to give the title compound (9 mg, 47%). LCMS (method A): R _T = 6.36 min, M + H ⁺ = 394. ¹ H-NMR (DMSO-d ₆ , 400 MHz) 3.58 (2H, t, J = 4.89 Hz), 3.84 (2H, t, J = 4.91 Hz), 6.89 (1H , t, J = 8.76), 6.98 (1H, dd, J = 8.41, 2.15 Hz), 7.21-7.26 (1H, m), 8.02 (1H, d , J = 5.61 Hz), 8.45 (1H, dd, J = 8.25, 5.61 Hz), 8.53-8.59 (1H, m).

Claims (11)

1. The compound of formula I

and its salts,
where Z ¹ represents CR ¹ ;
Z ² represents N;
Z ³ represents CR ³ ;
Z ⁴ represents CR ⁴ ;
R ¹ , R ³ and R ^{4 are} independently selected from H or halogen;
W represents

R ⁵ and R ⁶ are H;
X ¹ represents —OR ¹¹ ;
X ² represents phenyl optionally substituted with one or two groups selected from halogen or (C ₁ -C ₃ ) alkylsulfanyl;
R ¹¹ is (C ₁ -C ₁₂ ) alkyl substituted with one or two groups independently selected from - (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ ;
n is 0;
R ¹⁶ represents H, (C ₁ -C ₁₂ ) alkyl or (C ₂ -C ₈ ) alkenyl. 2. The compound according to claim 1, where X ^{1 is} selected from

3. The compound according to claim 1, where X ^{1 is} selected from

4. The compound according to claim 1, where X ² represents

5. The compound according to claim 1, where R ^{1 is} selected from H or Cl. 6. The compound according to claim 1, where R ³ selected from H or halogen. 7. The compound according to claim 1, where R ⁴ selected from H or halogen. 8. The compound according to claim 7, where R ^{4 is} selected from Cl, Br or F. 9. A compound selected from:

10. A pharmaceutical composition for treating a hyperproliferative disorder comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier. 11. A method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition of claim 10.