UA113187C2 - KINASE INHIBITORS - Google Patents

Abstract

The compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein R, W, A, Y and R Defined in the description of the invention is an inhibitor of p38 MAPK useful as anti-inflammatory agents for the treatment of, in particular, respiratory tract diseases.

Description

This invention relates to compounds and compositions that are p38 MAPK inhibitors useful as anti-inflammatory agents for the treatment of, in particular, diseases of the respiratory tract.

Mitogen-activated protein kinases (MAPKs) are a family of proline-directed serine/greonine kinases that activate their substrates by dual phosphorylation. There are four known isoforms of human p38 MAP kinase, pZva, rz38rD, rzvu, and p385b. Rzv8 kinases, which are also known as cytokine-suppressive anti-inflammatory drug binding proteins (C5BP), load-activated protein kinase (BARK) and KK, are responsible for phosphorylation (5ieip ei ai., App. Ker. May

Spet., 1996, 31, 289-298) and transcription factor activation (like ATP-2, MAX, SNOR and

C/EKRRB), as well as other kinases (such as MARKAR-K2/3 or MK2/3), which are themselves activated by physical and chemical stress (for example, UV, osmotic stress), pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) (Negiaag E. 8. Vgomlp 7., MoIesshag Medisipe Todau, 1999, 5, 439-447). It has been shown that p38 phosphorylation products mediate the production of inflammatory cytokines, including tumor necrosis factor alpha (TNF) and interleukin- (II -)-1, and cyclooxygenase-2 (COX-2). It is also known that 1-1 and TMEs stimulate the production of other pro-inflammatory cytokines, such as 1I-6 and II-8.

I/-1 and TMRa are biological substances produced by various types of cells, such as monocytes or macrophages. It has been shown that 1Y/-1 mediate a variety of biological activities believed to be important in immunoregulation and other physiological conditions, such as inflammation (eg, Oipageio ei ai., Kem. IpTesi. Oibsease, 1984, 6, 51). Excessive or unregulated production of TME (in particular, TMEsa) has been implicated in mediating or exacerbating a number of diseases, and it is believed that TME, in general, may cause or contribute to inflammation. HER-8 is a chemotactic factor produced by some cell types, including mononuclear cells, fibroblasts, endothelial cells, and keratocytes. Their production from endothelial cells is induced by 1-1, TME or lipopolysaccharide (I RB). I/-8 stimulates a number of functions of the brain.

It has been shown to have chemoattractant properties for neutrophils, T lymphocytes and basophils.

An increase in the production of I/-8 is also responsible for the chemotaxis of neutrophils to the site of inflammation and inflammation.

It is believed that the inhibition of signal transduction through p38, which, in addition to the above-described HER -1,

TME and 1C-8, is also required for the synthesis and/or action of some additional pro-inflammatory proteins

Ko) (for example, 1-6, CM-C5E, COX-2, collagenase and stromelysin), is a highly effective mechanism for regulating excessive and destructive activation of the immune system. This expectation is supported by the strong and different anti-inflammatory activities described for rzv-kinase inhibitors (Waddeg ei ai., U. Rpagt. Ehr. Tega., 1996, 279, 1453 -1461; Stivmoia ei ai, Rpagtaso!).

Sott., 1996, 7, 323-229). In particular, rZv kinase inhibitors have been described as potential agents for the treatment of rheumatoid arthritis. In addition to the links between riV activation and chronic inflammation and arthritis, there is also evidence implicating a role for p38 in the pathogenesis of airway disease, particularly COPD and asthma. A stressful stimulus (including tobacco smoke, infections, or oxidizing products) can cause inflammation in the pulmonary environment. It was shown that p38 inhibitors inhibit I P5 and ovalbumin-induced TME-a I -18, 1-6, 1-4, 11 -5 and 1-13 of respiratory tracts (Nadaav ei ai, Vg. U. Riaptasoi., 2001, 132 (8), 1715-1724; Opaegmoos ei ai, At.

U. Riuvzioi. And pa SeiYi. My. 2000, 279, 895-902; Yutsap evy ai!., 2005 At. U. Vezrig. Stia Sage Mead., 171, 571-578; Evsoi! Hey! Hg. ). Rpaptasoi., 2000, 191, 173-176; Opaegmooa ei ai., U. Rpaptasoi. Ex.

TNeg. 2000, 293, 281-288). In addition, they significantly inhibit neutrophilia and release MMP-9 in

IHRB5, ozone or cigarette smoke in experimental animal models. There is also a significant body of preclinical data that highlights the potential benefits of p38 kinase inhibition, which may be relevant in the lung (i ee ei ai., Ittiporpagptasoiodu, 2000, 47, 185-200). Thus, therapeutic inhibition of p3b activation may be important in regulating airway inflammation.

The involvement of the rZV8MARK pathway in various diseases was considered by R. Sporga ei ai. (Ekhregi Oripiop op

Ipmesiidaiopa! Ogia5, 2008, 17(10), 1411-1425). It is believed that the compounds of the claimed invention can be used for the treatment of diseases mediated by rz38, such as: chronic obstructive pulmonary disease (COPD), asthma, chronic or acute bronchoconstriction, bronchitis, acute lung injury and bronchiectasis, pulmonary arterial hypertension, tuberculosis, lung cancer, inflammation in general (eg, inflammatory bowel disease), arthritis, neuroinflammation, pain, fever, fibrotic diseases, pulmonary disorders and diseases (eg, hyperoxic alveolar injury), cardiovascular disease, simple ischemic reperfusion injury and congestive heart failure, cardiomyopathy , stroke, ischemia, reperfusion injury, renal reperfusion injury, cerebral edema, neurotrauma and brain injury, neurodegenerative disorders, central nervous system disorders, liver disease and 60 nephritis, gastrointestinal conditions, peptic ulcers, Crohn's disease, eye diseases,

ophthalmic conditions, glaucoma, acute ocular trauma and ocular trauma, diabetes, diabetic nephropathy, skin conditions, myalgia due to myalgia infection, influenza, endotoxic shock, toxic shock syndrome, autoimmune disease, transplant rejection, bone resorption disease , multiple sclerosis, psoriasis, eczema, disorders of the female reproductive system, pathological conditions (but not malignant) such as hemangiomas, nasopharyngeal angiofibroma, and avascular necrosis of bone, benign and malignant tumors/neoplasia, including the following: cancer, leukemia, lymphoma, systemic lupus erythematosus (5E), angiogenesis, including the following: neoplasia, hemorrhage, coagulation, radiation exposure, and/or metastasis. Chronic release of active TME can cause cachexia and anorexia, and

TME can be fatal. TME is also involved in infectious diseases. These include, for example, malaria, mycobacterial infection and meningitis. They also cover, among others, viral infections such as HIV, influenza virus, and herpes virus, including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella virus (VVV), Epstein-Barr virus, human herpes virus-b6 (NNU-6), human herpes virus-7 (NNM7), human herpes virus-8 (NNU-8), infectious bulbar paralysis and rhinotracheitis.

Known inhibitors of RZ8 kinase are considered in 0. u). Naphop (Ekhregi Oripiop5 op Tpegaretsiis

Raiepiv, 1997, 7, 729-733) In Nupez evi ai. (Sstepi Torisv ip Medisipa! Spetivigu, 2005, 5, 967-985), p. Ootipdie? her a! (Ekhrep Oripiop5 op TPnegareshisv Raiepiv, 2005, 15, 801-816) and I. N. Retsyz 8

A. R. Mpa (Stepi Torisv ip Medisipa! Spetivigu, 2008, 8, 1452-1467). RZ38 kinase inhibitors containing the triazolopyridine motif are known in the prior art, for example, MO 07/091152, MO 04/072072,

MO 06/018727.

MO 2010/094956 discloses triazolopyridine derivatives of the formula (I), which are MAP kinase inhibitors: o v 2 U ai - ny Oda; ze mo

In such compounds, A is an optionally substituted divalent arylene radical, a heteroarylene radical, a (C3-C8)-divalent cycloalkylene radical having 5 or 6 ring atoms or a piperidinylene radical.

The compounds are said to be useful as anti-inflammatory agents for the treatment of respiratory diseases

From the tract.

The purpose of the claimed invention is to identify new and potent inhibitors of p38 mitogen-activated protein kinase, which are useful in the treatment of inflammatory and obstructive diseases of the respiratory tract.

The second objective of the claimed invention is to identify new potent inhibitors of mitogen-activated protein kinases, which demonstrate a suitable development profile when used by inhalation for the effective treatment of respiratory obstructive or inflammatory diseases.

It is clear that such a profile can be achieved by a number of different ways of modulating specific properties; for example, this can be achieved by using small effective doses of drugs, thus limiting side effects, or by long-term action in the lungs, which can reduce the frequency of use.

The compounds of the claimed invention are p38 kinase inhibitors of the mitogen-activated protein ("eq

MARK", "p38 kinase" or "p38"), including Rzva kinase, and are inhibitors of cytokine and chemokine production, including TMEa production and 1-8. They have a number of therapeutic applications in the treatment of inflammatory diseases, particularly allergic and non-allergic respiratory diseases pathways, including, but not limited to, obstructive or inflammatory diseases of the respiratory tract, such as chronic obstructive pulmonary disease ("COPD") and asthma.Therefore, in particular, they are suitable for delivery to the lungs by nasal or oral inhalation.

According to the invention, a compound of formula (I) or its pharmaceutically acceptable salt is proposed:

Her ' 2 U-v

And m-(SAU

BO H () where;

MU is a heteroatom selected from M or 0, where M is replaced by the following: hydrogen, C1-C8 alkyl or C3-

C5-cycloalkyl;

U is selected from the group consisting of the following: group -5(O)p-, where p is 0, 1 or 2; group -"O(SAZAU)-; group -"SA»AU)-; group -MA"-; group -0OS(0)-; group -ОС(О)МН-; and group -

Oos(o-;

BZ, VU, B" and RU each independently - hydrogen, fluorine or C:-Cv alkyl; or, respectively, EZ and KE", or B? and K5 can create with the carbon atom to which they are attached, a 3-60-membered saturated carbocyclic monocyclic ring, optionally substituted by the following group: C1-Cv alkyl, hydroxyl or halogen, n -0,1,2 or 3;

B" is hydrogen, C:1-C6 alkyl, or C3-C7 cycloalkyl, where such C1-C7 alkyl or C3-C7 cycloalkyl is optionally substituted by the following group: C1-C3 alkyl, C3-C6 cycloalkyl, hydroxyl, cyano or halogen;

IN! - group selected from (Pa) - (Ps); in? in?

M x x x A y | 26 Mk m-i 13 IT Makh ar m M vi eh m zh XX M

ХК в" " otv (Pa) (PB) (Ps) de

BB is -(C1-Swalkylene)-MAVV, -(C3-Sucycloalkylene)-MAMAV, -MAAV, -M(VU)-(C2-Swalkylene)-

MASS, -Ш(ВУ)-(C3-С7cycloalkylene)-MAВВ, or -ВС;

ВХ and ВВ in each case independently - hydrogen, C-Salkyl or C3-C7 cycloalkyl, such C1-

C1-C7 alkyl and C3-C7 cycloalkyl are optionally substituted by the following group: C1-C3 alkyl, C3-C7 cycloalkyl, -OBE, -58O, -MBEBE, -CM or halogen; alternatively, KE and RE? can form, together with the nitrogen atom to which they are attached, a 5- to 11-membered saturated monocyclic or bicyclic heterocyclic ring system, in which said 5- to 11-membered saturated monocyclic or bicyclic heterocyclic ring is optionally substituted by one or more of the following groups : -ОВО, -СМ, halogen, C3-C7 alkyl or C3-C7 cycloalkyl, such C3-С7 alkyl and C3-С7 cycloalkyl are optionally substituted by the following group: C1-С3 alkyl, C3-С7cycloalkyl, -ОВО, -СМ or halogen; and wherein optionally said 5-11-membered saturated monocyclic or bicyclic heterocyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted with the following: C1-C6 alkyl or C3-C6 cycloalkyl, wherein any such C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted by the following group: C:-C6 alkyl,

C3-C7 cycloalkyl, -OVO, -CM, or halogen;

In each case independently - hydrogen, C1-C8 alkyl or C3-C8 cycloalkyl, such C1-C8 alkyl and C3-C8 cycloalkyl are optionally substituted by the following group: C1-C3 alkyl, OBO, CM or halogen;

IN? in each case independently - hydrogen, -СН3 or -С2Нб5;

VE and KR in each case independently - hydrogen, C-Cv alkyl or C3-C7 cycloalkyl, such C-

C1-C3 alkyl and C3-C7 cycloalkyl are optionally substituted by the following group: C1-C3 alkyl, C3-

Sucycloalkyl, -ONE, -5H85, -CM or halogen; and/or Be and PE" can form, together with the nitrogen atom to which they are attached, a 5-7-membered saturated heterocyclic ring system, in which said 5-7-membered saturated heterocyclic ring is optionally substituted by one or more of the following groups: -ONE, -CM, halogen, C-Cv alkyl or C3-C7 cycloalkyl, such C:i-Cv alkyl and

C3-C7 cycloalkyl is optionally substituted by the following group: C1-C3 alkyl, C3-C7cycloalkyl, -OVO, -CM or halogen; and wherein, optionally said 5-7 membered saturated heterocyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted with the following: C:-C6 alkyl or C3-C6 cycloalkyl, wherein any such C.: -Cv alkyl or C3-Cv cycloalkyl is optionally substituted by the following group: C1-Cv alkyl, C3-C7 cycloalkyl, -OHO, -CM, or halogen;

Вге - hydrogen, -СН3 or -С2Н5;

Xy and Xo - group -(CH)- or nitrogen atom;

B" and B" are independently Ci-Cv alkyl, C3-C6 cycloalkyl, phenyl, which is optionally substituted, 5- or b-membered monocyclic heteroaryl, which is optionally substituted, or a radical of the formula (Xa) or ( full name)

M day (Sha) Sv m (FIRST NAME) k ai ov where 4 equals 1 or 2; and K"" and B" are independently hydrogen or C:-S alkyl or B" and 25 together with the nitrogen to which they are attached optionally form a 6b-membered heterocyclic ring which contains a further heteroatom selected from M and 0;

A", B": and KZ independently - hydrogen, Si-Svalkyl, or halogen;

A is a divalent cycloalkylene radical that has 5, 6 or 7 ring atoms; said cycloalkylene ring is attached to M/ and Y, and is fused to a phenyl ring or to a monocyclic heteroaryl ring having 5 or more ring atoms, so that the phenyl or heteroaryl ring is optionally substituted with one or two Kg groups";

B2" in each case is independently selected from the group consisting of the following: C1-C8 alkyl, halogen and cyano;

IN? - the radical of the formula (ImMa), (IMB) or (IMc): leads to? in

In the child

with,

Okh22o Deu I same 18 same

On the 16th

IN

(Ma) (MB) (Me). where

B"" is selected from the group consisting of the following: -E, -CH2OMe, and -SER»CE:;

В!5 and ВЕЭ are independently -CH3 or -СеНб5;

B" is selected from the group consisting of the following: a lone electron pair, hydrogen, -SEz, -

MAE, -(C3-Sucycloalkyl), -(C3-Suheterocycloalkyl), aryl or heteroaryl, where any such -(C3-C7cycloalkyl), -(C3-Suheterocycloalkyl, aryl or heteroaryl is optionally substituted with the following group: C1- C1 alkyl, C3-C7 cycloalkyl, or halogen; or

B" - the group of the general formula (M) is B

Where

Vo is selected from the group consisting of the following: -E, -CH3, -СеН5, -СН2ОН, -СНгОМе, -

SeЕ2СЕ», -СНгЗСН»», -5СН3 and -5С2Нб5;

В"! is -СН3 or -СЕНбв; or

B2O and B, which are defined above, can form together with the carbon atom to which they are attached, a 3-7--len monocyclic ring;

ВЕ and КИ each independently - C:i-Cv alkyl, optionally substituted by the following group: C1-C3 alkyl, -OVU, -CM or halogen; alternatively, KE! and KI can also form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated monocyclic or bicyclic heterocyclic ring system, in which the named 5-11-membered saturated monocyclic or bicyclic heterocyclic ring is optionally substituted by one or more by the following groups: -OHVU, -CM, halogen, C1-C8 alkyl or C3-C7 cycloalkyl, such C1-C8 alkyl and C3-C7 cycloalkyl are optionally substituted by the following group: C1-C3 alkyl, C3-C7 cycloalkyl, - OBE, -CM or halogen; and where, optionally, said 5-11--len saturated monocyclic or bicyclic heterocyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted by the following: C1-C6 alkyl or C3-C6 cycloalkyl;

where is a group where hydrogen, -CH3 or -C2H5 are independently present in each group;

B'Z is selected from the group consisting of the following: lone pair, hydrogen, aryl, heteroaryl, -(Ci-Salkyl), -(C3-Sucycloalkyl), -(C3-Slteterocycloalkyl), (Ci-

C-heterocycloalkyl)-(C1-Salkyl) and (C5-Sheterocycloalkyl)-(C3-Ce cycloalkyl); where any of the following: aryl, heteroaryl, -(Ci-Salkyl), -(C3-C7cycloalkyl), -(C3-C7heterocycloalkyl), (Ci-

C-Heterocycloalkyl)-(C1-C alkyl) or (C5-C Heterocycloalkyl)-(C3-C6 cycloalkyl) is optionally substituted by the following group: -CM, -OH, halogen, -"SOOVM, C:-C6 alkyl, C3-C6 cycloalkyl, - O-(C1-

Svalkyl), -O-(C3-Cvcycloalkyl), -5-(C1-Svalkyl), -5-(C3-Cvcycloalkyl), -MANVU, -MSH(A(Ce-

Svalkylene)-MANVU, -MSCHAU(C3-C7cycloalkylene)-MANVU, -(C1-Svalkylene)-MANVU, -(C3-

Sucycloalkylene)-MANA»U, -O-(C8-Salkylene)-MANAU, /-O-(C3-C7cycloalkylene)-MANA»U, /-5-(C2-

Svalkylene)-MANNAU, -5-(C3-C7cycloalkylene)-MANA»U, -Щ(ВУС(0)-(С1-С1-Swаlkylene)-MANАУ, -Щ(ВУС(О)-(C3-Sucycloalkylene)-MANAU .

MANNU, -b. (О)М(ВУ-(С2-Salkylene)-ОВМ,. -С(О)М(АУ-(С3-С7cycloalkylene)-ОВМ,

В, -С(О)М(АНАУ), -"КВУС(ОЖМАУ-(С2-Salkylene)-MANНАУ, -ШЧАУС(ОМ(ВУ-(С3-С7cycloalkylene)-

MANVU, -0-(C2-Salkylene)-OVM, -O-(C3-C7cycloalkylene)-YOVM, -5-(C2-Salkylene)-OVM, -5-(C3-

Ccycloalkylene)-OVM, /-Ш(B8UB(O)2-(C1-Salkylene)-MANNU, -M OO (8U5(O)2-(C3-Sucycloalkylene)-

MANVU, -5(0)2M(VU)-(C2-Salkylene)-MANAU, -5(0)2M(8U)-(C3-C7cycloalkylene)-MANA»U, -5(0)2M(VU- ( Cg-Salkylene)-YUM, -5(0)2M(8U-(C3-C7 cycloalkylene)-YUM, -M(BU5(0)2-(C2-Salkylene)-OM, -

M(8U5(O)2-(C3-C7cycloalkylene)-OVM, -5(0)2M(VyB, -ShvUB(OgVe, -ShCAUS(OB, OVU, VU, - (C3-Sletero cycloalkyl)), ( C5e-C heterocycloalkyl)-(C1-C6 alkyl) and (C5-C7 heterocycloalkyl)-(C3-

Sv cycloalkyl)u; where any such part of the following:

Svalkylene)-, -(C3-C7cycloalkylene)-, -(C3-C7heterocycloalkyl), (C5-C7heterocycloalkyl)-(C1-C8 alkyl), (C5-C7 heterocycloalkyl)-(C3-C7 cycloalkyl)y and (C5 -Su7heterocycloalkyl)carbonyl. in the above groups, optionally substituted by the following group: C1-C8 alkyl, C3-C7 cycloalkyl, -OM or halogen;

B" and RU in each case independently - hydrogen, C-Salkyl or C3-Cv cycloalkyl, such C-

Svalkyl or C3-C3 cycloalkyl is optionally substituted by the following group: C1-C3 alkyl, -OM, -CM or halogen; alternatively, EN and BU can also form, together with the nitrogen atom to which they are attached, a 5-11-ene saturated monocyclic or bicyclic heterocyclic

From the ring system, in which the named 5-11-membered saturated monocyclic or bicyclic heterocyclic ring is optionally substituted by one or more of the following groups: -ОВМ, -

CM, halogen, C3-C7 alkyl or C3-C7 cycloalkyl, such C3-C7 alkyl and C3-C7 cycloalkyl are optionally substituted by the following group: C1-C3 alkyl, C3-C7 cycloalkyl, -"OMM, -CM or halogen; and wherein, optionally, said 5-11-membered saturated monocyclic or bicyclic heterocyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted with the following: C1-C6 alkyl or C3-C6 cycloalkyl, where any which is C1-C6 alkyl or C3-C6 cycloalkyl optionally substituted by the following group: C:-C6 alkyl,

C3-C7 cycloalkyl, -OM, -CM, or halogen; and/or PE" and E" can be attached to one carbon atom -(C6-C7alkylene)- or -(C3-C7cycloalkylene)- part of the group bonded to the nitrogen to which they are attached to create a saturated ring up to 6 atoms in the ring;

In each case independently - hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, such C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted by the following group: C1-C3 alkyl, -OM, -CM or halogen.

VM in each case is independently hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, such C1-C4 alkyl or C3-C6 cycloalkyl is optionally substituted by the following group: hydroxyl, -CM or halogen;

IN? selected from the group consisting of the following: hydrogen, -Сез, -MAЕВЕ, -(Сз-

C7cycloalkyl), -(C3-Suheterocycloalkyl) aryl and heteroaryl, where any such -(C3-

C7cycloalkyl), -(C3-Sugeterocycloalkyl) aryl or heteroaryl is optionally substituted by the following group: C1-C8 alkyl, C3-C7 cycloalkyl, or halogen; or

B" is a group of the general formula (M) is in"

Where 220, ID", DE and VE are defined above; 27, 22, 73, and 77" are independently selected from the group consisting of the following: C, M, 5, 0, group -

SNU, and the group -MN-, in such a combination that the resulting ring is an aromatic system;

T is-Me or -SV28-;

B28 - H, halogen, -CH3, or -CM;

Ddgg - H, halogen, -CH3, or -CM;

Provided that when 7/- -СН-, 22--0-, 23- -03-, 27- -М-, ФЩВЙ"8 is a single electron pair, В" is a group of the general formula (M), and K "! is -СН3 or -СеНб5; then 29 is -Е, -СН2ОМе or -СЕ»СЕ:; when 7!- -СН-, 22- -0-, 273- -М-, 27- -М- , B" is a group of the general formula (M), B"! is -CH3 or -

САНта 29 is -CH3, -СеН5; -CH2OH, -CHNa5CH», -5CH3 or -502H5, and Kiv is a phenyl ring; then such a phenyl ring is replaced by a group selected from the following group: -СМ, -СООВМ, Сз-

Secycloalkyl, -O-(C1-Cvalkyl), -O-(C3-Cvcycloalkyl), -5-(C1-Cvalkyl), -5-(C3-Cvcycloalkyl), -

MAU, -MZh(AU(C2-Csalkylene)-MANAU, -Zh(VU(C3-Stcycloalkylene)-MANA»U, -(C3-C7cycloalkylene)-

MANNU, -0-(C3-C7cycloalkylene)-MANNVU, -5-(C2-Salkylene)-MANVU, -5-(C3-C7cycloalkylene)-MANVU, -

M(VUS(O)-(C1-Salkylene)-MANVU, -SHCHAUS(O)-(C3-C7cycloalkylene)-MANVU, -FSCHOomM(VU-(Ce2-

Svalkylene)-MANAU, -C(0)M (8U-(C3-C7cycloalkylene)-MANNAU, -C(OM(BU-(C2-Svalkylene)-OM, - 15. C(OM(BU-(C3-C7cycloalkylene) )-ОВМ, /-ЖЩ(ВУС(ОМАНАУ, 0 -С(О)MANAU 0 -ШвУС(ОМАУ)-(Seg-

Svalkylene)-MANNU-M(VUS(OM(AU-(C3-St7cycloalkylene)-MAMAU, -O-(C2-Svalkylene)-OVM, /--O-(C3-

Ccycloalkylene)-OBM, /-5-(C2-Salkylene)-OBM, /-5-(C3-C7cycloalkylene)-OBM, /-Ш(AUB(O)2-(C1-

Svalkylene)-MANNAU, -Ж(ВУ)5(0)2-(C3-Стcycloalkylene)-MANАУ, -5 (02М(ВУ)-(С2-Svalkylene)-MANVU, - 5(0)2М(8У)- (C3-C7cycloalkylene)-MANVU, -(O)2M(VU)-(C2-Salkylene)-OVM, -6(02M(VU)-(C3-

Sucycloalkylene)-ЮВМ, -Ш(ВУБ(О)2-(С2-Svalkylene)-ОВМ, -МШ(ВУ5(0)2-(С3-Стcycloalkylene)-ОВМ, -

З(О)2М(ВНАУ, -ШвУОБ(Оз»Ве 0-ЖШЧАО ОС) 0О5AE /-(CzSleterocycloalkyl), /(Св-

C-heterocycloalkyl)-(C:1-C6 alkyl) and (C5-C7 heterocycloalkyl)-(C3-C6 cycloalkyl); where any part of the following group: C1-C6alkyl, C3-C6cycloalkyl, -(C6-C6alkylene)- , -(C3-C7cycloalkylene)-, - (C3-S-Sletero cycloalkyl), (C5-Sheterocycloalkyl)-(C1-C8 alkyl), (C5-C7 heterocycloalkyl)-(C3-C8 cycloalkyl) and (Ce-C7heterocycloalkyl)carbonyl in the groups specified above, optionally substituted by the following group: C.-Cv alkyl, C.sub.3-C.sub.7 cycloalkyl, -OM or halogen; or such phenyl ring is substituted with a group which is -(C-Salkylene)-MANA"U or -O-(C2-Salkylene)-

MACHRVU, where EB" and RU, both of which are not hydrogen, in each case independently - hydrogen, C1-Cv alkyl or C3-Cv cycloalkyl, such C1-Cv alkyl or C3-Ce cycloalkyl is replaced by the group -ОВМ, -СМ

Zo or halogen; alternatively, E" and EU may form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated heterocyclic monocyclic or bicyclic ring system in which said 5-11-membered saturated heterocyclic monocyclic or bicyclic ring is substituted with one or more by the following groups: -OM, -CM, halogen, C1-C8 alkyl or C3-C7 cycloalkyl, such C1-C7 alkyl and C3-C7 cycloalkyl are optionally substituted by the following group: C1-C3 alkyl, C3-C7cycloalkyl, -OM . C 1 -C 7 cycloalkyl, wherein any such C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with the following group: C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, -OM, -CM, or halogen; or such phenyl ring is substituted group (C5-Sugheterocycloalkyl)-(C1-Cv alkyl), which is replaced by the following I: C.-Cv alkyl, C3-C7 cycloalkyl, -OM or halogen; or such a phenyl ring is replaced by an -OVE group where B is C-Cv alkyl or C3-Ce cycloalkyl, such

C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted by the following group: C1-C3 alkyl, -ОВМ, -

SM or halogen; or such a phenyl ring is substituted by a C1-C6 alkyl group, which is substituted by the following group: C3-C7 cycloalkyl, OEM or halogen; and when KZ is a morpholine ring and T is -CH28- or -M-; then 22, if present at the position ortho 5O to the T group of the aromatic ring, is -CH3 or -CM.

In yet another aspect, the invention encompasses pharmaceutical compositions comprising a compound of the invention together with one or more pharmaceutically acceptable carriers and/or excipients. In particular, compositions suitable for inhalation for pulmonary use are preferred.

According to yet another approach, the invention encompasses the use of a compound of the invention for the treatment of diseases or conditions that benefit from inhibition of MAP p38 kinase activity.

Treatment of obstructive or inflammatory diseases of the respiratory tract is the predominant application.

All forms of obstructive or inflammatory diseases of the respiratory tract can be treated with the compounds of the claimed invention, in particular, obstructive or inflammatory disease of the respiratory tract, which is selected from the following group: chronic eosinophilic pneumonia, asthma, COPD, COPD, which includes chronic bronchitis, pulmonary emphysema or dyspnea, related or unrelated to

SARS, COPD, which is characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ADS5), exacerbation of airway hyperresponsiveness due to treatment with other drugs and airway disease that is associated with pulmonary hypertension, chronic inflammatory diseases, including cystic fibrosis, bronchiectasis and pulmonary fibrosis (idiopathic). Efficacy is predicted when rZv kinase inhibitors are administered locally to the lungs (eg, by inhalation and intranasal delivery) or by systemic routes (eg, by oral, intravenous, and subcutaneous delivery).

As used herein, the terms "halo" or "halogen" include the following atoms fluorine, chlorine, bromine and iodine.

As used herein, the term "Cx-Alkyl", where x and y are integers, refers to a straight or branched chain alkyl radical having x - y carbon atoms. Thus, when x is 1 and y is 6, the term includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein, the term "Х-Sualkilen", where x and y are integers, refers to the radical Х-

Sualkylu, which has a total of two unsaturated valences, is like a divalent radical of methylene or ethylene.

As used herein, the term "carbocyclic" ring refers to a mono-, bi-, or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.

As used herein, the term "C 1 -C 1 cycloalkyl", wherein 7 and K are integers, refers to a monocyclic saturated carbocyclic radical having 7 to K carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Included within the term "C1-C1 cycloalkyl" are those radicals having two unsaturated valences on the same carbon atom attached to any of the following: C1-

Sualkyl, CxSualkylene, C.-Skcycloalkyl, C.-Skcycloalkylene, C-Skheterocycloalkyl, C;-

C-heterocycloalkylCx-Sulfalkyl, C.-Scheterocycloalkyls-Cxcycloalkyl or (C;-

Suheterocycloalkylcarbonyl by substitution of two hydrogen atoms placed on the same carbon.

Under such conditions, this radical forms a disubstituted heme or spiro system together with the next one

C0 bound group: CxAlkyl, CxAlkylene C.-Cxcycloalkyl C.-Cxcycloalkylene, C;-

C-Heterocycloalkyl, C-C-HeterocycloalkylCx-Sulfalkyl, C-C-Heterocycloalkyls.-C-Ccycloalkyl or (C-C-Heterocycloalkyl Carbonyl, .

The term "C 1 -C 1 cycloalkylene radical" refers to a C 1 -C 2 cycloalkyl radical having two unsaturated valences on different carbon atoms in the ring, such as the following 1,3-cyclopentylene, 1,4-cyclohexylene, and 1,4-cycloheptylene:

As used herein, the non-limiting term "aryl" refers to a mono- or bi-cyclic carbocyclic aromatic radical, and encompasses radicals having two monocyclic carbocyclic aromatic rings that are directly covalently linked. Illustrative examples of such radicals are phenyl, biphenyl and naphthyl.

As used herein, the non-limiting term "heteroaryl" refers to a mono- or bicyclic aromatic radical that contains one or more heteroatoms selected from 5, M, and 0, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one a monocyclic aryl ring that is fused through a common bond. Illustrative examples of 5,6-membered heteroaryl are as follows: thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. Illustrative examples of 8,10-membered heteroaryl are: benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzotriazolyl, indolyl and indazolyl.

As used herein, the non-limiting term "heterocyclyl" or "heterocyclic" refers to a saturated mono-, bi-, or tricyclic non-aromatic radical that contains one or more heteroatoms selected from 5, M, and 0. In particular, the term "C 1 -Sq heterocycloalkyl " refers to monocyclic (C-C)cycloalkyl groups in which at least one ring carbon atom is replaced by a heteroatom (eg, M, MH, 5 or 0). Examples of (C1-C1)heterocycloalkyl include pyrrolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl.

By analogy, the term "C.--Skheterocycloalkylene" refers to the divalent C;- radical

sxheterocycloalkyl, where C--Sxheterocycloalkyl is defined above.

The term "C.sub.-SketerocycloalkylCx-Sulfalkyl" refers to the "C.sub.-Sketerocycloalkyl" group defined above, where one or more hydrogen atoms are replaced by one or more "C.sub.-Sketerocycloalkyl".

Included within the term "C-S-C heterocycloalkylC-Sulfalkyl" are systems where two hydrogen atoms bonded to the same carbon atom in the "Cx-Sulfalkyl" group are replaced by one "C;-

So, such a radical forms a heme-disubstituted system "С;-

"SkheterocycloalkylCx-Sulfalkyl", like the 1,2-dimethyl-pyrrolidin-2-yl radical.

The term "C-SketerocycloalkylC-C-C cycloalkyl" refers to the aforementioned group "C-C cycloalkyl" where one or more hydrogen atoms are replaced by one or more groups "C;-

"Skheterocycloalkyl".

The expression "(C-Sk)cycloalkylcarbonyl" refers to groups (C--Skcycloalkyl-2O-), where the group "(C;-

"cycloalkyl" has the meaning defined above.

The expression "(C-C) heterocycloalkylcarbonyl" refers to the groups (C--C)heterocycloalkyl-CO-, where the group (C-C)heterocycloalkyl" has the above-defined meaning.

Unless otherwise defined in the sense that it occurs, the term "substituted" as used herein for any aryl or heteroaryl moiety means substituted with at least one substituent selected, for example, from the following: (C 1 -C 6 )alkyl, (Si-Ce) fluoroalkyl, (C1-

C1-Cv) alkyl (covering the substitution of methylenedioxyl and ethylenedioxyl on adjacent carbon atoms of the aromatic ring), (C1-Cv) fluoroalkyl, (C1-Cv) alkoxy-(C1-Cv) alkyl, benzyloxy- (C1-Cv) alkyl, (C1- C 1 -C 1 -Alkoxy-(C 1 -C 2 )Alkoxyl, Benzyloxy-(C 1 -C 2 )Alkoxyl, Hydroxyl, Hydroxy (C 1 -C 2 )Alkyl, Hydroxy (C 1 -C 2 )Alkoxyl, Hydroxy (C 1 -C 2 )Alkylthio, Mercapto, mercapto (Si-

C1-alkyl, (C1-C1)alkylthio, cyclopropyl, halogen (including fluoro and chloro), O-benzyl, nitro, nitrile (cyano), -COOH, tetrazolyl, -COOHnha, -СОНе, -50282, -СОМН»h .

MNSOVA, -MNSOOna, -MASOOna, -MNBZO»OVA, -MA»BOGHOVA, -MNSOMN»:, -MAaSOMN», -

МНСОМНРе, -МВ2СОМНРАе, -МНСОМААВ», or -МАВаСОМНАаВ», where Ba and B? independently - (C1-

Ca)alkyl, or Ca and P, when attached to the same nitrogen, can form with that nitrogen a cyclic amino group such as morpholinyl, piperidinyl, or piperazinyl. An "optional substituent" can be one of the groups of substituents described above.

Compounds of the invention may exist in one or more geometric, optical, enantiometric, diastereometric and tautomeric forms, including but not limited to cis- and trans-forms, E- and 7-forms, K-, 5- and meso-forms, keto and enol forms. Unless otherwise stated, reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. If they are suitable, such isomers can be separated from their mixtures using or adapting known methods (eg, chromatographic methods and recrystallization methods). If they are suitable, such isomers can be obtained using adaptations of known methods (eg, asymmetric synthesis).

The use of the mark "7" in the description of the structural formula indicates the point of attachment of the radical group to the rest of the molecule.

As used herein, the term "salt" includes base-addition, acid-addition, and ammonium salts. The compounds of the invention briefly mentioned above, which are acidic, may form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, for example, sodium and potassium hydroxides; alkaline earth metal hydroxides, for example, calcium, barium and magnesium hydroxides; with organic bases, for example, the following: M-methyl-O-glucamine, choline tris(hydroxymethyl)amino-methane, I-arginine, I-lysine, M-ethyl piperidine, dibenzylamine and the like. Compounds of the invention which are basic may form salts, including pharmaceutically acceptable salts with inorganic acids, for example with hydrogen halide acids such as hydrochloric or bromic acids, sulfuric acid, nitric acid or phosphoric acid and the like, and with organic acids, for example with the following: formic, acetic, trifluoroacetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulfonic, p-toluenesulfonic, benzoic, benzenesulfonic, glutamic, lactic and mandelic acids and the like. Compounds (I) having an alkali nitrogen can also form quaternary ammonium salts with a pharmaceutically acceptable counterion such as ammonium, chloride, bromide, acetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene bis-sulfonate, methanesulfonate, trifluoroacetate, xinafoate, and the like. For an overview of the salts, see NaparookK oi Ripagtaseciisa! In addition: Rgorepgiev, ZeiIesiiop, and Oze Bu 2iayi apa Muegtyi (/Miiu-USN, M/vipneit, Septapu, 2002).

It is expected that these compounds of the invention can be obtained in the form of hydrates and solvates. Any reference herein, covering the claims, to "compounds to which the invention relates" or

"compounds of the invention" or "claimed compounds" and the like include references to hydrate salts and solvates of such compounds. The term "solvate" is used herein to describe a molecular complex that contains a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when the named solvent is water.

Individual compounds of the invention may exist in several polymorphic forms, and may be obtained in various forms of crystallization or co-crystallization, and are intended to be encompassed by the term "compounds of the invention."

The compounds can also be used in the form of their prodrugs. Therefore, certain derivatives of the compounds, which may be active as such, or may themselves have little or no pharmacological activity, they may, after administration inside or on the body, be transformed, for example, by hydrolysis into compounds of the invention, which have the desired activity. Such derivatives are classified as "prodrugs". Further information on the use of prodrugs can be found in Rgo-agid5 av

Momi! Oviyimegu Zuzietv, Moi. 14, AS5 butrovzisht 5egiev (T. Nidisni apa mm.). egeiIa) and Viohemegvirie

Satietz ip Ogpd Oevzidp, Regdatop Rge5z5, 1987 (ie. E. V. Vospe, Ategisap Rnaptasetsiisai!

Av5zosiaiop; 0.5. And agzep apa -). Uetegdaaga, Oezidp apa arriisayiop oi rgodgidv, Ip TehirookK oi Ogyd

Oezidp apa Oivzsomegu, 3'Ya Edyop, 2002, Taugiog and Rhapsiv).

Prodrugs according to the invention, for example, can be obtained by replacing suitable functional capabilities present in the compounds of formula (I) with certain particles, which are known to a specialist in the art as "pro-particles", which are described, for example, in Oezidp oi Rgoagid5 Bu N.

Vypadaaga (EiIbzemieg, 1985). Examples of this can be prodrugs of the carboxyl group (such as -С0О-

О-Сно»-О-СО-IVy, which is used in ampicillin-prodrugs of ampicillin), amide (-СО-МН-СН»-МАИК»2) or amidine (-С(-М-О-СН3)-МНг) .

It will be understood that all preferred groups or embodiments described hereinbelow for compounds of formula (1) can be combined with each other and applied also to compounds of formula (IA), (IV), (Ia), (IV) or (Ic) which defined below as amended.

In one embodiment, compounds of the formula (Ia) are proposed, which are compounds of the formula (1), which are defined above, where the stereogenic carbon center on the cycloalkylene ring A, which is connected to the group M/ and designated here below by the number (1), has an absolute the configuration shown here

From below: o 1 in Z and U-vV

MO 0M/n

N

(and)

In another embodiment, compounds of formula (IB) are proposed, which are compounds of formula (I), which are defined above, where the stereogenic center of the carbon on the cycloalkylene ring A, which is connected to the group UM and M and is designated here below respectively by numbers (1) and (2), have the absolute configuration depicted here below:

X in auto co

N

(IB)

In a further embodiment, a compound of the formula (Ic) is proposed, which is a compound of the formula (1), which is defined above, where the stereogenic center of the carbon on the cycloalkylene ring A, which is connected to the MU and M groups and is designated here below respectively by the numbers (1) and (2), has the absolute configuration depicted here below:

N

(Is)

In one embodiment, MU/ is MN or 0. In a further embodiment, UM is MN.

In one embodiment, U are the following groups: group -5(O)p-, group -"FO(SVZAU) -, group -""SARRU) -, or group -MVA"-; p is zero and n is 0, 1 or 2. In yet another embodiment, M is -5(O)p- or the group -"O(SAZAU)-, p is zero and n is 0 or 1. In a further embodiment, M is the group -

О(SVAZAU - and n equals 0.

In one embodiment, KZ, B", B" and Ke are each independently hydrogen, fluorine or C-Cv alkyl. In yet another embodiment, KU, VU, B" and Ke are hydrogen.

In one embodiment, B" is hydrogen, C1-C8 alkyl, or C3-C7 cycloalkyl.

In one embodiment, B" is hydrogen.

In one embodiment, A is a divalent cycloalkylene radical having 5 or 6 ring atoms; said cycloalkylene ring is attached to M/ and Y, and is fused to a phenyl ring or to a monocyclic heteroaryl ring having 5 or 6 ring atoms, and such phenyl or heteroaryl ring is optionally substituted with one or two K2 groups.

In a further embodiment, A is a group selected from the following: and | a s Mach «ХМ и х в в в М вд ж Ж Ж Ж рай ж р ж и жк

And And And And; | Y and I - xx Mach xx M shchi 27 27 27 M v v v v v 27 th

In the next embodiment, A is a group:

J

J

Poison; -5

Same in" in"

In the additional embodiment A - group: breath in"

In one embodiment, K2" is absent or, if present, in each case independently selected from the following: C1-C8 alkyl, -E, -CI, and cyano; in a further embodiment, K2" is absent or, if present, in each case independently, methyl or -R. In the subsequent incarnation, Kg" is absent.

In one embodiment, KE" is a group of formula (Ia): 11

IN

M

And I | what? and X 8 (b) in (Pa)

In one embodiment, B" is hydrogen.

In one embodiment, K25 is hydrogen, -CH3 or -C2H5; in another embodiment, K29 is hydrogen, or -

SN"; in the further embodiment, K26 is hydrogen.

In one embodiment, P is -(C1-Salkylene)-MA"B8, -M(B"A8), -M(BU)-(C2-Salkylene)-MA"AB8, -M(B2)-(C3-Sucycloalkylene )-МА2В8 or -ВС; in yet another embodiment, EZ is -В2.

In one embodiment, the REA is -CH2-OMe.

In another embodiment, K' is a group of the formula (NAME):

! In tva - M

M

12 in (Pb)

In one embodiment, X' is a nitrogen atom or a -CH- group; in another embodiment, X' is a nitrogen atom; in another embodiment X" is the -CH- group.

In one embodiment, K"2 is hydrogen.

In one embodiment, KZ is C1-C8 alkyl, C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6b-ene monocyclic heteroaryl. In the next incarnation

Vo - Ci-Cv alkyl, C3-Cv cycloalkyl. In the next embodiment of BU - C1-Sve alkyl, for example, isopropyl. In another incarnation of KE? - phenyl, which is optionally substituted by one or two halogen atoms, for example, chlorine.

In another embodiment of K? - the radical of the formula (Ша) or (FIRST NAME) о and Ша in. and

Y Me: (Sha) , chove (b)

In yet another embodiment, K' is a group of the formula (Is): 10 ? in hu - "M 13

A «y and aa; (Ps)

In one embodiment, X2 is a nitrogen atom or a -CH- group; in another embodiment, X2 is the -CH- group.

In one embodiment, VZ is hydrogen.

In one embodiment, KO is C1-C6 alkyl, C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or b-membered monocyclic heteroaryl. In a further embodiment, BO is Ci-Cv alkyl, C3-Ce cycloalkyl. In the next embodiment, KO is C1-Cv alkyl.

In yet another embodiment, Ko is the radical of the formula (Ша) or (FIRST NAME) о and Ша in.

I Y "MVV? ( ) same call" (full name)

In one embodiment of B? - the radical of the formula (IMa): вы в? at. 20 Rec

Men's 16-year-old (IMa)

In one embodiment, B" is selected from the group consisting of -E, -CHnOMe, and -CE2CE with.

In one embodiment, K"" and K"E are independently -CH3 or -С2Н5; in another embodiment of EK" and KE there is -

SN.

In another embodiment, K2 is the radical of the formula (IMB): в" х, 1 st

Lesson 7

This is (MV).

In one embodiment, K'" is selected from the group consisting of the following: lone pair, hydrogen, -C3, -MVEVRY, -(C3-Seccycloalkyl), -(CaC8heterocycloalkyl), aryl, or heteroaryl, wherein any such -( C3-C7cycloalkyl), -(C--Swheterocycloalkyl), aryl or heteroaryl is optionally substituted with the following group: methyl, isopropyl or halogen. In yet another embodiment, KE!" selected from the group consisting of a lone pair, hydrogen, -C3, morpholine, cyclohexyl, phenyl or pyridyl.

In yet another embodiment, K"7 is a group of the general formula (IM) that is B and po

In one embodiment, E2O is selected from the group consisting of the following: -E, -CH3; -CHnOH, -

SnNogOoMe and -СНо5СН:»; in yet another embodiment, 229 is selected from the group consisting of -CH3, -CH2OH, and -CH2OMe. In a further embodiment 20 is -CH3,

In one embodiment, B-" is -CH3.

In yet another embodiment, KO and K-", which are defined above, can form, together with the carbon atom to which they are attached, a cyclohexane or cyclopropyl ring; in a further embodiment

B29 and K-", which are defined above, can form a cyclopropyl ring together with the carbon atom to which they are attached.

In one embodiment, BE" and BP" are each independently C1-C3 alkyl, optionally substituted with the following group: C1-C2 alkyl, -OVU, CM or halogen. In the further incarnation of BU! and YOU are each independently C1-C3 alkyl.

In yet another embodiment, BE"! and YOU form, together with the nitrogen atom to which they are attached, a 5-6-membered saturated monocyclic or bicyclic ring system, which optionally contains a further heteroatom, such as oxygen or nitrogen, the said atom nitrogen is optionally substituted with the following: C1-C2 alkyl or C3-C7cycloalkyl. it is possible that the nitrogen atom is optionally replaced by methyl.

In one embodiment, "8" is phenyl, which is optionally substituted by the following group: -CM, OH, halogen, SOOBM, C-Salkyl, C3-Seccycloalkyl, -O-(C1-Salkyl), -O-(C3-Cscycloalkyl ), -5-(С1-

Svalkyl), -5-(C3-Secycloalkyl), -MANAU, -M(VU(C2-Salkylene)-MANAU, -M(VU(C3-C7cycloalkylene)-

MANVAU, -(C1-Salkylene)-MAMVU, -(C3-Ct7cycloalkylene)-MANVU, -O-(Cg-Salkylene)-MANVU, -O-(C3-

Sucycloalkylene)-MANVU, -5-(Cg-Svalkylene)-MANVU, -5-(C3-Ct7cycloalkylene)-MANVU, -M(ВУ)С(О0)-(Сч-

Svalkylene)-MANNAU, -Щ(ВУС(О)-(С3-Стcycloalkylene)-MANNAU, -С(О)М(ВУ)-(С2-Svalkylene)-MANВУ, - з35 С(ОМ(ВУ-(С3- C7cycloalkylene)-MANVU, -C(O)M(VU-(C2-Salkylene)-OVM, -FSyumVU-(C3-

Cycloalkylene)-OVM, "(VU C(OM(ANAU), -"C(OM(ANVU), -"SVUS(OMVU-(C2-Svalkylene)-MANVU, -

Mm(BUS(O)M(AU)-(C3-C7cycloalkylene)-MANVU, -0-(C8-Salkylene)-OBM, -0-(C3-C7cycloalkylene)-OBM, -5-(C2-Salkylene)- ОВМ, /-5-(C3-C7cycloalkylene)-ОВМ, /--Ж(ВУ5(О)2-(С1-Salkylene)-MANAU, -(--

M(28U5(O)2-(C3-C7cycloalkylene)-MANVU, -(0)2M(VU)-(C2-Salkylene)-MANVU, -SCHO)2M(NU)-(C3-

Sucycloalkylene)-MANVU, -5(0)2M(AU)-(C3-C7cycloalkylene)-OBM, -5(0)2M(2U-(C3-C7cycloalkylene)-OBM, -

M(VUB(O)2-(Cg-Svalkylene)-OVM, -ZHAU5(O)2-(C3-C7cycloalkylene)-OVM, -6(O2M(ANAU, - m(VUe(O)2ve, -ShVUS( О)B, ОВУ, ВУ, -(C3-C6 heterocycloalkyl), (C6-C6 heterocycloalkyl)-(C1-C6 alkyl) and (C5-C7 heterocycloalkyl)-(C3-C6 cycloalkyl), where any such C1-C6 alkyl , Sz-

Secycloalkyl, -(C3-Salkylene)-, -(C3-C7cycloalkylene)-, -(C3-Sheterocycloalkyl), / (C5-Sleterocycloalkyl)-(Ci-Ce alkyl), (C5-C7 heterocycloalkyl)-(C3-Ce cycloalkyl) and (Cv-

The heterocycloalkylcarbonyl in the above groups is optionally substituted by the following group: C1-C8 alkyl, C3-C7 cycloalkyl, -OM or halogen.

In yet another embodiment, K'8 is -(C1-Salkyl) or -(C3-C7cycloalkyl).

In one embodiment 7" - -CH-, 22-0, 73 and 727 are M; in another embodiment 71-00, 22-0.73 and? are M; in a further embodiment 7! - -CH-, 72 and 23 is M and 2" is -CH-; in the additional embodiment 72 -M, 22 -0.23 is

M and 27 are O; in the next incarnation, 72'-M, 22-C, 7236Ota; is M.

In the additional embodiment, K2 is the radical of the formula (IMB): 17 c

M 21 Fri 7 F 4 at 8 (MB)

Where 2-0, 22-0.723 is M, 27 is M, K!8 is an electron pair, and K!" is a group of the general formula (M) 21 va x (M)

Where 229 is -CH or -CH2OH, and KE"! is -CH".

In another embodiment, K2 is the radical of the formula (IMbB): c".

BU 1

With ch

Z rt

U x rya (MB)

Where 2-M, 22-60, 723 is M, 27 is O, K'8 is an electron pair, and K"" is a group of the general formula (M) 21 va x (M)

Where K29 is -CH or -CH2OH, and K-! is -CH..

In an additional embodiment, K2 is a radical of the formula (IMB): p; at 1 vyk

WITH; y od mozh rya (MV)

Where 27 is -CH-, 22-M, 23 is M, 27 is -0-, 88 is hydrogen, and K'" is a group of the general formula (M)

weight (M)

Where 229 is -CH or -CH2OH, and KE"! is -CH".

In the additional embodiment, K2 is the radical of the formula (IMB): 17 d

M 2 1 where kN and y 7

This (IMB)

Where 2 is CH-, 22-M, 23 is M, 27 is-O-, B'8 is hydrogen, and EC" is aryl, which is optionally substituted by the following group: (C1-C8) alkyl.

In the additional embodiment, K2 is the radical of the formula (IMB): her

E ' o 1 iy,

With h and shk 4 mch and their rya (M)

Where 2" is -CH-, 22-0.73 and 27" are M and K"" is a group of the general formula (M) 21 va x (M)

Where K29 is -CH or -CH2OH, and K-! is -CH..

In another embodiment, K2 is the radical of the formula (IMB): 17 z for 1 z,

Z « x kd- z Khot 7 x vv (MV)

Where 27 --CH-, 22-60, 73 and 2" are M and "7 is a group of the general formula (M) 21 va x (M)

Where 829 is -CH3 or -CH2OH, B2! is -SNztta, where

B'8- phenyl, which is substituted by the group -(C1-Svalkylene)-MANVA: or -O-(C2-Svalkylene)-MANVU, where ВН and РУ, which are both not hydrogen, in each case independently - hydrogen, C1- Cl alkyl or C3-C8 cycloalkyl, where such C:i-C8 alkyl or C3-C8 cycloalkyl is substituted by the following group: OKM, CM or halogen; alternatively, E" and E" may form, together with the nitrogen atom to which they are attached, a 5- to 11-membered saturated monocyclic or bicyclic heterocyclic ring system in which said 5- to 11-membered saturated monocyclic or bicyclic ring is substituted with one or more by the following groups: OEM, CM, halogen, C1-C6 alkyl or C3-C7 cycloalkyl, such C1-C8 alkyl and C3-C7 cycloalkyl are optionally substituted by the following group: C1-C3 alkyl, C3-

C7cycloalkyl, OBM, CM or halogen; and, where optionally, said 5-11 membered saturated monocyclic or bicyclic heterocyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted with the following: C1-C6 alkyl or C3-C6 cycloalkyl, where any alkyl or cycloalkyl is optionally substituted with the following group: C1-C8 alkyl, C3-C7 cycloalkyl, OBM, CM, or halogen; or where K'8 is phenyl, which is substituted by the group (C5-Sugeterocycloalkyl)-(C1-C6 alkyl), which is substituted by the following group: C3-C6 alkyl, C3-C7 cycloalkyl, ORBM or halogen; or where KZ is phenyl, which is substituted by a C1-Cv alkyl group, which is substituted by the following group: C3-

WITH; cycloalkyl, -OM or halogen; or where B"8 is phenyl, which is substituted by the following group: -CM, -O-(C1-Svalkyl), -MANVU, -O-(Ce2-

Svalkylene)-OVM, -5-(C2-Svalkylene)-OVM, -(C3-Stheterocycloalkyl), where any such cS--

Svalkyl, -(C3-Svalkylene)-, -(C3-Suheterocycloalkyl) in the above groups is optionally substituted by the following group: C1-C7 alkyl, C3-C7 cycloalkyl, OEM or halogen.

In the further embodiment, K2 is the radical of the formula (IMB): v, kha il

J

With No

Code, 18

IS

PV) !

Where 27 --CH-, 22-60, 73 and 2" are M and "7 is a group of the general formula (M) 21 va x (M)

Where Co is -CH3 or -CH»OH, and KK is -CH3. and 8 - a heteroaryl ring, optionally substituted by the group: (C5-Sugeterocycloalkyl)-(C1-Cv alkyl), optionally substituted by the following group: C-Cv alkyl, C3-C7 cycloalkyl, OBM or halogen; or BZ is a heteroaryl ring, optionally substituted by the following group: -(C1-Salkylene)-MANV: or -O-(C2-Svalkylene)-MANVU.

In an additional embodiment, K2 is the radical of the formula (IMB): 17

Eh 2 1 already t and xzh

And 18

IS

NAME x (m,

Where 2" is -CH-, 22-0.73 and 7" are M and K"" is a group of the general formula (M) 21 g x (M)

Where Co is -CH3 or -CH2OH, and KK" is -CH3 and K'8 - -(C4-Salkyl), optionally substituted by the following group: -OH, halogen or -MANN; or (C5-Suteterocycloalkyl or ( C5-

S-heterocycloalkyl)-(C1-Salkyl), which is optionally substituted by the following group: C1-C8 alkyl, halogen or -OH.

In the further embodiment, 2 is the radical of the formula (IMs): v'? tt" rya in the same (IMs) ;

In one embodiment, P" is selected from the group consisting of the following: hydrogen, -C3, -MAVEV", -(C3-Seccycloalkyl), -(C3-Swheterocycloalkyl), aryl, and heteroaryl, wherein any such -(C3 -

C1-C2 alkyl, C3-C5 cycloalkyl, or halogen. In yet another embodiment, K"" is selected from the group consisting of hydrogen, -C3, morpholine, cyclohexyl, phenyl, or pyridine, wherein any of the following: morpholine, cyclohexyl, phenyl, or pyridyl is optionally substituted with the following group: methyl, -E or -SI.

In another embodiment of the short circuit, the group of the general formula (M) is in" and (M)

In one embodiment, T is -M-. In yet another incarnation of T is -sva-.,

In one embodiment, K22 is H, P, -SI, -CH3, or -CM; in yet another embodiment, Kg is H or EC.

In one embodiment, K25 is H, P, -SI, -CH3, or -CM; in yet another incarnation of Kg there is -SI.

In one embodiment, compounds of the formula (IA) are proposed, where MU is MH, m is the group -"О(СВЗВАУ)- and n is 0, A is the group:

J. J

Poison og -5

J

27 27 in c

B - formula group (NAME): 9 ! in tin

M

-. in'? M (NAME) where X' is the -CH- group; B: hydrogen; KZ - C1-C8 alkyl, C3-C8 cycloalkyl, phenyl, which is optionally substituted, or 5- or b-membered monocyclic heteroaryl, which is optionally substituted;

B2 is a radical of the formula (IMbB):

And

WITH.

El Uzh y x dv (MV)

Where 27 --CH-, 22-60, 73 and 2" are M and "7 is a group of the general formula (M) 21 g x (M)

where in is -CH3 or -CH2OH, and KI is -CH3. and 28 - a group -(C1-Swalkyl), optionally substituted by the following group: -OH, halogen or -MANRV""; or a group (C5-Sueterocycloalkyl) or (Coe-Steterocycloalkyl)-(Ci-Swalkyl, which is optional necessarily substituted by the following group: C1-C6 alkyl, halogen or -OH.

In one embodiment, compounds of the formula (IV) are proposed, where MU is MH, m is the group -"О(СВЗВАУ)- and n is 0, A is the group:

J

J

Poison og -5

The same in

IN! - formula group (name): in?

Ck h! mo tYit- M

M in? (NAME) where X' is the -CH- group; IN? - hydrogen; KZ - C:-C8 alkyl, C3-C6 cycloalkyl, phenyl, which is optionally substituted, or 5- or b-membered monocyclic heteroaryl, which is optionally substituted;

B2 is the radical of the formula (IMB): 17

In, 21 same 8;

Yasya Mezh 7 Ex de (MV)

Where 27 --CH-, 22-60, 73 and 2" are M and "7 is a group of the general formula (M) 21 va x (M)

Where 29 is -CH3 or -CH2OH, and 22! is -СНз. and where

B'8- phenyl, which is substituted by the group -(C1-Svalkylene)-MANVA: or -O-(C2-Svalkylene)-MANVU, where ВН and РУ, which are both not hydrogen, in each case independently - hydrogen, C1- Cl alkyl or C3-C8 cycloalkyl, where such C:i-C8 alkyl or C3-C6 cycloalkyl is substituted by the following group: OBM, CM or halogen; alternatively, E" and E" may form, together with the nitrogen atom to which they are attached, a 5-11-ene saturated monocyclic or bicyclic ring system in which said 5-11-ene saturated monocyclic or bicyclic ring is substituted with one or more by the following groups: OBEM, CM, halogen, C1-C8 alkyl or C3-C7 cycloalkyl, such C:1-C8 alkyl and

C3-C7 cycloalkyl is optionally substituted by the following group: C1-C3 alkyl, C3-C7cycloalkyl, OBM,

SM or halogen; and, where optional, said 5-11-membered saturated monocyclic or bicyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted with the following: C-Ce alkyl or C 3-Ce cycloalkyl, where any which alkyl or cycloalkyl is optionally substituted by the following group: C1-C8 alkyl, C3-C7 cycloalkyl, OBM, CM, or halogen; or where K'8 is phenyl, which is substituted by the group (C5-Sugeterocycloalkyl)-(C1-C6 alkyl), which is substituted by the following group: C1-C6 alkyl, C3-C7 cycloalkyl, OBM or halogen; or where K'8 is phenyl, which is substituted by a C.1-C6 alkyl group, which is substituted by the following group: C3-

WITH; cycloalkyl, -OM or halogen; or where B"8 is phenyl, which is substituted by the following group: -CM, -O-(C1-Svalkyl), -MANVU, -O-(Ce2-

Svalkylene)-OVM, -5-(C2-Svalkylene)-OVM, -(C3-Stheterocycloalkyl), where any such cS--

Svalkyl, -(C3-Svalkylene)-, -(C3-C7heterocycloalkyl) in the above groups are optionally substituted by the following group: C3-C7 alkyl, C3-C7 cycloalkyl, ORBM or halogen.

In one embodiment, the compound of formula (I) is selected from the following: 1-(5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl)-3-K15,4H)-4-( 3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-K15, 4nH)-4-(3-isopropyl-(1,2,4|Itriazoloi4,3-a|pyridine) -b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-5-tert-Butyl-2-I3-(2-hydroxyethylsulfanyl)-phenyl|-2H-pyrazole- Z-yl)y-3-K15, 4nH)-4-(3- isopropyl-(1,2,4)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4- tetrahydro-naphthalene-1-yl|-urea; 1-15-tert-Butyl-2-I3-(2-hydroxy-ethoxy)-phenyl|-2H-pyrazol-3-yl)-3-K15, 4H)-4-(3-isopropyl-

Zo P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(5-tert-Butyl-|1,3,4oxadiazol-2-yl)-3-K15, 45)-4-(3-isopropyl-P1,2,4A|griazolo|4,3-a|pyridine -β-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|-urea; 1-K15, 45)-4-(3-Isopropyl-(1,2,A)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1- yl|-3-(1-p-tolyl-1H-pyrazol-4-yl)-urea; 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-K15, 45)-4-(3-isopropyl-1,2,4A)griazolo|4,3-a|pyridin-b-yloxy)-1 ,2,3,4-tetrahydro-naphthalene-1-yl|-urea; 1-(3-tert-Butyl-|1,2,4|oxadiazol-5-yl)-3-K15, 45)-4-(3-isopropyl-P1,2,4A|griazolo|4,3-a |pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(1-tert-Butyl-1H-pyrazol-4-yl)-3-K15, 45)-4-(3-isopropyl-(1,2,4|Hygriazolo|4,3-a|pyridine-6 - yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|-urea; 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl| -3-К15, 4Н)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(b-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl|-3-K15, 4H)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-15-tert-Butyl-2-I3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl|-2H-pyrazol-3-yl)-3-K15, 48)- 4-(3- isopropyl-P1,2,4A|griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea and 1-(5-tert-Butyl -2-4-(2-(4-methyl-piperazin-1-yl)-ethoxy|-phenyl)-2H-pyrazol-3-yl)-3-K15, 48)-4- (3-isopropyl-P1 ,2,4Hygriazolo|4,3-a|pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the compound of formula (I) is selected from the following: 1-(5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl)-3-K15,4H)-4- (3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-K15, 4nH)-4-(3-isopropyl-(1,2,4|Itriazoloi4,3-a|pyridine) -b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-5-tert-Butyl-2-I3-(2-hydroxyethylsulfanyl)-phenyl|-2H-pyrazole- Z-yl)y-3-K15, 4nH)-4-(3- isopropyl-(1,2,4)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4- tetrahydro-naphthalene-1-yl|-urea; 1-15-tert-Butyl-2-I3-(2-hydroxy-ethoxy)-phenyl|-2H-pyrazol-3-yl)-3-K15, 4H)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; bo 1-(5-tert-Butyl-|1,3,4oxadiazol-2-yl)-3-K15, 45)-4-(3-isopropyl-P1,2,4A|griazolo|4,3-

α|pyridin-β-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|-urea; 1-K15, 45)-4-(3-isopropyl-(1,2,4A)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1- ylI-3-(1-p-tolyl-1H-pyrazol-4-yl)-urea; 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-K15, 45)-4-(3-isopropyl-1,2,4A)griazolo|4,3-a|pyridin-b-yloxy)-1 ,2,3,4-tetrahydro-naphthalene-1-yl|-urea; 1-(3-tert-Butyl-|1,2,4|oxadiazol-5-yl)-3-K15, 45)-4-(3-isopropyl-P1,2,4A|griazolo|4,3-a |pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(1-tert-Butyl-1H-pyrazol-4-yl)-3-K15, 45)-4-(3-isopropyl-(1,2,4|Hygriazolo|4,3-a|pyridine-6 - yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl| -3-К15, 4Н)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(b-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl|-3-K15, 4H)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-15-tert-Butyl-2-I3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl|-2H-pyrazol-3-yl)-3-K15, 48)- 4-(3- isopropyl-P1,2,4A|griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea and 1-(5-tert-Butyl -2-4-(2-(4-methyl-piperazin-1-yl)-ethoxy|-phenyl)-2H-pyrazol-3-yl)-3-K15, 48)-4- (3-isopropyl-P1 ,2,4Hygriazolo|4,3-a|pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(b-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl|-3-K15, 45)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(b-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl|-3-K15, 45)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(5-tert-Butyl-2-piperidin-4-yl-2H-pyrazol-3-yl)-3-(15,4H)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(b-tert-Butyl-2-(1-methyl-piperidin-4-yl)-2H-pyrazol-3-yl|-3-(15,4H)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(b-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-K15, 4nH)-4-(3-isopropyl/1,2, 4-Itriazolo|4,3-a|pyridin-6b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-K15, 48)-7-fluoro-4-(3-isopropyl-

Zo P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-K15, 48)-4-(3-Isopropyl-(1,2,4A)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1- yl|-3-(2-p-tolyl-2H-pyrazol-3-yl)-urea; 1-(1-tert-Butyl-1H-pyrazol-4-yl)-3-K15, 48)-7-fluoro-4-(3-isopropyl-1,2,4|griazoloi|4,3- a| pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|-urea; 1-(5-tert-Butyl-2-13-(2-(4-hydroxy-piperidin-1-yl)-ethoxy|-phenyl)-2H-pyrazol-3-yl)-3-(15, 4nH )-4-(3-isopropyl-(1,2,4Hygriazolo|4,3-a|pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1- (b-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl|-3-K15, 4nH)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-5-tert-Butyl-2-|1-(2-morpholin-4-yl-ethyl)-1H-indazol-b-yl|-2H-pyrazol-3-ylHy-3-K15, 48)-4 -(3-isopropyl-(1,2,4)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-5-tert-Butyl-2-(2-(2-morpholin-4-yl-ethyl)-2H-indazol-b-yl|-2H-pyrazol-3-ylHy-3-K15, 48)- 4-(3-isopropyl-(1,2,4)griazoloyl|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-3-(15,4nH)-4-I3-(2,6-dichloro-phenyl)-

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea; 1-(b-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-(15,4nH)-4-I3-(2,6-dichloro - phenyl)-(1,2,4|)triazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalen-1-yl-urea; 1-(B- tert-Butyl-2-(2-dimethylamino-ethyl)-2H-pyrazol-3-yl|-3-(15, A)-A-I3-(2,6-dichloro-phenyl)-(1,2, 4|)triazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalen-1-yl-urea; 1-(B-tert-Butyl-2-(2- piperidin-1-yl-ethyl)-2H-pyrazol-3-yl|-3-(15,A)-A-I3-(2,6-dichloro-phenyl)-(1,2,4|)triazolo| 4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalen-1-yl-urea; 1-15-tert-Butyl-2-(2-(4-methyl-piperazine) -1-yl)-ethyl|-2H-pyrazol-3-yl)-3-(15, A)-A-I3-(2,6-dichloro-phenyl)-I(1,2,4|Itriazoloi| 4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalen-1-yl-urea; 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)- 2H-pyrazol-3-yl|-3-(15,4H)-4-I3-(2-chloro-phenyl)-

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea; 1-(b-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-415, 48)-4-IZ3-(2-chloro-phenyl) -

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea; 1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(15,4nH)-4-I3-(2,6-dichlorophenyl)-boP1,2,4)griazolo |4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydronaphthalen-1-yl|-urea;

1-(b-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-K15, 4H8)-4-(3Z-cyclohexyl-

P1,2,4Hygriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea; 1-(5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl)-3-(15,4nH)-4-I3-(2,6-dichlorophenyl)-

P1,2,4)griazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydronaphthalen-1-yl|-urea; or a pharmaceutically acceptable salt thereof.

As mentioned above, the compounds of the invention are inhibitors of pZv8MARK, and therefore may be useful in the treatment of diseases or conditions as an advantage of inhibiting the p38 enzyme. Such diseases and conditions are known from the literature and several of them are mentioned above. However, the compounds are commonly used as anti-inflammatory agents, particularly for the treatment of respiratory disease. In particular, the compounds can be used to treat the following: chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS5), pulmonary emphysema, or smoking-induced emphysema, infectious-allergic (non-allergic asthma and external ( allergic) asthma, mild asthma, moderate asthma, severe asthma, steroid-resistant asthma, neutrophilic asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced by the following bacterial infection: cystic fibrosis, pulmonary fibrosis, and bronchiectasis.

According to the claimed invention, it is proposed to use the compounds of the invention for the prevention and/or treatment of any disease or condition as a result of inhibition of the enzyme rzv.

According to a further approach of the claimed invention, it is proposed to use the compounds of the invention for the manufacture of a medicament for the prevention and/or treatment of any disease or condition as a result of inhibition of the p38 enzyme.

In addition, according to the claimed invention, a method of prevention and/or treatment of any disease as a result of inhibition of p38 enzyme is proposed, said method consists in applying to a patient in need of such treatment, a therapeutically effective amount of a compound of the invention.

As mentioned above, the compounds of the invention are inhibitors of p38 kinase, and are useful in the treatment of several diseases, for example, inflammatory diseases of the respiratory tract. Examples of such diseases relate to the above, and include the following: asthma, rhinitis, respiratory allergy syndrome

By the way, bronchitis and chronic obstructive pulmonary disease.

It should be understood that the specific dose level for any particular patient should depend on a variety of factors, including the following: activity of the particular compound administered, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, the combination of drugs and the severity of the specific disease being treated. Optimal dose levels and dosing frequency should be determined by a clinical trial, as required by the pharmaceutical industry. In general, the daily dose range for oral administration should be between about 0.001 mg - 100 mg per kg of human body weight, often about 0.01 mg - 50 mg per kg, for example, 0.1 - 10 mg per kg , in single or divided doses. In general, the daily dose range for inhalation should be in the range of approximately 0.1 mcg - 1 mg per kg of human body weight, preferably 0.1 mcg - 50 mcg per kg, in single or divided doses. On the other hand, in some cases it may be necessary to use dosages outside these limits. According to the purpose of the invention, it is preferable to use by inhalation.

The compounds according to the invention can be obtained for use in any way according to their pharmacokinetic properties. Oral compositions may be in the form of tablets, capsules, powders, granules, cakes, liquid or gel preparations such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose form, and may contain suitable excipients such as binders such as strop, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; a tablet lubricant, for example, magnesium stearate, talc, polyethylene glycol or silicon dioxide; disintegrants such as potato starch or an acceptable wetting agent such as sodium lauryl sulfate. The tablets may be coated according to methods well known in ordinary pharmaceutical practice. Oral liquid preparations may be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be a dry product to be reconstituted with water or other suitable excipient prior to use.

Such liquid preparations may contain appropriate additives, such as suspending agents, for example, sorbitol, syrup, methylcellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifiers, for example, lecithin, sorbitol monooleate or gum arabic; non-aqueous fillers (which may include edible oils) such as almond oil, fractionated coconut oil, oil esters such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, suitable flavorings or colorings.

For local application to the skin, the medicine can be made in the form of a cream, lotion or ointment.

Cream or ointment compositions that can be used for medicine are suitable compositions that are well known in the art, for example, those described in conventional pharmaceutical manuals, such as Vgiyizp Rpagtasoroeia.

It is also possible to apply the active ingredient in a sterile environment in parallel.

Depending on the excipient and the concentration used, the drug may be suspended or dissolved in the excipient. Preferably, adjuvants such as local anesthetic, preservative and buffering agents can be dissolved in the filler.

However, for the treatment of inflammatory disease of the respiratory tract, the compounds of the invention can also be formulated for inhalation, for example, as a nasal spray, or dry powder, or aerosol inhalers. For delivery by inhalation, the active compound is preferably used in the form of microparticles. They can be produced in a variety of ways, including spray drying, lyophilization and micronization. Aerosol generation can be done using, for example, pressurized dispensing nozzle nebulizers or ultrasonic nebulizers, preferably using metered aerosols driven by a propellant gas, or non-propeller gas application of finely ground active compounds, for example from an inhalation capsule or other "dry powder" supply systems.

For example, the composition of the invention can be prepared as a suspension for delivery from a nebulizer or as an aerosol in a liquid propellant, for example, for use in a metered dose inhaler with increased pressure (PMDI). Extruder gases suitable for use in the PMO are known to a person skilled in the art and include SES-12, NEA-134a, NEA-227, NSES-22 (ССИ2Е2) and NEA-152 (SNR and isobutane).

In a preferred embodiment of the invention, the composition of the invention is in the form of a dry powder for delivery using a dry powder inhaler (DI). Many types of ORI are known.

Microparticles for application can be formulated with excipients to facilitate delivery and release. For example, microparticles are possible in a dry powder composition

To compose with large particles of the carrier, which contributes to the flow of ORI in the lungs. Suitable carrier particles are known and include lactose particles; they can have an average aerodynamic diameter mass greater than 90 μm.

In a composition based on an aerosol, for example, there is: compound of the invention 24 mg / aerosol can lecithin, ME Liquid. Conc. 1.2 mg / aerosol can trichlorofluoromethane, ME 4.025 g / aerosol can dichlorodifluoromethane, ME 12.15 g / aerosol can.

The active compounds can be dosed as described depending on the inhaler system used.

In addition to active compounds, application forms may additionally contain fillers, such as, for example, displacer gases (for example, hydep in the case of measured aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (for example, lactose in powder inhalers) or, if appropriate, further active compounds.

For inhalation, a large number of systems are available with optimal particle size aerosols that can be generated and administered in an inhalation manner that is suitable for the patient. In addition to the use of adapters (gaskets, expanders) and pear-shaped containers (e.g., Mershayogte, MoiIshptayist), and automatic devices that release a nebulized aerosol (AtsiopVaiiegv)) for metered aerosols, in particular, in powder inhalers, a number of special solutions are available (e.g. OizKpaIegf), KoiadiekF, Tigropaieke or inhalers, for example, which are described in EP-A-0505321). Additionally, the compounds of the invention can be delivered from multi-chamber devices, thus allowing the delivery of a combination of agents.

Other compounds can be combined with the compounds of the invention for the prevention and treatment of inflammatory diseases, in particular, respiratory diseases. Therefore, the claimed invention also relates to pharmaceutical compositions that contain a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents. Suitable therapeutic agents for combination treatment with the compounds of the invention include, but are not limited to, the following: (1) corticosteroids such as fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone dipropionate, ciclesonide, budesonide, (35K 685698, Z5K 870086, OAE 397 , OME 149, TRI-1020; (2) β2-adrenergic agonists such as salbutamol, albuterol, terbutaline, fenoterol, and long-acting β-adrenergic agonists such as salmeterol, indacaterol, formoterol (including formoterol fumarate) , arformoterol, carmoterol, 55K 642444, Z5K 159797, 55K 159802, ak 597501, aZK 678007, AO03199; (3) a long-acting corticosteroid/p2 agonist combination product, such as salmeterol/ fluticasone propionate (Aaimaig/Zegeiide), formoterol /budesonide (Zutrbisog), formoterol/fluticasone propionate (RishioOgt), formoterol/ciclesonide, formoterol/mometasone furoate, formoterol/beclomethasone dipropionate, indacaterol/"mometasone furoate, indacaterol/"UAE 397, CC 159797/55K 685698, SK 159802/255K 68569 8, 15K 642444/555 685698, y5K 159797/2554 870086, 15K 159802/15K 870086, 5K 642444/55K 870086, arformoterol/ciclesonide; (4) anticholinergic agents, for example, muscarinic-3 (M3) receptor antagonists, such as ipratropium bromide, tiotropium bromide, Acridinium (I A5-34273), MMA-237, ZK 233705, Darotropium, OK 573719, С5К 961081,

OAT 370, OAK 028, ER-101; (5) dual pharmacological agonists of the M33-anticholinergic/p2-adrenergic receptor, such as 55К961081, А2О2115, and АБИ90792; (6) leukotriene modulators, such as leukotriene antagonists such as montelukast, zafirulast, or pranlukast, or leukotriene biosynthesis inhibitors such as Zileuton or VAU-1005, or GTV4 antagonists such as Amelubant, or EGAR inhibitors such as then SBK 2190914, AM-103; (7) phosphodiesterase-IM (POB-IM) inhibitors (oral or inhaled), such as roflumilast, cilomilast, oglemilast, OMO-6126,

Tetomilast, Tofimilast, OK 500,001, Z5K 256066; (8) antihistamines, such as selective histamine-7 (NO) receptor antagonists, such as fexofenadine, citirizine, loratidine, or astemizole, or dual NO1/NO receptor antagonists, such as Z5K 835726, B5K 1004723, or selective histamine receptor antagonists -4 (NU), somehow 2RI 3893787; (9) antitussives such as codeine or dextramorphan; (10), mucolytic agents, for example, M-acetylcysteine or fudosteine; (11) expectorant/mucokinetic modulator, eg, ambroxol, hypertonic solutions (eg, saline or mannitol), or surfactant; (12) mucolytic peptide, for example, recombinant; human deoxyribonuclease (domase-alpha and pOMavse) or helicidin; (13) antibiotics, such as azithromycin, tobramycin, and aztreonam; (14) non-selective COX-1 / COX-2 inhibitors, such as ibuprofen or ketoprofen; (15) COX-2 inhibitors such as celecoxib and rofecoxib; (16) MI A-4 antagonists, as described in MMO97/03094 and M/O97/02289; (17) TACE inhibitors and TME-o inhibitors, such as anti-TME monoclonal antibodies such as Remicade and COP-870, and receptor molecules

From immunoglobulin TME, such as Enbrel; (18) matrix metalloprotease inhibitors, for example, MMP-12; (19) inhibitors of human neutrophil elastase, such as OMO-6818 or described in MMO2005/026124,

UMO2003/053930 and M/006/082412; (20) A2b antagonists, as described in UMO2002/42298; (21) modulators of chemokine receptor function, for example, SSKZ and SSK8 antagonists; (22) compounds that modulate the action of other prostanoid receptors, for example, thromboxane A antagonist; ORI antagonists such as MK-0524, SKTN2 antagonists such as ОЮС9101 and ОС000459 and A2О1981, and mixed ORT/SKTNE2 antagonists such as AMO 009 and AMO853; (23) PRAC agonists, including

PPRAV-alpha-agonists (like fenofibrate), PPRAV-delta-agonists, PPRAGamma-agonists, like

Pioglitazone, Rsiglitazone and Balaglitazone; (24) methylxanthines such as theophylline or aminophylline and methylxanthine/corticosteroid combinations such as theophylline/budesonide, theophylline/fluticasone propionate, theophylline/uciclesonide, theophylline/mometasone furoate, and theophylline/beclomethasone dipropionate; (25) Aga agonists , as described in EP1052264 and EP1241176; (26) antagonists

СХСНа2 or 1-8, such as BSN 527123 or 5K 656933; (27) IC signaling modulators, such as Kineret and AC 885; (28) antagonists of MSR-1, such as AVIM-912.

The invention is also directed to a kit containing pharmaceutical compositions of the compounds of the invention as such or in combination with or admixed with one or more pharmaceutically acceptable carriers and/or excipients, and a device that can be a single or multi-dose dry powder inhaler, metered dose inhaler or nebulizer.

According to one approach of the claimed invention, a method of obtaining the compounds of the invention is proposed, according to the general methods of synthesis described in this section. In the following reaction schemes, unless otherwise indicated, the mentioned groups have the same values as reported for the compounds of formula (1).

A person skilled in the art can recommend suitable variants to the conditions specifically described in the experiments to adapt synthetic routes to provide further compounds of the invention.

Such options may include, but are not limited to, the use of suitable starting materials to produce different compounds, changes in the solvent and reaction temperature, substitution of reagents of similar chemical role, introduction or removal of protection/deprotection steps of functional groups sensitive to reaction conditions and reagents, and as well as the introduction or removal of specific stages of synthesis, focused on the further functionalization of the chemical framework.

The methods which can be used and which are described and reported in the examples and schemes should not be considered as limiting the synthetic methods available to obtain the compounds of the invention.

The described method, in particular, is conducive to appropriate modulation with respect to any suitable variant known to the person skilled in the art, in order to obtain any desired compounds of the invention. Such variants are covered within the scope of the claimed invention.

From all of the foregoing, it is clear to the skilled artisan that any of the groups described may be present as such or in any suitably protected form.

In particular, functional groups present in intermediates and compounds, and which may cause unwanted side reactions and by-products, require adequate protection against alkylation, acylation, conjugation or sulfonylation. Also, the subsequent deprotection of these protective groups can occur after the completion of the mentioned reactions.

In the claimed invention, unless otherwise indicated, the term "protecting group" means a protecting group adapted to preserve the function of the group to which it is linked. Typically, protecting groups are applied to preserve amino, hydroxyl, or carboxyl functions. Thus, suitable protecting groups may include, for example, benzyl, benzyloxycarbonyl, t-butoxycarbonyl, alkyl or benzyl esters, or the like, which are good |see common reference, T.M/. sgeep Rgoiesiime sgoiMyrz ip Ogdapis Zupipeviv (UMiIeu, M.U. 1981).

Also, selective protection and deprotection of any named groups, for example involving carbonyl, hydroxyl or amino groups, can be accomplished according to very well known methods commonly used in organic synthetic chemistry.

Optional formation of salts of compounds of formula (I) or M-oxyls on their pyridine ring can be done by appropriate conversion of any free acid or amino group to the corresponding pharmaceutically acceptable salts. In this case also, the operating conditions applied for the optional formation of salts of the compounds of the invention are all within the ordinary knowledge of the specialist.

From the foregoing, it is clear that the above-mentioned process, exhaustive of any option for obtaining suitable compounds of the invention, can be easily modified to adapt the reaction conditions to specific needs, for example, by choosing suitable condensing agents, solvents and protecting groups, depending on the circumstances.

For example, compounds of the invention of formula (I) can be obtained according to the route illustrated in scheme 1: o 2

Mo ra She u

SI U Ge) ran 2 1s1 SI i! 2 Sk)

Jan, with I book. Hk) "supply".

MI N

(a) in

Wa po)

M () 3o (12)

Scheme 1

Compounds of general formula (I) can be obtained from compounds of general formula (16) by reaction with a compound of general formula (1c1) or (162) in a suitable solvent, such as dimethylsulfoxide, 1,4-dioxane, DMF or acetonitrile, in the presence of a base, such as diisopropylethylamine or sodium hydroxide, in the temperature range, preferably between room temperature and 100 "C.

Compounds of the general formula (1c1) and (1c2) are known in the literature or can be obtained from amines of the general formula (14) according to procedures that are known from the literature (for example,

MO2006009741, ERT1609789, MO2008033999).

Alternatively, compounds of general formula (14) are known in the literature or can be synthesized by one skilled in the art by adapting suitable methods from the literature (e.g.

МО2010077836, МО2006009741, M/O2008125014, U. May Spet., 2007, 50, 4016, Vyieyyp dev zZosiyyez Spitidnez VeyYide5, 1987, 96, 675-709, Ogdapis 5 ViotoYesshag0404-15, 416, 415, 4016, 4016, 416, 416, 416, 416, 86, 8, 8, 8, 8, 8, 8, 4, 8, 8, 8, 4, 8, 8, 8, 8, 8, 1) )

Compounds of general formula (1da), i.e. compounds of formula (14), where Kg is a group of formula (IM) and "7, B'8, 21, 22, 73 and 77 are defined above, can be obtained from compounds of formula (1e),

in

M, 1 t MO, 18

And (c) using a suitable reducing agent, such as state (II) chloride, ferric or hydrogen gas, with a suitable catalyst, such as palladium on charcoal, in a suitable solvent, such as methanol, ethanol or acetic acid, in the range temperatures, preferably between room temperature and 100 "C.

Compounds of the general formula (Te) are known in the literature or can be obtained by a specialist in the art, using methods from the literature (for example, M/O 2008034008, UMO 20110189167, MO 2010068258).

Alternatively, the compounds of the general formula (1da), which are defined above, can be obtained from the compounds of the formula (15), where K'", B"8, 21, 22, 73 and 72" are defined above, and where PO is a suitable compatible protective a group known to one skilled in the art, such as benzyl, benzyl carbamate or tert-butyl carbamate, in

M 1 dynes 1 H 18 and (9) using suitable deprotection conditions, such as hydrochloric acid, trifluoroacetic acid, or hydrogen, catalyzed, for example, by palladium on carbon, in a suitable solvent, such as dichloromethane, methanol, ethanol, or acetic acid, in the temperature range, preferably between 0 "C and 100 26.

Compounds of the general formula (17 can be obtained by the reaction of the following compounds of the formula (19), where KK", B"8, 27, 22, 73 and 727 are defined above 17

AND

M 1 gas 18 NmM-ho Ya av RO dv with compounds of the formula (1) reported above, where RO is a suitable protecting group known to a person skilled in the art, such as benzyl, benzyl carbamate or tert-butyl carbamate, using suitable conditions , either in the presence of a base, such as potassium carbonate or diisopropylethylamine, or under conditions of Vispmalide (with a catalyst, such as RIA(OAc)), a ligand, such as 2,2-bisidiphenylphosphino)-1,1-binaphthyl , and a base such as sodium tert-butoxide) in a suitable solvent such as toluene or tetrahydrofuran in a temperature range, preferably between room temperature and 150 °C.

Compounds of the general formula (19) and (1) are known in the literature or can be obtained by a person skilled in the art by adapting suitable literature methods (for example,

MO2011042389, Spetivigu-A Epgoreap mildtai, 2011, 17, 6606-6609, 56606/1-56606/38).

Compounds of the general formula (1B) can be obtained according to the path illustrated in Scheme 2.

v' l (E. -dy MN (25) open! og

WITH

In the village in

From nN. , . m 12 M that in (ha) (15) og and d' xx aly

Scheme 2

Compounds of general formula (15) can be prepared from compounds of general formula (2a) by reaction with a compound of general formula (25), (2c) or (24), where b is a suitable chemical group known to one skilled in the art, which is chosen to facilitate a suitable coupling reaction, such as nucleophilic substitution or metal-catalyzed cross-coupling: For example, when Y is -O-, -5- or -MA"-, examples of C may include a halogen or a suitable leaving group such as a mesylate or triflate, connected directly or connected through the group - "SAZV) ..

Examples of coupling conditions used may include the use of a base such as sodium hydride or potassium tert-butoxide and 1,33-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in a suitable solvent such as M . can cover the conditions of Miizhypora (diethylazodicarboxylate/triphenylphosphine) in a suitable solvent such as tetrahydrofuran or 1,4-dioxane in the temperature range - preferably between -10 "C and 100 "C. For example, when U is -O-, - 5 - or -MA"- and b - group, such as halogen, triflate or boronic acid/ester, the method of carrying out this coupling may be under conditions of metal-catalyzed (for example, such as palladium or cuprum) coupling in the presence of a suitable ligand, as Xapyrpo5 or 1,10-phenanthroline, in the presence of a base, such as cesium carbonate in a suitable solvent, such as tetrahydrofuran, 1 ,4-dioxane or M,M-dimethylformamide, in the temperature range - preferably between -10 "C and 150 "C. For example, when U is -O- and b is a group such as -COOMEe, -COOH, isocyanate, -OSOCI, or -MNHSOOSNeCCi, examples of conditions for effecting this coupling may include the use of a base such as sodium hydride or triethylamine, or coupling reagent, as it were

NATY, in a suitable solvent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane or M, M-dimethylformamide, in the temperature range - preferably between -10 "C and 150 "C.

Compounds of formula (2B) are known in the literature, or can be obtained by a person skilled in the art by adapting suitable literature methods (for example, UMO 2006133006).

Compounds of formula (2c) can be obtained according to the path in scheme 3:

(c) noya (ZB1) (6) 1 9 (z3Bg) 2. HO 8 og - "M shu i sydy ra v Y t 1 schu

XX (For) you

Sho mn KE M

K- 2 o DY d? and in? M (for) baths

And WE what "M

With 12 M n in H (Zc) (Ze)

Scheme Z

Compounds of general formula (2c) can be prepared from compounds of general formula (Ce) reported above using a suitable oxidizing agent such as chloramine T, lead tetraacetate or phenyl iodo(I) diaacetate in a suitable solvent such as dichloromethane or ethanol, in the temperature range, preferably between room temperature and 100 "C.

Compounds of the general formula (Ze) can be obtained from compounds of the general formula (Za) by reaction with an aldehyde of the general formula (Cs) in a suitable solvent, such as ethanol or tetrahydrofuran, in a temperature range, preferably between room temperature and 80 °C.

Compounds of formula (Za) and (Zc) are known in the literature or can be obtained by a person skilled in the art by literature methods.

Alternatively, compounds of formula (2c) can be prepared from compounds of formula (39) using a suitable dehydrating agent, such as Vigde's reagent55, triphenylphosphine and hexachloroethane, phosphorus oxychloride, acetic acid, or Miizipoba conditions (diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in in the absence or presence of a suitable solvent, such as tetrahydrofuran, toluene or MMP, in the temperature range, preferably between room temperature and 120 76.

Compounds of formula (34) can be prepared from compounds of formula (Za) by reaction with a compound of general formula (301) using a suitable acylating/dehydrating agent such as triphenylphosphine/trichloroacetonitrile/"NOVU2-(7-aza-1H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.- in the presence of a base such as diisopropylethylamine in a suitable solvent such as dichloromethane or acetonitrile in temperature range, preferably between room temperature and 150 "C.

Alternatively, compounds of formula (3a) can be prepared from compounds of formula (Za) by reaction with a compound of general formula (3602) in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane or THF, in a temperature range, preferably between - 10 "C and the boiling point of the solvent.

Compounds of formulas (ZB1) and (3602) are known in the literature or can be obtained by a person skilled in the art by adapting suitable literature methods.

From the compound of formula (24) can be obtained according to the path in scheme 4:

(c) nov (461) o ve 10 (4rg) atscho g Do y z

SI in the "MN 13 (E. M She in': hK N he s HU TI s hek (4a) but you (ha)

Study; pru a xx M (4c) (4e)

Scheme 4

Compounds of general formula (294) can be prepared from compounds of general formula (4e) using a suitable oxidizing agent such as chloramine T, lead tetraacetate or phenyl iodo(P)diaacetate in a suitable solvent such as dichloromethane or ethanol over a range of temperatures , better - between room temperature and 100 "С.

Compounds of general formula (46) can be obtained from compounds of general formula (4a) by reaction with an aldehyde of general formula (4c) in a suitable solvent, such as ethanol or tetrahydrofuran, in a temperature range, preferably between room temperature and 80°C.

Compounds of formulas (4a) and (4c) are known in the literature, or they can be obtained by a person skilled in the art by literature methods.

Alternatively, compounds of formula (24) can be prepared from compounds of formula (484) using a suitable dehydrating agent, such as Vigde's reagent55, triphenylphosphine and hexachloroethane, phosphorus oxychloride, acetic acid, or the conditions of Miizipoba (diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in in the absence or presence of a suitable solvent, such as tetrahydrofuran, toluene or MMP, in the temperature range, preferably between room temperature and 120 76.

Compounds of formula (44) can be prepared from compounds of formula (4a) by reaction with a compound of general formula (4601) using a suitable acylating/dehydrating agent, such as triphenylphosphine/trichloroacetonitrile/"NEW/2-(7-aza-1H-benzotriazole) -1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in the presence of a base such as diisopropylethylamine in a suitable solvent such as dichloromethane or acetonitrile , in the temperature range, preferably between room temperature and 150 "С.

Alternatively, compounds of formula (44) can be prepared from compounds of formula (4a) by reaction with a compound of general formula (402) in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane or THF, in a temperature range, preferably between - 10 7 and the boiling point of the solvent.

Compounds of formulas (4601) and (402) are known in the literature or can be prepared by one skilled in the art by adapting suitable literature methods.

Alternatively, compounds of formula (2c) can be obtained according to the route in scheme 5: i H se av V a. 2 a ri (Be) a ro what y y ly х d'? M d'? shh d'? M (for) (55) (ge)

Scheme 5

Compounds of the general formula (2c) can be obtained by the reaction of compounds of the general formula (55) where 2 is a group, such as a halogen, with compounds of the general formula (5c), where 3 is a group such as a halogen, boronic acid, boronic acid ester or an organostannane using a cross-coupling method such as a suitable catalyst such as tetrakistriphenylphosphine)palladium(0) or palladium(II) acetate in the presence of a base such as cesium carbonate or sodium tert-butoxide in a suitable solvent such as toluene or DMF, in the temperature range, preferably between room temperature and 150 "С.

Compounds of formula (55) can be prepared from compounds of general formula (5a) using, for example, a suitable halogenating agent such as M-bromosuccinimide or M-iodosuccinimide in a solvent such as DMF or tetrahydrofuran in a temperature range preferably - between room temperature and 100 "C.

Compounds of formula (5a) can be obtained from compounds of general formula (Za) using a reagent, such as triethyl orthoformate, in the absence or presence of a solvent, such as ethanol, under neutral, alkaline or acidic conditions, in a range of temperatures, preferably room temperature temperature - 100 "C. Compounds of formula (A) can be obtained as described above.

It should be noted that the methods described in Scheme 5 can be adapted by one skilled in the art to provide a compound of formula (24) using compounds of formula (4a).

Compounds of the general formula (2aa), that is, compounds of the formula (2a), where У-О and М/-МН, can be obtained according to the path illustrated in scheme 6: o. m p! o, (6) bai o, and od zr

M Not bb (65) yu. (gag)

N

BUT, (bug)

Scheme 6

For example, compounds of the general formula (2aa;) can be obtained as described in

MMO2008/043019. Compounds of general formula (2aa) can be prepared from compounds of general formula (ba1) or (bag) where RO is a suitable protecting group (such as trifluoroacetate or tert-butylcarbamate) known to the person skilled in the art by applying suitable deprotection conditions such as sodium hydroxide in methanol and water or trifluoroacetic acid in dichloromethane.

Compounds of general formulas (ba1) and (bag) can be obtained from compounds of general formula (66B).

Compounds of the general formula (bai), where PO is amide, preferably trifluoroacetamide, can be obtained from compounds of the general formula (65), which are described in M/02008/043019, using

VysI(5, 5-Tzarep(p-cymene)).

Compounds of the general formula (bag), where PO is amide, preferably trifluoroacetamide, can be obtained from compounds of the general formula (65), which are described in M/02008/043019, using

VysSIA, V-Tzarep (p-tsymen)|. It should be understood that the compounds of formula (66) may be homochiral as illustrated, or be the opposite enantiomer or racemic.

One of skill in the art should understand that any combination of stereocenters in (2a) is possible

Zo is obtained by using both enantiomers (65) and using KyCsSi(E, K-T5zarep(p-cymene)) or Kysi|(5, 5-T5zarep(p-cymene)y. Compound (2aa) is depicted without definition of stereocenters, but any combination thereof can be obtained as illustrated in scheme 2.

Compounds of formula (6B) can be obtained from compounds of formula (6bs)

Ro. Hugh

M (bs) using a suitable oxidizing agent such as potassium permanganate and magnesium sulfate in a suitable methanol/water solvent in the temperature range, preferably between room temperature and the boiling point of the solvent. It should be understood that the compounds of formula (bs) may be homochiral as illustrated, or be the opposite enantiomer or racemic.

Compounds of formula (bs) can be obtained from compounds of formula (64), where PO is a suitable protecting group, such as trifluoroacetate or tert-butyl carbonate:

HO nom (va)

using ethyl trifluoroacetate or di-tert-butyl dicarbonate in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as methanol or dichloromethane in a temperature range, preferably between 0 C and the boiling point of the solvent. It should be understood that the compounds of formula (64) may be homochiral, as illustrated, or be the opposite enantiomer or racemic.

Compounds of formula (64) are known in the literature and can be prepared by a person skilled in the art by adapting literature methods (for example, for 5-(-)-1-amino-1,2,3,4-tetrahydronaphthalene, see docsigpa!oi Spetis! bosieiu , RezhZip Thapzasiopv 1: 1985, 2039-44, for (5)-(-)-8-amino-5,6,7,8-tetrahydroquinoline see Chuoigpa!oi Ogdapis Spetivigu, 2007, 72, 669-671 and for 1 - aminoindan, see Teigapeagop GI etseg5, 2011, 52, 1310-1312)

Compounds of formula (IB), that is, compounds of formula (I) where M-MK" and UM-MN and A, K", Be, and KK are defined above, can be obtained according to the route illustrated in scheme 7.

NM. di (7e) e-v' ! (7)

IN

NM. and (st) o in (Fo00-- (huya -----zh (bu -- x4hya BO), and

RO Sun N

In (t) (75) (IB)

MN, (79 bod (tv) (25), (ge), (24) they sho

Rodu -- I - - Ro i - 9 - (va) t (79)

Scheme 7

The compounds of the general formula (IB), which are defined above, can be obtained from the compounds of the general formula (75), where MAMA" and M/-MH, by reaction with a compound of the general formula (1c1) in a suitable solvent, such as dimethylsulfoxide, 1,4 -dioxane, DMF or acetonitrile, in the presence of a base such as diisopropylethylamine or sodium hydroxide, in the temperature range, preferably between 0 "C and 100 76.

Compounds of general formula (75) can be obtained from compounds of general formula (7a), where

U-MA and MU-MN and where PO is a suitable protecting group such as trifluoroacetamide, tert-butylcarbamate or benzylcarbamate using suitable deprotection conditions such as sodium hydroxide in methanol, trifluoroacetic acid in dichloromethane or hydrogen catalyzed , for example, palladium on charcoal in ethanol, in the temperature range, preferably between 0 "С and 100 70.

Compounds of general formula (7a) can be prepared from compounds of general formula (74) and (66) using a suitable reducing agent such as sodium triacetoxyborohydride or sodium borohydride in a suitable solvent such as 1,2-dichloroethane, methanol or acetic acid acid, in the temperature range, better - between 0 "C and 100 76.

Alternatively, compounds of general formula (7a) can be obtained from general compounds

From formulas (7a) and (79), where RO is a suitable protecting group known to those skilled in the art, such as trifluoroacetamide, tert-butylcarbamate, and benzylcarbamate, and 5 is a suitable chemical group known to those skilled in the art chosen to facilitate the reaction , such as nucleophilic substitution, for example, of a halogen or oxygen atom, which has a suitable substituent, such as a mesylate or triflate. Using a suitable base such as diisopropylethylamine or potassium carbonate in a suitable solvent such as DMF, tetrahydrofuran or acetonitrile in a temperature range, preferably between 0°C and 100°C.

Compounds of formula (79) may be prepared from compounds of formula (ba) using conditions such as carbon tetrabromide and triphenylphosphine or methanesulfonyl chloride and diisopropylethylamine in a suitable solvent such as dichloromethane or acetonitrile in a temperature range, preferably between 0 and 100 "S.

Alternatively, compounds of formula (7a) can be obtained from compounds of general formula (7p)

by reaction with (25), (2c) and (29), optionally in the presence of a catalyst, such as cuprum (I) iodide or tris(dibenzylideneacetone)dipalladium(0), optionally in the presence of a ligand, such as 2 ,2- bisidiphenylphosphino)-1,1-binaphthyl using a base such as diisopropylethylamine, sodium tert-butoxide or sodium hydride in a solvent such as DMF, toluene or tetrahydrofuran in a temperature range, preferably between room temperature and 150 "S.

Compounds of formula (7p) can be obtained from compounds of formula (7K) by reaction with compounds of formula (65); where PO is a suitable protecting group known to one skilled in the art, such as trifluoroacetamide, tert-butylcarbamate and benzylcarbamate. A suitable reducing agent such as sodium triacetoxyborohydride or sodium borohydride in a suitable solvent such as 1,2-dichloroethane, methanol or acetic acid was used in a temperature range, preferably between 0°C and 100°C.

Alternatively, compounds of formula (7n) can be obtained from compounds of formula (7K) using compounds of formula (74); where PO is a suitable protecting group known to those skilled in the art, such as trifluoroacetamide, tert-butylcarbamate, and benzylcarbamate, and 55 is a suitable chemical group known to those skilled in the art chosen to facilitate a nucleophilic substitution reaction, such as a halogen or an oxygen atom , which has a suitable substituent such as mesylate or triflate using a suitable base such as diisopropylethylamine or potassium carbonate in a suitable solvent such as DMF, tetrahydrofuran or acetonitrile in a temperature range, preferably between 0 °C and 100 70 .

Compounds of general formula (74) can be obtained from compounds of general formula (7e) and (77), where c? - a suitable chemical group known to one skilled in the art is chosen to facilitate a nucleophilic substitution reaction such as a halogen or an oxygen atom bearing a suitable substituent such as a mesylate or triflate using a suitable base such as isopropylethylamine or potassium carbonate , in a suitable solvent, such as DMF, tetrahydrofuran, or acetonitrile, in a temperature range, preferably between 0 "C and 100 C.

Compounds of formulas (7e) and (75) are known in the literature, or they can be obtained by a specialist in the art by applying literature procedures (for example, Ogdapis I etsegv5, 2002, 4, 3423-3426).

Compounds of the formula (1Bba), that is, compounds of the formula (15), where M is (SARA); and UU-MN, can be obtained according to the path illustrated in scheme 8.

B-y-B(He), oti (Vi) (huya (66) ------ oh, -- 7 (va) (85) hundred WILD

RO. in Well

Mon (Sun) (1ba)

Scheme 8

Compounds of formula (1ra) can be obtained from compounds of formula (8c), where RO is a suitable protecting group known to a person skilled in the art, such as trifluoroacetamide, tert-butylcarbamate, and benzylcarbamate, using suitable deprotection conditions, such as sodium hydroxide in methanol, trifluoroacetic acid in dichloromethane or hydrogen gas, catalyzed, for example, by palladium on carbon in ethanol, in the temperature range, preferably between 0 "C and 100 76.

Compounds of formula (8c) can be prepared from compounds of formula (85) where RO is a suitable protecting group known to those skilled in the art, such as trifluoroacetamide, tert-butylcarbamate, and benzylcarbamate by using hydrogen gas in the presence of a catalyst such as palladium on coal, in a suitable solvent, such as methanol or ethanol, in the presence or absence of an acid, such as NOCI, in a temperature range, preferably between 0 "C and 100 70.

Zo

Compounds of formula (85) can be prepared from compounds of formula (a) and (8) by a reaction, such as cross-coupling, using a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0) or palladium acetate, and a base, such as diisopropylethylamine, sodium tert-butoxide or cesium carbonate, in a suitable solvent such as MMP, toluene or

DMF, in the temperature range, is better - between 0"C and 100"C. Alternatively, (85) can be obtained by adapting literature procedures (for example, reported in UMO2009022633).

Compounds of formula (81) are known in the literature or can be obtained by a person skilled in the art by adapting literature procedures (for example, UMO 2008063287).

Compounds of formula (8a) can be prepared from compounds of formula (65) using a triflating agent such as triflic anhydride in the presence of a suitable base such as pyridine or 2,6-bis(tert-butyl)-4-methylpyridine , in a solvent, such as dichloromethane or chloroform, in a temperature range, preferably between 0"C and the boiling point of the solvent. Alternatively, (va) can be obtained by adapting literature procedures (for example, described in UMO2009022633).

Compounds of the invention of the formula (Id), that is, the compound of the formula (I), where U-O and MO and K",v2, as defined above, can be obtained according to the route illustrated in scheme 9.

H 7 tyn o odi on: Od ---ls- - - 2

Well, Ivan

N

(For) (95) (a)

Scheme 9

Compounds of general formula (14) can be obtained from compounds of general formula (95), where

UO and MO and (940) where c" is a suitable chemical group such as halogen or alkoxy using a suitable base such as diisopropylethylamine, potassium carbonate or sodium hydride in a suitable solvent such as DMF, tetrahydrofuran or acetonitrile , in the temperature range, better - between 0 C and 100 76.

The compound of formula (96) can be obtained from compounds of formula (9a) and (25), (2c), or (29).

Compounds of formula (9a) are known in the literature, and they can be obtained by a person skilled in the art by adapting literary methods (for example, Apdeul"apage Spitie, Ipegpaiopa! Eayiop, 2006, 45, 98-101 apa Spitia, 2007, 61, 169-171) .

Compounds of formula (94) are known in the literature and can be obtained by a person skilled in the art using literature methods. Alternatively, compounds of formula (94) can be prepared from compounds of formula (14) using alkyl chloroformate, dialkyl anhydride or phosgene

It is optional in the presence of a base, such as sodium hydroxide or diisopropylethylamine, in a solvent, such as dichloromethane, dioxane, or tetrahydrofuran, in a temperature range, preferably between 0 "C and the boiling point of the solvent.

Compounds of formula (ii), i.e. compounds of formula (I), where M-5:5 and МУ-МН, can be obtained according to the path illustrated in scheme 10: o Из

Vg 8 5 o, ZK o ze one one ode NO (1ba) (1065) (10s) (109) O ov) u (u (v), (gs)og(ha) I v Hv s o u rai , r shchi s "v! shchi - shchi -KA Z ot vi nai - cho), 6) o N poyu) (109) mon) (is)

Scheme 10

Compounds of the general formula (Ie) can be obtained from compounds of the general formula (10PY), where y-5 and UMAMN: using compounds of the formula (1c1) or (1c2) in a suitable solvent, such as dimethylsulfoxide, 1,4-dioxane, M, M-dimethylformamide or acetonitrile, in the presence of a base such as diisopropylethylamine, in a temperature range, preferably between room temperature and 100 76.

Compounds of formula (10), where U-5 and UUM-MN, can be obtained from compounds of formula (109) using deprotection conditions, such as hydrazine in methanol, in the temperature range, preferably between room temperature and the boiling point of the solvent.

Compounds of formula (109) where U is 5 can be prepared from compounds of formula (105) by reaction with compounds of formulas (25), (2c) or (24). Examples of the coupling conditions used may include the use of a base such as sodium hydride or potassium tert-butoxide and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, in a suitable solvent such as M,M-dimethylformamide, toluene, 1,4-dioxane or acetonitrile, in the temperature range, preferably between room temperature and 150 °C. Alternative methods of applying this coupling may include Miihypoba (diethylazodicarboxylate/triphenylphosphine) conditions or metal-catalyzed (e.g., palladium) coupling conditions in a suitable solvent such as tetrahydrofuran or 1,4 -dioxane, in the temperature range, preferably between -10 "C and 150 C.

Compounds of formula (10) can be obtained from compounds of formula (10e) using dithiothreitol, monopotassium phosphate, potassium carbonate in a solvent, such as methanol, in the presence of acetic acid, in a temperature range, preferably between room temperature and the boiling point of the solvent.

Compounds of formula (10e) can be obtained from compounds of formula (104) using 2-nitrobenzenesulfonyl chloride in acetic acid, in the temperature range, preferably between room temperature and 100 "С.

Compounds of formula (104) can be obtained from compounds of formula (10c) using phthalimide, triphenylphosphine and diisopropyl azodicarboxylate in a solvent such as tetrahydrofuran in a temperature range, preferably between 0 "C and the boiling point of the solvent.

Compounds of formula (10c) can be obtained from compounds of formula (10B) using a reducing agent, such as sodium borohydride, in a solvent, such as methanol, in a temperature range, preferably between 0 "С and the boiling point of the solvent.

Compounds of formula (106) can be obtained from compounds of formula (10a) using tert-butanethiol in the presence of a base, such as diisopropylethylamine, in a solvent, such as tetrahydrofuran, in a temperature range, preferably between 0 "С and the boiling point of the solvent.

Compounds of formula (10a) are known in the literature and can be obtained by a person skilled in the art,

Z using methods from the literature (for example, Z-bromo-indan-1-one, see UMO 2010108058)

Alternatively, compounds of general formula (165), i.e. compounds of formula (15), where X-CH" and

UAMN, can be obtained according to the path illustrated in scheme 11: odi odi OD

RO. RO. Rodu (ba) a) (115) (ku v'

Sun (165)

Scheme 11

Compounds of general formula (105) can be obtained from compounds of general formula (1165) by removal of the Po protecting group using known methods, such as aqueous sodium hydroxide, in a solvent such as methanol, in a temperature range, preferably between room temperature and 100 76.

Compounds of formula (115) can be prepared from compounds of general formula (11a) by reaction with a suitable reducing agent, for example, hydrogen gas in the presence of a suitable catalyst, such as palladium, on activated carbon, in a suitable solvent, such as ethanol, over a range of temperatures between room temperature and at 70 "C, and pressures between atmospheric and 4 bar.

Compounds of formula (1142) can be prepared from compounds of general formula (ba) by reaction methods such as MMiSHNid (or one of the close variants, such as Nogpeg-U/azumopy-Ettop5) with a suitable substrate, such as Ke'-CH2 -P(IOCHOMEe)»g, in the presence of a suitable base, such as sodium hydride, in a suitable solvent, such as tetrahydrofuran, in a temperature range, preferably between -10 C and 100 "C.

Compounds such as E"-CH"-P(FOHOMEe)2 can be synthesized from compounds of the general formula K'-CHe-

Na), where Nai is a halogen, such as -Vg or -Si, by reaction with a compound, such as trimethyl phosphate, in the temperature range, preferably between 0 "С and 100 70.

Compounds such as К'-СНо-Най can be synthesized from compounds of the formula К!-СН by reaction methods such as circular halogenation using a reagent such as M-bromosuccinimide in the presence of a catalyst such as AIVM in a suitable solvent, such as carbon tetrachloride, in the temperature range, preferably between 0 "C and 80 "C. Compounds such as К'-СНо-Най can also be synthesized from compounds of the formula К'-СНо-ОН by means of halogenation conditions, such as carbon tetrabromide and triphenylphosphine in dichloromethane, or activation conditions, such as methane sulfonyl chloride in dichloromethane, in the presence of a base such as diisopropylamine.

Compounds such as K"-CH3 and K"-CH".AON can be obtained by the methods described above for compounds (260), (2c) and (289).

Abbreviations used in the experimental section: ASON - acetic acid; hell. - aq.;

DCM - dichloromethane; SIAYU "- diisopropyl azodicarboxylate; OIREA - diisopropylethylamine;

OMARA-M, M-dimethylaminopyridine; dMF E M, M-dimethylformamide; DMSO E dimethylsulfoxide; EOS-1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrogen chloride; ЕХАСС - ethyl acetate; ETON - ethanol; EBO - diethyl ether; EizM - triethylamine; EiMiRg2 "- diisopropylethylamine; ECC - flash chromatography on a column; th - hour; NATI-2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetraamethyluronium hexafluorophosphate; nNOVve-1-hydroxybenzotriazole; HPLC - high performance liquid chromatography; IM5 - industrial methylated alcohols; РХМСО - liquid chromatography mass spectrometry; Mahon - sodium hydroxide; MeSM - acetonitrile; MEON-Meon; waves - minutes; МНз - ammonia; NMR - nuclear magnetic resonance;

CT - room temperature; CI - retention time; satiated - saturated; 5СХ-2 - strong cation exchange chromatography; TFOC - trifluoroacetic acid; THF - tetrahydrofuran; NGO - water; IM5 - industrial methylated alcohol; Hapyrpo5-4,5-bisb(idiphenylphosphino)-9,9-dimethylxanthene; X-5eiIesi - water X-selective HPLC column; IRA - propan-2-ol; And VA - lithium diisopropylamide; MOAR - mass-directed self-cleaning; MeoOH - methanol; RizR - triphenylphosphine; TVAE - tetrabutylammonium fluoride.

In the following procedures, reference to the intermediate/example number is usually applied after each starting material. This is proposed only to assist the specialist chemist. The starting material is not necessarily obtained from the described portion.

When reference is made to the use of a "similar" or "analogous" procedure, as would be understood by one of ordinary skill in the art, such procedure may include minor variations, such as the following: reaction temperature, amount of reagent/solvent, reaction time, conditions provided, or chromatographic purification conditions .

The nomenclature of the structures was determined using the Ashiopot 2000 software

Mate zoymzhage iot MY Ips. When the nomenclature of the structures was determined without using the Aitsiopot software, ASO/Mate Zoimage used useful parts from

ASOLARE KeIveaze 12.00 Rgodisi Megwiop 12.5 (Review 45133, 16 July 2010). Stereochemical interpretations of compounds are based on comparisons with data reported in UMO2008/043019 for key intermediates. All reactions were performed under anhydrous conditions and under a nitrogen or argon atmosphere, unless otherwise indicated. Unless otherwise specified, all conversions were made at ambient (room temperature) temperature.

The NMR spectrum was obtained on a Magiap Opyu Ipoma 400 5 resigoteseg spectrometer with a 5 mm triple resonance inversion detection probe operating at 400 MHz or on a Vgykeg Amapse OKH 400 5 resigoteseg spectrometer with a 5 mm triple resonance TCI inversion detection probe operating at 400 MHz, or on a VgyKkeg Amapse OPX 300 resolution spectrometer with a standard 5 mm dual frequency dual probe operating at 300

MHz. Landslides were received in millions! relative to tetramethylsilane (b - 0 million"). The values of .) are given everywhere in Hz. NMR spectra were determined using BagaStoga Zresigit Apaiuvzi Megviop 4.0.021 or Zripumogk5 Megviop 3.

If the products were purified by flash column chromatography, "flash silica" refers to silica gel for chromatography, 0.035 - 0.070 mm (220 - 440 mesh) (eg, silica gel 60 RiIyKa), and applied nitrogen pressure up to 10 psi square inch of accelerated column elution, or the use of the SotriBiazpF purification system

Sotrapiop or the use of the cleaning system Vioiade 5RI. All commonly recognized solvents and commercial reagents were used.

Compounds purified by preparative HPLC were purified using a C18 reversed-phase column (100 x 22.5 mm inner diameter, Sepebvi5 column with a particle size of 7 µm) or a Rpepu!-Nehui column (250 x 21.2 mm inner diameter diameter, Septipi column with a particle size of 5 μm), UV detection 220-254 nm, flow rate 5-20 ml/min.), eluting with gradients of 100-0 - 0-100 95 water/acetonitrile (containing 0.1 95 TFOC or 0.1 95 formic acid) or water/Meon (containing 0.1 95 TFOC or 0.1 95 formic acid), or a C18-reversed-phase column (19 x 250 mm, HVgidde OVO, with a particle size of 5 µm ), eluting with gradients of 100-0 - 0-100 95 water/acetonitrile (containing 0.1 95 MNAOH); or a SpigaIRak IC column (10 x 250 mm, inner diameter, with a particle size of 5 µm), unless otherwise specified. Fractions containing the desired product (identified by HPLC analysis) were combined, the organic solvent was removed by evaporation, and the remaining aqueous residue was lyophilized to give the final product.

Products purified by preparative HPLC were isolated as the free base, formate, or TFOC salts unless otherwise stated.

Applied systems: liquid chromatography - mass spectrometry (LCMS) and HPLC:

Method 1

Mass spectrometer Umayege Riachogpt C Ocaidgyroie with a C18-reversed-phase column (30 x 4.6 mm Rpepotepeh Hypa Z μm particle size), elution with the help of A: water and 0.1 95 formic acid; In: acetonitrile 0.1 956 formic acid. Gradient:

Gradient - Time flow ml/min. UA chUoV 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5

Determination - MS, EI5 (spectroscopy of energy loss of electrons), UV (200 μl split before MS with a current detector NRI100 AB). the method of Me-ionization is electrospraying (positive and negative ion).

Method 2

Quadrupole mass spectrometer Umaieg5 2MO with C18-reversed-phase column (30 x 4.6 mm Rpepotepeh I ipa, 3 μm particle size), elution A: water "with 0.1 96 formic acid; In: acetonitrile -- 0.1 96 formic acid. Gradient:

Gradient - Time flow ml/min. UA chUoV 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5

Determination - MS, EI 5, UV (200 μl split before MS with a current detector UmMaieg5 996 rAB). The method of Me-ionization is electrospraying (positive and negative ion).

Method C

Quadrupole mass spectrometer Umaieg5 2MO with C18-reversed-phase column (30 x 4.6 mm Rpepotepeh I ipa, 3 μm particle size), elution A: water "with 0.1 96 formic acid; In: acetonitrile and 0.1 95 formic acid. Gradient:

Gradient - Time flow ml/min. UA chUoV 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5

Determination - MS, EI 5, UV (200 μl split before MS with a current detector НР1100 раб). The method of Me-ionization is electrospraying (positive and negative ion).

Method 4

MO Ryatsnogt II quadrupole mass spectrometer with C186-reversed-phase column (30 x 4.6 mm Rpepotepeh I ipa, 3 μm particle size), elution with A: water «x 0.1 96 formic acid;

In: acetonitrile 0.1 95 formic acid. Gradient:

Gradient - Time flow ml/min. UA chUoV 0.00 2.0 95 5 0.30 2.0 95 5 4.30 2.0 5 95 5.30 2.0 5 95

5.80 2.0 95 5 6.00 2.0 95 5

Determination - MS, E!/5, UV (200 μl/min. cleave to leakage E5I with current detector NRITIO50 AB). The method of Mse-ionization is electrospraying (positive and negative ion).

Method 5

Quadrupole mass spectrometer Umaieg5 tisgotav55 202000 with Asdiyu VEN C18 1.7 μm 100 x 2/1 mm, Asdiyu VEN 5Pieia ER18 1.7 μm 100 x 2.1 mm or Asdiyu NZ5TZ 1.8 μm 100 x 2.1 mm, kept at 40 °C. Elution with A: water and 0.1 96 formic acid; B: acetonitrile and 0.1 95 formic acid. Gradient:

Gradient - Time flow ml/min. UA chUoV 0.00 0.4 95 5 0.40 0.4 95 5 6.00 0.4 5 95 6.80 0.4 5 95 7.00 0.4 95 5 8.00 0.4 95 5

Definition - MS, UV ROA. the method of Me-ionization is electrospraying (positive and negative ion).

Method 6

C18-reverse-phase column Rpepotepeh Septipi (250 x 21.20 mm, 5 μm particle size), elution with A: water "x 0.1 95 formic acid; In: СНзСМ--0.1 95 formic acid. Gradient - 90 95 A/10 95 V to 2 95 A/98 956 V after 20 min. - flow rate 18 ml/min. Definition - a current UV detector at a wavelength of 254 nm.

Method 7

Limitless cleaning system Adiyepi 1260. Column: ХЕ ЕСТ С5Н Ргер С18 OVO, particle size 5 μm, 30 x 150 mm, CT. Elution from A: water and 0.195 formic acid; IN:

СНаСМ--0.1 95 formic acid. Gradient - 90 95 A/10 95 V to 2 95 A/95 95 V after 22 min. - flow rate 60 ml/min. Definition - The current single Adiyepi 6100 series is quadrupole

RH/MS.

One skilled in the art will understand that the term "partial formate salt" is used to refer to derivatives where only a portion of the parent compound has been converted to a formate salt, and therefore which contains less than one equivalent of the formate counterion. The proposed exact salt/free base ratio is related to the MM5 analysis.

Example 1 1-(5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl)-3-K15, 4H)-4-(3-isopropyl-

P1,2,4Hygriazoloi|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea then in the winter

From NN

Ome

From a. 2,2,2-Trifluoro-M-(5)-1,2,3,4-tetrahydro-naphthalen-1-yl-acetamide (intermediate Ta)

E (c) art

E Nn

Ethyl trifluoroacetate (24.2 mL, 204 mmol) was added dropwise to a solution of (5)-(1,2,3,4-tetrahydro-naphthalene-1-ylluamine (AMa Aesag; 25.0 g, 170 mmol)) and triethylamine ( 35.5 mL, 255 mmol) in MeOH (250 mL) at RT and stirred for 18 h. The mixture was concentrated to approximately 1/3 of its volume and then partitioned between DCM (200 mL) and water (200 mL) . The aqueous layer was extracted into DCM (3x), and the combined organic layers were washed with brine, dried (M9505) and concentrated in vacuo to give the title compound (41.1 g, 169 mmol, 99 95).

NMR (400 MGu, SOSI"): 1.80-1.95 (ZH, t), 2.05-2.15 (1H, t), 2.75-2.90 (2H, t), 5, 18-5.25 (IN, 9, U 5.0 Hz), 6.38-6.48 (1H, Bi 5), 7.12-7.16 (1H, t), 7.20-7, 26 (ZN, t).

r. 2,2,2-Trifluoro-M-((5)-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide (intermediate 1B) (c) (c)

E E zu

IS

Magnesium sulfate monohydrate (46.6 g, 338 mmol) in water (500 mL) was added to an ice-cooled solution of Intermediate Ta (41.1 g, 169 mmol) in acetone (1.0 L). Potassium permanganate (80.1 g, 507 mmol) was added in measured portions (10.0 g portions) over a period of 45 min. The mixture was then stirred for 18 h. Sodium thiosulfate pentahydrate (126 g, 510 mmol) in water (400 mL) was added and the reaction was stirred for 30 min. The mixture was concentrated to approximately 300 ml, then water (1.0 L), Celite (60 g) and EtOAc (1.0 L) were added sequentially. The mixture was thoroughly mixed and then filtered through a celite pad. The aqueous layer was extracted into EtOAc (3 x), and the combined organic layers were washed with brine, dried (Md 5 O 5 4 ) and concentrated in vacuo to give the title compound (36.6 g, 142 mmol, 84 95). "H NMR (400 MHz, SOSI"): 2.20-2.30 (IN, aada, at 13.3, 10.0, 8.8, 4.5 Hz), 2.43-2.52 ( 1H, aadai, U 13.3, 7.2, 4.6, 4.6 Hz), 2.67-2.77 (1H, ada, 9 17.4, 10.1, 4.6 Gu), 2.78-2.88 (1H, aaa, 9 17.4, 7.1, 4.6 Hu), 5.39-5.47 (1H, y, 8.5, 4.5 Hu), 7 ,32-7.37 (1H, a, 9 7.7 Hz), 7.44-7.49 (YAN, i, U 7.6 Hz), 7.59-7.64 (1H, i, U 7.6, 1.4 Hu), 8.03-8.07 (1H, ad, 9 7.7, 1.4 Hz). p. 2,2,2- Trifluoro-M-(15, 4nH) -4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide (intermediate 1c) one (c)

E E u

IS

Degassed DMF (argon purged, 100 mL) was added to intermediate 10 (8.00 g, 31.3 mmol) and (M-KIA, 28)-2-(amino-kMm)-1,2-diphenylethyl|-4- methylbenzene sulfonamidato-kM|chloro|(1,2,3,4,5,6-p)-1-methyl-4-(1-methylethyl)benzene|-ruthenium (Zyget SVpetisai5 Ips.; 594 mg, 0.93 mmol). Triethylamine (8.66 mL, 62.6 mmol) was slowly added to the ice-cooled formic acid (2.34 mL, 62.6 mmol) and stirred for 20 min., then this was added to the DMF solution. The reaction was heated to 60 °C for 18 h. After cooling, the mixture was partitioned between DCM (200 mL) and water (600 mL). The aqueous layer was extracted with DCM (3x), and the combined organic layers were washed with brine, dried (M95O) and concentrated in a vacuum

Purification of ES using 0-100 906 EAs in cyclohexane afforded the title compound (7.10 g, 27.4 mmol, 88 95). "H NMR (400 MHz, SOSI"): 1.88-1.92 (1H, a, U 4.68 Hu), 1.98-2.18 (4H, t), 4.80-4.88 (1H, t), 5.165-5.24 (1H, t), 6.70-6.680 (1H, Bug 5), 7.25-7.30 (IN, t), 7.30-7.40 ( 2H, t), 7.45-

Koo) 7.50 (1H, t). and. (18, 45)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-ol (intermediate 14) he -

Sodium hydroxide (2.10 g, 53.0 mmol) was added to an ice-cooled solution of intermediate 1c (3.43 g, 13.2 mmol) in MeOH/water (2:11, 50 mL) and stirred for 3.5 h .

The mixture was loaded into a 5СХ-2 cartridge, eluting with MeonH, then - 2M MHz in MeonH, which gave the title compound (2.30 g, 13.2 mmol, 99 95). "H NMR (400 MHz, de-DMSO): 1.66-1.90 (4H, t), 3.71- 3.77 (IN, i, U 5.4 Gu), 4.46-4, 54 (IN, 1, U 5.4 Gu), 7.14-7.22 (2H, t), 7.32-7.38 (1H, t), 7.40-7.46 (1H, t ). e. Isobutyric acid M'-(5-fluoro-pyridin-2-yl)-hydrazide (intermediate Te)

IS

MN

J. M

Mo

To a solution of 5-fluoro-2-hydrazinyl-pyridine (ref. see M/O2010022076; 2.08 g, 16.4 mmol), isobutyric acid (1.82 mL, 19.6 mmol), and NOVI hydrate (251 mg, 1.64 mmol) in DCM (50 mL) was added EOS (3.76 g, 19.6 mmol), and the resulting orange solution was stirred at room temperature for 18 h. Saturation was added. aq. NaHCO3 (50 mL), and the mixture was vigorously stirred for 15 min. Organics were washed with sat. aq. MnSO 3 (50 mL), passed through a hydrophobic frit and concentrated in vacuo to leave a pale brown solid. The solid was suspended in ESO (50 mL) and filtered, washing

EtOH (25 mL), which left a white solid (1.48 g, 46 95). The ether washings were concentrated in vacuo and the residue suspended in ESO (10 mL), filtered, washed with ESO (2 x 2 mL) to leave a white solid (330 mg, 10 95). The solids were combined (1.81 g, 56 95). "H NMR (400

MHz, SOS"): 1.23 (6H, 49), 2.50 (1H, septet), 6.65 (1H, aa), 6.80 (1H, a), 7.29 (IN, aaa) , 7.77 (1H, Bg 105), 8.01 (IN, a).

I. 6-Fluoro-3-isopropyl-I(1,2,4|triazolo|4,3-a|pyridine (intermediate 11) cha and zy

To a solution of Intermediate Te (1.81 g, 9.18 mmol), triphenylphosphine (4.83 g, 18.4 mmol), and triethylamine (5.12 mL, 36.7 mmol) in THF (25 mL) at 0 " C was added in 2 portions of hexachloroethane (4.36 g, 18.4 mmol) at 1 min intervals. The resulting pale brown solution was allowed to warm to RT, then stirred for 2 h. The resulting yellow suspension was filtered, washing with THF (2 x 25 mL) . The combined organics were purified using a 5СХ-2 cartridge (washed with DXM-MeOnH (1:1, 100 mL) and MeON (50 mL), and then the product was eluted with 2 M Mn in

Meon), which gave a pale yellow solid (1.60 g, 97 95, contaminated with ca. 2.5 95

RIIzR-O). "H NMR (400 MHz, SOS"): 1.53 (6H, 4), 3.32 (1H, septet), 7.15 (1H, aaa), 7.75 (1H, aaa), 7.84 (1H, t).

G. (15, AB)-4-(3-Isopropyl-(1,2,4|griazolo|4,3-a|pyridin-6-yloxy)-cis-1,2,3,4-tetrahydro-naphthalene -1-ylamine (intermediate 19) va and nm M

Intermediate 14 (634 mg, 3.88 mmol) was added portionwise to a suspension of sodium hydride (60 95 in mineral oil, 466 mg, 11.65 mmol) in dry DMF (5 mL), and the mixture was stirred at RT for 20 min. Intermediate 17 (535 mg, 2.99 mmol) was then added in moderate portions, and the mixture was heated at 60 °C for 4 h. The reaction was cooled, quenched with water, and extracted with EIAs (3x). The combined organic extracts were washed with brine and dried (Mag2505) , evaporated and purified ZSC-2, eluting with Meon, then 2M MHz in MeonH, which gave the title compound (274 mg, 79 95). p. 1-(5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl)-3-K15, 4H)-4-(3-isopropyl-

P1,2,4)Hygriazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (example 1)

A solution of intermediate 19 (87 mg, 0.27 mmol), OIREA (318 μl, 1.86 mmol) and (5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl|- carbamic acid 2,2,2-trichloro-ethyl ester (reference see UMO2001004115; 260 mg, 0.62 mmol) in DMF (5 ml) was heated at 60 "C for 2 h.

After cooling, the solution was passed through a 5СХ-2 cartridge, eluting Meon, then - 2M МНз in

Meon, which gave the crude title compound. Further purification by HPLC (55-98 95 NgO in Mesm (0.1 95 MZz)) afforded the title compound as a colorless powder (35 mg, 9.5 95). RHMS (method 5): CI 4.46 min., t/2 594 MN). "H NMR (400 MGu, abe-DMSO): 1.21 (9H, 5), 1.31-1.35 (6H, aa, 9 5.8), 1.76-1.93 (ZH, t ), 2.01-2.08 (2H, t), 3.47-3.57 (1H, t), 3.75 (ZH, 5), 4.75-4.81 (1H, t), 5.48 (IN, 1, U 3.9), 6.26 (1H, 5), 6.98-7.05 (ZH, t), 7.09-7.13 (1H, t), 7 ,09-7.13 (6H, t), 7.62-7.65 (1H, a, U 9.98).

Example 2 a she pat zim / nn

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-K15, 4nH)-4-(3-isopropyl-(1,2,4|Itriazoloi4,3-a|pyridine) -b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|-urea

Diisopropylethylamine (54 μl, 0.31 mmol) was added to a solution of intermediate 1 9 (100 mg, 0.31 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)y-carbamic acid 2 . The reaction was heated to 100 °C for 18 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted into EtOAc (3x), and the combined organic layers were washed with brine, dried (M9505), and concentrated Purification of EES using 0-10 95 (2 M Mn in MeonNi in DCM followed by HPLC (10-98 96 Mesm in NebO, 0.1 95 formic acid) gave the title compound (63 mg, 0.13 mmol . 44 (ZN, y, U 6.9), 1.45-1.48 (ZN, 9, 9 6.9), 1.90-2.00 (1H, t), 2.04-2.17 (2H, t), 2.22-2.30 (1H, t), 3.18-3.29 (1H, zr, U 6.9), 3.72 (ZH, 5), 5.08- 5.15 (IN, yuyu, u 8.8, 5.2), 5.16-5.21 (1H, yu, U 3.8), 5.45-5.55 (1H, Bg a, U 7.4), 6.02 (1H, 5), 6.60-6.68 (1H, Big 5), 6.99-7.04 (1H, aa, in 9.9, 2.1), 7.24-7.28 (2H, t), 7.30-7.36 (1H, t), 7.36-7.44 (2H, t), 7.56-7.60 (1H, a , In 9,9).

Example C 1-5-tert-Butyl-2-I3-(2-hydroxyethylsulfanyl)-phenyl|-2H-pyrazol-3-yl)y-3-K15, 4nH)-4-(3- isopropyl-(1, 2,4)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea va o soy

M. "o xx M

NN

Soy a. Di-tert-butyl. 1-3-(2-tert-butyl(dimethyl)silyl|oxy)ethyl)sulfanyl|phenyl)hydrazine-1,2-hydrogencarbonate (intermediate Za) (c)

ЖЖ о сс ой b / 87 vi

eat

A mixture of 3-bromothiophenol (1.00 g, 5.29 mmol), bromoethoxydimethylsilyl ether (1.36 mL, 6.35 mmol), and potassium carbonate (1.46 g, 10.58 mmol) in acetone (15 mL) stirred at CT overnight. The mixture was filtered, evaporated, the residue was dried under vacuum, and then dissolved in dry THF (15 mL). (1.6M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise at -78 °C and stirred for 10 min. Di-tert-butyl azodicarboxylate (1.54 g, 6.68 mmol) was added in one portion at -78"C and stirred for 20 minutes. Then the mixture was allowed to heat up to RT for 2 h. The mixture was distributed between a saturated solution of ammonium chloride

SO (15 ml) and ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine (20 mL), dried (Mag504) and concentrated in vacuo. The residue was purified by EHS using 0-20 95 ethyl acetate in pentane to give the title compound as a pale yellow oil (1.68 g, 64 95). "H NMR (400 MGu, SOSI"): 0.04 (6H, 5), 0.84 (9H, 5), 1.48 (18H, t), 3.04 (2H, U), 3.79 (2H, U, 7.14-7.24 (2H, t), 7.42 (1H, 5). r. )|-ethanol (intermediate ZB) c.

M" Mn, sh y von

A mixture of intermediate Za (1.68 g, 3.37 mmol), pivaloyl acetonitrile (0.42 g, 3.37 mmol) and a concentrated solution of NCI (1.7 mL) in ethanol (10 mL) was heated under reflux for 3 hours After cooling, the pH was adjusted to 7 (using Mansoz saturated aq.), and the mixture was partitioned between water (20 mL) and EAs (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried (Mag25O054) and concentrated in vacuo. The residue was purified by ES, eluting with 20-80 95 EIOAc in pentane to give the title compound as a pale yellow oil (458 mg, 47 Vol).

RHMS (method 1): RI 2.35 min., t/2 292 NEU. with. (B-tert-Butyl-2-I3-(2-hydroxy-ethylsulfanyl)-phenyl|-2H-pyrazol-3-yl-carbamic acid 2,2,2-trichloro-ethyl ester. (intermediate Cc) c) c H

M. SI von

Trichloroethyl chloroformate (0.1 mL, 0.78 mmol) was added to a solution of intermediate ZB (176 mg, 0.60 mmol) and PIREA (0.31 mL, 1.81 mmol) in THF (10 mL), and the mixture was stirred within 3 hours The mixture was then partitioned between water (15 mL) and EtOAc (3 x 20 mL), and the combined organic extracts were dried (Mg 25 O:4) and concentrated in vacuo. The residue was triturated (cyclohexane) and filtered to give the title compound as a yellow solid (280 mg, 100 95). LCMS (method 1): CI 3.93 min., pt/: 466/468 MH") a. 0 1-(5-tert-Butyl-2-I3-(2-hydroxy-ethylsulfanyl)-phenyl|-2H -pyrazol-3-ylIu-3-K15, 48)-4-(3-isopropyl-(1,2,4)griazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4 -tetrahydro-naphthalene-1-yl|-urea (example 3)

A solution of intermediate 19 (100 mg, 0.31 mmol) in DMF (2 mL) with OPIREA (165 μL, 0.97 mmol) and intermediate Cs (145 mg, 0.31 mmol) was heated at 60 °C for 2 h. After cooling, the mixture was loaded into a 5СХ-2 cartridge, eluting with Men then - 2M МНз in Meоn, which gave the crude product. Further purification of the ЕС by eluting 0-10 95 (2M МНз in MeON| in DCM, followed by HPLC (eluting with 30 -95 95 MesmMm in NgO (0.1 925 HCO»2H)) gave the title compound as a colorless powder (45 mg). LCMS (Method 5): CI 4.22 min., t/2 640 MN. "H NMR ( 400 MHz, SOS"): 1.33 (9H, 5), 1.42-1.47 (6H, t), 1.89-1.97 (1H, t), 2.04-2.13 ( 2H, t), 2.21-2.28 (1H, t), 3.09 (2H, t), 3.24 (IN, t), 3.73 (2H, t), 5.08 (1H , t), 5.19 (1H, t, ), 5.78 (IN, t), 6.38 (1H, 5), 6.92 (1H, ru 5), 7.01 (IN, ad, at 1.92, 9.77), 7.24-7.34 (6H, t), 7.40-7.43 (2H, t), 7.54-7.75 (2H, t).

Example 4 1-5-tert-Butyl-2-I3-(2-hydroxy-ethoxy)-phenyl|-2H-pyrazol-3-yl-3-(15, 48)-4-(3-isopropyl-

Zo P1,2,4Hygriazoloi|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea a / iv) ah i ih a

NN about the United Nations. b-tert-Butyl-2-13-(2-(tetrahydro-pyran-2-yloxy)-ethoxy|-phenyl)-2H-pyrazol-3-ylamine (intermediate 4a)

MO Mn, ooo with rIAU (847 μl, 4.32 mmol) was added slowly to a solution of 3-(5-amino-3-tert-butyl-1H-

pyrazol-1-yl phenol (ref. see O5Z2006/35922; 500 mg, 2.16 mmol), 2-(tetrahydro-pyran-2-yloxy)-ethanol (439 μl, 3.25 mmol) and triphenylphosphine (1.13 g , 4.32 mmol) in THF (10.0 ml) and stirred for 72 h. The reaction mixture was partitioned between EtOAc (75 mL) and H2O (75 mL), and the aqueous layer was extracted with EtOAc (3 x). The combined organic layers were dried (Ma 5 O 5 ), filtered and evaporated in vacuo. Purification of ESS using 5-60 96 E(OAcS in cyclohexane gave the semipure title compound (1.26 g). This was used in the next reaction without further purification. LCMS (Method 4): RI 2.77, t/7 360 ( (b-tert-Butyl-2-13-(2-(tetrahydro-pyran-2-yloxy)-ethoxy|-phenyl)-2H-pyrazol-3-yl)-carbamic acid 2,2,2 -trichloro-ethyl-ester (intermediate 465) / IV) ra ZH p

That's why

With SI oo, o e o

The title compound was obtained starting from 2,2,2-trichloroethyl chloroformate and intermediate 4a using a procedure similar to that described in example C, step c. LCMS (method 4): RI 3.85, t/7 536 (MNU. p. 1-(5-tert-Butyl-2-(3-(2-(tetrahydro-pyran-2-yloxy)-ethoxy|- phenyl)-2H-pyrazol-3-yl)-3-K15, 4nH)-4-(3-isopropyl-(1,2,4Hriazoloi|4,3-a|pyridin-6-yloxy)-1,2, 3,4-tetrahydro-naphthalen-1-yl|-urea (intermediate 4c) and / (in; OM m. If M nn oto

The title compound was obtained, starting from intermediate 46 and intermediate 19, using a procedure similar to that described in example 1, stage RHMS (method 1): CI 3.63 min., t/2-708 |MNY. and. 1-5-tert-Butyl-2-I3-(2-hydroxy-ethoxy)-phenyl|-2H-pyrazol-3-yl-3-(15, 48)-4-(3-isopropyl-

P1,2,4)Hygriazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (example 4)

Pyridinium para-toluene sulfonate (44.0 mg, 0.17 mmol) was added to intermediate 4c (124 mg, 0.17 mmol) in MeonH (3.0 mL). After 2 hours pyridinium para-toluene sulfonate (100 mg, 0.39 mmol) was added, and the reaction was stirred for 12 h. The reaction was then heated to 5570 for 2 hours, then cooled, and the volume of the solvent was reduced under vacuum to approximately 1/3 of its volume. The residue was partitioned between EAs (50 mL) and saturated Mansoz (50 mL). The aqueous layer was extracted into EtOAc (3x), then the combined organic layers were washed with brine, dried (M9505) and evaporated in vacuo. The product was purified by ESS using 0-10 95 Meon in DCM,

It was then purified by HPLC (column C18 X-500, 10-98 95 Mesm in HO, 0.1 95 formic acid) to give the title compound (50.0 mg, 0.08 mmol, 47 90). RHMS (method 5): RI 4.04 min., t/72 624

NAME "H NMR (400 MHz, SOSIv): 1.30 (9H, 5), 1.40-1.44 (ZH, y, 9 6.9 Hu), 1.44-1.47 (ZH, a, 9 6.9

Hu), 1.84-1.98 (1H, t), 2.00-2.10 (2H, t), 2.18-2.26 (1H, t), 3.16-3.26 ( 1H, zr, y 6.9 Hu), 3.87-3.92 (2H, t), 4.03-4.07 (2H, t), 5.01-5.09 (1H, y, U 8.9, 5.3 Gu), 5.14-5.17 (IN, 1, U 4.0 Hz), 5.47-5.52 (1H, rga, U 8.7 Hz), 6, 29 (1H, 5) 6.60 (1H, Bg 5), 6.80-6.84 (1H, t), 6.96-7.00 (1H, yes, at 9.9, 21 Hz), 7.07-7.11 (2H, t), 7.23-7.30 (BN, t), 7.38-7.40 (1H, a, 9 1.6 Hu), 7.53-7 .57 (IN, а, В 9.9 Hz).

Example 5 1-(5-tert-Butyl-|1,3,4oxadiazol-2-yl)-3-K15, 45)-4-(3-isopropyl-P1,2,4A|griazolo|4,3-a |pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

And the earth is not. 2,2,2- Trifluoro-M-(15, 45)-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide (intermediate 5a) on o o) re

E N

Argon was bubbled through a solution of intermediate 16 (8.00 g, 31.1 mmol) and (M-K15, 25)-2-(amino-kM)-1,2-diphenylethyl|-4-methylbenzenesulfonamidato-kMm|chloro|( 1,2,3,4,5,6-1)-1-methyl-4-(1-methylethyl)benzene|-ruthenium (Zieget Spetis!5 Ips.; 0.06 g, 0.93 mmol) in dry DMF (100 ml) for 10 min. A premixed combination of formic acid (2.4 mL, 62.2 mmol) and EM (8.60 mL, 62.2 mmol) was added, and the mixture was stirred at 50 °C for 24 h.

The mixture was cooled to room temperature and concentrated to approximately 25 ml.

Water (70 mL) was added and the resulting precipitate was filtered and washed with DCM (3 x 30 mL) and diethyl ether (30 mL) to leave a solid (4.75 g). The filtrate was decanted, leaving a dark solid. Further purification of the ECS using 0-30 95 EOAc in cyclohexane gave a solid. This was combined with the previously obtained solid to give a beige solid (5.93 g, 74 95). "H NMR (400 MHz, a6e-DMSO): 1.60-1.83 (2H, t), 2.06-2.17 (2H, t), 4.60 (1H, t), 5.08 (1H, t), 5.28 (IN, a), 7.07 (IN, t), 7.25 (1H, ada), 7.28 (1H, aaa), 7.50 (1H, aa) , 9.78 (1H, a). r. (15, 45)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-ol (intermediate 55) "OH

To a gray solution of intermediate 5a (5.55 g, 21.4 mmol) in MeOH (50 mL) was added Mmaon (1.28 g, 32.1 mmol) in water (15 mL), and the mixture was stirred at room temperature for 3 days

Mahon (1.28 g, 32.1 mmol) was then added, and the brown solution was stirred for 5 h.

The solution was applied directly to a Z5CX-2 column, eluted with MeonH and eluted with 2M Mn in Meon, and concentrated in vacuo to leave a gray solid. Hardly suspended in

DCM (50 mL) with sonication, then filtered and dried under vacuum to leave a pale gray solid (2.93 g, 84 95). "H NMR (400 MHz, ae-dmeo): 1.41-1.64 (2H, t), 2.02-2.13 (2H, t), 3.82 (1H, aa), 4.55 (1H, aa), 5.08 (1H, p 5), 7.13-7.22 (2H, t), 7.35-7.49 (2H, t). pp. (15, 45)- 4-(3-Isopropyl-(1,2,4A)griazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-ylamine (intermediate 5c) mail es

Nm ATM

Coo)

Intermediate 5r (1.89 g, 11.6 mmol) was added in moderate portions to a suspension of sodium hydride (60 95 in mineral oil, 1.07 g, 26.8 mmol) in dry DMF (20 mL) at room temperature under nitrogen for 2 min., and the resulting brown solution was stirred for 20 min. Intermediate 1 (1.60 g, 8.93 mmol) was added, and the solution was stirred at 60° for 2 h. The dark brown solution was cooled to room temperature and concentrated in vacuo. The residue was purified by 5СХ-2, washing with Meon (200 mL) and eluting with 2M Mn in MeOnN, which left a dark brown foam (3.21 g). Further EHS purification using 2-10 95 (2M Mn in MeOnN in DCM gave a brown foam (2.11 g, 76 95). "H NMR (400

MHz, ave-DMSO): 1.37 (ZN, a), 1.39 (ZN, a), 1.59 (IN, t), 1.91 (1H, t), 2.11 (IN, t ), 2.33 (IN, t), 3.58 (1H, septet), 3.96 (1H, aa), 5.55 (1H, aa), 7.18-7.37 (4H, t) , 7.51 (IN, а), 7.68 (1Н, а), 8.20

(IN, a). and. (b-tert-Butyl-(1,3,oxadiazol-2-yl-carbamic acid 2,2,2-trichloro-ethyl-ester (intermediate 59) and 6)

M mem father

N si SI

To a suspension of 5-tert-butyl-1,3,oxadiazol-2-ylamine (AMapiis, 141 mg, 1.00 mmol) and EVM (279 μl, 2.00 mmol) in MesM (2 ml) was added in 4 portions 2,2,2-trichloroethyl chloroformate (207 μl, 1.50 mmol) for 1 min. with CT (caution: exothermic, approximately, up to 40 C).

The resulting suspension was stirred for 1 hour. The suspension was filtered, washing the solid

MesmMm (3 mL), and concentrated to form a yellow-brown paste. Purification of ESS using 0-2.5 96 MeOnN in DCM gave a tan foam (232 mg, 73 90). "H NMR (400 MHz, SOS"): 1.42 (9H, 5), 4.86 (2H, 5). c. 1-(5-tert-Butyl-P1,3,4|oxadiazole-2- yl)-3-K15, 45)-4-(3-isopropyl-1,2,A|griazolo|4,3- a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalene- 1-yl|-urea (example 5)

A solution of intermediate 5a (83.1 mg, 0.263 mmol), intermediate 5c (80.6 mg, 0.250 mmol) and OIREA (54.4 IU, 0.313 mmol) in DMF (2 mL) was stirred at 125 °C for 45 min. After cooling, the mixture was concentrated in vacuo to give a brown oil. This was suspended in water (5 mL) and extracted with DCM (2 x 5 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown oil. Purification of ECS, using 0-8 96 MeonN in EOAc, followed by trituration (diethyl ether) gave a tan solid (99.6 mg). as a fluffy white solid (25.9 mg, 21 95). LCMS (Method 5): RI 3.77 min, t/2 490 NMR. "H NMR (400 MHz, SOS"): 1.39 ( 9Н, 5), 1.52 (ЗН, а), 1.55 (ЗН, 9), 2.00 (IN, t), 2.21-2.36 (2Н, t), 2.43 (IN , t), 3.32 (1H, septet), 5.28-5.34 (2H, t), 7.12 (1H, aa), 7.30-7.38 (ЗН, t), 7, 47-7.50 (2H, t), 7.73 (IN, a), 8.95 (1H, Big 5), 8.49 (IN, rg a).

Example 6 1-K15, 45)-4-(3-isopropyl-(1,2,4A)griazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalene- 1-yl|-3-(1-p-tolyl-1H-pyrazol-4-yl)-urea

M d) kyu s Va s Fa; -- In - what lives M nn a. 4-Nitro-1-p-tolyl-1H-pyrazole (intermediate ba) -K y - zo MO,

To 4-tolylboronic acid (544 mg, 4.00 mmol), 4-nitropyrazole (226 mg, 2.00 mmol), cuprum(I) acetate (545 mg, 3.00 mmol) and 4A sieve (1.5 g ) in DCM (15 ml) was added pyridine (0.32 ml, 4 mmol) at RT and stirred for 5 h. The mixture was filtered through Celite, washing

DCM, then evaporated to dryness. The residue was purified by ESS eluting with 0-30 95 ethyl acetate in cyclohexane to give the title compound as a white solid (126 mg,

C1 95). RHMS (method 3): KI 3.93 min., t/2 2041 |IMNI. r. 4-Amino-1-p-tolyl-1H-pyrazole (intermediate 6B)

Ma / --АХ

MH,

Intermediate ba (212 mg, 1.04 mmol) was dissolved in ethanol (20 mL), then hydrogenated at 10 95 palladium on charcoal for 4 h. under a hydrogen atmosphere. The mixture was then filtered through

Celite was washed with ethanol and evaporated to dryness. The residue was purified by ESS, eluting with 0-10 95 MeonN in DCM to give the title compound as a pale brown solid (154 mg, 86 95). LCMS (method 3): RI 1.92 min., pt/2 174.1 (MNI. s. (1-p-tolyl-1H-pyrazol-4-yl-carbamic acid 2,2,2-trichloro-ethyl -ester (intermediate bs) and:

IN

MN

And oh, about that (Fi

Intermediate 656 (150 mg, 0.87 mmol) was dissolved in DCM (10 mL), cooled using an ice bath, and then treated sequentially with triethylamine (0.18 mL, 1.30 mmol) and trichloroethyl chloroformate (0.15 mL, 1.08 mmol). The mixture was stirred with cooling for 45 min., then evaporated to dryness. The residue was purified by ESS, eluting with 0-30% ethyl acetate in cyclohexane to give the title compound as a beige solid (286 mg, 95 95). RHMS (method 3): CI 4.25 min., t/72 348/350/352 MN. and. 1-15, 45)-4-(3-Isopropyl-P1,2,4griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|- 3-(1-p-tolyl-1H-pyrazol-4-yl)-urea (example 6)

A solution of intermediate bs (65.0 mg, 0.19 mmol), intermediate 5c (50.0 mg, 0.155 mmol), and OIREA (0.127 mL, 0.8 mmol) in DMF (1 mL) was heated at 110 °C for 75 minutes and 50 "C for 64 hours. After cooling, the mixture was concentrated to dryness, and the residue was purified by ESO, eluting with 0-10 95 MeonN in DCM to give impure product (63 mg). Further purification by HPLC (Method 6) afforded the title compound as a white solid (45 mg, 56 95). RHMS (method 5): KI 4.06 min., t/2 5221 |MNYAU. "H NMR (400 MHz, a6e-DMSO): 1.36-1.41 (6H, t), 1.76-1.85 (1H, t), 1.98-2.08 (1H, t) , 2.13-2.28 (2H, t), 2.33 (ZH, 5), 3.59 (1H, quintet, U 6.8), 4.96-5.03 (1H, t), 5.62 (1H,.9U4.6), 6.74 (1H, a, U 8.5), 7.24 (1H, aa, y 9.9, 2.1), 7.26-7, 46 (6H, t), 7.62-7.66 (2H, t), 7.68 (IN, 5), 7.70 (1H, aa, y 9.9, 0.8), 8.24 (IN, rg a), 8.26 (1H, 5), 8.91 (1H, 5).

Example 7

SI o es and a im

E nn 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-K15, 45)-4-(3-isopropyl-1,2,4A)griazolo|4,3-a|pyridin-b-yloxy) -1,2,3,4-tetrahydro-naphthalene-1-yl|-urea

The title compound was obtained starting from 4-chloro-3-trifluoromethyl)aniline (Alagisn) using procedures similar to those described in example 5. LCMS (method 5): RI 4.72 min., t/7 544 |MNY|; "H NMR (400 MHz, av-DMSO): 1.38 (ZH, 4), 1.40 (ZH, a), 1.83 (1H, t), 2.04 (1H, t), 2, 21 (2H, t), 3.58 (1H, septet), 5.00 (1H, t), 5.62 (1H, t), 6.84 (1H, 49), 7.24 (1H, aa ), 7.30-7.41 (ZH, t), 7.44 (1H, y), 7.56 (IN, 9), 7.58 (IN, 4), 7.70 (1H, 9) , 8.13 (1H, t), 8.24 (1H, 49), 8.683 (1H, 5).

Example 8

Mu and winter

M. Moda zo o dn 1-(3-tert-Butyl-|1,2,4|oxadiazol-5-yl)-3-K15, 45)-4-(3-isopropyl-P1,2,4A|griazolo |4,3- a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

The title compound was obtained starting from 3-tert-butyl-1,2,4-oxadiazol-5-amine (Enamine) using procedures similar to those described in example 5. LCMS (method 5): RI 4.12 min., t/ 7,490 | MNU); "H NMR (400 MHz, SOSIz): 1.25 (9Н, 5), 1.50 (ЗН, а), 1.54 (ЗН, 9), 1.99 (1ТН, т), 2.22- 2.34 (2H, t), 2.52 (1H, t), 3.29 (1H, septet), 5.27 (1H, aavd), 5.36 (1H, aa), 7.16 (1H , av), 7.32-7.41 (ZH, t), 7.49 (1H, 9), 7.52 (1H, ad), 7.75 (1H, aa), 8.64 (1H, 29), 8.76 (1H, 5).

Example 9

UA ch nn 1-(1-tert-Butyl-1H-pyrazol-4-yl)-3-K15, 45)-4-(3-isopropyl-(1,2,4|Hygriazolo|4,3-a| pyridine-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

The title compound was obtained starting from 1-tert-butyl-1H-pyrazol-4-amine (Enamine) using procedures similar to those described in example 5. LCMS (method 5): RI 3.50 min., t/7 488 |MNU ); "H NMR (400 MHz, SOSIz): 1.46 (ZH, a), 1.49 (ZH, a), 1.56 (9H, 5), 1.89 (1H, t), 2.10- 2.27 (2H, t), 2.38 (IN, t), 3.28 (1H, septet), 5.22 (1H, dav), 5.28 (1H, aa), 5.49 (1H , Bg 5), 6.63 (1H, Bg 5), 7.14 (1H, aa), 7.26-7.36 (ZH, t), 7.39 (1H, a), 7.45 ( IN, a), 7.48 (IN, t), 7.60 (1H, a), 7.71 (1H, 5).

Example 10 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-3-K15,4H)-4-(3-isopropyl-

P1,2,4Hygriazoles|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

A nn he a. 2-(5-Amino-3-tert-butyl-pyrazol-1-yl)-ethanol (intermediate 10a)

HH x c. he

A solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.00 g, 40.0 mmol), concentrated HCl (0.1 mL), and 2-hydrazinoethanol (2.98 mL, 44.0 mmol) in ethanol (40 ml) was heated under reflux for 20 h. The reaction mixture was then concentrated in vacuo. The resulting oily solid was washed with cyclohexane (30 mL) and dissolved in Meon (5 mL) and H 2 O (5 mL) and lyophilized to give the title compound as a white powder (7.13 g, 97 95). RHMS (method 3): RI 0.43 min., pt/2 184 IMNAU. r. B-tert-Butyl-2-(2-(tert-butyl-dimethyl-silanyloxy)-ethyl|-2H-pyrazol-3-ylamine (intermediate 106) g x

OtTV5

A solution of intermediate 10a (1.00 g, 5.46 mmol), tert-butyl-dimethyl-chlorosilane (823 mg, 5.46 mmol) and imidazole (774 mg, 11.38 mmol) in DMF (9 mL) was stirred at CT scan under a nitrogen atmosphere for 18 hours. additional tert-butyl-dimethylchlorosilane (823 mg, 5.46 mmol) and imidazole (774 mg, 11.38 mmol) were added to the reaction mixture and stirred for 6 h.

The reaction mixture was diluted with saturated aq. solution of MNASI (10 ml) and DCM (10 ml). Layers

Zo was separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried (Ma950O5), filtered, concentrated in vacuo, and purified by ESS using 0-50 95

EOAcC in cyclohexane to give the title compound (1.15 g, 70 95). RHMS (method 3): MI 3.06, 3.23 min., t/2 298 |MNYA.. p. (B-tert-Butyl-2-(2-(tert-butyl-dimethyl-silanyloxy)-ethyl|-2H-pyrazol-3-yl-carbamic acid 2,2,2-trichloro-ethyl-ester (intermediate 10c) and Y

M.M. o7so, and N

OotTV5

To a solution of intermediate 1056 (1.14 g, 3.85 mmol) and EM (0.80 mL, 5.77 mmol) in THF (38 mL) was added dropwise 2,2,2-trichlorochloroformate (583 μL, 4, 23 mmol) at 0 "С, and then heated to RT for 1 h. The reaction mixture was left to stand for a further 18 h.

The mixture was diluted with saturated aq. solution of MNASI (10 ml) and DCM (10 ml). The layers were separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried (M950O54), filtered, concentrated in vacuo and purified three times by ESF using 0-30 90 EtOAc in cyclohexane to give the title compound as a yellow oil (354 mg, 19 oz). VI-0.6 (50 95 EOAcS in cyclohexane); "H NMR (300 MHz, SOS"): 0.02 (z, 6H), 0.81 (5, 9H), 1.23 (5, 9H), 3.88 (I, U-4.5 Hz , 2H), 4.15 (I, 9U-4.5 Hz, 2H), 4.77 (5, 2H), 6.16 (5, 1H), 8.30 (Bbg 5, 1H). a. 1-(5-tert-Butyl-2-(2-(tert-butyl-dimethyl-silanyloxy)-ethyl|-2H-pyrazol-3-yl)-3-K15, 4B8)- 4-(3-isopropyl- P1,2,4A|griazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (intermediate 104)

M. in "A Zh v

C) nn

Open 5

A solution of intermediate 10c (176 mg, 0.37 mmol), intermediate 19 (100 mg, 0.31 mmol), and OIREA (0.16 mL, 0.93 mmol) in THF (2 mL) was heated at 60 °C for 19 h. The reaction mixture was diluted with HO (5 mL) and DCM (5 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried (M950O5), filtered, concentrated in vacuo, and then purified by ESS, using 0-5 95 (2M MHz in MeOnN1 in DCM) which gave the title compound as a white powder (108 mg, 19 U). HT-0.4 (5 95 (M MNz in MeOnN1 in DCM); : CI 4.27 min., t/2 646 MN. in, 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-3-K15, 4H) -4-(3-isopropyl

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (example 10)

To a solution of intermediate 104 (100 mg, 0.15 mmol) in THF (2 mL) was added TVAE (IM in THF, 0.23 mL, 0.23 mmol) at RT and stirred for 10 min. The reaction mixture was diluted with H2O (5 mL) and DCM (5 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 5 mL).

The combined organic layers were dried (Ma5O54), filtered, concentrated in vacuo, and then purified by ESS using 0-5 95 (2M MNz in MeonH|I in DCM). The residue was washed with water and

Z was purified by HPLC (30 95-100 95 Mesm in NegO, 0.1 95 formic acid) to give the title compound as a white powder (47 mg, 57 Us). NI-O0.2 (5 95 (2M MNz in MeOnNI|I in DCM) LCMS (method 5): MI 3.59 min., t/72 532 |MNUN NMR (400 MHz, SOSIv): "H NMR (300 MHz, SOSIv): 1.25 (5, 9H), 1.43 (а, 3-6.9 Hz, ЗН), 1.46 (а, 9-6.9 Hz, ЗН), 1.92- 2.30 (t, 4H), 3.25 (p, 9U-6.9 Hz, 1H), 3.95 (Yii, U-4.7 Hz, 2H), 4.15 (ai, 9-5 ,3, 3.5 Hz, 2H), 5.09-5.16 (t, 1H), 5.92 (y, 9U-8.0 Hz, 1H), 6.12 (5, 1H), 6 .92 (aa, 9U-9.8, 1.9 Hz, 1H), 7.22-7.27 (t, 2H), 7.33 (19, 9U-5.8, 3.0 Hz, 1H ), 7.40 (5, 1H), 7.43 (Bbg 5, 2H), 7.47 (y,

U-7.8 Hz, 1H), 7.70 (5, 1H).

Example 11 and 6) ah

What; 1-(b-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl|-3-K15, 4H)-4-(3-isopropyl-

P1,2,4Hygriazoles|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

The title compound was obtained starting from C|4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)/phenyl|methanol (reference see M/O02011070368), using procedures similar to those described in example 3. LCMS (method 5): CI 4.01 min., t/2 594.2 MN; "H NMR (400 MHz, SOSIi»v): 1.30 (9H, 5), 1.37-1.40 (3H, a, U 6.9 Hz), 1.40-1.43 (ZH, a, U 6.9 Hz), 1.84-1.96 (1H, t), 2.00- 210 (2H, t), 2.16-2.25 (1H, t), 3.17- 3.24 (IN, 5r, U 6.9 Gu), 4.60 (2H, 5), 5.01-5.09 (IN, Yuyu, U 9.0, 5.6

Gu), 5.14-5.19 (IN, i, U 3.9 Hz), 5.70-5.78 (1H, Bug 5), 6.32 (1H, 5), 6.86 (1H , horn 5), 6.95 (1H, ad, U 9.8, 2.0 Gsh), 7.23-7.31 (5H, t), 7.39-7.46 (4H, t).

Example 12 1-15-tert-Butyl-2-I3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl|-2H-pyrazol-3-yl)-3-K15, 48)- 4-( 3-isopropyl-P1,2,4A|griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

M. - x for

H NO

SOS" a. 1-(3-Bromo-benzyl)-4,4-difluoro-piperidine (intermediate 12a)

Ve

IS

IS

M

A mixture of 3-bromobenzyl bromide (3.43 g, 13.73 mmol), 4,4-difluoro-piperidine hydrogen chloride (2.20 g, 13.97 mmol) and potassium carbonate (4.82 g, 34.86 mmol) in acetonitrile (50 ml) was stirred at RT for 16 h. The mixture was filtered and evaporated, and the residue was partitioned between water (30 mL) and EOAc (3 x 30 mL). The combined organic extracts were washed with water (2 x 50 mL) and dried (Ma»5O4). The solvent was evaporated to give the title compound as a colorless oil (3.96 g, 99 95). RHMS (method 1): CI 1.89 min., t/72 290 / 292 MN. r. Di-tert-butyl 1--3-K4,4-difluoropiperidin-1-yl)umethyl|phenyl)hydrazine-1,2-hydrogencarbonate (intermediate 126) o

ЖЖ о сс о

IS

Su n -Butyllithium (1.6 M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise to a stirred solution of intermediate 12a (1.98 g, 6.82 mmol) in dry THF (15 mL) at -78 C under nitrogen. The mixture was stirred at -78 C for 10 min., then di-tert-butyl azodicarboxylate (1.73 g, 7.51 mmol) was added in one portion. The mixture was stirred at -78 C for 20 min. , then allowed to heat up to RT for 20 min. The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3 x 20 mL). Combined organic extracts

Zo was washed with brine (20 ml) and dried (Mag5054). The solvent was evaporated and the residue was purified

ESS, eluting with 0-100 95 EIOAc in pentane gave the title compound as a pale yellow oil (1.30 g, 43 95). RHMS (method 1): CI 2.54 min., pt/l 442 |MNYA. with. B-tert-Butyl-2-I3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl|-2H-pyrazol-3-ylamine. (intermediate 12s) c.

M" sMn, E

Oh and oh

A mixture of intermediate 1256 (1.30 g, 2.94 mmol), pivaloyl acetonitrile (0.37 g, 2.94 mmol) and concentrated HCl (1.5 mL) in ethanol (10 mL) was heated under reflux for 3 h.

The cooled mixture was brought to pH 7 aq. saturated Manso", and the mixture was distributed between water (15 ml) and EtOAc (3 x 15 ml). The combined organic extracts were washed with brine (20 mL) and dried (Mag25054). The solvent was evaporated and the residue was purified by ESS, eluting with 0-100 96 EAs in pentane to give the title compound as a pale yellow solid (450 mg, 43 95). RHMS (method 1): EI 1.93 min., t/7 349 NEU. and. (B-tert-Butyl-2-3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl|-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester. (intermediate 124)

IF) in Kh

M SI mm in

IS

Ce 2,2,2- Trichloroethyl chloroformate (0.077 mL, 0.57 mmol) was added to a solution of intermediate 12c (200 mg, 0.57 mmol) and OIREA (0.31 mL, 1.81 mmol) in THF (5 mL ), and the mixture was stirred for 3 h. The mixture was then partitioned between water (10 mL) and EtOAc (3 x 15 mL), and the combined organic extracts were dried (Mg 2 5 O 4 ). The solvent was evaporated and the residue was triturated under pentane and filtered to give the title compound as a yellow solid (215 mg, 72 95). LCMS (method 1): RI 2.89 min., t/72 523 / 525 MNY e.000/1-I5-tert-Butyl-2-I3-(44-difluoro-piperidin-1-ylmethyl)-phenyl| -2H-pyrazol-3-yl)-3-(15,4nH)-4-(3-isopropyl-(1,2,4Hygriazolo|4,3-a|pyridin-6-yloxy)-1,2,3 ,4-tetrahydro-naphthalene-1-yl|-urea (example 12)

The title compound was obtained using intermediate 124 and intermediate 19, in a procedure similar to the stage described in example 1 of the RHMS step (method 5): RI 2.52 min., t/7 697

NAME; "H NMR (300 MHz, SOSI"): 1.33 (9H, 5), 1.48 (6H, aa, U 7.0, 13.0 Hz), 1.90-2.15 (BH, t ), 2.24-2.31 (IN, t), 2.56 (4H, ri 5), 3.21-3.31 (IN, t), 3.59 (2H, Bi 5), 5, 06-5.13 (1H, t), 5.18-5.21 (1H, t), 5.34 (1H, Big 5), 6.30 (1H, Bu 5), 6.36 (1 H , Bi 5), 7.03-7.06 (1H, t), 7.29 (4H, ri 5), 7.39-7.47 (ZH, t), 7.53 (1H, horn 5) , 7.62-7.65 (1H, t).

Example 13 1-(5-tert-Butyl-2-4-(2-(4-methyl-piperazin-1-yl)-ethoxy|-phenyl)-2H-pyrazol-3-yl)-3-K15, 48 )-4- (Z-isopropyl-P1,2,4Hygriazoloi|4,3-a|pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea, formic acid salt and

M Y nn au a. 5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine (intermediate 1Za) xu

M

ЗМ МН, зо 5 4,4-Dimethyl-3-oxo-pentanenitrile (14.28 g, 114 mmol) and 4-methoxyphenyl hydrazine (19.89 g, 114 mmol) were dissolved in a mixture of absolute ethanol (170 ml) and ice-cold of acetic acid (5.0 ml), then heated under reflux for 3 h., and then allowed to stand overnight at RT. The resulting red/brown solid was filtered off and the filtrate was then diluted with water (500 mL) and basified with 880-ammonia solution to pH-5. This water the solution was extracted into diethyl ether (3 x). The combined organics were dried (M95O4) and evaporated in vacuo to a brown oil. Trituration (pentane) gave the title compound as a light purple/brown solid (23.07 g, 94.1 mmol, 82 95). LCMS (method 1): CI 2.87 min., t/2 246/247 |MNY.. r. 4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-phenol (intermediate 1360) t.

M

M MN, on

Intermediate 1Za (10.0 g, 40.8 mmol) was dissolved in DCM (80.0 mL) and aluminum trichloride (28.0 g, 204.0 mmol) was added in measured portions. The reaction was heated under reflux for 4 hours. Additional aluminum trichloride (28.0 g, 204.0 mmol) was added in moderate portions, and the reaction was heated under reflux overnight. After cooling, the mixture was carefully added in measured portions to saturated aq. ManSOz (300 ml). The mixture was extracted with ethyl acetate (300 mL) and separated. The aqueous layer was filtered under vacuum and acidified with 1M HCl to pH-7. This aqueous layer was then back-extracted into ethyl acetate, and the organic extracts were dried (Ma 5 O 4 ) and evaporated in vacuo. Purification of ES using 0-40 95 EAs in DCM afforded the title compound (5.0 g, 21.6 mmol, 53 95). RHMS (method 1): RI 2.77 min., t/2 232/233 |NAMES,. with. B-tert-Butyl-2-14-(2-(4-methyl-piperazin-1-yl)-ethoxy|-phenyl)-2H-pyrazole-3-ylamine (intermediate 13c) 7.

M MN, oh it mu

WITH

To a solution of intermediate 1356 (1.15 g, 5.0 mmol), 2-(4-methyl-piperazin-1-yl)-ethanol (864 mg, 6.0 mmol) and triphenylphosphine (2.62 g, 10, 0 mmol) in THF (10 mL) was added dropwise isopropyl azodicarboxylate (2.0 g, 10.0 mmol) and stirred for 75 min. The mixture was diluted with diethyl ether (50 mL) and extracted with 1095 aqueous citric acid solution (2x).

The combined aqueous layers were alkalized with solid potassium carbonate to pH-9. The aqueous layer was then extracted with ethyl acetate (3x). The combined ethyl acetate layers were washed with brine, dried (Mao) and evaporated in vacuo. Purification of ESS using 0-12 95 (9:1 Meon/880 ammonia) in DCM. The resulting product was crystallized (diethyl ether) to give the title compound (270 mg, 0.756 mmol, 15 95). RHMS (method 1): CI 2.31, 1.72 min., t/72 358/359 MN. and. 0 (b-tert-Butyl-2-14-(2-(4-methyl-piperazin-1-yl)-ethoxy|-phenyl/-2H-pyrazol-3-yl)-M,M-bis-carbamic acid 2,2,2-trichloro-ethyl ester (intermediate 134) 0); SI

M u Although m si ra at 9 si

Co

SI beating

WITH

Trichloroethyl chloroformate (144 mg, 0.8 mmol) was added dropwise to a solution of intermediate 13c (115 mg, 0.34 mmol) and diisopropylethylamine (129 mg, 1.0 mmol) in THF (4 mL) and stirred for 2 h. This mixture was diluted with ethyl acetate (25 mL) and washed with water, brine and dried (Md 5 O 2 ) and evaporated in vacuo to give the title compound (240 mg, 0.34 mmol, 100 95). LCMS (method 1): RI 3.02 min., t/: 708 (MNU.. v. 1-(5-tert-Butyl-2-4-(2-(4-methyl-piperazin-1-yl) -ethoxy|-phenyl)-2H-pyrazol-3-yl)-3-K15, 4nH)-4-(3-isopropyl-(1,2,4Hriazoloi|4,3-a|pyridin-6-yloxy)- 1,2,3,4-tetrahydro-naphthalen-1-yl|-urea, formic acid salt (example 13)

Intermediate 19 (95 mg, 0.295 mmol) and intermediate 13a (175 mg, 0.33 mmol) in a mixture of DMF (0.50 ml) and diisopropylethylamine (110 mg, 0.85 mmol) were heated to 60 °C for 3 h. The solution was loaded into a 5CX-2 cartridge, washing with MeonH and eluting with 2M Mn in MeonH.The resulting residue was purified by HPLC (C18 X-v5eiesi column, 10-30 96 Mesm in NegO, 0.1 95 formic acid) to give the title compound (15 mg, 6.4 95). RHMS (method 5): Ki 3.34 min., t/2-706.4 IMNYA. 'N

NMR (400 MHz, SOS"): 1.34 (9H, 5), 1.48 (6H, aa, at 7.0, 16.4 Hz), 1.90-2.30 (4H, t), 2.40 (ZN, 5), 2.75 (VN, Bg 5), 2.91 (2H, her, U 5.3 Hz), 3.28 (IN, t), 4.11 (2H, her , U) 5.3 Gu), 5.10 (1H, t), 5.20 (IN, 1, U 15. 4.0 Hz), 6.16 (IN, Bg a), 6.39 (1H , 5), 6.89 (2H, a, U 9.0 Gu), 7.04 (1H, ad, 9 2.1, 10.0 Hz), 7.18 (TN, Bg 5), 7, 25-7.34 (2H, t), 7.36-7.40 (ZH, t), 7.47 (IN, t), 7.60 (1H, y, U 10.1 Hu), 8, 14 (IN, rg 5).

Example 14 1-(b-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl|-3-K15, 45)-4-(3-isopropyl-

P1,2,4Hygriazoloi|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|-urea vol / Ge) i OM in IF;

NN

WITH

M. a. 4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-benzonitrile (intermediate 14a)

M- tu 2 L ) MN,

A cream suspension of 4-cyanophenylhydrazine hydrogen chloride (1.70 g, 10.0 mmol) and 4,4-dimethyl-

3-Oxopentannitrile (1.31 g, 10.5 mmol) in EUN (25 ml) was stirred under dephlegmation for 4 h, then under RT for 64 h, and again under dephlegmation for 24 h. The solution was cooled to RT, concentrated in vacuo and partitioned between water (50 mL) and EtOAc (75 mL). The organics were washed with brine (50 mL), dried (Mag5054), filtered and concentrated in vacuo to a residual orange solid (2.28 g, 95 95). RHMS (method 3): CI 3.45 min., etc./72 241

NAME

(b-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazole-3-yl|-carbamic acid 2,2,2-trichloro-ethyl ester (intermediate 145))

M. o77es m and si v

M

To a suspension of intermediate 14a (2.28 g, 9.49 mmol) in EOAc (25 ml) and aq. of a solution of MaOH (1M, 23.7 ml, 23.7 mmol) 2,2,2-trichloroethyl chloroformate (1.57 ml, 11.4 mmol) was added dropwise for 2 minutes. The formed precipitate dissolved after 15 min., then the orange solution was stirred at RT for 90 min. 2,2,2-trichloroethyl chloroformate (0.391 mL, 2.85 mmol) was added and the orange mixture was stirred at RT for 16 h. The layers were separated and the aqueous extracted with EOAc (25 mL). The combined organics were washed with brine (25 mL), dried (Mag2504), filtered, and concentrated in vacuo to leave an orange-red oil.

Recrystallization from cyclohexane gave an off-white solid (3.12 g, 79 95). RHMS

(method 3): RI 4.46 min., t/7 415, 417 (MNU. p. 1-(b-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl) -3-К15, 45)-4-(3-isopropyl-

P,2,Yatgriazolo!|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea. (example 14)

A solution of intermediate 14p (61.6 mg, 0.148 mmol), intermediate 5s (43.4 mg, 0.135 mmol) and

PIREA (0.029 ml, 0.169 mmol) in dioxane-DMF (3:1, 2.0 ml) was stirred at 60 "C for 18 h. Water (3 ml) was added, then the mixture was extracted with DCM-Meon (9:1, 2 x 3 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave an orange oil. EES using 2-8 95 Meon in DCM gave the title compound as a white solid after freeze-drying (35.0 mg, 44 90 ). LCMS (method 5): RI 4.46 min., t/2 589 MNYA|. "H NMR (400 MHz, ae-DMeSO): 1.28 (9H, 5), 1.37 (ZH, a , 9 7.1), 1.39 (ZN, a, 9 71), 1.75 (IN, t), 2.01 (IN, t), 2.09-2.22 (2Н, t), 3.57 (1H, septet, U 6.9), 4.88 (1H, t), 5.58 (IN,1, U 4.5), 6.38 (IN, 5), 7.06 ( 1H, y, U 8.2), 7.23 (1H, aa, y 9.9, 2.2), 7.27 (1H, y, 9 7.3), 7.29-7.38 ( 2H, t), 742 (11H, a, y 7.5), 7.69 (1H, ad, y 9.9, 0.9), 7.75 (2H, ay, Y 8.9), 7 .96 (2H, y, in 8.7), 8.21 (2H, 5).

Example 15

KD "Lm o nno 1-(b-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl|-3-K15, 45)-4-(3-isopropyl-

P1,2,4Hygriazoles|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

The title compound was obtained starting from (|4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl/uphenyl)|methanol (reference see M/O02011070368), using procedures similar to those described in example 5. LCMS ( method 5): CI 4.01 min., t/72 594.2 |MNUI. "N NMR (400 MHz, av-

DMSO): 1.27 (9H, 5), 1.37 (ZN, 9, 9 7.2), 1.38 (ZN, y, y 7.2), 1.74 (IN, t), 2 .01 (IN, t), 2.11-2.16 (2H, t), 3.56 (IN, t), 4.55 (2H, y, U 3.1), 4.89 (1H, t), 5.29 (1H, 5), 5.57 (IN, i, U 3.9), 6.33 (1H, 5), 7.04 1Hn, a,» 8.1), 7, 22 (IN, as, in 9.9, 2.1), 7.35-7.44 (8H, t), 7.68 (1H, t), 8.02 (1H, 5), 8.21 (IN, and, in 2.0).

Example 16 1-(5-tert-Butyl-2-piperidin-4-yl-2H-pyrazol-3-yl)-3-(15,4H)-4-(3-isopropyl-

P1,2,4Hygriazoloi|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|-urea and / (c) Ah re; IF;

F NN

M nN a. 4-Hydrazino-piperidine-1-carboxylic acid benzyl ester (intermediate 16ba) n

Sy

OHM

VI Fr

A solution of 1-C82-4-piperidone (2.92 g, 12.5 mmol) and hydrazine hydrate (2.01 mL, 18.8 mmol) in

Meon (25 mL) was stirred at 50 °C for 30 min., then cooled to RT and MavVNa (1.18 g, 31.3 mmol) was added (caution: gas evolution and exothermic reaction, up to about 45 °C). The solution was stirred at CT for 30 min., then - at 507 for 18 h. The cooled solution was concentrated in vacuo, suspended in water (25 ml) and extracted with DCM (2 x 25 ml). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a pure oil. ELC using 0-10 95 (2N MNz in MeonNI in DCM) afforded the title compound as a pure oil (1.80 g, 58 95). LCMS (Method 3): RI 2.03 min, t/7 250 MNY. r. 4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-piperidine-1-carboxylic acid benzyl ester (intermediate 166) 5О0

M- o I, o. MH,

AND

A yellow solution of intermediate 16a (1.80 g, 7.22 mmol), 4,4-dimethyl-3-oxopentannitrile (1.08 g, 8.66 mmol), and HCl (4M in dioxane, 2.70 mL, 10, 8 mmol) in EUN (25 ml) was stirred under reflux for 4 hours. The cooled solution was applied to the Z5СХ-2 cartridge (50 g), washed with Meon (100 ml). The product was eluted with 2 M Mn in MeonH (100 ml); concentration in vacuo afforded a yellow oil (772 mg). ESS using 0-5 96 MeonN in DCM afforded the title compound as a yellow resin (550 mg, 21 95). LCMS (method 3): CI 2.88 min., t/2 357 (Mn. p. 4-(3-tert-Butyl-5-(2,2,2-trichloro-ethoxycarbonylamino)-pyrazol-1-yl |-piperidine-1-carboxylic acid benzyl ester (intermediate 16bs)

M zo. og nm roko o o

To a solution of intermediate 166 (550 mg, 1.54 mmol) in aq. 2,2,2-trichloroethyl chloroformate (0.32 ml, 2.31 mmol) was added to a solution of Mahon (1M, 3.85 ml, 3.85 mmol) and EIAs (5 ml) at RT for 2 min., then the mixture stirred vigorously for 30 minutes. The aqueous layer was extracted with EtOAc (10 mL), then the combined organics were washed with brine (10 mL), dried (M9505), filtered, and concentrated in vacuo to leave a yellow-brown oil. Elution using 0-30 95 EOAc in cyclohexane afforded the title compound as a white foam (337 mg, 41 g).

LCMS (method 3): RI 4.81 min., t/2 531, 533 (MNU. a. 4-(3-tert-Butyl-5-13-(15, 48)-4-(3-isopropyl- 1,2,4Igriazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-ylI-ureido)-pyrazol-1-yl)y-piperidine-1- carboxylic acid benzyl ester (intermediate 164) moat ! (o; OM 90 vilo; o o. named after NN

VIJ

(in)

A brown solution of intermediate 16c (337 mg, 0.634 mmol), intermediate 19 (195 mg, 0.603 mmol), and OIREA (0.131 mL, 0.754 mmol) in DMF (5 mL) was stirred at 100 °C for 90 min. The cooled solution was concentrated in vacuo , suspended in water (5 ml) and extracted

DCM (2 x 5 ml). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown resin. Elution using 4.5 96 MeonN in DCM gave the title compound as a yellow-brown oil (364 mg, 86 95). RHMS (method 3): CI 3.96 min., t/7 705 |MNU. e. 1-(5-tert-Butyl-2-piperidin-4-yl-2H-pyrazol-3-yl)-3-(15,4H8)-4-(3-isopropyl-(1,2,4hya2o1o-

14,3-a|Ipyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (example 16)

A suspension of intermediate 16 (165 mg, 0.234 mmol), Ra/C (10 95, 16 mg) and 2 M Mn in MeOH (0.117 ml, 0.234 mmol) in EN (5 ml) under M" was vacuumed and purified by He" twice, then stirred at r.t. within 8 hours The suspension was filtered through Celite, then the precipitate on the filter was washed with EN (10 ml). The combined organics were concentrated in a vacuum to approximately 0.5 ml volume, then applied to the 5СХ-2 cartridge (5 g) and washed with Meon (5 ml). The product was eluted with 2 M Mn in MeOH (25 mL); concentration in vacuo afforded a pale yellow solid which was triturated with diethyl ether (10 mL) to leave a dark yellow solid (121 mg). Half of this material was purified by HPLC (HVGidde C18, 25-98 956 MesMm in HO, 0.1 95

MNAOH) to give the title compound as a white solid (20.0 mg, 15 95) after freeze-drying. RHMS (method 5): CI 3.16 min., t/7 571 (MNU). "H NMR (400 MHz, av-

DMS): 1.16 (9Н, 5), 1.33 (ЗН, и, У 6.8), 1.35 (ЗН, а, У 6.8), 1.68 (2Н, т), 1 .79 (2H, t), 1.91 (2H, t), 2.09 (2H, t), 2.47 (2H, t), 2.98 (2H, y, U 12.3), 3 .50 (1H, septet, U 6.8), 3.92 (1H, t), 4.82 (IN, t), 5.51 (IN, 1, U 4.5), 5.97 (1H , 5), 6.88 (IN, y, U 8.6), 7.14 (IN, yes, U 9.9, 2.1), 7.26 (1H, t), 7.31-7 ...

Example 17 vych / (o; OT re; IF;

F NN

M

/ 1-(b-tert-Butyl-2-(1-methyl-piperidin-4-yl)-2H-pyrazol-3-yl|-3-(15,4H)-4-(3-isopropyl-

P1,2,4Hygriazoles|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

A mixture of Example 16 (half of the crude material, ca. 64.8 mg, 0.114 mmol) and formaldehyde (37 95 in water, 0.092 mL, 1.14 mmol) in DCM (2 mL) was stirred at RT for min., then successively added ASON (0.013 ml, 0.227 mmol) and Mavn(oOgds) with (48.1 mg, 0.227 mmol), and the solution was stirred at RT for 3 h. The solution was concentrated under vacuum to approximately 0.5 ml volume, applied to the ZSh-2 cartridge (2 g) and washed with Meon (15 ml).

The product was eluted with 2 M Mn in MeOH (10 ml); concentration in vacuo afforded a pale yellow solid (82.6 mg). HPLC (HVGidde C18, 30-98 95 Mesm in NgO, 0.195 MNAOH) gave the title compound as a white solid after freeze-drying (30.8 mg, 46 g).

RHMS (method 5): RI 3.18 min., pt/2 585 |MNYA. "H NMR (400 MHz, ae-DMSO): 1.21 (9H, 5), 1.38 (H, a, Y 6.8), 1.40 (ZH, a, Y 6.8), 1 .75 (2H, i, U 12.2), 1.91-2.04 (6H, t), 2.07-2.17 (2H, t), 2.18 (ZH, 5), 2, 87 (2H, a, U 10.6), 3.58 (1H, septet, .) 6.8), 3.88 (1H, t), 4.88 (1H, t), 5.56 (IN , i, U 4.7), 6.02 (IN, 5), 6.89 (IN, a, U 8.6), 7.19 (IN, aa, U 9.8, 2.1), 7.31 (1H, t), 7.36-7.43 (ZH, t), 7.70 (IN, y, 9 9.8), 8.06 (1H, 5), 8.22 1H, ai, U 2.0).

Example 18

M in the name of

And NN

WITH

(c) 1-(b-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-K15, 4nH)-4-(3- isopropyl I1,2 ,4|Itriazolo|4,3-a|pyridin-6b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

To a stirred solution of example 10 (136 mg, 0.26 mmol) and EVM (0.11 ml, 0.77 mmol) in

To DCM (2.5 mL) was added mesyl chloride (31 μL, 0.31 mmol) at 0 "С under M2. After 15 min. the reaction mixture was heated to RT. After 15 min. HgO (5 mL) and DCM (5 The layers were separated and the aqueous layer was extracted with DCM. The combined organics were dried, filtered, and concentrated in vacuo. The resulting residue was dissolved in THF (2.5 mL), then OIREA (49 μL, 0.28 mmol) and morpholine (67 (μL, 0.77 mmol). The resulting mixture was heated under reflux for 21 h. The reaction mixture was cooled to RT, then HO (5 mL) and DCM (5 mL) were added. The layers were separated and the aqueous extracted with DCM (3 x 5 mL). The combined organics were dried (Mao), filtered and concentrated in vacuo

Zo was purified by ESS using 0-10 95 (2M Mn in Meon | in DCM followed by preparative HPLC (Setipi C18 column, 2055-9895 MesmMm in HO, 0.195 HCO2H, 20 min), which after freeze-drying gave the title compound as a white powder (64 mg, 41 965). LCMS (Method 5): KE 3.21 min., t/2 601 (MN. "H NMR (400 MHz, SOSIv): 1.22 (9H, 5), 1.47 (ZN, ay, U 6.9), 1.50 (ZN, a, U 6.9), 2.00-2.12 (ZN, t), 2.25-2.931 (1Н, t ), 2.53-2.56 (4H, t), 2.68-2.70 (2H, t), 3.28 (1H, t), 3.80 (4H, 1.97 4.7) . 5.89 (1H, 5), 7.09 (IN, aa), 7.27-7.30 (2H, t), 7.36-7.40 (1H, t), 7.4511H, a, 2.0), 7.47 (IN, a, U 7.9), 7.67 (IN, aa, y 9.9, 0.8), 9.43 (TN, 5).

Example 19 1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-K15, 48)-7-fluoro-4-(3-isopropyl-

П1,2,4)Hygriazoloi|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|.- urea vych / 6) SM Bemus IF / nn

And a. (18, 45)-4-Amino-6b-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ol (intermediate 19a) on nm B

IS

To a solution of 2,2,2-trifluoro-M-(15, 48)-7-fluoro-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl-acetamide (synthesized by a method similar to that described in UMO 2009/048474) (2.31 g, 8.34 mmol) in MeOnH (22.5 ml) was added to a solution of sodium hydroxide (0.834 g, 20.8 mmol) in water (15 ml) and the mixture was stirred at RT for 65 h . The mixture was concentrated in a vacuum, then applied to the ZSKH-2 cartridge (50 g), washing with methanol, then alkaline components with 0.2 - 1 M ammonia in methanol. The product containing fractions were combined and concentrated in vacuo. The residue was purified by ESS using 0-10 95 (2M MHz in Meon in DCM) to give the title compound (1.29 g, 86 90). 1H NMR (300 MHz, a6e-DMSO): 1.60-2.15 (6H, t), 3.62-3.71 (1H, t), 4.49 (1H, 1, U 4.7), 5.15 (1H, Bi 5), 6.98 (1H, a , In 8.6, 2.8), 7.28 (IN, as, in 10.7, 2.8), 7.36 (1H, aa,

In 8.6, 6.2). r. (15, 4H8)-7-Fluoro-4-(3-isopropyl-|1,2,4|griazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4- tetrahydronaphthalene -1-ilamine (intermediate 195) sohe -i M «to v;

IS

Intermediate 19a (837 mg, 4.62 mmol) was dissolved in dry DMF (15 mL) under Ar, then manne (60 95 in mineral oil, 556 mg, 13.9 mmol) was added, and the mixture was stirred for 15 min.

Intermediate 17 (893 mg, 4.99 mmol) was added, and the reaction was heated at 60 °C for 2 h.

The reaction was cooled, quenched by the addition of water and extracted with DCM (4 x 30 mL). The combined organic layers were washed with brine, dried (Mag50O»4), filtered and concentrated in vacuo.

The residue was purified by ESS, eluting with 0-20 95 (2M Mnz in MeOnNi| in DCM) to give the title compound (429 mg, 27,965). LCMS (method 3): RI 1.96, t/7 363 |MMach|. s 1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-K15, 4H8)-7-fluoro-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (example 19)

Intermediate 195 (85.0 mg, 0.250 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl-ester (Ш52004/192653, 99 mg, 0.300 mmol) was dissolved in 1,4-dioxane (3 ml) and SIREA (70 μl, 0.400 mmol). The reaction was heated under reflux for 1.75 hours, then more (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamine was added

From 2,2,2-trichloro-ethyl-ester acid (35 mg, 0.100 mmol) and OIREA (3 drops). After 4 hours the mixture was concentrated in vacuo. The residue was purified by ESS using 0-15 95 MeOnN in DCM to give impure product (82 mg). Further purification by HPLC twice (column C18 X-5eiYesi, 40-98 95

MmMesmMm in HgO, 0.195 HCO 2 H) gave the title compound as a white powder after freeze-drying (44 mg, 34 95). RHMS (method 5): CI 3.83 min., t/72 520.1 MN). "H NMR (400

MHz, dv--DMSO): 1.21 (9H, 5), 1.35-1.43 (6H, t), 1.85-2.25 (4H, t), 3.51-3.62 (AN, t), 4.80-4.91 (1H, t), 5.50-5.57 (IN, t), 6.02 (1H, 5), 7.09 (1H, y, U 8.8), 7.11-7.17 (2H, t), 7.20 (IN, aa, in 9.6, 2.2), 7.44-7.50 (IN, t), 7.69 (1H, y, U 9.6), 8.22 (1H, bg a), 8.40 (1H, 5).

Example 20 1-K15, 48)-4-(3-Isopropyl-(1,2,4A)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalene- 1-yl|-3-(2-p-tolyl-2H-pyrazol-3-yl)-urea kb ATM o NN a. (2-p-tolyl-2H-pyrazol-3-yl-carbamic acid 2,2,2-trichloro-ethyl ester (intermediate 2ba) te X si

Mahon (107 mg, 2.67 mmol) was added to a stirred solution of 2-p-tolyl-2H-pyrazol-3-ylamine (ref. see UMO2009/150614, 346 mg, 2.00 mmol) in water (1 mL) and EtOAc (4 ml).

The mixture was cooled to 0 °C and 2,2,2-trichloroethyl chloroformate (385 μl, 2.80 mmol) was added. Stirring was continued for 30 min at 0 °C and then for 2 h. at

CT. The mixture was partitioned between water and Eas. The organic phase was washed with brine and concentrated to dryness in vacuo to give the title compound as an orange residue.

LCMS (method 3): RI 3.90 min., t/: 348, 350 (Mn. r. 1-(15, 4nH)-4-(3-Isopropyl-P1,2,4|griazolo|4,3 -α|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-3-(2-p-tolyl-2H-pyrazol-3-yl)-urea (example 20)

A mixture of intermediate 19 (50.0 mg, 0.16 mmol), intermediate 20a (54.0 mg, 0.16 mmol), and OIREA (54.0 μL, 0.31 mmol) in DMF (2.5 mL) was heated to 100 "C for 1 h. After cooling, the mixture was partitioned between EOAc and water, and then extracted into EOAc (3x). The combined organic extracts were washed with saturated aqueous Mansoze solution, brine and evaporated in vacuo. The residue was purified by ECC using 0 -10 95 (2M Mnz in MeOnNi in DCM to give a beige solid (30 mg). Further purification by HPLC (5-98 95 Mesm in HgO, 0.1 95 HSO»H) gave, after freeze-drying, the title compound as a white solid substance (17 mg, 20 95).

RHMS (method 5): RI 3.68 min., t/7 522 MN). "H NMR (400 MHz, abe-DMeSO): 1.35-1.40 (6H, t), 1.81-1.98 (2H, t), 2.02-2.15 (2H, t) . IN, I, U 1.8), 7.16 (IN, as, y 9.6, 2.2), 7.21-7.42 (8H, t), 7.51 (1H, y, U 1.6), 7.67 (IN, a,

In 9.6), 8.20 (1H, t), 8.29 (1H, t), 8.45 (1H, ru 5).

Example 21 thanks

M (c) se se Fk; nn

IS

1-(1-tert-Butyl-1H-pyrazol-4-yl)-3-K15, 48)-7-fluoro-4-(3-isopropyl-1,2,4|griazoloi|4,3- a| pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

The title compound was obtained starting from 1-tert-butyl-1H-pyrazol-4-amine (Enamine) and

From intermediate 196, using a procedure similar to that described in example 5. RHMS (method 5):

KI 3.65 min., t/72 506.2 |MNUYA. "H NMR (400 MHz, de-DMSO): 1.36-1.42 (bH, t), 1.49 (9H, 5), 1.84-2.25 (AN, t), 3.57 (1H, septet, U 7.0), 4.80-4.89 (1H, t), 5.50-5.55 (1H, t), 6.72 (1H, a, U 8.8) , 7.09-7.21 (ZH, t), 7.37 (IN, y, 9 0.8), 7.43-7.49 (1H, t), 7.69 (1H, 0), 7.77 (IN, y), 8.14 (1H, 5), 8.21 (IN, 9).

Example 22

Salt 1-(5-tert-Butyl-2-13-(2-(4-hydroxy-piperidin-1-yl)-ethoxy|-phenyl)-2H-pyrazol-3-yl)-3- (15, 48 )-4-(3-isopropyl-(1,2,4)griazolo|4,3-a|Ipyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|- urea formate and

Y 9 If rn zo: M

NN

S. Sui

Look at it. 5-tert-Butyl-2-(3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-ylamine (intermediate 22a) in more mn, le

Triisopropylsilyl chloride (1.02 mL, 3.96 mmol) was added to a solution of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (915 mg, 3.96 mmol) and imidazole (646 mg, 9.50 mmol) in DMF (15 mL) at 0 °C. The reaction was stirred at RT over the weekend, then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Md9505), filtered and evaporated in vacuo. The residue was purified by EHS using 0-40 96 EtOAc in cyclohexane to give the title compound (1.53 g, 99 90). LCMS (Method 4): ET 4.78 min, t/7 388 (MNU ) (c) 3. HC

M. SI

MOm os

From "SOLUTION" 2,2,2-TRichloroethyl chloroformate (1.09 mL, 7.92 mmol) was added to a solution of intermediate 22a (1.53 g, 3.96 mmol) and OIREA (2.75 mL, 15.8 mmol) in THF (40 ml) at 0 "С. The reaction was stirred at CT for 3 h. then partitioned between EIOAc and water. The aqueous layer was then extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (MASO), filtered and evaporated in vacuo. The residue was purified by ESS using 0-50 96 EtOAc in cyclohexane to give the title compound (2.22 g, 99 95). LCMS (method 4): CI 5.55 min., t/72 560, 562 (MNU. p.0001-(5-tert-Butyl-2-(3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl) |-3-((15, 48)-4-(3-isopropyl-(1,2,4)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro- naphthalene-1-yl|-urea (intermediate 22c) va

Fi nn

OTIRZ

Intermediate 22p (390 mg, 0.69 mmol) was added to a solution of intermediate 19 (223 mg, 0.69 mmol) and OSIREA (240 μL, 1.38 mmol) in 1,4-dioxane (6.0 mL). The reaction was heated to 60°C for 3 hours and heated at 45°C overnight. The reaction was cooled and partitioned between

ETA and water. The aqueous layer was then extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (M9505), filtered and evaporated in vacuo. Remainder

Z was purified by ESS using 0-10 96 MeOH in DCM to give the title compound (258 mg, 50 95).

LCMS (method 2): RI 4.93 min., t/2 736 (MNU. a. 1-(b-tert-Butyl-2-(3-hydroxy-phenyl)-2H-pyrazol-3-yl|- 3-К15, 4Н)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (intermediate 22a)

vych ruk ooh A

NN on

TVAE (1M in THF, 350 μL, 0.35 mmol) was added to a solution of intermediate 22s (258 mg, 0.35 mmol) in THF (5.0 mL) at 0 °C. The reaction was stirred for 1 h, then partitioned between

ETA and water. The aqueous layer was then extracted with EAs (3x). The combined organic layers were washed with brine, dried (M9505), filtered and evaporated in vacuo. The residue was purified by ES using 0-10 95 MeOnN in DCM to give the title compound as an off-white solid (150 mg, 75 95). RHMS (method 1): CI 4.11 min., t/7 580 MN. "H NMR (400 MHz, a-MeOb): 1.30 (9H, 5), 1.42 (ZN, 4, 9 6.9), 1.45 (ZN, a, y 6.9), 1 ,88-2.16 (ZH, t), 2.20-2.30 (1H, t), 3.51 (1H, septet, U 6.9), 4.90 (1H, aa, y 8, 9, 5.6), 5.45 (IN, i, 9 4.1), 6.33 (1H, 5), 6.84 (1H, aaa, U 8.3, 2.6, 0.6 ), 6.88-6.94 (2H, t), 7.19-7.26 (2H, t), 7.26-7.33 (4H, t), 7.61 (IN, 4, 9U10 ,0), 8.01 (1H, 5). e. salt 1-(5-tert-Butyl-2-13-(2-(4-hydroxy-piperidin-1-yl)-ethoxy|-phenyl)- 2H-pyrazol-3-yl)-3-(15, 48)-4-(3-isopropyl-(1,2,4)griazolo|4,3-a|Ipyridine-b-yloxy)-1,2, 3,4-tetrahydro-naphthalene-1-yl|- urea formate (example 22)

PIAO (51.0 μl, 0.260 mmol) was added to a solution of intermediate 224 (75.0 mg, 0.13 mmol), 4-hydroxy-1-piperidine-ethanol (28.0 mg, 0.19 mmol), and RizR ( 68.0 mg, 0.26 mmol) in THF (1.5 mL) at 0 °C. The reaction was stirred at RT over days off, then partitioned between EIOAc and water. The aqueous layer was extracted with Es (Z x). Combined organic layers washed with brine, dried (M9505), filtered and evaporated in vacuo. The residue was purified by EES using 0-10 55 (2M Mnz in MeonNi in DCM. Further purification by HPLC (column C18 X-5eviesi, 25-98 95

MesmM in HgO, 0.1 95 HSO»N) gave the title compound as a white powder (57 mg, 62 965) after freeze-drying. LCMS (method 5): RI 3.32 min., t/7 707.4 (MNY|. "H NMR (400 MHz, a-meob): 1.31 (9H, 5), 1.42 (ZH, y, U 6.8), 1.45 (ZN, a, U 6.8), 1.62-1.72 (2H, t), 1.86-2.04 (4H, t), 2, 04-2.14 (1H, t), 2.21-2.30 (1H, t), 2.69-2.79 (2H, t), 3.11-3.19 (4H, t), 3.51 (1H, septet, U 6.9), 3.70-3.78 (IN, t), 4.26 (2H, i, U 5.3), 4.89 (IN, ad, U 8.9, 5.8), 5.45 (IN, i, U 4.1), 6.93 (1H, 5), 7.05 (IN, ad, y 8.4, 2.7, 0 ,8), 7.09-7.13 (2H, t), 7.19-7.25 (ZH, t), 7.26-7.33 (2H, t), 7.42 (1H, 19 81), 7.81 (1H, aa, y 9.7, 0.6), 8.01 (IN, y, y 1.7), 8.42 (1H, Bi 5).

Example 23 1-(b-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl|-3-K15, 4nH)-4-(3-isopropyl-

Zo P1,2,4Hygriazoloi|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea and / (6) SM hereno; IF

Fsh

M. G. A. 2-(3-Bromo-phenyl)-5-tert-butyl-2H-pyrazol-3-ylamine (intermediate 23Za) / oi

A mixture of 3-bromophenylhydrazine hydrogen chloride (5.00 g, 22.4 mmol) and 4,4-dimethyl-3-oxopentanitrile (4.29 g, 33.6 mmol) in absolute ethanol (55 mL) was stirred under reflux for 6 p.m. and cooled, then concentrated in vacuo. The residue was suspended in sat. aq. NaOH (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried (Mag2504) and concentrated in vacuo. The residue was cleaned by ESS, using 0-5 95 (2M МНз у

MeoniI in DCM to give the title compound (3.56 g, 54 95). RHMS (method 1): Ki 3.33 min., Etp/2 294, 296 |MNYA. r. Di-tert-butyl (1-(3-bromophenyl)-3-tert-butyl-1H-pyrazole-5-ylimido dicarbonate

(intermediate 236) (o)

Hu ish "M U (9)

Fe X-

Hg

Di-tert-butyl dicarbonate (3, 33 g, 15.3 mmol), and the mixture was stirred at room temperature for 20 h. The mixture was diluted with DCM, washed with water, then dried (Ma9505), filtered and concentrated in vacuo. The residue was purified by ESF using 0-2.5 96 MeOnN in DCM to give the title compound (1.97 g, 78 905). "H NMR (400 MHz, a-meon): 1.33 (27H, 5), 6.13 (1H, 5), 7.25 (1H, 4 3.93, 728 1H, and U 8.0) , 7.35-7.40 (1H, t), 7.41-7.A7 (IN, t). p. (b-tert-Butyl-2-(3Z-morpholin-4-yl-phenyl) 2H-pyrazol-3-yl|-carbamic acid tert-butyl ester (intermediate 23c) (c)

Hu ich - M

MN

Su,

Co

A mixture of intermediate 23p (900 mg, 1.80 mmol), morpholine (240 mg, 2.70 mmol), potassium tert-butoxide (303 mg, 2.70 mmol), 2-dicyclohexylphosphino-2,4,6 -triisopropyl biphenyl (87 mg, 0.18 mmol) and tris(dibenzylideneacetone)udipalladium(0) (81 mg, 0.09 mmol) in THF (9 mL) were irradiated with microwaves at 100 C for 20 min. The reaction was diluted with water and extracted with EOAc (x 2). The combined organics were washed with brine, dried (Ma950O5), filtered and evaporated in vacuo. The residue was purified by ESS using 0-100 96 EOAc in cyclohexane to give the title compound (290 mg, 40 95). RHMS (method 7): RI 3.94 min., t/2 401

IMNU and. 5-tert-Butyl-2-(Z-morpholin-4-yl-phenyl)-2H-pyrazol-3-ylamine (intermediate 23a) /

SA

Co

A solution of intermediate 23c (290 mg, 0.725 mmol) and TFOC (3 mL) in DCM (4 mL) was stirred at RT for 1 h. The reaction mixture was applied to the ZSKH-2 cartridge (10 g) and washed with mMeon. The product was eluted with 2M MHz in MeonN; concentrated in vacuo to give the title compound (190 mg, 86 95). RHMS (method 1): CI 2.29 min., t/: 301 MN). e. (b-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl|.-carbamic acid 2,2,2-trichloro-ethyl-ester (intermediate 23e) (9) Si

M Zh ottvs mi si o

Co

Zo 2,2,2-TRichloroethylchloroformate (175 mg, 0.82 mmol) was added dropwise to a solution of intermediate 234 (190 mg, 0.63 mmol) and OIREA (244 mg, 1.89 mmol) in THF (10 mL), and the mixture was stirred at RT for 1.5 h. The mixture was diluted with water and extracted with EOAS (x 2).

The combined organic layers were washed with brine, dried (Moa 5 O 4 ), filtered and evaporated in vacuo. The residue was purified by ESS using 0-50 96 EtOAc in cyclohexane to give the title compound (140 mg, 46 95). RHMS (method 4): KI 3.94, t/72 475 |MNY.

Y. 1-(b-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl|-3-K15, 4H)-4-(3-isopropyl-

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (example 23)

A solution of intermediate 19 (64 mg, 0.20 mmol), intermediate 23e (140 mg, 0.29 mmol), and OIREA (103 mg, 0.80 mmol) in DMF (2 mL) was stirred at 60 °C for 1 h. The reaction mixture was applied to a ZSKH-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M MNH

Meon; concentration in vacuo gave a residue. ESS, using 0-10 95 (2M MHz in MeOHnI in

DCM followed by HPLC (Sb-RP column, 10-70 95 MesmMm in HO, 0.195 HCO 2 H) gave, after freeze drying, the title compound as a white powder (46 mg, 38,965). LCMS (method 5): KE 4.39 min., t/7 649.2 MN"). "H NMR (400 MHz, a--Meon): 1.30 (OH, 5), 1.44 (6Н , t), 1.85-2.05 (2H, t), 2.05-2.16 (1H, t), 2.19-2.29 (1H, t), 3.15 (4H, i , U 3.8), 3.47-3.56 (1H, t), 3.76 (4H, i,

U 4.9), 4.86-4.92 (1H, t), 5.44 (IN, y, U 4.3), 6.32 (1H, 5), 6.91 (IN, y, U 8.1), 7.00-7.05 (2H, t), 7.19-7.38 (6H, t), 7.60 (TN, a, U 9.5), 8.00 ( 1H, a, U 1,6).

Example 24 1-5-tert-Butyl-2-|1-(2-morpholin-4-yl-ethyl)-1H-indazol-b-yl|-2H-pyrazol-3-ylHy-3-K15, 48) -4-(3-isopropyl-(1,2,4)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

M mm winter

NN I; and M c) -ki m a. 5-tert-Butyl-2-|1-(2-morpholin-4-yl-ethyl)-1H-indazol-b-yl|-2H-pyrazole-z-ylamine (intermediate 24a) and 5-tert-butyl -2-(2-(2-morpholin-4-yl-ethyl)-2H-indazol-b-yl|-2H-pyrazol-3-ylamine (intermediate 245) / that in

THE SAME

M. m MN

M;

M

Shh but h-

M more

M

A solution of 5-tert-butyl-2-(1H-indazol-b-yl)-2H-pyrazol-3-ylamine (052008/113967, 200 mg, 0.78 mmol) was formed in DMF (10 mL). 4-(2-Chloroethyl)morpholine hydrochloride salt (160 mg, 0.86 mmol) and K2CO3 (276 mg, 2.0 mmol) were added and the mixture was heated at 50 °C overnight. The mixture was allowed to cool to RT, then was partitioned between EtOAc/water and extracted with EtOAc.

The combined organics were dried over Mag50, filtered and concentrated in vacuo. Cleaning

ESS using 0-10 95 MeonN in EIOAc gave two products. First elution: 5-tert-butyl-2-1-(2-morpholin-4-yl-ethyl)-1H-indazol-b-yl|-2H-pyrazol-3-ylamine (intermediate 24a; 134 mg, 57 Ob ) as a yellow solid. LCMS (method 1): RI 1.81, t/2 369 MH"). Second elution: 5-third-

Zo butyl-2-(2-(2-morpholin-4-yl-ethyl)-2H-indazol-b-yl|-2H-pyrazol-3-ylamine (intermediate 2465; 86 mg, 3095) as a yellow solid. RHMS (method 1): B 1.68, t/72 369 |МН'). The regioisomeric structure was confirmed by H NMR poe.

B. 0/0 5-tert-Butyl-2-/1-(2-morpholin-4-yl-ethyl)-1H-indazol-b-yl|-2H-pyrazol-3-yl-carbamic acid 2, 2,2-trichloro-ethyl ester (intermediate 24c) and

SI and N o Co

SI

Ki what, -

A solution of intermediate 24a (134 mg, 0.36 mmol) was formed in THF (10 mL). OSIREA was added

(125 μl, 0.72 mmol), and then a solution of 2,2,2-trichloroethyl chloroformate (50

NO, 0.36 mmol) in THF (2 mL). The mixture was stirred at RT for 4 hours, then distributed between

EOAc/water and extracted with EIOAc. The combined organics were dried over Mag2505, filtered and concentrated in vacuo. Purification of ESS using 0-10 96 MeoN in EIOACsS afforded the title compound (200 mg, 99 95) as a colorless film. RHMS (method 4): CI 2.59, t/7 543, 545 MNY. with. 1-(5-tert-Butyl-2-(1-(2-morpholin-4-yl-ethyl)-1H-indazol-b-yl|-2H-pyrazol-3-yl)y-3-K15, 48 )-4-(3-isopropyl-P1,2,4H-triazolo|4,3-a|pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (example 24)

The title compound was obtained as an off-white solid (65 mg, 50 95) using intermediate 19 (71 mg, 0.22 mmol) and intermediate 24c (100 mg, 0.18 mmol) in a manner similar to that of Example 1. RHMS (method 5): RI 3.40 min., t/2 717 (MNYA. "N

NMR (400 MHz, de-DMSO): 1.30 (9H, 5), 1.37 (ZN, a, U 6.9), 1.38 (ZN, a, 9 6.9), 1.80 -1.97 (2H, t), 2.05-2.10 (2H, t), 2.41 (4H, horn 5), 2.75 (2H, Big 5), 3.49 (4H, Big 5), 3.56 (1H, septet, U 6.9), 4.52 (2H, t), 4.79-4.85 (1H, t), 5.52 (IN, i, U 4, 5), 6.40 (1H, 5), 7.06 (1H, y, U 8.5), 7.13 (1H, aa, y 9.7, 2.0), 7.22-1, 29 (AN, t), 7.36-7.39 (1H, t), 7.68 (IN, y, in 9.7), 7.83 (1H, 5), 7.87 (IN, a , U 8.5), 8.13-8.19 (ZN, t).

Example 25 1-5-tert-Butyl-2-(2-(2-morpholin-4-yl-ethyl)-2H-indazol-b-yl|-2H-pyrazol-3-ylHy-3-K15, 48 )-4-(3-isopropyl-(1,2,4)griazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea

We are in zi

NN tm and M t

M a (5-tert-Butyl-2-(2-(2-morpholin-4-yl-ethyl)-2H-indazol-b-yl|-2H-pyrazol-3-yl-carbamic acid 2,2,2 -trichloro-ethyl ester (intermediate 25a) v. Kh

SI nn slveh

SI and;

M

-

What;

M o

To a solution of intermediate 2460 (86 mg, 0.23 mmol) in THF (10 mL) was added OIREA (80 n, 0.46 mmol), followed by dropwise addition of a solution of 2,2,2-trichloroethyl chloroformate (32 mL, 0.23 mmol) in THF (2 mL). The mixture was stirred at RT for 4 h, then partitioned between EOAc/water and extracted with EOAc. The combined organics were dried over Ma»5O», filtered and concentrated in vacuo. Purification of ESS using 0-20 96 MeonN in EIOACsS afforded the title compound (32 mg, 26 95) as a yellow solid. RHMS (method 4): CI 2.64, t/: 543, 545 |MNYA.

From p. 1-(5-tert-Butyl-2-(2-(2-morpholin-4-yl-ethyl)-2H-indazol-b-yl|-2H-pyrazol-3-yl)y-3- K15, 48)-4- (3-isopropyl-P1,2,4H-triazolo|4,3-a|pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea ( example 25)

The title compound was obtained as an off-white solid (16 mg, 47b) using intermediate 19 (23 mg, 0.07 mmol) and intermediate 25a (32 mg, 0.06 mmol) in a manner similar to that of Example 1 RHMS (method 5): CI 3.43 min., t/2 717 (MN). "H NMR (400

MHz, a6e-DMSO): 1.29 (9H, 5), 1.37 (ZN, a, U 6.1), 1.38 (ZN, a, U 6.1), 1.81-1, 97 (2H, t), 2.03-2.13 (2H, t), 2.42 (AN, i, U 4.3), 2.85 (2H, 1, U 6.3), 3, 50-3.60 (5H, t), 4.56 (2H, i, U 6.3), 4.80-4.86 (1H, t), 5.52 (IN, 1, U 4.3 ), 6.96 (1H, 5), 7.11 (IN, a, y 8.5), 7.14-7.19 (2H, t), 7.25-7.30 (ЗН, t) , 7.36-7.39 (1H, t), 7.65 (1H, t), 7.68 (IN, y, Y 9.8), 7.83 (IN, y, Y 9.0) , 8.16 (1H, 5), 8.20 (IN, t), 8.48 (IN, 5).

Example 26 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-3-(15,4nH)-4-I3-(2,6-dichloro-phenyl) )-

P1,2,4Hygriazoles|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea -o si

M. - same m

A nn he a. (b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-carbamic acid 2,2,2-trichloro-ethyl-ester (intermediate 26ba) v. i

M. SI mu eye and SI on

To a mixture of intermediate 10a (367 mg, 2.0 mmol) in water (1 mL) and EIAs (4 mL) was added MaAON (107 mg, 2.67 mmol), followed by 2,2,2-trichlorochloroformate (385 μl, 2.80 mmol). The reaction mixture was stirred at RT for 2 h and then diluted with additional EtOAc. The organic layer was washed with water and then with brine, dried and concentrated in vacuo. The resulting residue was purified by ESS using 0-80 906 EtOAc in DCM to give the title compound (466 mg, 65 95) as a colorless oil which solidified on standing.

RHMS (method 3): RI 3.73 min., t/2 358, 360 MN. r. 2,6-Dichloro-benzoic acid M'-(5-fluoro-pyridin-2-yl)-hydrazide (intermediate 2660)

SI

SI

NM

NM

LEE:

M --

IS

OSIREA (2.73 mL, 15.7 mmol) was added dropwise to a solution of (5-fluoro-pyridin-2-yl)-hydrazine (reference see UMO2010022076; 1.0 g, 7.87 mmol) and 2,6-dichloro -benzoyl (1.65 g, 7.87 mmol) in DCM (50 mL). The reaction mixture was stirred at RT for 30 min., and then suspended in DCM and water. The resulting suspension was filtered and the solid collected by filtration, washed with water and air dried to give the title compound (1.66 g, 71 95) as a white solid. RHMS (method 3): MI 3.04 min., pt/7 300, 302 |MNYA. with. 3-(2,6-Dichloro-phenyl)-6-fluoro-(1,2,4H-triazolo|4,3-a|pyridine (intermediate 26c)

IF)

E SI

- Si

KU B

Hexachloroethane (2.60 g, 11.0 mmol) was added in moderate portions over 5 min. at

CT to a stirred mixture of intermediate 265 (1.65 g, 5.50 mmol), triphenylphosphine (2.88 g, 11.0 mmol), and triethylamine (3.06 mL, 22.0 mmol) in THF (50 mL). The reaction mixture was stirred at

CT for 18 hours, and then she was allowed to stand for CT for 72 hours. The obtained suspension was filtered and the filtrate was concentrated in a vacuum and purified by ESS using a 5СХ-2 cartridge.

The cartridge was washed with MeonH and the product eluted with 2M Mn in MeonH to give the title compound (1.44 g, 93 95) as a beige solid. RHMS (method 3): RI 3.08 min., pt/l 282, 284 |MNYA.. a. (15, 4nH)-4-I3-(2,6-Dichloro-phenyl)-1,2,4griazoloi|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene -1-ylamine (intermediate 264) bo

And about SI nom At

Intermediate 14 (404 mg, 2.48 mmol) was added to a stirred solution of sodium hydride (6095 in mineral oil, 298 mg, 7.44 mmol) in anhydrous DMF (15 mL) at RT under an argon atmosphere. The reaction mixture was stirred at RT for 15 min., then intermediate 26s (0.70 g, 2.48 mmol) was added, and stirring was continued at 60 °C for 1 h.

After cooling, the reaction mixture was quenched by the careful addition of a saturated aqueous solution of MNACI and water (1:1) and extracted with EtOAc (x 3). The combined organic layers were washed with saturated aq. with MansSoOz solution, and then with brine, dried and concentrated in a vacuum.

The resulting residue was purified by ECC using 0-20 95 (2M MNz in Meon | in DCM) to give the title compound (345 mg, 33 95) as a brown precipitate. LCMS (Method 3): CI 2.34 min, t/L 425, 427. |MNAU. e. 1-(B-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-3-(15, 48)-4-IZ3-( 2,6-dichloro-phenyl)-

P,2,4Hygriazolo|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea (example 26)

A mixture of intermediate 2ba (100 mg, 0.279 mmol), intermediate 26a (108 mg, 0.254 mmol) and

PIREA (73 μL, 0.419 mmol) in dioxane (2.5 mL) was stirred at 60 °C for 42 h and then allowed to stand at RT for 72 h. The volatiles were concentrated in vacuo and the resulting residue was purified by ESS using 0- 10 95 MeonN in DCM followed by MOAR (Method 7) to give the title compound (23 mg, 14 95) as a white solid LCMS (Method 5): GI 4.19 min, t/7 634

NAMES "H NMR (400 MGu, DMSO): 1.21 (9H, 5), 1.79-2.16 (4H, t), 3.62-3.70 (2H, t), 3.94 (2H , 1, 96.0 Hz), 4.78-4.88 (1H, t), 4.99 (1H, brg 5), 5.55 (1H, i, 9U-4.2 Hz), 6, 05 (IN, 5), 7.07 (1Н, а, 9у-8.6

Hu, 7.23-7.30 (1H, t), 7.31-7.38 (4H, t), 7.70-7.74 (1H, t), 7.74-7.80 (2H , t), 7.91 (1H, a, uU-9.9

Hz), 7.98 (IN, a, 9-21 Gu), 8.19 (1H, 5).

Example 27 (c) no she

MT JSC

And nn

WITH

(in)

Salt 1-(b-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-(15, 48)-4-I3-(2,6- dichloro-phenyl)-(1,2,4)griazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea formate

To a stirred solution of Example 26 (38 mg, 0.06 mmol) and methanesulfonyl chloride (7.0 μL, 0.09 mmol) in DCM (1 mL) was added OSIREA (31 μL, 0.18 mmol). The reaction mixture was stirred at RT for 1 hour, then diluted with DCM, washed with water, and then saturated. aq. MansSoOz solution and brine, dried and concentrated in a vacuum. The resulting residue was dissolved in THF (2 mL) and treated with morpholine (26 μL, 0.30 mmol). The reaction mixture was heated at 60 C for 18 hours, then the volatiles were concentrated in a vacuum. The resulting residue was partitioned between DCM and water. The organic layer was washed with brine, dried and concentrated in vacuo. The resulting residue was purified by MOAR (Method 7) to give the title compound (13 mg, 30 95) as an off-white solid. RHMS (method 5): RI 3.56 min., t/7 703

NAMES "H NMR (400 MGu, DMSO): 1.20 (9H, 5), 2.15-1.82 (4H, t), 2.41-2.35 (4H, t), 2.61 (2H , 1, u7.1 Hu, 3.53 (4H, 1, U-4.6 Hu), 3.98 (2H, 1, 9-71 Hu), 4.79-4.88 (1H, t) , 5.55 (1H, 1, 9-42 Hz), 6.02 (TN, 5), 6.95 (IN, a, 9-8.6 Hz), 7.24-7.30 (1H, t), 7.31-7.39 (4H, t), 768-7.80 (ZH, t), 7.91 (1H, a, 929.9 Hz), 7.98 (1H, a, U -2.1 Hu), 8.24 (2H, 5).

Example 28

1-(b-tert-Butyl-2-(2-dimethylamino-ethyl)-2H-pyrazol-3-yl|-3-(15, 48)-4-I3-(2,6-dichloro-phenyl) salt -(1,2,4)triazolo|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea formate

(o) but A

SI t o Sh

M. mm zy 4 nn

And a. Methanesulfonic acid 2-|3-tert-butyl-5-(3-(15, 4H)-4-I3-(-2,6-dichloro-phenyl)-

P,2,4griazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalen-1-yl)y-ureido)-pyrazol-1-yl|- ethyl ester (intermediate 28a) -o si

M. in winter

And nn (in) ogo

A mixture of Example 26 (350 mg, 0.55 mmol), methanesulfonyl chloride (55 μL, 0.72 mmol) and

PIREA (288 μL, 1.65 mmol) in DCM (4 mL) was stirred at RT for 45 min. An additional amount of methanesulfonyl chloride (15 μl) was added and stirring was continued for 30 min. An additional amount of methanesulfonyl chloride (15 μL) was added and stirring was continued for 20 min. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, dried through a phase centrifuge and concentrated in vacuo to give the title compound (0.33 g, 84 95) as a pale yellow solid. RHMS (method 3): RI 3.77 min., t/2 712, 714. (MNYA.

B, /1-(5-tert-Butyl-2-(2-dimethylamino-ethyl)-2H-pyrazol-3-yl|-3-(15,4H8)-4-(3-(2,6-dichloro - phenyl)-(1,2,4)triazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea (example 28)

A mixture of intermediate 2b8a (110 mg, 0.15 mmol) and dimethylamine (2.0 M in THF, 1.54 mL, 3.09 mmol) in anhydrous THF (2 mL) was stirred at 60 °C for 18 h in a sealed vessel . Volatiles were concentrated in vacuo and the resulting residue was purified by MOAR (Method 7) to give the title compound (44 mg, 43 95). LCMS (Method 5): CI 3.50 min., t/2 661 |MNUYA. "H NMR (400 MHz, DMSO): 1.19 (9H, 5), 1.83-2.14 (4H, t), 2.18 (6H, 5), 2.59 (2H, 1, U-6, 9 Hz), 3.96 (2H, 1, 3-6.9 Gu), 4.79-4.87 (IN, t), 5.53 (IN, i, 9U-4.0 Hz), 6 .01 (1H, 5), 6.92 (1H, a, 9-8.7 Gu, 7.22-7.28 (IN, t), 7.30-7.38 (4H, t), 7 .68-7.78 (ZH, t), 7.90 (1H, aa, U-9.9, 0.68 Hz), 7.96 (1H, a, 9U-2.0 Gu, 8.15 (1H, 5), 8.44 (1H, 5).

Example 29

Salt 1-(5-tert-butyl-2-(2-piperidin-1-yl-ethyl)-2H-pyrazol-3-yl|-3-(15,4H8)-4-(3-(2,6 -dichloro-phenyl)-(1,2,4)triazoloi|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea formate (c) non what are you

M - zi

A nn o

Z The title compound was obtained starting from intermediate 2b8a and piperidine, using procedures similar to those described in example 28. LCMS (method 5): CI 3.73 min., t/2 701 (MNY|. "H

NMR (400 MHz, DMSO): 1.20 (9H, 5), 1.30-1.39 (2H, t), 1.51-1.41 (AN, t), 1.81-2.16 (AN, t), 2.34-2.43 (AN, t), 2.60 (2H, her, 9-71 Hu), 3.97 (2H, her, 9-71 Hu), 4.79 -4.88 (1H, t), 5.55 (1H, i, U-4.2 Gu), 6.02 (1H, 5), 6.92 (1H, a, 9-8.6 Hz) , 7.20-7.31 (IN, t), 7.31-7.39 (4Н, t), 7.69-7.79 (ЗН, t), 7.91 (1Н, aa, 9- 9.9, 0.68 Hz), 7.97 (1H, a, U-2.0 Hz), 8.16 (1.5H, 5), 8.28 (1H, 5).

Example 30

(c) non she si she and M

And nn

Co

M

Salt /1-5-tert-Butyl-2-(2-(4-methyl-piperazin-1-yl)-ethyl|-2H-pyrazol-3-yl)-3-(15,4B8)-4-I3 - (2,6-dichloro-phenyl)-I|1,2,4|triazolo|4,3-a|Ipyridin-6b-yloxy|-1,2,3,4-tetrahydro-naphthalen-1-yl) - urea formate

The title compound was obtained starting from intermediate 28a and 1-methyl-piperazine using procedures similar to those described in Example 28. LCMS (method 5): CI 3.41 min., It/2 716.5 |MNY). "H NMR (400 MHz, DMSO): 1.20 (9Н, 5), 1.82-2.12 (4Н, t), 2.14 (ЗН, 5), 2.25-2.45 (ВН , t), 2.60 (2H, her, 9-7.15 Hz), 3.96 (2H, 1, 9-71 Gu), 4.79-4.88 (1H, t), 5.55 (IN, i, 9-42 Hu), 6.02 (1H, 5), 6.90 (1H, a, 9-86 Hu), 7.24-7.30 (1H, t), 7.31 -7.40 (4H, t), 7.68-7.79 (ZH, t), 7.91 (1H, a, U-9.9

Hu), 7.968 (1H, a, 9U-2.0 Hz), 8.16 (1.5H, 5), 8.22 (1H, 5).

Example 31 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-3-(15,4H)-4-I3-(2-chloro-phenyl)-

P1,2,4Hygriazoloi|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea si what sh-x M

A nn he a. 2-Chloro-benzoic acid M'-(5-fluoro-pyridin-2-yl)-hydrazide (intermediate Z1a)

SI

NM

NM

ICE

M --

IS

To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (ref. see UMO2010022076; 1.0 g, 7.87 mmol) and 2-chloro-benzoyl chloride (1 mL, 7.87 mmol) in DCM (50 ml) was added dropwise OSIREA (2.74 ml, 15.75 mmol). The reaction mixture was stirred at RT for 1 hour, then washed with water. The organic layer was dried via phase centrifugation and then concentrated in vacuo to give the title compound (1.95 g, 93 95) as a brown solid. RHMS (method 3): CI 2.82 min., t/2 266 MN. r. 3-(2-Chloro-phenyl)-6-fluoro-I1,2,4|griazolo|4,3-a|pyridine (intermediate 315)

E SI sa si zi i

Hexachloroethane (3.47 g, 14.68 mmol) was added in moderate portions at RT to a stirred mixture of intermediate Za (1.95 g, 7.34 mmol), triphenylphosphine (3.85 g, 14.68 mmol), and triethylamine (4 .12 mL, 29.36 mmol) in anhydrous THF (60 mL). The reaction mixture was stirred at RT for 3.5 h. The resulting suspension was filtered, washing the solid

ESO The filtrate was concentrated in vacuo and the resulting residue was purified by ESS using

From the 5СХ-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 2M MeOH to give the title compound (1.81 g, quant.) as a tan solid. RHMS (method 3):

KI2.96 min., t/2 248 |MNU.

with. (15, 48)-4-I3-(2-Chloro-phenyl)-(1,2,4)griazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro- Naphthalene-1-ylamine (intermediate Z31c) (o; SI soy

NM M

Sodium hydride (60 95 in mineral oil, 840 mg, 21.9 mmol) was added in moderate portions to a stirred solution of intermediate 14 (1.19 g, 7.31 mmol) in anhydrous DMF (30 mL) at RT under argon atmosphere. Intermediate Z1r (1.81 g, 7.31 mmol) was then added, and stirring was continued at 60 °C for 1.5 h. After cooling, the reaction mixture was quenched by careful addition of a saturated aqueous solution of MNACI and extracted with EOHUAcS (x 2).

The combined organic layers were washed with brine, dried (Moa5O5) and concentrated in vacuo.

The resulting residue was purified by ESS using 0-10 96 MeoN in DCM to give the title compound (1.48 g, 52 95) as a brown foam. RHMS (method 3): CI 0.42 and 2.33 min., t/2 391. |MNAU. and. 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-3-(15,4H)-4-I3-(2-chloro-phenyl)-

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea (example 31)

A mixture of intermediate 26ba (340 mg, 0.95 mmol), intermediate C1c (372 mg, 0.95 mmol) and OIREA (248 μl, 1.43 mmol) in dioxane (5 ml) was stirred at 70 °C for 18 h. After cooling to RT, the reaction mixture was partitioned between DCM and water. The organic layer was dried via phase centrifugation and then concentrated in vacuo. The resulting residue was purified by ESS using 0-10 96 Meon in DCM to give the title compound (536 mg, 94 95) as a brown solid. An aliquot of the resulting compound (100 mg) was then purified by MOAR (Method 7) to give the title compound (45 mg). LCMS (Method 5): CI 4.08 min, t/72 600 MN. "H NMR (400 MHz,

DMSO): 1.20 (9H, 5), 1.81-2.19 (4H, t), 3.66 (2H, a, U-6.1 Hz), 3.93 (2H, i, 9U -6.0 Hz), 4.78-4.84 (1H, t), 4.98 (1H, Bg 5), 5.51 (IN, i, 92-43 Gu), 6.05 (1H, 5), 7.06 (1H, a, 9-86 Hz), 7.23-7.30 (1H, t), 7.32-7.38 (4H, t), 7.60 (1H, yuyu , U-7.5, 1.3 Hu), 7.68 (1H, a, 97.7, 1.9 Hu), 7.73 (2H, 1, 9-75, 1.3

Hu), 7.82-7.92 (2H, t), 8.17 (1H, 5).

Example 32 (c) non a che a zi

And nn

WITH

(in)

Salt 1-(3-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-(15, 48)-4-3-(2-chloro- phenyl)-(1,2,4)triazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydro-naphthalene-1-yl-urea formate

From a mixture of Example 31 (100 mg, 0.17 mmol), methanesulfonyl chloride (38 μL, 0.33 mmol) and

PIREA (87 μl, 0.50 mmol) in DCM (1 ml) was stirred at RT for 45 min. An additional amount of methanesulfonyl chloride (20 μL) was added, and stirring at RT was continued for 20 min. The reaction mixture was diluted with DCM, washed with water (x 2) and then with brine, dried through a phase centrifuge and concentrated in vacuo. The resulting residue was dissolved in THF (1 mL) and treated with morpholine (73 μL, 0.83 mmol). An additional amount of morpholine (73 μL, 0.83 mmol) and THF (1 mL) were added, and the reaction mixture was heated at 60 °C for 18 h. After cooling, the volatiles were concentrated in vacuo, and the resulting residue was purified by MOAR (Method 7) to give afforded the title compound (46 mg, 41 90) as an off-white solid. "H NMR (400 MHz, DMSO): 1.20 (9Н, 5), 1.83-2.19 (AN, t), 2.35-2.41 (AN, t), 2.61 (2Н , her, 957.1 Hu), 3.54 (AN, her, 2-46 Hu), 3.99 (2H, 1, 9-71 Hu), 4.79-4.88 (1H, t), 5.52 (IN, i, 9-4.2 Hz), 6.03 (1H, 5), 6.94 (1H, a, 9U-8.6 Gu), 7.24-7.31 (1H , t), 7.32-7.39 (4H, t), 7.69 (1H, a,

U7.7, 1.8 Hu, 7.68 (1H, a, 9-77, 1.8 Hu, 7.72-7.78 (2H, t), 7.84-7.92 (2H, t ), 8.18 (1H, 5), 8.22 (IN, 5).

Example 33 1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(15,4nH)-4-I3-(2,6-dichlorophenyl)-

P1,2,4)griazolo|4,3-a|pyridin-b-yloxy|-1,2,3,4-tetrahydronaphthalen-1-yl|-urea a

SI ve o fe;

M yes - AsM! NN a. (b-tert-Butyl-2-methyl-2H-pyrazol-3-yl)y-carbamic acid 2,2,2-trichloro-ethyl-ester (intermediate ZZa) re m si

M note / and SI

A solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-ylamine (0.5 g, 3.26 mmol) in EtOAc (10 mL) was treated with aqueous Mahon (1M, 5.87 mmol), and then 2,2,2-trichloroethyl chloroformate (0.54 mL, 3.92 mmol), and the reaction mixture was stirred at RT for 1 h. The mixture was distributed between

EtOAc (10 mL) and water (2 x 10 mL). The organic layer was dried (M950O4), filtered and concentrated in vacuo. The residue was purified by ESS using 0-100 90 EAs in cyclohexane to give the title compound as a pale orange resin (0.915 g, 86 95). RHMS (method 3): RI 3.88 min., t/2 328/330 |NAME.

Yub. 0/01-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(15,4H8)-4-I3-((5)-2-methyl-piperidin-1-yl )-

P1,2,4Hygriazoloi|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydronaphthalen-1-yl|-urea (example 33)

A solution of intermediate ZZa (70 mg, 0.21 mmol), intermediate 26a (90 mg, 0.21 mmol) and OSIREA (55 μl, 0.32 mmol) in dioxane (1 ml) was heated at 70 °C for 18 h. The mixture was concentrated in vacuo and the residue was purified by MOAR (method 7) to give the title compound as a glassy solid (38 mg, 29 95). ). "H NMR (400

MHz, ave-DMSO): 1.20 (9H, 5), 1.83-2.15 (4H, t), 3.56 (ZH, 5), 4.79-4.88 (1H, t) , 5.55 (IN, 1, y) 4.6

Hu), 6.01 (1H, 5), 6.86 (1H, a, U 8.5 Hz), 7.23-7.29 (1H, t), 7.31-7.37 (4H, t), 7.69-7.79 (ZN, t), 7.91 (IN, aa, 9 9.7, 0.9 Gu), 7.98 (1H, y, U 2.2 Hz), 8.23 (1H, 5).

Example 34

Salt. 1-(B-tert-butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-K15, 48)-4-(3-cyclohexyl-

P1,2,4Hygriazoloi|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-yl|-urea partial formate o y (o; CM U ro: si t NN

WITH ; (9) but a. Cyclohexanecarboxylic acid M'-(5-fluoro-pyridin-2-yl)-hydrazide (intermediate C4a)

IS

MM Fr

To a solution of 5-fluoro-2-hydrazinyl-pyridine (reference see M/O2010022076; 1.00 g, 7.87 mmol), cyclohexanecarboxylic acid (1.21 g, 9.44 mmol) and NOVI.NgO (166 mg, 0.787 mmol) at 0 C under M" was added EOS (1.81 g, 9.44 mmol), then the mixture was stirred at 0 "C for 15 min., and at RT - for 17 h. Water was added, then the organics were separated, was cooled to 0 "C, then the resulting suspension was filtered to leave the title compound as a white solid (1.16 g, 62 95). "H NMR (400 MHz, SOSI"): 1.21-1.38 (ZH, t), 1.45-1.55 (2H, t), 1.66-1.73 (1H, t), 1.80-1.96 (4H, t), 2.22 (1H, y, U 11.6, 3.5 Hz), 6.62-6.66 (2H, t), 7.29 (IN , ada, 9 9.2, 7.9, 3.1 Hu), 7.55 (1H, a, 944.2 Hz), 8.03 (IN, a, 9 2.9 Hu). p. 3 -Diclohexyl-6-fluoro-11,2,4Itriazolo|4,3-a|pyridine (intermediate 3465)

Eh sia

In the academic

To a solution of intermediate Z4a (1.15 g, 4.83 mmol), triphenylphosphine (2.54 g, 9.67 mmol) and triethylamine (2.68 mL, 19.3 mmol) in dry THF (17 mL) at 0 Hexachloroethane (2.28 g, 9.67 mmol) was added under Me, and the mixture was stirred at 0 C for 15 min. and with CT within b hours. Water was added, then the organics were washed with brine, dried (Md5O4) and concentrated in vacuo. Flash chromatography (silica gel, 0-100 906 EtOAc in cyclohexane) gave the title compound as an off-white solid (330 mg, 31 95). "H NMR (400 MGu, SOSIz): 1.36-1.55 (ZH, t), 1.78-2.00 (5H, t), 2.05-2.14 (2H, t), 2 .97 (IN, H, 9U-11.5, 5.5

Go), 7.16 (1H, aaa, 9U-10.0, 7.5, 2.3 Gu), 7.76 (1H, aa, U-10.0, 4.9, 0.9 Hz) , 7.85 (1H, aaa, 9u-3.5, 2.2, 0.9 Hu). with. (15, 4H)-4-(3-Cyclohexyl-|1,2,4|triazolo|4,3-a|pyridin-b-yloxy)-1,2,3,4-tetrahydro-naphthalene-1-ylamine (intermediate З4с) o yo oi nm M

An opaque brown solution of intermediate 14 (171 mg, 1.05 mmol) and sodium hydride (60 95 dispersion in oil, 120 mg, 3.00 mmol) in dry DMF (2 mL) was stirred at CT under argon for 30 min. Intermediate 3456 (219 mg, 1.00 mmol) was added, and the resulting dark solution was stirred at 60 C for 2 h. The cooled solution was concentrated in a vacuum, redissolved in Meon (2 ml), applied to the 5СХ-2 cartridge and washed with Meon. The product was eluted with 2M MHz in MeonN; concentration in vacuo gave a brown oil. Flash chromatography (silicon dioxide 25 g, 2-10 95 (2M MNz in Meon in DCM) gave a yellow oil.

Freeze-drying with MesSmM-water (1:2, 3 mL) afforded the title compound as a pale yellow solid (203 mg, 56 95). RHMS (method 3): Kg 2.29 min., t/7 363 MN. and. 1-(b-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl|-3-(15,4H)-4-(3-cyclohexyl-

P1,2,4Hygriazolo|4,3-a|pyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea (intermediate

DYU Za) o / 6) M i reve: IFe t NN no

A brown solution of intermediate 26ba (94.2 mg, 0.263 mmol), intermediate 34c (90.6 mg, 0.250 mmol), and OSIREA (0.054 mL, 0.31 mmol) in dry dioxane (3 mL) was stirred at 75 °C for 16 h. The cooled solution was concentrated in a vacuum, suspended in water (3 ml) and

Z was extracted with DCM (2 x 3 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a dark brown oil. Flash chromatography (silica gel, 3-9 96 MeonN in DCM) gave a pale yellow solid. MOAR (Method 7) gave an off-white solid (72 mg, 50 95). RHMS (method 5): CI 3.98 min., pt/: 572.4 MN. in. 1-(b-tert-butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl|-3-(15,4nH)-4-(3- cyclohexyl-|1) salt ,2,4griazolo|4,3-a|Ipyridine-b-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl|-urea partial formate (example 34)

A solution of intermediate 344 (71 mg, 0.12 mmol), mesyl chloride (29 mg, 0.25 mmol), and SIREA (0.065 mL, 0.37 mmol) in DCM (2 mL) was stirred at 0 °C for 30 min. Add water (2 mL) and sat. aq. MnH 2 SO 3 (2 mL) The aqueous was extracted with DCM (2 mL), then the combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a pale yellow resin.

The resin was dissolved in DMF (1 mL) and morpholine (0.054 mL, 0.62 mmol) was added, and then stirred at 75 °C for 16 h. The cooled solution was concentrated in vacuo, redissolved in Meon (1 mL), and applied to the ZSC cartridge -2 (5 g) and washed with MeOHN.

The product was eluted with 2M MHz in MeonN; concentration in vacuo afforded a yellow resin.

Preparative HPLC (Setipi C18, 10-60 95 Meskm in water, 0.1 95 HSO2N, 20 min.) and freeze drying of the desired fractions gave a white solid (14.9 mg, 19 95). RHMS (method 5):

KI 3.46 min., t/72 641.4 MN"). "H NMR (400 MHz, ave-DdmsSo: 1.20 (9H, 5), 1.27-1.38 (1H, t), 1.44-1.55 (2H, t), 1.58-1.77 (ZH, t), 1.80-1.86 (2H, t), 1.92-2.21 (6H, t ), 2.39 (4H, i, 9U-4.4 Gu), 2.62 (2H, i, 9-71 Gu), 3.29 (IN, i, 9U-11.3, 3.7 Gu ), 3.54 (4H, i, 9U-4.5 Gu), 4.00 (2H, her, 2-71 Hz), 4.88 (IN, 19, 9-84, 5.7 Hz), 5.59 (IN, 1, U-4.3 Gu), 6.03 (1H, 5), 7.03 (1H, a, 9-86 Hz), 7.18 (1H, yes, 9-9 ,8, 2,1

Hz), 7.91 (IN, 4, 9-71, 2.0 Hz), 7.35-7.43 (ZH, t), 7.69 (1H, aa, 9U-9.8, 0, 8 Gu), 8.23 (IN, a, 9-2.0

Hz), 8.31 (IN, 5), 8.33 (0.3 N, 5).

Example 35 1-(5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl)-3-(15,4nH)-4-I3-(2,6-dichlorophenyl)-

P1,2,4)griazolo|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydronaphthalen-1-yl|-urea -o (o) rya (c) Seh wa ze g NN but a. 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-propan-1-ol (intermediate C5a) vo!

M" plural, p

A solution of 4,4-dimethyl-3-oxo-pentanenitrile (0.7 g, 5.58 mmol) in ethanol (grade IM5, 5 mL) was treated with 3-hydrazino-propan-1-ol dihydrochloride (1 g, 6.13 mmol), and then - conc. NSI (0.05 ml), and the reaction mixture was heated under reflux for 18 hours. The mixture was concentrated in vacuo and the residue was purified by ESS using 0-10 95 (2M Mnz in MeOnNi|I in DCM) to give the title compound as a white gummy solid (0.94 g, 85 965). LCMS (Method 3): RI 0.42 min., t/2 198 (MNY,. r. 1b-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl|-carbamic acid 2,2,2- trichloroethyl ester (intermediate 356) /y (6) re X As r Her otu (o) schi)

A solution of intermediate C5a (0.94 g, 4.76 mmol) in EtOAc (15 mL) was treated with aqueous MMA (1 M, 8.58 mmol) and then with 2,2,2-trichloroethyl chloroformate (0.79 mL, 5 .72 mmol) and stirred at CT for 1.5 hours. The two layers were separated and the organic layer was washed with water (2 x 10 mL), dried (M9505), filtered and concentrated in vacuo to give the title compound as a white solid (1.12 g, 63 95). RHMS (method 3): CI 3.72 min., t/72 372/374 MN. with. 1-(5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl)-3-(15, 48)-4-(3-(2,6-dichlorophenyl)-

Zo P1,2,4Hygriazoloi|4,3-a|pyridine-b-yloxy|-1,2,3,4-tetrahydronaphthalen-1-yl|-urea (example 35) -o (o)

M a im g NN no

A mixture of intermediate 3556 (200 mg, 0.54 mmol), intermediate 264 (228 mg, 0.54 mmol) and OIREA (140 μL, 0.80 mmol) in dioxane (2 mL) was stirred at 70 °C for 18 h. The reaction mixture was cooled to RT, diluted with DCM (10 mL) and washed with water (2 x 10 mL).The aqueous layer was extracted with DCM, and the combined organics were passed through a phase centrifuge and concentrated in vacuo, and the resulting residue was purified by ESS using 0-5 95 (2M MNz in

MeoniI in DCM to give the title compound (270 mg, 76 95). A 50 mg sample of this was purified by MOAR (Method 7) to give the title compound as a glassy solid (17 mg). RHMS (method 5):

KI 4.24 min., t/7 648.4 |MNU. "H NMR (400 MHz, de-DMSO): 1.20 (9H, 5), 1.79-1.87 (2H, t), 1.88- 2.14 (4H, t), 3.41 (2H, her, 2U-5.9 Hu), 3.91 (2H, 1, 9-7.2 Hu), 4.58 (1H, Bg 5), 4.79-4.87 (1H, t ), 5.55 (IN, i, 9U-4.2 Hz), 6.03 (1H, 5), 6.93 (1H, ad, 9U-8.8 Hz), 7.23-7.29 (1H, t), 7.32-7.38 (4H, t), 7.69-7.79 (ZH, t), 7.91 (1H, ad, 2-96 Hz, 0.9 Hz) , 7.98 (IN, a, 9-1.7 Gu), 8.17 (1H, 5).

Biological analyses

Assay of inhibition of Rzwalfa enzyme

The inhibitory activity of the compounds was determined using Alpha Screening (Regkip EIITeg), based on the analysis of kinase activity. Kinase reactions consist of 25 mM NEREZ pH 7.5, 10 mM

Masig, 100 µM MazUOx", 2 mM OT, 0.05 mg/ml Tugeep 20, 100 pM rZzulfa (Impygodep, RUZ3O04), 195 DMSO and 0.3 µg/ml ATP-2 hybrid white (Mem Epdiapa Vioyarkh, 9224) . The compounds were incubated under these conditions for 2 hours at 25°C until kinase activity was initiated by the addition of 250 μM ATP. The reaction volumes were equal to 20 μL. After 1 hour at 25°C, the reaction was stopped by adding 10 μL of 25 mM NEREF5, pH 7.5, which contains 62.5 mM EDTA, 0.05 95

Type Xx-100, 10 95 B5A and 0.83 ng/μl anti-phospho-ATP2 antibody (Arsat, ar28812). Determination was made by measuring luminescence accompanied by the addition of donor granules

Alphascreening (RegKkeep EITeg 6765300) and protein A acceptor granules of Alphascreening (Regkeep

EITeg 6760137), both - at a final concentration of 20 μg/ml. ICho values were determined from concentration-response curves.

The results are shown in the following table: 78611160 8111 write pi Fri

In the table above, the efficiency of the binding of rust (ICoo values) is shown as follows: 7000-500 NM --7 500-100 nM h--; 100-10 NM chn; "10 NM How.

Secretion analysis Rheo-stimulated RVMS TMEa

Peripheral blood mononuclear cells (PBMO5) were isolated from the blood of a healthy human volunteer using a standard density gradient centrifugation technique. Citrated blood was placed in Nizioradie"M and centrifuged. PBMO5 was removed from the surface of the density gradient and washed in phosphate-buffered saline (PB5). PBMO5 was suspended in ERMI 1640 medium (without serum), distributed in a 96-well plate and incubated at 37 "С within 3 hours in a humidified incubator. After incubation, the medium was replaced (with medium containing 1 95 fetal bovine serum) and the plate was incubated at 37 "C for 1 hour in the presence of the test compound or a suitable filler.

I RB (10 ng/ml), or a suitable vehicle control, was then added to the cells and the plate returned to the incubator for 18 h. Cell-free supernatants were removed and analyzed for levels

TMEa, using the EGISA kit from the KO system.

A dose response curve was created for each test compound and the effect of the compound in each experiment was displayed as a percentage of inhibition relative to control TMEs secretion. Dose-response curves were drawn and the effectiveness of the compound (ICvo)d was determined. Compounds were tested in at least three separate experiments.

The results are shown in the following table:

Inhibition 1,2,3,4,7,8,9, 11, 14, 15, 23, 26,27, 28, 29, 30, 31, 32, vv 33, 34

In the above-mentioned table of the efficiency of binding of tear (values of ICoo) it is shown as follows: 21000 NM z-; 1000-1000 nm h--; 100-100 NM chn; "10 NM h-n--". All tested compounds showed IR values of 1000 nM.

A preclinical mouse model of SORO - tobacco smoking, which induces lung inflammation.

Previous studies have shown that the number of inflamed cells treated by bronchoalveolar lavage (BALW) is significantly increased at the end of 24 hours of exposure to tobacco smoking for four consecutive days (T5). This point in time can be used in the described model.

The protocols for subjecting T5 mice to bronchoalveolar lavage (BAL) and making cytospin microscopic preparations for leukocyte cell count determinations are described below.

Daily exposure of T5 mice for 4 consecutive days

In this protocol, mice were treated in groups of 5 in separate clear polycarbonate chambers (27 cm x 16 cm x 12 cm). TK from cigarettes was allowed to enter the chambers at a flow rate of 100 ml/min. To minimize any potential problems caused by high levels of T5 upon rechallenge, exposure of mice to T5 was increased gradually over the exposure period to a maximum of b cigarettes. The list of applied exposure during four days is as follows:

Day 1: 5 cigarettes (approximately 25 minutes exposure)

Day 2: 7 cigarettes (approximately 35 minutes exposure)

Day 3: 9 cigarettes (approximately 45 minutes of exposure)

Day 4: 9 cigarettes (approximately 45 minutes exposure)

In addition, a group of mice, as a control, was exposed to air on a daily basis for equivalent lengths of time (without T5 exposure).

Analysis of bronchoalveolar lavage (BAL)

Bronchoalveolar lavage was performed as follows: the trachea was catheterized using a stainless steel cannula with a 10 mm Luzra fitting. Phosphate-buffered physiological solution (PB5) was used as a washing liquid. A volume of 0.4 ml was carefully added dropwise and stopped 3 times using a 1 ml syringe, then placed in an Errepadogi tube and kept on ice until subsequent determinations.

Cell counts:

The washing fluid was separated from the cells by centrifugation, and the supernatant was decanted and frozen for subsequent analyses. The cell pellet was resuspended in a known volume

RVZ and total cell numbers were determined by counting a stained aliquot (Tygk5 dye) under a microscope using a counting chamber.

The leukocyte formula was determined as follows:

The sediment after centrifugation was diluted to approximately 107 cells per ml. A volume of 500 μl was placed in a funnel for microscopic preparations of cytospin and centrifuged for 6 minutes at 800 rpm, KSE-72.26 x g (Zpapdop Suyuzrip 3). The microscopic preparation was air-dried and stained using M/hydnib/Zivetva dye according to the patented instructions.

When drying and removing the cover, the leukocyte cell formula was determined using optical microscopy. Approximately, four hundred cells are counted by an unbiased operator using optical microscopy. Cells were differentiated using standard morphometric methods.

Drug treatment

Rodents, such as mice and rats, were required to sniff the respiratory apparatus, so oral delivery of the test materials (as therapeutic agents) for inhalation did not cause a significant effect on the lungs. As a result, delivery of therapeutic agents to the lungs of rodents is usually achievable by intranasal, intratracheal, or sniff-only inhalation or whole-body aerosol exposure.

Sniff-only or whole-body aerosol methods use large amounts of test material, and are usually better backups for inhalation toxicology studies than more standard pharmacological efficacy studies. Intratracheal administration is a very efficient delivery method in which almost all of the test material is delivered to the lungs, but it is an invasive method. For mouse studies in particular, it is also technically demanding, while the diameter of the trachea is small. The intranasal route is less invasive than the intratracheal route, and thus is particularly suitable for repeated dosing studies, such as the described four-day mouse model. With such intranasal use, approximately 50 95 of the applied dose is delivered to the lungs (Euiez5 UE, M/Shiatwop

EO and AIrag NO. 1999, Ipig in Riagt, 189(1):75-9).

As an alternative route for oral inhalation, mice were dosed intranasally with

With fillers (0.2 9o im'eep 80 in physiological solution), which contains the compound of the test. Control groups of mice received filler in 1 hour. before exposure to air or T5.

Therapy data and statistical analysis:

All results are presented as individual data points for each animal and the mean value calculated for each group. If the tests of normality are positive, the data were subjected to one-way analysis of variance test (AMOMA), followed by correction

Ophthalmology for multiple comparisons was used to test for statistically significant differences between treatment groups. The "p" value, which is 0.05, is considered statistically significant. The percentage of inhibitions is automatically calculated within the Ehse spreadsheets! 5rgeyzpeei5 for cellular data using the following formula:

Fo Inhibition - (1 -

Correzrpnant for heartburn to treat. the result for the group in the air pi rezulnan Olya vruti With the 75-filler the result for the group naspovteyui | Wow Lowe.

Inhibition data for other parameters were calculated manually using the above formula.

The compounds of the invention can be tested in a notified model of lung inflammation, induced by tobacco, to evaluate their anti-inflammatory activity in an animal model of COPD.

Claims (11)

FORMULA OF THE INVENTION 1. The compound of formula (I) or its pharmaceutically acceptable salt: (c) ? ХХ U-8 number and M BO ;() where M - MN; M - 9; B" is a group selected from (Pa)-(Ps): in: in M x x! х2 " ше 26 З z хх AK M Ge DE M M ше / хо ше / re MM 12 Ж в) в? й , , (Pa) (PB) (Ps) where B8 is -(C1-Salkylene)-MA"AB, -(C3-Sucycloalkylene)-MA"BV8, -MAAB, -M(BU)-(C2-Salkylene)-MABV, - M(NU)-(C3- C7cycloalkylene)-MA"AB or -He; АХ and ВВ in each case independently - hydrogen, C-Salkyl or C3-C7cycloalkyl, such C- Salkyl and C3-C7cycloalkyl are optionally substituted by the following group: C--Salkyl, C3- C7cycloalkyl, -ONE, -585, -MAEVH, -CM or halogen; alternatively B" and B? may form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated monocyclic or bicyclic ring system, in which said 5-11-membered saturated monocyclic or bicyclic ring is optionally substituted by one or more of the following groups: - ONO, -SM, halogen, Si- Salkyl or C3-C7cycloalkyl, such C1-Salkyl and C3-C7cycloalkyl are optionally substituted by the following group: C1-C7alkyl, C3-C7cycloalkyl, -OVO, -CM or halogen; and wherein optionally said 5-11-membered saturated monocyclic or bicyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally replaced by: C1-C4alkyl or C3-C7cycloalkyl, wherein any such C1-C4alkyl or C3-C4cycloalkyl is optionally substituted with the following group: C1-C4alkyl, C3-C7cycloalkyl, -"OVO, -CM or halogen; And in each case independently - hydrogen, C-Salkyl or C3-Swcycloalkyl, such C-Salkyl and C3-C8cycloalkyl is optionally substituted by the following group: C3-C8alkyl, OH, CM or halogen; IN? in each case independently - hydrogen, -CH3 or -SeHb; ВЕ and ВР in each case independently - hydrogen, C-Salkyl or C3-C7cycloalkyl, such C- Salkyl and C3-C7cycloalkyl are optionally substituted by the following group: C--Salkyl, C3- Sucycloalkyl, -ONE, -585, -CM or halogen; and/or BE and BP can form, together with the nitrogen atom to which they are attached, a 5-7-membered saturated ring system, in which the named 5-7-membered saturated ring is optionally substituted by one or more of the following groups: -ORU , - CM, halogen, C1-C7alkyl or C3-C7cycloalkyl, such C1-C7alkyl and C3-C7cycloalkyl optionally substituted by the following group: C:-C6alkyl, C3-Succycloalkyl, -OVO, -CM or halogen; and wherein optionally said 5-7-membered saturated ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted with: or C3-Svecycloalkyl is optionally substituted by the following group: C:1-Salkyl, C3-C7cycloalkyl, -OBS, -CM or halogen; Бе - hydrogen, -CH3 or -СоНб5б; X and Xe are each independently a -(CH)- group or a nitrogen atom; IN? and B0 independently - C1-Salkyl, C3-Seccycloalkyl, phenyl, which is optionally substituted, 5- or b-membered monocyclic heteroaryl, which is optionally substituted, or a radical of the formula (Xa) or (surname) o in ME24r25 Org and x(Sha)" (Sab), where 4 is equal to 1 or 2; and VD" and AD" independently - hydrogen or C:-Svalkyl, or B?" and B?" together with the nitrogen to which they are attached, optionally form a b-membered heterocyclic ring containing a further heteroatom selected from M and 0; A", B": and BZ independently - hydrogen, Si-Svalkyl or halogen; A - divalent radical of 1,2,3,4-tetrahydronaphthalene; the specified radical is attached to M/ and U and can be substituted in the phenyl ring by one or two groups B?" and has the following formula: B2" in each case is independently selected from the group consisting of the following: C-Svalkyl, halogen and cyano; B2 is a radical of the formula (IMa), (IMB) or (IMc): in and rah Rakh n x 74 zh r o. Ud'V Dt ne " (IMa) (MB) (IMs) where В"" is selected from the group consisting of -Е, -"СНгОМе and -СЕ2СЕ:"; В ": and Bb are independently -CH»z or -СоНбБб; B" is selected from the group consisting of the following: lone electron pair, hydrogen, -SEz, - MAV, -(C3-Sucycloalkyl), -(C3-Suheterocycloalkyl) . (M) va and where Vo is selected from the group consisting of -E, -CH3, -С2Н5, -СН»2ОН, -СНгОМе, -СР»СЕ3, -СНоЗСОН, - ССН:з and -5С2Н5 ; В"! is -CH3 or -СеНбв; or В29 and В-", which are defined above, can form, together with the carbon atom to which they are attached, a 3-7-membered monocyclic ring; ВЕ t and VR! each independently - C-Svalkyl, optionally substituted by the following group: C1-Svalkyl, -OVU, -SM or halogen; alternatively VE! and BP can also form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated monocyclic or bicyclic ring system, in which said 5-11-membered saturated monocyclic or bicyclic ring is optionally substituted by one or more of the following groups : -ОВ2, -СМ, halogen, C1-Salkyl or C3-C7cycloalkyl, such C1-Salkyl and C3-С7cycloalkyl are optionally substituted by the following group: C:i-Salkyl, C3-С7cycloalkyl, -ОВУ, -СМ or halogen ; and where the optionally named 5-11-Zo membered saturated monocyclic or bicyclic ring contains the following heteroatom: oxygen or nitrogen, the named nitrogen atom is optionally replaced by the following: C-i-Salkyl or C3-Swicycloalkyl; Бе - a group where hydrogen, -СН3 or -С2Н5 are independently present in each; B is selected from the group consisting of the following: lone pair, hydrogen, aryl, heteroaryl, -(C 1 -Salkyl), -(C 3 -C 7 cycloalkyl), -(C 3 -Steterocycloalkyl), (C 1 -Steterocycloalkyl)-( C1i-Salkyl)y and (C5-Sheterocycloalkyl)-(C3-Secycloalkyl); where any of the following: aryl, heteroaryl, -(Ci-Salkyl), -"C3-C7cycloalkyl", -(C3-Sugeterocycloalkyl), (Cv- Steterocycloalkyl)-(C1-Salkyl or (C5-Sugeterocycloalkyl)-(C3-Secycloalkyl) is optionally substituted by the following group: -CM, -OH, halogen, -SOOVM, C-Salkyl, C3-C1cycloalkyl, -O-(C1 - Svalkyl), -O-(C3-Secycloalkyl), -5-(C1-Svalkyl), -5-(C3-Secycloalkyl), -MANAU, -MSH(VU(Cg- Svalkylene)-MANNU, -MAU(C3 -Ctcycloalkylene)-MANVU, -(C1-Salkylene)-MANVU, -(C3-Sucycloalkylene-MAMVU, /-O-(Co-Salkylene)-MAMAU, /-O-(C3-C7cycloalkylene)-MAMVU, /-5 -(C2- Svalkylene)-MANVU, -5-(C3-Ct7cycloalkylene)-MAVNVU, -MSH(VUS(0)-(C1-Svalkylene)-MANVU, -Ш(VUS(O)- (C3-Ct7cycloalkylene)- MANVU, -C(O)M(VU)-(C2-Salkylene)-MANAU, -C(O)M(8U-(C3-C7cycloalkylene)- MANVU, -C(O)M(VU)-(C2- Svalkylene)-OVM, -С(О)М(2У)-(C3-Sucycloalkylene)-ХОВМ, -ШХВУС(ОМ(АНВУ), -Ф(омМмАНАХ, /-ШЧАУС(О)МВАУ-(С2-Svalkylene) -MANAU, /--SHVUS(OMNAU-(C3-C7cycloalkylene)- MANAU, -O-(C2-Csalkylene)-OBM, -O-(C3-Cu7cycloalkylene)-OBM, -5-(C2-Salkylene)-OBM, -5-(C3-Ccycloalkylene)-OBM, -"ШХВ8УБ( О)2-(C1-Svalkylene)-MANNAU, -«M(ВУ5(О0)2-(C3-C7cycloalkylene)-MANVU, -ЧО)2М(2У-(С2-Svalkylene)-MANNAU, /-5(0 )2M(NU)-(C3-C7cycloalkylene)-MANVU, 5(02M(8U-(C2-Salkylene)-OBM, /-5(0)2M(2U-(C3-C7cycloalkylene)-OBM, /-MSH( AUB(O)2-(Cg-Svalkylene)-OVM, /- M(VUB(O)2-(C3-St7cycloalkylene)-OVM, -5(0)2M(ANAU), MSH(VUB(O2gVe, -SCHAUS (О)В, ОВ, 58, -(Сз- Sleterocycloalkyl), (C5-Suheterocycloalkyl)-(C1-Salkyl) and (C5-Sueterocycloalkyl)-(C3-Svecycloalkyl); where any such C:i-Salkyl, C3-Secycloalkyl, -(C2o-Salkylene)-, -(C3-C7cycloalkylene)-, -(C3-Steterocycloalkyl), (C5-Sueterocycloalkyl)-(C1-Salkyl), (C1-Suheterocycloalkyl)-(C3-C8cycloalkyl) and (C5-Sulheterocycloalkyl)ucarbonyl in the above groups are optionally substituted by the following group: C1-Salkyl, C3-C7cycloalkyl, -OM or halogen; AN and VU in each case are independently hydrogen, C1-Salkyl or C3-Seccycloalkyl, such C1-Salkyl or C3-Seccycloalkyl is optionally substituted by the following group: C:i-Salkyl, -OM, -CM or halogen; alternatively, B" and VU can also form, together with the nitrogen atom to which they are attached, a 5-11-ene saturated monocyclic or bicyclic ring system, in which said 5-11-ene saturated monocyclic or bicyclic ring is optionally substituted by one or more by the following groups: -OM, -CM, halogen, C1-Salkyl or C3-Sucycloalkyl, such C1-Salkyl and C3-C7cycloalkyl are optionally substituted by the following group: C1-Salkyl, C3-Sucycloalkyl, -OM, -CM or halogen; and wherein optionally said 5-11 membered saturated monocyclic or bicyclic ring contains the following heteroatom: oxygen or nitrogen, The said nitrogen atom is optionally substituted by the following: C1-Salkyl or C3-C8cycloalkyl, where any such C:1-Salkyl or C3-C8cycloalkyl is optionally substituted by the following group: C1-Salkyl, C3-C7cycloalkyl, -OM, - CM or halogen; and/or ВН and ВУ can be attached to one carbon atom of the following group: -(Cg-Salkylene)- or -(C3-C7cycloalkylene)-, bonded to the nitrogen to which they are attached, to create a saturated cycle of up to 6 atoms in rings; B" in each case is independently hydrogen, C1-Salkyl or C3-Swecycloalkyl, such C:-Salkyl or C3-Secycloalkyl is optionally substituted by the following group: C:1-Salkyl, -OM, -SM or halogen. VM in each case is independently hydrogen, C1-Slalkyl or C3-Svcycloalkyl, such C1-Salkyl or C3-Svcycloalkyl is optionally substituted by the following group, hydroxyl, -CM or halogen; B" is selected from the group consisting of the following: hydrogen, -C3, -MVEVE, -(C3-C7cycloalkyl), -(C3-C1heterocycloalkyl), aryl and heteroaryl, wherein any such -(C3-C7cycloalkyl), -(C3-S heterocycloalkyl), aryl or heteroaryl is optionally substituted by the following group: C1-Salkyl, C3-C7cycloalkyl or halogen; or B""- group of the general formula (M) and ; (U) where 20, В-", ВЕ and ВЕ are defined above; 27, 22, 73, and 77 are independently selected from the group consisting of the following: C, M, 5, 0, a -CH- group and a -MH- group in such a combination that the resulting ring is an aromatic system; T is-M- or -СВА28--; BO B28 - H, halogen, -CH3 or -CM; Bg2 - H, halogen, -CH3 or -CM; provided that when 72!--CH-, 22--6-, 273--03-, 75--M-, II)'8 is a single electron pair, B" is a group of the general formula (M), and B"! is -CH3 or -SeH5, then IZ2o is -P, -"CH"2OMe or -СР2СЕ:"; when 2!--CH-, 22--C0-, 73--M-, 21--M-, IV" is a group of the general formula (M), B? is -CH3 or -СаН5 and B2o is -CH»z, -C2H5, -CH2OH, -CHno5CH»z, -5CH3 or -5C2Hv, and Viv is a phenyl ring; then such a phenyl ring is replaced by a group selected from the following group: -СМ, -СООВМ, C3-Swcycloalkyl, -O-(Ci-Salkyl), -O-(C3-Swcycloalkyl), -5-(Ci-Swalkyl), -5-(C3-Seccycloalkyl), - MANNU, -Х(VU(C2-Salkylene)-MANAU, -M(VU(C3-Scycloalkylene)-MANVA»U, -(C3-C7cycloalkylene)- MANVU, -0- (C3-Stcycloalkylene)-MANNVU, -5-(C2-Salkylene)-MANVU, -5-(C3-Sucycloalkylene)-MANNVU, - M(АУС(О)-(С1-Svalkylene)-MANVU, -ШЖЖАУС(О )-(C3-Stcycloalkylene)-MANVU, -FSchompU-(Se-Svalkylene)-MANNU, -С(О)М(ВУ)-(С3-Stcycloalkylene)-MANАУ, -С(О)М(ВУ-(Сг -Svalkylene)-OVM, -- C(OM(VU-(C3-C7cycloalkylene)-OVM, /-ЖХ(ВУС(ОМАНАУ, 0 -С(О)МАНАУ, 0 -ЩвУС(ОМВАУ)-(Seg-Svalkylene) -MANNA»U-, Х(АУС(ОМВУ)-(С3-Стcycloalkylene)-МАНВУ, -О-(С2-Salkylene)-ОВМ, -О-(С3-С7cycloalkylene)-ОВМ, -5-(Co-Svalkylene) )-OBM, /-5-(C3-Sucycloalkylene)-OBM, /--Ш(VUB(O)2-(C1-Salkylene)-MANVU, -Ш(VUB(O)2-(C3-C7cycloalkylene)- MANAU, -550)2M(VU)-(C2-Svalkylene)-MANVU, - 5(02M(8U)-(C3-C7cycloalkylene)-MANVU, C(0)2M(VU-(C2-Svalkylene)-OMV, -SCHO)2M(NU)-(C3-Ccycloalkylene)-OB M, -Щ(АУБ(О)2-(Cg-Svalkylene)-ОВМ, -МШ(АУБ(О)2-(С3-С7cycloalkylene)-ОВМ, - 5(О0)2М(ВНВУ), m(ВУ( О)2ВУ, -ШЧАУС(О)ВУ, ЗВУ, -(C3-Suheterocycloalkyl), (Св-Stuheterocycloalkyl)-(Ci-Salkyl)u and (С5-Suheterocycloalkyl)-(C3-Свcycloalkyl); where any such C:-Salkyl, C3-Seucycloalkyl, -(Ce-Swalkylene)-, -(C3-C7cycloalkylene)-, -(C3- S-S-Swylalkyl), (C5-Sueterocycloalkyl)-(C1-Swalkyl), ( C5-Suheterocycloalkyl)-(C3-Swecycloalkyl) and (C5-Steterocycloalkylcarbonyl) in the above groups are optionally substituted by the following group: C1-Salkyl, C3-Sucycloalkyl, -OM or halogen; or such a phenyl ring is substituted by the following group: - (Ci-Salkylene)-MACHA or -O-(C2-Salkylene)-MANVU, where VM and VU, both of which are not hydrogen, are in each case independently hydrogen, C-Salkylene, or C3-Salkylene, such C-Salkylene or C3-Swicycloalkyl is substituted by the following group: -OM, -CM or halogen; alternatively, A" and VU can form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated monocyclic or bicyclic ring system, in which the named 5 -11--the saturated monocyclic or bicyclic ring is substituted by one or more of the following groups: -OM, -CM, halogen, C-Salkyl or C3-C7cycloalkyl, such C-Salkyl and C3-C y7cycloalkyl is optionally substituted by the following group: C1-C7alkyl, C3-C7cycloalkyl, -OM, -CM or halogen; and wherein optionally said 5-11 membered saturated monocyclic or bicyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted with the following: C.sub.1-C alkyl or C.sub.3-C.sub.3 cycloalkyl, wherein any such C -Salkyl or C3-Svecycloalkyl is optionally substituted by the following group: C:i-Salkyl, C3-S7cycloalkyl, -OM, -CM or halogen; or such a phenyl ring is substituted by the following group: (C5-C7heterocycloalkyl)-(C1i-Salkyl), which is substituted by the following group: C1-Salkyl, C3-Sucycloalkyl, -OM or halogen; or such a phenyl ring is substituted by a group -OVU, where VI is C1-Salkyl or C3-Seccycloalkyl, such C1-Salkyl or C3-Seccycloalkyl is optionally substituted by the following group: C:i-Salkyl, -OM, -CM or halogen; or such a phenyl ring is substituted by the following group: C-Salkyl, which is substituted by the following group: C3-C7cycloalkyl, OBM or halogen; and when B" is a morpholine ring and T is -СВ828- or -M-, then 822, if present in the ortho-position to the T group of the aromatic ring, is -CH3 or -CM. 2. The compound of formula (I) according to claim 1, which is a compound of formula (Ia), where the stereogenic center of the carbon on the cycloalkylene ring A, which is attached to the MU group and designated by the number (1) here below, has the absolute configuration shown here below: (c) 'VH HD schu v y MA ; (c) or a pharmaceutically acceptable salt thereof. 3. The compound of formula (I) according to claim 1 or 2, which is a compound of formula (IB), where the stereogenic carbon centers are on the cycloalkylene ring A, which is attached to the group M/ and M and is designated by the numbers (1) and (2) here, respectively below, have the absolute configuration depicted here below: (c) 2 c! After all, in their MA; (IB) or its pharmaceutically acceptable salt. 4. The compound of the formula (I) according to any of claims 1-3, where B: - the radical of the formula (MB): в" is C 7 x 18 y (МВ) where 2'--СН-, 272-С, 73 and 77 are M, and В" is a group of the general formula (M) and Y; (M) where H2o is -CH3 or -CH2OH, B?! is -CH3 and where BB is phenyl, which is substituted by the group -(Ci-Svalkylene)-MANAU or -O-(Cg2-Svalkylene)-MV"VU, where B" and VU, both of which are not hydrogen, in each case independently - hydrogen, C-Salkyl or C3-Seccycloalkyl, where such C-Salkyl or C3-Seccycloalkyl is replaced by the following group: OBM, CM or halogen; alternatively, B" and VU can form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated monocyclic or bicyclic ring system in which said 5-11-membered saturated monocyclic or bicyclic ring is substituted by one or more of the following groups: OBM, CM, halogen, C1-Salkyl or C3-C7cycloalkyl, such C1-Salkyl and C3-C7cycloalkyl are optionally substituted by the following group: C1-Salkyl, C3-Sucycloalkyl, OBM, CM or halogen; and where optional optionally the named 5-11--len saturated monocyclic or bicyclic ring contains the following heteroatom: oxygen or nitrogen, said nitrogen atom is optionally substituted with the following: C1-C6alkyl or C3-C6cycloalkyl, where any alkyl or cycloalkyl is optionally substituted the following group: C1-Salkyl, C3-C7cycloalkyl, OBM, CM or halogen; or where B" is phenyl, which is substituted by the following group: (C5-St-heterocycloalkyl)-(C1-Salkyl), which is substituted by the following group: C1-Salkyl, C3-Sucycloalkyl, OBM or halogen; or where B'8 is phenyl, which is substituted by the following group: C-Salkyl, which is substituted by the following group: C3-Ct7cycloalkyl, -OM or halogen; or where B'8 is phenyl, which is substituted by the following group: -CM, -O-(Si-Svalkylene), -MANVU, -O-(C2-Svalkylene)-OVM, -5-(Cg-Svalkylene)-OVM, -(C3-Suheterocycloalkyl), where any such C:-Salkyl, -(Co-Salkylene)-, -(C3-Stuheterocycloalkyl) in the above groups is optionally substituted by the following group: C3-Salkyl, C3-C7cycloalkyl , OVM or halogen. 5. The compound of formula (I) according to any claims 1-3, where B? - a radical of the formula (IMB): в" Хр С 7 хи ж 18 в ; (MB) where 2'--SIN-, 272-С, 73 and 77 are M and В" - a group of the general formula (U) va Zo y ; (Y) where Vo is -CH3 or -CHNoOH, and B" is -CH»3, and B" is a heteroaryl ring, optionally substituted by the following group: (C15-Sugeterocycloalkyl)-(C1-Salkyl), optionally substituted by the following group: C-Salkyl, C3-Sucycloalkyl, OBM or halogen; or BZ is a heteroaryl ring, optionally substituted by the following group: -(C1-Svalkylene)-MANA" or -O-(Cg-Svalkylene)-MANNAU. 6. The compound of the formula (I) according to any of claims 1-3, where B: - the radical of the formula (IMB): Kk is ОХ 73 in: 4 7 ж 18 y , (Mb) where 2'--SIN-, 272-С, 73 and 77 are M and B" - the group of the general formula (U) 20 21 Y ; (M) where But is -CH3 or -CH2OH, and B is -CH3, and B'8 - -(Ci-Salkyl), optionally substituted by the following group: -OH, halogen or -MANN; or (C5-Sueterocycloalkyl or (C5- Steterocycloalkyl-(Ci-Salkyl)u, which is optionally substituted with the following group: C-Salkyl, halogen or -OH. 7. A pharmaceutical composition comprising a compound according to any of claims 1-6 together with one or more pharmaceutically acceptable carriers. 8. A compound according to any one of claims 1-6 for use in the treatment of diseases or conditions which are beneficial due to inhibition of MAP p38 kinase activity. 9. Compounds according to any one of claims 1-6 for use in the treatment of diseases or conditions that are beneficial due to inhibition of MAP p38 kinase activity according to claim 8, where the diseases or conditions are chronic eosinophilic pneumonia, asthma, OSA, adult respiratory distress syndrome ( ABO5), exacerbation of hyperreactivity of the respiratory tract due to treatment with other drugs or disease of the respiratory tract, which is associated with pulmonary hypertension. 10. Use of a compound according to any one of claims 1-6 in the manufacture of a medicament for the treatment of diseases or conditions, which is beneficial due to the inhibition of p38 MAR kinase activity. 11. Use according to claim 10, where the disease or condition is chronic eosinophilic pneumonia, asthma, OSA, adult respiratory distress syndrome (ARDS5), exacerbation of hyperreactivity of the respiratory tract due to treatment with other drugs or disease of the respiratory tract that is associated with pulmonary hypertension.