RU2381219C2 - DERIVATIVES OF 5-MEMBER HETEROCYCLES AS KINASE p38 INHIBITORS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below

, in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

Description

Field of Invention

The present invention relates to derivatives of 5-membered heterocycles, including pyrazole and imidazole derivatives, which are effective in inhibiting cytokines. The present invention also relates to the use of such compounds for the treatment of conditions associated with the activity of 38α and β kinases, as well as p38 kinase.

BACKGROUND OF THE INVENTION

Many cytokines are involved in the inflammatory response, including IL-1, IL6, IL-8 and TNF-α. Excessive production of cytokines, such as IL-1 and TNF-α, is observed in a number of diseases, including intestinal inflammation, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxic shock, osteoporosis, Alzheimer's disease, and congestive heart failure (Henry et al., Drugs Fut., 24, cc. 1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6, cc. 807-823 (1999)). Clinical trials indicate the effectiveness of protein cytokine antagonists in the treatment of chronic inflammatory diseases, such as, for example, monoclonal antibodies to TNF-α (Remicad, Rankin et al., Br. J. Rheumatol., 34, cc. 344-342 (1995) ) and a soluble fusion protein receptor-Fc TNF-α (entanercept) (Moreland et al., 25 Ann. Intern. Med., 130, cc. 478-486 (1999)).

TNF-α biosynthesis occurs in many types of cells in response to an external stimulus, such as, for example, mitogen, infection, or trauma. Important mediators of TNF-α production are mitogen-activated proteins, kinases (MAPs), and especially p38 kinases. Such kinases are activated in response to various stress factors, including, but not limited to, pro-educational cytokines, endotoxin, ultraviolet radiation, and osmotic shock. Activation of p38 requires double phosphorylation at earlier stages of the metabolic pathway by MAP kinases (MKK3 and MKK6) by threonine and tyrosine residues in the Thr-Gly-Tyr fragment contained in p38 isoenzymes.

Four isoforms of p38 kinase are known, i.e. p38α, p38β, p38γ and p38δ. α- and β-isoforms are expressed in inflammatory cells and are the main modulators of TNF-α production. Inhibition of p38α and β enzymes in cells leads to a decrease in TNF-α expression. It was found that with the introduction of p38α and β inhibitors when tested on models of animals with inflammatory diseases, such inhibitors are effective in the treatment of these diseases. In this regard, p38 enzymes play an important role in inflammatory processes mediated by IL-1 and TNF-α (see, for example, US patents Nos. 6277989, 6130235, 6147080, 5945418, 6251914, 5977103, 5658903, 5932576 and 6087496, and also international applications for the grant of patents WO 00/56738, WO 01/27089. WO 01/34605, WO 00/12497, WO 00/56738, WO 00/12497 and WO 00/12074, US patents Nos. 6376527, 6316466 and 6444696 and international patent applications WO 99/57101, WO 02/40486, WO 03/032970, WO 03/033482, WO 03/032971, WO 03/032986, WO 03/032980, WO 03/032987, WO 03/033483 WO 03/033457 and WO 03/032972.

Thus, there is a need for the development of p38 kinase inhibitors, including p38a and p38b kinases, for treating, preventing, or alleviating one or more symptoms of diseases and disorders associated with p38 kinase activity.

Summary of the invention

The present invention provides compounds, compositions and methods for treating, preventing, or alleviating one or more symptoms of conditions associated with p38 kinase activity. In one embodiment, the compounds used in the compositions and methods of the present invention are pyrazole or imidazole derivatives. In another embodiment, pyrazole or imidazole derivatives are used as kinase inhibitors, including p38α and p38β kinases.

In one embodiment, compounds of the formula are provided.

or their pharmaceutically acceptable derivatives, where:

R ¹ is hydrogen, acyl or —P (O) (OH) ₂ ;

R ² means hydrogen, halogen, optionally substituted alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted alkoxy, optionally substituted heterocyclyloxy or alkylamino;

G is aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl or heterocyclyl, optionally fused to a phenyl ring and substituted with R ³ and R ⁴ , provided that the heterocyclic ring is attached to the carbonyl group through a carbon atom in the ring or G is OR ⁸³ or NR ⁸⁰ R ⁸¹ ;

B is aryl or heteroaryl;

C is a 5 membered heteroaryl ring containing one or two heteroatoms in the ring;

D is heteroaryl, optionally substituted heteroaryl or —C (O) NR ⁸⁰ R ⁸¹ ;

each R ⁸⁰ and R ⁸¹ independently means hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl;

R ⁸³ is hydrogen, alkyl, cycloalkyl, heteroaryl or optionally substituted heteroaryl;

R ₃ selected from the group including:

(a) amino, alkylamino or dialkylamino,

(b) acylamino,

(c) optionally substituted heterocyclyl,

(d) optionally substituted aryl or heteroaryl,

(e) heteroalkyl,

(e) heteroalkenyl,

(g) heteroalkynyl,

(h) heteroalkoxy,

(i) heteroalkylamino,

(k) optionally substituted heterocyclylalkyl,

(l) optionally substituted heterocyclylalkenyl,

(m) optionally substituted heterocyclylalkynyl,

(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy,

(o) optionally substituted heterocyclylalkylamino,

(o) optionally substituted heterocyclylalkylcarbonyl,

(p) heteroalkylcarbonyl;

(c) —NHSO ₂ R ⁶ , where R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;

(t) —NHSO ₂ NR ⁷ R ⁸ , where R ⁷ and R ^{8 are} independently hydrogen, alkyl or heteroalkyl;

(y) -Y- (alkylene) -R ⁹ where Y is a single bond, -O-, -NH- or -S (O) _n- (where n is a prime number from 0 to 2) and R ⁹ is halogen , cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —COOH, —COR ¹⁰ , —COOR ¹¹ , —CONR ¹² R ¹³ , —SO ₂ R ¹⁴ , —SO ₂ NR ¹⁵ R ¹⁶ , —NHSO ₂ R ¹⁷ or —NHSO ₂ NR ¹⁸ R ¹⁹ , where R ¹⁰ is alkyl or an optionally substituted heterocycle, R ¹¹ is alkyl, and R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ independently from each other mean hydrogen, alkyl or heteroalkyl;

(f) -C (= NR ²⁰ ) (NR ²¹ R ²² ), where R ²⁰ , R ²¹ and R ²² independently mean hydrogen, alkyl or hydroxy, or R ²⁰ and R ²¹ together mean - (CH ₂ ) _n- , where n is 2 or 3, and R ²² is hydrogen, alkyl;

(x) —NHC (X) NR ²³ R ²⁴ , where X is —O— or —S—, and R ²³ and R ^{24 are} independently hydrogen, alkyl or heteroalkyl;

(c) —CONR ²⁵ R ²⁶ , where R ²⁵ and R ^{26 are} independently hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R ²⁵ and R ²⁶ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl;

(h) —S (O) _n R ²⁷ , where n is a prime from 0 to 2 and R ²⁷ is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or —NR ²⁸ R ²⁹ , where R ²⁸ and R ^{29 are} independently hydrogen, alkyl or heteroalkyl;

(iii) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl, all of which are optionally substituted with alkyl, halogen, hydroxy or amino groups;

(y) arylaminoalkylene or heteroarylaminoalkylene;

(e) Z-alkylene-NR ³⁰ R ³¹ or Z-alkylene-OR ³² , where Z is —NH—, —N (lower) alkyl) or —O—, and R ³⁰ , R ³¹ and R ³² independently, hydrogen, alkyl or heteroalkyl;

(y) -OC (O) -alkylene-CO ₂ H or —OC (O) -NR′R ″ (where R ′ and R ″ independently are hydrogen or alkyl),

(i) heteroarylalkenylene or heteroarylalkynylene,

(aa) hydrogen

(bb) halogen,

(cc) pseudo-halogen,

(gg) hydroxy,

(dd) optionally substituted alkoxy,

(her) C (L) R ⁴⁰ , where L is O, S or NR ⁵⁵ ; R ⁴⁰ means hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C (L) R ⁵⁶ , halogen, pseudohalogen, OR ⁵⁵ , SR ⁵⁵ , NR ⁵⁷ R ⁵⁸ or SiR ⁵² R ⁵³ R ⁵⁴ , where R ⁵² , R ⁵³ and R ⁵⁴ are selected as described in the following (i) or (ii): (i) R ⁵² , R ⁵³ and R ⁵⁴ each independently means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cyclic loalkyl, heterocyclyl, OR ⁵⁵ and NR ⁶² R ⁶³ ; or (ii) any two of R ⁵² , R ⁵³ and R ⁵⁴ together form alkylene, alkenylene, alkynylene, heteroalkylene, and the others are selected as described in paragraph (i); R ⁵⁵ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R ⁵⁶ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶⁴ R ⁶⁵ , where R ⁶⁴ and R ⁶⁵ each independently means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁶⁶ or NR ⁶² R ⁶³ , or R ⁶⁴ and R ⁶⁵ together form alkylene, alkenylene, alkynylene, heteroalkylene, where R ⁶⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R ⁵⁷ and R ⁵⁸ are selected as described in the following (i) or (ii): (i) R ⁵⁷ and R ^{58 are} each independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl , OR ⁵⁵ , NR ⁶⁷ R ⁶⁸ or C (L) R ⁶⁹ , where R ⁶⁷ and R ⁶⁸ each independently mean hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl, or both of these substituents together form alkylene , alkenylene, alkynylene, heteroalkylene, and R ⁶⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl , Heterocyclyl, OR ⁷⁰ or NR ⁶² R ^63, where R ⁷⁰ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or (ii) R ⁵⁷ and R ⁵⁸ together form alkylene, alkenylene, alkynylene, heteroalkylene or alkyleneoxyalkylene; R ⁶² and R ⁶³ each independently mean hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or R ⁶² and R ⁶³ together form alkylene, alkenylene, alkynylene, heteroalkylene, and

(ii) optionally substituted alkyl;

R ⁴ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl,

(g) alkoxy and

(e) hydroxy;

R ⁵ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl,

(g) haloalkyl,

(e) thioalkyl,

(e) hydroxy,

(g) amino

(h) alkylamino,

(i) dialkylamino,

(k) heteroalkyl,

(k) an optionally substituted heterocycle,

(m) optionally substituted heterocyclylalkyl,

(m) optionally substituted heterocyclylalkoxy,

(o) alkylsulfonyl,

(o) aminosulfonyl, monoalkylaminosulfonyl or dialkylaminosulfonyl,

(p) heteroalkoxy and

(c) carboxy;

R ⁶ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl and

(g) alkoxy.

The present invention also provides pharmaceutical compositions comprising a compound of the present invention in combination with a pharmaceutically acceptable carrier.

The present invention also provides methods for treating, preventing, or alleviating one or more symptoms of diseases in mammals mediated by cytokines, the methods comprising administering to a mammal in need of such treatment a compound of formula I. Diseases and disorders that can be treated, prevented, or alleviated symptoms include, but are not limited to, chronic inflammatory diseases, intestinal inflammation, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxic shock , osteoporosis, Alzheimer's disease and congestive heart failure.

The present invention also provides methods for preventing or suppressing an inflammatory response using the compounds and compositions of the present invention.

In another embodiment, methods for inhibiting p38 kinases, including p38α and p38β kinases, using the compounds and compositions of the present invention, are provided.

Also provided are products containing a packaging material, compound or composition of the present invention, intended to treat, prevent or ameliorate one or more symptoms of diseases or disorders mediated by p38 kinase, as well as labels that indicate that the compound or composition is used for treatment, prevention or amelioration of one or more symptoms of diseases or disorders mediated by p38 kinase.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

A. Definitions

Unless otherwise specified, all technical and scientific terms used in this context have the usual meanings adopted in the technical field to which the invention (s) relates. All patents, patent applications, published applications and publications, sequences from the gene bank, databases, Internet sites and other published materials referenced in the description of the present invention, unless otherwise indicated, are fully included in the scope of the present invention in as links. If there are many meanings for these terms, then the values defined in this section of the description are preferred. If a link to a URL is mentioned or another similar identifier or address is used, it should be understood that such identifiers may change and certain information on the Internet may appear and be absent, but similar information can be found on the Internet. In addition, links to such identifiers indicate the availability and prevalence of such information.

Used in this context, the term p38α means an enzyme described in the work of Han and others, Biochim. Biophys. Acta 1265 (2-3): 224-7 (1995). Used in this context, the term p38β means an enzyme described in the work of Jiang and others, J. Biol. Chem. 271 (30): 17920-6 (1996). Used in this context, the term p38γ means an enzyme described in the work of Li and others, Biochem. Biophys. Res. Commun. 228: 334-340 (1996). Used in this context, the term p38δ means an enzyme described in the work of Wang and others, J. Biol. Chem. 272 (38): 23668-74 (1997).

The pharmaceutically acceptable derivatives of the compounds used in this invention include their salts, esters, enol esters, enol ethers, acetals, ketals, orthoesters, half acetals, half ketals, acids, bases, solvates, hydrates or prodrugs. Such derivatives can be obtained by known methods for such a modification. The resulting compounds can be administered to animals or humans, while they are pharmaceutically active or are prodrugs and do not exhibit significant toxicity. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as, but not limited to, N, N'-dibenzylethylenediamine, chlorprocaine, choline, ammonia, diethanolamine and other hydroxylalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkali metal salts such as, but not limited to, potassium and sodium; alkaline earth metal salts, such as, but not limited to, barium, calcium and magnesium; salts of transition metals, such as, but not limited to, zinc, and salts of other metals, such as, but not limited to, sodium hydrogen phosphate and disodium phosphate, and also include, without limitation, nitrates, borates, methanesulfonates, benzenesulfonates, toluenesulfonates, salts inorganic acids, such as, without limitation, hydrochlorides, hydrobromides, hydroiodides and sulfates; organic acid salts such as, but not limited to, acetates, trifluoroacetates, oxalates, benzoates, salicylates, maleates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates. Zwitterionic (internal) salts are also used. In some embodiments, the salt forms of the compounds have an increased dissolution rate and oral bioavailability. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroalkyl, cycloalkyl and heterocyclyl acid esters, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C = C (OR), where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of compounds of the formula C = C (OC (O) R), where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3, or 4 molecules of a solvent or water.

The term “alkyl” means a linear saturated monovalent hydrocarbon radical containing from 1 to 6 carbon atoms, or a branched saturated monovalent hydrocarbon radical containing from 3 to 6 carbon atoms, for example methyl, ethyl, propyl, 2-propyl, pentyl, etc. .

The term “cycloalkyl” means a saturated or partially unsaturated non-aromatic cyclic hydrocarbon ring system, preferably containing 1 to 3 rings and 3 to 7 carbon atoms in the ring, which may mean a condensed system with a C ₃ -C ₇ carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. “Substituted cycloalkyl” is substituted by one or more alkyl or substituted alkyl groups as described above, or one or more groups described above as alkyl substituents. The term "(ness.) Cycloalkyl" means an unsubstituted saturated or unsaturated non-aromatic cyclic hydrocarbon ring system containing from 3 to 5 carbon atoms.

The term “alkylene” means a linear saturated divalent hydrocarbon radical containing from 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon radical containing from 3 to 6 carbon atoms, for example methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc. .

The term “alkenyl” means a linear monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical containing from 3 to 6 carbon atoms, containing at least one double bond, for example, ethenyl, propenyl, and the like.

The term “alkenylene” means a linear divalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched divalent hydrocarbon radical containing from 3 to 6 carbon atoms, containing at least one double bond, for example, ethenylene, propenylene, and the like.

The term “alkynyl” means a linear monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched divalent hydrocarbon radical containing from 3 to 6 carbon atoms, containing at least one triple bond, for example ethynyl, propynyl, and the like.

The term “alkynylene” means a linear divalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical containing from 3 to 6 carbon atoms, containing at least one triple bond, for example ethynylene, propynylene and the like.

The term “alkoxy” means the radical —OR, where R is alkyl as described above, for example, methoxy, ethoxy, propoxy, 2-propoxy and the like.

The term “acyl” means the radical —C (O) R, where R is alkyl or haloalkyl, for example acetyl, trifluoroacetyl and the like.

The term “acylamino” means the radical —NRC (O) R ′, where R is hydrogen or alkyl, and R ′ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, for example acetylamino, 2-amino-2-methylpropionamide and the like.

The term “halogen” means fluoro, chloro, bromo or iodo, mainly fluoro and chloro.

The term “haloalkyl” means alkyl substituted with one or more identical or different halogen atoms, for example —CH ₂ Cl, —CF ₃ , —CH ₂ CF ₃ , —CH ₂ CCl ₃ and the like.

The term “aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical containing from 6 to 10 atoms in the ring, for example phenyl, 1-naphthyl, 2-naphthyl, and the like. The aryl ring is optionally fused to a 5-, 6- or 7-membered monocyclic saturated ring, optionally containing 1 or 2 heteroatoms, which are independently selected from the group consisting of oxygen, nitrogen or sulfur, with the remaining atoms in the cycle being carbon atoms, and 1 or 2 carbon atoms are optionally replaced with a carbonyl group. Examples of aryl radicals fused to other rings include, but are not limited to, 2,3-dihydrobenzo [1,4] dioxane, chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, benzo [1,3] dioxole , 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-indole, 2,3-dihydro-1H-isoindole, benzimidazol-2-one, 3H-benzoxazole -2-on, etc.

The term “heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical containing from 5 to 10 atoms in the ring, while containing 1, 2 or 3 heteroatoms in the ring, which are selected from N, O or S, while the remaining atoms in the cycle mean atom carbon. The term also includes radicals in which the heteroatom in the ring is oxidized or quaternized, such as, for example, forming an N-oxide or a quaternary salt. Representative examples include, but are not limited to, thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazole, 2-azole, 4-pyridonyl, N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl and their corresponding N-oxides (e.g., pyridyl N-oxide, quinolinyl N-oxide), their quaternary salts and the like.

The term “heterocycle or heterocyclyl” means a cyclic non-aromatic radical containing from 3 to 8 atoms in a cycle in which 1 or 2 cyclic atoms are heteroatoms selected from N, O or S (O) _n (n is an integer from 0 to 2 ), with the remaining atoms in the ring being carbon, and 1 or 2 carbon atoms are optionally replaced with a carbonyl group. The term also includes radicals in which the nitrogen atom in the ring is oxidized or quaternized, such as, for example, forming an N-oxide or a quaternary salt. Typical examples include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidino, morpholino, piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl, 2,2-dimethyl-1,3-dioxolanyl, sulfolanyl, 2-oxazolidonyl 2-imidazolidonyl, S, S-dioxothiomorpholino and the like.

The term “heterocycloamino” means a saturated monovalent cyclic group containing from 4 to 8 atoms in the cycle, in which at least 1 atom in the cycle means N and optionally contains one additional cyclic atom selected from N or O, and the remaining atoms in the cycle mean C. The term includes groups such as pyrrolidino, piperidino, morpholino, piperazino, and the like.

The term “optionally substituted alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl” means an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl group as described above, which are optionally independently substituted with 1 or 2 substituents selected from the group consisting of alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halogen, cyano, heterocyclyl, acyl, —OR (where R is hydrogen or alkyl), —NRR ′ (where R and R ′ are independently selected from the group consisting of hydrogen, acyl or alkyl, which are optionally substituted with hydroxy groups, alkoxy, cyano, halogen or hetero cyclic), —NHCOR (where R is alkyl, which is optionally substituted with hydroxy, alkoxy, cyano, halogen or heterocyclyl groups), —NRS (O) _n R ′ (where R is hydrogen or alkyl, n is an integer from 0 to 2 ; and R 'is hydrogen, alkyl or heteroalkyl, and is optionally substituted with hydroxy, alkoxy, cyano, halogen or heterocyclyl groups), -NRS (O) _n NR'R''(where R is hydrogen or alkyl, n is an integer from 0 to 2; and R ′ and R ″ independently mean hydrogen, alkyl or heteroalkyl, which are optionally substituted with hydroxy, alkoxy, cyano, halogen or hetero groups hiklil), -S (O) _n R (where n is an integer from 0 to 2; and R is hydrogen, alkyl or heteroalkyl, and is optionally substituted with hydroxy, alkoxy, cyano, halogen or heterocyclyl groups), -S (O) _n NRR '(where n is an integer from 0 to 2 and R and R' are independently hydrogen , alkyl or heteroalkyl and optionally substituted with hydroxy, alkoxy, cyano, halogen or heterocyclyl groups), -COOR, - (alkylene) COOR (where R is hydrogen or alkyl), -CONR'R '' or - (alkylene) CONR'R '' (where R 'and R''independently mean hydrogen or alkyl, or together with the nitrogen atom to which they are attached form a heterocyclic ring).

The term “optionally substituted aryl, heteroaryl or heterocyclyl” means an aryl, heteroaryl or heterocyclyl ring as described above, which is optionally independently substituted with 1 or 2 substituents selected from the group consisting of alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halogen, cyano, acyl, -OR (where R is hydrogen or alkyl), -NRR '(where R and R' are independently selected from the group consisting of hydrogen, acyl or alkyl), -NHCOR (where R is alkyl), -NRS (O) _n R '(where R is hydrogen or alkyl, n is an integer from 0 to 2 and R' is in hydrogen, alkyl or heteroalkyl), —NRS (O) _n NR′R ″ (where R is hydrogen or alkyl, n is a prime from 0 to 2, and R ′ and R ″ are independently hydrogen, alkyl or heteroalkyl), -S (O) _n R (where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl), -S (O) _n NRR '(where n is an integer from 0 to 2 and R and R' independently mean hydrogen, alkyl or heteroalkyl), -COOR, - (alkylene) COOR (where R is hydrogen or alkyl), -CONR'R '' or - (alkylene) CONR'R '' (where R 'and R'' independently mean hydrogen or alkyl).

The term “heteroalkyl” means an alkyl radical as defined above containing 1, 2 or 3 substituents selected from —NR ^a R ^b , —OR ^c , where R ^a , R ^b and R ^{c are} independently hydrogen, alkyl or acyl, or R ^a and R ^b together form a heterocycloamino group. Representative examples include, but are not limited to, hydroxymethyl, acetoxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-acetylaminomethyl, 3- [pyrrolidin-1-yl] ethyl and t .P.

The term “heteroalkenyl” means an alkenyl radical as defined above containing 1 or 2 substituents selected from —NR ^a R ^b , —OR ^c or —S (O) _n R ^d , where R ^a , R ^b and R ^{c are} independently from each other, hydrogen or alkyl; R ^d is alkyl or —NRR ′ (where R and R ′ are independently hydrogen or alkyl). Representative examples include, but are not limited to, 3-hydroxy-1-propenyl, 3-aminoprop-1-enyl, 2-aminosulfonylethenyl, 2-methylsulfonylethenyl, and the like.

The term “heteroalkynyl” means an alkynyl radical as defined above containing 1 or 2 substituents selected from —NR ^a R ^b , —OR ^c , —S (O) _n R ^d or —S (O) _n NRR ′ (where R and R 'are independently hydrogen or alkyl), where R ^a , R ^b and R ^{c are} independently hydrogen or alkyl and R ^d is alkyl and n is an integer from 0 to 2. Typical examples include, without limitation, 3-hydroxy-1-propynyl, 3-dimethylaminoprop-1-ynyl, and the like.

The term “heteroalkoxy” means the radical —OR, where R is a heteroalkyl group as defined above, for example, 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2-aminoethoxy and the like.

The term “heteroalkylamino” means the radical —NR ^a R ^b , where R ^a is hydrogen or alkyl, and R ^b is a heteroalkyl group as defined above, for example 2-hydroxyethylamino, 3-dimethylaminopropylamino, and the like.

The term “optionally substituted heterocyclylalkyl” means the radical —R ^a R ^b , where R ^a is an alkylene group, and R ^{b is} optionally substituted with a heterocyclyl group as defined above, for example 2- (morpholin-4-yl) ethyl, 3- (piperidin-1 -yl) -2-methylpropyl and the like.

The term “optionally substituted heterocyclylalkenyl” means the radical —R ^a R ^b where R ^a is an alkenylene group and R ^{b is} optionally substituted with a heterocyclyl group as defined above, for example 3- (morpholin-4-yl) prop-1-enyl, 3- (piperidin-1-yl) prop-1-enyl, 3- (4-methylpiperazin-1-yl) prop-1-enyl, and the like.

The term “optionally substituted heterocyclylalkynyl” means the radical —R ^a R ^b where R ^a is an alkynyl group and R ^{b is} optionally substituted with a heterocyclyl group as defined above, for example 3- (morpholin-4-yl) prop-1-ynyl, 3- (piperidin-1-yl) prop-1-ynyl and the like.

The term “optionally substituted heterocyclylalkoxy” means an —OR radical, where R is optionally substituted with a heterocyclyl group as defined above, for example 2- (morpholin-4-yl) ethoxy, 3- (piperazin-1-yl) propoxy, 2- [2-oxopyrrolidinyl -1-yl] ethoxy and the like.

The term “optionally substituted heterocyclylalkylamino” means the radical —NR ^a R ^b , where R ^a is hydrogen or alkyl, and R ^{b is} optionally substituted with a heterocyclylalkyl group as defined above, for example 2- (pyrrolidin-2-yl) ethylamino, 3- (piperidin- 1-yl) propylamino, etc.

The term “optionally substituted heteroaralkyloxy” means the radical —OR ^a , where R ^a is a heteroaralkyl radical, for example 2- (pyridin-3-yl) ethoxy, 2- [3 (2H) -pyridazon-1-yl] ethoxy, and the like .

The term “optionally” means that successively described events or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, the term “aryl group, optionally mono- or disubstituted by an alkyl group” means that an alkyl group is present or absent, and the description includes cases where the aryl group is mono- or disubstituted by an alkyl group, and cases where the heterocyclyl group is not substituted by an alkyl group .

The term “amino protecting group” means those organic groups which are intended to protect nitrogen atoms from undesired reactions during the synthesis, for example benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (BOC), trifluoroacetyl and the like.

In the present invention, only those groups and their substituents are selected which form stable residues and compounds, as is known to those skilled in the art. It should also be understood that the chemical groups described in this context are substituted or unsubstituted, branched or unbranched, as the case may be.

The present invention includes all stereoisomers of the compounds in the form of mixtures thereof, in pure form or in substantially pure form. The definitions of the compounds of the present invention include all possible stereoisomers and mixtures thereof. Racemic forms, individual optical isomers characterized by specific activity are included in the present invention. Racemic forms are separated by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chromatography on a chiral column. Individual optical isomers are prepared from racemates by standard techniques, such as, for example, salt formation with an optically active acid followed by crystallization.

The compounds of the present invention may also include prodrugs thereof. Any compound that is converted in vivo to a bioactive agent is called a prodrug. Various forms of prodrugs are known in the art. Examples of such prodrugs, see, for example, in:

a) Design of Prodrugs, ed. H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, ed. C. Widder, et al. (Acamedic Press, 1985);

b) A Textbook of Drug Design and Development, ed. Krosgaard-Larsen and H. Bundgaard, chapter 5, “Design and Application of Prodrugs,” H. Bundgaard, p. 113-191 (1991) and

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992),

each of which is included in the description by reference.

Used in this context, the term "treatment" means any method according to which one or more symptoms of the disease or disorder is reduced or otherwise changed for the better. The term “treatment” also includes any pharmaceutical use of the compounds and compositions of the present invention, such as the use for the treatment of diseases or disorders mediated by p38 kinase, or diseases and disorders associated with p38 kinase activity, including p38α and p38β kinases.

As used herein, the term “alleviating the symptoms of a particular disease upon administration of a particular compound or specific pharmaceutical composition” means any decrease in the intensity of symptoms, either permanent or temporary, lasting or short-term, which occurs when the action is or is associated with the administration of the composition.

Used in this context, the term "IC ₅₀ " means the amount, concentration or dose of a particular test compound that causes 50% inhibition of the maximum response, such as modulation of p38α kinase activity, which is determined by a special analysis method.

B. Compounds

Analysis of p38 kinase activity, including p38α and p38β kinases, indicates that the compounds of the present invention are active. In one embodiment, the invention includes compounds of the present invention, characterized by formula I

or their pharmaceutically acceptable derivatives, where:

R ¹ is hydrogen, acyl or —P (O) (OH) ₂ ;

R ² means hydrogen, halogen, alkyl or alkylthio;

A means an aryl, heteroaryl or heterocyclic ring, optionally fused to the phenyl ring, provided that the heterocyclic ring is attached to the carbonyl group through a carbon atom in the ring;

B is aryl or heteroaryl;

C is a 5 membered heteroaryl containing one or two heteroatoms in the ring;

D is heteroaryl, optionally substituted heteroaryl or —C (O) NR ⁸⁰ R ⁸¹ , where R ⁸⁰ and R ^{81 are} independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl;

R ³ selected from the group including:

(a) amino, alkylamino or dialkylamino,

(b) acylamino,

(c) optionally substituted heterocyclyl,

(g) optionally substituted aryl or heteroaryl,

(e) heteroalkyl,

(e) heteroalkenyl,

(g) heteroalkynyl,

(h) heteroalkoxy,

(i) heteroalkylamino,

(k) optionally substituted heterocyclylalkyl,

(l) optionally substituted heterocyclylalkenyl,

(m) optionally substituted heterocyclylalkynyl,

(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy,

(o) optionally substituted heterocyclylalkylamino,

(o) optionally substituted heterocyclylalkylcarbonyl,

(p) heteroalkylcarbonyl,

(c) —NHSO ₂ R ⁶ where R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl,

(t) —NHSO ₂ NR ⁷ R ⁸ , where R ⁷ and R ^{8 are} independently hydrogen, alkyl or heteroalkyl,

(y) -Y- (alkylene) -R ⁹ where Y is a single bond, -O-, -NH- or -S (O) _n - (where n is an integer from 0 to 2), R ⁹ is halogen , cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —COOH, —COR ¹⁰ , —COOR ¹¹ , —CONR ¹² R ¹³ , —SO ₂ R ¹⁴ , —SO ₂ NR ¹⁵ R ¹⁶ , —NHSO ₂ R ¹⁷ or —NHSO ₂ NR ¹⁸ R ¹⁹ , where R ¹⁰ is alkyl or optionally substituted heterocyclyl, R ¹¹ is alkyl, and R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ independently from each other mean hydrogen, alkyl or heteroalkyl,

(f) -C (= NR ²⁰ ) (NR ²¹ R ²² ), where R ²⁰ , R ²¹ and R ²² independently mean hydrogen, alkyl or hydroxy, or R ²⁰ and R ²¹ together mean - (CH ₂ ) _n -, where n is 2 or 3, and R ²² means hydrogen or alkyl,

(x) —NHC (X) NR ²³ R ²⁴ , where X is —O— or —S—, and R ²³ and R ^{24 are} independently hydrogen, alkyl or heteroalkyl,

(c) —CONR ²⁵ R ²⁶ , where R ²⁵ and R ^{26 are} independently hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R ²⁵ and R ²⁶ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring,

(h) —S (O) _n R ²⁷ , where n is an integer from 0 to 2, or R ²⁷ is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or —NR ²⁸ R ²⁹ , where R ²⁸ and R ^{29 are} independently of one another mean hydrogen, alkyl or heteroalkyl,

(iii) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl, all optionally substituted with alkyl, halogen, hydroxy or amino groups,

(y) arylaminoalkylene or heteroarylaminoalkylene,

(e) Z-alkylene-NR ³⁰ R ³¹ or Z-alkylene-OR ³² , where Z is —NH—, —N (lower) alkyl) or —O—, and R ³⁰ , R ³¹ and R ³² independently, hydrogen, alkyl or heteroalkyl,

(y) -OC (O) -alkylene-CO ₂ H or -OC (O) -NR'R "(where R 'and R" independently mean hydrogen or alkyl),

(i) heteroarylalkenylene or heteroarylalkynylene;

(aa) hydrogen,

(bb) halogen,

(cc) pseudo-halogen,

(gg) hydroxy,

(dd) optionally substituted alkoxy,

(her) C (L) R ⁴⁰ , where L is O, S or NR ⁵⁵ , R ⁴⁰ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C (L) R ⁵⁶ , halogen, pseudohalogen, OR ⁵⁵ , SR ⁵⁵ , NR ⁵⁷ R ⁵⁸ or SiR ⁵² R ⁵³ R ⁵⁴ ; where R ⁵² , R ⁵³ and R ⁵⁴ are selected as described in the following paragraphs (i) or (ii): (i) R ⁵² , R ⁵³ and R ⁵⁴ each independently means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶² R ⁶³ , or (ii) any two of R ⁵² , R ⁵³ and R ⁵⁴ together form alkylene, alkenylene, alkynylene, heteroalkylene, and the others are selected as described in point (s) ; R ⁵⁵ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R ⁵⁶ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶⁴ R ⁶⁵ , where R ⁶⁴ and R ⁶⁵ each independently means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁶⁶ or NR ⁶² R ⁶³ , or R ⁶⁴ and R ⁶⁵ together form alkylene, alkenylene, alkynylene, heteroalkylene, where R ⁶⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R ⁵⁷ and R ⁵⁸ are selected as described in the following (i) or (ii): (i) R ⁵⁷ and R ⁵⁸ each independently means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁵⁵ , NR ⁶⁷ R ⁶⁸ or C (L) R ⁶⁹ , where R ⁶⁷ and R ⁶⁸ each independently mean hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl, or these substituents together form alkylene, alkenylene, alkynylene, heteroalkylene, and R ⁶⁹ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁷⁰ or NR ⁶² R ⁶³ , where R ⁷⁰ means alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or (ii) R ⁵⁷ and R ⁵⁸ together form alkylene, alkenylene, alkynylene, heteroalkylene; R ⁶² and R ⁶³ each independently mean hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or R ⁶² and R ⁶³ together form alkylene, alkenylene, alkynylene, heteroalkylene, and

(ii) optionally substituted alkyl,

R ⁴ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl,

(g) alkoxy and

(d) hydroxy,

R ⁵ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl,

(g) haloalkyl,

(e) thioalkyl,

(e) hydroxy,

(g) amino

(h) alkylamino,

(i) dialkylamino,

(k) heteroalkyl,

(k) an optionally substituted heterocycle,

(m) optionally substituted heterocyclylalkyl,

(m) optionally substituted heterocyclylalkoxy,

(o) alkylsulfonyl,

(o) aminosulfonyl, monoalkylaminosulfonyl or dialkylaminosulfonyl,

(p) heteroalkoxy and

(c) carboxy;

R ⁶ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl and

(g) alkoxy.

In one embodiment, C is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms in the ring. In another embodiment, C is selected from the group consisting of pyrazole, imidazole, pyrrole, thiazole, isothiazole, oxazole, isoxazole, furan and thiophene. In another embodiment, C is pyrazole or imidazole. In yet another embodiment, C is imidazole. In one embodiment, C is pyrazole.

1. Derivatives of pyrazole

In one embodiment of the present invention, C is a pyrazole ring, and the invention includes compounds of formula II

or their pharmaceutically acceptable derivatives in which said substituents are defined in this context.

In this embodiment, the hydrogen in the NH group in the ring is replaced by one of the substituents shown on the structure (e.g., -C (O) - (A) (R ³ ) (R ⁴ ), -R ² or -B (D) (R ⁶ ) R ⁵ )).

In another embodiment, the present invention includes compounds characterized by formula III

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In one embodiment, the present invention includes compounds characterized by formula IV

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In another embodiment, the present invention includes compounds characterized by formula V

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In one embodiment, the present invention includes compounds characterized by the formula Va

or their pharmaceutically acceptable derivatives, where A, D, R ³ , R ⁴ and R ^{6 are} defined in this context.

2. Derivatives of imidazole

In another embodiment, the present invention includes imidazole compounds of formula VI

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In this embodiment, the hydrogen in the NH group in the cycle is replaced by one of the substituents shown on the structure (e.g., —C (O) —A (R ³ ) (R ⁴ ), —R ^2, or —B (D) (R ⁶ ) (R ⁵ )).

In another embodiment, the invention includes compounds characterized by formula VII

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In yet another embodiment, the invention includes compounds characterized by formula VIII

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

3. Other embodiments of the present invention

In other embodiments, use is made of compounds characterized by the above formulas, or pharmaceutically acceptable derivatives thereof, wherein R ¹ is hydrogen. In one embodiment, R ² means hydrogen or (ness.) Alkyl. In another embodiment, R ² means hydrogen.

In yet another embodiment, G is OR ⁸³ or NR ⁸⁰ R ⁸¹ . In another embodiment, R ⁸³ means alkyl or cycloalkyl. In one embodiment, R ⁸³ means alkyl. In another embodiment, R ⁸³ means ethyl. In yet another embodiment, R ⁸⁰ and R ⁸¹ each independently mean hydrogen or cycloalkyl. In one embodiment, R ⁸⁰ and R ⁸¹ each independently mean hydrogen, alkyl or cycloalkyl. In another embodiment, R ⁸⁰ and R ⁸¹ each independently mean hydrogen or cyclohexyl. In one embodiment, G is NH ₂ or NH (cyclohexyl).

In another embodiment, G is an aryl, heteroaryl, cycloalkyl, heterocyclyl or heterocyclic ring optionally fused to a phenyl ring and substituted with R ³ and R ⁴ , provided that the heterocyclic ring is attached to the carbonyl group through a carbon atom in the ring. In one embodiment, G is phenyl, cyclohexyl, cyclopentyl or benzyl and is substituted with R ³ and R ⁴ . In another embodiment, G is phenyl and is substituted with R ³ and R ⁴ .

In one embodiment, A means an aryl ring. In another embodiment, A is a phenyl ring.

In one embodiment, B is an aryl ring. In another embodiment, B is a phenyl ring.

In one embodiment, D is —C (O) NR ⁸⁰ R ⁸¹ . In another embodiment, R ⁸⁰ and R ⁸¹ each independently mean hydrogen, cycloalkyl or alkoxy. In one embodiment, R ⁸⁰ means hydrogen. In another embodiment, R ⁸¹ means cycloalkyl or alkoxy. In one embodiment, R ⁸¹ is C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkoxy. In another embodiment, R ⁸¹ means cyclopropyl or methoxy.

In one embodiment, D is optionally substituted heteroaryl. In another embodiment, D is an optionally substituted triazolyl. In one embodiment, D is 1,2,4-triazol-3-yl.

In another embodiment, R ³ is hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C (L) R ⁴⁰ , halogen, pseudo-halogen, or OR ⁴¹ , where L is O, S or NR ⁵⁵ , R ⁴⁰ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C (L) R ⁵⁶ , halogen, pseudohalogen, OR ⁵⁵ , SR ⁵⁵ , NR ⁵⁷ R ⁵⁸ or SiR ⁵² R ⁵³ R ⁵⁴ , R ⁴¹ means hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C (L) R ⁵⁹ , NR ⁶⁰ R ⁶¹ or SiR ⁵² R ⁵³ R ⁵⁴ , where R ⁵² , R ⁵³ and R ⁵⁴ are selected as described in the following (i) or (ii): (i) R ⁵² , R ⁵³ and R ⁵⁴ each independently means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶² R ⁶³ ; or (ii) any two of R ⁵² , R ⁵³ and R ⁵⁴ together form alkylene, alkenylene, alkynylene, heteroalkylene, and the others are selected as described in paragraph (i); R ⁵⁵ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R ⁵⁶ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶⁴ R ⁶⁵ , where R ⁶⁴ and R ⁶⁵ each independently means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁶⁶ or NR ⁶² R ⁶³ , or R ⁶⁴ and R ⁶⁵ together form alkylene, alkenylene, alkynylene, heteroalkylene, where R ⁶⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R ⁵⁷ and R ⁵⁸ are selected as described in the following (i) or (ii): (i) R ⁵⁷ and R ⁵⁸ each independently means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁵⁵ , NR ⁶⁷ R ⁶⁸ or C (L) R ⁶⁹ , where R ⁶⁷ and R ⁶⁸ each independently mean hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl, or these substituents together form alkylene, alkenylene, alkynylene, heteroalkylene and R ⁶⁹ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁷⁰ or NR ⁶² R ⁶³ , where R ⁷⁰ means alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or (ii) R ⁵⁷ and R ⁵⁸ together form alkylene, alkenylene, alkynylene, heteroalkylene; R ⁵⁹ means hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁷⁰ or NR ⁶² R ⁶³ ; R ⁶⁰ and R ⁶¹ each independently mean hydrogen, alkyl, alkenyl, alkynyl, arylteteroaria, heteroaryl, cycloalkyl, heterocyclyl or C (L) R ⁷¹ ; where R ⁷¹ means alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶² R ⁶³ ; R ⁶⁰ and R ⁶¹ together form alkylene, alkenylene, alkynylene, heteroalkylene; R ⁶² and R ⁶³ each independently mean hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or R ⁶² and R ⁶³ together form alkylene, alkenylene, alkynylene, heteroalkylene.

In one embodiment, R ³ means hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C (L) R ⁴⁰ , halogen or OR ⁴¹ . In another embodiment, R ³ means hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C (L) R ⁴⁰ , iodine, chlorine or OR ⁴¹ . In one embodiment, R ³ means hydrogen, optionally substituted dioxolanyl, optionally substituted methyl, C (L) R ⁴⁰ , iodine, chlorine or OR ⁴¹ . In another embodiment, R ³ means hydrogen, 2-dioxolanyl, optionally substituted methyl, C (O) R ⁴⁰ , iodine, chlorine or OR ⁴¹ . In one embodiment, R ³ means hydrogen, 2-dioxolanyl, optionally substituted methyl, CHO, iodine, chlorine or OR ⁴¹ . In another embodiment, R ³ means hydrogen.

In one embodiment, R ³ means optionally substituted methyl. In another embodiment, R ³ is methyl, which is optionally substituted with heterocyclyl, hydroxy, aralkylamino or heterocyclylalkylamino groups. In one embodiment, R ³ is N-morpholinylmethyl, hydroxymethyl, N- (2- (3-chlorophenyl) -1-ethyl) aminomethyl, N- (2-morpholinyl-1-ethyl) aminomethyl or 4-piperisinylmethyl.

In another embodiment, A is O. In one embodiment, R ⁴⁰ is hydrogen, optionally substituted alkyl or cycloalkyl. In another embodiment, R ⁴⁰ means hydrogen or alkyl. In one embodiment, R ⁴⁰ means hydrogen.

In yet another embodiment, R ⁴¹ means hydrogen or optionally substituted alkyl. In another embodiment, R ⁴¹ is hydrogen or alkyl, which is optionally substituted with heterocyclyl, aryl, dialkylamino, halogen or hydroxy groups. In one embodiment, R ⁴¹ is hydrogen or C ₁ -C ₃ alkyl, which is optionally substituted with heterocyclyl, phenyl, dialkylamino, halogen or hydroxy groups. In another embodiment, R ⁴¹ means hydrogen, 2- (N-morpholinyl) eth-1-yl, benzyl, 2- (N, N-di- (2-hydroxy-1-ethyl) amino) -1-ethyl, 2- bromo-1-ethyl, 2,2-dioxolan-4-ylmethyl, 2- (4-methylpiperazin-1-yl) -1-ethyl or 2,3-dihydroxy-1-propyl. In one embodiment, R ⁴¹ means (S) -2,3-dihydroxy-1-propyl.

In another embodiment, R ⁴ means hydrogen. In one embodiment, R ⁵ means alkyl. In another embodiment, R ⁵ means methyl. In one embodiment, R ⁶ means hydrogen.

In another embodiment, use is made of compounds characterized by the above formulas, including formulas I-VIII, or their pharmaceutically acceptable derivatives, where:

R ¹ is hydrogen, acyl or —P (O) (OH) ₂ ;

R ² means hydrogen, halogen, alkyl or alkylthio;

A means an aryl, heteroaryl or heterocyclic ring, optionally fused to the phenyl ring, provided that the heterocyclic ring is attached to the carbonyl group through a carbon atom in the ring;

B is aryl or heteroaryl;

D is heteroaryl, optionally substituted heteroaryl or —C (O) NR ⁸⁰ R ⁸¹ ; where R ⁸⁰ and R ⁸¹ independently mean hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl;

R ³ selected from the group including:

(a) amino, alkylamino or dialkylamino,

(b) acylamino,

(c) optionally substituted heterocyclyl,

(g) optionally substituted aryl or heteroaryl,

(e) heteroalkyl,

(e) heteroalkenyl,

(g) heteroalkynyl,

(h) heteroalkoxy,

(i) heteroalkylamino,

(k) optionally substituted heterocyclylalkyl,

(l) optionally substituted heterocyclylalkenyl,

(m) optionally substituted heterocyclylalkynyl,

(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy,

(o) optionally substituted heterocyclylalkylamino,

(o) optionally substituted heterocyclylalkylcarbonyl,

(p) heteroalkylcarbonyl,

(c) —NHSO ₂ R ⁶ where R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl,

(t) —NHSO ₂ NR ⁷ R ⁸ , where R ⁷ and R ^{8 are} independently hydrogen, alkyl or heteroalkyl,

(y) -Y- (alkylene) -R ⁹ where Y is a single bond, -O-, -NH- or -S (O) _n - (where n is an integer from 0 to 2) and R ⁹ is cyano optionally substituted heteroaryl, —COOH, —COR ¹⁰ , —COOR ¹¹ , —CONR ¹² R ¹³ , —SO ₂ R ¹⁴ , —SO ₂ NR ¹⁵ R ¹⁶ , —NHSO ₂ R ^17, or —NHSO ₂ NR ¹⁸ R ¹⁹ , where R ¹⁰ means alkyl or optionally substituted heterocyclyl, R ¹¹ means alkyl and R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ independently from each other mean hydrogen, alkyl or heteroalkyl,

(f) -C (= NR ²⁰ ) (NR ²¹ R ²² ), where R ²⁰ , R ²¹ and R ²² independently mean hydrogen, alkyl or hydroxy, or R ²⁰ and R ²¹ together mean - (CH ₂ ) _n -, where n is 2 or 3, and R ²² means hydrogen or alkyl,

(x) —NHC (X) NR ²³ R ²⁴ , where X is —O— or —S—, and R ²³ and R ^{24 are} independently hydrogen, alkyl or heteroalkyl,

(c) —CONR ²⁵ R ²⁶ , where R ²⁵ and R ^{26 are} independently hydrogen, alkyl heteroalkyl or optionally substituted heterocyclylalkyl, or R ²⁵ and R ²⁶ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring

(h) —S (O) _n R ²⁷ , where n is an integer from 0 to 2, or R ²⁷ is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or —NR ²⁸ R ²⁹ , where R ²⁸ and R ^{29 are} independently of one another mean hydrogen, alkyl or heteroalkyl,

(iii) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl, all optionally substituted with alkyl, halogen, hydroxy or amino groups,

(y) arylaminoalkylene or heteroarylaminoalkylene,

(e) Z-alkylene-NR ³⁰ R ³¹ or Z-alkylene-OR ³² , where Z is —NH—, —N (lower) alkyl) or —O—, and R ³⁰ , R ³¹ and R ³² independently, hydrogen, alkyl or heteroalkyl,

(y) -OC (O) -alkylene-CO ₂ H or -OC (O) -NR′R ″ (where R ′ and R ″ independently are hydrogen or alkyl) and

(i) heteroarylalkenylene or heteroarylalkynylene;

R ⁴ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl,

(g) alkoxy and

(d) hydroxy,

R ⁵ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl,

(g) haloalkyl,

(e) thioalkyl,

(e) hydroxy,

(g) amino

(h) alkylamino,

(i) dialkylamino,

(k) heteroalkyl,

(k) an optionally substituted heterocycle,

(m) optionally substituted heterocyclylalkyl,

(m) optionally substituted heterocyclylalkoxy,

(o) alkylsulfonyl,

(o) aminosulfonyl, monoalkylaminosulfonyl or dialkylaminosulfonyl,

(p) heteroalkoxy and

(c) carboxy.

R ⁶ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl and

(g) alkoxy;

their prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.

In another embodiment, compounds are provided wherein:

R ¹ means hydrogen or acyl,

R ² means hydrogen or alkyl,

A means an aryl or heteroaryl ring.

In one embodiment, compounds are provided wherein:

R ¹ is hydrogen, acyl or —P (O) (OH) ₂ ;

R ² means hydrogen, halogen, alkyl or alkylthio;

A means aryl, heteroaryl or heterocyclyl, optionally fused to the phenyl ring, provided that the heterocyclic ring is attached to the carbonyl group through a carbon atom in the ring;

B is aryl or heteroaryl;

R ³ selected from the group including:

(a) amino,

(b) acylamino,

(c) an optionally substituted heterocycle,

(d) heteroaryl, optionally substituted with substituents selected from the group consisting of halogen, alkyl or alkoxy,

(e) heteroalkyl,

(e) heteroalkenyl,

(g) heteroalkynyl,

(h) heteroalkoxy,

(i) heteroalkylamino,

(k) optionally substituted heterocyclylalkyl,

(l) optionally substituted heterocyclylalkenyl,

(m) optionally substituted heterocyclylalkynyl,

(m) optionally substituted heterocyclylalkoxy,

(o) optionally substituted heterocyclylalkylamino,

(o) optionally substituted heterocyclylalkylcarbonyl,

(p) heteroalkylcarbonyl,

(c) —NHSO ₂ R ⁶ where R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl,

(t) —NHSO ₂ NR ⁷ R ⁸ , where R ⁷ and R ^{8 are} independently hydrogen, alkyl or heteroalkyl,

(y) -Y- (alkylene) -R ⁹ where Y is a single bond, -O-, -NH- or -S (O) _n - (where n is an integer from 0 to 2) and R ⁹ is cyano , heteroaryl, —COOH, —COR ¹⁰ , —COOR ¹¹ , —CONR ¹² R ¹³ , —SO ₂ R ¹⁴ , —SO ₂ NR ¹⁵ R ¹⁶ , —NHSO ₂ R ¹⁷ or —NHSO ₂ NR ¹⁸ R ¹⁹ , where R ¹⁰ is alkyl or an optionally substituted heterocycle, R ¹¹ is alkyl, and R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ^{19 are} independently hydrogen, alkyl or heteroalkyl,

(f) -C (= NR ²⁰ ) (NR ²¹ R ²² ), where R ²⁰ , R ²¹ and R ²² independently mean hydrogen, alkyl or hydroxy, or R ²⁰ and R ²¹ together mean - (CH ₂ ) _n- , where n is 2 or 3, and R ²² means hydrogen or alkyl,

(x) —NHC (X) NR ²³ R ²⁴ , where X is —O— or —S—, and R ²³ and R ^{24 are} independently hydrogen, alkyl or heteroalkyl,

(c) —CONR ²⁵ R ²⁶ , where R ²⁵ and R ^{26 are} independently hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R ²⁵ and R ²⁶ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring,

(h) —S (O) _n R, where n is an integer from 0 to 2, and R ²⁷ is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl, or —NR ²⁸ R ²⁹ , where R ²⁸ and R ^{29 are} independently of one another mean hydrogen, alkyl or heteroalkyl,

R ⁴ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl and

(g) alkoxy;

R ⁵ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl,

(g) haloalkyl,

(e) thioalkyl,

(e) hydroxy,

(g) amino

(h) alkylamino,

(i) dialkylamino,

(k) heteroalkyl,

(k) an optionally substituted heterocycle,

(m) optionally substituted heterocyclylalkyl; and

(m) optionally substituted heterocyclylalkoxy.

R ⁶ selected from the group including

(a) hydrogen,

(b) halogen,

(c) alkyl and

(g) alkoxy.

In another embodiment, compounds are provided wherein R ³ is

(a) optionally substituted heterocyclyl,

(b) aryl or heteroaryl, both optionally substituted with substituents selected from the group consisting of halogen, alkyl, amino, alkoxy, carboxy, lower alkoxycarbonyl, SO ₂ R ′ (wherein R ′ is alkyl) or —O ₂ NHR 'R''(whereR' and R '' independently mean hydrogen or alkyl),

(c) heteroalkyl,

(g) heteroalkenyl,

(e) heteroalkylamino,

(e) heteroalkoxy,

(g) optionally substituted heterocyclylalkyl or heterocyclyloxy,

(h) optionally substituted heterocyclylalkenyl,

(i) optionally substituted heterocyclylalkynyl,

(k) optionally substituted heterocyclylalkoxy,

(l) optionally substituted heterocyclylalkylamino,

(m) optionally substituted heterocyclylalkylcarbonyl,

(n) —Y— (alkylene) —R ⁹ where Y is a single bond, —O—, —NH— and R ^{9 are} optionally substituted heteroaryl, —CONR ¹² R, —SO ₂ R ¹⁴ , —SO ₂ NR ¹⁵ R ¹⁶ , —NHSO ₂ R ¹⁷ or —NHSO ₂ NR ¹⁸ R ¹⁹ , where R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ^18, and R ^{19 are} independently heteroalkyl, hydrogen, alkyl or heteroalkyl,

(o) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl, all optionally substituted with alkyl, halogen, hydroxy or amino groups,

(o) arylaminoalkylene or heteroarylaminoalkylene; or

(p) Z-alkylene-NR ³⁰ R ³¹ , where Z is —NH—, —N (alkyl) - or —O—, and R ³⁰ and R ^{31 are} independently hydrogen, alkyl or heteroalkyl.

In another embodiment, compounds are provided wherein R ¹ and R ^{2 are} hydrogen and B is phenyl. In a further embodiment, compounds are provided wherein R ⁴ is hydrogen and R ⁵ is halogen or alkyl. In another embodiment, compounds are provided wherein R ⁵ is chloro, fluoro or methyl, and R ⁶ is hydrogen, chloro, fluoro, methyl or methoxy. In one embodiment, compounds are provided wherein R ³ is optionally substituted heteroaryl.

In another embodiment, compounds are provided wherein R ³ is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxide pyridin-2-yl, N-oxide pyridin-3-yl, N-oxide pyridin-4- sludge or pyridon-2-yl, all optionally substituted. In another embodiment, compounds are provided wherein R ³ is at position 3. In another embodiment, compounds are provided wherein R ⁵ is 4-F or 2-Me and R ⁶ is hydrogen. In one embodiment, compounds are provided wherein R ^{3 is} optionally substituted with a phenyl group.

In a further embodiment, compounds are provided wherein R ³ is 3-sulfamoylphenyl, 3-methylsulfonylphenyl, 3-carboxyphenyl or 3-ethoxycarbonylphenyl. In another embodiment, compounds are provided wherein R ⁵ is 4-F and R ⁶ is hydrogen.

In another embodiment, compounds are provided wherein R ³ is

(a) heteroalkyl,

(b) heteroalkoxy,

(c) heteroalkylamino,

(g) optionally substituted heterocyclylalkyl,

(e) optionally substituted heterocyclylalkoxy,

(e) optionally substituted heterocyclylalkylamino,

(g) —Y— (alkylene) —R ⁹ where Y is a single bond, —O— or —NH— and R ⁹ is an optionally substituted heteroaryl, —CONR ¹² R ¹³ , —SO ₂ R ¹⁴ , —SO ₂ NR ¹⁵ R ¹⁶ , —NHSO ₂ R ^17, or —NHSO ₂ NR ¹⁸ R ¹⁹ , where R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ^{19 are} independently hydrogen, alkyl or heteroalkyl, or

(h) Z-alkylene-NR ³⁰ R ³¹ , where Z is —NH—, —N (alkyl) - or —O—, and R ³⁰ and R ^{31 are} independently hydrogen, alkyl or heteroalkyl.

In another embodiment, compounds are provided wherein R ³ is heteroalkyl. In another embodiment, compounds are provided wherein R ³ is at position 3 and is selected from the group consisting of 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 2-dimethylaminoethylamino, 3-dimethylaminopropylamino, hydroxymethyl, 1,2-dihydroxyethyl, 3- hydroxy-3-methyl-1-butyl or 3-hydroxybutyl. In one embodiment, compounds are provided wherein R ⁵ is 2-F and R ⁶ is 4-F.

In another embodiment, compounds are provided wherein R ⁵ is 2-Me and R ⁶ is hydrogen. In a further embodiment, compounds are provided wherein R ⁹ is heteroalkoxy or heteroalkylamino. In one embodiment, compounds are provided wherein R ³ is at position 3 and is selected from the group consisting of 3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 2-dimethylaminoethylamino and 3-dimethylaminopropylamino.

In another embodiment, compounds are provided wherein R ³ is optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy, or optionally substituted heterocyclylalkylamino. In one embodiment, compounds are provided wherein R ³ is at position 3 and is selected from the group consisting of 3- (morpholin-4-yl) propoxy, 2- (morpholin-4-yl) ethoxy, 2- (2-oxopyrrolidin-1 -yl) ethoxy, 3- (morpholin-4-yl) propyl, 2- (morpholin-4-yl) ethyl, 4- (morpholin-4-yl) butyl, 3- (morpholin-4-yl) propylamino, 2 - (morpholin-4-yl) ethylamino, 4-hydroxypiperidinylmethyl, 2- (S, S-dioxothiamorpholin-4-yl) ethyl, 3- (S, S-dioxothiamorpholin-4-yl) propyl and N-methylpiperazinylmethyl.

In yet another embodiment, compounds are provided wherein R ³ is —Y- (alkylene) —R ⁹ , where Y is a single bond, —O— or —NH— and R ⁹ is an optionally substituted heteroaryl, —CONR ¹² R ¹³ , —SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ¹⁷ or -NHSO ₂ NR ¹⁸ R ¹⁹ , where R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ independently, hydrogen, alkyl or heteroalkyl. In yet another embodiment, compounds are provided wherein Y is a single bond and R ⁹ is —SO ₂ R ¹⁴ or —SO ₂ NR ¹⁵ R ¹⁶ .

In another embodiment, compounds are provided wherein R ³ is 5-methylsulfonylethyl or sulfamoylethyl.

In one embodiment, the compounds are selected from the group consisting of 5-amino-1- (4-fluorophenyl) -4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazole, 5-amino-1- (2,4- difluorophenyl) -4- [3- (3-morpholin-4-ylpropyl) benzoyl] pyrazole, 5-amino-4- (3-aminobenzoyl) -1- (4-fluorophenyl) pyrazole, 5-amino-1- (4 -fluorophenyl) -4- [3- (3-morpholin-4-ylpropyl) benzoyl] pyrazole, 5-amino-4- [3- (2-aminosulfonylethenyl) benzoyl] -1- (4-fluorophenyl) pyrazole, 5- amino-4- (3-acetylaminobenzoyl) -1-phenylpyrazole, 5-amino-4- [3- (2-aminoethyl) benziol] -1- (4-fluorophenyl) pyrazole, 5-amino-1- (4-fluorophenyl ) -4- [3- (3-morpholin-4-ylpropylamino) benzoyl] pyrazole, 5-amino-4- [3- (2-aminosulfon onylethyl) benzoyl] -1- (4-fluorophenyl) pyrazole and 5-amino-1- (4-fluorophenyl) -4- (3-pyridin-3-ylbenzoyl) pyrazole.

In another embodiment, the compounds are selected from the group consisting of 5-amino-1- (2-methylphenyl) -4- [3-pyridin-3-yl) benzoyl] pyrazole, 5-amino-1- (2-methylphenyl) -4- [3- (N-oxidopyridin-3-yl) benzoyl] pyrazole, 5-amino-4- [3- (2,3-dihydroxypropoxy) benzoyl] -1- (4-fluorophenyl) pyrazole, 5-amino-4- [3- (1,2-dihydroxyethyl) benzoyl] -1- (4-fluorophenyl) pyrazole, 5-amino-1- (4-fluorophenyl) -4- [3- (sulfamoylbenzoyl] pyrazole, 5-amino-1- (4-fluorophenyl) -4- [3- (3-hydroxy-3-methylbutyl) benzoyl] pyrazole, 5-amino-1- (4-fluorophenyl) -4- [3- (2- (1-hydroxycyclopentyl) ethyl ) benzoyl] pyrazole, 5-amino-4- [3- (2-methylsulfonylethyl) benzoyl] -1- (4-fluorophenyl) pyrazole 5-amino-1- (2,4-difluorophenyl) -4- [3- (2-gidroksietilsulfonil) benzoyl] pyrazole.

In one embodiment, the compounds are selected from the group consisting of 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-methoxy-4-methylbenzamide, 3- (5-amino-4-benzoylpyrazole-1 -yl) -N-methoxy-4-methylbenzamide, 3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid, 3- (5-amino-4-benzoylpyrazol-1-yl) -N -cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -4-methylbenzoic acid, 3- [5-amino-4- (3-iodobenzoyl) pyrazole-1 -yl] -N-cyclopropyl-4-methylbenzamide, {5-amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] -1H-pyrazol-4 -yl} phenylmethanone, 3- [5-amino-4- (3- [1,3] dioxolan-2-ylbenzoyl) pyrazol-1-yl] -N-cyclo propyl-4-methylbenzamide, 3- [5-amino-4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (3-hydroxymethylbenzoyl) pyrazole -1-yl] -N-cyclopropyl-4-methylbenzamide, 3- {5-amino-4- [3- (4-methylpiperazin-1-ylmethyl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4- methylbenzamide, 3- [5-amino-4- (3-morpholin-4-ylmethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (3-morpholin-4 -ylmethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (3-benzyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [ 5-amino-4- (3-hydroxybenzoyl) pyrazol-1-yl] -N-cyclopropyl- 4-methylbenzamide, 3- [5-amino-4- (4-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide and 3- (5-amino-4-benzoylimidazol-1-yl) -N -cyclopropyl-4-methylbenzamide.

In another embodiment, the compounds are selected from the group consisting of 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-methoxy-4-methylbenzamide, 3- (5-amino-4-benzoylpyrazole-1 -yl) -N-methoxy-4-methylbenzamide, 3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, {5-amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] -1H -pyrazol-4-yl} phenylmethanone, 3- [5-amino-4- (3- [1,3] dioxolan-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [ 5-amino-4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (3-hydroxymeth lbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- {5-amino-4- [3- (4-methylpiperazin-1-ylmethyl) benzoyl] pyrazol-1-yl} -N-cyclopropyl -4-methylbenzamide, 3- [5-amino-4- (3-morpholin-4-ylmethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (3- morpholin-4-ylmethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (3-benzyloxybenzene) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 3- [5-amino-4- (3-hydroxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, 3- [5-amino-4- (4-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide or 3- (5-amino-4-benzoylimidazol-1-i ) -N-cyclopropyl-4-methylbenzamide.

In another embodiment, the compounds are selected from the group including

3- {5-amino-4- [3- (2-dimethylaminoethylcarbamoyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (5-chlorothiophen-2-carbonyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-hydrazinocarbonylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-cyclohexanecarbonylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-cyclopentanecarbonylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-phenylacetylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (tetrahydropyran-4-carbonyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-ethylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide and

3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide.

In yet another embodiment, the compounds are selected from the group including

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester,

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester,

3- (5-amino-4-cyclopentanecarbonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-hydrazinocarbonylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid benzylamide,

3- (5-amino-4-cyclohexanecarbonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide and

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid cyclohexylamide.

In another embodiment, the compounds are selected from the group including:

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide,

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methanesulfonyl-1H-pyrazole-4-carboxylic acid amide,

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester,

5-amino-3 - [(3-chlorobenzylcarbamoyl) methoxy] -1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester,

3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-benzoyl-3-methanesulfonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-benzoyl-3-methoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3- (2-hydroxyethoxy) -1H-pyrazole-4-carboxylic acid ethyl ester,

4- [5-amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazol-3-yloxy] piperidine tert-butyl ester

1-carboxylic acid

3- (5-amino-4-benzoyl-3-methylsulfanylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide and

3- [5-amino-4-benzoyl-3- (2-methoxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide.

In another embodiment, the compounds are selected from the group including:

3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-methoxy-4-methylbenzamide,

3- (5-amino-4-benzoylpyrazol-1-yl) -N-methoxy-4-methylbenzamide,

3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid,

3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -4-methylbenzoic acid,

3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

{5-amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] -1H-pyrazol-4-yl} phenylmethanone,

3- [5-amino-4- (3- [1,3] dioxolan-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-hydroxymethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- {5-amino-4- [3- (4-methylpiperazin-1-ylmethyl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-morpholin-4-ylmethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-benzyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-hydroxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (4-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-benzoylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-cyclohexanecarbonylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-cyclopentanecarbonylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-phenylacetylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- {5-amino-4- [3- (2-dimethylaminoethylcarbamoyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-ethylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-methylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-cyclopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (3-cyclopentylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- {5-amino-4- [3- (morpholin-4-carbonyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide,

3- {5-amino-4- [3- (cyclopropylmethylcarbamoyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4- (tetrahydropyran-4-carbonyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-benzoyl-3-methoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-benzoyl-3-ethoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4-benzoyl-3- (2-methoxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

3- [5-amino-4-benzoyl-3- (2-benzyloxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,

4- [5-amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazol-3-yloxy] piperidin-1- tert-butyl ester

carboxylic acid

3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide trifluoroacetate,

3- (5-amino-4-benzoyl-3-methylsulfanylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

3- (5-amino-4-benzoyl-3-methanesulfonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide,

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methanesulfonyl-1H-pyrazole-4-carboxylic acid amide and

5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester.

B. Synthesis of compounds

The present invention also provides a process for preparing a compound of formula (I), said process comprising the following steps:

(i) the interaction of 2-keto-3-phenylaminoacrylonitrile of the formula 1:

with hydrazine of formula 2

where R ³ , R ⁴ , R ⁵ and R ^{6 are as} defined above, whereby a compound of formula (I) is obtained, wherein R ¹ is hydrogen, or

(ii) the interaction of 2-keto-3-phenylaminoacrylonitrile formula 3

where Z is hydroxy, nitro or halogen, and R ^{4 is as} defined above with hydrazine of formula 2, whereby a compound of formula 4 is obtained

followed by conversion of the Z group to the desired R ³ group, whereby a compound of formula (I) is obtained, where R ¹ is hydrogen;

(iii) optional modification of any groups R ¹ , R ³ , R ′, R ⁵ or R ⁶ ;

(iv) optionally converting the compound of formula (I) obtained in steps (i), (ii) or (iii) described above into the corresponding acid addition salt when treated with an acid;

(v) optionally converting a compound of formula (I) obtained in steps (i), (ii) or (iii) described above into an appropriate free base upon treatment with a base and

(vi) optionally separating the stereoisomer mixture of the compound of formula (I) obtained in steps (i) to (v) described above, wherein an individual stereoisomer is obtained.

The present invention also provides a process for preparing a compound of formula I, which comprises reacting compounds of formula 5

where R ⁵ and R ^{6 are} defined above, a L is a leaving group under the conditions of an organometallic substitution reaction, which includes, without limitation, halogen, pseudohalogen, aryloxy, perfluoroaryloxy, N-alkoxyamino, including N-methoxyamino,

with an organometallic reagent of the formula

where R ³ and R ^{4 are as} defined above, and M is a metal atom including, but not limited to, an alkali metal, an alkaline earth metal, and a transition metal such as Li, K, and Mg, whereby a compound of formula (I) is obtained, where R ¹ means hydrogen,

(ii) optional modification of any groups R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ ;

(iii) optionally converting the compound of formula (I) obtained in steps (i) or (ii) described above into the corresponding acid addition salt when treated with an acid;

(iv) optionally converting a compound of formula (I) obtained in steps (i) or (ii) described above into an appropriate free base when treated with a base, and optionally separating a stereoisomer mixture of a compound of formula (I) obtained in steps (i) or (iv) described above, wherein an individual stereoisomer is obtained.

The compounds described in this context are presented as examples, and can be obtained by known methods, similar to that described in the present invention, using known methods of chemical synthesis, including methods similar to those described in the Examples section.

Proposed in the present invention, the compounds are mainly obtained by the following schemes, as well as by known methods. Additional synthesis methods are described, for example, in US patent No. 6376527, 6316466 and 6444696 and in international application No. WO 99/57101, all of which are incorporated into this invention by reference.

In addition to the above documents, the present invention provides the following examples of methods (without limitation to those listed) for preparing the compounds of the present invention (see Schemes 1-8 below).

Amines attached to an aryl or heteroaryl ring system are used as intermediates of the present invention. Many methods are known for preparing such intermediates. Several methods for producing amines used to prepare the compounds of the present invention are shown in Schemes 1-7.

The substituted type (II) anilines used in the present invention are obtained from a commercial preparation of 3-amino-4-methylbenzoic acid, as shown in Scheme 1, using methods similar to that described in international application No. WO 02/40486. The amino group of aniline is protected by the Boc group. Then, condensation with methylamine is carried out in the presence of the condensing agents EDC and HOBt. The Boc group is removed using HCl in dioxane to give the desired substituted type (II) aniline as hydrochloride.

Scheme 1

The substituted type (III) anilines used in the present invention are obtained from a commercial preparation of 3-amino-4-methylbenzoic acid, as shown in Scheme 2. After condensation with cyclopropylamine in the presence of an EDC condensing agent, type (III) aniline is obtained.

Scheme 2

The substituted type (IV) anilines used in the present invention are obtained from a commercial preparation of 4-methyl-3-nitrobenzoic acid, as shown in Scheme 3, using methods similar to that described in international application No. WO 03/033482. After condensation of the acid with tert-butoxycarbonyl hydrazide in the presence of HBTU and HOBt condensing agents, a protected acyl hydrazide is obtained. After removal of the protective groups in the presence of TFA and condensation with triethyl orthoformate, oxadiazolyl substituted nitrotoluene is obtained. After hydrogenation of the nitro groups, the desired type (IV) aniline is obtained.

Scheme 3

The substituted type (V) anilines used in the present invention are obtained from the commercial preparation of 4-methyl-3-nitrobenzamide, as shown in Scheme 4, using the methods described by Han et al. J. Med. Chem., 41, 2019-2028 (1998). The specified arylcarboxamide is condensed with N, N-dimethylformamide diethyl acetal. Then, a reaction with hydrazine in acetic acid is carried out, and a triazolyl-substituted nitrotoluene is obtained. After hydrogenation of the nitro groups, the desired type (V) aniline is obtained.

Scheme 4

Замещенные анилины типа (VI), используемые в настоящем изобретении, получают из коммерческого препарата метилового эфира 4-иодбензойной кислоты, как показано на схеме 5. После нитрования ароматического предшественника с последующим восстановлением нитрогруппы получают анилин. Затем проводят конденсацию с этинилтриметилсиланом в присутствии катализатора на основе палладия с последующим десилилированием и омылением, при этом получают требуемую этинилзамещенную аминобензойную кислоту. При конденсации с метоксиамином в присутствии конденсирующего агента EDC получают требуемый анилин (VI). См., например, работу Eur. J. Org. Chem; 4607 (2001).

The substituted type (VI) anilines used in the present invention are obtained from the commercial preparation of 4-iodobenzoic acid methyl ester, as shown in Scheme 5. After nitration of the aromatic precursor followed by reduction of the nitro group, aniline is obtained. Then, condensation is carried out with ethynyltrimethylsilane in the presence of a palladium-based catalyst, followed by desilylation and saponification, whereby the desired ethynyl substituted aminobenzoic acid is obtained. By condensation with methoxyamine in the presence of an EDC condensing agent, the desired aniline (VI) is obtained. See, for example, Eur. J. Org. Chem; 4607 (2001).

Scheme 5

В другом варианте замещенный анилин типа (VI), используемый в настоящем изобретении, получают из 4-амино-3-нитробензойной кислоты, как показано на схеме 6. После реакции замещения диазогруппы на иод с использованием соли диазония с последующей этерификацией метанолом получают метиловый эфир 4-иод-3-нитробензойной кислоты. Нитрогруппу восстанавливают SnCl₂, при этом получают требуемый анилин. Затем проводят конденсацию с этинилтриметилсиланом в присутствии катализатора на основе палладия с последующим десилилированием и омылением, при этом получают этинилзамещенную аминобензойную кислоту. При конденсации с метоксиамином в присутствии конденсирующего агента EDC получают требуемый анилин (VI). См., например, Eur. J. Org. Chem., 4607 (2001).

In another embodiment, the substituted type (VI) aniline used in the present invention is prepared from 4-amino-3-nitrobenzoic acid, as shown in Scheme 6. After the diazogroup is replaced by iodine using a diazonium salt, followed by etherification with methanol, methyl ester 4 iodine-3-nitrobenzoic acid. The nitro group is reduced with SnCl ₂ , and the desired aniline is obtained. Then, condensation is carried out with ethynyltrimethylsilane in the presence of a palladium-based catalyst, followed by desilylation and saponification, whereby an ethynyl substituted aminobenzoic acid is obtained. By condensation with methoxyamine in the presence of an EDC condensing agent, the desired aniline (VI) is obtained. See, for example, Eur. J. Org. Chem., 4607 (2001).

Scheme 6

Как показано на схеме 7, замещенные анилины типа (VII), используемые в настоящем изобретении, получают из промежуточного метилового эфира 4-иодтринитробензойной кислоты, который синтезируют, как показано на схеме 6. Затем проводят конденсацию с винилтрибутилоловом с использованием катализатора на основе палладия, с последующим присоединением карбена к образующейся стирольной двойной связи, при этом получают циклопропилзамещенный метиловый эфир нитробензойной кислоты. После восстановления нитрогруппы с последующим введением защитной группы Boc и омылением получают защищенную 3-амино-4-циклопропилбензойную кислоту. После конденсации с алкоксиамином в присутствии конденсирующего агента EDC получают требуемый анилин (VII). См., например, международные заявки № WO 02/092087 и WO 02/40486.

As shown in Scheme 7, the substituted type (VII) anilines used in the present invention are prepared from 4-iodotrinitrobenzoic acid methyl ester, which is synthesized as shown in Scheme 6. Condensation is then carried out with vinyl tributyltin using a palladium-based catalyst, with the subsequent attachment of carbene to the resulting styrene double bond to give a cyclopropyl substituted methyl ester of nitrobenzoic acid. After reduction of the nitro group, followed by the introduction of a Boc protecting group and saponification, a protected 3-amino-4-cyclopropylbenzoic acid is obtained. After condensation with alkoxyamine in the presence of a condensing agent, EDC, the desired aniline (VII) is obtained. See, for example, international applications No. WO 02/092087 and WO 02/40486.

Scheme 7

В качестве промежуточных соединений по настоящему изобретению используют гидразины, присоединенные к арильной или гетероарильной кольцевой системе. Известно множество методов получения таких промежуточных соединений. Пример такого метода получения некоторых гидразинов, используемых в настоящем изобретении, показан на схеме 8.

Hydrazines attached to an aryl or heteroaryl ring system are used as intermediates of the present invention. Many methods are known for preparing such intermediates. An example of such a method for producing certain hydrazines used in the present invention is shown in Scheme 8.

Type (VIII) arylhydrazines used in the present invention are prepared from 3-amino-N-methoxy-4-methylbenzamide hydrochloride, which is prepared according to the procedures described in international application No. WO 02/40486. After the formation of the aryldiazonium salt and its subsequent reduction with SnCl ₂ , the desired type (VIII) hydrazine is obtained.

As shown in Scheme 8, type (IX) aryl hydrazines used in the present invention are prepared from 3-amino-N-cyclopropyl-4-methylbenzamide, which is prepared according to the procedures shown in Scheme 2. After the formation of the aryldiazonium salt and its subsequent reduction with SnCl ₂ get the desired type (IX) hydrazine.

In a similar manner, other hydrazines from amines shown above in Schemes 1-7 can be obtained.

Scheme 8

As shown in Scheme 9, type (X) acrylonitriles used in the present invention are prepared from aryl ether and acetonitrile. Acetonitrile is treated with lithium diisopropylamide in THF at -78 ° C, then aryl ether is added to give the corresponding aryloylacetonitrile. The resulting intermediate compound is reacted with N, N'-diphenylformamidine in a solvent such as toluene at the boiling point of the solvent to give the corresponding Acrylonitrile type (X).

Scheme 9

As shown in Scheme 10, type (XI) aminopyrazoles used in the present invention are prepared from type (X) acrylonitrile, which is prepared according to the procedures shown in scheme 9, and hydrazines, such as type (VIII) and (IX) hydrazines, which are prepared according to the procedures shown in Scheme 8. Acrylonitrile and hydrazine are heated at a temperature of 60 to 100 ° C. in a solvent such as DMF or ethanol, whereby the desired aminopyrazole type (XI) is obtained.

Pattern 10

As shown in Scheme 11, type (XIII) aminopyrazoles used in the present invention are obtained from type (XII) acrylonitrile, which is obtained by processing type (X) acrylonitrile obtained according to the procedures shown in scheme 9, with sodium hydride and carbon disulfide with subsequent treatment with iodomethane and hydrazines, such as hydrazines of type (VIII) and (IX), which are obtained according to the methods shown in scheme 8. Acrylonitrile and hydrazine are heated at a temperature of from 60 to 100 ° C in a solvent such as DMF or ethanol, wherein the desired aminopyr is obtained ol type (XIII).

Scheme 11

Как показано на схеме 12, аминопиразолы типа (XIV), используемые в настоящем изобретении, получают из акрилонитрила типа (XII), который получают по методикам, показанным на схеме 11, и гидразинов, таких как гидразины типа (VIII) и (IX), которые получают по методикам, показанным на схеме 8. При обработке полученного промежуточного соединения (XII) спиртовым раствором алкоксида с последующим нагреванием при температуре от 60 до 100°С в присутствии гидразина в растворителе, таком как ДМФА или этанол, получают требуемый аминопиразол типа (XIII).

As shown in Scheme 12, type (XIV) aminopyrazoles used in the present invention are prepared from type (XII) acrylonitrile, which is prepared according to the procedures shown in scheme 11, and hydrazines, such as type (VIII) and (IX) hydrazines, which are prepared according to the procedures shown in Scheme 8. When the obtained intermediate compound (XII) is treated with an alcohol solution of alkoxide, followed by heating at a temperature of from 60 to 100 ° C in the presence of hydrazine in a solvent such as DMF or ethanol, the desired aminopyrazole of type (XIII )

Pattern 12

As shown in Scheme 13, type (XV) aminoimidazoles used in the present invention are prepared from substituted type (III) anilines which are prepared according to the procedures shown in Scheme 2. Aniline is heated in triethylorthoformate. After removing the solvent in vacuo, the product is reacted with aminomalononitrile p-toluenesulfonate and sodium acetate in acetic acid to give an intermediate aminocyanimidazole derivative. After the reaction of the intermediate with the Grignard reagent, the desired aminoimidazole of type (XV) is obtained.

Pattern 13

The compounds of the present invention are prepared from hydrazines attached to an aryl or heteroaryl ring system using the methods described in US Pat. Nos. 6,316,466, 6,337,527 and 6,444,696.

Additional synthesis methods used in the synthesis of compounds of the present invention are described in the following scientific journals, which are incorporated by reference in the description of the invention:

1. J. Heterocyclic Chem. 17, 631 (1980)

2. Tetrahedron 55 (48), 13703 (1999)

3. European Patent No. EP 0713876

4. Chemische Berichte 126 (10), 2317 (1993)

5. Journal of Organic Chem. 58 (24), 6620 (1993)

6. Tetrahedron Letters 35, 3239 (1973)

7. Journal of Chemical Research, Synopses 1, 2 (1997)

8. Boletin de la Sociedad Quimica del Peru 53 (3), 150 (1987)

9. Journal of the Chemical Society, Chemical Communications 2, 35 (1973)

10. Comptes Rendus des Seances de l'Academie des Sciences, Series C: Sciences Chimiques 274 (20), 1703 (1972)

The present invention also provides compounds that are prepared using the method described in the present invention.

G. Formulations of Pharmaceutical Compositions

The present invention also provides a pharmaceutical composition comprising the compounds of the present invention. The composition is used, for example, as a medicine. The composition contains, for example, a pharmaceutically acceptable excipient or carrier. The composition or drug of the present invention is used to treat, prevent or ameliorate one or more symptoms, diseases or disorders mediated by p38 kinase, including inflammatory diseases.

Thus, the present invention provides pharmaceutical compositions for treating conditions associated with p38 kinase, including conditions mediated by TNF-α, IL-1 and / or IL-8, as described above. The compositions contain other therapeutic agents, as described in this context, and they are obtained, for example, using standard solid or liquid carriers or diluents, as well as pharmaceutical additives, the type of which depends on the route of administration (for example, excipients, binders, preservatives, stabilizers , flavors, etc.), by known methods.

The compounds of the present invention are administered by any means suitable for a given condition intended for treatment, which depend on the specific interaction with the binding site or on the amount of drug administered. Local administration is usually used in the treatment of skin diseases, and systemic treatment is usually used in the treatment of cancer or precancerous conditions, while other methods of drug delivery are also used. For example, the compounds are administered orally, in the form of tablets, capsules, granules, powders or liquid compositions including syrups, topically in the form of solutions, suspensions, gels or ointments, in a sublingual manner; in the buccal way, in the parenteral way in the form of subcutaneous, intravenous, intramuscular, intrathoracic injections or infusions (for example, using sterile aqueous or non-aqueous solutions or suspensions for injection), the nasal method in the form of inhalation sprays, the local method in the form of rectal creams or ointments in the form of suppositories or in the form of liposomes. The compositions are administered in unit dosage form containing non-toxic pharmaceutically acceptable carriers or diluents. The compounds are administered in forms suitable for immediate or sustained release. Immediate or sustained release is achieved using suitable pharmaceutical compositions, or especially in the case of extended release using agents such as subcutaneous implants or osmotic pumps. Examples of compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gel in polyethylene).

Examples of compositions for oral administration include suspensions which contain, for example, microcrystalline cellulose as an excipient, alginic acid or sodium alginate as a suspending agent, methyl cellulose as a thickening agent, and sweeteners or flavorings known to those skilled in the art; immediate release tablets which contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, fillers, disintegrating agents, diluents and lubricants known to those skilled in the art. The compounds of the present invention are also administered by the oral, sublingual and / or buccal route, for example, using tablets obtained by molding, compression or lyophilization. Typical compositions include instant diluents, such as mannitol, lactose, sucrose and / or cyclodextrins. These compositions also include high molecular weight fillers such as celluloses (AVICEL®) or polyethylene glycols (PEG); fillers to enhance mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (NCCM) and / or maleic anhydride copolymer (e.g. GANTREZ®), and drug controlling agents such as acids (e.g. CARBOPOL 934®). To simplify the preparation and use of compositions, lubricants, glidants, flavors, colorants and stabilizers are also added to them.

Typical compositions for nasal administration in aerosol form or by inhalation include solutions that contain, for example, benzyl alcohol or other suitable preservatives, absorption accelerators to enhance absorption and / or to increase bioavailability and / or other solubilizers or dispersants known to those skilled in the art technicians.

Typical compositions for parenteral administration include solutions or suspensions for injection, which include, for example, non-toxic suitable parenterally acceptable solvents or diluents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides and fatty acids, including oleic acid.

Typical compositions for rectal administration include suppositories which contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic esters of glycerides or polyethylene glycols, which are solid at ordinary temperatures and melt and / or dissolve in the rectum to release the drug.

An effective amount of a compound of the present invention is determined by those skilled in the art, and a typical dose for mammals is from about 0.05 to 100 mg / kg body weight of the active ingredient per day, which is administered once or in several separate doses, for example, from 1 up to 4 times a day. It should be understood that the amount of a single dose and frequency of use for each subject varies and depends on many factors, including the activity of the compound used, metabolic stability and duration of the compound, age, body weight, general health, gender and diet of the subject, mode and time administration, rate of excretion, combination with other drugs and the severity of a particular disease. Subjects in need of treatment include animals, especially mammals, such as humans and domestic animals, such as dogs, cats, horses, and the like. Thus, the term “patient” as used in this context includes all subjects, especially mammals, including humans, who suffer from a disease associated with different levels of the p38 enzyme.

In one embodiment of the present invention, there is also provided a method for preparing medicaments, which comprises mixing a compound of the present invention with a pharmaceutically acceptable excipient and processing the mixture into a finished galenic form.

D. Methods of Using Compounds and Compositions

In another embodiment, the compounds of the present invention are used to treat, prevent, or ameliorate one or more symptoms of inflammatory diseases. In one embodiment, the compounds of the present invention are used to produce a medicament for the treatment or prevention of inflammatory diseases.

The compounds of the present invention are selective inhibitors of p38 kinase activity, and in particular p38α and p38β isoforms. In this regard, the compounds of the present invention are used to treat conditions associated with p38 kinase activity. Such conditions include diseases in which the cytokine level is modulated in response to an intracellular signal involving p38, and especially diseases that are associated with excess production of the cytokines IL-1, IL-4, IL-8 and TNF-α. The present invention provides methods of treating diseases by administering a compound of the present invention that inhibits p38 kinase activity. The present invention also provides methods of suppressing or arresting the development of a disease or disorder by administering a compound of the present invention. The methods of the present invention can be used to completely eliminate or partially reduce the intensity of the symptoms of the disease or condition and / or to alleviate, reduce the intensity or eliminate the disease or disorder and / or their symptoms. The term "inhibition of p-38α / β kinase" means the inhibition of p38α and p38β kinase. Thus, an IC ₅₀ value for inhibition of p-38α / β kinase means that the compound is characterized by an efficiency of inhibition of at least one or both of p38α and p38β kinases.

Since the compounds of the present invention are active as p-38α / β kinase inhibitors, they are used to treat p38 mediated conditions, including, but not limited to, inflammatory diseases, autoimmune diseases, increased bone fragility, proliferative diseases, angiogenic disorders , infectious diseases, neurodegenerative diseases and viral infections.

More preferably, specific conditions or diseases intended for treatment with the compounds of the present invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, red lupus, scleroderma, chronic thyroiditis, Graves disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, bulbospinal paralysis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft versus host disease, endotoxin-induced inflammatory reaction, tuberculosis, atherosclerosis, muscular tissue dystrophy, general exhaustion, arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella, acute synovitis, pancreatitis mediated by basophilic islets of Langerhans, diseases characterized by many neutrophil infiltration, rheumatoid spondylitis, gouty arthritis and other arthritis-like conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, bone resorption, rejection of allograft, fever and muscle pain caused by infection, infection, infection keloid, scarring, ulcerative colitis, paresis, influenza virus, osteoporosis, osteoarthritis and bone disease associated with the formation of m of multiple myelomas, acute myelogenous leukemia, chronic myelogenous leukemia, metostatic melanoma, Kaposi’s sarcoma, multiple myeloma, sepsis, septic shock and bacterial dysentery, Alzheimer's disease, Parkinson’s disease, cerebral ischemia or neurodegenerative disease caused by traumatic tumor , ocular tissue revascularization and infantile hemangiomas, viral diseases including acute hepatitis (including hepatitis A, hepatitis B and hepatitis C ), human immunodeficiency virus (HIV), cytomegalovirus-induced retinitis, acquired immunodeficiency syndrome (AIDS), severe acute respiratory syndrome (SARS), AIDS-associated complex or malignant disease and herpes, stroke, myocardial ischemia, myocardial ischemia, hypoxia organs, vascular hyperplasia, cardiac or renal reperfusion, thrombosis, cardiac hypertrophy, platelet aggregation caused by thrombin, endotoxemia and / or toxic shock syndrome and conditions associated with prostaglandin en doperoxide synthase-2.

The p38 inhibitors of the present invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin endoperoxide synthase-2 (PGHS-2), also called cyclooxygenase-2 (COX-2). In this regard, conditions mediated by p38 include edema, lack of pain sensitivity, fever and pain, such as neuromuscular pain, headache, pain accompanying cancer, toothache and arthritis pain. The compounds of the present invention are also used to treat animal viral diseases, such as lentiviral infections, including, but not limited to, equine infectious anemia virus or retroviral infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus. The terms "conditions associated with p38" or "diseases or disorders associated with p38" used in this context, combine all the conditions described above, as well as all other conditions associated with the activity of p38 kinase.

Thus, the present invention provides methods of treating these conditions, comprising administering to a subject in need of such treatment an effective amount of at least one compound of the present invention or a pharmaceutically acceptable derivative thereof. Methods of treating conditions associated with p38 kinase activity include administering the compounds of the present invention alone or in combination with other suitable therapeutic agents for treating such conditions. Examples of such other therapeutic agents include corticosteroids, rolipram, calphostine, CSAIDs, 4-substituted imidazo [1,2-A] quinoxalines, as described in US Pat. No. 4,200,750 and S. Ceccarelli et al. European Journal of Medicinal Chemistry, 33, 943-955 (1998), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants, cell nuclear translocation inhibitors such as deoxyspergualin (DSG), non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib, such as prednisone and dexamethasone, an antivirus agents such as abacavir, anti-proliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, prograf), cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-α inhibitors such as tenidap, anti-TNF antibodies or a soluble TNF receptor and rapamycin (sirolimus or rapamun) or their derivatives.

The other therapeutic agents described above, when used in combination with the compounds of the present invention, are administered, for example, in amounts indicated in the Physicians' Desk Reference (PDR) or as determined by those skilled in the art. According to the methods described in the present invention, such other therapeutic agents are administered prior to, simultaneously with or after administration of the compounds of the present invention.

The following examples are intended only to illustrate embodiments of the present invention and do not limit its scope as defined in the claims. The abbreviations used in the examples are described below. The compounds described in the examples are indicated by the number of the example and the stage in which they were obtained (for example, “1A” means that the title compound was obtained in example 1, step A), or only by the number of the example in which the compound is indicated in the title (for example, “2” means the compound indicated in the title of example 2).

Abbreviations

Ph = phenyl

Bz = benzyl

t-Bu = tert-butyl

Me = methyl

Et = ethyl

Pr = cut

Iso-P or i-Pr = isopropyl

MeOH = methanol

EtOH = Ethanol

EtOAc = ethyl acetate

Boc = tert-butyloxycarbonyl

CBZ = carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

DCM or CH ₂ Cl ₂ = dichloromethane

DCE = 1,2-dichloroethane

DMF = dimethylformamide

DMSO = dimethyl sulfoxide

TFA = trifluoroacetic acid

THF = tetrahydrofuran

HATU = O- (7-Azabenzotriazol-1-yl-N, N, N ', N'-tetramethylurea hexafluorophosphate

KOH = potassium hydroxide

K ₂ CO ₃ = potassium carbonate

POCl ₃ = phosphorous oxychloride

KQtBu = potassium tert-butoxide

EDC or EDCl = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

DIPEA = Diisopropylethylamine

HOBt = 1-hydroxybenzotriazole hydrate

m-CPBA = meta-chloroperbenzoic acid

NaH = sodium hydride

NaOH = sodium hydroxide

Na ₂ S ₂ O ₃ = sodium thiosulfate

Na ₂ SO ₄ = sodium sulfate

Pd = palladium

Pd / C = palladium on carbon

min = minute (you)

l = liter

ml = milliliter

μl = microliter

g = gram (s)

mg = milligram (s)

mole = mole

mmol = millimole (s)

meq = milliequivalent

CT = room temperature

VU = retention time on an HPLC column (min)

General methods. Mass spectra were obtained using a Thermo Finnigan LCQ Duo Ion Trap mass spectrometer. In the examples: “HPLC (gradient for 6 min)” means a Keystone C 18 Beta Basic column, elution rate 0.4 ml / min, eluent: linear gradient for 6 min (starting solvent% B = 0, final solvent% B = 100), solvent A: acetonitrile + 0.025% TFA; solvent B = H ₂ O + 0.025% TFA. “HPLC (gradient for 4 min)” means a Keystone C 18 Beta Basic column, elution rate 0.5 ml / min, eluent: linear gradient for 4 min (starting solvent% B = 0, final solvent% B = 100) solvent A: acetonitrile + 0.025% TFA; solvent B = H ₂ O + 0.025% TFA.

Example 1

Preparation of 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-methoxy-4-methylbenzamide

A. 3-Hydrazino-N-methoxy-4-methylbenzamide

To a solution of 3-amino-N-methoxy-4-methylbenzamide 1 (102 mg, 0.56 mmol, preparation is described in WO 02/40486 A2, p.66) in water (5 ml) with stirring at 0 ° C, was added conc. HCl (5 ml) and sodium nitrite (43 mg, 0.62 mmol). The reaction mixture was stirred at 0 ° C for 40 min, then a solution of tin (II) chloride (241 mg, 1.27 mmol) was added to conc. HCl (1 ml) and the mixture was stirred for 1 h, then kept at -20 ° C for 20 h and heated to RT, followed by concentration to a white solid. The solid was triturated in ethanol, filtered and the filtrate was concentrated to give 3-hydrazino-N-methoxy-4-methylbenzamide 2 (486 mg) as a white solid in the form of a mixture with tin salts and ethanol, the obtained product was used without further cleaning up. HPLC (gradient for 6 min): v.u. 0.78 minutes MS: m / z 195.9 [M + H] ⁺ .

B. 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-methoxy-4-methylbenzamide

To a stirred solution of 3-hydrazino-N-methoxy-4-methylbenzamide 2 (116 mg, calculated 0.14 mmol) in EtOH (10 ml) was added 2- (3-iodobenzoyl) -3-phenylaminoacrylonitrile 3 (59 mg, 0, 14 mmol, preparation: described in application No. WO 02/57101 A1, p. 84) and the resulting mixture was heated in a bath (at a temperature of 65-70 ° C) for 4 hours, then another portion of 3-hydrazino-N was added -methoxy-4-methylbenzamide 2 (80 mg, 0.11 mmol) and the mixture was heated at the indicated temperature for 27 hours. The mixture was cooled to room temperature, concentrated and re-dissolved in EtOAc, then washed with water and brine. water, dried over Na ₂ SO ₄ and concentrated to obtain a crude semi-solid. The mixture was then purified by flash chromatography (eluent: EtOAc / Hexane, 1: 1), impurities were removed, and then 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl was obtained by elution with 100% EtOAc ] -N-methoxy-4-methylbenzamide 4 (38 mg, 0.08 mmol, 55%) as an off-white solid. HPLC (gradient for 6 min): v.u. 3.49 minutes MS: m / z 476.96 [M + H] ⁺ .

¹ H-NMR (300 MHz, CD ₃ OD): δ 8.10 (s, 1H), 7.95 (d, J 8.0, 1H), 7.88 (d, J 8.0. 1H) 7.82 (m, 2H), 7.78 (s, 1H), 7.58 (d, J 8.0, 1H), 7.33 (t, J 7.8, 1H), 5.02 (s, 3H); 2.33 (s, 3H).

¹³ C-NMR (125 MHz, DMSO-d ₆ ): δ 189.3, 154.3, 143.5, 143.3, 142.0, 138.3, 137.4, 133.5, 132.9 , 132.0, 130.4, 128.8, 128.4, 104.8, 95.4, 64.8, 18.2.

Example 2

Preparation of 3- (5-amino-4-benzoylpyrazol-1-yl) -N-methoxy-4-methylbenzamide

To a stirred solution of 3-amino-N-methoxy-4-methylbenzamide 1 (104 mg, 0.58 mmol) in water (2 ml) at 0 ° C was added conc. HCl (2 ml), then sodium nitrite (44 mg, 0.63 mmol) was added. The reaction mixture was stirred at 0 ° C for 40 min, then a solution of tin (II) chloride (245 mg, 1.30 mmol) was added to conc. HCl (1 ml) and the resulting mixture was stirred for 40 minutes, then kept at -20 ° C for 20 hours and then the mixture was warmed to room temperature and concentrated to give a white solid. The solid was triturated in ethanol, the solid was removed, and 2-benzoyl-3-phenylaminoacrylonitrile 5 (144 mg, 0.58 mmol, preparation described in Grothaus, J. Am. Chem. Soc., 58, 1334 (1936)) was added. and the mixture was heated in a bath (at a temperature of 65-70 ° C) for 16 hours. The mixture was cooled to room temperature, concentrated and purified by flash chromatography (eluent: EtOAc / Hexane, 1: 1), while removing impurities, and then eluting with 100% EtOAc gave 3- (5-amino-4-benzoylpyrazol-1-yl) -N-methoxy-4-methylbenzamide 6 as an off-white solid (41 mg, 0.12 mmol, 28%) . HPLC (gradient over 4 min): vu 1.93 minutes MS: m / z 351.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.88 (s, 1H, NH), 7.803 (m, 4H), 7.56 (m, 4H), 7.01 (s, 2H, NH ₂ ), 3.32 (s, 3H), 2.162 (s, 3H).

¹³ C-NMR (125 MHz, DMSO-d ₆ ): δ 187.6, 151.9, 141.2, 139.7, 139.6, 135.7, 131.4, 131.2, 130.9 , 128.5, 128.1, 127.8, 126.4, 102.6, 63.2, 17.2.

Example 3

Preparation of 3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid

A. 3-Hydrazino-4-methylbenzoic acid hydrochloride

To a stirred solution of 3-amino-4-methylbenzoic acid 1 (5.64 g, 31.2 mmol, 1.0 equiv.) In 100 ml of dioxane and 100 ml of water at 0 ° C was added 100 ml of conc. HCl, then sodium nitrite (2.82 g, 40.9 mmol, 1.1 eq.) Was added in portions as a solid over 45 minutes at a suitable rate to ensure a satisfactory rate of gas evolution and a foaming rate, whereby a clear brown solution. Anhydrous tin (II) chloride (15.62 g, 83.7 mmol, 2.25 equiv.) Was dissolved in conc. HCl (25 ml) and approximately 25 ml were added dropwise to the solution at 0 ° C. After 1 h, the precipitate was filtered off and washed with dioxane, then dried in vacuo to give 3-hydrazino-4-methylbenzoic acid 2 hydrochloride as a tan solid (4.98 g, 66%). HPLC (gradient over 4 min): vu 0.97 minutes MS: m / z 167 [M + H] ⁺ .

¹ H-NMR δ (300 MHz, DMSO-d ₆ ) 10.03 (s, 1H, COOH), 7.89 (s, 1H), 7.51 (s, 1H), 7.27 (d, J 8.0, 1H), 3.38 (s, 3H, NHNH ₂ ), 2.23 (s, 3H).

B. 3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid

To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride 2 (242 mg, 1.19 mmol, 1.0 equiv.) In 25 ml of ethanol was added 2-benzoyl-3-phenylaminoacrylonitrile 4 (296 mg, 1.19 mmol, 1.0 eq., Preparation described in Grothasu, Davis, J. Am. Chem. Soc., 58, 1334 (1936)) and triethylamine (161 μl, 1.19 mmol, 1.0 eq.) And the mixture was heated up to 65 ° C. All solids were dissolved upon reaching a temperature of 65 ° C. After 3 hours, the total hydrazine intake was determined by LC-MS. The solid was filtered off to give 3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid 5 (95 mg, 25%) as a beige solid. HPLC (gradient over 4 min): vu 2.10 minutes MS: m / z 322 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 7.99 (d, J 7.6, 1H), 7.81 (s, 2H), 7.78 (s, 1H), 7.57 (m, 4H), 7.02 (s, 2H, NH ₂ ), 2.18 (s, 3H).

¹² C-NMR (75 MHz, DMSO-d ₆ ): δ 187.6, 166.3, 152.0, 141.3, 141.2, 139.6, 135.9, 131.6, 131.2 130.1, 129.8, 128.6, 127.8, 102.6, 17.4.

Example 4

Preparation of 3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

EDCI (855) was added to a stirred solution of 3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid 5 (Example 3, 700 mg, 2.18 mmol, 1.0 eq.) In 30 ml of DMF. mg, 4.35 mmol, 2.0 equiv.), HOBt (589 mg, 4.35 mmol, 2.0 equiv.) and diisopropylethylamine (1.59 ml, 8.71 mmol, 4.0 equiv.) and the solution was stirred for 15 min at room temperature, then cyclopropylamine (302 μl, 4.35 mmol, 2.0 eq.) was added and the reaction mixture was stirred for 1 h. The mixture was diluted with EtOAc (300 ml), washed with water (2 × 25 ml) and brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated. The product was purified by flash chromatography on silica gel (eluent: EtOAc / MeOH, 8: 2) to give the product as a brown oil. The product was then purified by trituration in a mixture (EtOAc / hexane / CH ₂ Cl ₂ , 1: 1: 1) and dried in vacuo to give 3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl- 4-methylbenzamide 6 (387 mg, 50%) as a white powder. HPLC (gradient over 4 min): vu 2.11 minutes MS: m / z 361 [M + H] ⁺ .

¹ H-NMR (300 MHz, CD ₃ OD): δ 7.92 (d, J 7.6, 1H), 7.81 (m, 4H), 7.54 (m, 4H), 2.85 ( m, 1H), 2.22 (s, 3H), 0.80 (d, J 5.7, 2H), 0.63 (s, 2H).

¹³ C-NMR (75 MHz, CD ₃ OD): δ 191.2, 170.1, 153.8, 143.3, 142.0, 141.1, 136.9, 134.8, 132.9, 132.7, 130.1, 129.7, 129.2, 128.1, 104.8, 24.1, 17.7, 6.6.

Example 5

Preparation of 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -4-methylbenzoic acid

В перемешиваемый раствор гидрохлорида 3-гидразино-4-метилбензойной кислоты 1 (пример 3А, 314 мг, 1,54 ммоля, 1,0 экв.) в 50 мл этанола и 5 мл метанола добавляли 2-(3-иодбензоил)-3-фениламиноакрилонитрил 2 (579 мг, 1,54 ммоля, получение: описано в заявке No. WO 02/57101 А1, с.84). Смесь нагревали при 75°С в течение 18 ч. Полученный осадок собирали на стеклянном пористом фильтре и промывали этанолом, при этом получали 3-[5-амино-4-(3-иодбензоил)пиразол-1-ил]-4-метилбензойную кислоту 3 (153 мг, 22%) в виде твердого вещества белого цвета. МС: m/z 448 [М+Н]⁺.

To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride 1 (Example 3A, 314 mg, 1.54 mmol, 1.0 eq.) In 50 ml of ethanol and 5 ml of methanol was added 2- (3-iodobenzoyl) -3- phenylaminoacrylonitrile 2 (579 mg, 1.54 mmol, preparation: described in application No. WO 02/57101 A1, p. 84). The mixture was heated at 75 ° C. for 18 hours. The resulting precipitate was collected on a glass porous filter and washed with ethanol to give 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -4-methylbenzoic acid 3 (153 mg, 22%) as a white solid. MS: m / z 448 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 2.18 (s, 3H), 7.05 (br.s.s, 2H), 7.34 (dd, J ₁ = J ₂ 7.7 Hz ), 7.58 (d, J 8.1 Hz, 1H), 7.78 (s, 1H), 7.81 (m, 2H), 7.94 (m, 1H), 7.98 (m, 1H), 8.03 (m, 1H).

Example 6

Preparation of 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 3- (N'-tert-Butoxycarbonylhydrazino) methylbenzoic acid

3-Hydrazino-4-methylbenzoic acid hydrochloride 1 (Example 3A, 13 g, 64.5 mmol) was dissolved in dioxane (200 ml) and H ₂ O (100 ml), aqueous NaOH (5.16 g NaOH in 100 ml) was added. H ₂ O, 2 × 64.5 mmol), then (Boc) ₂ O (15.5 g, 1.1 × 64.5 mmol) was immediately added. The reaction mixture was stirred at room temperature for 2 hours and concentrated on a rotary evaporator. Then, H ₂ O and CH ₂ Cl ₂ (containing MeOH) were added and a strong ion-exchange resin in H ⁺ form was added with stirring to neutralize the mixture to pH <2, the resin was filtered off and washed with CH ₂ Cl ₂ and MeOH. The aqueous layer was washed with two portions of CH ₂ Cl ₂ (with the addition of a small amount of MeOH). The combined organic layers were dried over Na ₂ SO ₄ (with the addition of a small amount of EtOAc). After filtration and concentration, 3- (N'-tert-butoxycarbonylhydrazino) -4-methylbenzoic acid 4 (16 g, 94%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.48 (s, 9H), 2.27 (s, 3H), 5.76 (s, 1H), 7.14 (d, J 7.7 Hz, 1H), 7.56 (d, J 7.7 Hz, 1H), 7.61 (s, 1H).

B. N '- (5-cyclopropylcarbamoyl-2-methylphenyl) hydrazinecarboxylic acid tert-butyl ester

3- (N'-tert-Butoxycarbonylhydrazino) -4-methylbenzoic acid 4 (14 g, 52.6 mmol) was dissolved in DMF (250 ml), EDCI (20 g, 105.2 mmol) and HOBt (16 g, 105.2 mmole). The mixture was stirred at room temperature for 30 minutes, cyclopropylamine (7.4 ml, 105.2 mmol) was added, then DIPEA (37 ml, 4 × 52.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. After the reaction mixture was concentrated in vacuo, H ₂ O was added. The mixture was then extracted with three portions of CH ₂ Cl ₂ . The organic layer was washed with an aqueous solution of NaCl. After drying over Na ₂ SO ₄ , filtration and concentration, a white solid was obtained. The crude product was dissolved in CH ₂ Cl ₂ / MeOH and then purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / EtOAc, gradient from 2: 1 to 1: 1), and the desired product was obtained, which was purified by recrystallization from EtOAc / CH ₂ Cl ₂ , the resulting solid was washed with EtOAc to give N ′ - (5-cyclopropylcarbamoyl-2-methylphenyl) hydrazinecarboxylic acid tert-butyl ester 5 (11 g, 69%).

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.58 (m, 2H), 0.84 (m, 2H), 1.48 (s, 9H), 2.23 (s, 3H), 2 87 (m, 1H), 5.69 (broad s, 1H), 6.17 (broad s, 1H), 6.39 (broad s, 1H), 7.70 (m, 2H), 7.32 (s, 1H).

B. N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate

N '- (5-cyclopropylcarbamoyl-2-methylphenyl) hydrazinecarboxylic acid tert-butyl ester 5 was dissolved in a mixture of CH ₂ Cl ₂ / TFA (2: 1) containing 2% H ₂ O, and the mixture was stirred at room temperature for 3 h. After concentration in vacuo, a syrup was obtained, to which CH ₂ Cl ₂ and toluene were added, concentrated in vacuo to give N-cyclopropyl-3-hydrazino-4-methylbenzamide 6 trifluoroacetate (100%) as an off-white solid colors. MS: m / z 206 [M + H] ⁺ .

¹ H-NMR (300 MHz, D ₂ O): δ 0.68 (m, 2H), 0.88 (m, 2H), 2.31 (s, 3H), 2.79 (m, 1H), 7.31 (s, 1H); 7.36 (broad s, 2H).

G. 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

To a stirred solution of N-cyclopropyl-3-hydrazino-4-methylbenzamide 6 trifluoroacetate (648 mg, 1.74 mmol, 1.0 eq.) In 2 ml of ethanol was added 2- (3-iodobenzoyl) -3-phenylaminoacrylonitrile 2 (550 mg, 1.74 mmol, preparation is described in Application No. WO 02/57101 A1, p. 84) and DIEA (0.50 ml, 2.9 mmol). The mixture was heated at 160 ° C. for 40 minutes in a microwave reactor, then the mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: EtOAc / Hexane, gradient from 1: 1 to 2: 1) to give 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 7 (589 mg, 70%) as a white solid. MS: m / z 497 [M + H] ⁺ .

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.60 (m, 2H), 0.86 (m, 2H), 2.24 (s, 3H), 2.87 (m, 1H), 5 81 (br 8, 2H), 6.35 (br.s, 1H), 7.25 (dd, J ₁ = J ₂ 7.8 Hz, 1H), 7.45 (d, J 8.1 Hz, 1H), 7.69 (d, J 1.7 Hz, 1H), 7.80 (m, 3H), 7.89 (m, 1H), 8.00 (s, 1H).

Example 7

Preparation of {5-amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] -1H-pyrazol-4-yl} phenylmethanone

А. N-Диметиламинометилен-4-метил-3-нитробензамид

A. N-Dimethylaminomethylene-4-methyl-3-nitrobenzamide

4-Methyl-3-nitrobenzamide 1 (10 g, 56 mmol) was suspended in 80 ml of N, N-dimethylformamide dimethyl acetal and then heated at 95 ° C for 2 hours. The resulting red solution was cooled to room temperature with stirring. After another 2 hours, the resulting red precipitate was collected on a glass porous filter and washed with three portions of Et ₂ O to give N-dimethylaminomethylene-4-methyl-3-nitrobenzamide 2 (8.7 g, 66%) as a red solid colors. HPLC (gradient over 4 min): vu 1.76 minutes MS: m / z 236.0 [M + H] ⁺ .

B. 3- (4-Methyl-3-nitrophenyl) -4H- [1.2.4] triazole

Anhydrous hydrazine (4.7 ml, 180 ml) was added dropwise to a solution of N-dimethylaminomethylene-4-methyl-3-nitrobenzamide 2 (8.6 g, 37 mmol) in 250 ml of acetic acid. The resulting light orange solution was heated at 95 ° C for 1.5 hours, then cooled and stirred at room temperature for 18 hours. Acetic acid was removed in vacuo and the residue was partitioned between H ₂ O and EtOAc. The organic layer was washed with two portions of a saturated solution of NaHCO ₃ , then dried over MgSO ₄ . After filtration and concentration in vacuo, the residue was triturated with warm EtOAc and the resulting off-white solid was collected on a glass porous filter to give 3- (4-methyl-3-nitrophenyl) -4H- [1,2,4] triazole 3 (5.8 g, 77%). HPLC (gradient over 4 min): vu 1.82 minutes MS: m / z 205.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.57 (broad 8, 1H), 8.46 (s, 1H), 8.12 (d, J 7.9, 1H), 7 56 (d, J 7.9, 1H); 2.5 (s, 3H).

¹³ C-NMR (125 MHz, DMSO-d ₆ ): δ 149.1, 133.5, 130.1, 121.3, 19.5.

B. 2-Methyl-5- (4H- [1.2.4] triazol-3-yl) phenylamine

3- (4-Methyl-3-nitrophenyl) -4H- [1,2,4] triazole 3 (5.75 g, 28.2 mmol) was suspended in 220 ml of ethanol and 2.35 ml (approximately 28.2 mmol) ) concentrated aqueous HCl. Then, 900 mg of 10% palladium on activated carbon (dry) was carefully added under nitrogen atmosphere and hydrogen gas was passed through the mixture for 5 minutes using a balloon attached to the needle from the syringe. Then the reaction mixture was stirred in an atmosphere of hydrogen gas (from a balloon) at room temperature for 5 hours. The catalyst was removed by filtration through a thin layer of celite. The filtrate was concentrated in vacuo and the residue was neutralized with saturated NaHCO ₃ solution. The mixture was extracted with six portions of EtOAc and the combined organic layers were dried over MgSO ₄ . After filtration and concentration in vacuo, the residue was recrystallized from EtOAc to give 2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenylamine 4 (4.5 g, 92%) as a solid substances off-white. HPLC (gradient over 4 min): vu 0.79 minutes MS: m / z 175.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, MeOH-d ₃ ): δ 8.10 (br s, 1H), 7.54 (s, 1H), 7.29 (m, 2H), 7.15 (d, J 7.6, 2H); 2.23 (s, 3H).

G. [2-Methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] hydrazine

To a solution of 2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenylamine 4 (200 mg, 1.15 mmol) in dioxane (5 ml) and water (5 ml) was added conc. HCl (10 ml) at 0 ° C, then sodium nitrite (87 mg, 1.26 mmol) was added. The reaction mixture was stirred at 0 ° C. for 40 minutes, then a tin (II) chloride solution (481 mg, 2.59 mmol) was added dropwise to conc. HCl (1 ml). The mixture was stirred at 0 ° C. for 2 hours, whereby a white solid precipitate was obtained. The solid was filtered off and identified as [2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] hydrazine 5 (261 mg), which was used without further purification. HPLC (gradient over 4 min): vu 0.71 minutes MS: m / z 190.1 [M + H] ⁺ .

D. {5-amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] -1H-pyrazol-4-yl} phenylmethanone

To a stirred solution of [2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] hydrazine 5 (261 mg, calculated 1.15 mmol) in EtOH (25 ml) was added 2-benzoyl -3-phenylaminoacrylonitrile 6 (285 mg, 1.15 mmol, preparation is described in Grothaus, J. Am. Chem. Soc., 58, 1334 (1936)) and the mixture was heated at 65-70 ° C for 12-16 h, then cooled to room temperature and concentrated to give a crude product. The mixture was then purified by flash chromatography (eluent: EtOAc / Hexane, 1: 1) to give {5-amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl ) phenyl] -1H-pyrazol-4-yl} phenylmethanone 7 (21 mg, 0.09 mmol, 8%) as a white solid. HPLC (gradient over 4 min): vu 1.89 minutes MS: m / z 345.2 [M + H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.40 (d, 1H), 8.24 (br s, 1H), 8.14 (s, 1 H), 8.12 (d , 2H), 7.34 (broad s, 2H), 7.92-7.85 (m, 4H), 2.49 (s, 3H).

¹³ C-NMR (500 MHz, DMSO-d ₆ ): δ 152.9, 142.2, 140.5, 137.1, 132.7 132.2, 129.4, 128.8, 127.6, 126.0, 103.6, 18.1.

Example 8

Preparation of 3- [5-amino-4- (3- [1,3] dioxolan-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 3- [1,3] dioxolan-2-yl-benzoic acid methyl ester

A mixture of 3-formylbenzoic acid methyl ester 1 (6.09 g, 37.2 mmol), ethylene glycol (2.28 ml, 40.9 mmol) and para-toluenesulfonic acid monohydrate (0.78 g, 4.09 mmol) was heated with reflux condenser and using the Dean-Stark nozzle overnight. TLC analysis showed complete consumption of the starting material. The reaction mixture was poured into chilled aqueous NaHCO ₃ and EtOAc. The organic layer was separated and dried over Na ₂ SO ₄ , then filtered and concentrated to give a crude product, which was purified by silica gel chromatography (eluent: hexane / ethyl acetate, 8: 1), whereby the desired 3- methyl ester was obtained [1, 3] dioxolan-2-yl-benzoic acid 2 (6.41 g, 83%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.92 (s, 3H), 4.01 (m, 2H), 4.13 (m, 2H), 5.85 (s, 1H), 7.46 (dd, J ₁ = J ₂ 7.7 Hz, 1H), 7.68 (dt, J ₁ 7.7 Hz, J ₂ 1.2 Hz, 1H), 8.05 (dt, J ₁ 7.7 Hz, J ₂ 1.5 Hz, 1H), 8.16 (dd, J ₁ = J ₂ 1.5 Hz, 1H).

B. 3- (3- [1,3] dioxolan-2-ylphenyl) -2-oxopropionitrile

To a mixture of acetonitrile (1.90 ml, 36.4 mmol) in THF (60 ml) was added LDA (1.8 M in THF, 33.9 ml) at -78 ° C. After the mixture was stirred at -78 ° C for 20 minutes, 3- [1,3] dioxolan-2-yl-benzoic acid 2 methyl ester 2 (6.06 g, 29.1 mmol) in THF (20 ml) was added in one portion. The mixture was stirred at −78 ° C. for 1.5 hours, then heated to 0 ° C. and stirred for 1 hour at the same temperature. The reaction was stopped by the addition of saturated NH ₄ Cl. The mixture was extracted with three portions of EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ . After filtration and concentration in vacuo, a residue was obtained which was purified by silica gel chromatography (eluent: CH ₂ Cl ₂ , then CH ₂ Cl ₂ / ethyl acetate, 20: 1), whereby the desired 3- (3- [1,3] dioxolane was obtained -2-ylphenyl) -2-oxopropionitrile 3 (5.71 g, 96%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 4.12 (m, 6H), 5.86 (s, 1H), 7.55 (dd, J ₁ = J ₂ 7.7 Hz, 1H), 7.77 (d, J 7.7 Hz, 1 H), 7.92 (d, J 7.7 Hz, 1 H), 8.01 (s, 1 H).

B. 2- (3- [1,3] dioxolan-2-ylbenzoyl) -3-phenylaminoacrylonitrile

A mixture of 3- (3- [1,3] dioxolan-2-ylphenyl) -2-oxopropionitrile 3 (3.07 g, 15.0 mmol) and N, N'-diphenylformamidine (4.10 g, 21 mmol) in toluene was heated under reflux for 18 hours. After concentration in vacuo, a residue was obtained, which was purified by silica gel chromatography (eluent: hexane / EtOAc, gradient from 3: 1 to 2: 1, then 1: 1), whereby the desired 2 - (3- [1,3] dioxolan-2-ylbenzoyl) -3-phenylaminoacrylonitrile 4 (3.88 g, 81%) as a yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 4.12 (m, 4H), 5.92 (s, 1H), 7.26 (m, 4H), 7.47 (m, 3H), 7 65 (d, J 7.7 Hz, 1H); 7.94 (dt, J ₁ 7.7 Hz; J ₂ 1.3 Hz, 1H); 8.05 (m, 2H).

G. 3- [5-amino-4- (3- [1,3] dioxolan-2-yl-benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A mixture of 2- (3- [1,3] dioxolan-2-ylbenzoyl) -3-phenylaminoacrylonitrile 4 (0.20 g, 0.62 mmol), N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate 8 (Example 6B , 0.20 g, 0.62 mmol) and DIEA (0.5 ml) in DMF (3 ml) were heated at 160 ° C for 40 min in a microwave reactor. Then the mixture was cooled to room temperature and concentrated. The resulting residue was purified by silica gel chromatography (eluent: hexane / EtOAc, gradient from 1: 4 to 100% EtOAc) to give the desired 3- [5-amino-4- (3- [1,3] dioxolan-2-ylbenzoyl ) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 5 (0.26 g, 100%) as an orange solid. MS: m / z 433.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.60 (m, 2H), 0.86 (m, 2H), 2.24 (s, 3H), 2.87 (m, 1H), 4 11 (m, 4H), 5.85 (m, 3H), 6.51 (br.s, 1H), 7.43 (d, J 8.0 Hz, 1H), 7.45 (dd, J ₁ = J ₂ 7.6 Hz; 1H) 7.70 (m, 2H), 7.82 (m, 3H), 7.95 (s, 1H), 8.00 (s, 1H).

Example 9

Preparation of 3- [5-amino-4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A mixture of 3- [5-amino-4- (3- [1,3] dioxolan-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 5 (example 8, 1.14 g, 2, 6 mmol) was suspended in aqueous AcOH (10 ml, 1.5 M in H ₂ O). Ice AcOH was added dropwise until a clear solution was formed. The reaction mixture was stirred at room temperature overnight. After evaporation of the solvent under reduced pressure, a residue was obtained, toluene and EtOAc were added, the mixture was concentrated again, and a crude product was obtained, which was purified by silica gel chromatography (eluent: hexane / EtOAc, 1: 4) to obtain the desired 3- [5-amino -4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 6 (0.91 g, 89%) as a yellow solid foam. MS: m / z 389.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.61 (m, 2H), 0.85 (dd, J ₁ 6.9 Hz, J ₂ 12.4 Hz, 2H), 2.25 (s , 3H), 2.87 (m, 1H), 5.95 (br.s, 2H), 6.57 (br.s, 1H), 7.44 (d, J 8.0 Hz, 1H), 7.67-7.78 (m, 4H), 8.07 (s, 1H), 8.09 (d, J 1.3 Hz, 1H), 8.31 (s, 1H), 10.12 ( s, 1H).

Example 10

Preparation of 3- [5-amino-4- (3-hydroxymethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

To a mixture of 3- [5-amino-4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 6 (38 mg, 0.098 mmol) in methanol (3 ml) was added NaBH ₄ (11 mg 0.29 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction was stopped by the addition of aqueous NaOH and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel chromatography (eluent: hexane / EtOAc, 1: 4) to obtain the desired 3- [5-amino-4- (3 -hydroxymethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 7 (22 mg, 58%) as a white solid. MS: m / z 391.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.56 (m, 2H), 0.82 (m, 2H), 2.22 (s, 3H), 2.82 (m, 1H), 4 75 (s, 2H), 5.91 (broad s, 2H), 6.75 (broad s, 1H), 7.49 (m, 3H), 7.76 (m, 4H), 7, 99 (s, 1H).

Example 11

Preparation of 3- {5-amino-4- [3- (4-methylpiperazin-1-ylmethyl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

To a mixture of 3- [5-amino-4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 6 (Example 9, 1.0 eq.) And 1-methylpiperazine (1.09 eq. .) in a mixture of equal volumes of 1,2-dichloroethane and dichloromethane, AcOH (0.96 equiv.) was added, then sodium triacetoxyborohydride (1.5 equiv.) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was stopped by the addition of aqueous NaOH and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated to give a residue, which was purified by silica gel chromatography (eluent: CH ₂ Cl ₂ / methanol, 9: 1, then CH ₂ Cl ₂ / MeOH / NH ₃ H ₂ O, 9: 1: 0.05) and the product was obtained (67%). MS: m / z 473.3 [M + H] ⁺ .

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.61 (m, 2H), 0.86 (m, 2H), 2.26 (s, 3H), 2.30 (s, 3H), 2 52 (broad s, 8H), 2.90 (m, 1H), 3.60 (s, 2H), 5.87 (broad s, 1H), 6.30 (broad s, 2H), 7.45 (m, 3H); 7.70 (m, 2H); 7.83 (m, 3H).

Example 12

Preparation of 3- [5-amino-4- (3-morpholin-4-ylmethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The compound is obtained in the same manner as described in example 11, but when replacing 1-methylpiperidine with morpholine, the product is obtained (45%). MS: m / z 460.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.61 (m, 2H), 0.87 (m, 2H), 2.26 (s, 3H), 2.25 (s, 3H), 2 49 (m, 4H). 2.90 (m, 1H), 3.59 (s, 2H), 3.72 (t, J 4.4 Hz, 2H), 5.85 (br.s, 2H), 6.35 (br. s, 1H), 7.45 (m, 3H), 7.71 (m, 2H), 7.83 (m, 3H).

Example 13

Preparation of 3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

A. Ethyl ester of 3- (2-morpholin-4-yl-ethoxy) benzoic acid

Into a solution of ethyl 3-hydroxybenzoate 1 (3.32 g, 20 mmol), 4- (2-chloroethyl) morpholine hydrochloride (5.58 g, 30 mmol) and 18-crown-6 (20 mg) in DMF (100 ml) potassium carbonate (6.2 g, 45 mmol) was added. The mixture was stirred at 100 ° C. for 20 hours. The solvent was removed in vacuo and the residue was suspended in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ solution, then brine and dried over sodium sulfate. The solvent was evaporated, to give the product 3- (2-morpholin-4-yl-ethoxy) benzoic acid ethyl ester 2 (5.3 g, 95%) as a pale yellow oil. HPLC (gradient over 4 min): vu 1.47 minutes MS: m / z 280.2 [M + H] ⁺ .

B. 3- [3- (2-Morpholin-4-yl-ethoxy) phenyl] -3-oxopropionitrile

Lithium diisopropylamide (16.4 ml, 29.6 mmol, 1.8 M solution in heptane / tetrahydrofuran / ethylbenzene) was added dropwise in a nitrogen atmosphere to a solution of acetonitrile (1.2 g, 29.6 mmol) in dry tetrahydrofuran (20 ml) at -78 ° C. After stirring the reaction mixture for 30 minutes, a solution of 3- (2-morpholin-4-yl-ethoxy) -benzoic acid 2 ethyl ester (5.5 g, 19.7 mmol) in dry tetrahydrofuran (20 ml) was added dropwise and stirred at - 78 ° C for 1 h, then water was added, the aqueous layer was separated and acidified with diluted hydrochloric acid to pH 7. The product was extracted with ethyl acetate. The organic layer was washed with brine and then dried over sodium sulfate. The solvent was removed in vacuo to give 3- [3- (2-morpholin-4-yl-ethoxy) phenyl] -3-oxopropionitrile 3 (4.8 g) as a pale yellow oil. HPLC (gradient over 4 min): vu 1.11 minutes MS: m / z 275.2 [M + H] ⁺ .

B. 2- [3- (2-Morpholin-4-yl-ethoxy) benzoyl] -3-phenylaminoacrylonitrile

A mixture of 3- [3- (2-morpholin-4-yl-ethoxy) phenyl] -3-oxopropionitrile 3 (4.8 g, 17.5 mmol) and N, N-diphenylformamidine (1.2 g, 24.5 mmol) in dry toluene (100 ml) was heated at 110 ° C for 3 hours in a nitrogen atmosphere. The solvent was removed and the oily residue was purified by silica gel column chromatography (eluent: gradient from 100% EtOAc to EtOAc / MeOH / Et ₃ N, 100: 10: 1) to give 2- [3- (2-morpholin-4- ilethoxy) benzoyl] -3-phenylaminoacrylonitrile 4 (3.1 g, 47%) as a pale yellow solid. HPLC (gradient over 4 min): vu 2.04 minutes MS: m / z 378.2 [M + H] ⁺ .

G. 3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazol-1-yl} -4-methylbenzoic acid

2- [3- (2-Morpholin-4-yl-ethoxy) benzoyl] -3-phenylaminoacrylonitrile 4 (189 mg, 0.5 mmol) and 3-hydrazino-4-methylbenzoic acid hydrochloride 7 (Example 3A, 152 mg, 0, 75 mmol) was suspended in N, N-dimethylformamide (5 ml) and heated at 160 ° C in a microwave reactor for 30 minutes. The solvent was evaporated and the residue was purified by column chromatography (eluent: EtOAc ~ MeOH) to give the product 3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazol-1-yl} -4-methylbenzoic acid 5 (200 mg) as a pale yellow solid. HPLC (gradient over 4 min): vu 1.60 minutes MS: m / z 451.2 [M + H] ⁺ .

D. 3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

A mixture of 3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazol-1-yl} -4-methylbenzoic acid 5 (400 mg, 0.89 mmol), cyclopropylamine (0, 89 mmol), EDCI (340 mg, 1.78 mmol), HOBt (272 mg, 1.78 mmol) and diisopropylethylamine (459 mg, 3.56 mmol) in dry N, N-dimethylformamide (10 ml) were stirred at room temperature for 18 hours. The solvent was evaporated, the residue was suspended in EtOAc and washed with water, saturated NaHCO ₃ solution and brine. The organic layer was dried over sodium sulfate. Purification by column chromatography (eluent: EtOAc / MeOH / Et ₃ N, 100: 10: 1) gave the product 3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazol-1 -yl} -N-cyclopropyl-4-methylbenzamide 6 (45 mg, 10%) as a pale yellow solid. HPLC (gradient over 4 min): vu 1.69 minutes MS: m / z 490.24 [M + H] ⁺ .

Example 14

Preparation of 3- [5-amino-4- (3-benzyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. Ethyl 3-benzyloxybenzoic acid

To ₂ CO ₃ (6.9 g, 50 mmol) and 18-crown-6 were added to a solution of 3-hydroxybenzoic acid ethyl ester 1 (8.3 g, 50 mmol) in acetone (100 ml) and the mixture was stirred at room temperature for 18 hours. The solid was filtered off, the filtrate was concentrated in vacuo to give 3-benzyloxybenzoic acid 2 ethyl ester as a colorless liquid.

B. 3- (3-Benzyloxyphenyl) -3-oxopropionitrile

LDA (1.8 M, 100 mmol, 56 ml) was added to a solution of acetonitrile (4.1 g, 100 mmol) in THF (100 ml, dry) at -78 ° C under a nitrogen atmosphere. The mixture was stirred at -78 ° C for 30 minutes. Then, a solution of 3-benzyloxybenzoic acid 2 ethyl ester 2 in 50 ml of anhydrous THF was added dropwise to the reaction mixture. The mixture was stirred at -78 ° C for 1 h, then water was added, the organic layer was separated, the aqueous layer was acidified with hydrochloric acid to pH ~ 2 and extracted with EtOAc. The THF and EtOAc layers were combined and washed with water and brine, dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the solid residue was triturated in Et ₂ O and dried in vacuo to give the desired product, 3- (3-benzyloxyphenyl) -3-oxopropionitrile 3 (11.0 g, 87%) as a light solid -Brown.

B. 2- (3-Benzyloxybenzoyl) -3-dimethylaminoacrylonitrile

N, N-dimethylformamide dimethyl acetal (10 ml) was added to a solution of 3- (3-benzyloxyphenyl) -3-oxopropionitrile 3 (2.5 g, 10 mmol) in DMF (20 ml, dry) and the mixture was stirred at 100 ° C in for 3 hours. The solvent was removed and the residue was purified by silica gel column chromatography (eluent: EtOAc) to obtain the desired product, 2- (3-benzyloxybenzoyl) -3-dimethylaminoacrylonitrile 4 (2.6 g, 90%), as solid light yellow.

G. 3- [5-amino-4- (3-benzyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

2- (3-Benzyloxybenzoyl) -3-dimethylaminoacrylonitrile 4 (147 mg, 0.5 mmol) and N-cyclopropyl-3-hydrazino-4-methylbenzamide 8 trifluoroacetate (Example 6 B, 240 mg, 0.75 mmol) were dissolved in DMF (5 ml) and heated at 160 ° C in a microwave reactor for 30 minutes. The solvent was removed and the residue was purified by column chromatography (eluent: EtOAc / Hexane, 3: 1) to obtain the desired product, 3- [5-amino-4- (3-benzyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl -4-methylbenzamide 6 (120 mg, 52%), as a pale yellow solid.

Example 15

Preparation of 3- [5-amino-4- (3-hydroxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

3- [5-amino-4- (3-benzyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 6 (200 mg, 0.43 mmol) was dissolved in MeOH (10 ml), 10% catalyst was added palladium on activated carbon (dry) and stirred in a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, the solvent was removed in vacuo to give the desired product, 3- [5-amino-4- (3-hydroxybenzoyl) pyrazole-1- yl] -N-cyclopropyl-4-methylbenzamide 7 (140 mg, 87%), as a pale yellow solid.

Example 16

Preparation of 3- [5-amino-4- (4-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 2- (4-Methylbenzoyl) -3-phenylaminoacrylonitrile

A mixture of 4-toluoylacetonitrile 1 (4.0 g, 25 mmol) and N, N-diphenylformamidine (4.9 g, 25 mmol) in dry toluene (50 ml) was heated at 85 ° C for 16 hours under nitrogen. The mixture was cooled to room temperature and 170 ml of hexane was added. After the mixture was stirred at room temperature for 5 minutes, a yellow precipitate formed. The solid was collected in a glass filter flask and washed with hexane to give pure 2- (4-methylbenzoyl) -3-phenylaminoacrylonitrile 2 (4.5 g, 68%).

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.04 (d, J 13.0, 1H), 7.86 (d, J 7.9, 2H), 7.42 (t, J 7, 4, 1H), 7.28-7.25 (m, 3H), 7.19 (d, J 7.6, 1H), 2.41 (s, 3H).

B. 3- [5-amino-4- (4-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A mixture of 2- (4-methylbenzoyl) -3-phenylaminoacrylonitrile 2 (205 mg, 0.78 mmol), N-cyclopropyl-3-hydrazino-4-methylbenzamide 7 trifluoroacetate (Example 6B, 250 mg, 0.78 mmol) and diisopropylamine (0.14 ml, 0.78 mmol) in 8 ml of ethanol was heated at 65 ° C for 18 hours. The solvent was removed and the residue was purified by silica gel column chromatography (eluent: EtOAc / hexane, gradient from 1: 3 to 3: one). The product was then purified by trituration in Et ₂ O to give 3- [5-amino-4- (4-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 3 (64 mg, 22%) as solid white. HPLC (gradient over 4 min): vu 2.26 minutes MS: m / z 375.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.51 (d, J 4.0, 1H), 7.93 (d, J 8.0, 1H), 8.51 (d, J 4.0, 1H), 7.83 (br.s, 1H), 7.82 (s, 1H), 7.70 (d, J 7.9, 2H), 7.53 (d, J 8, 0, 1H), 7.35 (d, J 7.9, 2H), 6.95 (broad s, 2H), 2.86 (m, 1H), 2.40 (s, 3H), 2, 14 (s, 3H), 0.68 (m, 2H), 0.56 (m, 2H).

¹³ C-NMR (300 MHz, DMSO-d ₆ ): δ 187.4, 166.0, 151.9, 141.3, 141.1, 139.2, 136.9, 135.6, 133.0 , 131.2, 129.1, 128.3, 128.0, 126.5, 102.6, 23.1, 21.0, 17.2, 5.6.

Example 17

Preparation of 3- (5-amino-4-benzoylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

A. 3- (5-amino-4-cyanoimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

A mixture of 3-amino-N-cyclopropyl-4-methylbenzamide 1 (380 mg, 2.0 mmol) in 2.0 ml of triethylorthoformate was stirred in a microwave reactor at 120 ° C for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in 5 ml of acetic acid and then aminomalononitrile p-toluenesulfonate (506 mg, 2.0 mmol) and sodium acetate (164 mg, 2.0 mmol) were added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with 20 ml of water and then aqueous NaOH was added to pH 8. The resulting mixture was extracted with EtOAc (3 × 50 ml). The combined organic layers were washed with water (10 ml) and brine (10 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol, 10: 1) to obtain 3- (5-amino-4-cyanoimidazol-1-yl] -N-cyclopropyl-4-methylbenzamide 3 (170 mg, 30%) as a colorless solid. HPLC (gradient for 4 minutes): v. 1.39 min. MS: m / z 282 [M + H] ⁺ .

B. 3- (5-amino-4-benzoylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

To a solution of 3- (5-amino-4-cyanoimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide 3 (56.4 mg, 0.2 mmol) in dry THF (10 ml) was added phenylmagnesium bromide (1 M, 1 ml) at room temperature under nitrogen. After 1 h, a HCl solution (3 N, 10 ml) was added and the mixture was stirred overnight. The solution was neutralized by the addition of aqueous NaOH. The mixture was extracted with ethyl acetate (2 × 100 ml), washed with water and dried over Na ₂ SO ₄ . After evaporation of the solvent, the residue was purified by HPLC to obtain 3- (5-amino-4-benzoylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide (56 mg, 78%) as a white solid. LCMS (gradient over 4 min): v.u. 2.07 minutes MS: m / z 316.17 [M + H] ⁺ .

Example 18

Preparation of 3- (5-amino-4-cyclohexanecarbonylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 17, but when replacing phenylmagnesium bromide with cyclohexylmagnesium bromide. HPLC (gradient 10-90 over 4 min): v.u. 2.01 minutes MS: m / z 367.29 [M + H] ⁺ .

Example 19

Preparation of 3- (5-amino-4-cyclopentanecarbonylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 17, but when replacing phenylmagnesium bromide with cyclopentylmagnesium bromide. HPLC (gradient 10-90 over 4 min): v.u. 1.92 minutes MS: m / z 353.22 [M + H] ⁺ .

Example 20

Preparation of 3- (5-amino-4-phenylacetylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 17, but when replacing phenylmagnesium bromide with benzylmagnesium bromide. HPLC (gradient 10-90 over 4 min): v.u. 2.14 minutes MS: m / z 375.20 [M + H] ⁺ .

Example 21

Preparation of 3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

А. 3-[5Амино-1-(5-циклопропилкарбамоил-2-метилфенил)-1Н-имидазол-4-карбонил]бензойная кислота

A. 3- [5Amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-imidazole-4-carbonyl] benzoic acid

To a solution of 3-iodobenzoic acid tert-butyl ester (4.6 g) in THF (20 ml) was added cyclohexyl magnesium chloride (2 M in THF, 8.5 ml) in an atmosphere of N ₂ at -40 ° C. The temperature of the solution was maintained from -40 ° C to 0 ° C for 20 minutes, while 3- (5-amino-4-cyanoimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide was added and the reaction was carried out at room temperature in for 1 h. Then, HCl (4 M, 10 ml) was added and the mixture was heated at a temperature of from 40 ° C to 45 ° C overnight. The mixture was neutralized with a solution of K ₂ CO ₃ and extracted with EtOAc (2 × 100 ml), the combined organic layers were dried over Na ₂ SO ₄ and concentrated. After purification of the crude product by column chromatography (eluent: EtOAc / MeOH, 6: 1), the desired product (0.46 g) was obtained.

B. 3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A solution of acid 4 (160 mg), EDCl (90 mg) and N-hydroxysuccinimide (53 mg) in DMF (2 ml) was kept at room temperature overnight, water (12 ml) was added, the solution was extracted with EtOAc (2 × 15 ml ) and dried over Na ₂ SO ₄ . Evaporation of the solvent gave a residue to which EtOAc (4 ml) and 2-propylamine (1.2 eq.) Were added. The reaction was carried out at room temperature for 1 h, then the reaction mixture was concentrated and the crude product was purified by column chromatography to obtain the desired product (80%). HPLC (gradient over 4 min): vu 2.00 minutes MS: m / z 446.19 [M + H] ⁺ .

Example 22

Preparation of 3- {5-amino-4- [3- (2-dimethylaminoethylcarbamoyl) benzoyl] imidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with 2-dimethylaminoethylamine. HPLC (gradient 10-90 over 4 min): v.u. 2.18 minutes MS: m / z 475.15 [M + H] ⁺ .

Example 23

Preparation of 3- [5-amino-4- (3-ethylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with ethylamine. HPLC (gradient 10-90 over 4 min): v.u. 1.70 minutes MS: m / z 432.18 [M + H] ⁺ .

Example 24

Preparation of 3- [5-amino-4- (3-methylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with methylamine. HPLC (gradient 10-90 over 4 min): v.u. 1.61 minutes MS: m / z 418.15 [M + H] ⁺ .

Example 25

Preparation of 3- [5-amino-4- (3-cyclopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with cyclopropylamine. HPLC (gradient 10-90 over 4 min): v.u. 1.74 minutes MS: m / z 444.14 [M + H] ⁺ .

Example 26

Preparation of 3- [5-amino-4- (3-cyclopentylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with cyclopentylamine. HPLC (gradient 10-90 over 4 min): v.u. 1.95 minutes MS: m / z 472.24 [M + H] ⁺ .

Example 27

Preparation of 3- {5-amino-4- [3- (morpholin-4-carbonyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with morpholine. HPLC (gradient 10-90 over 4 min): v.u. 1.67 minutes MS: m / z 474.17 [M + H] ⁺ .

Example 28

Preparation of 3- {5-amino-4- [3- (cyclopropylmethylcarbamoyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with cyclopropylmethylamine. HPLC (gradient 10-90 over 4 min): v.u. 1.86 minutes MS: m / z 458.23 [M + H] ⁺ .

Example 29

Preparation of 3- [5-amino-4- (tetrahydropyran-4-carbonyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 4-Bromotetrahydropyran

Tetrahydro-4H-pyran-4-ol (1.0 g, 10 mmol), carbon tetrabromide (3.6 g, 11 mmol) and triphenylphosphine (3.1 g, 12 mmol) were dissolved in CH ₂ Cl ₂ (25 ml ) and stirred at room temperature overnight. The crude reaction mixture was concentrated, then purified by flash chromatography on silica gel (eluent: EtOAc / Hexane, 1:20) to give the product (1.4 g, 87%) as a colorless oil.

B. 3- [5-amino-4- (tetrahydropyran-4-carbonyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A solution of 4-bromotetrahydropyran (0.82 g, 5 mmol) in dry THF (10 ml) was added dropwise to a suspension of magnesium (132 mg, 5.5 mmol) and iodine (25 mg) in dry THF (20 ml) at 50 ° C in an atmosphere of N ₂ . After adding the reagents, the mixture was stirred for 30 min at 50 ° C, then cooled to room temperature. A solution of 3- (5-amino-4-cyanoimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide (90 mg, 0.32 mmol) in THF (10 ml) was added to the reaction mixture, and the mixture was stirred at room temperature in for 3 hours, then the reaction was stopped by the addition of HCl (2 N) and the mixture was stirred at room temperature overnight. Saturated aqueous K ₂ CO _{3 was} added to the solution to pH ~ 8 and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (eluent: EtOAc ~ EtOAc / MeOH / Et ₃ N, 100: 10: 1) to give the product (35 mg, 30%) as a beige solid. HPLC (gradient over 4 min): vu 3.05 minutes MS: m / z 369.18 [M + H] ⁺ .

Example 30

Preparation of 3- (5-amino-4-benzoyl-3-methoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

A. 3-Benzoyl-3,3-bis-methylsulfanylacrylonitrile

Dry sodium hydride (2.61 g, 103 mmol) was added to a stirred solution of benzoylacetonitrile 1 (7.50 g, 51.7 mmol) in THF (100 ml) at 0 ° C. The resulting suspension was stirred at 0 ° C. for 45 minutes, then carbon disulfide (2.39 ml, 54.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting red solution was cooled to 0 ° C and iodomethane (6.75 ml, 109 mmol) was added. The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo. The residue was diluted with ether and washed with brine. The aqueous layer was extracted with two portions of ether. The combined organic layers were washed with two portions of 5% sodium thiosulfate and then with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated to give 3-benzoyl-3,3-bis-methylsulfanyl acrylonitrile 2 as a yellow powder (9.5 g, 74%). The product was used in the next step without further purification.

B. 3- (5-amino-4-benzoyl-3-methoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

Sodium (317 mg, 13.8 mmol) was added to methanol (10 ml) at 0 ° C. After the total amount of sodium was consumed, the resulting sodium methylate solution at 0 ° C. was added to a stirred solution of 3-benzoyl-3,3-bis-methylsulfanylacrylonitrile 2 (3.12 g, 12.5 mmol) in dioxane (30 ml). The reaction mixture was warmed to room temperature and then heated at 80 ° C. for 3 hours. The resulting dark red solution was cooled to room temperature and N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate acetate (4.00 g) was added. , 12.5 mmol) and diisopropylethylamine (2.18 ml, 12.5 mmol) in dioxane (15 ml). The mixture was heated at 85 ° C for another 6 hours. The solvent was removed in vacuo, the residue was diluted with saturated NaHCO ₃ solution and extracted with three portions of EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography on silica gel (eluent: EtOAc / Hexane, EtOAc gradient from 75% to 90%) and recrystallized from EtOAc to give the desired 3- (5-amino-4-benzoyl-3-methoxypyrazole-1- il) -N-cyclopropyl-4-methylbenzamide 3 (950 mg, 19%) as a white solid. HPLC (gradient 10-90 over 4 min): v.u. 2.33 minutes MS: m / z 391.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.50 (d, J 3.4, 1H), 7.91 (d, J 7.9, 1H), 7.85 (s, 1H ), 7.61 (d, J 6.9, 2H), 7.41-7.62 (m, 4H), 7.00 (br s, 2 H), 3.66 (s, 3H), 2.87 (m, 1H), 2.20 (s, 3H), 0.70 (m, 2H), 0.85 (m, 2 H).

¹³ C-NMR (125 MHz, DMSO-d ₆ ): δ 188.1, 166.0, 159.5, 152.8, 140.1, 139.5, 135.5, 132.9, 131.1 , 130.6, 128.1, 128.0, 127.4, 126.8, 91.0, 55.2, 23.0, 15.1, 5.6.

Example 31

Preparation of 3- (5-amino-4-benzoyl-3-ethoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

Этанол (0,47 мл, 8,0 ммоля) добавляли в суспензию сухого гидрида натрия (41 мг, 1,6 ммоля) в диоксане (2 мл). Смесь перемешивали при комнатной температуре в течение 10 мин, добавляли 2-бензоил-3,3-бис-метилсульфанилакрилонитрил 2 (0.20 г, 0.80 ммоля) и смесь перемешивали при 85°С в течение 2,5 ч. Смесь охлаждали до комнатной температуры, добавляли трифторацетат N-циклопропил-3-гидразино-4-метилбензамида (0,26 г, 0,80 ммоля) и реакционную смесь нагревали при 85°С в течение еще 3 ч. Растворители удаляли в вакууме, остаток разбавляли насыщенным раствором NaHCO₃ и экстрагировали тремя порциями EtOAc. Объединенные органические слои сушили над MgSO₄, фильтровали и концентрировали. Неочищенный продукт очищали экспресс-хроматографией на силикагеле (элюент: EtOAc/гексан, градиент EtOAc от 75% до 85%). Затем продукт очищали промывкой теплой смесью EtOAc и гексана, при этом получали требуемый 3-(5-амино-4-бензоил-3-этоксипиразол-1-ил)-N-циклопропил-4-метилбензамид 4 (27 мг, 8,3%) в виде твердого вещества белого цвета. ЖХВР (градиент 10-90 в течение 4 мин): в.у. 2,37 мин. МС: m/z 405,2 [М+Н]⁺.

Ethanol (0.47 ml, 8.0 mmol) was added to a suspension of dry sodium hydride (41 mg, 1.6 mmol) in dioxane (2 ml). The mixture was stirred at room temperature for 10 minutes, 2-benzoyl-3,3-bis-methylsulfanylacrylonitrile 2 (0.20 g, 0.80 mmol) was added and the mixture was stirred at 85 ° C for 2.5 hours. The mixture was cooled to room temperature. N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (0.26 g, 0.80 mmol) was added and the reaction mixture was heated at 85 ° C for another 3 hours. The solvents were removed in vacuo, the residue was diluted with saturated NaHCO ₃ solution and extracted with three portions of EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography on silica gel (eluent: EtOAc / Hexane, EtOAc gradient from 75% to 85%). The product was then purified by washing with a warm mixture of EtOAc and hexane to give the desired 3- (5-amino-4-benzoyl-3-ethoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide 4 (27 mg, 8.3% ) as a white solid. HPLC (gradient 10-90 over 4 min): v.u. 2.37 minutes MS: m / z 405.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.49 (d, J 4.0, 1H), 7.90 (d, J 8.0, 1H), 7.85 (s, 1H ), 7.62 (d, J 7.1, 2H), 7.50 (d, J 7.5, 2H), 7.41-7.45 (m, 2H), 6.99 (broad.s , 2H), 4.05 (q, J 7.0, 2H), 2.87 (m, 1H), 2.19 (s, 3H), 1.09 (t, J 7.0, 3H), 0, 69 (m, 2H); 0.58 (m, 2H).

¹³ C-NMR (125 MHz, DMSO-d ₆ ): δ 188.2, 166.0, 158.9, 152.6, 140.0, 139.5, 135.5, 132.9, 131.1 , 130.6, 128.1, 127.2, 126.7, 91.2, 63.4, 23.0, 17.3, 14.2, 5.6.

Example 32

Preparation of 3- [5-amino-4-benzoyl-3- (2-methoxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Dry sodium hydride (21 mg, 0.84 mmol) was added to a solution of 2-methoxyethanol (0.63 ml, 8.0 mmol) in dioxane (2 ml) at 0 ° C. The mixture was stirred at room temperature for 30 minutes, 2-benzoyl-3,3-bis-methylsulfanylacrylonitrile 2 (0.20 g, 0.80 mmol) was added and the mixture was stirred at 85 ° C. for 4 hours. The mixture was cooled to room temperature. temperature, N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (0.26 g, 0.80 mmol) was added, then diisopropylethylamine (0.14 ml, 0.80 mmol) was added and the reaction mixture was heated at 85 ° C for another 11 hours. Solvents were removed in vacuo, the residue was diluted with saturated NaHCO ₃ solution and extracted with three portions of EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography on silica gel (eluent: EtOAc / Hexane, EtOAc gradient from 70% to 90%). The product was then purified by washing with a warm mixture of EtOAc and hexane to give the desired 3- [5-amino-4-benzoyl-3- (2-methoxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 5 (60 mg , 17%) as a white solid. HPLC (gradient 10-90 over 4 min): v.u. 2.17 minutes MS: m / z 435.2 [M + H]. ⁺

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.47 (s, 1H), 7.89 (d, J 7.9, 1H), 7.83 (s, 1H), 7.64 (d, J 7.4, 2H), 7.49 (d, J 7.7, 2H), 7.40-7.43 (m, 2H), 6.99 (br s, 2H), 4 12 (m, 2, H), 3.42 (m, 2H), 3.12 (s, 3H), 2.86 (m, 1H), 2.07 (s, 3H), 0.69 ( m, 2H); 0.56 (m, 2H).

Example 33

Preparation of 3- [5-amino-4-benzoyl-3- (2-benzyloxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Dry sodium hydride (21 mg, 0.84 mmol) was added to a solution of 2-benzyloxyethanol (1.1 ml, 8.0 mmol) in dioxane (2 ml) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 35 minutes. Then 2-benzoyl-3,3-bis-methylsulfanylacrylonitrile 2 (0.20 g, 0.80 mmol) was added, the reaction mixture was stirred at 80 ° C for 2.5 hours and cooled to room temperature, N- trifluoroacetate was added. cyclopropyl-3-hydrazino-4-methylbenzamide (0.26 g, 0.80 mmol) and the reaction mixture was heated at 80 ° C for another 8.5 hours. After cooling the reaction mixture to room temperature, the solvent was removed in vacuo. The resulting residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , eluent: EtOAc / hexane gradient, 60% to 85%). The resulting product was purified by washing with warm EtOAc to give the desired 3- [5-amino-4-benzoyl-3- (2-benzyloxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 6 as a dirty solid white (74 mg, 18%). HPLC: (gradient 10-90% for 4 min), v. 2.57 minutes MS: m / z 511.2

[M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.49 (d, J 4.0 Hz, 1H), 7.90 (d, J 8.0 Hz, 1H), 7.85 (s, 1H ), 7.66 (d, J 7.1 Hz, 2H), 7.49 (m, 2H), 7.27-7.40 (m, 5H), 7.22 (d, J 6.7 Hz) , 2H), 7.02 (br s, 2H), 4.34 (s, 2H), 4.19 (m, 2H), 3.57 (m, 2H), 2.87 (m, 1H) 2.17 (s, 3H); 0.69 (m, 2H); 0.59 (m, 2H).

Example 34

Preparation of 4- [5-amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazol-3-yloxy] piperidine tert-butyl ester

1-carboxylic acid

Dry sodium hydride (41.0 mg, 1.60 mmol) was added to a solution of 4-hydroxypiperidin-1-carboxylic acid tert-butyl ester 7 (0.565 g, 2.81 mmol) in dioxane (2 ml) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 45 minutes. Then 2-benzoyl-3,3-bis-methylsulfanylacrylonitrile 2 (0.20 g, 0.80 mmol) was added, the reaction mixture was stirred at 65 ° C for 4 hours and cooled to room temperature, N-cyclopropyl trifluoroacetate was added. 3-hydrazino-4-methylbenzamide (0.26 g, 0.80 mmol) and the reaction mixture were heated at 80 ° C for another 3 hours. After cooling the reaction mixture to room temperature, the solvent was removed in vacuo. The resulting residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , eluent: EtOAc / hexane gradient, 65% to 85%). The resulting product was purified by washing with warm EtOAc to give the desired 4- [5-amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazol-3-yloxy] piperidine tert-butyl ester

1-carboxylic acid 8 as an off-white solid (70 mg, 16%). HPLC: (gradient 10-90% for 4 min), v. 2.63 minutes MS: m / z 559.9 [M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.49 (d, J 3.6 Hz, 1H), 7.90 (d, J 8.1 Hz, 1H), 7.84 (s, 1H ), 7.59 (d, J, 7.7 Hz, 2H), 7.40-7.51 (m, 4H), 6.99 (br s, 2H), 4.75 (m, 1H), 3.18 (m, 2H), 2.99 (m, 2H), 2.87 (m, 1H), 2.19 (s, 3H), 1.68 (m, 2H), 1.43 (m , 2H), 1.37 (s, 9H), 0.71 (m, 2H), 0.58 (m, 2H).

Example 35

Preparation of 3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide trifluoroacetate

To a solution of 4- [5-amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazol-3-yloxy] piperidine-tert-butyl ester

1-carboxylic acid 8 (5.0 mg, 0.0089 mmol) in dichloromethane (2.0 ml) was added trifluoroacetic acid (0.5 ml). The resulting reaction mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue washed with ether and a small amount of EtOAc to give the desired 3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) trifluoroacetate ) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide 9 as a white solid (3.0 mg, 59%). HPLC: (gradient 10-90% for 4 min), v. 1.75 minutes MS: m / z 460.1 [M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.50 (d, J 4.0 Hz, 1H), 8.33 (br.s, 2H), 7.90 (d, J 8.0 Hz , 1H), 7.83 (s, 1H), 7.62 (d, J 7.0 Hz, 2H), 7.44-7.52 (m, 4H), 7.03 (br.s, 2H ), 4.82 (m, 1H), 2.97 (m, 2H), 2.85 (m, 1H), 2.73 (m, 2H), 2.27 (s, 3H), 1.91 (m, 2H), 1.73 (m, 2H), 0.71 (m, 2H), 0.57 (m, 2H).

Example 36

Preparation of 3- (5-amino-4-benzoyl-3-methylsulfanylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

To a solution of benzoyl-3,3-bis-methylsulfanylacrylonitrile 2 (0.218 g, 0.874 mmol) in ethanol (5 ml) was added N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (0.243 g, 0.874 mmol) and diisopropylethylamine (0.152 ml , 0.874 mmol). The resulting mixture was heated at 65 ° C for 18 hours, then cooled to room temperature and the solvent was removed in vacuo. The resulting residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , eluent: EtOAc / hexane gradient, 65% to 100%). The resulting product was purified by washing with warm EtOAc and hexane to give the desired 3- (5-amino-4-benzoyl-3-methylsulfanylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide 10 as an off-white solid ( 57 mg, 16%). HPLC: (gradient 10-90% for 4 min), v. 2.34 minutes MS: m / z 407.1

[M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.50 (d, J 4.0 Hz, 1H), 7.93 (dd, J 1.2, 7.9 Hz, 1H), 7.86 (s, 1H), 7.45-7.57 (m, 6H), 6.85 (broad s, 2H), 2.88 (m, 1H), 2.23 (s, 3H), 2, 18 (s, 3H), 0.69 (m, 2H), 0.58 (m, 2H).

¹³ C NMR (DMSO-d ₆ , 125 MHz) δ 189.3, 165.9, 152.8, 148.0, 140.4, 139.3, 135.4, 132.9, 131.2, 130 6, 128.4, 128.1, 127.2, 126.6, 102.0, 23.0, 17.3, 13.4, 5.6.

Example 37

Preparation of 3- (5-amino-4-benzoyl-3-methanesulfonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

To a suspension of 3- (5-amino-4-benzoyl-3-methylsulfanylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide 10 (40 mg, 0.098 mmol) in dichloromethane (1 ml) was added 3-chloroperoxybenzoic acid (70 -75%, 53 mg, 0.22 mmol). The resulting solution was stirred at room temperature for 2 hours, and then kept at 4 ° C overnight. When heated to room temperature, a precipitation was observed in the solution. A white solid was collected on a porous filter and washed with dichloromethane and ether to give the desired 3- (5-amino-4-benzoyl-3-methanesulfonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide 11 (27 mg, 63%). HPLC: (gradient 10-90% for 4 min), v. 1.98 minutes MS: m / z 439.08 [M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.53 (d, J 3.7 Hz, 1H), 7.97 (d, J 8.1 Hz, 1H), 7.92 (s, 1H ), 7.76 (d, J 7.2 Hz, 1H), 7.48-7.64 (m, 5H), 6.30 (br s, 2H), 3.29 (s 3H), 2 88 (m, 1H), 2.17 (s, 3H), 0.69 (m, 2H), 0.58 (m, 2H).

Example 38

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide

To a solution of 2-cyano-3,3-bis-methylsulfanyl acrylamide 12 (100 mg, 0.574 mmol) in ethanol (5 ml) was added N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (0.183 g, 0.574 mmol) and diisopropylethylamine ( 0.100 ml, 0.574 mmol). The resulting mixture was heated at 65 ° C for 18 hours, then cooled to room temperature and the solvent was removed in vacuo. EtOAc was added to the resulting residue, and precipitation was observed. The solid was collected on a porous filter and washed with EtOAc and ether to give the desired 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide 13. HPLC: ( gradient 10-90% for 4 min), v. 1.98 minutes MS: m / z 439.08 [M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 8.47 (d, J 3.7 Hz, 1H), 7.90 (d. J 7.9 Hz, 1H), 7.78 (s, 1H ), 7.49 (d, J 8.0 Hz, 1H), 6.81 (br.s, 2H), 6.30 (s, 2H), 2.86 (m, 1H), 2.45 ( s, 3H), 2.11 (s, 3H), 0.68 (m, 2H), 0.57 (m, 2H).

Example 39

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methanesulfonyl-1H-pyrazole-4-carboxylic acid amide

В суспензию амида 5-амино-1-(5-циклопропилкарбамоил-2-метилфенил)-3-метилсульфанил-1Н-пиразол-4-карбоновой кислоты 13 (100 мг, 0,289 ммоля) в дихлорметане (3 мл) добавляли 3-хлорпероксибензойную кислоту (70-75%, 157 мг, 0,637 ммоля). Полученный прозрачный раствор перемешивали при комнатной температуре в течение 16 ч, а затем добавляли насыщенный раствор NaHCO₃ и реакционную смесь интенсивно перемешивали в течение мин. Полученную суспензию фильтровали на пористом фильтре и полученное твердое вещество три раза промывали Н₂О и три раза эфиром, при этом получали требуемый амид 5-амино-1-(5-циклопропилкарбамоил-2-метилфенил)-3-метансульфонил-1Н-пиразол-4-карбоновой кислоты 14 в виде твердого вещества белого цвета (87 мг, 80%). ЖХВР: (градиент 10-90% в течение 4 мин), в.у. 1,66 мин. МС: m/z 378,1 [М+Н]⁺.

To a suspension of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid 13 amide 13 (100 mg, 0.289 mmol) in dichloromethane (3 ml) was added 3-chloroperoxybenzoic acid (70-75%, 157 mg, 0.637 mmol). The resulting clear solution was stirred at room temperature for 16 hours, and then a saturated solution of NaHCO _{3 was} added and the reaction mixture was stirred vigorously for min. The resulting suspension was filtered on a porous filter and the resulting solid was washed three times with H ₂ O and three times with ether to give the desired 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methanesulfonyl-1H-pyrazole- amide 4-carboxylic acid 14 as a white solid (87 mg, 80%). HPLC: (gradient 10-90% for 4 min), v. 1.66 minutes MS: m / z 378.1 [M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 8.49 (s, 1H), 7.95 (d, J 7.6 Hz, 1H), 7.83 (s, 1H), 7.53 ( d, J 7.8 Hz, 1H), 7.46 (br.s, 2H), 6.74 (br.s, 2H), 3.40 (s, 3H), 2.84 (m, 1H) 2.09 (s, 3H); 0.68 (m, 2H). 0.55 (m, 2H).

Example 40

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester

To a solution of 2-cyano-3,3-bis-methylsulfanylacrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was added N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol). The resulting mixture was heated at 65 ° C for 2 hours, then cooled to room temperature and the solvent was removed in vacuo. EtOAc and ether were added to the resulting residue, and precipitation was observed. The solid was collected on a porous filter and washed with EtOAc and ether to give the desired 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester 16 as a solid white matter (80 mg, 59%). HPLC: (gradient 10-90% for 4 min), v. 2.18 minutes MS: m / z 375.1 [M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.47 (d, J 3.7 Hz, 1H), 7.90 (d, J 7.9 Hz, 1H), 7.78 (s, 1H ), 7.49 (d, J 8.0 Hz, 1H), 6.81 (br.s, 2H), 6.30 (s, 2H), 2.86 (m, 1H), 2.45 ( s, 3H), 2.11 (s, 3H), 0.68 (m, 2H), 0.57 (m, 2H). HPLC: (gradient 10-90% for 4 min), v. 1.66 minutes MS m / z 378.1 [M + H] ⁺ .

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.50 (d, J 2.6 Hz, 1H), 7.92 (dd, J 7.9, Hz, 1H), 7.81 (s, 1H), 7.51 (d, J 7.9 Hz, 1H), 6.24 (br.s, 2H), 4.22 (q, J 6.6 Hz, 2H), 2.88 (m, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 1.29 (t, J 6.7 Hz, 3H), 0.72 (m, 2H), 0.58 (m , 2H).

¹³ C NMR (DMSO-d ₆ 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8, 132.9, 131.1, 128.2, 126, 7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6.

Example 41

Preparation of 3- [5-amino-4- (3-chlorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 2- (3-Chlorobenzoyl) -3-phenylaminoacrylonitrile

A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq.) And diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq.) In 25 ml of toluene was stirred at room temperature for 2 hours, and then heated at 100 ° C. overnight. The resulting solution was cooled and diluted with hexane. The resulting solid was filtered and dried to give the desired product (566 mg, 75%). HPLC: (gradient 10-95% for 4 min), v.u. 2.97 minutes MS: m / z 283.2 [M + H] ⁺ .

¹ H NMR (CDCl ₃ ) δ 8.06 (d, J 13.2 Hz, 1H), 7.85 (m, 2H), 7.46 (m, 4H), 7.27 (m, 4H).

B. 3- [5-amino-4- (3-chlorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Solution of 2- (3-chlorobenzoyl) -3-phenylaminoacrylonitrile (63 mg, 0.22 mmol, 1.0 eq.), N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (72 mg, 0.22 mmol, 1 .eq.) and triethylamine (31 μl, 0.22 mmol, 1.0 eq.) in 10 ml of ethanol was heated at 65 ° C for 20 hours. After cooling, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel to remove by-products (eluent: hexane / ethyl acetate, 7: 3) and then to isolate the title compound (eluent: ethyl acetate / hexane, 3: 2) as a brown solid (33 mg, 38% ) HPLC: (gradient 10-95% for 4 min), v.u. 2.35 minutes MS: m / z 395.1 [M + H] ⁺ .

¹ H NMR (CD ₃ OD) δ 7.92 (dd, J 7.2, Hz, 1H), 7.77 (m, 4H), 7.55 (m, 3H), 2.85 (m, 1H ), 2.23 (s, 3H), 0.80 (d, J 5.5 Hz, 2H), 0.63 (d, J 2.0 Hz, 2H).

¹³ C NMR (CD ₃ OD) δ 187.1, 168.1, 151.9, 141.0, 140.9, 140.0, 134.9, 133.8, 132.8, 130.9, 130 5, 129.4, 128.1, 127.0, 126.1, 125.6, 102.6, 22.1, 15.7, 4.6.

Example 42

Preparation of 3- [5-amino-4- (3-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 41, but when replacing 3-chlorobenzoylacetonitrile with 3-methylbenzoylacetonitrile. HPLC: (gradient 10-95% for 4 min), v.u. 2.27 minutes MS: m / z 375.16 [M + H] ⁺ .

¹ H NMR (CD ₃ OD) δ 7.92 (d, J 7.0 Hz, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.57 (m, 3H) 7.42 (m, 2H), 2.85 (heptet, J 3.6 Hz, 1H), 2.45 (s, 3H), 2.23 (s, 3H), 0.80 (d, J 5.4 Hz, 2H); 0.64 (s, 2H).

Example 43

Preparation of 3- [5-amino-4- (2-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 41, but when replacing 3-chlorobenzoylacetonitrile with 2-methylbenzoylacetonitrile. HPLC: (gradient 10-90% for 4 min), v. 2.21 minutes MS: m / z 375.15 [M + H] ⁺ .

Example 44

Preparation of 3- [5-amino-4- (2-methoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 41, but when replacing 3-chlorobenzoylacetonitrile with 2-methoxybenzoylacetonitrile. HPLC: (gradient 10-90% for 4 min), v. 2.03 minutes MS: m / z 391.16 [M + H] ⁺ .

Example 45

Preparation of 3- [5-amino-4- (4-chlorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 41, but when replacing 3-chlorobenzoylacetonitrile with 3-methylbenzoylacetonitrile. HPLC: (gradient 10-90% for 4 min), v. 1.65 minutes MS: m / z 394.2 [M + H] ⁺ .

Example 46

Preparation of 3- [5-amino-4- (2-chlorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 2- (2-Chlorobenzoyl) -3-phenylaminoacrylonitrile

A solution of 2-chlorobenzoylacetonitrile (1.0 g, 5.6 mmol, 1.0 eq.) And diphenylformamidine (1.10 g, 5.6 mmol, 1.0 eq.) In 50 ml of toluene was heated at 85 ° C. overnight. The heat source was removed, while the desired product slowly precipitated from the solution. The resulting solid was filtered and dried to give the desired product (826 mg, 52%). HPLC: (gradient 10-90% for 4 min), v. 3.13 minutes MS: m / z 283.2 [M + H] ⁺ .

B. 3- [5-amino-4- (2-chlorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Solution of 2- (2-chlorobenzoyl) -3-phenylaminoacrylonitrile (93 mg, 0.33 mmol, 1.0 eq.), N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (104 mg, 0.33 mmol, 1 equiv.) and triethylamine (31 μl, 0.22 mmol, 1.0 equiv.) in 20 ml of ethanol was heated at 60 ° C for 48 hours. After cooling, the reaction mixture was concentrated and the residue was dissolved in a minimum amount of ethyl acetate, 100 ml was added diethyl ether, the resulting precipitate was filtered off and dried, and the desired product was obtained (50 mg, 39%). HPLC: (gradient 10-90% for 4 min), v. 2.51 minutes MS: m / z 395.1 [M + H] ⁺ .

¹ H NMR (DMSO) δ 8.50 (d, J 3.8 Hz, 1H), 7.93 (d, J 8.0 Hz, 1H), 7.84 (s, 1H), 7.57 ( m, 5H), 7.32 (s, 1H), 7.01 (s, 2H), 3.37 (m, 2H), 2.86 (m, 1H), 2.14 (s, 3H), 1, 09 (t, 2H), 0.68 (m, 2H), 0.58 (m, 2H).

Example 47

Preparation of 3- [5-amino-4- (3-methoxybenzoyl) pyrazol-1-yl] -4, N-cyclopropyl-4-methylbenzamide

A. 3-Methoxybenzoylacetonitrile

In a solution of 3-methoxybenzoic acid ethyl ester (3.05 ml, 18.6 mmol, 1.0 equiv.) And acetonitrile (1.19 ml, 22.9 mmol, 1.23 equiv.) In 5 ml of THF at - 50 ° C in an atmosphere of N ₂ with stirring through a tube was added a freshly prepared solution of LDA (diisopropylamine, 5.3 ml, 38.0 mmol, 2.04 equiv. And 2.5 M n-butyl lithium in hexane, 15.25 ml, 38 , 0 mmol, 2.04 equiv.). The reaction mixture was stirred at the indicated temperature for 3 hours, and then heated to 0 ° C for 1 hour. The reaction was stopped by adding 10 ml of a saturated solution of NH ₄ Cl and the reaction mixture was heated to room temperature. The resulting mixture was extracted with EtOAc, the organic layer was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel, and the product was obtained as an off-white solid.

B. 2- (3-Methoxybenzoyl) -3-phenylaminoacrylonitrile

A solution of 3-methoxybenzoylacetonitrile (1.20 g, 68.5 mmol, 1.0 eq.) And diphenylformamidine (1.34 g, 68.5 mmol, 1.0 eq.) In 25 ml of toluene was stirred at room temperature for 2 hours, and then heated at 100 ° C. overnight. The resulting solution was cooled and diluted with hexane. The resulting solid was filtered and dried to give the desired product. HPLC: (gradient 10-90% for 4 min), v. 3.05 minutes MS: m / z 279.2 [M + H] ⁺ .

B. 3- [5-amino-4- (3-methoxybenzoyl) pyrazol-1-yl] -4-methylbenzoic acid

Solution of 2- (3-chlorobenzoyl) -3-phenylaminoacrylonitrile (63 mg, 0.22 mmol, 1.0 eq.), 3-hydrazino-4-methylbenzoic acid hydrochloride (72 mg, 0.22 mmol, 1 eq.) and triethylamine (31 μl, 0.22 mmol, 1.0 equiv.) in 10 ml of ethanol was heated at 65 ° C for 20 h. After cooling, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel to remove by-products (eluent : hexane / ethyl acetate, 7: 3) and then to isolate the title compound (eluent: ethyl acetate / hexane, 3: 2) as a brown solid (15 mg, 32%). HPLC: (gradient 10-90% for 4 min), v. 2.13 minutes MS: m / z 352.2 [M + H] ⁺ .

G. 3- [5-amino-4- (3-methoxybenzoyl) pyrazol-1-yl] -4, N-methylbenzamide

EDCI was added to a solution of 3- [5-amino-4- (3-methoxybenzoyl) pyrazol-1-yl] -4-methylbenzoic acid (50 mg, 0.14 mmol, 1.0 eq.) With stirring. (41 mg, 0.21 mmol, 1.5 eq.), HOBt (29 mg, 1.5 mmol, 2.0 eq.) And diisopropylethylamine (55 mg, 0.43 mmol, 3.0 eq.), the solution was stirred at room temperature for 15 minutes, then methylamine hydrochloride (13 mg, 0.19 mmol, 1.5 eq.) was added and the reaction mixture was stirred for 1 h. The resulting reaction mixture was diluted with EtOAc (300 ml) and washed with water (2 × 25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel to give the product (15 mg, 32%) as a brown solid. HPLC: (gradient 10-90% for 4 min), v. 1.97 minutes MS: m / z 365.2 [M + H] ⁺ .

Example 48

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester

A. 5-amino-1- (5-carboxy-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester

Ethyl (ethoxymethylene) cyanoacrylate (399 mg, 2.36 mmol, 1) was added to a solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 478 mg, 2.36 mmol, 1.0 equiv.) In 20 ml of ethanol. 0 equiv.) And triethylamine (329 μl, 2.36 mmol, 1.0 equiv.), The resulting mixture was heated at 65 ° C with stirring for 5 hours. After standing at room temperature overnight, another portion of hydrochloride 3 was added. -hydrazino-4-methylbenzoic acid (159 mg, 0.78 mmol, 0.3 eq.) and triethylamine (110 μl, 0.78 mmol, 0.3 eq.), was heated for 2.5 hours. The resulting mixture cooled to room temperature temperature and concentrated. The crude residue was purified by flash chromatography on silica gel to remove by-products (eluent: hexane / EtOAc, 7: 3 to 1: 1) and then to isolate the title compound (eluent: EtOAc to EtOAc / MeOH, 9: 1 ) as a brown solid (464 mg, 68%). HPLC: (gradient 10-95% for 4 min), v.u. 1.87 minutes MS: m / z 290.1 [M + H] ⁺ .

¹ H NMR (CD ₃ OD) δ 8.08 (d, J 7.0 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.54 (d, J 8 , 0 Hz, 1H), 4.29 (q, J 7.1 Hz, 2H), 2.19 (s, 3H), 1.35 (d, J 7.1 Hz, 3H).

¹³ C NMR (CD ₃ OD) δ 166.5, 163.8, 150.4, 141.7, 139.9, 135.3, 130.8, 129.5, 128.6, 93.8, 58 8, 15.8, 12.9.

B. Ethyl 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid

A solution of 5-amino-1- (5-carboxy-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester (47 mg, 0.16 mmol, 1.0 eq.), EDCl (62 mg, 0, 32 mmol, 2.0 equiv.), HOBt (44 mg, 0.32 mmol, 2.0 equiv.) And diisopropylethylamine (119 μl, 0.32 mmol, 2.0 equiv.) In DMF (5 ml) was stirred at CT for 15 minutes, then cyclopropylamine (23 μl, 0.32 mmol, 2.0 eq.) was added. After stirring overnight, the solution was diluted with EtOAc and water, the organic layer was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude residue was purified by flash chromatography on silica gel (eluent: EtOAc / Hexane, 8: 2) to give the product as a colorless oil (42 mg, 79%). HPLC: (gradient 10-95% for 4 min), v.u. 1.84 minutes MS: m / z 329.09 [M + H] ⁺ .

¹ H NMR (CD ₃ OD) δ 7.96 (s, 1H, NH), 7.88 (d, J 7.9 Hz, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.50 (d, J 8.0 Hz, 1H), 4.28 (q, J 7.1 Hz, 2H), 2.83 (m, 1H), 2.16 (s, 3H) 1.35 (d, J 7.0 Hz, 3H), 0.78 (dd, J 12.3, 7.0 Hz, 2H), 0.63 (dd, J 7.0, 4.5 Hz , 2H).

¹³ C NMR (CD ₃ OD) δ 170.1, 165.8, 152.3, 142.1, 141.8, 137.2, 134.6, 132.8, 130.0, 128.2, 128 , 1, 95.8, 60.8, 24.1, 17.6, 14.9, 6.6.

Example 49

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

A. 5-amino-1- (5-carboxy-2-methylphenyl) -3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

To a solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 353 mg, 1.74 mmol, 1.0 equiv.) In 15 ml of ethanol was added ethyl 2-cyano-3-ethoxybut-2-enoic acid (obtained as described in Xia et al., J. Med. Chem., 40, 4372, (1997), 319 mg, 1.746 mmol, 1.0 equiv.) and triethylamine (242 μl, 1.74 mmol, 1, 0 equiv.), The resulting mixture was stirred at 65 ° C. overnight with stirring. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel (applied in CH ₂ Cl ₂ ), then the column was filled and eluent: hexane / EtOAc, 6: 4 was used to remove by-products, and then to isolate the product (eluent: EtOAc / hexane, 8: 2 and EtOAc / MeOH, 8: 2) as a brown solid (464 mg, 68%). HPLC: (gradient 10-95% for 4 min), v.u. 1.97 minutes MS: m / z 304.1 [M + H] ⁺ .

B. Ethyl 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methyl-1H-pyrazole-4-carboxylic acid

A solution of 5-amino-1- (5-carboxy-2-methylphenyl) -3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (150 mg, 0.49 mmol, 1.0 eq.), EDCl (190 mg, 0.98 mmol, 2.0 equiv.), HOBt (134 mg, 0.98 mmol, 2.0 equiv.) and diisopropylethylamine (362 μl, 0.98 mmol, 2.0 equiv.) in DMF ( 5 ml) was stirred at RT for 15 minutes, then cyclopropylamine (68 μl, 0.98 mmol, 2.0 eq.) Was added. After stirring overnight, the solution was diluted with EtOAc and water, the organic layer was washed with water (2 times) and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude residue was purified by flash chromatography on silica gel (eluent: gradient from EtOAc / Hexane, 3: 2 to 100% EtOAc) to give the product as a white solid (29 mg, 17%). HPLC: (gradient 10-95% for 4 min), v.u. 1.97 minutes MS: m / z 343 [M + H] ⁺ .

¹ H NMR (CD ₃ OD) δ 7.87 (d, J 7.1 Hz, 1H), 7.76 (s, 1H), 7.50 (d, J 8.0 Hz, 1H), 4, 29 (q, J 7.0 Hz, 2H), 2.84 (m, 1H), 2.34 (s, 3H), 2.18 (s, 3H), 1.36 (t, J 7.0 Hz, 3H), 0.79 (d, J 5.5 Hz, 2H), 0.62 (s, 2H).

¹³ C NMR (CD ₃ OD) δ 168.1, 164.4, 151.3, 149.8, 140.1, 135.2, 132.6, 130.7, 127.9, 126.3, 92 0, 58.6, 22.1, 15.7, 12.9, 12.6, 4.6.

Example 50

Preparation of 5-amino-3 - [(3-chlorobenzylcarbamoyl) methoxy] -1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester

A. 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3- (2-hydroxyethoxy) -1H-pyrazole-4-carboxylic acid ethyl ester

A solution of cyano [1,3] dioxolan-2-ylideneacetic acid ethyl ester (prepared as described in Neidlein and Kikelj, Synthesis, 981, (1988, 266 mg, 1.45 mmol, 1.0 eq.), Trifluoroacetate N β-cyclopropyl-3-hydrazino-4-methylbenzamide (Example 6C, 463 mg, 1.45 mmol, 1.0 equiv) and triethylamine (405 μl, 2.9 mmol, 2.0 equiv) were heated in 20 ml of ethanol overnight at 65 ° C. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (eluent: 1: 1 hexane / EtOAc gradient to 100% EtOAc) to give the desired compound in ide yellow-brown solid (350 mg, 62%). HPLC: (gradient 10-95% for 4 minutes), vu 1.59 minutes MS: m / z 389.06 [M + H ] ⁺ .

¹ H NMR (CD ₃ OD) δ 7.87 (d, J 7.9 Hz, 1H), 7.78 (s, 1H), 7.49 (d, J 7.8 Hz, 1H), 4, 29 (dd, J 14.9, 6.9 Hz, 2H), 4.19 (d, J 4.3 Hz, 2H), 3.84 (d, J 4.4, Hz, 2H), 2, 84 (m, 1H), 2.22 (s, 3H), 1.35 (t, J 7.3 Hz, 3H), 0.81 (d, J 5.3 Hz, 2H), 0.63 ( s, 2H).

B. 5-amino-3-carboxymethoxy-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester

To a 50A alcohol solution (48 mg, 0.12 mmol, 1.0 eq.) In 5 ml of acetonitrile, 2.2 ', 6.6'-tetramethylpiperidinyl oxyl (TEMPO) (catalytic amount) was added with stirring, and the resulting solution was heated to 35 ° C. Then, sodium chlorite (17 mg, 0.24 mmol, 2.0 equiv.) In water (2 ml) was successively added dropwise and an aqueous solution of sodium hypochlorite diluted to 2% (1 ml) was heated for 24 hours, the solution was stained in a bright orange color. The resulting reaction mixture was cooled to RT and diluted with water, then the reaction was stopped with 1 M Na ₂ SO ₃ and the mixture was stirred for 30 min, washed with EtOAc, the pH of the aqueous layer was adjusted from 8 to 2 with 3 M HCl and extracted with CH ₂ Cl ₂ . The CH ₂ Cl ₂ extracts were dried and concentrated to give the product as a yellow solid. HPLC: (gradient 10-95% for 4 min), v.u. 1.70 minutes MS: m / z 403.02 [M + H] ⁺ .

¹ H NMR (CD ₂ OD) δ 7.83 (d, J 7.9 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J 7.9 Hz, 1H), 4, 73 (s, 2H), 4.19 (q, J 7.1 Hz, 2H), 2.84 (m, 1H), 2.18 (s, 3H), 1.31 (t, J 7.0 Hz, 3H), 0.78 (d, J 6.1 Hz, 2H), 0.62 (s, 2H).

¹³ C NMR (CD ₃ OD) δ 171.1, 170.2, 168.4, 163.6, 159.7, 151.3, 140.5, 135.2, 132.5, 130.7, 127 6, 126.2, 80.9, 59.6, 58.7, 22.1, 15.8, 12.5, 4.6.

B. Ethyl 5-amino-3 - [(3-chlorobenzylcarbamoyl) methoxy] -1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid

Into a solution of acid 50B (28 mg, 0.7 mmol, 1.0 equiv.), EDCl (32 mg, 0.17 mmol, 2.4 equiv.), HOBt (22 mg, 0.16 mmol, 2.4 equiv.) in DMF (3.0 ml) at room temperature was added 3-chlorobenzylamine (18 μl, 0.07 mmol, 1.0 equiv.) and the resulting mixture was stirred overnight. Then the reaction mixture was diluted with EtOAc, washed with water (2 times) with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel (eluent: EtOAc / Hexane, 9: 1) to give the product as a colorless oil (16 mg, 44%). HPLC: (gradient 10-95% for 4 min), v.u. 2.34 minutes MS: m / z 525.99 [M + H] ⁺ .

¹ H NMR (CD ₃ OD) δ 7.85 (d, J 7.9 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J 8.0 Hz, 1H), 7, 25 (m, 3H), 4.73 (s, 2H), 4.45 (s, 2H), 4.25 (q, J 7.0 Hz, 2H), 2.84 (m, 1H), 2 , 17 (s, 3H), 1.27 (t, J 7.0 Hz, 3H), 0.80 (dd, J 12.3, 6.7 Hz, 2H), 0.62 (d, J 2 , 2 Hz, 2H).

¹³ C NMR (CD ₃ OD) δ 168.9, 168.3, 163.4, 159.6, 151.1, 140.3, 140.1, 135.2, 133.6, 132.6, 130 , 8, 129.1, 127.7, 126.6, 126.4, 125.0, 66.3, 58.8, 41.1, 22.1, 15.9, 12.9, 4.6 .

Example 51

Preparation of 3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

A. 3-Hydrazino-4-methylbenzoic acid hydrochloride

A solution of 3-amino-4-methylbenzoic acid 1 (100 g, 0.66 mol, 1.0 equiv.) In water (1.78 L) was cooled to a temperature of 0-5 ° C. using ice water. At the indicated temperature, conc. HCl (1.78 L) and sodium nitrite (68.5 g, 0.99 mol, 1.5 eq.), The resulting reaction mixture was stirred at 0-5 ° C for 1 h. Chloride dihydrate was added at the same temperature. tin (II) (336 g, 1.488 mol, 2.25 equiv.) in conc. HCl (540 ml) and the mixture was stirred for 2 hours. The resulting solid was filtered and washed with water (3 × 500 ml), dried in vacuum at 25-30 ° C for 15 hours, while obtaining the crude material (110 g) which was dissolved in ethanol (1 L) and stirred at 70 ° C for 1 h. The resulting material was filtered while hot, washed with ethanol (50 ml) and dried in air, to give pure hydrazine 2 (60 g, 45% ) as a off-white solid.

B. 3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid

To a solution of hydrazine 2 (59 g, 0.29 mol, 1.0 equiv.) In ethanol (4.5 L), compound 3 (65 g, 0.262 mol, 0.9 equiv.) Obtained as described in Grothasu Davis, J. Am. Chem. Soc., 58, 1334 (1936)) and triethylamine (29 g, 0.29 mol, 1.0 eq.), the resulting mixture was heated at 65 ° C. The resulting homogeneous mixture was stirred at 65 ° C for 4 hours, while the product precipitated. The solid was filtered while hot and dried, whereby acid 4 (45 g, 53%) was obtained as an off-white crystalline solid. HPLC: (Waters X-Terra C18 column, 5 μm, 4.6 mm × 250 mm, elution rate 1.0 ml / min, eluent: 0.1% TEA in H ₂ O / acetonitrile, 40:60, over 30 min) 2.12 min, 96.6% purity. Data ¹ H NMR (DMSO-d ₆ , 400 MHz), see example 3.

B. 3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

To a solution of acid 4 (46 g, 0.143 mol, 1.0 equiv.) In DMF (1.9 l) was added with stirring EDCl (57.5 g, 0.299 mol, 2.09 equiv.), HOBt (41.4 g, 0.306 mol, 2.14 equiv.) and diisopropylethylamine (76.6 g, 0.59 mol, 4.15 equiv.), the resulting solution was stirred at room temperature for 20 minutes. Then the solution was cooled to 15-20 ° C, cyclopropylamine (20.6 g, 0.36 mol, 2.51 equiv.) Was added and stirred at room temperature. The progress of the reaction was monitored by TLC. Since the reaction was not completed after 14 hours, another portion of cyclopropylamine (9.36 g, 0.16 mol, 1.14 equiv.) Was added and stirred for another 2 hours. DMF was removed under reduced pressure at a temperature of 50-55 ° FROM. EtOAc (1 L) and water (500 ml) were added to the residue, the resulting mixture was stirred for 10 minutes, extracted and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 × 250 ml). The combined organic layers were washed with sodium bicarbonate (2 × 500 ml) and brine (2 × 500 ml), dried over anhydrous sodium sulfate and concentrated. EtOAc / dichloromethane / hexane (50 ml: 50 ml: 50 ml) was added to the residue, the mixture was stirred for 10 min and filtered, to give the product (34.1 g, 65.7%) as a crystalline dirty solid white color. HPLC: (Waters X-Terra C18 column, 5 μm, 4.6 mm × 250 mm, elution rate 1.0 ml / min, eluent: 0.1% TFA in H ₂ O / acetonitrile, 50:50, over 30 min) 5.53 min, 99.3% pure. MC: m / z 360 [M] ⁺ . ¹ H NMR (DMSO-d ₆ , 400 MHz), see Example 4.

Example 52

Preparation of 3- [5-amino-4- (3-cyanobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

To a solution of 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide (110 mg, 0.23 mmol) in DMF (5 ml) was added CuCN (40 mg 0.45 mmol) and tetrakis (triphenylphosphine) palladium (catalytic amount), the resulting mixture was heated at 100 ° C in an atmosphere of N ₂ overnight. The solvent was removed and the residue suspended in EtOAc, the solid was filtered off, the filtrate was washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (eluent: EtOAc). The product was obtained as a beige solid (30 mg, 34%). HPLC: (gradient 10-90% for 4 min), v. 2.02 minutes MS: m / z 386.13 [M + H] ⁺ .

Example 53

Preparation of 3- [5-amino-4- (3- [1,3,4] oxadiazol-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

А. 3-[5-Амино-1-(5-циклопропилкарбамоил-2-метилфенил)-1Н-пиразол-4-карбонил]бензойная кислота

A. 3- [5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carbonyl] benzoic acid

To a solution of 3- [5-amino-4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide (900 mg) in CH ₃ CN (25 ml) was added NaH ₂ PO ₄ (55 mg in 2 ml of water) and H ₂ O ₂ (1.3 g, 30% solution in water), and then an aqueous solution of NaClO ₂ (365 mg) was added dropwise at 10 °. The resulting mixture was stirred at the indicated temperature for 4 hours, then Na ₂ SO _{3 was} added. The solvent was removed and the residue was dissolved in EtOAc, the organic layer was washed with water and brine, then concentrated. The crude product was purified by silica gel column chromatography (eluent: gradient from EtOAc to EtOAc / AcOH, 100: 1), and the desired intermediate was obtained as a beige foam (345 mg, 37%).

B. 3- [5-amino-4- (3-hydrazinocarbonylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Compound 53A (50 mg, 0.12 mmol), tert-butyl carbazate (33 mg, 0.24 mmol), EDCl (46 mg, 0.24 mmol), HOBt (37 mg, 0.24 mmol) were dissolved in dry DMF (5 ml) and stirred at room temperature overnight. The solvent was removed and the residue was dissolved in EtOAc, the organic layer was washed with water, an aqueous solution of K ₂ CO ₃ and brine, dried over Na ₂ SO ₄ . Then, TFA / DCE (5 ml, 1: 1) was added and stirred at room temperature for 30 minutes. The solvent was removed and the residue was dissolved in EtOAc, washed with an aqueous solution of K ₂ CO ₃ and dried over Na ₂ SO ₄ . The solvent was removed, and Compound B was obtained as a beige solid (45 mg, 88%).

C. 3- [5-amino-4- (3- [1,3,4] oxadiazol-2-yl-benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Trimethylorthoformate (2 ml) was added to a solution of compound 53B in MeOH (2 ml), and the resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in 1,4-dioxane, then 5 drops of a 4 M solution of HCl in dioxane were added and the mixture was heated in a microwave reactor at 120 ° C for 30 minutes. The solvent was removed and the residue was dissolved in EtOAc, the organic layer was washed with water and brine, the crude product was purified by preparative TLC (eluent: EtOAc / MeOH, 95: 5) to give the product as a beige solid (25 mg, 63%) . HPLC: (gradient 10-90% for 4 min), v. 1.81 minutes MS: m / z 429.13 [M + H] ⁺ .

Example 54

Preparation of 3- {5-amino-4- [3- (5-methyl [1,3,4] oxadiazol-2-yl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 53, but when replacing trimethyl orthoformate with trimethyl orthoacetate. HPLC: (gradient 10-90% for 4 min), v. 1.84 minutes MS: m / z 443.15 [M + H] ⁺ .

Example 55

Preparation of 3- {5-amino-4- [3- (pyrrolidin-1-carbonyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with pyrrolidine. HPLC: (gradient 10-90% for 4 min), v. 1.93 minutes MS: m / z 458.2 [M + H] ⁺ .

Example 56

Preparation of 3- [5-amino-4- (3-cyclopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with cyclopropylamine. HPLC: (gradient 10-90% for 4 min), v. 1.74 minutes MS: m / z 444.14 [M + H] ⁺ .

Example 57

Preparation of 3- [5-amino-4- (3-carbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 21, but when replacing isopropylamine with ammonia. HPLC: (gradient 10-90% for 4 min), v. 1.51 minutes MS: m / z 404.2 [M + H] ⁺ .

Example 58

Preparation of 3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 21B, but when replacing 3- [5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-imidazole-4-carbonyl] benzoic acid with 3- [5- amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carbonyl] benzoic acid. HPLC: (gradient 10-90% for 4 min), v. 1.89 minutes MS: m / z 446.2 [M + H] ⁺ .

Examples 59-69

The compounds shown in the following examples were obtained in the same manner as described in example 58, but when replacing isopropylamine with the corresponding amine.

Examples 70-75

The compounds shown in the following examples were obtained in the same manner as described in example 11, but when replacing 1-methylpiperazine with the corresponding amine.

Examples 76-93

The compounds shown in the following examples were obtained in the same manner as described in example 17, but when phenylmagnesium bromide was replaced with the corresponding Grignard reagent.

Example 94

Preparation of 3- (5-amino-4-benzoyl-2-methylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 17, but when replacing triethyl orthoformate with triethyl orthoacetate. HPLC: (gradient 10-90% for 4 min), v. 1.56 minutes MS: m / z 375 [M + H] ⁺ .

Example 95

Preparation of 3- (5-amino-4-benzoyl-2-propylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 17, but when replacing triethyl orthoformate with triethyl orthobutyrate. HPLC: (gradient 10-90% for 4 min), v. 2.14 minutes MS: m / z 403 [M + H] ⁺ .

Example 96

Preparation of 3- [5-amino-4- (3-carbamoylmethoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamyl

A. {3- [5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carbonyl] phenoxy} acetic acid

Into a solution of 3- [5-amino-4- (3-hydroxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide (400 mg, 1.06 mmol) and tert-butyl chloroacetate (319 mg, 2.12 mmol) in DMF (20 ml), K ₂ CO ₃ (292 mg, 2.12 mmol) was added with stirring, and the resulting mixture was heated at 100 ° C overnight. The solvent was removed and the residue was suspended in EtOAc, washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (eluent: EtOAc / Hexane, 3: 1) to give the product as a pale yellow oil (140 mg, 27%).

B. {3- [5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carbonyl] phenoxy} acetic acid

The oil (180 mg, 0.37 mmol) obtained in the last step was dissolved in DCM (5 ml), TFA (5 ml) was added and stirred at room temperature overnight. Volatile organic components were removed, toluene was added, then it was removed in vacuo to give the product as a white solid (140 mg, 88%).

B. 3- [5-amino-4- (3-carbamoylmethoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

SOCl ₂ (1 ml) was added to a solution of the intermediate compound obtained in the previous step in THF (5 ml) and the mixture was stirred at room temperature for 2 hours. Volatiles were removed, then NH ₃ (0.5 M solution in dioxane) was added. ) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was purified by preparative TLC (eluent: EtOAc / MeOH / Et ₃ N, 100: 10: 1) and then preparative HPLC to give the product as a beige solid (4.2 mg, 10%). HPLC: (gradient 10-90% for 4 min), v. 1.78 minutes MS: m / z 434.14 [M + H] ⁺ .

Examples 97-105

The compounds shown in the following examples were obtained in the same way as described in example 96, but when replacing ammonia with the corresponding amine.

Example 106

Preparation of 3- [5-amino-4- (3-pyrazin-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

To a solution of 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide (130 mg, 0.27 mmol) and 2-tributylstannylpyrazine (119 mg, 0.32 mmol) in DMF (2 ml), tetrakis (triphenylphosphine) palladium (catalytic amount) was added with stirring, and the resulting mixture was heated in a microwave reactor at 160 ° C for 15 min. The solvent was removed and the residue was dissolved in EtOAc. The organic layers were washed with water, brine and concentrated. The crude material was purified by preparative HPLC to give the desired product as a beige solid (6.2 mg, 5%). HPLC: (gradient 10-90% for 4 min), v. 2.12 minutes MS: m / z 439.19 [M + H] ⁺ .

Example 107

Preparation of 3- [5-amino-4- (3-pyridin-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 106, but when replacing 2-tributylstannylpyrazine with 2-tributylstannylpyridine.

HPLC: (gradient 10-90% for 4 min), v. 1.94 minutes MS: m / z 438.26 [M + H] ⁺ .

Example 108

Preparation of 3- [5-amino-4- (pyridin-2-carbonyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 3- (5-amino-4-cyanopyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

To a solution of N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (8.45 g, 26.5 mmol) and 2-ethoxymethylene malononitrile (3.2 g, 26.5 mmol) in EtOH (100 ml) was added DIPEA (3 , 4 g, 26.5 mmol) and stirred at 65 ° C for 3 hours. The solvent was removed and the residue was suspended in EtOAc (~ 100 ml), then water was added to the resulting suspension. The solid was filtered off, the filtrate was washed with water, brine, dried over Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (eluent: EtOAc), the filtrate and the fractions obtained after chromatography were combined to give the product as a solid beige (7.1 g, 96%).

B. 3- [5-amino-4- (pyridin-2-carbonyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Cyclohexyl magnesium chloride (5 ml, 2.0 M solution in Et ₂ O) was added dropwise to a solution of 2-iodopyridine (1.03 g, 5 mmol) in THF (15 ml) at -20 ° C. The mixture was stirred at the indicated temperature for 20 minutes, then 3- (5-amino-4-cyanopyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide (140 mg, 0.5 mmol) was added and stirring was continued at room temperature during the night. The reaction was stopped by the addition of an aqueous solution of K ₂ CO ₃ , the resulting mixture was extracted with EtOAc, and the organic layers were washed with water and brine. After purification by silica gel column chromatography (eluent: EtOAc), the product was obtained as a white solid (60 mg, 33%). HPLC: (gradient 10-90% for 4 min), v. 2.09 minutes MS: m / z 362.20 [M + H] ⁺ .

Example 109

Preparation of 3- (5-amino-4-cyclopentanecarbonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 17B, but when replacing 3- (5-amino-4-cyanoimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide with 3- [5-amino-4- (3 -cyanobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide and phenyl magnesium bromide on cyclopentyl magnesium bromide. HPLC: (gradient 10-90% for 4 min), v. 2.54 minutes MS: m / z 353.19 [M + H] ⁺ .

Examples 110-126

The compounds shown in the following examples were obtained in the same manner as described in example 109, but by replacing cyclopentyl magnesium bromide with the corresponding Grignard reagent.

Example 127

Preparation of 3- {5-amino-4- [3 - ([1,3,4] oxadiazol-2-ylmethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

A. 3- [5-amino-4- (3-hydrazinocarbonylmethoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Compound 97A (300 mg, 0.69 mmol), tert-butyl carbazate (182 mg, 1.38 mmol), EDCl (263 mg, 1.38 mmol) and HOBt (211 mg, 1.38 mmol) were dissolved in dry DMF (10 ml) and stirred at room temperature for 2 hours. The solvent was removed, the residue was dissolved in EtOAc, washed with water, an aqueous solution of K ₂ CO ₃ , brine and dried over Na ₂ SO ₄ . TFA / DCE (5 ml, 1: 1) was added to the resulting mixture and stirred at room temperature for 30 minutes. The solvent was removed, the residue was dissolved in EtOAc, washed with an aqueous solution of K ₂ CO ₃ and dried over Na ₂ SO ₄ . The crude residue was purified by silica gel column chromatography (eluent: EtOAc / MeOH, 10: 1) to obtain the desired compound as a white solid (88 mg, 28%).

B. 3- {5-amino-4- [3 - ([1,3,4] oxadiazol-2-ylmethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

Trimethylorthoformate (3 ml) was added to a solution of compound 52 V (48 mg, 0.11 mmol) in MeOH (3 ml), and the resulting mixture was stirred at room temperature overnight. The solvent was removed, the solid residue was dissolved in 1,4-dioxane, 5 drops of HCl in dioxane (4 M) were added, and the mixture was heated in a microwave reactor at 120 ° C for 30 min. The solvent was removed, the residue was dissolved in EtOAc, washed with water and brine. The crude product was purified by preparative HPLC to give the product as a white solid (3.3 mg, 6.7%). HPLC: (gradient 10-90% for 4 min), v. 2.07 minutes MS: m / z 459.13 [M + H] ⁺ .

Example 128

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl) amide

A. 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid

A solution of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, see Example 44), LiOH (1.2 g) in water / ethanol (15 ml: 20 ml) was heated at 50 ° C. overnight. The solution was neutralized with dilute HCl (2 M) and extracted with ethyl acetate (2 × 200 ml), dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, then ethyl acetate and diethyl ether were added. The resulting solid was ^- filtered to give the desired 3-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (0.8 g, 88% yield).

B. (2-methylcyclohexyl) amide 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid

A solution of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCl (28 mg) and HOBt (12 mg) in DMF (0.75 ml) was kept at room temperature for 24 h, water (4 ml) was added and the solution was extracted with ethyl acetate (2 × 3 ml). The organic phase was washed with water (3 ml), dried over Na ₂ SO ₄ and evaporated. The residue was purified on a preparative TLC plate to obtain the desired 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl) amide (19 mg, 70%). HPLC: (gradient for 4 min), v.u. 2.34 minutes MS: m / z 396.31 [M + H] ⁺ .

Example 129-156

The compounds shown in the following examples were obtained in the same manner as described in example 128, but when replacing 2-methylcyclohexylamine with the corresponding amine.

Example 157

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2,2-dimethylpropyl) amide

The specified compound was obtained in the same manner as described in example 128, but when replacing isopropylamine with neopentylamine. HPLC: (gradient 10-90% for 4 min), v. 2.19 minutes MS: m / z 370.32 [M + H] ⁺ .

Example 158

Preparation of (1-ethylpyrrolidin-2-ylmethyl) amide 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid

The specified compound was obtained in the same manner as described in example 128, but when replacing isopropylamine with 2- (aminomethyl) -1-ethylpyrrolidine. HPLC: (gradient 10-90% for 4 min), v. 1.41 minutes MS: m / z 411.25 [M + H] ⁺ .

Example 159

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2-pyrrolidin-1-yl-ethyl) amide

The specified compound was obtained in the same manner as described in example 128, but when replacing isopropylamine with 1- (2-aminoethyl) pyrrolidine. HPLC: (gradient 10-90% for 4 min), v. 1.34 minutes MS: m / z 397.22 [M + H] ⁺ .

Example 160

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid cyclohexylmethylamide

The specified compound was obtained in the same manner as described in example 57, but when replacing isopropylamine with N-methylcyclohexylamine. HPLC: (gradient 10-90% for 4 min), v. 2.37 minutes MS: m / z 396.3 [M + H] ⁺ .

Example 161

Preparation of 3- [5-amino-4- (3-cyanobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -4-methylbenzoic acid

To a solution of hydrazine 2 (32.5 g, 0.160 mol, 1.0 equiv.) In ethanol (3.6 L) was added with stirring compound 1 (60 g, 0.160 mol, 1.0 equiv.), Obtained as described WO 02/57101 A1, p. 84, and triethylamine (16.56 g, 0.16 mol, 1.0 eq.), the resulting mixture was heated to 65 ° C. All solids were dissolved at 65 ° C. After cooling, the solid was filtered, and acid 3 (22 g, 30%) was obtained as a light brown solid. HPLC: (C18 Waters X-Terra column, 5 μm, 4.6 mm × 250 mm, elution rate 1.0 ml / min, eluent: 0.1% TEA in H ₂ O / acetonitrile, 40:60, over 30 min) 6.74 min, purity 95.2%.

B. 3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

To a solution of acid 3 (21 g, 0.0469 mol, 1.0 equiv.) In DMF (30 ml) was added EDCl (17 g, 0.0886 mol, 2.0 equiv.), HOBt (12.6 g, 0.0939 mol, 2.0 equiv.) And diisopropylethylamine (24.2 g, 0.18 mol, 4.0 equiv.), The resulting solution was stirred at room temperature for 15 minutes, then cyclopropylamine (10.7 g) was added. , 0.0939 mol, 2.0 equiv.) And the reaction mixture was stirred for 1 h. The resulting mixture was added to water and extracted with EtOAc (1 L), washed with water (2 × 200 ml) and brine (200 ml), dried over anhydrous sodium sulfate and concentrated. The product was purified by flash chromatography on silica gel (eluent: EtOAc / Hexane, 8: 2) to give the product as a brown oil. For further purification, the product was triturated in isopropyl ether (1 L) and dried in vacuo to give amide 4 (12 g, 50%) as an off-white solid.

B. 3- [5-amino-4- (3-cyanobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

To a solution of iodide 4 (7.4 g, 0.015 mol, 1.0 equiv.) In N, N-dimethylformamide (25 ml) in an atmosphere of n _{2 was} added copper cyanide. The resulting suspension was refluxed for 1 h. The completion of the reaction was monitored by TLC. Heating was stopped and the reaction mixture was cooled to 80 ° C. The reaction was stopped by the addition of ice water (15 ml), 25% aqueous ammonia (15 ml) and ethyl acetate (50 ml). The mixture was filtered to remove solids, the organic layer was separated from the filtrate, which was washed with water, saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude material was dried at 60 ° C. under high vacuum, then purified on a column (eluent: ethyl acetate) to give the product (3 g, 51%) as an off-white solid. HPLC: (Waters X-Terra C18 column, 5 μm, 4.6 mm × 250 mm, elution rate 1.0 ml / min, eluent: 0.1% TEA in H ₂ O / acetonitrile, 70:30, over 30 min) 23.70 min, 99.4% purity.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (t, J 2.9 Hz, 1H), 8.06 (t, J 2.7 Hz, 1H), 8.04 (m, 1H), 7.85 (t, J 2.5 Hz, 1H), 7.83 (m, 1H), 7.81 (d, J 1.8 Hz, 1H), 7.95 (d, J 1.6 Hz , 1H), 7.37 (s, 1H), 7.65 (t, J 7.8 Hz, 1H), 7.45 (d, J 8.0 Hz, 1H), 6.41 (s, 1H) ), 5.94 (s, 2H), 2.88 (m, 1H), 2.24 (s, 3H), 0.86 (dd, J 6.9, 6.1 Hz, 2H), 0, 61 (m, 2H).

¹³ C NMR (400 MHz, CDCl ₃ ) δ 186.6, 167.2, 151.5, 141.3, 140.7, 140.3, 135.1, 134.5, 134.0, 132.2 , 131.8, 129.5, 128.7, 126.2, 118.1, 113.0, 103.7, 30.9, 23.2, 17.7, 6.8.

Example 162

Preparation of 3- [5-amino-4- (3-pyrazin-2-ylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

A. 3- [5-amino-4- (3-bromobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Cyclohexyl magnesium chloride (2 M solution in THF, 6 ml) was added to a solution of 3-bromo-1-iodobenzene (2.82 g) in THF (20 ml) at -40 ° C under N ₂ atmosphere. The solution was kept at a temperature of from -40 ° C to 0 ° C for 20 minutes, then 3- (5-amino-4-cyanoimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide (0.18 g) was added and the reaction mixture was kept at RT for 1 h. Then, HCl (4 M, 20 ml) was added and the mixture was kept at RT for 2 days. The mixture was neutralized with a solution of K ₂ CO ₃ and extracted with EtOAc (2 × 100 ml), the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (eluent: EtOAc) to give the desired product (0.15 g, 54%). HPLC: (gradient 10-90% for 4 min), v. 1.85 minutes MS: m / z 438.10, 441.07 [M + H] ⁺ .

B. 3- [5-amino-4- (3-pyrazin-2-ylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

Solution of 3- [5-amino-4- (3-bromobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide (60 mg), 2-tributylstannylpyrazine (120 μl) and tetrakis (triphenylphosphine) palladium (0) (30 mg) in 1,4-dioxane (0.8 ml) was heated in a microwave reactor at 160 ° C for 25 min, then water (3 ml) was added and the mixture was extracted with ethyl acetate (2 × 4 ml), the solvent was evaporated and the residue was purified by preparative TLC (eluent: EtOAc / MeOH, 10: 1), and the desired product was obtained (38 mg, 63%). HPLC: (gradient 10-90% for 4 min), v. 2.18 minutes MS: m / z 439.27 [M + H] ⁺ .

Example 163

Preparation of 3- [5-amino-4- (3-pyrimidin-5-ylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 162, but when replacing 2-tributylstannylpyrazine with 4-tributylstannylpyrimidine. HPLC: (gradient 10-90% for 4 min), v. 1.93 minutes MS: m / z 439.19 [M + H] ⁺ .

Example 164

Preparation of 3- [5-amino-4- (3-pyridin-2-ylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 162, but when replacing 2-tributylstannylpyrazine with 2-tributylstannylpyridine. HPLC: (gradient 10-90% for 4 min), v. 2.04 minutes MS: m / z 438.25 [M + H] ⁺ .

Example 165

Preparation of 3- [5-amino-4- (3-pyrimidin-2-ylbenzoyl) imidazol-1-yl-1-N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 162, but when replacing 2-tributylstannylpyrazine with 2-tributylstannylpyrimidine. HPLC: (gradient 10-90% for 4 min), v. 2.49 minutes MS: m / z 439.24 [M + H] ⁺ .

Example 166

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4-methylsulfonylbenzoyl-1H-imidazole

A solution of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4-methylsulfonylbenzoyl-1H-imidazole (64 mg) and oxone (242 mg) in water / methanol (2 ml: 2 ml) was kept at room temperature in for 2 hours. Then the solution was evaporated and THF / MeOH (2 ml: 2 ml) was added. The resulting mixture was heated to dissolve the solids and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the product (1.6 mg). HPLC: (gradient 10-90% for 4 min), v. 1.90 minutes MS: m / z 439.15 [M + H] ⁺ .

Example 167

Preparation of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4- [3- (5-methyl) oxadiazol-3-ylbenzoyl] -1H-imidazole

A mixture of N-hydroxy-3-iodobenzimidine (1.31 g), acetic anhydride (1 ml) and a catalytic amount of para-toluenesulfonic acid was heated in acetic acid (10 ml) at 90 ° C for 6 hours. The solvent was evaporated and water was added. and methanol (1: 1, 100 ml). The precipitate formed was filtered off to give the desired product (1.1 g).

To a solution of 3- (3-iodophenyl) -5-methyloxadiazole (0.286 g) in THF (15 ml) in an atmosphere of N _{2 was} added cyclopentyl magnesium bromide (2 M, 1.1 ml) at -20 ° C, then the temperature was gradually raised over a period of about 20 minutes to 5-10 ° C., 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4-cyanoimidazole (96 mg) was added and the reaction mixture was kept at room temperature for 0.5 hours. Then was added diluted HCl (4 M, 12 ml) and the reaction mixture were heated at 60 ° C for 3 hours. After distribution in water and ethyl acetate, the final product was purified by column chromatography (elu ent: ethyl acetate / hexane, 1: 1). HPLC: (gradient 10-90% for 4 min), v. 2.03 minutes MS: m / z 443.20 [M + H] ⁺ .

Example 168

Preparation of 3- (5-amino-4- {3- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

A. 3- {5-amino-4- [3- (2-bromoethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

To a solution of 3- [5-amino-4- (3-hydroxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide (472 mg, 1.26 mmol) in dry THF (20 ml) at 0 ° C 2-bromoethanol (785 mg, 6.3 mmol), PPh ₃ (1.3 g, 5.04 mmol) and diethyl azodicarboxylate (877 mg, 5.04 mmol) were added, and the resulting mixture was stirred at room temperature for 72 hours. An aqueous solution of NH ₄ Cl was added to the mixture, then the THF layer was separated. The aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, purified by preparative HPLC to give the product as a white solid (360 mg, 59%).). HPLC: (gradient 10-90% for 4 min), v. 2,723 minutes MS: m / z 483.14 / 485.09 [M + H] ⁺ .

B. 3- (5-amino-4- {3- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} pyrazol-1-yl) -] - N-cyclopropyl-4-methylbenzamide

To a suspension of 3- {5-amino-4- [3- (2-bromoethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide (24 mg, 0.05 mmol) in EtOH (1 ml) 1-methylpiperazine (100 mg, 1 mmol) was added, and the resulting mixture was stirred at 80 ° C. overnight. The solvent was removed, the residue was dissolved in EtOAc, washed with water, dried over Na ₂ SO ₄ . The solvent was removed, and the desired product was obtained as a colorless oil (18 mg, 72%). HPLC: (gradient 10-90% for 4 min), v. 1.33 minutes MS: m / z 503.29 [M + H] ⁺ .

Example 169

Preparation of 3- [5-amino-4- (3- {2- [bis- (2-hydroxyethyl) amino] ethoxy} benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 168, but when replacing 1-methylpiperazine with 2- [bis- (2-hydroxyethyl) amino] ethanol. HPLC: (gradient 10-90% for 4 min), v. 1.39 min. MS: m / z 508.24 [M + H] ⁺ .

Example 170

Preparation of 3- {5-amino-4- [3- (2-dimethylaminoethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained in the same manner as described in example 168, but when replacing 1-methylpiperazine with 2-dimethylaminoethanol. HPLC: (gradient 10-90% for 4 min), v. 1.59 minutes MS: m / z 448.22 [M + H] ⁺ .

Example 171

Preparation of 3- {5-amino-4- [3- (2,3-dihydroxypropoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

A. 3- {5-amino-4- [3- (2,2-dimethyl [1,3] dioxolan-4-ylmethoxy) benzoyl] pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

Into a solution of 3- [5-amino-4- (3-hydroxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide (75 mg, 0.2 mmol) and 4-chloromethyl-2,2-dimethyl [ 1,3] dioxolane (36 mg, 0.24 mmol) in DMF (4 ml) was added K ₂ CO ₃ with stirring, and the resulting mixture was stirred at 150 ° C in a microwave reactor for 2 hours. The solvent was removed, the residue was dissolved in EtOAc , washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (eluent: EtOAc / Hexane, 3: 1) to give the product as a colorless oil (18 mg, 18%). HPLC: (gradient for 4 min), v.u. 2.57 minutes MS: m / z 491.11 [M + H] ⁺ .

B. 3- {5-amino-4- [3- (2,3-dihydroxypropoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

Compound 171A (10 mg) was dissolved in HOAc (1 ml), 0.5 ml of water was added, and the resulting mixture was stirred at 50 ° C. overnight. The solvent was removed, the residue was purified by preparative TLC (eluent: EtOAc), and the product was obtained as a pale yellow oil (4.1 mg, 45%). HPLC: (gradient 10-90% for 4 min), v. 1.73 minutes MS: m / z 451.21 [M + H] ⁺ .

Example 172

Preparation of 3- (5-amino-4- {3- [2- (4-chlorophenoxy) ethoxy] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide

To a solution of 3- {5-amino-4- [3- (2-bromoethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide (24 mg, 0.05 mmol) and 4-chlorophenol (128 mg, 1 mmol) in DMF (1 ml) was added K ₂ CO ₃ (138 mg, 1 mmol) and the resulting mixture was stirred at 100 ° C for 2 hours. Then the mixture was cooled and the solid was filtered off. The filtrate was concentrated and purified by preparative HPLC to give the product as a beige solid (10 mg, 38%). HPLC: (gradient 10-90% for 4 min), v. 2.77 minutes MS: m / z 531.21 [M + H] ⁺ .

Example 173

Preparation of 3- {5-amino-4- [3- (4H- [1,2,4] triazol-3-yl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide

To a solution of 3- [5-amino-4- (3-carbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide (120 mg), in DMF (2 ml) was added dimethylacetal N, N-dimethylformamide (5 ml) and the resulting solution was stirred at 80 ° C. overnight. The solvent was removed, the residue was dissolved in AcOH (5 ml), hydrazine monohydrate (3 ml) was added, and the resulting mixture was stirred at 90 ° C. overnight. The solution was acidified with hydrochloric acid to pH ~ 1 and stirred at 80 ° C. overnight. The solvent was removed, the residue was resuspended in EtOAc, then washed with an aqueous solution of K ₂ CO ₃ , water, brine and concentrated. The crude product was purified by silica gel column chromatography (eluent: EtOAc) to give the product as a white solid (65 mg, 51%). HPLC: (gradient 10-90% for 4 min), v. 1.58 minutes MS: m / z 428.18 [M + H] ⁺ .

Example 174

Preparation of 3- {5-amino-4- [3- (4H- [1,2,4] triazol-3-yl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide

The specified compound was obtained as described in example 173, but when replacing 3- [5-amino-4- (3-carbamoylbenzoyl) pyrazol-1-yl] -1-cyclopropyl-4-methylbenzamide with 3- [5-amino-4 - (3-carbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide. HPLC (gradient, 10-90% for 4 min), v. 1.58 min; MS: m / z 428.24 [M + H] ⁺ .

Example 175

The ability of the compounds of the present invention to inhibit the synthesis or activity of cytokines was evaluated using the following in vitro assay methods.

Obtaining p38 kinases

Human p38α and β cDNA preparations were obtained by cloning by PCR. α and β isoform cDNAs were subcloned into the DEST2 plasmid (Gateway, In Vitrogen). The His ₆ -p38 fusion protein was expressed in E. coli and isolated from bacterial lysates by affinity chromatography using Ni ^{+ 2} -NTA agarose. The His ₆ -p38 protein was activated by incubation in the presence of MKK6 active kinase. Active p38 kinase was separated from MKK6 by affinity chromatography. Constitutive active MKK6 was obtained by the method described in the work of Raingeaud et al. Mol. Cell. Biol., 1247-1255 (1996).

TNF-α production in PBMCs stimulated with lipolisaccharide (LPS)

Heparinized human whole blood was obtained from healthy volunteers. Peripheral blood mononuclear cells (PBMCs) were isolated from human whole blood by centrifugation in an Accu-paque density gradient and resuspended at a concentration of 5 × 10 ⁶ / ml in assay medium (RPMI medium containing 10% fetal bovine serum). 175 μl Cell suspensions were incubated in the presence of 10 μl of the test compound (in 4% DMSO) in 96-well tissue culture plates for 30 min at RT. Then 15 μl of LPS (stock solution 13.33 ng / ml) was added to the cell suspension and the plate was incubated for 18 h at 37 ° C in a humid atmosphere containing 5% CO ₂ . After incubation, the culture medium was collected and stored at -20 ° C.

THP-1 cells (TIB-202, ATCC) were washed and resuspended at a concentration of 1 × 10 ⁵ / ml in assay medium (RPMI medium containing 3% fetal bovine serum). 175 μl Cell suspensions were incubated in the presence of 10 μl of the test compound (in 4% DMSO) in 96-well tissue culture plates for 30 min at RT. 15 μl LPS (stock solution 13.33 ng / ml) was added to the cell suspension and the plate was incubated for 18 h at 37 ° C in a humid atmosphere containing 5% CO ₂ . After incubation, the culture medium was collected and stored at -20 ° C.

The concentration of TNF-α in the medium was quantified using a standard ELISA kit (ELISA, BioSource International, Camarillo, CA). The TNF-α concentration and IC ₅₀ values of the test compounds (the concentration of the compound at which 50% inhibition of LPS stimulated TNF-α production is inhibited) was calculated using a four-parameter logistic equation (SigmaPlot, SPSS, Inc.).

Analysis of p38α kinase

P38α kinase activity was determined by the amount of ATP released in the test reaction during NADH oxidation, which occurs during the condensation of pyruvate kinase and lactate dehydroginase. The analysis was carried out in 384-well plates intended for investigation by UV spectroscopy. The final well volume was 25 μl, which was obtained by adding 2.5 μl of a solution of the compound in 10% DMSO, 17.5 μl of assay buffer and 5 μl of ATP. The buffer solution for analysis contains the following reagents, which are added to the final concentration necessary for analysis: 25 mM HEPES, 20 mM 2-glycerophosphate, pH 7.6, 10 mM MgCl ₂ , 0.1 mM sodium orthovanadate, 0.5 mM phosphoenolpyruvate , 0.12 mM NADH, 3.1 mg / ml LDH, 6.67 mg / ml pyruvate kinase, 0.25 mM peptide substrate, 2 mM DTT, 0.005% Tween 80 and 20 nM Upstate p38α kinase. The test compounds were preincubated in the presence of p38α kinase for 60 min, and the reaction was initiated by the addition of ATP at a final concentration of 0.15 mM. The reaction rate was determined at 340 nm on a SpectraMax spectrophotometer to read the plate for 10 min at 37 ° C. Inhibition data was analyzed by non-linear least squares regression using the SigmaPlot application.

The production of TNF-α in mice stimulated by lipolysaccharide (LPS)

Mice (female Balb / s, age 6-8 weeks, Taconic Labs; no. 8 animals in the group (n = 8)) were injected intraperitoneally with lipopolysaccharide (LPS, 50 ng / kg E. coli, strain 0111: B4, Sigma) suspended with sterile saline. After 90 minutes, the mice were euthanized in a CO ₂ / O ₂ atmosphere and blood samples were taken. The resulting serum was determined by the content of TNF-α using a commercial ELISA kit (ELISA) according to the manufacturer's instructions (BioSource International). Test compounds were administered orally at various time periods prior to administration of LPS. The compounds were administered as compounds or solutions in the presence of various carriers or solubilizing agents.

results

All compounds obtained in the examples exhibit activity as p38 kinase inhibitors according to the assays described above. The inhibitory activity of certain compounds of the present invention in relation to p38 kinase is presented in the table below. The value of IC ₅₀ in relation to p38 kinase, indicated by the sign “+++”, means activity <1 μM, the sign ”++” - from 1.0 to 10 μM and the sign ”+” -> 10 μM.

Example IC ₅₀ in relation to p38α kinase one +++ 2 +++ 3 ++ four +++ 5 ++ 6 +++ 7 +++ 8 +++ 9 +++ 10 +++ eighteen +++ 29th +++ thirty +++ 33 +++ 34 +++ 48 +++ 49 +++ fifty +++ 52 +++ 53 +++ 76 +++ 87 +++ 128 +++ 129 +++ 135 +++ 148 +++ 171 +++

Since modifications to the variants of the present invention appear obvious to those skilled in the art, the claimed subject matter and scope of the invention are defined in the appended claims.

Claims (31)

1. The compound of the formula:

or a pharmaceutically acceptable salt thereof,
where R ¹ means hydrogen;
R ² is hydrogen, alkyl, alkylthio, alkylsulfonyl, optionally substituted alkoxy, wherein the substituent is selected from —OR, where R is alkyl; 3-chlorobenzoylaminocarbonylmethoxy, or R ² is optionally substituted with —COOR piperidinyloxy, where R is alkyl;
G is phenyl, pyridyl, cyclohexyl, cyclopentyl, tetrahydropyranyl or benzyl, and is substituted with R ³ and R ⁴ , provided that the pyridyl ring is attached to the carbonyl group through a carbon atom in the ring, or G is OR ⁸³ or NR ⁸⁰ R ⁸¹ ;
B is phenyl;
C means a pyrazole or imidazole ring of the formulas

or

respectively,
where high bonds are linked to GC (= 0), low bonds are linked to ring B, and middle bonds are linked to R ¹ NH;
D is triazolyl or —C (O) NR ^80x R ^81x , where R ^80x and R ^{81x are} hydrogen, alkoxy or cycloalkyl comprising one ring of 3-7 carbon atoms;
each R ⁸⁰ and R ⁸¹ independently means hydrogen, alkyl, cycloalkyl, which means a saturated non-aromatic cyclic hydrocarbon system containing 1-2 rings and three to seven carbon atoms in the ring, where cycloalkyl may optionally be fused to a benzene ring, and which is unsubstituted or substituted by one or two substituents independently selected from alkyl, 1-ethynylcyclohexyl, methoxybenzyl, benzyl, 3-chlorobenzyl, cyclopentyl, 2,4-dichlorobenzyl, cyclohexylmethyl, 3,4-dichlorobenzyl, 3-trifluoromethylbenzyl, fluoroben zyl, N-ethyl-2-pyrrolidinylmethyl, methylbenzyl, pyridylmethyl, morpholinyl ethyl, 1-cyclohexylethyl, 1-phenylethyl or 2-pyrrolidinyl ethyl; or R ⁸⁰ and
R ⁸¹ together form optionally substituted with one or two alkyl C ₄ -C ₅ alkylene;
R ⁸³ means hydrogen or alkyl, or cycloalkyl, which is a saturated non-aromatic hydrocarbon ring containing from three to seven carbon atoms;
R ³ selected from the group including:
(b) optionally substituted heterocyclyl, where heterocyclyl means a cyclic non-aromatic radical containing 5-6 ring atoms, where one or two ring atoms are hetero atoms selected from N and O, and the remaining atoms are C atoms, where the substituents may be one or two substituents independently selected from alkyl;
(c) an optionally substituted heteroaryl, which is a monocyclic radical containing 5-6 ring atoms, where one or two ring atoms are heteroatoms selected from N and O, and the remaining atoms are C atoms, where one or two substituents can be a substituent independently selected from alkyl;
(d) optionally substituted heterocyclylalkyl, where heterocyclyl means a cyclic non-aromatic radical containing 5-6 ring atoms, where one or two ring atoms are hetero atoms selected from N and O, and the remaining atoms are C atoms, where two substituents can be substituents independently selected from alkyl;
(f) -Y- (alkylene) -R ⁹ , where Y is —O—, and R ⁹ is an optionally alkyl substituted heterocyclyl containing 5-6 ring atoms, where one or two ring atoms are heteroatoms selected from N and Oh, and the remaining atoms are C, oxadiazolyl, —COOH, —COOR ¹¹ or —CONR ¹² R ¹³ , where R ¹¹ is alkyl and R ¹² and R ^{13 are} each independently hydrogen or alkyl;
(g) —CONR ²⁵ R ²⁶ , where R ²⁵ and R ²⁶ independently mean hydrogen or alkyl, or R ²⁵ and R ²⁶ together with the nitrogen atom to which they are attached form pyrrolidine, piperidine, morpholine or piperazine;
(h) hydrogen;
(i) halogen;
(j) cyano;
(k) hydroxy;
(1) alkoxy optionally substituted with one substituent selected from phenyl, —CONR′R ″, where R ′ and R ″ together form pyrrolidine, piperazine or morpholine, NRR ′, where R and R ′ are independently selected from hydrogen and alkyl optionally substituted with hydroxy, and —OR wherein R is hydrogen or alkyl;
(m) C (L) R ⁴⁰ , where L is O; R ⁴⁰ means hydrogen, OR ⁵⁵ or NR ⁵⁷ R ⁵⁸ , where R ⁵⁵ means hydrogen or alkyl, R ⁵⁷ and R ⁵⁸ each independently means hydrogen, cycloalkyl containing one ring of 3-7 carbon atoms, alkyl substituted with dialkylamino, di ( hydroxyalkyl) amino or the above cycloalkyl;
(n) alkyl or hydroxyalkyl;
(o) 2- (4-methylpiperazin-1-yl) -2-oxoethoxy, 2- (3-aminopyrrolidin-1-yl) -2-oxoethoxy, 2- (3-methylaminopyrrolidin-1-yl) -2-oxoethoxy , [(1H-benzoimidazol-2-ylmethyl) carbamoyl] methoxy, [2- (2-benzyloxy-5-chlorophenyl) ethylcarbamoyl] methoxy, [2- (5-chloro-2-hydroxyphenyl) ethylcarbamoyl] methoxy, 2- ( 3,5-dimethylpiperisin-1-yl) -2-oxoethoxy or 4-chlorophenoxyethoxy;
(p) cyclopropoxy;
(q) methylthio; and
(r) methylsulfonyl;
R ⁴ selected from the group including
(a) hydrogen;
(b) halogen;
(c) alkyl;
(d) alkoxy; and
(e) hydroxy;
or R ³ and R ⁴ , which are substituents of adjacent atoms in the ring, together form alkylenedioxy;
R ⁵ means hydrogen;
R ⁶ selected from the group including
(a) hydrogen; and
(b) alkyl;
or the compound is
3- (5-amino-4- {3 - [(3-chlorobenzylamino) methyl] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3 - {[2- (3-chlorophenyl) ethylamino] methyl} benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3- [4- (3-chlorophenyl) piperazin-1-ylmethyl] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3 - {[2- (2-benzyloxy-5-chlorophenyl) ethylamino] methyl] benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3 - [(2-morpholin-4-yl-ethylamino) methyl] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3 - [(3-morpholin-4-ylpropylamino) methyl] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-vinyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid phenylamide,
3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid,
3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -4-methylbenzoic acid,
3- [5-amino-4-benzoyl-3- (2-benzyloxyethoxy) pyrazol-1-yl] N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (2-dimethylaminoethylcarbamoyl) benzoyl] imidazol-1-yl} -] N-cyclopropyl-4-methylbenzamide, or
{3- [5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-imidazole-4-carbonyl] phenoxy} acetic acid tert-butyl ester, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where G means OR ⁸³ or NR ⁸⁰ R ⁸¹ . 3. The compound according to claim 1, where R ⁸⁰ and R ⁸¹ each independently mean hydrogen, cyclohexyl, 2-methylcyclohexyl, 3-pentyl, bicyclo [2.2.1] heptyl, 1-ethynylcyclohexyl, methoxybenzyl, benzyl, cyclopropyl, 3-chlorobenzyl , cyclopentyl, 2,4-dichlorobenzyl, cyclohexylmethyl, 3,4-dichlorobenzyl, 4-methylcyclohexyl, 3-trifluoromethylbenzyl, 4-tert-butylcyclohexyl, neopentyl, fluorobenzyl, N-ethyl-2-pyrrolidinylmethyl, methylbenzylethyl, pyridyl 1 β-cyclohexylethyl, 1-phenylethyl or 2-pyrrolidinyl ethyl. 4. The compound according to claim 1, where G is NH ₂ or NH (piclohexyl). 5. The compound according to claim 1, where G means phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl, substituted by groups R ³ and R ⁴ . 6. The compound according to claim 1, where G means phenyl substituted by groups R ³ and R ⁴ . 7. The compound according to claim 1 of formula III:

which corresponds to the formula given in claim 1, or a pharmaceutically acceptable salt thereof, wherein A corresponds to G and means phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl. 8. The compound according to claim 1 of formula VII:

which corresponds to the formula given in claim 1, or a pharmaceutically acceptable salt thereof, wherein A corresponds to G and means phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl. 9. The compound according to claim 1, where R ² means hydrogen or (ness.) Alkyl. 10. The compound according to claim 1, where R ² means hydrogen, methyl, n-propyl or 3-chlorobenzylaminocarbonylmethoxy. 11. The compound of claim 7, wherein A is phenyl. 12. The compound of claim 7, wherein B is phenyl. 13. The compound of claim 7, wherein D is 1,2,4-triazol-3-yl. 14. The compound according to claim 7, where R ³ means cyano. 15. The compound according to claim 1, where R ³ means hydrogen, dioxolanyl, pyrimidinyl, pyridyl, pyrazinyl, cyano, oxadiazolyl, triazolyl, methylthio or methanesulfonyl. 16. The compound according to claim 7, where R ³ means N-morpholinyl methyl, hydroxymethyl, N- (2- (3-chlorophenyl) -1-ethyl) aminomethyl, N- (2-morpholinyl-1-ethyl) aminomethyl, (3 -chlorobenzylamino) methyl, 4- (3-chlorophenyl) piperazin-1-ylmethyl, [2- (2-benzyloxy-5-chlorophenyl) ethylamino] methyl, (3-morpholin-4-ylpropylamino) methyl, carbamoylmethoxy, 2- ( 4-methylpiperazin-1-yl) -2-oxoethoxy, 2-oxo-2-piperazin-1-ylethoxy, 2- (3-aminopyrrolidin-1-yl) -2-oxoethoxy, 2- (3-methylaminopyrrolidin-1- il) -2-oxoethoxy, 2- (3,5-dimethylpiperazin-1-yl) -2-oxoethoxy, 2-morpholin-4-yl-2-oxoethoxy, [(1H-benzoimidazol-2-ylmethyl) carbamoyl] methoxy , [2 - (2-benzyloxy-5-chlorophenyl) ethylcarbamoyl] methoxy, [2- (5-chloro-2-hydroxyphenyl) ethylcarbamoyl] methoxy or 4-piperisinylmethyl. 17. The compound according to claim 7, where R ⁴ means hydrogen. 18. The compound according to claim 1, which has one of the following formulas III or VII, respectively,

or

in which A corresponds to G in the formula given in claim 1, and where
R ¹ means hydrogen;
R ² means hydrogen, alkyl or alkylthio;
A means phenyl;
B is phenyl;
D is triazolyl or —C (O) NR ^80x R ^81x , where R ^80x and R ^{81x are} hydrogen, alkoxy or cycloalkyl comprising one ring of 3-7 carbon atoms;
R ³ selected from the group including:
(b) optionally substituted heterocyclyl, where heterocyclyl means a cyclic non-aromatic radical containing 5-6 ring atoms, where one or two ring atoms are hetero atoms selected from N and O, and the remaining atoms are C atoms, where the substituents may be one or two substituents independently selected from alkyl;
(c) an optionally substituted heteroaryl, which is a monocyclic radical containing 5-6 ring atoms, where one, two or three ring atoms are heteroatoms selected from N and O, and the remaining atoms are C atoms, where the substituents can be one or two substituents independently selected from alkyl;
(d) optionally substituted heterocyclylalkyl, where heterocyclyl means a cyclic non-aromatic radical containing 5-6 ring atoms, in which one or two ring atoms are hetero atoms selected from N and O, and the remaining atoms are C atoms, where the substituents can be two a substituent independently selected from alkyl;
(f) -Y- (alkylene) -R ⁹ , where Y is —O—, and R ⁹ is an optionally alkyl substituted heterocyclyl containing 5-6 ring atoms, where one or two ring atoms are heteroatoms selected from N and Oh, and the remaining atoms are C, oxadiazolyl, —COOH, —COOR ¹¹ or —CONR ¹² R ¹³ , where R ¹¹ is alkyl and R ¹² and R ^{13 are} each independently hydrogen or alkyl;
(g) —CONR ²⁵ R ²⁶ , where R ²⁵ and R ²⁶ independently mean hydrogen or alkyl, or R ²⁵ and R ²⁶ together with the nitrogen atom to which they are attached form pyrrolidine, piperidine, morpholine or piperazine;
(h) hydrogen;
(j) cyano;
R ⁴ selected from the group including
(a) hydrogen;
(b) halogen;
(c) alkyl;
(d) alkoxy; and
(e) hydroxy;
R ⁵ means hydrogen;
R ⁶ selected from the group including
(a) hydrogen; and
(b) alkyl;
or a pharmaceutically acceptable salt thereof. 19. The compound of claim 18, wherein R ¹ and R ^{2 are} hydrogen and B is phenyl. 20. The compound according to claim 7, where R ³ is in position 3. 21. The compound of claim 7, wherein R ³ is at position 3 and is selected from the group consisting of hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-1-butyl, or 3-hydroxybutyl. 22. The compound according to claim 1, which is selected from the group including
3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-methoxy-4-methylbenzamide,
3- (5-amino-4-benzoylpyrazol-1-yl) -N-methoxy-4-methylbenzamide,
3- (5-amino-4-benzoylpyrazol-1-yl) -4-methylbenzoic acid,
3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -4-methylbenzoic acid,
3- [5-amino-4- (3-iodobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
{5-amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) phenyl] -1H-pyrazol-4-yl} phenylmethanone,
3- [5-amino-4- (3- [1,3] dioxolan-2-yl-benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-formylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-hydroxymethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (4-methylpiperazin-1-ylmethyl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-morpholin-4-ylmethylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-benzyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-hydroxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide, and
3- (5-amino-4-benzoylimidazol-1-yl) -] - N-cyclopropyl-4-methylbenzamide. 23. The compound according to claim 7, which is 3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide. 24. The compound according to claim 1, which is selected from the group including
3- (5-amino-4-benzoylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-cyclohexanecarbonylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-cyclopentanecarbonylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-phenylacetylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) imidazol-1-yl] -H-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-ethylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-methylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-cyclopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-cyclopentylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (morpholin-4-carbonyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (cyclopropylmethylcarbamoyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (tetrahydropyran-4-carbonyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-benzoyl-3-methoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-benzoyl-3-ethoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4-benzoyl-3- (2-methoxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4-benzoyl-3- (2-benzyloxyethoxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
4- [5-amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazol-3-yloxy] piperidine-1-carboxylic acid tert-butyl ester,
3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-benzoyl-3-methylsulfanylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-benzoyl-3-methanesulfonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1 N-pyrazole-4-carboxylic acid amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methanesulfonyl-1 H-pyrazole-4-carboxylic acid amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester,
3- [5-amino-4- (3-chlorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (2-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (2-methoxybenzoyl) pyrazol-1-yl] -H-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-chlorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (2-chlorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-methoxybenzoyl) pyrazol-1-yl] -4-N-cyclopropyl-4-methylbenzamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester,
5-amino-3 - [(3-chlorobenzylcarbamoyl) methoxy] -1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester,
3- (5-amino-4-benzoylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-cyanobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3- [1,3,4] oxadiazol-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (5-methyl [1,3,4] oxadiazol-2-yl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (pyrrolidin-1-carbonyl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-cyclopropylcarbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-carbamoylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-methylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-cyclopropylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-carbamoylbenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (piperazin-1-carbonyl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-dimethylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (cyclopropylmethylcarbamoyl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-ethylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-methylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-cyclopentylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-cyclopropylcarbamoylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3 - [(3-chlorobenzylamino) methyl] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3 - {[2- (3-chlorophenyl) ethylamino] methyl} benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3- [4- (3-chlorophenyl) piperazin-1-ylmethyl] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3 - {[2- (2-benzyloxy-5-chlorophenyl) ethylamino] methyl] benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3 - [(2-morpholin-4-yl-ethylamino) methyl] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3 - [(3-morpholin-4-ylpropylamino) methyl] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (pyridin-2-carbonyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (2-methylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3,4-difluorobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-fluorobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3,4-dichlorobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-methoxybenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-fluorobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3,5-dichlorobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-methoxybenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-imidazole-4-carbonyl] benzoic acid tert-butyl ester,
3- [5-amino-4- (3,5-difluorobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (benzo [1,3] dioxol-5-carbonyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-chlorobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3,4-dimethoxybenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-benzyloxybenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-fluoro-3-methylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-chlorobenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-benzoyl-2-methylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-benzoyl-2-propylimidazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-carbamoylmethoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3- [2- (4-methylpiperazin-1-yl) -2-oxoethoxy] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (2-oxo-2-piperazin-1-yl-ethoxy) benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3- [2- (3-aminopyrrolidin-1-yl) -2-oxoethoxy] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3- [2- (3-methylaminopyrrolidin-1-yl) -2-oxoethoxy] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3- [2- (3,5-dimethylpiperazin-1-yl) -2-oxoethoxy] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (2-morpholin-4-yl-2-oxoethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3 - {[((1H-benzoimidazol-2-ylmethyl) carbamoyl] methoxy} benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3 - {[2- (2-benzyloxy-5-chlorophenyl) ethylcarbamoyl] methoxy} benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3 - {[2- (5-chloro-2-hydroxyphenyl) ethylcarbamoyl] methoxy} benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-pyrazin-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-pyridin-2-ylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (pyridin-2-carbonyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-cyclopentanecarbonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (benzo [1,3] dioxol-5-carbonyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (2-fluorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-ethoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-methoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-cyclopropoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-methoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3,4-dimethoxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-methylsulfanylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-methylsulfanylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-fluorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-fluorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3,4-difluorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3,5-difluorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-fluoro-3-methylbenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (4-fluorobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4-cyclohexanecarbonylpyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-vinyloxybenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3 - ([1,3,4] oxadiazol-2-ylmethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid phenylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1-N-pyrazole-4-carboxylic acid (1-ethylpropyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid bicyclo [2.2.1] hept-2-ylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (1-ethynylcyclohexyl) amide,
3- [5-amino-4- (2,5-dimethylpyrrolidin-1-carbonyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid 4-methoxybenzylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid indan-1-ylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid benzylamide,
3- [5-amino-4- (piperidin-1-carbonyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid cyclohexylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid cyclopropylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid 3-chlorobenzylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid cyclopentylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid 2,4-dichlorobenzylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid cyclohexylmethylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid 3,4-dichlorobenzylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (4-methylcyclohexyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid 3-trifluoromethylbenzylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (4-tert-butylcyclohexyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2,2-dimethylpropyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid 3-methoxybenzylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid 4-fluorobenzylamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (1-ethylpyrrolidin-2-ylmethyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid 2-methylbenzylamide,
(pyridin-2-ylmethyl) amide 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (1-cyclohexylethyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (1-phenylethyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2,2-dimethylpropyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2-pyrrolidin-1-yl-ethyl) amide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid cyclohexylmethylamide,
3- [5-amino-4- (3-cyanobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-pyrazin-2-ylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-pyrimidin-5-ylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-pyridin-2-ylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3-pyrimidin-2-ylbenzoyl) imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4-methylsulfonylbenzoyl-1H-imidazole,
5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4- [3- (5-methyl) oxadiazol-3-ylbenzoyl] -1H-imidazole,
3- (5-amino-4- {3- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- [5-amino-4- (3- {2- [bis- (2-hydroxyethyl) amino] ethoxy} benzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (2-dimethylaminoethoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (2,3-dihydroxypropoxy) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
3- (5-amino-4- {3- [2- (4-chlorophenoxy) ethoxy] benzoyl} pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide,
3- {5-amino-4- [3- (4H- [1,2,4] triazol-3-yl) benzoyl] pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide, and
3- {5-amino-4- [3- (4H- [1,2,4] triazol-3-yl) benzoyl] imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide,
or a pharmaceutically acceptable salt thereof. 25. The compound according to claim 7, which is 3- (5-amino-4-benzoyl-3-methoxypyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide. 26. The compound according to claim 7, which is 3- [5-amino-4- (3-cyanobenzoyl) pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide. 27. A pharmaceutical composition that inhibits p38 kinase, comprising a compound according to claim 7 or 26 and a pharmaceutically acceptable carrier. 28. The pharmaceutical composition according to item 27, obtained for administration in the form of a single dosage form. 29. The compound according to claim 7 or 26, designed to treat, prevent or reduce the intensity of one or more symptoms of p38 kinase-mediated disease or condition. 30. The use of a compound according to claim 7 or 26 for the manufacture of a medicament for the treatment, prophylaxis or reduction of the intensity of one or more symptoms of a disease or condition mediated by p38 kinase. 31. A method for inducing a cytokine response, wherein the cytokine response is induced using p38 kinase activity, comprising administering to a subject in need thereof a compound according to claim 7 or 26.