RU2483069C2 - Azaindolizines and methods for preparing them - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel azoindolizines or pharmaceutically acceptable salts thereof having Mek-kinase inhibitory activity in formula

: Z^A means CR^A; R^A means H or halogen; each of R¹, R² and R³ means H; W means:

, each R⁴ and R⁵ means H; X¹ represents -OR⁷; each R⁷ means C₂-C₁₂-hydroxyalkyl, 2,3-dihydroxypropyl, C₂-C₃-alkenoxyC₁-C₆-alkoxy, (2,2-dimethyl-[1,3]dioxalan-4-yl)-methyl or piperidinyl; X⁴ means:

R⁶ means halogen or -SR¹⁶; R⁶ means halogen; p is equal to 1; R¹⁶ means C₁-C₁₂-alkyl.

EFFECT: invention relates to a pharmaceutical compositions containing these compounds, to a method of inhibiting the abnormal cell growth and the use of the compounds for preparing a drug preparation for inhibiting the abnormal cell growth.

9 cl, 10 ex

Description

Cross reference to related applications

This application claims priority based on provisional patent application US No. 61/015942, filed December 21, 2007, the contents of which in its entirety are incorporated into this description by reference.

FIELD OF THE INVENTION

The present invention relates to azaindolysins with anticancer activity and, more particularly, to azaindolysins that inhibit the activity of MEK kinase. The present invention also relates to methods of using the compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells or associated pathological conditions.

BACKGROUND OF THE INVENTION

In search of an understanding of how Ras transmits extracellular signals to growth, the MAP (mitogen-activated protein) kinase (MAPK) pathway appears as a very important pathway between the Ras membrane-bound and the nucleus. The MAPK pathway encompasses 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 activation and indirect phosphorylation of Raf kinase. Raf then phosphorylates MEK1 and MEK2 to two serine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (Ahn et. Al., Methods in Enzymology, 2001, 332, 417-431). Activated MEK then phosphorylates only its known substrates, MAP kinases, ERK1 and ERK2. ERK phosphorylation by MEK occurs in Y204 and T202 in the case of ERK1 and in Y185 and T183 in the case of ERK2 (Ahn et. Al., Methods in Enzymology, 2001, 332, 417-431). Phosphorylated ERK dimerizes and then translocates to 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 transport, signal transduction, DNA repair, nucleosome assembly and translocation, and mRNA processing and translation (Ahn et. Al., Molecular Cell, 2000, 6, 1343-1354). Everywhere, treatment of cells with growth factors leads to activation of ERK1 and ERK2, resulting in proliferation and, in some cases, differentiation (Lewis et. Al., Adv. Cancer Res., 1998, 74, 49-139).

It has been convincingly proven that genetic mutations and / or overexpression of protein kinases involved in the MAP kinase pathway lead to uncontrolled cell proliferation and, ultimately, to the formation of a tumor in proliferative diseases. For example, some cancers include mutations that result in continuous activation of this pathway due to the continuous production of growth factors. Other mutations can lead to defects in the deactivation of the activated complex of GTP-linked Ras, again leading to the activation of the MAP kinase pathway. Mutated oncogenic forms of Ras have been found in 50% of colon cancers and> 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 the case of more than 60% malignant melanoma (Davies H., et. Al., Nature, 2002, 417, 949-954). These mutations in bRaf result in a constitutively active cascade of MAP kinases. Studies of primary tumor samples and cell lines also indicate a constitutive or overactive MAP kinase pathway for cancer of the pancreas, colon, lung, ovary and kidney (Hoshino R., et. Al., Oncogene, 1999, 18, 813-822) .

MEK appears as an attractive therapeutic target in the case of the pathway of the MAP kinase cascade. MEK, located downstream of Ras and Raf during transcription, is very specific for phosphorylation of MAP kinase; indeed, only known substrates for MEK phosphorylation are MAP kinases, ERK1 and ERK2. Inhibition of MEK has been shown to have potential therapeutic benefits in some studies. For example, small molecules of MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts (Sebolt-Leopold et. Al., Nature-Medicine, 1999, 5 (7), 810-816); Trachet et. al., AACR, April 6-10, 2002, abstract No. 5426; Tecle H., IBC 2.sup.nd International Conference of Protein Kinases, September 9-10, 2002), block static allodynia in animals (WO 01/05390, published January 25, 2001) and inhibit cell growth in acute myeloid leukemia ( Milella et. Al., J. Clin. Invest., 2001, 108 (6), 851-859).

Some small molecules of MEK inhibitors have also been discussed, for example, in WO 02/06213, WO 03/077855 and WO 03/077914. However, there is a need for new MEK inhibitors as effective and safe therapeutic agents for the treatment of a variety of proliferative disease statuses, such as conditions associated with MEK hyperactivity, as well as diseases modulated by the MEK cascade.

Summary of the invention

This invention generally relates to azaindolysins of formula I-a or I-b (and / or their solvates, hydrates and / or salts) with anti-cancer and / or anti-inflammatory activity and, more specifically, with MEK kinase inhibitory activity. Some hyperproliferative and inflammatory disorders are characterized by modulation of the function of the MEK kinase, for example, by mutations or overexpression of proteins. Therefore, the compounds of this invention and compositions containing them are suitable for the treatment of hyperproliferative disorders, such as cancer and / or inflammatory diseases, such as rheumatoid arthritis.

Where

Z ^A means CR ^A or N;

R ^A is H, CF ₃ , halogen, C ₁ -C ₆ alkyl or CN;

each of R ¹ , R ² and R ³ independently means H, C ₁ -C ₆ -alkyl, halogen, CN, CF ₃ , - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ , -OR ¹⁶ , -SR ¹⁶ or -C (= O) NR ¹⁶ R ¹⁷ ;

W means:

или

or

R ⁴ and R ⁵ independently mean H or C ₁ -C ₁₂ alkyl;

X ^{1 is} selected from R ⁷ and —OR ⁷ ; when X ¹ is R ⁷ , then X ¹ (i.e., R ⁷ ), optionally, together with R ⁵ and 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, wherein said cycle is optionally substituted with one or more groups selected from halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, - (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 ¹⁶ ;

each R ⁷ independently means H, C ₁ -C ₁₂ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl;

X ⁴ means:

R ⁶ is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, carbocyclyl, heteroaryl, heterocyclyl, —OCF ₃ , —NO ₂ , —Si (C ₁ -C ₆ -alkyl), - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ or - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ ;

R ^{6 '} is H, halogen, C ₁ -C ₆ alkyl, carbocyclyl, CF ₃ , -OCF ₃ , -NO ₂ , -Si (C ₁ -C ₆ alkyl), - (CR ¹⁹ R ²⁰ ) _n NR ¹⁶ R ¹⁷ , - (CR ¹⁹ R ²⁰ ) _n OR ¹⁶ , - (CR ¹⁹ R ²⁰ ) _n SR ¹⁶ , C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, heterocyclyl, aryl or heteroaryl;

p is 0, 1, 2 or 3;

each n independently means 0, 1, 2 or 3;

where each specified alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{6 '} , R ⁷ and R ^{A are} independently 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 ¹⁶ ;

each R ¹⁶ , R ¹⁷ and R ¹⁸ independently means H, C ₁ -C ₁₂ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein 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), -N HSO 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) NH (C ₁ -C ₆ -alkyl), -NHC (O) N (C ₁ -C ₆ -alkyl) ₂ , -NHC (O ) O (C ₁ -C ₆ alkyl) and -N (C ₁ -C ₆ alkyl) C (O) O (C ₁ -C ₆ alkyl);

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, wherein said ring 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 - 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) NH (C ₁ -C ₆ alkyl), -NHC (O) N (C ₁ -C ₆ -alkyl) ₂ , -NHC (O) O (C ₁ -C ₆ -alkyl) and -N (C ₁ -C _6- alkyl) C (O) O (C ₁ -C ₆ -alkyl);

R 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;

each Y ′ independently is O, NR ²¹ or S; and

R ²¹ means H or C ₁ -C ₁₂ -alkyl.

The present invention relates to a composition (eg, a pharmaceutical composition) comprising a compound of formula I-a or I-b (and / or its solvates, hydrates and / or salts) and a carrier (pharmaceutically acceptable carrier). The present invention also relates to a composition (eg, a pharmaceutical composition) comprising a compound of formula Ia or Ib (and / or its solvates, hydrates and / or salts) and a carrier (pharmaceutically acceptable carrier), further comprising a second chemotherapeutic agent and / or a second anti-inflammatory means. The compositions of the present invention are suitable for inhibiting abnormal cell growth or for treating a hyperproliferative disorder in a mammal (e.g., human). The compositions of the present invention are also suitable for the treatment of inflammatory diseases in a mammal (e.g., a 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 Ia or Ib (and / or its solvates and salts) or a composition containing it, individually 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 Ia or Ib (and / or its solvates and salts) or a composition containing it, individually or in combination with a second anti-inflammatory agent .

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

Detailed Description of Typical Embodiments

The following is a detailed description of some embodiments of the present invention, examples of which are illustrated using the accompanying structures and formulas. Although the invention will be described in conjunction with the listed embodiments, it should be understood that the invention is not limited to these embodiments. On the contrary, it is intended that this invention covers all alternatives, modifications, and equivalents that may be included within the scope of the present invention as set forth in the claims. A person skilled in the art knows 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 included literature, patents and similar materials differs from or contradicts this application, including, but not limited to, certain terms, use of terms, described methods or the like, this is controlled in this application .

Definitions

The term "alkyl", as used herein, refers to a saturated monovalent straight or branched chain 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 (i-Pr, isopropyl, -CH (CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, isobutyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl (s-Bu, sec-butyl, -CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl ( t-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 ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl ( -CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-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, and the like.

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

The term "alkynyl" refers to a monovalent straight or branched chain hydrocarbon radical with two to twelve carbon atoms, with at least one unsaturation site, i.e., a carbon-carbon sp-triple bond. 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 having 3-12 carbon atoms, in the form of a monocycle, or 7-12 carbon atoms, in the form of a bicycle. Bicyclic carbocycles having 7-12 carbon atoms can be classified, for example, as a bicyclo [4,5] -, [5,5] -, [5,6] - or [6,6] system, and bicyclic carbocycles, having 9 or 10 ring atoms can be classified as a bicyclo [5,6] - or [6,6] system, or as bridged 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 obtained by removing one hydrogen atom from one carbon atom of the original aromatic ring system. Some aryl groups are presented in the form of typical structures, like "Ar". Aryl includes bicyclic radicals containing an aromatic ring fused to a saturated, partially unsaturated ring or an aromatic carbocycle or heterocycle. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.

The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” are used interchangeably herein, and they refer to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds in a ring) carbocyclic radical with 3 -18 atoms of the cycle, in which at least one atom of the cycle is a heteroatom selected from an atom of nitrogen, oxygen and sulfur, and the remaining atoms of the cycle mean carbon atoms, where one or more atoms of the cycle are independently optionally substituted by one or more substituents, opio annymi below. The heterocycle can be a monocycle having 3-7 members of the cycle (2-6 carbon atoms and 1-4 heteroatoms selected from N, O, P and S), or a bicycle having 7-10 members of the cycle (4-9 carbon atoms and 1-6 heteroatoms selected from N, O, P and S), for example, a bicyclo [4,5] -, [5,5] -, [5,6] - or [6,6] -system. Heterocycles are described by Paquette, Leo A .; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), especially chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 and to the present), in particular, volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960), 82: 5566. The term “heterocyclyl” also includes radicals, where the heterocycle radicals are fused to a saturated, partially unsaturated ring or aromatic carbocycle or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, tioksanil, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oksepanil, tiepanil, oxazepinyl, diazepinyl , thiazepinyl, 2-pyrroinyl, 3-pyrroinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianil, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pi azolidines, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl and azabicyclo [2.2.2] hexanyl. Spiro residues are also included within the scope of this definition. Examples of a heterocyclic group where the ring atoms are substituted with oxo groups (= O) are pyrimidinonyl and 1,1-dioxothiomorpholinyl.

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

Heterocyclic or heteroaryl groups can be attached at carbon (carbon-linked) or nitrogen (nitrogen-linked), where possible. By way of example, and without limitation, carbon-linked heterocycles or heteroaryls are linked at the 2, 3, 4, 5, or 6 position of pyridine, at the 3, 4, 5, or 6 position of pyridazine, at the 2, 4, 5, or 6 position of pyrimidine, in position 2, 3, 5 or 6 of pyrazine, in position 2, 3, 4 or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, in position 2, 4 or 5 of oxazole, imidazole or thiazole, in position 3, 4 or 5 isoxazole, pyrazole or isothiazole, at position 2 or 3 of aziridine, at position 2, 3 or 4 of azetidine, at position 2, 3, 4, 5, 6, 7 or 8 of quinoline, or at position 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

By way of example and without limitation, nitrogen-binding heterocycles or heteroaryls are linked 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, at position 2 of isoindole or isoindoline, at position 4 of morpholine, and at 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 treatment and prophylactic or preventive measures, where an object needs to prevent or slow down (reduce) an unwanted physiological change or disorder, such as the development or spread of cancer. For the purposes of this invention, favorable or desirable clinical outcomes include, but are not limited to alleviating symptoms, reducing the spread of the disease, stabilizing (i.e., not worsening) the status of the disease, delaying or reducing the development of the disease, reducing the intensity or temporarily alleviating the status of the disease and remission (either partial or complete), either detectable or not detectable. The term “treatment” can also mean prolonged survival, compared to expected survival, if no treatment is received. Patients with the need for treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder, or those in whom the condition or disorder should be prevented.

The phrase “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 the drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or alleviate to some extent one or more symptoms associated with cancer. To some extent, the drug can prevent the growth and / or destroy existing cancer cells, and this drug can be cytostatic and / or cytotoxic. In the case of cancer therapy, efficacy can be determined, for example, by estimating the time to progression of the disease (TTR) and / or determining the response rate (RR).

The terms "abnormal cell growth" and "hyperproliferative disorder" are used interchangeably in this application. The term "abnormal cell growth", as used herein, except as otherwise indicated, refers to cell growth that is independent of the usual regulatory mechanism (eg, loss of contact inhibition). This term includes, for example, the 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 in the case of other proliferative diseases in which aberrant tyrosine kinase is activated; (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 in the case of other proliferative diseases in which aberrant activation of serine / threonine kinase occurs.

The terms "cancer" and "cancer" refer to or describe the physiological condition in mammals, which is usually characterized by unregulated cell growth. A "tumor" includes one or more cancer cells. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or malignant lymphoma. More specific examples of such cancers include squamous cell cancer (eg, epithelial squamous cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma and squamous cell carcinoma, peritoneal cancer, hepatocellular cancer, areas of the stomach or stomach, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, lorectal cancer, endometrial or uterine carcinoma, salivary carcinoma, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, acute leukemia, and head / brain and neck cancer .

A "chemotherapeutic agent" is a compound suitable for the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), sutent (SU11248, Pfizer), letrozole (FEMARA®, Novinimate,) (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, , Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs) and gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide ; alkyl sulfonates such as bisulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquion, meturedopa and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylene melamine, triethylene phosphoramide, triethylene thiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue of topotecan); bryostatin; callistatin; SS-1065 (including its synthetic analogues, adocelesin, carcelesin, and bicelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pankratistatin; sarcodiktiin; spongistatin; chloromethines, such as chlorambucil, chloronafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, fenesterin, prednimustine, trophosphamide, uracil methyl; nitrosureases, such as carmustine, chlorzotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics such as enediin-type antibiotics (e.g. calicheamicin, especially 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 neocarcinostatin chromophore and related chromoprotein enediin antibiotic chromophores), aclacinomisins, actinomycin, autramycin, azaserin, bleomycin, cactinomycin, carabicin, carcinomycinin, carcinomycinin, dacinofincinin 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycinomycinomycephyrincyrinomycinomycephyrycinomycinomycephyrycinomycinomycephyrincyrinomycinomycephyrycinomycinomycephyrycinomycinomycephyrycinomycinomycinomycinomycephyrycinomycinomycephyrincycinomycinomycinomycephyrincycinomycinomycinomycinomycin , tibercidin, 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; antiadrenal agents such as aminoglutethimide, mitotan, trilostane; a folic acid excipient such as frolinic acid; Aceglaton; aldophosphamide glucoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisanthrene; edatraxate; defofamine; demecolcin; diaziquon; elfornithine; elliptinium acetate; epothilone, etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainin; maytansinoids such as maytansine and anzamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pyrarubicin; loxoxantrone; podophyllic acid; 2-ethyl hydrazide; procarbazine; PSK® Polysaccharide Complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sisofiran; spiro germanium; tenuazonic acid; triaziquon; 2,2 ', 2 "trichlorotriethylamine; trichotecenes (especially T-2 toxin, verracirin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobromane; gacitosin; arabinoside (" C "); cyclophosphamide; thiotepa; taxoids such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ™ (cremophorum-free), paclitaxel dosage forms in the form of paclitaxel albumin-bound nanoparticles (American Pharmaceutical Partners, Schaumberg, Illinois) and TAXOTERE® (doxetaxel; Rhône-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; Xanecitabate® CPT-11; RFS 2000 topoisomerase inhibitor; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i) anti-hormonal agents that regulate or inhibit hormonal effects on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifencitrate), raloxifene , droloxifene, 4-hydroxy tamoxifen, trioxifene, keoxifen, LY117018, onapriston and FARESTON® (toremifincitrate); (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), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVOR ® (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-dioxolane-nucleoside-cytosine); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, especially those that inhibit gene expression in signaling pathways involved in aberrant cell proliferation, such as, for example, PKC alpha, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g. ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, such as vaccines for gene therapy, for example, ALLOVECTIN®, LEUVECTIN® and VAXID®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above. Other anti-angiogenic agents include MMP-2 inhibitors (matrix metalloproteinase 2), MMP-9 inhibitors (matrix metalloproteinase 9), COX-II inhibitors (cyclooxygenase II), and VEGF receptor tyrosine kinase inhibitors. Examples of such suitable matrix metalloproteinase inhibitors that can be used in combination with the compounds of the present invention / compositions of the present invention (such as any one of the compounds indicated in the headings of Examples 5-10) are described in International Applications 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, in EP 945864, in US patent 5863949, in US patent 5861510 and EP 780386, all of which are incorporated herein in their entireties by reference. Examples of inhibitors of VEGF receptor tyrosine kinase include 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474; example 2 from WO 01/32651), 4- ( 4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171; example 240 from WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds such as the compounds described in PCT International Publication Nos. 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 (such as any one of the title compounds of Examples 5-10) include PI3K (phosphoinositide-3-kinase) inhibitors, such as those described by Yaguchi et. al., (2006), Jour. of the Nat. Cancer Inst., 98 (8): 545-556; in US patent 7173029; U.S. Patent 7,037,915; U.S. Patent 6,608,056; U.S. Patent 6,608,053; U.S. Patent 6,838,457; U.S. Patent 6,770,641; U.S. Patent 6,653,320; US patent 6403588; U.S. Patent 2008/0242665; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; U.S. 2004/092561; WO 2004/007491; WO 2004/006916; WO 2003/037886; U.S. Patent 2003/149074; WO 2003/035618; WO 2003/034997; U.S. Patent 2003/158212; EP 1,417,976; US 2004/053946; JP 2001247477; JP 08175990; JP 08176070; US patent 6703414 and WO 97/15658, all of which are incorporated herein by reference in their entireties. Specific examples of such PI3K inhibitors include SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.) and GDC-0941 (PI3K inhibitor, Genentech, Inc .).

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

“Anti-inflammatory agent” means a compound suitable for treating inflammation. Examples of anti-inflammatory drugs include injectable protein therapeutic agents 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 relieve pain); disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate; 5-aminosalicylates (sulfasalazine and sulfur-free products); corticosteroids; immunomodulators such as 6-mercaptoputin ("6-MP"), azathioprine ("AZA"), cyclosporins, and biological response modifiers such as Remicade.RTM. (infliximab) and Enbrel.RTM. (etanercept); fibroblast growth factors; platelet growth factors; enzyme blockers such as Arava.RTM. (leflunomide); and / or cartilage protective agent, such as hyaluronic acid, glucosamine and chondroitin.

The term "prodrug", as used in this application, refers to a precursor or derivative of a compound according to this invention, which is capable of enzymatically or hydrolytically activated or converted into 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 the present invention include, but are not limited to, ester-containing prodrugs, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, optionally substituted phenoxide prodrugs, optionally substituted prodrugs containing phenylacetamide, 5-fluorocytosine and other 5-fluoruridine prodrugs which can be converted into the more active drug is noncytotoxic. Examples of cytotoxic drugs that can be derivatized to form a prodrug for use in accordance with this invention include, but are not limited to, the compounds of this invention and chemotherapeutic agents, such as those described above.

A "metabolite" is a product obtained from the metabolism of a particular compound or its salt in the body. Metabolites of a compound can be identified using standard techniques known in the art, and their activity is determined using tests such as, for example, those described herein. Such products can be obtained, for example, by oxidation, hydroxylation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage and the like, of the introduced compound. Accordingly, this invention relates to metabolites of compounds of this invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to form its metabolic product.

A "liposome" is a small membrane vesicle (vesicle), including various types of lipids, phospholipids and / or surfactants, which is suitable for drug delivery (such as the MEK inhibitors described herein and, optionally, a chemotherapeutic agent) to a mammal. The components of the liposome are usually arranged in a bilayer formation, similar to the lipid bilayer of biological membranes.

The term "instructions for use", as used in this description, refers to instructions usually enclosed in industrial packaging of therapeutic drugs that contain information about the indications, uses, doses, administration, contraindications and / or warnings regarding the use of such therapeutic products.

The term “chiral” refers to molecules that are incompatible with its mirror image, while the term “achiral” refers to molecules that are compatible with its mirror image.

The term "stereoisomer" refers to compounds that have the same chemical structure and compound of atoms, but differ in the location of these atoms relative to each other in space, and cannot interconvert when rotated around simple bonds.

The term "diastereomer" refers to a stereoisomer with two or more centers of chirality, and 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 using analytical techniques with a high degree of separation, such as crystallization, electrophoresis and chromatography.

The term "enantiomers" refers to two stereoisomers of a compound in which mirror reflections of one another are incompatible.

The stereochemical definitions and conventions used throughout this specification are typically guided by 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 include 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 in the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L, or 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 the compound in the plane of plane-polarized light, where the prefix (-) or 1 means that the compound is levorotatory. A connection prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical, except when they are mirror images of each other. A single stereoisomer can also be considered as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is considered as 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 types of enantiomers that do not have optical activity.

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible due to the low energy barrier. For example, proton isomerism tautomers (also known as prototropic tautomers) include interconversions due to proton migration, such as keto-enol and imino-enamine isomerizations. Tautomers with valence isomerism (valence tautomers) include interconversions due to the redistribution of some of the bond electrons.

The phrase "pharmaceutically acceptable salt", as used in this context, refers to pharmaceutically acceptable organic or inorganic salts of the compounds according to this invention. Examples of salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate , ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sugar, formate, benzoate, glutamate, mesylate methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylenebis 2-hydroxy-3-naphthoate), alkali metal salts (e.g. sodium and potassium), alkaline earth salts meta llov (for example, magnesium) and ammonium salts. Another molecule, such as acetate ion, succinate ion or other counterion can be added to the pharmaceutically acceptable salt. The counterion can be any organic or inorganic "moiety" that stabilizes the charge of the starting compound. In addition moreover, a pharmaceutically acceptable salt may have more than one charged atom in its structure.In cases where multiply charged atoms are part of a pharmaceutically acceptable salt, it may have many 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, then the desired pharmaceutically acceptable salt can be prepared using any suitable technique available in the art, for example by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumar hydrochloric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosydic 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 the like.

If the compound of this invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable technique, 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 hydroxide metal, or the like Illustrative examples of suitable salts include, but are not limited to, organic salts obtained using amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts originating from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The phrase "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with other ingredients included in the finished dosage form, and / or the mammal, which is subjected to treatment.

The term “solvate” refers to an association or complex of one or more solvent molecules and a compound according to this 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 wherein the solvent molecule is water.

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

The terms “compound according to this invention”, “compounds according to the present invention”, “compounds of formula Ia or Ib”, “azaindolizines” and “azaindolizines of formula Ia or Ib”, except as otherwise indicated, include compounds / azaindolizines of formula Ia or Ib and their stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts (e.g. pharmaceutically acceptable salts) and prodrugs.

The present invention relates to azaindolizines of formula Ia or Ib, as described above, suitable as kinase inhibitors, especially suitable as MEK kinase inhibitors. The present invention relates to compounds of formula II-a or II-b (i.e., Z ^A is CR ^A ) and all other variables are as defined in the case of formulas Ia or Ib.

In one embodiment of the present invention, R ¹ is H, halogen, CN, CF ₃ , C ₁ -C ₆ alkyl, —NR ¹⁶ R ¹⁷ , —OR ¹⁶ or —SR ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b.

In another embodiment of the present invention, R ¹ is H, Cl, Br, F, CN, CF ₃ , CHF ₂ , methyl, ethyl, —NH ₂ , —NH (CH ₃ ), —N (CH ₃ ) ₂ , —OH or —OCH ₃ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b.

In another embodiment of the present invention, R ¹ is H, Cl, F, CF ₃ or methyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b.

In another embodiment of the present invention, R ¹ is H or F; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b.

In one embodiment of the present invention, R ² is H, halogen, CN, CF ₃ , C ₁ -C ₆ alkyl, —NR ¹⁶ R ¹⁷ , —OR ¹⁶ or —SR ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ² is H, Cl, F, CN, CF ₃ , CHF ₂ , methyl, ethyl, —NH ₂ , —NH (CH ₃ ), —N (CH ₃ ) ₂ , —OH, or - OCH ₃ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ² is H, Cl, F, CF ₃ or methyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ² is H; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, R ³ is H, halogen, CN, CF ₃ , C ₁ -C ₆ alkyl, —NR ¹⁶ R ¹⁷ , —OR ¹⁶ or —SR ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ³ is H, Cl, F, CN, CF ₃ , CHF ₂ , methyl, —NH ₂ , —NH (CH ₃ ), —N (CH ₃ ) ₂ , —OH, or —OCH ₃ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ³ is H, Cl, F, CF ₃ or methyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ³ is H; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, R ^A is H, halogen or CF ₃ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ^A is H, F or Cl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, R ⁴ is H or C ₁ -C ₆ alkyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁴ is H or methyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁴ is H; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, R ⁵ is H or C ₁ -C ₆ alkyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁵ is H or methyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁵ is H; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁵ means methyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, X ¹ is OR ⁷ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ¹ is OR ⁷ , where R ⁷ is H or 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, - (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 ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ¹ is OR ⁷ , where R ⁷ is heterocyclyl (e.g., 4-6 membered heterocyclyl) optionally substituted with one or more groups independently selected from halogen, CN, CF ₃ , —OCF ₃ , - NO ₂ , oxo, - (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 ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ¹ is OR ⁷ , where R ⁷ is a 4-6 membered heterocyclyl having 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, - (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 ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ¹ means:

;

;

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ¹ means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, X ¹ is R ⁷ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ¹ is R ⁷ , where R ⁷ is H or 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 ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ¹ means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁵ means H and X ¹ means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁵ means H, R ^A means H, and X ¹ means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ¹ means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁵ means methyl, and X ¹ means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, X ¹ is R ⁷ and X ¹ (i.e., R ⁷ ), together with R ⁵ and the nitrogen atom to which they are bonded, form a 4-5 membered saturated ring having 0-2 additional heteroatoms selected from O, S and N, wherein said cycle is optionally substituted with one or more groups selected from halogen, CN, CF ₃ , —OCF ₃ , —NO ₂ , oxo, - (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 ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, W means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, W is —OR ⁷ where R ⁷ is H or C ₁ -C ₁₂ alkyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, W is —OR ⁷ , where R ⁷ is H; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, W is —OR ⁷ , where R ⁷ is C ₁ -C ₆ alkyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, R ⁶ is halogen, C ₂ -C ₈ alkynyl, carbocyclyl or —SR ¹⁶ ; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, R ⁶ is halogen, C ₂ -C ₃ alkynyl, C ₃ carbocyclyl or —SR ¹⁶ , where R ¹⁶ is C ₁ -C ₂ alkyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, R ^{6 ′} is H, halogen or C ₁ -C ₃ alkyl; and all other variables are as defined in the case of formulas Ia, Ib, II-a or II-b, or as indicated in any one of the embodiments described above.

In one embodiment of the present invention, p is 1 or 2; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

In another embodiment of the present invention, X ⁴ means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as indicated in any one of the embodiments described above.

Another embodiment of the present invention relates to compounds described in examples 5-10, and the following compounds:

Obtaining compounds of formula I-a or I-b

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

For example, azaindolizines of formula (II-a) can be prepared using the synthetic routes shown in Schemes 1 and 2.

Scheme 1

Anilines of the formula (IV) (including the corresponding substituents R1) can be obtained commercially or obtained in accordance with the methods described in the literature. Compounds of formula (VI) can be prepared from anilines of formula (IV) by reacting with acid chlorides of acids of formula (V) in the presence of a base such as triethylamine and a catalyst such as DMAP in a solvent such as DMF. Compounds of formula (VI) can be converted to compounds of formula (VIII) by reacting with alkyl halides of formula (VII) in the presence of a base such as potassium hydroxide in a solvent such as ethanol. Compounds of formula (IX) can be prepared from compounds of formula (VIII) by treatment with phosphorus oxychloride, in a solvent such as toluene, at a temperature of from 50 ° C. to reflux temperature.

Compounds of formula (X) can be prepared from compounds of formula (IX) by reacting with a base such as sodium hydroxide in a solvent such as methanol, ethanol or dioxane at a temperature from room temperature to reflux temperature. Alternatively, compounds of formula (X) can be prepared from compounds of formula (IX) by treatment with a Lewis acid, such as boron tribromide, in a solvent, such as dichloromethane, at a temperature of from -78 ° C to a boiling point under reflux.

Compounds of formula (X) may be reacted with a functionalized hydroxylamine of formula (XII) (commercially available or prepared according to Scheme 3) or with an amine and a suitable coupling agent such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or N, N'-dicyclohexylcarbodiimide, 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, so ohms like tetrahydrofuran, N, N-dimethylformamide or dichloromethane, at about room temperature, to give compounds of formula (XI). Alternatively, compounds of formula (XI) can be directly prepared from compounds of formula (IX) by reacting them with an amine or hydroxylamine DNHR, in the presence of a Lewis acid such as trimethylaluminum, in a solvent such as DCM, at a temperature from room temperature to temperature boiling under reflux.

Alternatively, compounds of formula (IX) can be prepared according to Scheme 2.

Scheme 2

Chloromethylpyrimidines of the formula (VII) can be reacted with a cyanoacetic acid ester such as cyanoacetic acid methyl ester in the presence of a base such as sodium hydride in a solvent such as THF at a temperature from 0 ° C. to reflux temperature , to obtain the compounds of formula (XV). Compounds of formula (XVI) can be prepared from compounds of formula (XV) by treatment with an acid, such as trifluoroacetic acid, undiluted or in a solvent, such as dioxane, at a temperature of from 50 ° C to a boiling point under reflux, or using microwave radiation, at temperatures from 90 ° C to 180 ° C. Compounds of formula (IX) can be prepared from compounds of formula (XVI) by reacting them with an aryl halide or aryl triflate (including the corresponding R1 substituents), in the presence of a catalyst such as Tris (dibenzylideneacetone) dipalladium (0) or palladium acetate, a base such like potassium phosphate, sodium tert-butoxide, 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-dicyclohexyl sphino-2 ', 6' - (dimethoxy) biphenyl or tributylphosphine, in a suitable solvent such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at a temperature from room temperature to the boiling point of the solvent, or under microwave irradiation, at from 70 ° C to 150 ° C. Compounds of formula (IX) can be converted to compounds of formula (XI) using the procedures shown in Scheme 1.

Hydroxylamines of the formula (XII) can be prepared using the procedures described in the literature or the synthesis route shown in Scheme 3.

Scheme 3

Primary or secondary alcohols of the general formula (XX) can be prepared using methods described in the literature. They can be reacted with N-hydroxyphthalimide using phosphine and a coupling reagent such as diethyl azodicarboxylate to give compounds of general formula (XXI). Compounds of general formula (XXI) can be deprotected using hydrazine or methylhydrazine to give hydroxylamines of general formula (XII-a). The compounds of formula (XII-a) can further be 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 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).

It should be appreciated that when there are appropriate functional groups, compounds of formula (I) or any intermediates used to prepare them, they can additionally be derivatized using one or more standard synthetic methods using substitution, oxidation, reduction, or cleavage reactions. Specific substitution methods include standard alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and binding.

For example, aryl bromide or aryl chloride groups can be converted to aryl iodides using the Finkelstein reaction, using an iodide source 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, and heating the reaction mixture to reflux. Aryl trialkylsilanes can be converted to aryl iodides by treating the silane with an iodide source, such as iodine monochloride, in a solvent, such as dichloromethane, with or without a Lewis acid such as silver tetrafluoroborate, at a temperature from -40 ° C to the boiling point with a reverse a refrigerator.

In a further example, primary amino groups (—NH ₂ ) can be alkylated by 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, when necessary, in the presence of an acid, such as acetic acid, at approximately ambient temperature. Secondary amino groups (—NH—) can be similarly alkylated using an aldehyde.

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

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

In a further example, amino groups (—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, such as, for example, palladium on a support such as carbon , 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 the boiling point of the solvent.

In a further example, amino groups (—NH ₂ ) can be prepared from carboxylic acid groups (—CO ₂ H) by conversion to the corresponding acyl azide (—CON ₃ ), Curtius rearrangement, and hydrolysis of the resulting isocyanate (—N = C = O).

Aldehyde groups (—CHO) can be converted to amino groups (—CH ₂ NR′R ″) by reductive amination using an amine and 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, when necessary, in the presence of an acid, such as acetic acid, at approximately ambient temperature.

In a further example, aldehyde groups can be converted to alkenyl groups (—CH = CHR ′) by the Wittig or Wadsworth-Emmons reaction using the appropriate phosphorane or 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 nitrile groups (—CN) using diisobutylaluminum hydride in a suitable solvent such as toluene. Alternatively, aldehyde groups can be prepared by oxidizing alcohol groups using any suitable oxidizing agent known to those skilled in the art.

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

Carboxyl groups (—CO ₂ H) can be converted to amides (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 a further example, carboxylic acids can be homologated 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 a further example, —OH groups can be prepared from the corresponding esters (eg —CO ₂ R ′) or aldehydes (—CHO) 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 by 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, alcohol can be reacted with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to give the corresponding chloride. A base (e.g. triethylamine) can also be used for reaction.

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

Halogen-aromatic substituents in the compounds can be halogen-metal exchanged by treatment with a base such as, for example, a lithium base such as n-butyllithium or tert-butyl lithium, optionally at a low temperature, for example about -78 ° C, in a solvent such as tetrahydrofuran and then quench using an electrophile to introduce the desired substituent. Thus, for example, a formyl group can be introduced by using N, N-dimethylformamide as an electrophile. Haloaromatic substituents may alternatively 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, Stille, Buchwald or Hartwig. Haloaromatic substituents can also be nucleophilically substituted, followed by reaction with an appropriate nucleophile, such as an amine or an alcohol. Advantageously, such an interaction can be carried out at elevated temperature, in the presence of microwave radiation.

The compounds of the present invention were tested for their ability to inhibit MEK activity and activation (basic assay) and for their biological effects on growing cells (minor assay), as described below. Compounds of the present invention having an IC _{50 of} less than 5 μM (more preferably less than 0.1 μM, most preferably less than 0.01 μM) according to an MEK activity assay according to Example 1, IC ₅₀ less than 5 μM ( more preferably, less than 1 μM, even more preferably less than 0.1 μM, most preferably less than 0.01 μM) according to the MEK activation assay in accordance with Example 2, EC ₅₀ less than 10 μM (more preferably less more than 1 μM, even more preferably less than 0.5 μM, most preferred of less than 0.1 uM) according to the analysis of cell proliferation in accordance with Example 3, and / or EC _{50 of} less than 10 microns (more preferably less than 1 .mu.M, more preferably less than 0.5 uM, and most preferably less than 0.1 μM) according to the ERK phosphorylation assay according to Example 4 are suitable as MEK inhibitors.

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

The compounds of the present invention (such as any one of the headings of the compounds of Examples 5-10) and the compositions are also suitable 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. , person). Examples of such diseases / disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retrolental fibroplasia, age-related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, organ transplant rejection, cachexia, stroke, septic shock, heart failure, organ transplant rejection, more Hb Alzheimer's, chronic or neuropathic pain, and viral infections such as HIV, hepatitis (B) (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 numerous conditions that include, but are not limited to, inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, nerve plexus avulsion, neuroma, vasculitis, viral infection, crush, constriction damage, tissue damage, amputation of the limb, pain with arthritis and nerve damage between the peripheral nervous system and the central nervous system.

The compounds of the present invention (such as any one of the title compounds of Examples 5-10) and the compositions are also useful for treating pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-caused kidney disease) in a mammal (e.g., a human).

Compounds of the present invention (such as any one of the title compounds of Examples 5-10) and compositions are also useful in preventing the implantation of blastocytes in a mammal (e.g., human).

The present invention relates to a method for inhibiting abnormal cell growth or a method for treating a hyperproliferative disorder in a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula Ia or Ib (and / or its solvates and / or its salts) or containing it composition. Also related to the present invention is 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-a or I-b (and / or its solvates and / or its salts) or a composition containing it.

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 Ia or Ib (and / or its solvates and / or its salts) or a composition containing it in combination with a second chemotherapeutic agent, such as those described herein. 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 Ia or Ib (and / or its solvates and / or its salts) or a composition containing it, in combination with a second anti-inflammatory agent, such as those described herein.

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 (e.g., a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula Ia or Ib (and / or its solvates and / or its salts) or a composition containing it and optionally further comprising administering a second tera evticheskogo means. Examples of such diseases / disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retrolental fibroplasia, age-related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, organ transplant rejection, cachexia, stroke, septic shock, heart failure, organ transplant rejection, more Hb Alzheimer's, chronic or neuropathic pain, and viral infections such as HIV, hepatitis (B) (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 Ia or Ib (and / or its solvates, and / or salts thereof) or compositions containing it and optionally further comprising administering a second therapeutic agent.

The present invention relates to a method for preventing implantation of blastocytes in the case of a mammal (eg, a human), comprising administering to said mammal a therapeutically effective amount of a compound of formula Ia or Ib (and / or its solvates and / or its salts) or a composition containing it and further optionally including the introduction of a second therapeutic agent.

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

It is also believed that the compounds of the present invention can make abnormal cells more sensitive to radiation treatment, for the purpose of killing such cells and / or inhibiting the growth of such cells. Accordingly, the present invention further relates to a method for sensitizing abnormal cells in a mammal (eg, a human) with respect to radiation treatment, which method comprises administering to said mammal a certain amount of a compound of formula Ia or Ib (and / or its solvates and its salts) or a composition containing it and this amount is effective in relation to sensitization of abnormal cells for radiation treatment.

The administration of the compounds of the present invention (hereinafter, the “active compound (s)”) can be effective in any method in which delivery of the compounds to the site of action is possible. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical administration, inhalation and rectal administration.

The amount of active compound administered depends on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the attending physician. However, an effective dose is in the range of from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg / kg / day, in single or divided doses. For a person weighing 70 kg, this amount is from about 0.05 to 7 g / day, preferably from about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the above range may be more than sufficient, while in other cases much larger doses can be used without causing any harmful side effect, provided that such much large doses are first divided into several small doses for administration throughout the day.

The active compound can be used as monotherapy or in combination with one or more chemotherapeutic or anti-inflammatory agents, for example, such as those described in this description. Such combined treatment can be carried out by synchronous, sequential or separate dosage of the individual components of the treatment.

The pharmaceutical composition, for example, may be in the form suitable for oral administration, in the form of a tablet, capsule, pill, powder, sustained release drug formulation, solution, suspension, for parenteral injection in the form of a sterile solution, suspension or emulsion, for topical administration in the form of an ointment or cream, or for rectal administration in the form of a suppository. The pharmaceutical composition may be in the form of unit dosage forms suitable for single administration of exact dosages. The pharmaceutical composition includes a standard pharmaceutical carrier or excipient and a compound according to this invention as an active ingredient. In addition, the composition may include other therapeutic or pharmaceutical agents, carriers, adjuvants, etc.

Exemplary forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, such as, for example, aqueous solutions of propylene glycol or dextrose. Such dosage forms may be suitably 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. So, for oral administration, tablets containing various excipients, such as citric acid, can be used in conjunction with various disintegrating agents, such as starch, alginic acid and some complex silicates, and with binding agents such as sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often suitable for tabletting purposes. Solid compositions of a similar type can also be used in soft and hard, drug-filled gelatin capsules. Preferred substances therefore include lactose or milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound in this case can be combined with various sweeteners or flavorings, colorants or coloring agents, and, if desired, emulsifiers or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.

Methods for preparing various pharmaceutical compositions with a specific amount of active compound are known or 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

DCM Dichloromethane Dipa diisopropylethylamine DMAP 4-dimethylaminopyridine DMF (DMF) dimethylformamide EDCI 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide Hcl hydrochloric acid Hobt 1-hydroxybenzotriazole Ims industrial methylated alcohols Meon Methanol NCS N-chlorosuccinimide RT room temperature

General experimental conditions

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

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

Method A: The experiments were carried out using a Waters Micromass ZQ quadrupole mass spectrometer connected to a Hewlett Packard HP1100 LC system with a diode array detector. In the case of this system, a Higgins Clipeus, C18, 5 micron column, 100 × 3.0 mm in size, and a volumetric flow rate of 1 ml / min are used. The initial solvent system includes 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B), for the first minute, then a gradient of up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system is held constant for the next 5 minutes.

Method B: The experiments were carried out using 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 Phenomenex Luna C18 (2) column with a size of 30 × 4.6 mm and a volumetric flow rate of 2 ml / min. The solvent system includes 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) in the first 0.50 minutes, then a gradient of up to 5 % solvent A and 95% solvent B over the next 4 minutes. The final solvent system is held constant for the next 0.50 minutes.

Experiments using microwave radiation are carried out using Personal Chemistry Emrys Iniatiator ™ or Optimizer ™, which uses a single-mode resonator and dynamic field tuning (tuning), both of which have the functions of reproduction and control. One can reach a temperature of 40-250 ^{° C} and can reach pressures up to 20 bar.

Example 1

MEK analysis (MEK activity analysis)

Constitutively activated human mutant MEK1 expressed in insect cells was used as a source of enzymatic activity at a final concentration in the analysis of 15 nm kinase.

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 was detected and quantified using HTRF reagents manufactured by Cisbio. They consist of an anti-GST antibody conjugated with allophycocyanin (XL665) and an anti-phospho (Thr202 / Tyr204) -ERK antibody (anti-phospho antibody) conjugated to europium cryptate. These antibodies were used at a final concentration of 4 μg / ml and 0.84 μg / ml, respectively. The anti-phospho antibody recognizes ERK1 double phosphorylated by Thr202 and Tyr204. When both antibodies are bound to ERK1 (i.e., when the substrate is phosphorylated), energy is transferred from cryptate to allophycocyanine after excitation at 340 nm, resulting in emitted fluorescence, which is proportional to the amount of phosphorylated substrate produced. Fluorescence was detected using a multi-channel fluorimeter.

Compounds were diluted in DMSO before being added to the assay buffer, and the final concentration of DMSO in the analysis was 1%.

IC _{50 was} defined as the concentration at which this compound causes 50% inhibition relative to the control. IC ₅₀ values were calculated using XLfit software (version 2.0.5).

The title compounds of Examples 5-6 and 8-10 showed an IC _{50 of} less than 0.5 μM in the case of the assay described in Example 1.

Example 2

BRaf Assay (MEK Activation Assay)

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

The analysis was 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 was detected and quantified using HTRF reagents manufactured by Cisbio. They consist of an anti-GST antibody conjugated with allophycocyanin (XL665), and an anti-phospho antibody (Ser217 / Ser221) -MEK (anti-phospho antibody) conjugated to europium cryptate. The anti-phospho antibody recognizes MEK double phosphorylated at Ser217 and Ser221 or once phosphorylated at Ser217. When both antibodies are bound to MEK (i.e., when the substrate is phosphorylated), energy is transferred from cryptate to allophycocyanin after excitation at 340 nm, resulting in emitted fluorescence, which is proportional to the amount of phosphorylated substrate produced. Fluorescence was detected using a multi-channel fluorimeter.

Compounds were diluted in DMSO before being added to the assay buffer, and the final concentration of DMSO in the analysis was 1%.

IC _{50 was} defined as the concentration at which this compound causes 50% inhibition relative to the control. IC ₅₀ values were calculated using XLfit software (version 2.0.5).

Example 3

Cell Proliferation Assay

Compounds were tested by assay for cell proliferation using the following cell lines:

HCT116 human colorectal carcinoma (ATCC)

A375 human malignant melanoma (ATCC)

Both cell lines were kept in DMEM / F12 (1: 1) (Gibco) medium supplemented with 10% fetal calf serum at 37 ° C in a humidified incubator with 5% CO ₂ .

Cells were plated on 96-well plates at 2000 cells / well and after 24 hours they were exposed to various concentrations of compounds with 0.83% DMSO. Cells were cultured for the next 72 hours, and the same volume of CellTiter-Glo (Promega) reagent was added to each well. It lyses cells 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-channel luminometer.

EC _{50 was} defined as the concentration at which this compound causes 50% inhibition relative to the control. IC ₅₀ values were calculated using XLfit software (version 2.0.5).

In this assay, the title compounds of Examples 5-6 and 8-9 showed an EC _{50 of} less than 11.5 μM in the case of both cell lines.

Example 4

Cell-Based Phospho-ERK Analysis

Compounds were tested by cell-based enzyme-linked immunosorbent assay (ELISA) phospho-ERK using the following cell lines:

HCT116 human colorectal carcinoma (ATCC)

A375 human malignant melanoma (ATCC)

Both cell lines were kept in DMEM / F12 (1: 1) (Gibco) medium supplemented with 10% fetal calf serum at 37 ° C in a humidified incubator with 5% CO ₂ .

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

EC _{50 was} defined as the concentration at which this compound leads to a half signaling path between the baseline and the maximum response. EC ₅₀ values were calculated using XLfit software (version 2.0.5).

In this assay, the title compounds of Examples 5-6 and 8-9 showed an EC _{50 of} less than 1 μM for both cell lines.

N- (2-fluoro-4-iodophenyl) malonamic acid ethyl ester

To a solution of 2-fluoro-4-iodaniline (15.1 g, 63.7 mmol), triethylamine (8.9 ml, 63.7 mmol) and DMAP (100 mg, 0.8 mmol) in DMF (45 ml) ethyl malonyl chloride (9.8 ml, 76.4 mmol) was added. The reaction mixture is heated at a temperature of 60 ° C for 2 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (30 ml), washed with water (20 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 20-30% ethyl acetate in cyclohexane) to give the title compound as a white solid (19.5 g, 87% yield).

LCMS (method B): R _T = 3.43 min, M + H ⁺ = 352.

N- (2-Fluoro-4-iodophenyl) -2-pyrimidin-4-ylmethylmalonamic acid ethyl ester

N- (2-fluoro-4-iodophenyl) malonamic acid ethyl ester (20.5 g, 58.4 mmol), 4-chloromethylpyrimidine (5.0 g, 38.9 mmol) and potassium hydroxide (3.28 g, 58.4 mmol) was dissolved in IMS (200 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (30 ml), washed with water (20 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 10-40% ethyl acetate in cyclohexane) to give the title compound as an off-white solid (6.9 g, 39% yield).

LCMS (method B): R _T = 3.29 min, M + H ⁺ = 444.

7- (2-Fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid ethyl ester

To a solution of N- (2-fluoro-4-iodophenyl) -2-pyrimidin-4-ylmethylmalonamic acid ethyl ester (4 g, 9.02 mmol) in toluene (120 ml) was added phosphorus (V) oxychloride (4.2 ml) 45.1 mmol). The reaction mixture was refluxed for 16 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (30 ml), washed with a saturated aqueous solution of sodium bicarbonate (20 ml), and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-40% ethyl acetate in cyclohexane) to give a dark brown solid. This solid was triturated with diethyl ether (10 ml) to give the title compound as a pale brown solid (0.63 g, 16% yield).

LCMS (method B): R _T = 3.95 min, M + H ⁺ = 426.

7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

To a solution of 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid ethyl ester (230 mg, 0.54 mmol) in a mixture of dioxane (2 ml) and water (1 ml ) lithium hydroxide monohydrate (45 mg, 1.08 mmol) is added. The reaction mixture is heated at a temperature of 60 ° C for 1 hour. An aqueous solution of hydrochloric acid (1 M solution) is added dropwise until a pH of ~ 5 is reached, which causes a precipitate to form. The reaction mixture was filtered and the solid was washed with ethyl acetate (5 ml) to obtain the title compound as an off-white solid (67 mg, 31% yield).

LCMS (method B): R _T = 3.22 min, M + H ⁺ = 398.

N- (2-Fluoro-4-methylsulfanylphenyl) malonamic acid methyl ester

To a solution of 2-fluoro-4-methylsulfanylphenylamine (13 g, 82.7 mmol), triethylamine (9.3 ml, 86.8 mmol) and DMAP (100 mg, 0.8 mmol) in DMF (50 ml) was added methylmalonyl chloride (11.5 ml, 82.7 mmol). The reaction mixture is heated at a temperature of 60 ° C for 2 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (30 ml), washed with water (20 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 10-30% ethyl acetate in cyclohexane) to give the title compound as a white solid (15.4 g, 72% yield).

LCMS (method B): R _T = 2.94 min, M + H ⁺ = 258.

N- (2-Fluoro-4-methylsulfanylphenyl) -2-pyrimidin-4-ylmethylmalonamic acid methyl ester

N- (2-Fluoro-4-methylsulfanylphenyl) -Malonamic acid methyl ester (15.4 g, 59.9 mmol), 4-chloromethylpyrimidine (5.13 g, 39.9 mmol) and potassium hydroxide (3.36 g , 59.9 mmol) was dissolved in IMS (150 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (30 ml), washed with water (20 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-100% ethyl acetate in cyclohexane) to give the title compound as an off-white solid (4.9 g, 23% yield).

LCMS (method B): R _T = 3.02 min, M + H ⁺ = 350.

7- (2-Fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid methyl ester

To a solution of N- (2-fluoro-4-methylsulfanylphenyl) -2-pyrimidin-4-ylmethylmalonamic acid methyl ester (2 g, 5.72 mmol) and diisopropylethylamine (2.9 ml, 17.2 mmol) in dioxane (30 ml) phosphorus (V) oxychloride (2.7 ml, 28.6 mmol) was added and the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled to 0 ° C and quenched with water (10 ml). The reaction mixture was diluted with saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (3 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 10-20% ethyl acetate in cyclohexane) to give the title compound as a light brown solid (0.80 g, 42% yield).

LCMS (method B): R _T = 3.70 min, M + H ⁺ = 332.

7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

To a solution of 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid methyl ester (635 mg, 1.9 mmol) in dioxane (8 ml) and water (2.5 ml) lithium hydroxide monohydrate (161 mg, 3.8 mmol) is added. The reaction mixture was stirred at 55 ° C for 2 hours, then cooled to room temperature. An aqueous solution of hydrochloric acid (1 M solution) was added dropwise until a pH of ~ 3 was reached. The reaction mixture was extracted twice with ethyl acetate (2 times in 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a dark brown solid (600 mg, 99% yield).

LCMS (method B): R _T = 3.20 min, M + H ⁺ = 318.

5-Chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid methyl ester

To a solution of 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid methyl ester (576 mg, 1.40 mmol) in DCM (10 ml) was added NCS (206 mg, 1.54 mmol), and the reaction mixture was refluxed for 3 hours. More NCS (37 mg, 0.28 mmol) was added and the reaction mixture was refluxed for 2 hours. The reaction mixture was diluted with water, and the product was extracted with DCM (3 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-40% ethyl acetate in cyclohexane) to give the title compound as an off-white solid (300 mg, 48% yield).

LCMS (method B): R _T = 4.11 min, M + H ⁺ = 446.

5-Chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

To a solution of 5-chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid methyl ester (300 mg, 0.67 mmol) in DCM (6 ml) was added tribromide boron (0.65 ml, 6.7 mmol). The reaction mixture was refluxed for 1 hour. The reaction mixture was cooled to 0 ° C and quenched carefully by adding water (5 ml). The reaction mixture was diluted with an aqueous solution of hydrochloric acid (2 ml, 1 M solution) and extracted with ethyl acetate (3 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the product as a dark brown solid (335 mg, 115% yield).

LCMS (method B): R _T = 3.58 min, M + H ⁺ = 432.

Example 5

(2-Hydroxyethoxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

Stage 1: (2-Vinyloxyethoxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

7- (2-Fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (67 mg, 0.18 mmol), O- (2-vinyloxyethyl) hydroxylamine (18 mg, 0.18 mmol), HOBt (26 mg, 0.19 mmol), EDCI hydrochloride (37 mg, 0.19 mmol) and DIPEA (31 μl, 0.18 mmol) are suspended in DMF (3 ml). The reaction mixture was stirred at room temperature for 16 hours, during which the reagents were dissolved. The reaction mixture was concentrated in vacuo, the resulting residue was dissolved in ethyl acetate (10 ml), washed with aqueous saturated sodium bicarbonate solution (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-100% ethyl acetate in cyclohexane) to give the title compound as a yellow solid (54 mg, 65% yield).

LCMS (method B): R _T = 3.38 min, M + H ⁺ = 483.

Stage 2: (2-Hydroxyethoxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

To a solution of (2-vinyloxyethoxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (54 mg, 0.11 mmol) in IMS (3 ml) was added aqueous hydrochloric acid solution (0.5 ml, 1 M solution, 0.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The product was triturated with MeOH / diethyl ether to give the title compound as a light brown solid (20 mg, 39% yield).

¹ H-NMR (d ₆ -DMSO, 400 MHz) 11.32 (1H, s), 8.69 (1H, s), 7.98 (1H, s), 7.49 (1H, dd, J = 11.0, 2.0 Hz), 7.40 (2H, s), 7.18-7.14 (1H, m), 6.74 (1H, s), 5.92 (1H, t, J = 8.8 Hz), 4.65 (1H, t, J = 5.6 Hz), 3.75 (2H, t, J = 5.0 Hz), 3.46 (2H, q, J = 5 , 0 Hz).

LCMS (method A): R _T = 8.14 min, M + H ⁺ = 457.

Example 6

((R) -2,3-dihydroxypropoxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

7- (2-Fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (90 mg, 0.23 mmol), O - ((R) -2,2-dimethyl- [1 , 3] dioxolan-4-ylmethyl) hydroxylamine (35 mg, 0.23 mmol), HOBt (35 mg, 0.26 mmol), EDCI hydrochloride (50 mg, 0.26 mmol) and DIPEA (40 μl, 0, 23 mmol) was dissolved in DMF (3 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml), and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was dissolved in a solution of hydrogen chloride in dioxane (2 ml, 4 M solution) and stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo, and the resulting residue was subjected to reverse phase HPLC (gradient: 20-80% acetonitrile / water with 0.1% formic acid, Phenominex gemini PhC6 column, 5 microns, size 250 × 20 mm). The product was dissolved in ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a yellow solid (22 mg, 20% yield).

NMR (d ₆ -DMSO, 400 MHz) 11.39 (1H, s), 8.68 (1H, s), 7.99 (1H, s), 7.49 (1H, dd, J = 10.9 , 1.8 Hz), 7.41 (2H, s), 7.14-7.17 (1H, m), 6.74 (1H, s), 5.92 (1H, t, J = 8, 9 Hz), 4.80-4.81 (1H, m), 4.53 (1H, s), 3.80 (1H, dd, J = 9.6, 3.6 Hz), 3.56-3, 66 (2H, m).

LCMS (method A): R _T = 7.57 min, M + H ⁺ = 487.

Example 7

(Piperidin-4-yloxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

Stage 1: 4 - {[7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidin-6-carbonyl] aminooxy} piperidine-1-carboxylic acid tert-butyl ester

7- (2-Fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (190 mg, 0.48 mmol), 4-aminooxypiperidine-1-carboxylic acid tert-butyl ester (154 mg 0.72 mmol), HOBt (106 mg, 0.79 mmol), EDCI hydrochloride (150 mg, 0.79 mmol) and DIPEA (120 μl, 0.72 mmol) are suspended in DMF (5 ml). The reaction mixture is stirred at room temperature for 1 hour, during which time the reagents dissolve. The reaction mixture was concentrated in vacuo, the resulting residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-100% ethyl acetate in cyclohexane) to give the title compound as a brown solid (180 mg, 65% yield).

LCMS (method B): R _T = 3.69 min, M + H ⁺ -tBu = 540 (100%), M + H ⁺ -Boc = 496 (95%).

Stage 2: (Piperidin-4-yloxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

4 - {[7- (2-Fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidin-6-carbonyl] aminooxy} piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.30 mmol ) dissolved in a solution of hydrogen chloride in dioxane (1 ml, 4 M solution). The reaction mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo. The obtained residue was subjected to reverse phase HPLC (gradient: 10-60% acetonitrile / water with 0.1% formic acid, Phenominex gemini PhC6 column, 5 microns, size 250 × 20 mm). The product was dissolved in ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to afford the title compound as a yellow solid (37 mg, 25% yield).

¹ H-NMR (DMSO-d ₆ ): 8.73 (1H, s), 7.92 (1H, s), 7.49 (1H, dd, J = 10.98, 1.92 Hz), 7 , 41-7.38 (2H, m), 7.16-7.13 (1H, m), 6.72 (1H, d, J = 0.92 Hz), 5.93 (1H, t, J = 8.84 Hz), 3.72-3.62 (1H, m), 2.87 (2H, dt, J = 12.72, 4.49 Hz), 2.41-2.31 (2H, m), 1.67 (2H, dt, J = 12.84, 4.01 Hz), 1.32-1.21 (2H, m).

LCMS (method A): R _T = 6.17 min, M + H ⁺ = 496.

Example 8

((R) -2,3-dihydroxypropoxy) amide 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

Stage 1: ((R) -2,2-Dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidin-6 carboxylic acid

7- (2-Fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (287 mg, 0.90 mmol), O - ((R) -2,2-dimethyl- [1 , 3] dioxolan-4-ylmethyl) hydroxylamine (133 mg, 0.90 mmol), HOBt (135 mg, 0.99 mmol), EDCI hydrochloride (191 mg, 0.99 mmol) and DIPEA (169 μl, 0, 99 mmol) was dissolved in DMF (5 ml). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 30-100% ethyl acetate in cyclohexane) to give the title compound as a brown solid (246 mg, 61% yield).

LCMS (method B): R _T = 3.28 min, M + H ⁺ = 447.

Stage 2: ((R) -2,3-dihydroxypropoxy) amide 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

To a solution of ((R) -2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) amide 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carbon acid (246 mg, 0.56 mmol) in methanol (1 ml) add a solution of hydrogen chloride in dioxane (1 ml, 4 M solution, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-10% DCM in methanol) to give a light brown solid. This solid was triturated in acetonitrile (3 ml) to give the title compound as a beige solid (100 mg, 45% yield).

¹ H-NMR (DMSO-d ₆ ): 11.38 (1H, s), 8.64 (1H, t, J = 1.0 Hz), 7.86 (1H, s), 7.41-7 39 (2H, m), 7.15 (1H, dd, J = 12.09, 2.09 Hz), 6.82-6.79 (1H, m), 6.73 (1H, s), 6.06 (1H, t, J = 8.82 Hz), 4.82 (1H, s), 4.53 (1H, s), 3.80 (1H, dd, J = 9.68, 3, 51 Hz), 3.67-3.57 (2H, m), 3.31-3.24 (2H, m).

(SMe is the same as solvent).

LCMS (method A): R _T = 7.14 min, M + H ⁺ = 407.

Example 9

7- (2-Fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (2-hydroxyethoxy) amide

Stage 1: (2-Vinyloxyethoxy) amide 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

7- (2-Fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (200 mg, 0.63 mmol), O- (2-vinyloxyethyl) hydroxylamine (106 mg, 0.69 mmol), HOBt (94 mg, 0.69 mmol), EDCI hydrochloride (132 mg, 0.69 mmol) and DIPEA (118 μl, 0.69 mmol) were dissolved in DMF (5 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-100% ethyl acetate in cyclohexane) to give the title compound as a brown solid (139 mg, 55% yield).

LCMS (method B): R _T = 3.35 min, M + H ⁺ = 403.

Stage 2: (2-Hydroxyethoxy) amide 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

To a solution of (2-vinyloxyethoxy) amide 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid in IMS is added an aqueous solution of hydrochloric acid (4 N solution, 0.5 ml) . The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 5 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-10% DCM in methanol) to give the title compound as an off-white solid (73 mg, 56% yield).

¹ H-NMR (DMSO-d ₆ ): 11.31 (1H, s), 8.65 (1H, s), 7.85 (1H, s), 7.42-7.37 (2H, m) 7.15 (1H, dd, J = 12.10, 2.09 Hz), 6.82-6.79 (1H, m), 6.73 (1H, s), 6.06 (1H, t , J = 8.82 Hz), 4.66 (1H, s), 3.75 (2H, dd, J = 5.34, 4.47 Hz), 3.46 (2H, t, J = 4, 82 Hz), 2.36 (3H, s).

LCMS (method A): R _T = 7.35 min, M + H ⁺ = 377.

Example 10

((R) -2,3-dihydroxypropoxy) amide 5-chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

Stage 1: ((R) -2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) amide 5-chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine -6-carboxylic acid

5-Chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (145 mg, 0.34 mmol), O - ((R) -2,2- dimethyl- [1,3] dioxolan-4-ylmethyl) hydroxylamine (50 mg, 0.34 mmol), HOBt (50 mg, 0.37 mmol), EDCI hydrochloride (71 mg, 0.37 mmol) and DIPEA (63 μl, 0.37 mmol) was dissolved in DMF (3 ml). The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 25-100% ethyl acetate in cyclohexane) to give the title compound as a brown solid (57 mg, 25% yield).

LCMS (method B): R _T = 3.63 min, M + H ⁺ = 561.

Stage 2: ((R) -2,3-dihydroxypropoxy) amide 5-chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid

To a solution of ((R) -2,2-dimethyl [1,3] dioxolan-4-ylmethoxy) amide 5-chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidin-6 -carboxylic acid (57 mg, 0.1 mmol) in methanol (1 ml) add a solution of hydrogen chloride in dioxane (1 ml, 4 M solution, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2 times 10 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was flash chromatographed (SiO ₂ , gradient 0-10% methanol in DCM) to give a light brown solid. This solid was triturated in acetonitrile (3 ml) to give the title compound as an off-white solid (13 mg, 45% yield).

¹ H-NMR (CH ₃ OH-d ₄ ): 8.74 (1H, d, J = l, 57 Hz), 7.49 (1H, d, J = 6.61 Hz), 7.42 (1H dd, J = 10.78, 1.91 Hz), 7.38 (1H, dd, J = 6.61, 1.58 Hz), 7.21 (1H, ddd, J = 8.48, 1 , 90, 1.11 Hz), 6.14 (1H, t, J = 8.76 Hz), 3.89-3.80 (1H, m), 3.79-3.71 (2H, m) 3.56-3.42 (2H, m).

LCMS (method A): R _T = 7.70 min, M + H ⁺ = 521.

Claims (9)

1. The compound of formula I-a

and its pharmaceutically acceptable salts,
where Z ^A means CR ^A ;
R ^A is H or halogen;
each of R ¹ , R ^2, and R ³ is H;
W means:

each R ⁴ and R ⁵ means H;
X ¹ represents —OR ⁷ ;
each R ⁷ is C ₂ -C ₁₂ hydroxyalkyl, 2,3-dihydroxypropyl, C ₂ -C ₃ -alkenoxyC ₁ -C ₆ -alkoxy, (2,2-dimethyl- [1,3] dioxalan-4-yl) methyl or piperidinyl; X ⁴ means:

R ⁶ means halogen or -SR ¹⁶ ;
R ⁶ means halogen;
p is 1;
R ¹⁶ means C ₁ -C ₁₂ -alkyl. 2. The compound according to claim 1, where R ^A means H, F or Cl. 3. The compound according to claim 2, where X ^{1 is} selected from:

4. The compound according to claim 3, where X ^{4 is} selected from:

5. The compound according to claim 1, where the compound is selected from the group consisting of:
7- (2-Fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (2-hydroxyethoxy) amide;
((R) -2,3-dihydroxypropoxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid;
(piperidin-4-yloxy) amide 7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid;
((R) -2,3-dihydroxypropoxy) amide 7- (2-fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid;
7- (2-Fluoro-4-methylsulfanylphenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid (2-hydroxyethoxy) amide;
((R) -2,3-dihydroxypropoxy) amide 5-chloro-7- (2-fluoro-4-iodophenylamino) pyrrolo [1,2-c] pyrimidine-6-carboxylic acid;
or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition that inhibits the activity of Mek kinase containing the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier. 7. A method of inhibiting abnormal cell growth, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition according to claim 6. 8. The use of compounds according to any one of claims 1 to 5 for inhibiting abnormal cell growth. 9. The use of compounds according to any one of claims 1 to 5 for the preparation of a medicament for inhibiting abnormal cell growth.