UA109412C2 - 5-METHYL-N2- [4- (4-METHYLPIPERAZIN-1-yl) PHENYL] -PYRIMIDINE-2,4-DIAMINE AND ITS APPLICATION IN THE METHOD OF PREPARATION - Google Patents

Abstract

The invention provides biarylmethapyrimidine compounds having a general structure (A) and capable of inhibiting kinases that are members of the Jak kinase family, as well as other specific receptor and non-receptor kinases.

Description

The present invention relates to inhibitors of protein tyrosine kinases, pharmaceutically acceptable compositions containing such inhibitors, as well as methods of using these compositions in the treatment of various disorders. In particular, the invention relates to inhibitors of the UAK family of protein tyrosine kinases.

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins. In general, they are divided into tyrosine and serine/greonine kinases. Inappropriate kinase activity resulting from mutation, overexpression, or inappropriate regulation, deregulation, or deregulation, as well as from overproduction or underproduction of growth factors or cytokines, has been implicated in explaining the mechanisms of many diseases, including cancer, cardiovascular disease, allergies, asthma, and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity initiates a wide variety of biological cellular reactions related to cell growth, differentiation, survival, apoptosis, mitogenesis, regulation of the cell cycle, and cell motility involved in the above-mentioned and related diseases.

Thus, protein kinases constitute an important class of target enzymes for therapeutic intervention. In particular, the UAK family of cellular protein tyrosine kinases (act, dakg,

Chuakz and Tukg) plays a central role in the transmission of cytokine signals (Kihzeiema et al., bepe, 2002, 285, 1; Mataoka et al., zZepote Vioiodu 2004, 5, 253)). After binding to their receptors, cytokines activate ZCHAK kinases, which, as a result, phosphorylate the cytokine receptor, thus creating docking sites for signaling molecules, namely for members of the family of signal transducers and transcription activators (ZTAT: 5idpa! yhapzdyseg apa asiimatogo oi igapzsgyriop) , which ultimately lead to gene expression. Numerous cytokines that activate kinases of the ZAK family are known. These cytokines include the IEM family (IEM- av/B/oyu/limitin (Hipayip), IRM-u, 1-10, 17-19, 1-20, 1/-22), the dr130 family (11-6, 11-11, OM, PE,

SMTE, MMT-1/B85E-3, 1-C5E, ST-1, leptin, 1-12, I -23), uC-family (II -2, 1-7, TO R, 1-9, - 15 , 11-21, 1-4, 1-13), family 1-3 (1-3, 1/-5, ЯМ-С5Е), family of signal chains (ЕРО,

CH, RK, TRO), receptor tyrosine kinases (ESE, ROSE, C5BE-1, NOR) and C-protein-coupled receptors (AT).

Until recently, the therapeutic potential of ZAK-kinase inhibitors was focused on diseases affecting various pathologies of the immune system. These were atopy (allergic asthma, atopic dermatitis, allergic rhinitis), cell-mediated hypersensitivity (allergic contact dermatitis, allergic pneumonitis), rheumatic diseases (systemic lupus erythematosus (5IE: 5zuyaketis Ishry5 eguipetaiyo5y5), rheumatoid arthritis, juvenile arthritis, Sjogren's syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), transplantation (graft rejection, graft-versus-carrier reaction), viral diseases (virus

Epstein-Barr, hepatitis B, hepatitis C, HIV, human T-cell leukemia virus NTIM'1, virus

Weizella-Zoster (MaiseiIPMa-2o51eg), human papilloma virus), cancer (leukemia, lymphoma), cardiovascular diseases (cardiac hypertrophy, atherosclerosis and arteriosclerosis), neurodegenerative diseases (motoneuron disease), food allergy, inflammatory bowel disease,

Crohn's disease, skin inflammation and immune suppression caused by solid tumors. To date, the greatest efforts have been directed at the inhibition of ZAKZ for the purpose of immunosuppression, for example, for organ transplantation and engraftment of allografts, see review (Vope ei ai!., Sitepi

Oripiop ip Ipueviidaiopa! Ogydv, 2003, 4(11), 1297).

Recently, two significant pieces of evidence for the role of the signaling pathway have been discovered

ERO-9HAK2 in myeloproliferative disorders and proliferative diabetic retinopathy. First, gain-of-function, it has been reported that a somatic (acquired) MK2-kinase mutation (M617P) is a causative factor in a number of "typical" myeloproliferative disorders, including erythremia, essential thrombocythemia, and myelofibrosis with myeloid metaplasia, and that this mutation has been observed in patients with "atypical" myeloproliferative disorders or with myelodysplastic syndrome, see review (TeiPegi apa siShapa, Seyi Susie 2005, 4(8), eb1;

Cut her. AI. MoiIesciag Ipiegulepip5 2005, 5(4), 211). Furthermore, it was found that (a) mutation

M617E UAK2 was associated with constitutive phosphorylation of ZAKa2-kinase and its right-sided effectors, as well as induction of erythropoietin hypersensitivity in cell experiments, (5) M617E OAKg-induced cell proliferation signals were inhibited by small-molecule inhibitors of CHUAK2-kinase, and (c) mouse bone marrow , transduced with a retrovirus containing M617E UAK2, induced erythrocytosis in transplanted mice.

In addition, mutations in EPO-K have also recently been found to keep the UAC pathway constitutively activated, leading to myeloproliferative disorders.

Second, EPO has been found to be a potent angiogenic factor in proliferative diabetic retinopathy, the leading cause of vision loss in working-age diabetics, see, for example, (Aiieyo, Mem Epdiapa uoshtpai oi Medisipe, 2005, 353 (8) , 839; Maiapabe ei ai.

Mem Epdiapa mahtpai oi Medisipe 2005 353 (8), 782).

In addition, Watanabe (Uumaiapare, see above) in his studies showed that: (a) the levels of intraocular EPO and MESE (vascular endothelial growth factor - another well-known angiogenic factor in proliferative diabetic retinopathy) were significantly higher in people who had proliferative diabetic retinopathy than those with inactive disease and non-diabetic controls; (B) levels of ERO and MESE were not closely correlated; (c) levels

ERO correlated more with the presence of proliferative diabetic retinopathy than MESE levels; (4) EPO stimulated growth and intracellular signaling in retinal endothelial cells; and (e) inhibitors of both EPO and MESE reduced hypoxia-induced retinal neovascularization in experimental rodents.

Recently, it has been shown that mutations in the EPO receptor can also affect signaling related to the UAC pathway, and that this may be involved in the treatment of disease states in which UAC signal transduction plays an important role in the cell cycle.

We can mention one more feature of AK-pathway inhibitors. It was shown that the CHAK pathway can be involved in cell survival and proliferation. For example, there is evidence that the Chdak pathway is involved in constitutive activation in cells that test positive for the Philadelphia chromosome, leading to chronic myelogenous leukemia (CML). Thus, the use of a SHK-kinase inhibitor may be useful in cases of SMi in which the Philadelphia chromosome has demonstrated its ability to produce a Vesg-ABI hybrid and thus maintain cells constitutively active.

More tellingly, in cases of resistance mutations that arise due to specific inhibitors to ACE-AVI, as is the case with the sentinel mutation 73151 or any other mutation, there is an opportunity through the dac pathway to use an inhibitor of ZAK- kinase due to the pathway used by the VSK-AVI mutant (as in the case of the VSK-AVI mutation (T3151)). Thus, Dak inhibitors can be used in the treatment of patients with resistance to known methods of therapy, where the direct target is VSK-AVI, and resistance to drugs

Zo is found in the majority (50-90 95) of patients in whom traditional therapeutic means are not successful.

AK inhibitors can also be effective when used in other myeloid disease states, both in blood disorders and in other disease states with myeloid involvement, as well as in other disease states in which the AK pathway is directly or indirectly involved.

In accordance with the above, there is a need for the development of compounds suitable to serve as inhibitors of kinases and, in particular, UAK-kinase, in cases of inadequacy of treatment by known methods of the above-mentioned diseases, in which the "AK-signaling pathway is deregulated or in which it is directly or indirectly involved.

In one of the variants of implementation of the invention, a compound is offered which has the structure (A): (ev

A,

IB

Z Ге и ОМ и и Зв р р -х р 4 pVY sce spe o n M M 1 2 yiv yiv nn nn (A)

According to another embodiment of the invention, there is provided a method of treating a disorder associated with the development of blood vessels, which comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound having structure (A) or a pharmaceutically acceptable salt thereof , hydrates, solvates, polymorphs, crystalline forms, M-oxides, and individual enantiomers and diastereomers.

According to other variants of implementation of the invention, pharmaceutical compositions and products are offered, which contain at least one compound having the structure (A), or its pharmaceutically acceptable salts, hydrates, solvates, crystalline forms or individual diastereomers.

A Terms and definitions

Below are the definitions of the terms used in this application, which are generally consistent with the terminology recommended by the International Union for Theoretical and

of Applied Chemistry (RAS).

The term "heteroatom" means any atom other than carbon, for example, M, 0.5.

The term "aromatic" means a cyclically conjugated molecular substance, the stability of which, due to delocalization, is much greater than that of a hypothetical localized structure, which is, for example, the Kekule (Kekiye) structure.

The term "heterocyclic," when used to denote an aromatic ring, applies to aromatic rings that contain at least one heteroatom as defined above.

The term "heterocyclic," when used other than as an indication of an aromatic ring, applies to cyclic (ie, ring-containing) groups other than aromatic groups where the cyclic group is formed of from 3 to about 14 carbon atoms and at least one heteroatom, definition which is given above.

The term "substituted heterocyclic", as applied to both aromatic and non-aromatic structures, is used to refer to heterocyclic groups having, in addition, one or more substituents as defined below.

The term "alkyl" means a monovalent straight or branched chain hydrocarbon group having from one to about 12 carbon atoms, ie, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n- pentyl (also known as p-amyl), p-hexyl, etc. The term "lower alkyl" applies to alkyl groups having from 1 to about 6 carbon atoms.

The term "substituted alkyl" applies to alkyl groups having one or more substituents such as hydroxy, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, sulfuryl, etc.

The term "alkenyl" is a name for hydrocarbon groups with straight or branched chains that have at least one carbon-carbon double bond and

From about 2 to 12 carbon atoms, and the term "substituted alkenyl" is a name for alkenyl groups which additionally contain one or more of the substituents listed above.

The term "alkynyl" is the name for straight or branched chain hydrocarbon groups having at least one carbon-carbon triple bond and from about 2 to 12 carbon atoms, and the term "substituted alkynyl" is the name for alkynyl groups that contain , in addition, one or more of the substituents listed above.

The term "aryl" serves as a name for aromatic groups having from about 5 to 14 carbon atoms, and the term "substituted aryl" serves as a name for aryl groups that contain, in addition, one or more of the substituents listed above.

The term "heteroaryl" is the name for aromatic rings in which the ring structure is formed by about 3 to 14 carbon atoms and at least one heteroatom as defined above, and the term "substituted heteroaryl" is the name for heteroaryl groups that additionally contain one or more the substitutes listed above.

"Alkoxy" means a component described by the formula -O-alkyl, wherein alkyl is as defined above, and the term "substituted alkoxy" means an alkoxy group which contains, in addition, one or more of the substituents listed above.

The term "cycloalkyl" serves as a name for alkyl groups having from 3 to about 8 carbon atoms forming a ring, and the term "substituted cycloalkyl" serves as a name for cycloalkyl groups that additionally contain one or more of the substituents listed above.

The term "alkylaryl" is a name for alkyl-substituted aryl groups, and the term "substituted alkylaryl" is a name for alkylaryl groups that additionally contain one or more of the substituents listed above.

The term "arylalkyl" serves as a name for aryl substituted alkyl groups, and the term "substituted arylalkyl" serves as a name for arylalkyl groups that additionally contain one or more of the substituents listed above.

The term "arylalkenyl" is a name for aryl-substituted alkenyl groups, and the term "substituted arylalkenyl" is a name for arylalkenyl groups that contain, in addition to those, one or more of the substituents listed above.

The term "arylalkynyl" is a name for aryl-substituted alkynyl groups, and the term "substituted arylalkynyl" is a name for arylalkynyl groups that additionally contain one or more of the substituents listed above.

The term "arylene" serves as a name for divalent aromatic groups having from 5 to about 14 carbon atoms, and the term "substituted arylene" serves as a name for arylene groups that additionally contain one or more of the substituents listed above.

The term "chemically bonded" means a chemical substance in which two components form a direct chemical bond.

The term "kinase" means any enzyme that catalyzes the addition of a phosphate group to a protein residue; for example, serine and threonine kinases catalyze the addition of phosphate groups to serine and threonine residues.

The term "UAK-kinase" means an enzyme that is in the cells of the immune system and is involved in the cellular process of signal transmission, resulting in the development of white blood cells.

The term "therapeutically effective amount" means an amount of a compound or pharmaceutical composition that produces a biological or medical response in a tissue, system, animal, or human that is expected to be obtained by an investigator, veterinarian, supervising physician, or other clinician, such as, for example, restoration or maintenance vasculostasis or prevention of abnormality or loss, or vasculostasis; reduction of tumor load; reduction of morbidity and/or mortality.

The term "pharmaceutically acceptable" is used to denote a carrier, diluent, or excipient that must be compatible with the other ingredients of the preparation and harmless to the recipient.

The term "administration of a compound" means the therapeutic effect of delivering a compound of the present invention or a pharmaceutical composition containing it to a patient in need of such treatment.

The term "antibody" means an intact molecule of a polyclonal or monoclonal antibody or a fragment thereof, such as Rab and E(ab)» Em or ZSA, which is capable of binding to an epitope determinant.

The term "vasculostasis" means maintenance of homeostatic vascular functioning leading to normal physiological functioning.

The term "vasculostatic agents" means agents designed to create conditions in which vasculostasis is regulated by preventing loss or by restoring or maintaining vasculostasis.

V. Variants of implementation of the invention

In one of the variants of implementation of the invention for the treatment of various diseases, disorders and pathologies, compounds having the structure (A): (c)

A vo N s v" 2 y Zv r b, ra 3-x r 4 p V even SCHO i n M M 1 2 yiv yiv

In structure (A), component X may be a bond, O, C-O, 502 or CH", and M may be a bond or ME"; or X and Y taken together may form a bond. Further , in structure (A) components K' and K2 can be H, C1i-Ce substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or KK and K-2, taken together, may form a bond; or

A and KU, taken together, can form (CHg)t, (CHg)-5-(CHg)t, (CHg)-5O-(CHeg)t, (CHg)-5O»- (CHg)t, (CHg )-MA»-(CH?g)t or (CHg)-O-(CHeg)t, where the indices p, ad, r, p, t, independently of each other, are integers that take values from 0 to 6.

In addition, in the structure (A) the component KE? can be H, C:i-Salkyl, C1-C8cycloalkyl, C1-C8 branched alkyl, C1-C8 substituted alkyl, C1-Swaminoalkyl or C:-Swehydroxyalkyl; Co can be M, O, H, or CH, provided that when Co is M, then B3 and B" can be H, C1-C6 alkyl, C1-C8 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C1-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or KZ and KVC" taken together can form (CHg)t, (CHg)-5-(CHg)t, (CHg)-50- (CHg) t.

There are also other prerequisites for Co in structure (A). Yes, when So is M, then B! and KU taken together can form (CHg)t, (CHg)-5-(CHg)t, (CHg)5O-(CHg)t, CHg)-502-(CHg)t, (CHg)-

MAZ(CH?g)t or (CHg),-O-(CHeg)t; or K' and K", taken together, can form (CHg)t, (CHg)-5-(CHg)t, (CHg)-5O-(CHg)t, (CHg)-505-(CHg)t, (CHg)-MAZ-(CHg)t or (CHg)-O-(CHg)t; or KZ and P", taken together, can form (CHg)t, (CHg)-5-(CHg)t, ( CHg)-5O-(CHe)t, (CHg)-5O»2-(CHg)t. (CHg)-MA»-(CHe)t or (CHg)-O-(CHg)t; or KZ and KU, taken together, can form (CHg)t, (CHg)-

C-(CHe)t, (CHg)-5O-(CHg)t, (CHg)-5O»2-(CHg)t, (CHg)-MAv-(CHg)t or (CHg)-O-(CHg) ) t.

If in the structure (A) the component Co is O, then EZ can be H, C:i-Salkyl and Ci-Cv substituted or unsubstituted hydroxyalkyl or aminoalkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cycloalkyl, substituted heterocycle, connected through a carbon or nitrogen atom, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, connected through a carbon or nitrogen atom, without the KU group; AND! and KU taken together can form (CHg)t, (CHg)-5-(CHg)t, (CHg)-50-(CHg)a, (CHg)-5O2-(CHg)t, (CHg)- MAZ-(CHg)t or (CHg)-O-(CHg)t; or K' and KU taken together can form (CHg)t, (CHg)-5-(CHg)t, (CHg)-5O-(CHg)t, (CHg)-5O»2-(CHg)t , (CHg)-MA»Z-(CHg)t or (CHg)-O-(CHg)t; or KZ and Z taken together can form (CHg)t, (CHg)-5-(CHg)t, (CHg)-50-(CHg) a, (CHg)-502-(CHg)t, (CHg )-MA»-(CHg)t or (CnHg)-O-(CHe)t.

If in the structure (A) the component Co is CH, then KZ and KE" can be H, C-Salkyl, C1-Cv substituted or unsubstituted hydroxyalkyl or aminoalkyl, C-Ce substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, C- A fully substituted or unsubstituted heterocycle connected through a carbon or nitrogen atom, or a substituted or unsubstituted heteroaryl connected through a carbon or nitrogen atom, or KZ and K", taken together, can form (СНЕУ)-(СНАУ)т- (SNEAU)r, (SNAYA)-5-(SNEA)t, (SNA?)BZO-(SNVAU)t, (SNAU)-505- (SNAU) t, (SNAU)-MA?Z-(SNRAZ) t or (SNE?),-O-(SNRAZ) t.

In addition, in the structure (A), the component C can be M or SKe, and each o is independent of the other Z, provided that no more than two groups b can be M, and also provided that in each SKe, each Ke is independent of other Kb.

In addition, in the structure (A) component K? is methyl, and component C is as shown below: в' в в?

TO about ,; min; m

In the OO component, each of Ke, B", AB? can be H, C:1-Sve substituted or unsubstituted alkyl,

C1i-Cv substituted or unsubstituted alkenyl, C1-Cb substituted or unsubstituted alkynyl, C1-Cv substituted or unsubstituted hydroxyalkyl or aminoalkyl, C--Ce substituted or unsubstituted branched alkyl, C-Ce substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, with "bonded through a carbon atom or heteroatom, substituted or unsubstituted heteroaryl, bonded through a carbon atom or heteroatom, C-Sulfoxy, halogen, CEz, -OSEz, SNAZV", 583,

ZOV, 50283, 502MAZAYA, 5OzAZ, ROVU, RO2AZ, RO»2MAZA", RO2SAZA", ROzAZ, MAZA", MO», SM,

ON, SOMAZA" Sov SOOVZ MAZSOV", MAZSOMAZA OSOMAZ SeMAZA, S5VU,

MAZSOMAZAYA, 5SOMAZAYA, 5S5MAZA? or 5C5MEZNU; or Ke and K", taken together, or K" and KU, taken together, or Kb and KU, taken together, can form a component independently selected from any of the following groups: -НМ-СН-СН-, -« НМ-М-СН-, -НМ-М-М-, -О(СНг)пО-, -(СНг)п5-, -М-СН-5-, -СН-М-о-, -СНММ- 5-, -М-СН-О-, -С-М-0-, -6-М-0-, -СН-СнН-сн-Ссн-, -М-СнН-СнН-СнН-, -«СН -M-SN-SNAYA, -

Oo-snNeCsH and -5-CH-CH-; or ВЗ and В", taken together, can form (СНЕЗ)-А(СНАУ)t-(СНРЗ)р, (СНАУ)-5-(СНАУ) t, (СНА?)-50-(СНА) t, ( SNAU); 502-(SNAU) t, (SNA?)-MAZ-(SNAZ) tp or (SNRAZ);-

O-(SNRAZ) t.

In addition, in the structure (A), component A can be O, MEZ, SVAZV", 5, 50 or 502: and in component 0, C can be CH, M, MH, 5 or O, component CO can be SV, M , МН, 5 or 0, and each group K" is independent of every other group K7; and when C: or 2 is MH, 5 or 0, then 0) is a five-membered heteroaromatic ring, optionally fused to a six-membered aromatic or non-aromatic ring; and when and or Co is M, then OO is a five- or six-membered aromatic ring, optionally fused to a six-membered aromatic or non-aromatic ring, with the further proviso that X or Co includes at least one heteroatom, including X, selected from O, 5 and M, or Co contains at least four atoms that are not hydrogen, including a heteroatom, and VZi g, both RU, or and

B", or KZ and KU, taken together, can form an aromatic, heteroaromatic, cyclic or heterocyclic ring system, or in the case of a non-cyclic system, more than one heteroatom is present, and if A is MEz, then any of Kv, B7, Bv or any combination thereof independently includes at least two non-hydrogen substituents, or if A is MEz, then O forms a fused ring with Ke-H?7 or with K7-Bv.

Below are shown the structures of some typical compounds of the I-SYCHIA described by formula (A) and which can be used in this invention: (c) ra ne

MN about and

WHAT H"

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(in)

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Zh and N; XI

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unit

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MN cha duto ra

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ХК and Н; CHEM

Residential complex with hollow

A and n HM

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60th century BC

ZhK y i , KhM v

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MN that's it

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MN I'm in a hurry

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N, XXXIX

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In the 1st "M.N." I am studying at the State University of

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M M

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Yes

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M M

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AND

M M

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M i MN i no mo

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Same chn

AI; ho to one KU rche and N , Khsi gra

M MN g

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N, Khsii

N

M

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(F)

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M M

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Yes

M M

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M M

N , KhSMI (c) that 24

MN to

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M M

N, Khsmii

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Me

Same MN

M M

N;, KhSM i

Co

MN oshShena:

Residential complex named after

M M

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same day

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UNTIL

M M y and SIHI ko Ya

J

M M

N ; SI HII.

According to another variant of the implementation of this invention, for the treatment of various diseases, disorders and pathologies, compounds that have the general structure (2): in-c. (2)

The general structure (7) includes two chemically bonded parts - B and C. Part B in the general structure (7) can be any part selected from the following groups: и и И и и 7о МН 7о МН ОМ МН

SHI SHI SHI SHI

M M M M M M

N N N will start and ho so

/ ooo she lice oh, t STO highway xx Oh solo ron ovy

Y NM X b b plo

AND! WITH

MN shk MN no o nF 2 2

Nm X Ohme

Fe ko sh

I chn MN meo MN o n s n (in) nya

Es bak MN MN nd no tk 2 ! ! nya o se me ss Fe

МН МН t 7 МН зо зо о nF 2 2 same osno

Yi so and chi ah ah their So

LA, Z,

A, M, o. gi in V Y on

IH Fe sen xx nM-M NM x X

IS

Zv MN MN MN l,

NM nF | M | floor

A Z or sa sa

Н Н N o no cho m., is І MO chn МН and 5 МН

Yi Yi no Shchi Shchi

J

2 2 M i-

Part C in the structure (7) shown above can be any part selected from among the following groups: (c) -ko re (c) i i o Hn schu ; ; o on pe s, V (c) dn rai oo M

M 5 M what-- MN

SA r S generics --

Oh, A

IF) and 7 c) And braid Mo kto rosche: And in,

M (about Y kola mo Mogo and Ge) Ge) WE,

(c) li" schu le sh. AG; and shk; relatives

The compounds of the present invention, or their pharmaceutically acceptable salts, hydrates, solvates, crystalline forms, and individual diastereomers, administered alone or in combination with other therapeutic agents (eg, chemotherapeutic agents or protein therapeutic agents described below), can be used in the treatment of a variety of disorders , including, for example, myeloproliferative disorders, proliferative diabetic retinopathy, and other associated disorders involving the development of blood vessels, including solid tumors and other cancers, eye diseases, inflammation, psoriasis, and viral infection. A variety of cancers can be treated, including gastrointestinal cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myelogenous leukemia and chronic myelogenous leukemia ), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer.

Such diseases and disorders can also be treated with the compounds and methods of the invention, such as, for example, the formation of new blood vessels in the eyes, infantile hemangioma, organ oxygen deficiency, vascular hyperplasia, organ transplant rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes and complications from diabetes, inflammatory diseases, acute pancreatitis, chronic pancreatitis, asthma, allergies, respiratory distress syndrome in adults, cardiovascular diseases, liver diseases, other blood disorders, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, cytokine-associated conditions, and other autoimmune diseases, including glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia , thrombocytopenia, atopy (for example, allergic asthma, atopic dermatitis and allergic rhinitis), chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft vs. disease caused by traumatic injury, stroke, glutamate neurotoxicity or hypoxia, ischemic or reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ failure and platelet aggregation.

In addition, diseases and disorders such as, for example, cell-mediated hypersensitivity (allergic contact dermatitis, allergic pneumonitis), rheumatic diseases (for example, systemic lupus erythematosus (5 E: 5uzietis Ishra5) can also be treated with the compounds and methods according to the invention eguipetaiiosiv5), juvenile arthritis, Sjögren's syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein-Barr virus, hepatitis B, hepatitis C, HIV, human T-cell leukemia virus NTIM1, Weitzel-Zoster virus (MaysePa -2o5ieg), human papilloma virus), food allergy, skin inflammation and immune suppression caused by solid tumors.

The invention also offers industrial products that can have a packaging material and a pharmaceutical composition contained in this packaging material. The packaging material 5O0 may have a label stating that this pharmaceutical composition may be used in the treatment of one or more of the disorders listed above.

The pharmaceutical composition may contain a compound according to the present invention. In addition to the compound of the present invention, the proposed pharmaceutical composition may also contain other therapeutic agents, and in its preparation may be used, for example, conventional solid or liquid carriers or diluents, as well as pharmaceutical additives of types corresponding to the selected method of administration (for example, excipients, binders , preservatives, stabilizers, taste and smell correctors, etc.), in accordance with the methods used in the preparation of pharmaceutical preparations.

Thus, in one of the 3 variants of implementation of this invention, a pharmaceutical composition is proposed, which, along with the compound according to the invention, contains a therapeutic agent. The concentration of the compound in such a composition is such as to provide an effective treatment for, for example, cancer or another disease or disorder listed above.

The compounds of this invention can be used in therapeutic formulations in their natural form or in the form of salts. Suitable pharmaceutically acceptable non-toxic salts may be base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases (eg sodium, potassium, ammonium, calcium or iron hydroxides) or organic bases (eg isopropylamine , trimethylamine, 2-ethylaminoethanol, histidine, procaine, etc.). They can also be addition salts of acids with any free cationic groups and in general be formed with such inorganic acids as hydrochloric, sulfuric or phosphoric, or with such organic acids as acetic, citric, p-toluenesulfonic, methanesulfonic, oxalic, tartaric, mandelic and other acids.

Suitable for use in this invention may also be salts of amines formed by protonation of an amino group with inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc. Also suitable are salts of amines formed by protonation of an amino group appropriate organic acids, for example p-toluenesulfonic acid, acetic acid, methanesulfonic acid, etc. Additional excipients suitable for

For use in the practice of the present invention, there are conventional suitable materials known to those skilled in the art, and in particular, materials listed in the United States Pharmacopoeia

My. XXII) and in the State Pharmacological Directory (Maiyopa! Roptsiagu Moi. KhM, 0.5.

Rpaptasoreia Sopmepiyop, Ips., KosKkmyPe, MO (1989)), the respective contents of which are incorporated herein by reference. In addition, the invention also covers polymorphic modifications of the proposed compounds.

Pharmaceutical compositions according to the present invention can be administered in any suitable way, for example: oral in the form of tablets, capsules, granules or powders; sublingual; transbuccal; parenterally and in particular, for example, by methods of subcutaneous, intravenous, intramuscular, intramembranous and intrasternal injections or infusions (in the form of, for example, sterile aqueous or non-aqueous solutions or suspensions for injections); nasally with the help of, for example, an inhalation nebulizer; local, for example, in the form of a cream or ointment; or rectal in the form of, for example, suppositories.

At the same time, their dosage forms will contain non-toxic, pharmaceutically acceptable carriers or diluents. The proposed compounds can be administered, for example, in a form designed for immediate release or in a form designed for prolonged release. Both immediate release and sustained release forms of the active ingredient may be prepared from a suitable pharmaceutical composition containing the compounds of the invention, or, particularly in sustained release forms, using devices such as subcutaneous implants and osmotic pumps. In addition, the compounds according to the invention can be administered liposomally.

In addition to primates and, in particular, humans, a variety of other mammalian species may be amenable to treatment with the present invention, including, for example, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, and other bovine, ovine, equine species. , canine, feline, rodent or mouse. However, this invention can also be applied to other types of animals and in particular, for example, to birds (eg, chickens).

Pharmaceutical compositions for the administration of compounds according to the embodiment of the present invention, alone or in combination with other therapeutic agents, can be prepared in a convenient dosage form using any process known to those skilled in the pharmaceutical industry. Such processes, in one way or another, must involve bringing the active ingredient into combination with a carrier formed by one or more auxiliary ingredients. In general, such pharmaceutical compositions are prepared by homogeneously and intimately bringing the active ingredient into combination with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, providing the product with the desired drug form. The active compound is included in the pharmaceutical composition in an amount sufficient to create the desired therapeutic effect on the development or state of the disease. Pharmaceutical compositions that contain the active ingredient can have a form that corresponds to their oral administration, that is, the form of tablets, lozenges, cakes, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

Formulations intended for oral administration may be prepared by any process known to those skilled in the art of pharmaceutical manufacture, and such formulations may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives, which make it possible to give drugs a pharmaceutical and taste appeal. Tablets contain the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example: inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binders, such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated using known methods to inhibit the processes of their disintegration and absorption in the gastrointestinal tract and thus maintain their effect for a long time. For this purpose, such prolongation materials as glyceryl monostearate or glyceryl distearate can be used. Tablets can also be coated to create osmotic therapeutic preparations with controlled release of the active ingredient.

Oral preparations may also be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or with an oily medium, for example

With peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain active materials in a mixture with excipients suitable for the production of an aqueous suspension. Such excipients serving as suspending agents can be, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents may be a naturally occurring phosphatide, such as lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Polyethylene glycol can also be used as a solubilizer. Aqueous suspensions may also contain preservatives, such as ethyl or l-propyl, p-hydroxybenzoate, dyes, flavorings, sweeteners such as sucrose or saccharin.

Oil suspensions can be prepared by suspending the active ingredient in, for example, peanut, olive, sesame or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent, such as wax, solid paraffin or cetyl alcohol. To give the oral preparation pleasant taste qualities, the sweeteners and flavorings listed above can be added to it. Antioxidant additives such as ascorbic acid can serve as preservatives for such compositions.

In the form of dispersed powders or granules, suitable for preparing aqueous suspensions by adding water, the active ingredient is used in a mixture with a dispersing or wetting agent, a suspending agent and a preservative or preservatives.

The same dispersing or wetting agents and suspending agents listed above are suitable for this. Additional excipients can be used, for example, sweeteners, taste and smell correctors, as well as dyes.

Sweeteners, such as glycerin, propylene glycol, sorbitol or sucrose, can be included in the composition of drugs along with syrups and elixirs. Such preparations may also contain a sedative, a preservative, flavor and odor correctors, as well as dyes.

Pharmaceutical compositions according to the invention can be in the form of sterile aqueous or oily suspensions for injections. Such a suspension can be prepared using well-known processes using the same dispersing or wetting and suspending agents as described above. A sterile injectable preparation may also be in the form of a sterile solution or suspension for injection in a diluent or solvent or co-solvent acceptable for parenteral administration, with a complexing or dispersing agent, or with an excipient or a combination thereof, which may serve, for example, as 1 ,3-butanediol, polyethylene glycols, polypropylene glycols, ethanol or other alcohols, povidones, TM/EEM surfactants of various brands, sodium dodecyl sulfate, sodium deoxycholate, dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, and excipients such as inorganic salts (eg, sodium chloride), buffers (for example, sodium citrate, sodium phosphate) and sugars (for example, sucrose and dextrose). Carriers and solvents suitable for use in these preparations are aqueous and dextrose solutions, Ringer's solutions and isotonic sodium chloride solution. Alternatively, sterile fatty oils can usually be used as a solvent or suspending medium. Any soothing fatty oil is suitable, including synthetic mono- and diglycerides. In addition, fatty acids and, in particular, oleic acid are used in preparations for injections.

Depending on the condition to be treated, appropriately prepared pharmaceutical compositions can be administered both systemically and locally. The methods of their preparation and administration are described in detail in the latest edition ("Keptipdiopye Rpaptasetzshiisa! Zsiepsev", Mask Rybiyepipd So, Easiop

Ra. Suitable routes of drug delivery include, for example, oral and transmucosal administration, as well as parenteral routes, including intramuscular, subcutaneous, intramedullary, intramembranous, intraventricular, intravenous, intraperitoneal, and intranasal routes of administration. For administration by injection, the pharmaceutical compositions according to the present invention can be prepared in aqueous solutions. Physiological buffer solutions such as saline are best for this

Hanks' solution (Napk5), Ringer's solution, and appropriately buffered saline. Penetrants corresponding to the barrier to be overcome are used in drugs for introduction into tissues or cells. Such penetrants are suitable substances generally known in the field. Pharmaceutical preparations for parenteral administration contain aqueous solutions of active compounds in a water-soluble form. In addition, suspensions of active compounds can be prepared in appropriate oil suspensions for injections. Suitable lipophilic solvents and carriers for these include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate and triglycerides, as well as liposomes. Aqueous suspensions for injections may contain substances that increase the viscosity of the suspension, namely sodium carboxymethyl cellulose, sorbitol or dextran. If necessary, such a suspension may also contain stabilizers or means of increasing the solubility of compounds, suitable for preparing solutions of high concentration.

The compounds of the present invention can also be supplied in the form of suppositories for rectal administration of drugs. Such formulations can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at room temperature and liquid at rectal temperature, and will melt in the rectum, releasing the drug. Suitable materials for such an excipient are cocoa butter and polyethylene glycol.

For local administration, creams, ointments, gels, solutions, suspensions, etc., containing compounds according to the present invention are used. (For the purposes of this invention, preparations for local administration are also prepared in the form of a liquid for rinsing the mouth and throat).

In one embodiment of the invention, the proposed compounds are administered to a patient in need of such treatment in combination with an anti-inflammatory agent, antihistamines, a chemotherapeutic agent, an immunomodulator, a therapeutic antibody, or a protein kinase inhibitor, for example, a tyrosine kinase inhibitor. Suitable chemotherapeutic agents are, for example: antimetabolites such as methotrexate, DNA crosslinkers such as cisplatin and carboplatin; alkylating agents such as kanbuzil; topoisomerase ! inhibitors such as dactinomycin; microtubule inhibitors such as taxol (paclitaxel), etc. Other suitable chemotherapeutic agents include, for example, vinca alkaloid, a mitomycin-type antibiotic, a bleomycin-type antibiotic, an antifolate, colchicine, demecoline, etoposide, a taxane, an anthracycline antibiotic, doxorubicin, because daunorubicin, carminomycin, epirubicin, idarubicin, mitoxantrone, 4-dimethoxydaunomycin, 11-

deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate, adriamycin-14-octanoate, adriamycin-14-naphthalene acetate, amsacrine, carmustine, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topotecan, oxalaplatin, chlorambucil, methotrexate, lomustine, thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, and mechlorethamine. Suitable therapeutic antibodies include: antibodies against the HEK2 protein, such as trastuzumab; antibodies against growth factors or growth factor receptors, such as bevacizumab, which targets vascular endothelial growth factor, and 051-774, which targets epidermal growth factor; antibodies directed against integrin receptors, such as Vitaxin (also known as

MEOBI-522), etc. Anticancer agents suitable for use in the compositions and methods proposed by the present invention include, for example, the following classes: 1) alkaloids, including microtubule inhibitors (for example, Vincristine, Vinblastine and Vindesine, etc.), microtubule stabilizers (e.g., Paclitaxel |Taxol)i and Docetaxel, Taxotere, etc.), and inhibitors of chromatin function, including topoisomerase inhibitors, such as epipodophyllotoxins (e.g., Etoposide (MP-16|Y and Teniposide IMM-26)| etc.), and means aimed at topoisomerase | (for example, Camptothecin and Isirinotecan ISRT-11) etc.); 2) covalent DNA binding agents (alkylating agents| including nitrogen mustards (eg, Mechlorethamine, Chlorambucil, cyclophosphamide, Ifosfamide and Busulfan (|Millerani, etc.), nitrosoureas (eg, Carmustine, Lomustine, and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine, Thiotepa, and Mitocicin: etc.); 3) non-covalent DNA binding agents (antitumor antibiotics), including nucleic acid inhibitors (e.g., Dactinomycin (Actinomycin 0), etc.), anthracyclines (e.g.,

Daunorubicin |Daunomycin and Cerubidins, Doxorubicin I (Adriamycin| and Idarubicin (Idamycin, etc.), anthracenediones (eg, anthracycline analogs such as (|Mitoxantrone| etc.), bleomycins (Blenoxan), etc., and plicamycin (Mitliramycin), etc.); 4) antimetabolites , including antifolates (for example, Methotrexate, Folex and Mexate, etc.), purine antimetabolites (for example, 6-Mercaptopurine I6-MR, Purinthol, b-thioguanine IE-TO|, Azathioprine, Acyclovir,

Ganciclovir, Chlordeoxyadenosine, 2-Chlorodeoxyadenosine |СаА| and 2'-deoxychoformycin

IPentostatin etc.), pyrimidine antagonists (for example, fluoropyrimidines and, for example, 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine (EdOga) (Floxuridine) | etc.) and

From cytosinarabinosides (for example, Cytozar H(aga-C| and Fludarabine, etc.); 5) enzymes, including

I - asparaginase; 6) hormones, including glucocorticoids, such as antiestrogens (for example,

Tamoxifen, etc.), non-steroidal anti-androgens (for example, Flutamide, etc.) and aromatase inhibitors (for example, Anastrozole IArimidex, etc.); 7) platinum compounds (for example,

Cisplatin and Carboplatin, etc.); 8) monoclonal antibodies conjugated with cancer drugs, toxins and/or radionuclides, etc.; 9) biological reaction modifiers (for example, interferons I, for example, OEM-alpha, etc.) and interleukins I, for example, 1-2, etc.) etc.); 10) means of adoptive immunotherapy; 11) hematopoietic growth factors; 12) means that cause the differentiation of tumor cells (for example, all-trans-retinoic acid, etc.); 13) means of gene therapy; 14) antisense therapy methods; 15) tumor vaccines; 16) therapeutic agents against tumor metastases (for example, Batimistat, etc.); and 17) inhibitors of the development of blood vessels.

The pharmaceutical composition and method according to the present invention may also include the use of other therapeutically active compounds in accordance with this description, which are commonly used in the treatment of the above-mentioned pathological conditions. Such other therapeutic agents can be, for example: cyclosporins (for example, cyclosporin A), STI A4-Id, antibodies such as ISAM-3, anti-1II-2 receptor (Anti-Tas), anti-cOr45EV, anti-CO2 , anti-COS (OKT-3), anti-CO4, anti-CO5O, anti-CO86, means of blocking the interaction between CO40 and dr39, such as antibodies specific for CO40 and/or dr39 (i.e. CO 154), fusion proteins , constructed from CO40 and dr39 (CO401Id and COvorz9), inhibitors, such as inhibitors of the nuclear translocation of ME-kappa B function, such as deoxyspergualin (055), cholesterol biosynthesis inhibitors, such as NMO CoA reductase inhibitors (lovastatin and simvastatin), nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, EC5BO6 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TME-a inhibitors, such as tenidap, antibodies and anti-TME or soluble TME receptor and rapamycin (sirolimus or Rapamun) or its derivatives.

Other agents that may be administered in combination with the compounds of the present invention include protein therapeutics such as cytokines, immunomodulatory agents, and antibodies.

As used herein, the term "cytokine" includes chemokines, interleukins, lymphokines, monokines, colony-stimulating factors, receptor-associated proteins, and their functional fragments. As used herein, the term "functional fragment" means a polypeptide or peptide that has a biological function or activity that identified by a certain functional analysis.

Cytokines include endothelial monocyte-activating polypeptide II (EMAR-II), granulocyte-macrophage-C5E (YAM-C5E), granulocyte-C5E (2-C5E), macrophage-C5E (M-C5BRE), 1-1, I - 2, 1-3, 1-4, 11-5, 1-6, 11-12 and 1/-13, interferons, etc., which is associated with a specific biological, morphological or phenotypic change in a cell or cellular mechanism .

When other therapeutic agents are used in combination with the compounds of the present invention, they may be taken in amounts recommended by, for example, a physician's guide (Rpuzisiap Yue5K Ketegepse (ROC)) or in amounts otherwise recognized by a person skilled in the art.

In the treatment or prevention of pathological conditions in which cell proliferation occurs, the dose of the active ingredient is usually from about 0.01 to 1000 mg per 1 kg of the patient's body weight per day and can be administered all at once or divided into several subdoses.

Thus, for example, the dose of the active ingredient can lie in the range from about 0.01 to 250 mg/kg per day or in the narrowed range from about 0.5 to 100 mg/kg per day. A suitable dosage of the active ingredient is from about 0.01 to 250 mg/kg per day, from about 0.05 to 100 mg/kg per day, or from about 0.1 to 50 mg/kg per day, or from about 1.0 mg/kg per day. In this interval, the dose of the active ingredient can be, for example, from 0.05 to 0.5 mg/kg per day, or from about 0.5 to 5 mg/kg per day, or from about 5 to 50 mg/kg per day.

When administered orally, the pharmaceutical composition in tablet form may contain the active ingredient in an amount of about 1.0 to 1,000 mg, for example, about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1,000.0 mg for symptomatic dose adjustment in the patient being treated. The compounds of the invention can be administered on a schedule of 1 to 4 times per day, for example, once or twice per day. At the same time, you can set a certain period of time without the administration of drugs and change the mode of their administration after this idle period.

It is quite clear that the specific amounts of doses and the frequency of their administration for different patients may be different depending on a number of factors, including the activity of the compound used, the metabolic stability and duration of action of this compound, age, body weight, general health, gender, diet , the method and time of administration of the dose, the rate of elimination of drugs from the body, the used combination of drugs, the severity of a specific pathological condition and the ongoing therapy of the patient.

The compounds of the present invention can be used alone or in combination with an effective amount of a therapeutic antibody (or therapeutic fragment thereof), a chemotherapeutic or an immunotoxic agent for the treatment of tumors. Chemotherapeutic agents used for these purposes can be, for example, doxorubicin, docetaxel or taxol.

In addition, it is clear that the invention also contemplates combination therapy using a compound of the present invention and, for example, vasostatic agents such as tyrosine-, serine-, or threonine kinase inhibitors, as well as any chemotherapeutic agent or therapeutic antibody.

S. Examples

Below are examples illustrating the advantages and features of this invention, without imposing any limitations on its scope.

Example 1. General processes

All experiments described here were conducted under anhydrous conditions (ie, with dry solvents) in an argon atmosphere, with the exception of separately noted cases, using cabinet-dried equipment and standard methods of handling air-sensitive materials.

Saturated aqueous solutions of sodium bicarbonate (MansSoO»z) and sodium chloride (salt solution) were used. Analytical studies using thin-layer chromatography (TLC) were performed on MegskK KiezeIdeI 60 25 tablets with ultraviolet visualization and/or solutions of anisaldehyde, potassium permanganate, or phosphomolybdic acid. Experiments using NRI C-chromatography with inverted phase were carried out on a liquid manipulator Siivop 215, equipped with a cartridge of the Rger-Rak type of the Buipteyuzpiviylm KRI8 7 micron (40x100 mm) production of the Umayeg5 company. The mobile phase consisted of standard acetonitrile (ACN) and deionized water, both of which were supplemented with 0.1 95 TEA. Cleaning was carried out with an eluent consumption of 40 ml/min. NMR spectra: "H nuclear magnetic resonance was recorded at a frequency of 500 b MHz. NMR data are presented in chemical shift values, with multiplicity (5 - singlet, a - doublet, y -

triplet, 4 - quartet, dp - quintet, aa - double doublet, t - multiplet, Bbg 5 - broad singlet), coupling constants (9/H2) and integration. The coupling constants were taken directly from the spectra and were not corrected. Low-resolution mass spectrometry used electrospray ionization. The protonated parent ion (PAN) or the largest mass fragment is given as

Example. Unless otherwise noted, the analytical gradient consisted of 10 956 acetonitrile (ACN) in water rising to 100 95 ACM over 5 min.

Example 2. M'-(4-Methoxyphenylpyrimidine-2,4-diamine (intermediate product 1): tp

MN

WITH

J

M Mn,

A mixture of 4-chloropyrimidin-2-ylamine (0.30 g, 2.3 mmol) and 4-methoxyphenylamine (0.30 g, 2.4 mmol) was suspended in acetic acid (10 mL) and heated at 100 °C for 2 hours

The mixture was then allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH-7 with a 7M solution

Mahon. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. Next, the organic layer was washed with saline, dried over Modzoh and filtered. The filtrate was concentrated in vacuo and the crude product was purified by silica gel flash chromatography (eluent: hexane to EIAs) to give the title intermediate 1 (0.23 g, 45 95) as a white solid. "H NMR (500 MHz, OM50-а6): 3.69 (5, ЗН), 5.84 (а, 9-5.8 Hz, 1Н), 6.79 (а, 9-9.1 Hz, 2H), 7.63 (a, 9-91 Gu, 2H), 7.78 (0, 9-5.8 Hz, 1H), 8.65 (5, 1H); M5 (EBI w): t/ 2,217 (MAN).

Example 3. M'-(4-Methoxyphenyl)-Me-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound 1): so.

MN

(in)

Even MO,

J

M M

N

For the synthesis of the compound | intermediate 1 and intermediate 2 described above were used. Intermediate 2, 1-(2-(4-bromophenoxy)ethyl|pyrrolidine, shown below, is commercially available and was used as supplied:

Co., Ltd. (c) Mr. M,

A suspension of intermediate 1 (74 mg, 0.34 mmol), intermediate 2 (0.10 g, 0.37 mmol), Ra(OAc)" (5 mg, 0.022 mmol), xanthophos (Khapirpov5: 4,5- bis-(diphenylphosphino)-9,9-dimethylxanthene, 26 mg, 0.05 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in a mixture of dioxane/io ME (3/1; 4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 min. After cooling to room temperature, the lid of the tube was removed and the resulting mixture was filtered and the filtered solid was washed with OCM. The filtrate was concentrated, and the residue was purified by HRIS chromatography, obtaining the title compound I (20 mg of TEA trifluoroacetic acid salt, 11 95), which was a brown solid.

IN NMR (500 MHz, OM5O-a6): 1.80-1.95 (t, 2H), 1.95-2.10 (t, 2H), 3.05-3.20 (t, 2H), 3.55-3.65 (t,

B AN), 3.77 (5, ZN), 4.29 (I, 9-4.9 Hz, 2H), 6.30 (a, 9-6.8 Gu, 1H), 6.96 (a , 9-8.3 Gu, 2H), 6.98 (y, U-8.3

Gu, 2H), 7.41 (a, 9U-8.8 Gu, 2H), 7.55 (a, 9U-8.8 Hz, 2H), 7.89 (a, 9U-6.2 Hz, 1H), 9.87 (rg 5, 1H), 10.22 (Bg 5, 1H), 10.44 (rg 5, 1H); M5 (EB5I-): t/2 406 (MAN).

Example 4. 4-(4--4-Methoxyphenylamino)pyrimidin-2-ylamino|-M-(2-pyrrolidin-1-yl-ethyl)benzenesulfonamide (compound 1Y): c

MN her f c) M

M Y o V -

M M

N .

Intermediate 1, described above, and intermediate 3 were used for the synthesis of compound II. Intermediate 3, 4-bromo-M-(2-pyrrolidin-1-yl-ethyl/benzenesulfonamide, the formula of which is shown below) was obtained from 4-bromophenylsulfonyl chloride and 2-aminoethylpyrrolidine using well-known synthesis methods: (c)

DI ey o Nn

Vg, Z

A suspension of intermediate 1 described above (70 mg, 0.32 mmol), intermediate

C (0.12 g, 0.36 mmol), PaY(OAc)" (5 mg, 0.022 mmol), xanthophos (26 mg, 0.05 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in a mixture of dioxane/ioME (3/1; 4 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 min. After cooling to room temperature, the lid of the tube was removed, and the resulting mixture was filtered and the filtered solid washed OSM.

The filtrate was concentrated, and the residue was purified by NRI C-chromatography to give the title compound II (0.16 g of TEA salt, 85 95), which was a white solid. "H NMR (500 MHz, OM5O-av): 1.80-1.95 (t, 2H), 1.95-2.05 (t, 2H), 2.95-3.05 (t,

AN), 3.23 (4, 9U-5.8 Hz, 2H), 3.50-3.60 (t, 2H), 3.79 (5, ЗН), 6.41 (a, U-6 ,8 Gu, 1H), 6.99 (a, 9U-8.9 Hz,

Zo 2H), 7.43 (a, 9-8.9 Hz, 2H), 7.71 (a, 9U-8.6 Gu, 2H), 7.85-7.95 (t, 2H), 7 .96 (I, 9-61 Hz, 1H), 8.02 (a, 3-6.2 Hz, 1H), 9.64 (Bg 5, 1H), 10.21 (Bg 5, 1H), 10 .71 (Bg 5, 1H); M5 (EBI-): t/2 469 (MAN).

Example 5. 4-I(4--(4-Hydroxyphenylamino)-pyrimidin-2-ylamino|-M-(2-pyrrolidin-1-yl-ethyl)benzenesulfonamide (compound IP): no.

MN her F

With M

There is YZm7 7 o and -

M M

N SHI

To a solution of compound ІІ described above (50 mg, 0.09 mmol) in OSM (6 ml) at room temperature was added ВВгз (0.1 ml), and the resulting mixture was stirred at room temperature for 2.5 h. The reaction was quenched by adding a saturated solution of ManCO3 to the pH value. and the mixture was extracted with EtOAc (30 mL). The organic layer was separated and washed with brine, dried over MgSO, and filtered. The filtrate was concentrated and the resulting solid was re-dissolved in a minimal amount of EtOAc. Hexane was added to the solution until the solid was displaced, and the title compound III was filtered to give a white solid (25 mg, 64 95) without further purification. "H NMR (500 MHz, OM5O-α): 1.55-1.65 (t, 4H ), 2.30-2.40 (t, 4H), 2.43 (I, 9-7.0 Hz, 2H), 2.82 (I, 9-6.6 Gu, 2H), 6.20 (a, 9-5.8 Gu, 1H), 6.70 (a, 9U-8.8 Hz, 2H), 7.40 (a, U-8.6 Hz, 2H), 7.64 (a , 98.6 Hz, 2H), 7.92 (a, 9-8.4 Hz, 2H), 8.03 (9, 9U-5.5 Gu, 1H), 8.93 (5, 1H), 9.08 (Bg 5, 1H), 9.70 (5, 1H); M5 (EB5I-yu): t/2 455 (M.-H)".

Example b. 4-(4-Chloropyrimidine-2-ylamino)-M-(2-pyrrolidin-1-ylethyl)-benzenesulfonamide (intermediate 4):

SI (c) that m Юм7

AI

-

M M

N

A mixture of 4-chloropyrimidin-2-ylamine (1.0 g, 7.8 mmol), the above-described intermediate C (2.6 g, 7.8 mmol), RIZHOAS)" (90 mg, 0.40 mmol), xanthophos (0.50 g, 0.86 mmol) and potassium tert-butoxide (2.2 g, 20 mmol) were suspended in dioxane (30 mL) and refluxed in an argon atmosphere for 16 h. The mixture was poured into water (30 mL) and extracted with EtOAc (60 mL). The organic layer was separated and washed with saline solution, dried over Md5oO»x and filtered. The filtrate was concentrated in vacuo and the crude product was purified by silica gel flash chromatography (OM to 2555 MeOn/OM) to afford the title intermediate 4 (0.15 g, 5 95) as a brown solid. M5 (E5BI zhk): t/2 382 (MN).

Example 7. 4-(4--(3-Methoxyphenylamino)pyrimidin-2-ylamino|-M-(2-pyrrolidin-1-yl-ethyl)benzenesulfonamide (compound IM):

Koo) o o

I) M

M ЮМ7 and what -

M M

N. M

A mixture of the above-described intermediate 4 (0.10 g, 0.26 mmol) and 3-methoxyphenylamine (0.05 mL, 0.45 mmol) was suspended in acetic acid (b mL) and heated at 100 C for 1.5 hours After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH-7. The resulting solution was extracted with EIOAc (30 ml) and the organic layer was separated.

Next, the organic layer was washed with saline solution, dried over Md5Ox4 and filtered.

The filtrate was concentrated in vacuo and this crude product was purified by HRIS chromatography to give the title compound IM (55 mg TEA salt, 36 95) as a white solid. "H NMR (500 MHz, OM50O-av): 1.80-1.90 (t, 2H), 1.95-2.05 (t, 2H), 2.95-3.05 (t, 4H) , 3.24 (d, U-6.0 Hz, 2H), 3.50-3.60 (t, 2H), 3.73 (5, ЗН), 6.40 (a, 9U-6.3 Hz, 1H), 6.68 (a, U-7.3 Hz, 1H), 7.18 (a, 9-8.2 Gu, 1H), 7.26 (I, 9-8.0 Hz, 1H), 7.30 (5, 1H), 7.72 (a, U-8.9

Hz, 2H), 7.91 (Her, 9-61 Hz, 1H), 7.95 (a, 9U-8.7 Hz, 2H), 8.10 (a, 9U-6.2 Gu, 1H) , 9.59 (Bg 5, 1H), 9.87 (bg 5, 1H), 10.38 (rg 5, 1H); M5(E5I): t/2 469(М-Н)".

Example 8. 4-I4-(3-Hydroxyphenylamino)pyrimidin-2-ylamino-1-M-(2-pyrrolidin-1-yl-ethyl)benzenesulfonamide (compound M):

I oh

With M m Ym7 7 on -

M M

N .

To a solution of the above-described IM compound (30 mg, 0.05 mmol) in OSM (b ml) at room temperature was added BVgz (0.1 ml), and the resulting mixture was stirred at room temperature for 2.5 h. The reaction was quenched by adding a saturated solution of MansSoO3 to reach pH-7 and the mixture was extracted with EtOAc (30 ml). The organic layer was separated and washed with saline solution, dried over M95O4 and filtered. The filtrate was concentrated, and the residue was purified by HRIS chromatography to give the title compound M (13 mg TEA salt, 46 95), which was an off-white solid.

IN NMR (500 MHz, ОМ5О-ав6): 1.80-1.90 (t, 2Н), 1.95-2.05 (t, 2Н), 2.95-3.05 (t, 4Н), 3.20-3.30 (t, 2H), 6.39 (a, U-6.3 Hz, 1H), 6.53 (a, 9-7.2 Hz, 1H), 7.01 (a , 9-9.2 Hz, 1TN), 7.09 (5, 1Н), 7.14 (1, 9-8.1

Gu, 1), 7.73 (a, 9-88 Hz, 2H), 7.90 (I, 9-62 Gu, 1), 7.97 (a, 9U-8.8 Hz, 2H), 68 .08 (a, 9-6.4 Gu, 1H), 9.48 (horn 5, 1H), 9.57 (Bi 5, 1H), 9.86 (Brg 5, 1H), 10.41 (rg 5, 1H); M5 (EB5I-):t/2455 (M.N).

Example 9. Benzo|1,3|dioxol-5-yl-(2-chloro-5-methylpyrimidin-4-yl)-amine (intermediate product 5):

S o MN

Shit

AND

M SI in

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5-bromobenzo|1,3|dioxol (0.45 g, 2.2 mmol), RA(OAcS)» 2 (30 mg, 0.13 mmol), xanthophos (0.15 g, 0.26 mmol) and potassium tert-butoxide (0.45 g, 4.0 mmol) were suspended in dioxane (15 mL) and boiled with a reflux condenser in an argon atmosphere for 16 h. After that, the reaction mixture was cooled to room temperature and diluted with USM (20 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: hexane to 50 95 EtOAc/hexane) to give the title intermediate

From product 5 (0.10 g, 18 95), which was a white solid. M5 (E5BIZ): t/2 264 (MaAN)".

Example 10. Me-Benzo|1,3|dioxol-5-yl-o-methyl-M2-(I4-(2-pyrrolidin-1-ylethoxy)phenyl|- pyrimidine-2,4-diamine (compound MI):

St o MN (c) nF mm, a

M M

N "M

For the synthesis of compound MI, intermediate 5, described above, and intermediate 6 were used. Intermediate 6, 4-(2-pyrrolidin-1-ylethoxy)phenylamine, the formula of which is shown below, was synthesized in two stages, the first of which was alkylation of 4 -nitrophenol with the help of 2-xporeethylpyrrolidine, followed by reduction. As a result, an aniline derivative was obtained: na oraya

UV with nm in

To obtain intermediate product 6, well-known synthesis methods were used.

A mixture of the above-described intermediate 5 (90 mg, 0.34 mmol), intermediate 6 (95 mg, 0.46 mmol), Raz(ava)z (20 mg, 0.02 mmol), xanthophos (30 mg, 0 .05 mmol) and cesium carbonate (0.30 g, 0.9 mmol) were suspended in dioxane (10 mL) and refluxed in an argon atmosphere for 20 h. After that, the reaction mixture was cooled to room temperature and diluted with OSM (20 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by HRIS chromatography to give the title compound MI (40 mg TEA salt, 21 95), which was a brown solid. "H NMR (500 MHz, OM50O-av): 1.85-1.95 (t, 2H), 1.95-2.05 (t, 2H), 2.13 (5,

ZN), 3.10-3.20 (t, 2H), 4.26 (Her, 9-5.0 Hz, 2H), 6.07 (5, 2H), 6.90-7.00 (t , 4H), 7.19 (5, 1H), 7.37 (a, 9U-9.0 Hz, 2H), 7.84 (5, 1H), 9.60 (Brg 5, 1H), 9, 89 (Bg 5, 1H), 10.32 (Bg 5, 1H); M5 (EBI-): t/2 434 (MAN).

Example 11. (4-Chloro-3-methoxyphenyl)(2-chloro-5-methylpyrimidin-4-yl)amine (intermediate 7):

SI schi . "MN

SHI

J

M SI 7

A mixture of /2-chloro-5-methylpyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-bromo-1-chloro-2-methoxybenzene (0.65 ml, 4.8 mmol), Raz( ava)z (0.17 g, 0.19 mmol), xanthophos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) were suspended in dioxane (20 ml) and boiled They were with

Reflux in an argon atmosphere for 5 hours. After that, the reaction mixture was cooled to room temperature and diluted with OSM (30 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: hexane to 40 95 EOAc/hexane) to give the title intermediate 7 (0.55 g, 55 95) as a yellow solid. "H NMR (500 MHz, OM50-a6): 2.18 (5, ZN), 3.85 (5, ZN), 7.35 (ai, 9-8.6 Gu, U-2.3 Hz, 1H), 7.39 (a, U-8.7 Hu, 1H), 7.56 (a, 9-2.3 Hz, 1H), 8.09 (a, 9-0.9 Hu, 1H) , 8.91 (5, 1N); M5 (EBIzh): t/2 284 (M.N).

Example 12. (4-Chloro-3-methoxyphenyl)(2-chloro-5-methylpyrimidin-4-yl)umethylamine (intermediate product 8): still M.

SHI

Residential complex

M SI 8

A suspension of intermediate 7 (0.50 g, 1.8 mmol) and sodium hydride (60 95 in mineral oil, 0.15 g, 3.8 mmol) in TNE (10 mL) was stirred in an argon atmosphere at a temperature of 0 7C for 5 min. At the same temperature, methyl iodide (0.15 mL, 2.4 mmol) was added to the mixture using a syringe. The resulting solution was stirred at a temperature from 0 C to room temperature for 15 min., and then at room temperature for another 17 h.

The reaction was quenched with water (10 mL) and the mixture was extracted with EOAc (30 mL). The organic layer was separated and washed with saline solution, dried over Md5ZoOx and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: hexane to 20 95 EIOAc/hexane) to give the title intermediate 8 (0.20 g, 38 95) as a white solid. M5 (EBI): m/2 298 (MN).

Example 13. M2-(4-(2-(Pyrrolidin-1-ylethoxy)phenyl)-My-(4-chloro-33-methoxyphenyl)-M?Y, - 5-dimethylpyrimidine-2,4-diamine (compound MI ):

SI about ts | t i wa

UNTIL

M M and MI

A mixture of the above described intermediate 8 (0.15 g, 0.49 mmol) and intermediate 6 (0.15 g, 0.73 mmol) was suspended in acetic acid (8 ml) and heated at a temperature of 100 C for 17 h. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH-7 with 7M Mahon solution. The resulting solution was extracted with EtOAc (30 mL) and the organic layer was separated. Next, the organic layer was washed with a saline solution, dried over

Ma5o" and filtered. The filtrate was concentrated in vacuo and this crude product was purified by NRI C-chromatography to give the title compound MI! (0.14 g of TEA salt, 49 95), which was a white solid. "H NMR (500 MHz, OM5O-av): 1.85-1.95 (t, 2H), 2.00-2.10 (t, 2H), 3.08-3.18 (t, 2H) . a, U-7.4 Gu, 1H), 7.01 (a, 9-9.0 Hz, 2H), 7.15 (5, 1H), 7.46 (a, 2-8.4 Hz, 1H), 7.58

Zo (ad, 9-8.9 Hz, 2H), 7.83 (5, 1H), 9.85 (Bg 5, 1H), 10.04 (Bg 5, 1H), 10.32 (Bg 5, 1H); M5 (EB5I-): t/72 468 (MAN.

Example 14. (2-Chloro-5-methylpyrimidin-4-yl)(4-chlorophenyl)amine (Intermediate 9):

SI and

MN and A

M SI

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.30 g, 2.1 mmol), 1-bromo-4-chlorobenzene (0.60 g, 3.1 mmol), Raz(abva)z (95 mg, 0.10 mmol), xanthophos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (20 mL) and refluxed under atmosphere argon for 4 hours. After that, the reaction mixture was cooled to room temperature and diluted with OSM (20 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: hexane to 30 95 EIOAc/hexane) to give the title intermediate 9 (0.15 g, 28 95) as a pale yellow solid. M5 (EBIzh): t/2 254 (MEN).

Example 15. M'-(4-Chlorophenyl)-5-methyl-Me-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (MIP compound): juice and

MN di ve,

AH

M M and M

A mixture of the above-described intermediates 9 (0.15 g, 0.60 mmol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 ml) and heated at a temperature of 100 "C for 6 h. After this mixture was allowed to cool to room temperature and acetic acid was removed under reduced pressure.The residue was taken up in water (15 mL) and neutralized to pH-7 with 7M Mahon's solution.

The resulting brown solid was filtered off and then purified by NRI C-chromatography to afford the title compound MI! (38 mg of TRA salt, 12 95) in the form of brown oil. "H NMR (500 MHz, OM5O-av): 1.80-1.95 (t, 2H), 2.00-2.10 (t, 2H), 2.15 (5, ЗН), 3.10 -3.20 (t, 2H), 3.55-3.65 (t, 4H), 3.77 (5, ЗН), 4.28 (I, U-5.0 Hz, 2H), 6, 95 (a, 9-9.0 Hz, 2H), 7.38 (a, 9-8.9 Gu, 2H), 7.42 (y, 9-8.9 Hz, 2H), 7.62 ( a, 9-88 Hz, 2H), 7.90 (5, 1H), 9.48 (rg 5, 1H), 9.84 (ri 5, 1H), 10.10 (rg 5, 1H); M5 (EBI-k): t/2 424 (M.N).

Example 16. 2-(4-Aminophenoxy)ethanol (intermediate product 10): o. in

Dt Y pom 10

A solution of 2-(4-nitrophenoxy)ethanol (2.1 g, 12 mmol) in MeOH (30 mL) was purged with argon and

Ra/C (10 Fo(wt.)) was placed from it. After that, the mixture was evacuated under a vacuum cap and filled with balloon hydrogen. Then this cycle was repeated, and the mixture thus created was stirred at room temperature for 2 h. This heterogeneous reaction mixture was filtered through a pad of celite, washed with Meon, and concentrated in vacuo to give the title intermediate 10 (1.8 g, 9995) as a brown solid. M5 (EBI-): t/72 154 (MN).

Example 17. 2-14-(4-(4-Chloro-3-methoxyphenylamino)-5-methylpyrimidin-2-ylamino|phenoxy)ethanol (compound IX): i i bo MH (c)

With in

J

M M

H. H

A suspension of the above-described intermediates 7 (50 mg, 0.17 mmol) and 10 (40 mg, 0.26 mmol),

Rag(avra)" (8 mg, 0.01 mmol), xanthophos (10 mg, 0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in dioxane (3 ml) were sealed in a microwave reaction tubes and irradiated with microwaves at a temperature of 160 "C for 15 min. After cooling to room temperature, the lid of the tube was removed, and the resulting mixture was filtered, and the filtered solid was washed with OCM. The filtrate was concentrated, and the residue was purified using flash chromatography on silica gel (eluent : from hexane to EIOAc) to give the title compound IX (14 mg, 21 95), which was a light brown solid. "H NMR (500 MHz, OM50-a6): 2.10 (5, ЗН ), 3.69 (I, U-5.3 Hz, 2H), 3.75 (5, ЗН), 3.92 (Ii, 9-5.1 Hz, 2H), 4.83 (I, 9 -5.6 Hz, 1H), 6.78 (a, 9-9.0 Gu, 2H), 7.29 (a, 9U-8.5 Hz, 1H), 7.43 (aa, 98.6 Gu, U-2.2 Hz, 1), 7.48 (a, 2-2.3 Gu, 1H), 7.52 (a, 9-9.0 Hz, 2H), 7.88 (5, 1H), 8.31 (5, 1H), 8.80 (5, 1H); M5 (EBIK): t/2 401 (MAN).

Example 18. 5-Methyl-M"-I(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (intermediate product 11):

MN, dear,

J

M M

What

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.13 g, 0.87 mmol) and intermediate 6 described above (0.30 g, 1.5 mmol) was suspended in acetic acid (8 mL) and heated at a temperature of 100 C for 2 hours. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH-7 with a 7M solution of NaOH. The resulting solid was filtered (30 mg) and washed with ether. The filtrate was extracted with Es (30 mL) and the organic layer was separated. Next, the organic layer was washed with saline solution, dried over Mo5ox and filtered. The filtrate was concentrated to obtain an additional amount of solid product (02 g), which was combined with the first batch of product to give the title intermediate 11 (0.23 g, 85 95) as a light brown solid. "H NMR (500 MHz, OM50-av): 1.65-1.70 (t, 4H), 1.89 (5, ZH), 2.74 (I, 9U-6.0 Hz, 2H), 3.98 (i, y-61 Gu, 2H), 6.30 (5, 2H), 6.78 (a, 9-91 Hz, 2H), 7.62 (a, 9-91 Hz, 2H) , 7.64 (5, 1H), 8.50 (5, 1H);

M5 (EBI): t/2 314 (M.N).

Example 19. 5-Methyl-M"-phenyl-M2-I(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound X):

OK

(in)

ХХ ММ, part ХХ

M M

N gh

A suspension of the above-described intermediate 11 (25 mg, 0.08 mmol), bromobenzene (0.05 mL, 0.50 mmol), Raz(ava)" (5 mg, 0.006 mmol), xanthophos (10 mg, 0.02 mmol) and cesium carbonate (70 mg, 0.21 mmol) in dioxane (3 mL) were hermetically sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 °C for 15 min. After cooling to room temperature, the lid of the tube was removed, and the resulting the resulting mixture was filtered and the filtered solid washed with OCM.The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: OCM to 3095 Meon/OMC) to give the title compound X (10 mg, 32 95) which was a light-brown solid substance. "H NMR (500 MHz, OM50O-av): 1.65-1.72 (t, 4H), 2.10 (5, ЗН), 2.48-

2.568 (t, 4H), 2.75-2.82 (t, 2H), 4.00 (Her, 92-5.9 Hz, 2H), 6.77 (a, 9-9.0 Gu, 2H ), 7.04 (I, 9-7.3 Hz, 1H), 7.32 (I, 97.9 Hz, 2H), 7.54 (a, 9-9.0 Hz, 2H), 7, 71 (y, 9U-7.8 Hz, 2H), 7.84 (5, 1H), 8.20 (5, 1H), 8.76 (5, 1H); M5 (EBI-): t/2 390 (MAN).

Example 20. (4-Chloro-3-fluorophenyl)(2-chloro-5-methylpyrimidin-4-yl)uamine (intermediate 12): ve

E MN nFf

J

M si

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-bromo-1-chloro-2-fluorobenzene (1.0 g, 4.8 mmol), Rag(aba )z (0.16 g, 0.17 mmol), xanthophos (0.20 g, 0.34 mmol) and cesium carbonate (2.3 g, 7.0 mmol) were suspended in dioxane (25 ml) and boiled were kept under reflux in an argon atmosphere for 15 hours. After that, the reaction mixture was cooled to room temperature and diluted with OSM (30 ml). The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: hexane to 40 95 EIOAc/hexane) to give the title intermediate 12 (0.75 g, 80 95) as an off-white solid. M5 (EBI same): t/2 272 (MAN).

Example 21. M'-(4-Chloro-3-fluorophenyl)-5-methyl-Me-I4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound XI): in

E Mn but to

J

M M and "XI

A mixture of the above-described intermediates 12 (0.20 g, 0.74 mmol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 ml) and heated at a temperature of 100 "C for 6 h. After this mixture was allowed to cool to room temperature and acetic acid was removed under reduced pressure.The residue was taken up in water (15 mL) and neutralized to pH-7 with 7M Mahon's solution.

The resulting solution was extracted with EIAs (30 ml) and the organic layer was separated. Next, the organic layer was washed with saline solution, dried over Md5O5 and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (eluent: OSM to 30 96 MeEOH/OSM) to give the title compound XI (90 mg, 28 95) as a white solid . "H NMR (500 MHz, OM5O-dv)71.65-1.71 (t, 4H), 2.10 (5, ЗН), 2.45-2.55 (t, 4H), 2.77 ( 1, 9-6.0 Hz, 2H), 4.01 (i, 9-6.0 Hz, 2H), 6.82 (a, 9-9.0 Hz, 2H), 7.44 (I, 9U-8.8 Hu, 1), 7.50 (a, 9-9.0 Hz, 2H), 7.55 (aa, 9U-8.9 Hz, U-2.0 Hu, 1H), 7 .91 (5, 1H), 8.07 (yes, 9U-12.5 Hz, U-2.0 Hz, 1H), 8.43 (5, 1H), 8.90 (5, 1H); M5 (EBI zhk): t/2 442 (MAN).

Example 22. M'-(4-Chloro-5-methoxyphenyl)-5-methyl-Me-(4-morpholin-4-ylmethylphenyl)pyrimidin-2,4-diamine (compound XIII): i and 7o MH

B 77

M M y - ХИЙ

A suspension of the above-described intermediate product 7 (50 mg, 0.17 mmol), 4-morpholin-4-ylmethylphenylamine (50 mg, 0.26 mmol), Raz(ara)»2 (8 mg, 0.009 mmol), xanthophos (10 mg, 0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in dioxane (3 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 °C for 15 min. After cooling to room temperature the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM.

The filtrate was concentrated, and the residue was purified by NRI C-chromatography to give the title compound XII (40 mg TEA salt, 43 95), which was a pale yellow solid. "H NMR (500 MHz, OM5O-adv): 2.16 (5, ЗН), 3.05-3.15 (t, 2Н), 3.10-3.20 (t, 2Н), 3.60 -3.70 (t, 2H), 3.90-4.00 (t, 2H), 4.28 (5, 2H), 4.01 (Ii, 9-6.0 Gu, 2H), 7, 25-7.35 (t, ZN), 7.35-7.41 (t, 2H), 7.65 (a, 9U-8.3 Hz, 2H), 7.98 (5, 1H), 9 .10 (Bg 5, 1H), 9.86 (Bg 5, 1H), 9.95 (rg 5, 1H);

M5 (EBI): t/2 440 (M.N).

Example 23. Benzo|b|Ithiophen-5-yl-(2-chloro-5-methylpyrimidin-4-yl)amine (intermediate 13):

Fe

H

MN no

AND

M SI

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5-bromobenzoic acid (0.6 g, 2.8 mmol), Rag(ava)z (95 mg, 0.10 mmol), xanthphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (25 mL) and refluxed under argon for From After that, the reaction mixture was cooled to room temperature and diluted with SOCM (30 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by flash chromatography on silica gel (eluent: hexane to 30 96 EOAc/hexane) to give the title intermediate 13 (0.23 g, 40 9) as a white solid. M5 (EBIzh): t/2 276 (MAN).

Example 24. M"-Benzo|Bigiophen-5-yl-5-methyl-Me2-(4-(2-pyrrolidin-1-ylethoxy)phenyl|Ipyrimidine-2,A-diamine (compound CP):

S h

MN

(c) to Cha FI

M M

N XII

Coo)

A mixture of the above-described intermediates 13 (0.23 g, 0.83 mmol) and 6 (0.35 g, 1.7 mmol) was suspended in acetic acid (8 mL) and heated at 100 °C for 1 day.

After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH-7 with 7M Mahon solution. The resulting solution was extracted with EtOAc (30 mL) and the organic layer was separated. Next, the organic layer was washed with saline solution, dried over Mo5ox and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (eluent: 100 ppm to 1595 ppm) to give the title compound XII (0.13 g, 35 90) as a white solid. "H NMR (500 MHz, OM5O-adv): 1.65-1.75 (t, 4H), 2.12 (5, ЗН), 2.50-2.62 (t, 4H), 2.75 -2.85 (t, 2H), 3.99 (i, U-5.9 Hz, 2H), 6.70 (a, 9-9.0 Hz, 2H), 7.36 (a, 9U- 5.4 Hu, 1 H), 7.51 (a, 9-91 Hu, 2H),

7.61 (ai, 9-8.7 Hz, U-2.0 Gu, 1H), 7.74 (a, 2-5.4 Hz, 1 H), 7.85 (a, 9-08 Hz , 1 H), 7.92 (a, U-8.6 Hz, 1

H), 8.29 (9, 9-1,7 Hu, 1 H), 8.34 (5, 1 H), 8.76 (5, 1 H); M5 (EBIZH): t/2 446 (M4-H)".

Example 25. Benzo|bithiophen-3-yl-(2-chloro-5-methylpyrimidin-4-yl)amine (intermediate product 14): and

MN

SHI

Residential complex

B and SI 14

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.30 g, 2.1 mmol), 3-bromobenzoic acid (0.6 g, 2.8 mmol), Rag(ava)z (95 mg, 0.10 mmol), xanthphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (25 mL) and refluxed under argon for From After that, the reaction mixture was cooled to room temperature and diluted with USM (30 ml). The mixture was then filtered and the filtrate was concentrated in vacuo.

The residue was purified by silica gel flash chromatography (eluent: hexane to 30 96 EOAc/hexane) to give the title intermediate 14 (65 mg, 11 Or) as a yellow solid. M5 (EBIZH): t/2 276 (Man).

Example 26. M"-Benzo|Bigiophen-3-yl-b-methyl-Me-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound CHM): and

IN

MN

(c) nf U

J

M M

H. CHEM

A mixture of the above-described intermediates 14 (50 mg, 0.18 mmol) and 6 (0.10 g, 0.48 mmol) was suspended in acetic acid (8 ml) and heated at a temperature of 100 "C for 15 h. After this mixture allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure.The residue was taken up in water (10 mL) and neutralized to pH-7 with 7M solution

MaonN. The resulting solution was extracted with EtOAc (20 ml) and the organic layer was separated. Next, the organic layer was washed with saline solution, dried over Mdzoh and filtered. The filtrate was concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel (eluent: 100 ppm to 1595 ppm) to give the title compound KHIM (10 mg, 13 95) as an off-white solid . "H NMR (500 MHz, OM50O-av): 1.70-1.80 (t, 4H), 2.19 (5, ЗН), 2.65-2.80 (t, 4H),

Zo 2.85-3.00 (t, 2H), 3.98-4.03 (t, 2H), 6.63 (y, 9-8.8 Hu, 2H), 7.37 (a, 9 -86 Hz, 2H), 7.38-7.45 (t, 2H), 7.79-7.83 (t, 1H), 7.87 (5, 1H), 7.90-8.03 ( t, 1H), 8.33 (5, 1H), 8.78 (5, 1H); M5 (EBIzh): t/2 446 (MAN.

Example 27. (2-Chloro-5-methylpyrimidin-4-yl)(3-chlorophenyl)amine (intermediate 15):

SI and MN

SHI

KK

M SI 15

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.30 g, 2.1 mmol), 1-bromo-3-chlorobenzene (0.60 g, 3.1 mmol), Raz(abva)z (95 mg, 0.10 mmol), xanthophos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (20 mL) and refluxed in an atmosphere argon for 4 hours. After that, the reaction mixture was cooled to room temperature and diluted with SOCM (20 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by silica gel flash chromatography (eluent: hexane to 40 95 EOAc/hexane) to afford the title intermediate 15 (0.30 g, 56 Ohr) as a pale yellow solid. M5 (EBIzh): t/2 254 (MAN).

Example 28. /M'-(3-Chloro)-5-methyl-Me-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound XU):

SI "MN (in) ra

M M

N HM

A mixture of the above-described intermediates 15 (0.15 g, 0.59 mmol) and 6 (0.25 g, 1.2 mmol) was suspended in acetic acid (8 ml) and heated at a temperature of 100 "C for 21 h. After this mixture was allowed to cool to room temperature and acetic acid was removed from it under reduced pressure.The residue was taken up in water (15 mL) and neutralized to pH-7 with 7M solution

Mahon. The resulting solution was extracted with EtOAc (30 mL), and the organic layer was separated. Next, the organic layer was washed with saline, dried over Modzoh and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (eluent: 100 ppm to 1095 ppm) to give the title compound XM (60 mg, 24 95) as a white solid. "H NMR (500 MHz, OM5O-av): 1.65-1.72 (t, 4H), 2.10 (5, ЗН), 2.50-2.60 (t, 4H), 2.78 -2.83 (t, 2H), 4.01 (1, 9U-5.9 Gu, 2H), 6.81 (a, 9-91 Hz, 2H), 7.05-7.08 (t, 1H), 7.32 (i, 9-81 Hz, 1H), 7.52 (a, 9-9.0 Hz, 2H), 7.71 (a, 9-8.3 Gu, 1H), 7 .85 (I, 9-21 Hz, 1 N), 7.89 (i, 9U-0.7 Hz, 1 N), 8.33 (5.1 N), 8.86 (5, 1 N) M5 (EB5I): t/2 424 (M.N)".

Example 29. 3-Bromo-M-methylbenzamide (intermediate product 16):

Coo)

M t Vg at 16

A solution of 3-bromobenzoyl chloride (2.93 g, 13.3 mmol, 1 eq; in 30 mL of TNE) was vigorously stirred and mixed with 2.0 M methylamine in TNE (15 mL, 29.4 mmol, 2.2 eq.) It was observed the appearance of a white precipitate, and the reaction mixture was allowed to stir for 20 minutes. The mixture was then poured into ethyl acetate (100 mL) and washed with water (2 x 150 mL) and brine (1 x 150 mL). The organic phase was separated from the aqueous phase and dried over sodium sulfate, filtered and evaporated to give the title intermediate 16 as a white powder (2.29 g, 82 95 yield).

Example 30. 3-(2-Chloro-5-methylpyrimidin-4-ylamino)-M-methylbenzamide (intermediate 17):

M r (c)

OHM

XX, X

MO21317

In a dry 50 mL round-bottom flask, 2-chloro-5-methylpyrimidin-4-ylamine (0.3 g, 2.09 mmol, 1 equiv.), 3-bromo-N-methylbenzamide (0.489 g, 2.29 mmol, 1.1 eq.), cesium carbonate (2.04 g, 6.27 mmol, 3 eq.), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (0.242 g, 0.418 mmol, 0.2 eq.) and tris(idibenzylideneacetone)dipalladium (0.191 g, 0.209 mmol, 0.1 eq.). The reagents were diluted with dioxane (20 mL), purged with argon, and the flask was equipped with a reflux condenser. The reaction mixture was refluxed for 16 hours. After that, the mixture was transferred to a centrifuge tube, spun, decanted and subjected to evaporation. The resulting solid yellow particles were diluted with OSM and adsorbed on silica gel. After chromatography (with a gradient from 50 95 ethyl acetate in hexane to 100 95 ethyl acetate), the title intermediate 17 was obtained as a pale yellow powder (0.25 g, 43 95 yield). M5 (EBIU): 277.01 (MAN), retention time - 1.92 min.

Example 31. Trifluoroacetic acid salt of M-methyl-3-(5-methyl-2-I|4-(2-pyrrolidin-1-yl-ethoxy)phenylamino|pyrimidin-4-ylamino)benzamide (KMI compound):

SI

Wow

MN about M t

J

M M

N HM

Intermediate 17 described above (0.068 g, 0.246 mmol, 1 equiv), 4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.061 g, 0.296 mmol, 1.2 equiv), cesium carbonate (0.241 g, 0 .74 mmol, C eq.), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (0.029 g, 0.05 mmol, 0.eq.) and tris(dibenzylideneacetone)dipalladium (0.023 g, 0.025 mmol , 0.1 equiv.) were mixed in 15 ml

From a microwave oven. After that, the reagents were diluted with 7 ml of dioxane and heated with microwave radiation for 15 minutes at a temperature of 160 "C. After that, the reaction vessel was spun on a centrifuge, decanted and evaporated to dryness. After purification by HRI C-chromatography, the salt of trifluoroacetic acid indicated in the title was obtained of the KMI product (0.084 g, 76 96). M5 (EBI-4): 447.20 (MAN), retention time - 1.53 min. "H NMR (0M50O-dv): 6 1.87-1.91 ( t, 2H), 2.02-2.06 (t, 2H), 2.16 (5, ЗН), 2.79 (а, У-4.6 Hz, ЗН), 3.11-3.15 (t, 2H), 3.57-3.61 (t, 5H), 4.23 (Y, U-5.0 Hz, ЗН), 6.84 (a, 9-88 Hz, 2H), 7 .34 (a, 9-8.9 Hz, 2H), 7.47 (I, 9-7.9

Gu, 1), 7.68-7.70 (t, 2H), 7.93 (5, 1H), 8.00 (5, 1H), 8.46-8.47 (t, 1H), 9.80 (p5, 1 N), 9.93 (65, 1 N), 10.41 (65, 1 N).

Example 32. Trifluoroacetic acid salt of M'-(4-Chloro-3-methoxyphenyl-5-methyl-Me-4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound CHMII):

OH oh MN and vo,

J

M M

H - HM

Intermediate 7 described above (0.083 g, 0.293 mmol, 1 equiv), 4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.073 g, 0.352 mmol, 1.2 equiv), cesium carbonate (0.287 g, 0.879 mmol, C eq.), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (0.034 g, 0.059 mmol, 0, eq.) and tris(dibenzylideneacetone)dipalladium (0.027 g, 0.029 mmol, 0, eq. 1 equiv.) were mixed in a 15 ml microwave-safe dish. After that, the reagents were diluted with 7 ml of dioxane and heated with microwave radiation for 15 minutes at a temperature of 160 "C. Then the reaction vessel was spun in a centrifuge, decanted and evaporated to dryness. After purification by HRIS-chromatography, the salt of trifluoroacetic acid indicated in the title of the product CHMII was obtained (0.1 g, 75 95). M5 (EBI): 454.13 (M.N), retention time - 1.82 min. "H NMR (0M50- dv): 5 1.87-1.90 ( t, 2H), 2.02-2.05 (t, 2H), 2.15 (5, ЗН), 3.11-3.14(t, 2H), 3.58-3.61 (t, 5H), 3.70 (5,

ЗН), 4.26 (i, 9У-5.0 Hz, ЗН), 6.91 (а, 9-8.9 Hz, 2Н), 7.23 (t, 1Н), 7.34-7, 4 (t, AN), 7.93 (5, 1H), 9.63 (b5, 1H), 9.96 (p, 1H) 10.40 (p5, 1H).

Example 33. M-(2-Chloro-5-methylpyrimidin-4-yl)-M",M'-dimethylbenzene-1,3-diamine (intermediate product 18): that and "MH

SHI

J

M CI 18 2-Chloro-5-methylpyrimidin-4-ylamine (0.343 g, 2.38 mmol, 1 equiv.), (3-bromo-phenyl)dimethylamine (0.524 g, 2.62 mmol, 1.1 equiv. ), cesium carbonate (2.3 g, 7.15 mmol, 3 equiv.), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (0.276 G, 0.476 mmol, 0.2 equiv.) and Tris (dibenzylideneacetone)dipalladium (0.218 g, 0.238 mmol, 0.1 eq.) was mixed in a 30 mL microwavable vessel. After that, the reagents were diluted with 12 ml of dioxane and heated with microwave radiation for 25 minutes at a temperature of 160 "C. After that, the reaction vessel was spun in a centrifuge, decanted and evaporated to dryness. The solids formed as a result were diluted with OSM and adsorbed on silica gel. After chromatographic treatment (with a gradient from 0 95 methanol in OSM to 25 95 methanol in OSM) gave the title intermediate 18 as an orange solid (0.184 g, 29 95

From exit). M5 (EBIzh): 263.02 (MAN), retention time - 1.72 min.

Example 34. Trifluoroacetic acid salt of M'-(3-dimethylaminophenyl)-5-methyl-Me-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound HMIPI): in: g

She is MN

(c) ra

M M

N HM

Intermediate 18 described above (0.092 g, 0.35 mmol, 1 equiv), 4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.087 g, 0.42 mmol, 1.2 equiv), cesium carbonate ( 0.343 g, 1.05 mmol, C eq.), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (0.041 g, 0.0702 mmol, 0, eq.) and tris(dibenzylideneacetone)dipalladium ( 0.032 g, 0.035 mmol, 0.1 eq.) were mixed in a 15 mL microwavable dish. After that, the reagents were diluted with 7 ml of dioxane and heated with microwave radiation for 15 minutes at a temperature of 160 "C. Then the reaction vessel was spun in a centrifuge, decanted and evaporated to dryness. After NRI C-chromatographic purification, the trifluoroacetic acid salt of HMIII indicated in the title was obtained ( 0.035 g, 23 95). M5 (EBI): 433.21 (MAN), retention time - 1.52 min. "H NMR (0M50-av): 5 1.87- 1.90 (t, 2H), 2.03-2.06 (t, 2H), 2.15 (5, ЗН), 2.87 (5, 6H), 3.12-3.15 (t, 2H), 3.57-3, 60 (t, 4H), 3.70 (5, ZN), 4.25 (I, 9-5.0 Gu, ZN), 6.34 (ai, 9U-8.4 Hz, 9U-2.3 Hz, 1H), 6.82-6.90 (t, 4H), 7.20 (I, 9-8.0 Gu, 1H), 7.39 (a, 9-91 Hz, 2H), 7, 85 (5, 1H), 9.63 (65, 1H), 9.90 (65, 1H) 10.39 (65, 1H).

Example 35. (2-Chloro-5-methylpyrimidin-4-yl)(3,4-dichlorophenyl)amine (intermediate 19):

In

SI MN

What

J

M CI 19 2-Chloro-5-methylpyrimidin-4-ylamine (0.408 g, 2.83 mmol, 1 eq.), 4-bromo-1,2-dichlorobenzene (0.704 g, 3.12 mmol, 1.1 eq. .), cesium carbonate (2.8 g, 8.9 mmol, 3 equiv.), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (0.328 G, 0.57 mmol, 02 equiv.) and tris(dibenzylideneacetone)dipalladium (0.26 g, 0.283 mmol, 0.1 eq.) was mixed in a 30 mL microwavable vessel. After that, the reagents were diluted with 12 ml of dioxane and heated with microwave radiation for 25 minutes at a temperature of 160 "C. After that, the reaction vessel was spun in a centrifuge, decanted and evaporated to dryness. The solids formed as a result were diluted with OSM and adsorbed on silica gel. After chromatographic purification (with a gradient from 15 95 ethyl acetate and hexane to 80 95 ethyl acetate in hexane) gave the title intermediate 19 as a pale yellow powder (0.366 g, 45 95 yield). M5 (E5I4-):287.97 (MAN ), retention time - 3.12 min.

Example 36. M"-(3,4-Dichlorophenyl)-5-methyl-Me-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-

Zo diamine salt of trifluoroacetic acid (compound XIX):

SI and

SI MN

(c) and about a

M M

H -XIXX

Intermediate 19 described above (0.09 g, 0.313 mmol, 1 eq.), 4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.078 g, 0.376 mmol, 1.2 eq.), cesium carbonate (0.307 g , 0.941 mmol, C equiv), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (0.036 g, 0.063 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.029 g, 0, 0314 mmol, 0.1 equiv.) were mixed in a 15 mL microwaveable dish. After that, the reagents were diluted with 7 ml of dioxane and heated with microwave radiation for 15 minutes at a temperature of 160 "C. Then the reaction vessel was spun in a centrifuge, decanted and evaporated to dryness. After NRI C-chromatographic purification, the salt of trifluoroacetic acid XIX indicated in the title was obtained

(0.056 g, 39 95). M5 (E5I-): 458.1 (MN), retention time - 1.93 min. "H NMR (OM50O-a4bv): δ 1.87-1.91 (t, 2H), 2.03-2.06 (t, 2H), 2.14 (5, ЗН), 3.12-3 ... 1H), 7.40 (a, 9-9 Hz, 2H), 7.60 (5, 2H), 7.97 (a, 9U-15.35 Hz, 2H), 9.46 (p5, 1H) , 9.89 (p5, 1H) 10.17 (65, 1H).

Example 37. Tert-butyl ester of 4-13-(4-(4-chloro-3-methoxyphenylamino)-5-methylpyrimidin-2-ylamino|benzyl)piperazine-1-carboxylic acid (intermediate product 20): sie - ee ( o) MN (o) from Zh

And I am

M M

H.20 (4-Chloro-3-methoxyphenyl)(2-chloro-5-methylpyrimidin-4-yl)amine (0.092 g, 0.325 mmol, 1 equiv.), 4-(3-aminobenzyl)piperazine tert-butyl ester -1-carboxylic acid (0.114 g, 0.39 mmol, 1.2 equiv.), cesium carbonate (0.318 g, 0.975 mmol, 3 equiv.), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (0.038 g, 0.065 mmol, 0.2 equiv.) and tris(dibenzylideneacetone)dipalladium (0.03 g, 0.0325 mmol, 0.1 equiv.) were combined in a 15 mL microwavable vessel. After that, the reagents were diluted with 7 ml of dioxane and heated with microwave radiation for 15 minutes at a temperature of 160 "C. Then the reaction vessel was spun in a centrifuge, decanted and evaporated to dryness. After purification by NRI C-chromatography, the trifluoroacetic acid salt of the intermediate indicated in the title was obtained of product 20 (0.075 g, 43 Vol).

M5 (E5Izh): 539.32 (MN), retention time - 2.09 min.

Example 38. M'-(4-Chloro-3-methoxyphenyl|-5-methyl-Me-(3-piperazin-1-ylmethylphenyl)pyrimidin-2,A-diamino salt of trifluoroacetic acid (compound XX):

SI oh ee oh MN oh,

And I am

M M

N XX

TEA (2 mL) was added to a stirred solution of the above-described intermediate 20 (0.075 g, 0.14 mmol, 1 equiv.) in OCM (6 mL). After 2 hours, the solvents of the reaction mixture were evaporated, and the resulting residue was triturated with ether to obtain the title compound

XX, salt of trifluoroacetic acid, in the form of white hygroscopic solid particles (0.05 g, 82 95). M5 (EBIzh): 439.13 (MN), retention time - 1.67 min. "H NMR (0OM5O-dv): 6 2.17 (5, ЗН), 2.89 (65, 4Н), 3.2 (5, 4Н), 3.68 (5, ЗН), 3.82 ( B5, ZN), 7.16-7.20 (t, 2H), 7.28 (I, 9-7.7 Hz, 1H), 7.33 (a, 922.3 Hz, 1H), 7, 39 (5, 1H), 7.42 (a, 9-8.5 Gu, 1H), 7.49-7.51 (t, 1H), 7.98 (5, 1H), 8.87 (p5 , 1H), 9.79 (p, 1H) 10.57 (65, 1H).

Example 39. 2-(4-(2-(Pyrrolidin-1-yl/ethoxy)phenylamino)-4-aminopyrimidine-5-carbonitrile (intermediate 21): mno

Mo (in) no U ra

M M

N SHI

To a solution of 2,4-diaminopyrimidine-5-carbonitrile (135 mg, 1.00 mmol) in 1,4-dioxane (20 mL) was added 1-(2-(4-bromophenoxy)ethyl)pyrrolidine (270 mg, 1, 0 mmol), C520Oz (1.3 g, 4.0 mmol),

Rag(ava)z (92 mg, 0.1 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Rozv, 174 mg, 0.3 mmol). The mixture was refluxed for 4 hours in an argon atmosphere.

The solid phase was filtered and the filtrate was washed with saline solution (1x100 ml). The organic solution was separated and dried (Mag5O4). The solvent was removed to 5 mL and hexane (50 mL) was added.

The solid was collected by filtration. This crude product was purified by HRIS chromatography to give the title intermediate 21 (32 mg, 10 Vol).

Example 40. 4-(2,4-Dichloro-5-methoxyphenylamino)-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidine-5-carbonitrile (compound XXI):

She is MN

Maybe that

J

M M

N . XXI

To a solution of the above-described intermediate 21 (32 mg, 0.1 mmol) in 1,4-dioxane (10 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (28 mg, 0.11 mmol), С52С0Оз (97 mg, 0.Zmmol),

Rach(abra)z (7 mg, 0.0074 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Ppo5, 13 mg, 0.022 mmol). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered, and the filtrate was washed with saline (1x50 ml).

The organic solution was separated and dried (Mag504). The solvent was removed in vacuo. This crude product was purified by chromatography (5iO2/SNeSi», followed by CNOSiIg:MeOH:MnH2H2O-100:10:1) to give the title compound XXI (35 mg, 67 95). "H NMR (500 MHz, pM50-dv): 1.88-1.90 (t, 2H); 2.00-2.03 (t, 2H); 3.07-3.11 (t, 2H) ; 3.54-3.56 (t, 4H); 3.81 (5, ZN); 425 (ri, 2H); 6.68 (rg, 2H); 7.32 (ri, 2H); 7, 33 (5, 1H); 7.75 (5, 1H): 8.50 (5, 1H); 9.73 (rg, 1H); 9.94 (bg, 1H); 10.60 (bg, 1H ). M5 (EI): 499.0.

Example 41. 2-(3-(2-(Pyrrolidin-1-yl/ethoxy)phenylamino)-4-aminopyrimidine-5-carbonitrile (intermediate 22):

MH,

Mo and Fe Wu,

Zh. M

M M 077 zo H -22

1-(2-(3-bromophenoxy)ethyl)pyrrolidine (290 mg, 1, 07 mmol), С52СО3 (1.43 g, 4.4 mmol),

Rag(ava)z (92 mg, 0.1 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Rozv, 174 mg, 0.3 mmol). The mixture was refluxed for 4 hours in an argon atmosphere.

The solid phase was filtered and the filtrate was washed with saline solution (1x100 ml). The organic solution was separated and dried (Mag504). The solvent was removed to 5 mL and hexane (50 mL) was added.

The solid was collected by filtration. This crude product was purified by HRIS chromatography to give the title intermediate 22 (55 mg, 16 Ov).

Example 42. 4-(2,4-Dichloro-5-methoxyphenylamino)-2-(3-(2-(pyrrolidin-1-yl)phenylamino)pyrimidine-5-carbonitrile (compound XXII):

ve i MN

Mo no Phi U, ra t

M M 07

N . XXII

To a solution of the above-described intermediate 22 (50 mg, 0.15 mmol) in 1,4-dioxane (10 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (44 mg, 0.17 mmol), C520Oz (200 mg, 0.62 mmol), Raz(ava)z (14 mg, 0.015 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi

Ripo5, 27 mg, 0.05 mmol). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x50 ml). The organic solution was separated and dried (Mag50»4). The solvent was removed in vacuo. This crude product was purified by HRIS chromatography to give the title compound XXIII (6 mg, 8 Us). "H NMR (500 MHz, OM5O-av): 1.87-1.89 (t, 2H); 1.90-2.03 (t, 2H); 3.04-3.08 (t, 2H) ; 3.52-3.56 (t, 4H); 3.80 (5, ЗН); 4.23 (Bg, 2H); 6.62 (y, 9-64 Hz, 2H); 6.97 ( bg, 1H); 7.14 (bg, 2H); 7.34 (5, 1H); 7.74 (5, 1H); 8.54 (5, 1H); 9.70 (Bg, 1H); 9.95 (Bg, 1H); 10.83 (bBg, 1H).

M5 (YAY!): 499.0.

Example 43. 2-Chloro-M-(2,4-dichloro-5-methoxyphenyl)-5-methylpyrimidin-4-amine (intermediate product 23): y

MeOo MN

What

J

M SI, 23

1-Bromo-2,4-dichloro-5-methoxybenzene (96 mg, 0.37 mmol), С52СО3 (408 mg, 1.25 mmol),

Rag(ava)z (37 mg, 0.04 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Prppo5, 70 mg, 0.12 mmol). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x100 ml).

The organic solution was separated and dried (Mag504). The solvent was removed in vacuo. This crude product was used in the next step without purification.

Example 44. M2-(3-(2-(Pyrrolidin-1-yl)ethoxy)phenyl|-M-(2,4-dichloro-5-methoxyphenyl)-5-methylpyrimidine-2,4-diamine (compound XXI) :

MeOo MN no Fe I,

AJ M

M M 077

N . XXI

Zo

To a solution of intermediate 23 described above in 1,4-dioxane (10 mL) was added 3-(2-(pyrrolidin-1-yl)ethoxy)benzeneamine (77.3 mg, 0.38 mmol), C52CO3 (488 mg, 1.25 mmol), Raz(ava)z

(28 mg, 0.03 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Khapi Ppo5, 53 mg, 0.09 mmol). The mixture was refluxed for 4 hours in an argon atmosphere.

The solid phase was filtered and the filtrate was washed with saline solution (1x50 ml). The organic solution was separated and dried (Mag25O04). The solvent was removed in vacuo. This crude product was purified by NRI C-chromatography to afford the title compound

XXI (25 mg, 15 96). "H NMR (500 MHz, OM5O-av): 1.87-1.89 (t, 2H); 1.90-2.03 (t, 2H); 2.18 (5, ЗН); 3.04 -3.08 (t, 2H); 3.52-3.56 (gl, 4H); 3.80 (5, ЗН); 4.24 (I, 9-5.0 Hz, 2H); 6, 71 (a, 9-7.65 Hz, 1H); 6.91 (5, 1H); 6.96 (a, 9-8.5 Hz, 1H); 7.02 (Ii, 9-8.2 Hz, 1H); 7.37 (5, 1H); 7.83 (5, 1H); 8.02 (5, 1H); 10.09 (rt, 1H); 10.66 (g, 1H); 10.82 (rg, 1H). M5 (E)i): 488.2.

Example 45. 2-Chloro-M-(3-methoxyphenyl)-5-methylpyrimidin-4-amine (intermediate product 24): meo" and MH

What

AK

M SI 24

To a solution of 2-chloro-5-methylpyrimidin-4-amine (320 mg, 2.23 mmol) in 1,4-dioxane (40 mL) was added 1-bromo-33-methoxybenzene (458.5 mg, 2.45 mmol ), C52CO3 (2.9 g, 8.9 mmol), Raz(ava)z (201 mg, 0.22 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Khapi Ppo5, 382 mg, 0.66 mmol).

The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x100 ml). The organic solution was separated and dried (Ma»5O4). The solvent was removed to 5 mL and hexane (100 mL) was added. The solid was collected by filtration. This crude product, i.e. the title intermediate 24 (500 mg, 90 95), was used in the next reaction without further purification.

Example 46. Me-(4-(2-(Pyrrolidin-1-yl)phenyl)-My-(3-methoxyphenyl)-5-methylpyrimidine-2,A-diamine (compound XXIM): meo MH (c)

Even MO,

J

M M

N -XXM

To a solution of the above-described intermediate 24 (240 mg, 0.96 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yluethoxy)benzeneamine (200 mg, 0.96 mmol), C52bOz (1.3 mg, 4.0

Zo mmol), Raz(ara)z (82 mg, 0.09 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi

Rio5, 156 mg, 0.27 mmol). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x50 ml). The organic solution was separated and dried (Mag250»4). The solvent was removed in vacuo. This crude product was purified by HRIS chromatography to give the title compound XXIM (85 mg, 20 95). "H NMR (500 MHz, OM5O-adv): 1.89-1.91 (t, 2H); 1.98-2.05 (t, 2H); 2.16 (5, ЗН); 3.07 -3.12 (t, 2H); 3.52-3.56 (t, 4H); 3.73 (5, ЗН); 4.33 (Her, 9-45 Hz, 2H); 6.83- 6.85 (t, 1H); 6.91 (a, 9U-8.8 Hz, 2H); 7.17 (5, 1H); 7.34 (y, 9-88 Hz, 2H); 7, 41 (i, 9-7.7 Hz, 1H); 7.56 (a, 9U-7.7 Hz, 1H); 7.89 (5, 1H); 9.75 (5, 1H); 10, 51 (5, 1H); 10.96 (Bg, 1H). M5 (EI): 420.2.

Example 47. 3-(2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)phenol (compound XXM):

but MN (c)

what are we doing

J

M M

N XX

To a solution of the above-described compound XXIM (50 mg, 0.1 mmol) in anhydrous SNeSi" (10 ml) was added 1.0 M VVgz in SNeSi" (0.3 ml, 0.3 mmol). The resulting mixture was stirred for 3 hours at room temperature. After that, a saturated solution of Mansoz (20 ml) was added to the mixture, and the organic layer was separated. The aqueous phase was extracted in СНоСи» (3 x 10 ml). The combined organic solution was dried (Mag25O4). The resulting product was purified by HRIS chromatography to give the title compound XXM (17 mg, 35 95), which was a yellow solid. "H NMR (500 MHz, OM50O-av): 1.89 (bg, 2H); 2.00 (Bg, 2H); 2.14 (5, 3H); 3.09 (bg, 2H); 3, 42 (Bg, 4H); 4.33 (bg, 2H); 6.72 (a, 9-71 Hz, 1H); 6.91 (j, 9U-8.4 Hz, 2H); 6.96 ( a, 9U-7,6

Hz, 1H); 7.00 (5, 1H); 7.18 (i, 9U-8.0 Hz, 1); 7.38 (y, 9U-8.6 Hz, 2H); 7.88 (5.1 N); 9.70 (5.1 N); 9.74 (5.1 N); 10.55 (5.1 N); 11.09 (Bg, 1 H). M5 (E):406 2.

Example 48. 2-Chloro-5-methyl-M-(3-nitrophenyl)pyrimidin-4-amine (intermediate product 25):

OM and "MN

Me

What am I?

IB M SI 25

To a solution of 2-chloro-5-methylpyrimidin-4-amine (232 mg, 1.61 mmol) in 1,4-dioxane (40 mL) was added 1-bromo-3-nitrobenzene (359 mg, 1.78 mmol), C52CO3 (2.1 g, 6.4 mmol), Raz(ava)z (146 mg, 0.16 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Ppo5, 278 mg, 0.48 mmol).

The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x100 ml). The organic solution was separated and dried (Mag250O54). The solvent was removed to 5 mL and hexane (100 mL) was added to the mixture. The solid was collected by filtration. This crude product, which was the title intermediate 25, was used in the next reaction without further purification.

Example 49. Me-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl|-5-methyl-My-(3-nitrophenyl)pyrimidine-2,4-diamine (compound XXMI):

OM" | Mn (c) fi MO, a

M M

N . HUMI

Zo To a solution of the intermediate product 25 described above in 1,4-dioxane (40 ml) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzeneamine (367 mg, 1.78 mmol), С52СО3 (2.1 g , 6.4 mmol), Raz(ava)z (146 mg, 0.16 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Ppo5, 218 mg, 0.48 mmol) .

The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x50 ml). The organic solution was separated and dried (Mag504). The solvent was removed in vacuo. This crude product was purified by NRI C-chromatography to give the title compound XXMI (51 mg, 7 Uv). "H NMR (500 MHz, ОМ5О-ав6): 1.89-1.92 (t, 2Н); 1.98-2.05 (t, 2Н); 2.21 (5, ЗН); 3.10 -3.12 (t, 2H); 3.52-3.57 (t, 4H); 4.33 (Her, 9-48 Hz, 2H); 6.90 (y, 9-8.9 Hz, 2H); 7.32 (a, U-8.9 Hz, 2H); 7.67 (and 9U-8.2 Hu, 1H); 7.99 (5, 1H); 7.56 (aa, 9U -8.4 Hz, 9U-1.8 Hz, 1H); 8.09 (a, 9U-7.4 Hz, 1H); 8.45(5, 1H); 10.14 (5, 1H); 10.60 (5, 1H); 11.17 (Bg, 1H). M5 (EI): 435.2.

Example 50. 4-(2-Chloro-5-methylpyrimidin-4-ylamino)-2-chlorobenzonitrile (intermediate 26):

In

SI MN

Me

Shit

J and SI 26

To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-2-chlorobenzonitrile (217 mg, 1.0 mmol), C52CO3 (1.3 g, 4.0 mmol), Raz(ava)z (91 mg, 0.1 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Ppo5, 173 mg, 0.3 mmol).

The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x100 ml). The organic solution was separated and dried (Ma»5O4). The solvent was removed to 5 mL and hexane (100 mL) was added. The solid was collected by filtration. This crude product, ie the title intermediate 26, was used in the next reaction without further purification.

Example 51. 4-(2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)-2-chlorobenzonitrile (compound XXMII): ve

SI MN

(c) but MO,

Residential complex

M M

N HM

To a solution of the above described intermediate 26 (140 mg, 0.5 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)benzoylamine (113 mg, 0.55 mmol) ), C520Oz (660 mg, 2.0

Zo mmol), Raz(ara)z (46 mg, 0.05 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi

Ripo5, 87 mg, 0.15 mmol). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x50 ml). The organic solution was separated and dried (Mag50»4). The solvent was removed in vacuo. This crude product was purified by HRIS chromatography to give the title compound XXMII (11.5 mg, 5 95) as a yellow solid. "N

NMR (500 MHz, YOM50O-yv): 1.89-1.92 (t, 2H); 1.98-2.05 (t, 2H); 2.20 (5, ZN); 3.08-3.13 (t, 2H); 3.56-3.59 (t, 4H); 4.36 (I, U-4.9 Hz, 2H); 7.03 (a, 9U-9.0 Hz, 2H); 7.40 (a, 9U-9.0 Hz, 2H); 7.87 (Bg, 1H); 7.92 (a, 9U-8.6 Hz, 1H); 8.03 (5.1H); 8.16 (5.1H); 9.82 (Bg, 1H); 10.37 (Bg, 1H); 10.90 (Bg, 1H). M5 (EI)): 4491.

Example 52. M2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-M"-p-tolylpyrimidine-2,4-diamine (compound XXMII):

MN

Something else

J

M M

N "XX

To a solution of the above-described intermediate 11 (50 mg, 0.16 mmol) in 1,4-dioxane (20 mL) was added 1-bromo-4-methylbenzene (28 mg, 0.16 mmol), C52CO3 (210 mg, 0 .64 mmol), Razhava)z (10 mg, 0.01 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Khapi Ppo5, 18 mg, 0.03 mmol). The mixture was refluxed for 4 hours in an argon atmosphere.

The solid phase was filtered, the solvent was removed under vacuum. This crude product was purified by NRI C-chromatography to give the title compound XXMIII (15.7 mg, 6 95) as a yellow solid. "H NMR (500 MHz, OM5O-av): 1.85-1.89 (t, 2H); 1.96-2.01 (t, 2H); 2.12 (5, ЗН); 2.31 (5, ZN); 3.04-3.08 (t, 2H); 3.51-3.55 (t, 4H); 4.32 (Bg, 2H); 6.89 (bg, 2H); 7.18 (Lg, 2H); 7.31 (Bg, 2H); 7.41 (Bg, 2H); 7.84 (5, 1H); 9.71 (5, 1H); 10.46 (5, 1 NU; 11.13 (Bg, 1 H). M5 (EI): 404.2.

Example 53. M2-(4-(2-Pyrrolidin-1-yl)ethoxy)phenyl)-My-(4-chloro-3-methylphenyl)-5-methylpyrimidine-2,4-diamine (compound XXIX): and and

MN

(c) but MO,

J

M M

N XXIX

4-bromo-1-chloro-2-methylbenzene (63 mg, 0.30 mmol), C52bOz ( 326 mg, 1.0 mmol),

Rag(ava)z (18 mg, 0.02 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Roz, 36 mg, 0.06 mmol). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered. The solvent was removed in vacuo. This crude product was purified by NRI C-chromatography to afford the title compound

XXIX (17.5 mg, 15 95), which was a yellow solid. "H NMR (500 MHz,

PM50-dv):1.85-1.89 (t, 2H); 1.96-2.01 (t, 2H); 2.12 (5, ZN); 2.25 (5, ZN); 3.04-3.08 (t, 2H); 3.51-3.55 (t, 4H); 4.32 (ri, 2H); 6.91 (ri, 2H); 7.04 (ri, 1H); 7.91 (BI, 1H); 7.41 (rt, 2H); 7.58 (5, 1H); 7.89 (Bg, 1); 9.75 (in, 1H); 10.54 (in, 1H); 11.13 (bg, 1H). M5 (EI): 438.1.

Example 54. M-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-4-benzyl-5-methylpyrimidin-2-amine

Zo (compound XXX): (c) d MO, ra

M M

N XXX

To a solution of 4-benzyl-2-chloropyrimidine (286 mg, 1.4 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzeneamine (288 mg, 1, 4 mmol), C52CO3 (1.82 g, 5.6 mmol), Raz(aba)z (92 mg, 0.1 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Ppo5 , 173 mg, 0.3 mmol).

The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered. The solvent was removed in vacuo. This crude product was purified by

NRI C-chromatography and as a result obtained the title compound XXX (42 mg, 10 95), which was a yellow solid. "H NMR (500 MHz, OM5O-ie) 1.89 (Brg, 2H); 2.00 (p, 2H); 3.09 (g, 2H); 3.54 (rg, 4H); 4.31 (Bbg, 2H); 6.71 (a, 9-5.0 Hz, 1Hn); 6.93 (a, 9-88 Hz, 2H); 7.24 (t, 1H); 7.32 (t , 4H); 7.62 (y, 9-8.8 Hz, 2H); 8.32 (a, 9U-5.0 Hz, 1H); 9.66 (5, 1H); 10.92 (Bg , 1H).

M5 (YAY!): 375.2.

Example 55. 4-(1H-indol-4-ylylmethyl)-M-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methylpyrimidin-2-amine (compound XXXI): c

MN

(c) but M,

J

M M

N . XXXI

To a solution of the above-described intermediate 11 (460 mg, 1.46 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-1H-indole (288 mg, 1.46 mmol), C5zCO3 (1.95 g , 6.0 mmol), Rag(ava)z (128 mg, 0.14 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Ppo5, 243 mg, 0.42 mmol).

The mixture was refluxed overnight in an argon atmosphere. The solid phase was filtered. The solvent was removed in vacuo. This crude product was purified by HRIS chromatography to afford the title compound XXXI (66 mg, 10 95 ) as a yellow solid. "H NMR (500 MHz, OM5O-4av): 1.87 (Bg, 2H); 1.98-2.05 (t, 2H); 2.21 (5, ЗН); 3.15 (bg, 2H ); 3.52 (bg, 2H); 3.69 (Bg, 2H); 4.24 (Bg, 2H); 6.33 (5, 1H); 6.60 (g, 2H); 6.82 (Bg, 1H); 6.92 (Bg, 1H); 7.02 (Bg, 2H); 7.16 (Bg, 1H); 7.26 (bg, 1H); 7.43 (t, 1H) ;7 88(t, 1H); 10.11 (5, 1H); 11.40 (5, 1H). M5 (EI): 4291.

Example 56. 2-Chloro-5-methyl-N-(naphthalen-1-yl)/pyrimidin-4-amine (intermediate product 27):

MN

What

ZhK and SI 27

Zo To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 ml) was added 1-bromonaphthalene (227 mg, 1.1 mmol), C520Oz (1 .3 g, 4.0 mmol), Raz(ava)z (91 mg, 0.1 mmol) and 4,5-bis-diphenylphosphino)-9,9-dimethylxanthene (Hapi Rio5, 183 mg, 0.3 mmol ). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x100 ml). The organic solution was separated and dried (Mag2504). The solvent was removed to 5 mL and hexane (100 mL) was added. The solid was collected by filtration. This crude product, ie the title intermediate 27, was used in the next reaction without further purification.

Example 57. M-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-4-(naphthalen-1-yl)/pyrimidin-2-amine (compound XXXI):

МН что ра и . 20th century

To a solution of the above-described intermediate 27 (235 mg, 0.87 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzeneamine (183 mg, 0.87 mmol) ), C520Oz (1.3 g, 4.0 mmol), Raz(ara)z (46 mg, 0.05 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi

Ripo5, 87 mg, 0.15 mmol). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x50 ml). The organic solution was separated and dried (Mag50»4). The solvent was removed in vacuo. This crude product was purified by HRIS chromatography to yield the title compound XXXI! (89 mg, 21 95), which was a yellow solid. "N

NMR (500 MHz, ЮОМ50-ав6): 1.88-1.90 (t, 2Н); 1.97-2.03 (t, 2H); 2.30 (5, ZN); 3.03-3.08 (t, 2H); 15. 3.50-3.53 (t, 4H); 4.21 (1.9-4.9 Hz, 2H); 6.50 (a, 9-7.2 Hz, 2H); 6.82 (a, 9-8.6 Hz, 2H); 7.54 (a, 9-78

Hz, 2H); 7.57-7.61 (t, 1H); 7.63 (Her, 9-74 Hz, 1H); 7.89 (y, 9-8.3 Hz, 2H); 7.95 (5, 1H); 8.02 (a, 9-83

Hz, 1H); 8.08 (a, 9-7.7 Hu, 1H); 10.37 (5, 1H); 10.43 (5, 1H); 10.93 (Bg, 1H). M5 (EI): 4401.

Example 58.1-(2-Chloro-5-methylpyrimidin-4-yl)isoquinoline (intermediate product 28): / ВХ pt,

M MN

SHI

Zh and SI, 28

1-chloroisoquinoline (164 mg, 1.0 mmol), C52CO3 (1, 3 g, 4.0 mmol), Raz(ava)z (91 mg, 0.1 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi Ppo5, 183 mg, 0.3 mmol ). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x100 ml). The organic solution was separated and dried (Ma»5O4). The solvent was removed to 5 mL and hexane (100 mL) was added. The solid was collected by filtration. This crude product, ie the title intermediate 28, was used in the next reaction without further purification.

From Example 59. M-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-4-(isoquinolin-1-yl)-5-methylpyrimidin-2-amine (compound XXXI): .

M and to

R, and XXXI

To a solution of the above-described intermediate 28 (90 mg, 0.33 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yluethoxy)benzeneamine (76 mg, 0.37 mmol), C52bOz (391 mg, 1.2 mmol), Raz(ara)z (28 mg, 0.03 mmol) and 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Hapi

Ripo5, 52 mg, 0.09 mmol). The mixture was refluxed for 4 hours in an argon atmosphere. The solid phase was filtered and the filtrate was washed with saline solution (1x50 ml). The organic solution was separated and dried (Mag50»4). The solvent was removed in vacuo. This crude product was purified by HRIS chromatography to yield the title compound XXXI! (21 mg, 15 95), which was a yellow solid. "N

NMR (500 MHz, OM50O-av): 1.64-1.70 (t, 6H); 2.23 (5, ZN); 2.78 (I, 9-5.9 Hz, 2H); 4.04 (her, 9U-5.9 Hz, 2H); 6.38 (a, 9U-7.2 Hz, 1); 6.93 (y, 9U-9.0 Hz, 2); 6.97 (a, 9U-7.2 Hz, 1H); 7.45 (Bbg, 1H); 7.57 (a, 3-8.8 Hz, 1H); 7.58-7.62 (t, 1H); 7.70-7.78 (t, 2H); 8.04 (5.1H); 8.75 (y, 9-81 Hz, 1H); 9.06 (5.1H); 9.19 (5.1H). M5 (EI): 441.2.

Example 60. M2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-My-(3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine (compound XXIII):

AH

(in)

I o x I

M M

N. XXIII

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (143 mg, 1.0 mmol), 1-bromo-3-(trifluoromethyl)benzene (225 mg, 1.0 mmol), Rag(dba)z (9, 0 mg, 0.01 mmol), xanthophos (12 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) were suspended in dioxane (15 mL) and refluxed under argon for 15 hours After that, the reaction mixture was cooled to room temperature and diluted with OSM (30 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. After purification of the residue using NRI C-chromatography, M'-(3-"-trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine was obtained as a not quite white solid (192 mg, 6795). M5 (E5I -)M t/2 288 (MH). A mixture of Me-(3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine (28.7 mg, 0.1 mmol) and 4-(2-( Pyrrolidin-1-yl)ethoxy)benzeneamine (22 mg, 0.12 mmol) was dissolved in acetic acid (5 ml) and heated under microwave irradiation at a temperature of 150 "C for 10 minutes.

After that, the mixture was cooled to room temperature, and acetic acid was removed from it under reduced pressure. The residue was purified by NRI C-chromatography to give the title compound XXXIM as a brown solid (16 mg, 35 95). "H NMR (500 MHz, OM5O-adv): 1.65-1.71 (t, 4H), 2.11 (5, ZN), 2.45-2.55 (t, AN), 2.74 (i, 9U-6.0 Gu, 2H), 3.98 (I, 9U-6.0 Hz, 2H), 6.76 (a, 9U-9.0 Hz, 2H), 7.35 (a , 9-51 Hz, 1H), 7.45-7.57 (t,

ЗН), 7.9-7.97 (t, 2Н), 8.20 (а, 9-7.6 Hz, 1Н), 8.41 (5, 1Н), 8.85 (5, 1Н), t/2 458 (MAN).

Example 61. 2-Chloro-M-(4-"-trifluoromethyl)phenyl)-5-methylpyrimidin-4-amine (intermediate product 29):

ES m and

MN

SHI

AND

M SI 29

A suspension of /2-chloro-5-methylpyrimidin-4-amine (159 μl, 1.2 mmol), 1-bromo-4-(trifluoromethyl)benzene (150 mg, 1.0 mmol), potassium tert-butoxide (224 mg , 2.0 mmol), xanthophos (120 mg, 0.2 mmol) and palladium acetate (26 mg, 0.1 mmol) were sealed in a microwave reaction tube and irradiated at a temperature of 160 "C for 15 min.

After that, the mixture was allowed to cool to room temperature, the solid was filtered off, washed with OSM, and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: hexane to EtOAc) to give the title intermediate 29 (128.7 mg, 43 95) as a white solid. M5 (EBIya): t/2 288 (MAN)".

Example 62. M2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-My-(4-trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine (compound XXXM):

MN

(c) fi MO,

J

M M

N -XXXM

A mixture of the above-described intermediates 29 (128 mg, 0.5 mmol) and 6 (212 mg, 1.0 mmol) was suspended in acetic acid (5 mL) and heated at 75 °C for 18 hours. After that, the mixture was allowed to cool to room temperature, and the acetic acid was removed under reduced pressure. The residue was basified with sat. with the reversed phase on a C18 column (eluent: from water to CHSSM, 0.1 95 TEA). The aqueous fractions were neutralized with a saturated aqueous solution of MansSoc and extracted with EtOAc ethyl acetate. The organic phases were concentrated in vacuo, and the residue was taken up in 10SSM. NCI in dioxane was added together with ether and the resulting solid was filtered to give the hydrochloride of the title compound XXXM (166 mg, 70 95), which was a gray solid. "H NMR (500 MHz, OM5O-dv): 1.80-1 .95 (t, 2H), 1.95-2, 10 (t, 2H), 2.19 (5, ЗН), 3.05-3.20 (t, 2H), 3.55-3.65 (t, 6H), 4.33 (i, y- 4.7 Hz, 2H), 6.97 (a, U-8.7 Hz, 2H), 7.34 (a, 9-8.8 Hz, 2H), 7.73 (a, L - 8, 5Hz, 2H), 7.683(a, U-8.0Hz, 2H), 7.94(5, 1H), 9.92 (riv, 1H), 10.44(rgv, 1H), 10.85 (horn 5, 1H); M5 (EI): t/2 458.5 (MAN).

Example 63. Benzo|1,3|dioxol-4-yl-(2-chloro-5-methylpyrimidin-4-yl amine) (intermediate product 30):

R sg

MN

What the hell

SI zo

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (1.4 g, 9.7 mmol), 4-bromobenzo|1,3|dioxole (2.0 g, 10 mmol), Raz(ava)z (0 .80 g, 0.87 mmol), xanthophos (1.0 g, 1.7 mmol) and cesium carbonate (6.3 g, 19 mmol) were suspended in dioxane (40 mL) and refluxed in an atmosphere argon for 5 hours. After that, the reaction mixture was cooled to room temperature and diluted with SOCM (30 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified using flash chromatography on silica gel (eluent: from hexane to

50 956 EOAc/hexane) to give the title compound (1.0 g, 39 95) as a white solid. "H NMR (500 MHz, OM5O-av): 5 2.13 (5, ЗН), 5.99 (5, 2Н), 6.80- 6.90 (t, ЗН), 8.01 (5, 1H), 8.92 (5, 1H). M5 (Ebzh): t/2 264 (M.N).

Example 64. M"-Benzo|1,3|dioxol-4-yl-5-methyl-M2-I4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound XXXMI):

R su

MN

(c) but o

J

M M

N. Khkhumi

A mixture of intermediate 30 (0.25 g, 0.95 mmol) and 4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.40 g, 1.9 mmol) in acetic acid (15 mL) was heated at a temperature of 100 "C for 20 h. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH-7 with 10 95 solution

MaonN. The resulting solution was extracted with EMUAs (2x30 ml) and the organic layer was separated. Next, the organic layer was washed with saline solution, dried over anhydrous

Ma?5O" and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (eluent: 100 ppm to 2055 Meon/rpm) to give the title compound (0.14 g, 34 95) as a white solid.

NMR NMR (500 MHz, OM5O-av): 6 1.65-1.75 (t, 4H), 2.06 (5, ЗН), 2.55-2.65 (t, 4H), 2 ,78-2.88 (t, 2H), 3.98 (Her, 9U-5.8 Hz, 2H), 5.89 (5, 2H), 6.65 (a, U-9.0 Gu, 2H), 6.79-6.84 (t, 2H), 6.89 (ai, 9U-7.7, 1.7 Hz, 1H), 7.45 (a, 20-91 Hz, 2H), 7.81 (5, 1H), 8.23 (5, 1H), 8.73 (5, 1H). M5 (Eb-k):t/2434 (MAN).

Example 65. M-Benzo|1,3|dioxol-4-yl-5-methyl-M2-I(4-methylpiperazin-1-yl)phenyl|Ipyrimidin-2,A4-diamine (compound XXXMII): shk c

MN Yak

But

J

M M

N . XXXMI

A mixture of intermediate 30 (0.10 g, 0.38 mmol) and 4-(4-methylpiperazin-1-yl)phenylamine (0.12 g, 0.51 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 150 C for 15 min. After

After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was taken up in water (20 mL), and the mixture was neutralized with 10 95 Mahon's solution until a solid precipitate formed. This solid was filtered and then purified by flash chromatography on silica gel (eluent: OSM to 15 95 Meon/oCsM) to afford the title compound (22 mg, 14 95) as a pale red solid .

IN NMR (500 MHz, OM5o-av): 6 2.06 (5, ЗН), 2.21 (5; ЗН), 2.44 (Й, 9-4.8 Hz, 4Н), 2.97 ( i, 9-49

Hu, 4H), 5.89 (5, 2H), 6.67 (a, 9-91 Hu, 2H), 6.80-6.86 (t, 2H), 6.91 (aa, 9-76 , 1.7 Gu, 1H), 7.41 (a, 3-9.0 Hz, 2H), 7.79 (5, 1H), 8.17 (5, 1H), 8.63 (5, 1H) . M5 (Eb, w): t/2 419 (MAN).

Example 66. (4-Chloro-3-methoxyphenyl)(2-chloro-5-methylpyrimidin-4-yl)amine (intermediate product in 7o MH

SHI

Zh and SI, 81

A mixture of /2-chloro-5-methylpyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-bromo-1-chloro-2-methoxybenzene (0.65 ml, 4.8 mmol), Raz( aba)z (0.17 g, 0.19 mmol), xanthophos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) were suspended in dioxane (20 ml) and boiled refluxed in an argon atmosphere for 5 h. After that, the reaction mixture was cooled to room temperature and diluted with OSM (30 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: hexane to 4095 EOAc/hexane) to give the title compound (0.55 g, 55 95) as a yellow solid.

IN NMR (500 MHz, OM5O-av): 6 2.18 (5, ZN), 3.85 (5, ZN), 7.35 (yes, 9U-8.6,2.3 Hz, 1H), 7.39 (a, 9U-8.7 Hz, 1H), 7.56 (a, 9-2.3 Hz, 1H), 8.09 (a, 9-0.9 Gu, 1H), 8, 91 (5, 1H). M5 (Ebu): t/2 284 (MAN).

Example 67. M'-(4-Chloro-33-methoxyphenyl)-5-methyl-M2-(4-pyrazol-1-ylmethylphenyl)pyrimidin-2,A-diamine (compound XXXMII):

In and

Meo MN

M Mt h

Same thing

M M

N XXX

A suspension of intermediate 31 (0.20 g, 0.70 mmol), 4-pyrazol-1-ylmethylphenylamine (0.14 g, 0.81 mmol), Rag(abba)z (40 mg, 0.044 mmol), xanthophos ( 50 mg, 0.086 mmol) and cesium carbonate (0.50 g, 1.5 mmol) in a mixture of dioxane/UME (3/1.4 ml) were hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 min After cooling to room temperature, the tube was capped, and the resulting mixture was filtered, and the filtered solid was washed with OSM. The filtrate was concentrated, and the residue was purified by HPLC. The fractions were combined and poured into a saturated solution of MansCO3 (40 mL) The combined aqueous layers were extracted with EtOAc (2 x 30 ml), and the combined organic layers were washed with brine, dried over anhydrous Ma»b5O4 (and

It was filtered. The filtrate was concentrated, and the resulting solid was dissolved in minimal amounts of EtOH and hexane added until a solid precipitate formed. After filtration, the title compound was obtained as an off-white solid (0.13 g, 44 g).

NMR NMR (500 MHz, OM5O-av): 6 2.11 (5, ЗН), 3.74 (5, ЗН), 5.22 (5, 2Н), 6.25 (1, 9-21 Hz, 1H), 7.08 (a, 9-8.6 Hz, 2H), 7.27 (a, 9-9.3 Gu, 1H), 7.40-7.45 (t, ЗН), 7.60 (a, U-8.6 Hz, 2H), 7.75 (a, 9U-1.68 Hz, 1 H), 7.91 (5, 1 H), 8.36 (5, 1 H), 9.04 (5.1 H) M5 (Eb.yu): t/2 421 (MAN).

Example 68. 5-Methyl-M2-I4-(4-methylpiperazine-1-iluphenyl-1-pyrimidine-2,4-diamine (intermediate product 32):

Mn, pe et schu

J

M M and "32

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (1.0 g, 6.9 mmol) and 4-(4-methylpiperazin-1-yl)uphenylamine (1.5 mL, 7.8 mmol) in acetic acid (15 ml) was heated at a temperature of 1007 for 2.5 hours. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 mL) and the mixture was neutralized with 95 Mahon solution until a solid precipitate formed. After filtration and washing with water, the title compound was obtained as a gray solid (1.3 g, 63 Vol). 10 IN NMR (500 MHz, OM5o-av): 6 1.88 (5, ZN), 2.21 (5, ZN), 2.21 (5, ZN), 2.44 (i, 9-48 Hz , 4H), 3.00 (I, 9-48 Gu, 4H), 6.27 (5, 2H), 6.79 (a, 9-9.0 Hz, 2H), 7.57 (a, 7 -9.0 Hu, 2H), 7.63 (5, 1H), 8.42 (5, 1H). M5 (Ebhzh): t/2 299 (MAN).

Example 69. My-(4-Chloro-3-methoxyphenyl)-5-methyl-Me-(4-(4-methylpiperazin-1-yl)uphenyl|pyrimidin-2,4-diamine (compound XXXIX): si

Sh. "MN pt tem that

J

M M

H - XXXIX

A suspension of intermediate 32 (0.30 g, 1.0 mmol), 4-bromo-1-chloro-2-methoxybenzene (0.20 mL, 1.5 mmol), Raz(abva)z (50 mg, 0.055 mmol ), xanthphos (65 mg, 0.11 mmol) and cesium carbonate (0.70 g, 2.1 mmol) in a mixture of dioxane/oME (3/1.8 ml) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature 160 "C for 20 min. After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered, and the filtered solid was washed with OSM. The filtrate was concentrated, and the residue was purified using NRI C-chromatography. The fractions were combined and poured into saturated NaCl solution (40 mL). The combined aqueous layers were extracted with EAs (2 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous MaCl 5 O 4 , and filtered. The filtrate was concentrated, and the residue was triturated in a mixture of E( oAc/hexane (1/5, 30 mL).After filtration, the title compound was obtained as a solid with white ilcom (0.20 g, 46 95).

Koo) IN NMR (500 MHz, OM5O-av): 6 2.09 (5, ZN), 2.21 (5, ZN), 2.45 (I, 92-4.9 Hz, 4H), 3, 02 (th, 9-49

Hz, 4H), 3.73 (5, ZN), 6.79 (a, 9-91 Hz, 2H), 7.27 (a, U-8.6 Gu, 1H), 7.42-7, 47 (t, ZN), 7,49 (j, 9-23

Hz, 1 N), 7.86 (5, 1 N), 8.28 (5, 1 N), 8.72 (5, 1 N). M5 (Eb-k): t/2 439 (MAN).

Example 70. M'-(4-Chloro-33-methoxyphenyl)-5-methyl-M2-(4-morpholin-4-ylphenyl)pyrimidine-2,4-diamine (compound XI):

SI

Sh. "I'm sorry

SHI

Phi t

M M

N - Kh

A mixture of intermediate 31 (0.10 g, 0.35 mmol) and 4-morpholin-4-yl-phenylamine (80 mg, 0.45 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 min. After cooling to room temperature, the cap of the test tube was removed and the mixture was concentrated. The residue was taken up in water (20 mL), and the mixture was neutralized with 10 95 Mahon solution until a solid precipitate formed. This solid was filtered, and then purified by silica gel flash chromatography (eluent: OSM to 10,956 Meon/OSM) to give the title compound (55 mg, 37 9o) as a light brown solid.

IN NMR (500 MHz, OM5O-av): 6 2.10 (5, ZN), 3.00 (i, 9-48 Hz, 4H), 3.71-3.76 (t, 7H), 6, 80 (a, 9-9.0 Hz, 2H), 7.28 (a, 9-8.6 Hz, 1H), 7.45 (aa, 9-8.7, 2.2 Hz, 1H), 7.47-7.50 (t, ZN), 7.87 (5, 1H), 8.29 (5, 1H), 8.75 (5, 1H). M5 (Eb-yu): t/2 426 (MAN).

Example 71. M'-(4-Chloro-3-methoxyphenyl)-5-methyl-M2-(4-pyrazol-1-yl-phenyl)pyrimidin-2,4-diamine (compound XII): 7ro meo MH What;

M.M

Me too

M M

H

A mixture of intermediate 31 (90 mg, 0.32 mmol) and 4-pyrazol-1-ylphenylamine (70 mg, 0.44 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 20 min. After cooling to room temperature, the tube was capped and the mixture was concentrated. The residue was taken up in water (20 mL) and the mixture was neutralized with 10 956 Mahon solution until a solid precipitate formed. This solid was filtered off and then purified by HRIS - chromatography.

The neutralized fractions were combined and concentrated to give the title compound (40 mg TEA salt, 24 95) as a white solid.

I"N NMR (500 MHz, OM5O-av): 6 2.17 (5, ZN), 3.75 (5, ZN), 6.54 (I, 9U-1.9 Hz, 1H), 7, 30 (a, L - 6b, bHz, 1), 7.39 (a, 9-21 Hz, 1 N), 7.40 (a, 2-8.6 Gu, 1), 7.59 (a, 9-8.9 Hz, 2H), 7.71 (a, U-8.9 Hz, 2H), 7.73 (a, 9-1.6 Gu, 1 H), 7.93 (5, 1 H), 8.41 (a, 9U-2.5 Hu, 1 H), 9.41 (5, 1 H), 10.05 (5, 1H). M5 (Eb-yu): t/2 407 (MAN):.

From Example 72. M'-(4-Chloro-3-methoxyphenyl)-5-methyl-M2-(4-piperidin-1-ylphenyl)pyrimidine-2,4-diamine (XII): 7ro

MmeO MN p

M "

J

M M

N XII

A mixture of intermediate 31 (0.11 g, 0.39 mmol) and 4-piperidin-1-ylphenylamine (90 mg, 0.51 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwaves at 160 "C for 20 min. After cooling to room temperature, the tube was capped and the mixture was concentrated. The residue was taken up in water (20 mL) and the mixture was neutralized with 10 95 Mahon's solution until a solid precipitate formed. This solid was filtered and then purified by flash chromatography on silica gel (eluent: hexane to 7095 EtOAc/hexane) to give the title compound (10 mg, 6 95) as a light brown solid.

NMR NMR (500 MHz, OM5O-av): 5 1.48-1.53 (t, 2H), 1.59-1.65 (t, 4H), 2.09 (5, ЗН), 3 ,00 (th, 9-54

Hu, 4H), 3.73 (5, ZN), 6.78 (a, 9-9.0 Hz, 2H), 7.27 (a, U-8.7 Hu, 1H), 7.40- 7.47 (t, ZN), 7.50 (a, 9-22

Hu, 1 N), 7.86 (5, 1 N), 8.28 (5, 1 N), 8.71 (5, 1 N). M5 (Ebzh): t/2 424 (MAN).

Example 73. M'-(4-Chloro-3-methoxyphenyl)-5-methyl-M2-I4-(4-methylpiperazin-1-ylmethyl)phenyl1-pyrimidin-2,4-diamine (XE):

Meo MN obligatory

A. sh

M M in:

H

A suspension of intermediate 31 (50 mg, 0.18 mmol), 4-(4-methylpiperazin-1-ylmethyl)phenylamine (50 mg, 0.24 mmol), Raz(ava)z (10 mg, 0.011 mmol), xanthophos (13 mg, 0.022 mmol) and cesium carbonate (0.12 g, 0.37 mmol) in a mixture of dioxane/JuOiME (3/1, 4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM.

The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: OM to 10 96 MEOH/OM) to afford the title compound (35 mg, 44 905) as an off-white solid.

IN NMR (500 MHz, OM50O-av): 5 2.11 (5, ЗН), 2.15 (5, ЗН), 2.20-2.45 (t, 8Н), 3.35 (5, 2Н ), 3.75 (5, ZN), 7.07 (a, 9U-8.5 Hz, 2H), 7.28 (a, 9U-8.5 Gu, 1H), 7.44 (da, O -8.7, 2.3 Hz, 1H), 7.47 (a, 9-2.3 Gu, 1H), 7.57 (a, 9-8.5 Hz, 2H), 7.91 (5 , 1H), 8.36 (5, 1H), 8.98 (5, 1H). M5 (Ebzh): t/2 453 (M.N).

Example 74. M'-(4-Chloro-3-methoxyphenyl)-5-methyl-Me-(4-piperazin-1-yl-phenyl)pyrimidin-2,4-diamine (compound XH IM):

SI

Sh. "MH Hon

MU M schu

Residential complex

M M

N HOM

A mixture of intermediate 31 (0.20 g, 0.70 mmol) and 4-(4-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 0.79 mmol) in acetic acid (4 mL )

Zo was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 150 C for 15 min. After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was purified by NRI C-chromatography, and the purified fractions were combined and poured into a saturated solution of MansSoOz solution (40 ml). The combined aqueous layers were extracted with EtOAc (2x30 mL), and the combined organic layers were washed with brine, dried over anhydrous NaCl and filtered. The filtrate was concentrated, a minimal amount of EOAcC was dissolved in the formed solid, and hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as an off-white solid (0.10 g, 33 g). "H NMR (500 MHz, OM5o-av): 6 2.10 (5, ЗН), 3.16 (5, 8Н), 3.73 (5, ЗН), 6.83 (a, U-9, 0 Hz, 2H), 7.29 (0.9-8.8 Hu, 1H), 7.44 (aa, O-8.7, 2.1 Hz, 1H), 7.49-7.52 ( t, ZN), 7.88 (5, 1H), 8.32 (5, 1H), 8.81 (5, IN) M5 (Eb-): t/2 425 (M.H)".

Example 75. M-Tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylamino|1-benzenesulfonamide (compound CHM): (c)

Fe and

Kr Her MN d c) hmm schu

J

M. M. and KHIM

A suspension of intermediate 32 (0.30 g, 1.0 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (0.35 g, 1.2 mmol), Raz(ava)z (60 mg, 0.066 mmol ), xanthophos (70 mg, 0.12 mmol) and cesium carbonate (0.70 g, 2.1 mmol) in a mixture of dioxane/OME (3/1, 8 ml) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature 160 "C for 20 min. After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered, and the filtered solid was washed with OCM.

The filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions were combined and poured into a saturated solution of MnSOO (40 ml). The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag505 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EOAc/hexane (1/7, 40 ml). After filtration, the title compound was obtained as an off-white solid (0.30 g, 59 95).

IN NMR (500 MHz; OM5o-av): 5 1.12 (in, 9H), 2.11 (5, ZN), 2.22 (5, ZN), 2.45 (Her, 9-4.7 Hz, 4H), 3.02 (I, 9-46 Hz, 4H), 6.81 (a, 9-91 Gu, 2H), 7.45-7.52 (t, 4H), 7.56 ( c, 1H), 7.89 (5, 1H), 8.10-8.16 (t, 2H), 8.51 (5, 1H), 8.70 (5, 1H) M5 (EB): t/2 510 (MAN).

Example 16. M-Tert-butyl-3-(2-chloro-5-methylpyrimidin-4-ylamino)benzenesulfonamide (intermediate product 33): (c) p 7 МН

A. and Si, 33

A mixture of /2-chloro-5-methylpyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo-N-tert-butylbenzenesulfonamide (1.0 g, 3.4 mmol), Rag(aba) of (0.17 g, 0.19 mmol), xanthophos (0.2 g, 3.5 mmol) and cesium carbonate (2.0 g, 6.1 mmol) were suspended in dioxane (25 mL) and boiled with a reflux condenser in an argon atmosphere for 3 hours. After that, the reaction mixture was cooled to room temperature and diluted with OSM (30 ml). Then the mixture was filtered and

The filtrate was concentrated in vacuo. The residue was dissolved in EOAc and hexane was added to the solution until a solid precipitate formed. After filtration, the title compound (12 g, 9895) was obtained as a light brown solid. This product was used in the next step without purification. M5 (Ebzh): t/72 355 (MN).

Example (77. M-tert-butyl-3-(5-methyl-2-(4-morpholin-4-ylmethylphenylamino)pyrimidin-4-ylamino|benzenesulfonamide (compound XI MI): (c)

Фе и и Мн (в) | - M le

M. M. and "CHEM

A mixture of intermediate 33 (0.50 g, 1.4 mmol), 4-morpholin-4-ylmethylphenylamine (0.35 g, 1.8 mmol), Rah(ava)z (0.10 g, 0.11 mmol ), xanthophos (0.12 g, 0.21 mmol) and cesium carbonate (1.0 g, 3.1 mmol) were suspended in dioxane (25 ml) and refluxed under an argon atmosphere for 3 h. After that, the reaction mixture was cooled to room temperature and diluted with OSM (30 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by NRI C-chromatography and the purified fractions were combined and poured into a saturated solution of MansoOz (50 ml). The combined aqueous layers were extracted with EtOAc (2x50 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag50Ox and filtered. The filtrate was concentrated and the formed solid was dissolved in a minimum amount of EIHUAs. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as an off-white solid (0.23 g, 31 9).

IN NMR (500 MHz, OM5O-av): 5 1.12 (5, 9H), 2.13 (5, ЗН), 2.28-2.34 (t, 4Н), 3.35 (5, 2Н ), 3.55 (Her, 1594-46 Hz, 4H), 7.10 (a, 9-8.5 Hz, 2H), 7.45-7.52 (t, 2H), 7.57 (5 , 1H), 7.59 (a, U-8.5 Hz, 2H), 7.94 (5, 1H), 8.10 (5, 1H), 8.13-8.16 (t, 1H) , 8.58 (5, 1H), 8.95 (5, 1H). M5 (Eb-): t/2 511 (MAN).

Example 78. M-Tert-butyl-3-(5-methyl-2-(4-(4-oxymorpholin-4-ylmethyl)phenylamino|pyrimidin-4-ylamino|1benzenesulfonamide (compound XI MI): this

MN op oh Ge! - m Z

Same about

M M

H. CHEM

A solution of the above compound XI MI (30 mg, 0.06 mmol) and 3-chloroperbenzoic acid (77 95, 14 mg, 0.06 mmol) in chloroform (30 mL) was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation and the resulting mixture was purified by silica gel eluting with 2095 CH2OH/CHCl3 to give the title compound as an off-white solid (15 mg, 48 vol).

IN NMR (500 MHz, OM5O- av): 6 1.12 (5, 9Н), 2.14 (5, ЗН), 2.71 (а, 9-10.9 Hz, 2Н), 3.63 ( a, 9U-9,9

Hz, 2H), 4.08 (Her, 9-11.6 Gu, 2H), 4.28 (5, 2H), 7.38 (y, 9-8.5 Hz, 2H), 7.50 ( a, 9U-5.0 Hz, 2H), 7.61 (5, 1H), 7.66 (a, 9-8.5 Hz, 2H), 7.96 (5, 1H), 8.13 ( t, 2H), 8.63 (5, 1H), 9.13 (5, 1H). M5 (EBzhk):

Koo) t/2527(М--Н)".

Example 19. M-tert-butyl-3-(5-methyl-2-(4-pyrazol-1-ylphenylamino)pyrimidin-4-ylamino|1-benzenesulfonamide (compound KHIM): (c)

Fe r y MN What;

M

J

M M

N. CHEMISTRY

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-pyrazol-1-ylphenylamine (50 mg, 0.31 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwaves at 130 "C for 15 min. After cooling to room temperature, the tube was capped and the mixture was concentrated. The residue was taken up in water (20 mL) and neutralized with 10 95 Mahon's solution until a solid precipitate formed. This brown solid was filtered and then purified by NRI C-chromatography.

The processed fractions were combined and poured into a saturated solution of MansSoOz (30 ml). The combined aqueous layers were extracted with EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag50Ox and filtered. The filtrate was concentrated and the formed solid was dissolved in a minimum amount of EtOAc and hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (15 mg, 11 95).

IN NMR (500 MHz, OM5o-av): 6 1.12 (5, 9H), 2.15 (5, ЗН), 6.49 (i, 9-2.2 Hz, 1Н), 7.50- 7.55 (t, 2H), 7.58 (5, 1H), 7.62 (9, 9-91 Hz, 2H), 7.68 (a, U-1.3 Hz, 1H), 7, 77 (a, 9-91 Hu, 2H), 7.96 (5, 1H), 8.11 (5, 1H), 8.13-8.16 (t, 1H), 8.33 (90, 9 -2.5 Hz, 1H), 8.64 (5, 1H), 9.17 (5, 1H). M5 (EbBzh): t/2 478 (MAN.

Example 80. M-Tert-butyl-3-(5-methyl-2-(b-piperazin-1-ylpyridin-3-ylamino)pyrimidine-4ylamino|1benzenesulfonamide (compound XII IX): (c) rai 7 МН ге о "X M

Residential complex

M M

N. KhkhyKh

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(5-aminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.32 mmol) in acetic acid ( 3 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 130 "С for 15 min. After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was dissolved in OSM (5 ml) and a mixture of 30 95 TEA/ OSM (6 mL). The mixture was stirred at room temperature for 1 h, concentrated, and the residue was purified by HRI C chromatography. The thus-treated fractions were combined and poured into sat. ManCO 3 (30 mL). The combined aq.

It was extracted with EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag50Ox and filtered. The filtrate was concentrated and the formed solid was dissolved in a minimal amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (10 mg, 7 Vol).

IN NMR (500 MHz, OM5o-av): 6 1.12 (5, 9Н), 2.11 (5, ЗН), 2.83 (и, 9-5.0 Hz, 4Н), 3.28- 3.33 (t,

AN), 6.73 (a, 9-91 Hz, 1H), 7.40-7.49 (t, 2H), 7.57 (5, 1H), 7.86 (ad, 9U-9.1 ,2.7 Hz, 1H), 7.88 (5, 1H), 8.10-8.16 (t, 2H), 8.28 (y, 9U-2.5 Hz, 1H), 8.53 (5, 1H), 8.72 (5, 1H). M5 (EB w): t/2 497 (MAN).

Example 81. M-tert-butyl-3-(5-methyl-2-(4-pyrazol-1-ylmethylphenylamino)pyrimidin-4-ylamino|1benzenesulfonamide (compound G): (c) p 7 MH is) with M Я

M M

H 1

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-pyrazol-1-ylmethylphenylamine (50 mg, 0.29 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwaves at 130 "C for 15 min. After cooling to room temperature, the lid of the test tube was removed and the mixture was concentrated. The residue was purified by HRIS chromatography and the fractions processed in this way were combined and poured into a saturated solution of MansSoOz (30 ml). The combined aqueous layers extracted with EAc (2x30 mL), and the combined organic layers were washed with brine, dried over anhydrous Mag250Ox, and filtered. The filtrate was concentrated and the solid formed was dissolved in a minimum amount of EIOAc. Hexane was added to the solution until a solid precipitate formed. After After filtration, the title compound was obtained as a white solid (12 mg, 9 Vol).

IN NMR (500 MHz, OM5o-av): 5 1.12 (v, 9H), 2.13 (5, ЗН), 5.21 (5, 2H), 6.24 (Her, 9-1.9 Hz, 1H), 7.08 (9, 9-8.5 Hz, 2H), 7.27-7.50 (t, ЗН), 7.56 (5, 1H), 7.60 (a, 9 -84 Hz, 2H), 7.75 (a, 9-21 Gu, 1H), 7.94 (5, 1H), 8.14 (a, 9U-7.9 Hz, 1H), 8.59 ( 5, 1H), 9.01 (5, 1H). M5 (Eb'.yu): t/2 492 (MAN).

Example 82. 5-Methyl-M2-3-(piperidine-1-sulfonyl)/phenyl|pyrimidine-2,4-diamine (intermediate product 34):

MN, from C and

F | M

M M 87 at 34

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(piperidine-1-sulfonyl)phenylamine (0.50 g, 2.1 mmol) in acetic acid (4 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 130 C for 15 min. After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and the pH was adjusted to -9 10 95 with a solution

MaonN. The resulting solution was extracted with EMUAs (2x30 ml) and the organic layer was separated. The combined organic layers were washed with saline, dried over anhydrous

Ma?5O: and filtered. The filtrate was concentrated in vacuo and this crude product (-0.6 g) was used in the next step without purification. M5 (Ebzh): t/72 348 (MN).

From Example 83. M-Tert-butyl-3-(5-methyl-2-(3-(piperidine-1-sulfonyl)/phenylamino|pyrimidine-4-ylaminobenzenesulfonamide (compound 11): (c)

Fe and 7 MN (in) but o and

F | m

M M s / about what)

A suspension of intermediate 34 (0.10 g, 0.29 mmol), 3-bromo-N-tert-butylbenzenesulfonamide (84 mg, 0.29 mmol), Rag(ava)z (15 mg, 0.016 mmol), xanthophos ( 20 mg, 0.035 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in a mixture of dioxane/OME (3/1.4 ml) were hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 min After cooling to room temperature, the tube was capped, and the resulting mixture was filtered.The filtered solid was washed with OCM.

The filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions were combined and poured into a saturated solution of MnSOO (30 ml). The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag5O: and filtered. The filtrate was concentrated and the residue was dissolved in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed.

After filtration, the title compound was obtained as a white solid (20 mg, 12 Vol).

NMR (500 MHz, OM50-av): 6 1.12 (5, 9H), 1.30-1.40 (t, 2H), 1.50-1.56 (t, 4H), 2.16 (5, ЗН), 2.88 (I, 9-5.3 Gu, 4Н), 7.17 (а, 9-78 Hz, 1Н), 7.43 (Й, 9У-8.0 Hz, 1Н ), 7.59-7.60 (t, 2H), 7.58 (5, 1H), 8.13 (5, 1H), 7.16 (aa, 9-7.9, 1.9 Hz, 1H), 8.18-8.22 (t, 1H), 8.67 (5, 1H), 9.37 (5, 1H). M5 (Eb-): t/2 559 (MAN).

Example 84. M-Tert-butyl-3-(5-methyl-2-(I4-(4-methylpiperazin-1-ylmethyl)phenylamino-1-pyrimidin-4-ylamino)benzenesulfonamide (compound I I): (c) TV MN is) | See more

But

M M V:

N "I

A suspension of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-methylpiperazin-1-ylmethyl)phenylamine (65 mg, 0.32 mmol), Raz(ava)z (20 mg, 0.022 mmol) , xanthophos (25 mg, 0.043 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in a mixture of dioxane/O ME (3/1, 4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 170 C for 15 minutes After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OSM. The filtrate was concentrated, and the residue was purified by HRIS chromatography. The fractions were combined and poured into a saturated solution of Mansoz (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous NaCl 5 O, and filtered. The filtrate was concentrated and the residue was dissolved in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (53 mg, 36 9b5).

IN NMR (500 MHz, OM50O-av): 6 1.12 (5, 9H), 2.13 (5, ЗН), 2.15 (5, ЗН), 2.20-2.45 (t, 4Н ), 3.25-3.40 (t, 6H), 7.08 (a, 9-8.6 Gu, 2H), 7.45-7.52 (t, 2H), 7.56 (5, 1 H), 7.57 (y, 9U-8.6 Hz, 2H), 7.94 (5, 1H), 8.09 (5, 1 H), 8.13-8.16 (t, 1H ), 8.58 (5, 1H), 8.94 (5, 1H). M5 (Ebhzh): t/2 524 (M.ANU.

Example 85. M-tert-butyl-3-(5-methyl-2-(4-piperazin-1-yl-3-trifluoromethylphenylamino)pyrimidin-4-ylamino|1benzenesulfonamide (compound IP): (c) rai and: MH SE, Otin o "X M schu

J

M M

N "AI

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-amino-2-trifluoromethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.29 mmol), Raz (ava)z (20 mg, 0.022 mmol), xanthophos (25 mg, 0.043 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in a mixture of dioxane/uME (3/1, 4 ml) was sealed in microwave reaction tube and irradiated with microwaves at a temperature of 170 "C for 15 min. After cooling to room temperature, the lid of the tube was removed and the resulting mixture was filtered.

The filtered solid was washed with SOHC and the filtrate was concentrated. The residue was dissolved in

OSM (5 ml) and 50 95 TEA/OSM (6 ml) was added to the solution. The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was purified by HRIS chromatography. The fractions treated in this way were combined and poured into a saturated solution of MansCO3 (30 ml). The combined aqueous layers were extracted with EAs (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous NaCl5Ox4 and filtered. The filtrate was concentrated and the resulting crude product was dissolved in a minimal amount of EOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (42 mg, 26 b).

IN NMR (500 MHz, OM50O-av): 6 1.12 (5, 9H), 2.14 (5, ЗН), 2.70-2.75 (t, 4Н), 2.80-2.85 (t, 4H), 7.36 (9, 9-8.5 Hz, 2H), 7.45-7.52 (t, 2H), 7.55 (5, 1H), 7.90-8, 00 (t, ZN), 8.07 (5, 1H), 8.15 (a, U-7.6

Hz, 1H), 8.63 (5, 1H), 9.22 (5, 1H) M5 (Ebk): t/2564 (МН).

Example 86. 3-(2-(4-(4-Acetylpiperazin-1-yl)-3-trifluoromethylphenylamino|-5-methylpyrimidin-4-ylamino)-M-tert-butylbenzenesulfonamide (compound I IM): (c) ( c) i UF r r 75 MN SE, shk (c) ee schu

J

M M

N "PM

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 1-(4-(4-amino-2-trifluoromethylphenyl)piperazin-1-yl|ethanone (0.1 g, 0.35 mmol), Raz (aba)z (15 mg, 0.016 mmol), xanthophos (20 mg, 0.035 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in a mixture of dioxane/OME (3/1.4 ml) were sealed in microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 15 min. After cooling to room temperature, the lid of the tube was removed, and the resulting mixture was filtered.

The filtered solid was washed with OCM, the filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions processed in this way were combined and poured into a saturated solution of MansSoOz (30 ml). The combined aqueous layers were extracted with EAs (2x30 ml), and the combined organic layers were washed with brine and dried over anhydrous Ma250Ox. and filtered. The filtrate was concentrated and the formed solid was dissolved in minimal

From the number of EIOAs. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (64 mg, 38 Vol).

IN NMR (500 MHz, OM5O-av): 6 1.12 (5, 9H), 2.04 (3, H), 2.14 (5, ZN), 2.73 (I, 9U-4.9 Hz, 2H), 2.79 (I, 9-4.7 Hz, 2H), 3.50-3.60 (t, 4H), 7.40 (y, 9-8.7 Hz, 2H), 7.45-7.52 (t, 2H), 7.56 (5, 1H), 7.90-8.00 (t, ZH), 8.07 (5, 1H), 8.14 (y, 9-72 Hz, 1H), 8.64 (5, 1H), 9.26 (5, 1H). M5 (Ebzh): t/2 606 (M.N).

Example 87. 5-Methyl-M2-I3-(4-methylpiperazine-1-sulfonyl)phenyl|pyrimidine-2,4-diamine (intermediate product 35):

MH,

DOC

Yes, I am

M M This is about . 35

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(4-methylpiperazine-1-sulfonyl)phenylamine (0.50 g, 2.0 mmol) in acetic acid (4 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 1307 for 15 min. After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and the pH was adjusted to "9 10 95 with a solution of

MaonN. The resulting solution was extracted with EOAc (2x30 ml) and the organic layer was separated. The combined organic layers were washed with saline, dried over anhydrous

Ma?5O.: and filtered. The filtrate was concentrated in vacuo and this crude product (-0.42 g) was used in the next step without purification. M5 (Ebzh): t/7 363 (MN).

Example 88. M-tert-butyl-3-(5-methyl-2-I3-(4-methylpiperazine-1-sulfonyl)/phenylamino|pyrimidin-4-ylaminobbenzenesulfonamide (compound I M): (c)

Fe and 5 MN (c) in XX U

And | IN

M M 87

It is about lm

A suspension of intermediate 35 (0.10 g, 0.28 mmol), C3-bromo-L/-tert-butylbenzenesulfonamide (80 mg, 0.27 mmol), Rag(aba)z (15 mg, 0.016 mmol) , xanthophos (20 mg, 0.035 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in a mixture of dioxane/OH ME (3/1, 4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 " C for 15 min After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM.

The filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions were combined and poured into a saturated solution of MnSOO (30 ml). The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag5O4 and filtered. The filtrate was concentrated, and the residue was dissolved in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed.

After filtration, the title compound was obtained as a white solid (10 mg, 6 Vol).

IN NMR (500 MHz, OM50O-av): 6 1.12 (5, 9H), 2.13 (5, ЗН), 2.16 (5, ЗН), 2.33-2.40 (t, 4Н ), 2.85-2.94 (t, 4H), 7.18 (0, 9-8.1 Hz, 1H), 7.44 (I, 9-80 Hz, 1H), 7.49-7 .54 (t, 2H), 7.58 (5, 1H), 8.00-8.03 (t, 2H), 8.13 (5, 1H), 8.15 (aa, 9-8.6 ,1.6 Hz, 1H), 8.18-8.23 (t, 1H), 8.66 (5, 1H), 9.38 (5, 1H). M5 (Eb-yu): t/2 574 (MAN):

Example 89. M-Tert-butyl-3-(5-methyl-2-(4-piperazin-1-ylmethylphenylamino)pyrimidin-4-

Zoylamino1-benzenesulfonamide (compound I MT): (c)

S r i MN

What's up?

J. Eat

M M

N. M

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-aminobenzyl)piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.34 mmol), Rag(ava)z (15 mg, 0.016 mmol), xanthophos (20 mg, 0.035 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in a mixture of dioxane/OME (3/1.4 mL) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 170 C for 15 min. After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered.

The filtered solid was washed with SOHC and the filtrate was concentrated.

The residue was dissolved in OSM (6 mL) and TEA (3 mL) was added to it. The mixture was stirred at room temperature for 1 hour, concentrated, and the residue was purified using

NRI C-chromatography. The treated fractions were combined and poured into a saturated solution

Mansoz (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 300 mL), and the combined organic layers were washed with brine, dried over anhydrous MgSO 4 , and filtered.

The filtrate was concentrated, and the resulting solid was triturated in a mixture of hexane/EtOAc (10/1.55 mL). After filtration, the title compound was obtained as a white solid (32 mg, 22 95). "H NMR (500 MHz, OM5o-av): 6 1.12 (5, 9H), 2.13 (5, ЗН), 2.30-2.40 (t, 4Н), 2.85 (i, 9-4.7 Hz,

AN), 3.38 (5, 2H), 7.09 (y, 9-8.5 Hz, 2H), 7.45-7.52 (t, 2H), 7.56 (5, 1H), 7.59 (a, 9U-8.5 Hz, 2H), 7.94 (5, 1H), 8.10 (5, 1H), 8.13-8.16 (t, 1H), 8.59 (5, 1H), 8.96 (5, 1H). M5 (Eb-): t/2 510(M-AN)".

Example 90. M-tert-butyl-3-(5-methyl-2-(4-(2-pyrrolidin-1-ylethoxy)phenylamino|pyrimidin-4-ylaminobenzenesulfonamide) (compound I MI):

VE MN

2725

M in,

J

M M

N MI

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 150 C for 20 min. After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was purified by NRI C-chromatography, and the thus treated fractions were combined and poured into a saturated solution of MansoOz (30 mL). The combined aqueous layers were extracted with EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag50Ox and filtered. The filtrate was concentrated, and the formed solid was dissolved in a minimum amount of EIHAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (40 mg, 27 Vol).

Koo) IN NMR (500 MHz, OM50-av): 6 1.12 (5, 9H), 1.65-1.70 (t, 4H), 2.12 (5, ЗН), 2.45 -2.55 (t, 4H), 2.76 (I, 9U-5.8 Hz, 2H), 3.99 (I, 9U-6.0 Hz, 2H), 6.79 (a, 9U- 9.0 Hz, 2H), 7.46-7.53 (t, 4H), 7.56 (5, 1H), 7.90 (5, 1H), 8.10-8.15 (t, 2H ), 8.53 (5, 1H), 8.77 (5, 1H). M5 (Eb-yu): t/2 525 (MANU.

Example 91. 3-5-Methyl-2-I4-(4-methyl-piperazin-1-yl)phenylamino|pyrimidin-4-ylamino|Ibenzenesulfonamide (compound I MI):

Oh nm. MN HU ate it

Yi I

(c) I am

M

M M

N. M

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromobenzenesulfonamide (0.10 g, 0.42 mmol), Rag(aba)z (20 mg, 0.022 mmol), xanthophos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 ml) were hermetically sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 °C for 15 min. After cooling to room temperature, the lid of the tube was removed, and the resulting mixture was filtered, and the filtered solid was washed with OSM. The filtrate was concentrated, and the residue was purified by HRI C chromatography. The fractions were combined and poured into a saturated solution of ManH 2 SO 3 (30 mL). The combined aqueous layers were extracted with EIOAc ( 2 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous NaCl, and filtered. The filtrate was concentrated to give the title compound as a gray solid (10 mg, 7 U).

IN NMR (500 MHz, OM5O-av): 6 2.10 (5, ZN), 2.22 (5, ZN), 2.44 (I, 92-4.9 Hz, 4H), 3.03 ( i, 9-49

Hu, 4H), 6.81 (a, U-9.0 Hz, 2H), 7.34 (5, 2H), 7.45-7.50 (t, AN), 7.89 (5, 1H ), 8.06 (5, 1H), 8.13-8.18 (t, 1H), 8.54 (5, 1H), 8.70 (5, 1H). M5 (Eb-): t/2 454 (M.N).

Example 92. M-Methyl-3-/5-methyl-2-(4-(4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylaminophenzolsulfonamide (compound GIX): (c) M schu

J

M M

N them

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-M-methylbenzenesulfonamide (0.11 g, 0.44 mmol), Raz(ava)z (20 mg, 0.022 mmol), xanthophos ( 25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in a mixture of dioxane/OME (3/1, 4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 min After cooling to room temperature, the lid of the tube was removed, and the resulting mixture was filtered, and the filtered solid was washed with OSM. The filtrate was concentrated, and the residue was purified by NRI C chromatography. The fractions were combined and poured into a saturated solution of MansSoOz solution (30 ml ). The combined aqueous layers were extracted with EtOAc (2 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous Ma»5O4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of OSM/ESO (1/5 , 30 ml).After filtration, the title compound was obtained, which was a solid light brown wine (65 mg, 42 Ob).

IN NMR (500 MHz, OM5O-av): 6 2.11 (5, ZN), 2.23 (5, ZN), 2.44 (y, 9U-5.0 Hz, ZN), 2.45- 2.50 (t,

AN), 3.03 (Her, U-4.9 Hz, 4H), 6.81 (a, 9-9.1 Gu, 2H), 7.40-7.43 (t, 2H), 7, 46 (a, 9-91 Hz, 2H), 7.52 (i, 9U-8.0 Gu, 1H), 7.89 (5, 1H), 7.94 (I, 9-1.8 Hz, 1H), 8.29 (rga, 9U-8.3 Gu, 1H), 8.56 (5, 1H), 8.72 (5, 1H).

M5 (Eb-): t/2 468 (M.N).

Example 93. M, M-Dimethyl-3-/5-methyl-2-(4-"4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylaminobenzenesulfonamide (compound IX):

Ya. m.. HER paradise V: MN I o ЗХ M schu

AND

M M

N them

A suspension of intermediate 32 (0.13 g, 0.43 mmol), 3-bromo-M, M-dimethylbenzenesulfonamide (0.14 g, 0.53 mmol), Raz(ava)z (25 mg, 0.027 mmol), xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.33 g, 1.0 mmol) in a mixture of dioxane/oME (3/1, 4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 20 min. After cooling to room temperature, the lid of the tube was removed, and the treated mixture was filtered and the filtered solid was washed

OSM The filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions were combined and poured into a saturated solution of MnSOO (30 ml). The combined aqueous layers were extracted

EAs (2 x 30 ml), and the combined organic layers were washed with brine, dried over anhydrous Ma»5Ox and filtered. The filtrate was concentrated, and the residue was triturated in a mixture of EOAc/hexane (1/5, 30 mL). After filtration, the title compound was obtained as an off-white solid (60 mg, 29 95).

IN NMR (500 MHz, OM5O-av): 6 2.17 (5, ZN), 2.23 (5, ZN), 2.44 (y, 9U-5.0 Hz, ZN), 2.45- 2.50 (t,

AN), 2.63 (5, 6H), 3.03 (I, 9-4.9 Hz, 4H), 6.81 (a, 9-91 Hz, 2H), 7.36 (a, U- 8.0 Hz, 1H), 7.45 (a, 9-91

Hz, 2H), 7.54 (I, U-8.0 Hz, 1 H), 7.84 (I, 9-1.9 Hz, 1 H), 7.90 (5, 1 H), 8 .46 (Bg a, 2-7.8 Hz, 1 N), 8.57 (5, 1 N), 8.74 (5, 1 N). M5 (Eb.yu): t/2 482 (MAN):

Example 94. M-Isopropyl-3--5-methyl-2-(4-"4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylaminophenzolsulfonamide (compound I XII): (c)

Fe

I) MN ytO

Yi I

(c) M

SHI

J

M M

H hee

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-M-isopropylbenzenesulfonamide (0.11 g, 0.39 mmol), Rag(ava)z (20 mg, 0.022 mmol), xanthophos ( 25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in a mixture of dioxane/OME (3/1, 4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 20 min. After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM. The filtrate was concentrated, and the residue was purified by HRIS chromatography. The fractions were combined and poured into a saturated solution of Mansoz (30 ml). The combined aqueous layers were extracted with EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag25O4 and filtered. The filtrate was concentrated and the residue was triturated in E(OAc/hexane (1/10, 33 mL). After filtration, the title compound was obtained as an off-white solid (47 mg, 29 Vol).

Koo) IN NMR (500 MHz, OM5o-av): 6 0.98 (y, 9U-6.6 Hz, 6H), 2.11 (5, ZN), 2.24 (5, ZN), 2, 45-2.50 (t,

AN), 3.03 (I, 9U-4.68 Hu, 4H), 3.20-3.27 (t, 1H), 6.680 (a, 9-9.0 Hu, 2H), 7.40- 7.52 (t, 4H), 7.59 (a, 9-71 Gu, 1 H), 7.89 (5, 1 H), 8.21 (rha, 9-7.9 Hz, 1 H) , 8.53 (5, 1 N), 8.71 (5, 1 N). M5 (EbBu): t/7 496 (MAN).

Example 95. My-(3-Methanesulfonyl-4-methylphenyl)-5-methyl-M2-(4-(4-methylpiperazin-1-yl)/phenyl|pyrimidin-2,4-diamine (compound XHII): (in )

II

TV MN r (in) M

SHI

J

M M

N IHII

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 4-bromo-2-methanesulfonyl-1-methylbenzene (0.10 g, 0.40 mmol), Raz(ara)z (20 mg, 0.022 mmol ), xanthphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in a mixture of dioxane/ioME (3/1.4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 " C for 15 min After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM.

The filtrate was concentrated, and the residue was purified by NRI C-chromatography.

The fractions were combined and poured into a saturated solution of MansCO3 (30 ml). The combined aqueous layers were extracted with EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag25O4 and filtered. The filtrate was concentrated and the residue was triturated in EtOAc/hexane (1/5, 30 mL). After filtration, the title compound was obtained as a light brown solid (41 mg, 27 Vol).

IN NMR (500 MHz, OM5o-av): 6 2.09 (5, ZN), 2.22 (5, ZN), 2.45 (I, 9-4.7 Hz, 4H), 2.61 ( 5, ЗН), 3.03 (I, 9-4.9 Hu, 4Н), 3.20 (5, ЗН), 6.680 (a, 9-91 Hu, 2Н), 7.35 (y, 9- 8.5 Hu, 1H), 7.44 (a, 9-9.0 Hu, 2H), 7.87 (5, 1 H), 8.05 (a, 9-24 Hz, 1 H), 8 .21 (Bg a, U-7.0 Hz, 1 N), 8.55 (5, 1 N), 8.71 (5, 1 N). M5 (Eb-yu): t/2 467 (M.-AN):.

Example 96. M-Cyclohexyl-3-/5-methyl-2-(4-"4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylaminobenzenesulfonamide (compound I-KHIP): o

Fi 7 Mn pt o U M schu ry

M M and "I XII

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-M-cyclohexylbenzenesulfonamide (0.13 g, 0.41 mmol), Rag(ava)z (20 mg, 0.022 mmol), xanthophos ( 25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in a mixture of dioxane/o.ME (3/1, 4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 min. After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OSM. The filtrate was concentrated, and the residue was purified by HRIS chromatography. The fractions were combined and poured into saturated Mansoz solution (30 ml ).The combined aqueous layers were extracted with EtOAc (2x30 ml), and the combined organic layers were washed with brine,

Zo was dried over anhydrous Mag25O4 and filtered. The filtrate was concentrated, and the residue was triturated in E(OAc/hexane (1/10, 33 mL). After filtration, the title compound was obtained as an off-white solid (45

MG, 25 Ob). "H NMR (500 MHz, OM5O-av): 5 1.07-1.17 (t, 6H), 1.53-1.63 (t, 4H), 2.11 (5, ЗН), 2, 22 (5, ZN), 2.45 (I, 9U-4.7 Hz, 4H), 2.90-3.00 (t, 1H), 3.02 (I, 9-48 Hz, 4H), 6.80 (a, 9-9.1 Hu, 2H), 7.43-7.53 (t,

AN), 7.65 (a, Yu-7.3 Hu, 1H), 7.89 (5, 1H), 8.05 (5, 1H), 8.18 (rg a, 9-7.7 Hz , 1H), 8.52 (5, 1H), 8.71 (5, 1H). M5 (Eb-): t/2 536 (M.N).

Example 97. M, M-Diethyl-3-15-methyl-2-(4--4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4- ylaminobfbenzenesulfonamide (compound I of the Chem.):

With Fr

And MN I (in) I am in

II c

M M

Hmmm

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-M, M-diethylbenzenesulfonamide (0.12 g, 0.41 mmol), Raz(ava)z (20 mg, 0.022 mmol), xanthophos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in a mixture of dioxane/OME (3/1.4 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 min After cooling to room temperature, the tube cap was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM.

The filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions were combined and poured into a saturated solution of MnSOO (30 ml). The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Ma»5Ox and filtered. The filtrate was concentrated, and the residue was triturated in a mixture of EOAc/hexane (110, 33 mL). After filtration, the title compound was obtained as an off-white solid (45 mg, 27 95).

IN NMR (500 MHz, OM50O-av): 5 1.06 (1.7-7.1 Hz, 6H), 2.11 (5, ZN), 2.22 (5, ZN), 2.44 (i, 9U-4,7

Hu, 4H), 3.03 (Y, 9-48 Hz, 4H), 3.16 (d, 9-7.1 Hu, 4H), 6.80 (a, 9-91 Hz, 2H), 7 .39 (a, 9-81 Gu, 1H), 7.45 (a, 9-9.0 Hz, 2H), 7.50 (I, 9-81 Hz, 1H), 7.89 (i, 9 -1.9 Hz, 1H), 7.89 (5, 1H), 8.39 (rga, 9U-7.9 Hz, 1H), 8.53 (5, 1H), 8.74 (5 , 1 N). M5 (Ebzh): m/7 510 (MAN):

Example 98. 5-Methyl-M2-(4-(4-methylpiperazin-1-yl)uphenylI|-MU-IZ-("morpholine-4-sulfonyl)phenyl|pyrimidine-2,4-diamine (compound I XM) :

So not sh or o in sh

AND

M M

N HU

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 4-(3-bromobenzenesulfonyl)umorpholine (0.12 g, 0.39 mmol), Raz(ara)z (20 mg, 0.022 mmol), xanthophos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in a mixture of dioxane/OME (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 min. After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OSM. The filtrate was concentrated, and the residue was purified by HRIS chromatography. The fractions were combined and poured into a saturated solution of ManHsCOz solution (30 ml ).

The combined aqueous layers were extracted with EOAc (2x30 mL), and the combined organic layers were washed with brine, dried over anhydrous NaCl and filtered. the filtrate was concentrated, and the residue was triturated in EtOAc/hexane (1/10, 33 mL). After filtration, the title compound was obtained as a light red solid (90 mg, 52 Vol).

IN NMR (500 MHz, OM5O-av): 6 2.12 (5, ZN), 2.22 (5, ZN), 2.45 (I, 92-48 Hz, 4H), 2.89 (i, 9-46

Hz, 4H), 3.03 (Her, 9-48 Hz, 4H), 3.64 (I, 9U-4.7 Hz, 4H), 6.81 (a, 9-91 Hz, 2H), 7 .35 (a, 9-81 Hz, 1H), 7.45 (90, 9-9.0 Hz, 2H), 7.56 (I, 9-81 Hz, 1H), 7.84 (I, 9 -1.9 Hz, 1H), 7.91 (5, 1H), 8.47 (Bha, 9-8.4 Gu, 1H), 8.59 (5, 1H), 8.75 (5 , 1 H). M5 (Ebhzh): t/2 524 (MANU.

Example 99. Ethyl ester of 3-15-Methyl-2-(4-«4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylaminophenzoic acid (intermediate product 36):

Job)

Uh, I'm here

M M

H - 36

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromobenzoic acid ethyl ester (0.07 mL, 0.44 mmol), Raz(aba)z (20 mg, 0.022 mmol), xanthophos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 min. After cooling to room temperature, the lid of the tube was removed and the resulting mixture was filtered and the filtered solid was washed with OCM.The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: OCM to 10 95

MmMeon/OSmM) to give the title compound (0.10 g, 6895). M5 (Eb-): t/2 447 (MaAN)".

Example 100. 3-5-Methyl-2-(4-(4-methylpiperazin-1-yl)/uphenylamino|pyrimidin-4-ylaminophenzamide (compound I HMI):

BY HIM

MN ki

M

b, and

J

M M

N WHAT

A mixture of intermediate 36 (0.10 g, 0.22 mmol) in concentrated MNAOH was hermetically closed in a reaction tube and heated at a temperature of 50 °C for 3 days. After that, the mixture was poured into water (15 ml) and extracted with EtOAc EtOAc (2x30 ml). The combined organic layers were washed with brine, dried over anhydrous Ma»5O4 and filtered. The filtrate was concentrated, and the residue was purified using HRI C-chromatography. The fractions treated in this way were combined and poured into a saturated solution of ManHsCO3 solution (30 The aqueous layer was extracted with EtOAc (2 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous Mag25O4 and filtered. The filtrate was concentrated, and the residue was triturated in a mixture of E(OAc/hexane (1/10, 33 After filtration, the title compound was obtained as a white solid (10 mg, 11 Vol).

IN NMR (500 MHz, OM50-av): 6 2.10 (5, ZN), 2.22 (5, ZN), 2.40-2.50 (t, 4H), 2.95-3.05 (t, 4H), 6.75 (9, 9-91 Hz, 2H), 7.30-7.40 (t, 2H), 7.45 (a, 2-9.1 Hz, 2H), 7 .53-7.58 (t, 1H), 7.85 (5.1 H), 7.90 (horn 5, 2H), 8.03 (5, 1H), 8.37 (in, 1H), 8.71 (5.1H). M5 (Eb-): t/2 418 (M.N).

Example 101. Ethyl ester 2-methyl-3-15-methyl-2-I(I4-(4-methylpiperazine-1-

Zoyl/phenylamino|pyrimidin-4-ylamino)benzoic acid (compound I CHMI):

AND

MN I'm looking

What do you do?

M M

N LAHMI

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-2-methylbenzoic acid ethyl ester (0.10 ml, 0.41 mmol), Raz(ava)z (20 mg, 0.022 mmol) , xanthophos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 20 min. After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM.

The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: OSM to 30 95 Meon and 1 95 TEA in OSM) to give the title compound (0.14 g, 92 95) as a light brown oil. "H NMR (500 MHz, OM5O-av): δ 1.32 (Y, 9-71 Gu, 3), 2.10 (5, ЗН), 2.21 (5, ЗН), 2.32 ( 5, ZN), 2.40-2.45 (t, 4H), 2.94 (I, 90-48 Gu, 4H), 4.30 (ad, 9-71 Gu, 2H), 6.57 ( a, 9-91 Hu, 2H), 7.25 (a, U-8.9 Hz, 2H), 7.35 (I, 9-7.8 Hz, 1H), 7.48 (ad, 9- 7.9,1.0 Hu, 1H), 7.70 (aa, U-7.8, 1.1 Hz, 1 H), 7.78 (5.1 H), 8.23 (5, 1 H), 8.58 (5.1 H). M5 (EbB:yu): t/2 461 (M.N).

Example 102. 2-Methyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino|pyrimidin-4-ylamino)benzamide (compound I XM):

You are MN

M

Co. F

J

M M

N HM

To a mixture of the above-described compound HCMII (0.10 g, 0.22 mmol) and formamide (0.05 ml, 1.3 mmol) in OME (5 ml) at a temperature of 100 "C in an argon atmosphere was added MaOMe (0.10 g, 0.46 mmol).

The mixture was stirred at the same temperature for 2 hours and then at room temperature for another 15 hours. After that, the mixture was poured into water (15 ml) and extracted with EtOAc ethyl acetate (2x15 ml). The combined organic layers were washed with brine, dried over anhydrous NaCl and filtered. The filtrate was concentrated, and the residue was purified by HRIS chromatography. The fractions processed in this way were combined and poured into a saturated solution of ManHCO3 (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag250Ox and filtered. The filtrate was concentrated, and the residue was triturated in a mixture of EtOAc/hexane (1/5, 30 ml) After filtration, the title compound was obtained as a white solid (20 mg, 21 Vol).

IN NMR (500 MHz, OM5O-av): 5 2.09 (5, ЗН), 2.21 (5, ЗН), 2.23 (5, ЗН), 2.40-2.45 (t, 4Н ), 2.97 (i, 9-46 Hu, 4H), 6.69 (a, 9-91 Hu, 2H), 7.24-7.28 (t, 2H), 7.35 (j, 9 -9.0 Hz, 2H), 7.39-7.43 (t, 2H), 7.69 (5, 1H), 7.78 (5, 1H), 8.01 (5, 1H), 8 ,53 (5, 1H). M5 (Eb-): t/2 432(M.N).

Example 103. (2-Chloro-5-methylpyrimidin-4-yl)(4-chloro-3-trifluoromethylphenyl)amine (intermediate

From product 37):

SI

In "MN

What

J

M SI 87

A mixture of /2-chloro-5-methylpyrimidin-4-ylamine (0.30 g, 2.1 mmol), 4-bromo-1-chloro-2-trifluoromethylbenzene (0.40 ml, 2.7 mmol), Raz( avba)z (0.10 g, 0.11 mmol), xanthophos (0.13 g, 0.22 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in a mixture of dioxane/OME (6/1 , 7 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 15 min. After cooling to room temperature, the lid of the tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM.

The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: hexane to 50 956 EIOAc/hexane) to afford the title compound (0.65 g, 96 95) as a white solid. M5 (Eb-): t/2 322 (MN).

Example 104. M'-(4-Chloro-3-trifluoromethylphenyl)-5-methyl-M2-(4-(piperidin-4-yloxy)phenyl|pyrimidine-2,4-diamine (compound I XIX):

V i es ch et o

Same MN

M M

Н LХХХ

A mixture of intermediate 37 (0.10 g, 0.31 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) in acetic acid (3 mL ) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 150 C for 15 min. After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was taken up in water (20 mL) and neutralized with 10 95 Mahon's solution until a solid precipitate formed. The resulting solid was filtered and purified by HRIS chromatography. The fractions treated in this way were combined and poured into a saturated solution of MansSoO:z (30 ml). The aqueous layer was extracted with EtOAc (2x30 mL), and the combined organic layers were washed with brine, dried over anhydrous NaCl and filtered. The filtrate was concentrated to give the title compound as a white solid (30 mg, 20 95).

IN NMR (500 MHz, OM5O-av): 6 1.69-1.77 (t, 2H), 2.00-2.04 (t, 2H), 2.11 (5, ЗН), 2.90 -3.00 (t, 2H), 3.10-3.20 (t, 2H), 4.40-4.48 (t, 1H), 6.84 (a, 9-9.0 Gu, 2H ), 7.49 (a, 2-9.0 Hz, 2H), 7.58 (a, y3-8.8 Hz, 1H), 7.94 (5, 1H), 8.12 (9, 9 -26 Hz, 1H), 8.21 (Bg a, 9U-8.2 Hz, 1H), 8.64 (5, 1H), 8.93 (5, 1H). M5 (Eb-): t/2 478 (M.N).

Example 105. 5-Methyl-M2-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (intermediate product 38):

MN" (c)

I am about x DG

M M

N . 38

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.50 g, 3.5 mmol) and 4-(2-pyrrolidin-1-

Zoylethoxy)phenylamine (1.1 g, 5.3 mmol) in acetic acid (8 mL) was sealed in a microwave reaction tube and irradiated with microwaves at 150°C for 15 min. After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was taken up in water (30 ml) and neutralized with 10 95 Mahon solution until the pH was 10. The resulting aqueous layer was extracted with EtOAc (2x30 ml), and the combined organic layers were washed with saline solution and dried over anhydrous Mag250Ox. and filtered. The filtrate was concentrated to give the title compound as a gray solid (0.80 g, 73 95). This product was used in the next step without purification. M5 (Ebzh): t/2 314 (MAN).

Example 106. 3-15-Methyl-2-(4-(2-pyrrolidin-1-ylethoxy)phenylamino|pyrimidin-4-ylamino|benzenesulfonamide (compound I XX):

ОХ nat y t МН (c) (c) | Zm M,

J

M M

N ХхХ

A mixture of intermediate 38 (0.10 g, 0.32 mmol), 3-bromobenzenesulfonamide (0.10 g, 0.42 mmol), Rag(ava)z (20 mg, 0.022 mmol), xanthophos (25 mg, 0.043 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in a mixture of dioxane/UME (3/1.4 ml) was hermetically sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 170 C for 25 min. After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered and the filtered solid was washed with OCM. The filtrate was concentrated, and the residue was purified by NRI C-chromatography. The treated fractions were combined and poured into a saturated solution of ManHsSoO:z (30 ml). The aqueous layer was extracted with EtOAc (2x30 ml), and the combined organic layers were washed with saline, dried over anhydrous Mag50Ox and filtered. The filtrate was concentrated and the solid was ground to a powder in the mixture

EOAc/hexane (1/10, 33 mL). After filtration, the title compound was obtained as a white solid (11 mg, 7 Vol).

NMR NMR (500 MHz, OM5O-av): 6 1.65-1.72 (t, 4H), 2.11 (5, ZN), 2.49-2.52 (t, AN), 2 .75-2.80 (t, 2H), 4.00 (I, 9-5.9 Hz, 2H), 6.680 (a, 9U-9.0 Hz, 2H), 7.34 (5, 2H) , 7.45-7.50 (t, 2H), 7.52 (a, U-9.0 Hz, 2H), 7.90 (v, 1H), 8.05 (v, 1H), 8, 10-8.15 (t, 1H), 8.57 (5, 1H), 8.77 (5, 1H). M5 (Eb-): t/2 469 (MAN).

Example 107. 5-Methyl-Me-(4-morpholin-4-ylmethylphenyl|pyrimidin-2,4-diamine (intermediate product 39):

MN.

Still more

That's it

M M

H - 39

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.40 g, 2.8 mmol) and 4-morpholin-4-ylmethylphenylamine (0.60 g, 3.1 mmol) in acetic acid (15 mL) heated at a temperature of 70" for 17 hours. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (30 ml) and neutralized with 10 95 Mahon solution to pH -10. The resulting aqueous layer was extracted with EOAc (2 x 30 ml) , and the combined organic layers were washed with brine, dried over anhydrous Mag5O:4 and filtered. The filtrate was concentrated,

From obtaining the title compound in the form of a brown syrup (0.70 g, 83,905). This product was used in the next step without purification. M5 (Ebzh): t/72,300 (MAN).

Example 108. MA(1H-Indol-4-yl)-5-methyl-M2-(4-morpholin-4-ylmethylphenyl)pyrimidin-2-4-diamine (compound I XXI): ni X

Still more

Same about

M M

N XXI

A mixture of intermediate 39 (0.40 g, 1.3 mmol), 4-bromo-1-triisopropylsilanyl-1H-indole (0.50 g, 1.4 mmol), Raz(ava)z (0.10 g, 0.11 mmol), xanthophos (0.12 g, 0.21 mmol) and cesium carbonate (0.90 g, 2.8 mmol) were suspended in dioxane (20 mL) and refluxed under an argon atmosphere for 4 hours After that, the reaction mixture was cooled to room temperature and diluted with USM (30 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: hexane to EIAs) to give the TI Re-protected precursor as a yellow oil.

To the above TIR5-protected precursor (50 mg, 0.088 mmol) in TNE (5 ml) was added TVAE (0.5 ml, 1 M ip TNE). The mixture was stirred at room temperature for 1 hour and then poured into water (20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL), and the combined organic layers were washed with brine, dried over anhydrous Ma»b5O4 (and filtered. The filtrate was concentrated, and the residue was purified by HPLC chromatography. The fractions treated in this way were combined and poured into saturated NaCl solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous NaCl, and filtered. The filtrate was concentrated, and the solid was dissolved in a minimal amount of EtOAc. hexane was added to the solution until a solid precipitate formed Filtration afforded the title compound as a light brown solid (6 mg, total yield 1 9b).

IN NMR (500 MHz, OM5O-av): 6 2.17 (in, ЗН), 2.25-2.30 (t, 4Н), 3.29 (in, 2Н), 3.54 (I, 9 -45 Gu,

AN), 6.40 (I, 90-22 Gu, 1H), 6.89 (a, U-8.5 Hz, 2H), 7.09 (her, 9-7.8 Hz, 1H), 7 .25 (y, 92-8.0 Hu, 1H), 7.27 (I, 9U-2.8 Hz, 1H), 7.30 (a, 9U-7.5 Hu, 1H), 7.43 (a, 9-8.5 Hz, 2H), 7.85 (5, 1H), 8.14 (5, 1H), 8.77 (5, 1H), 11.10 (5, 1H). M5 (Eb): t/2 415 (MAN)".

Example 109. Tert-butyl ester of 4-(4-(4-amino-5-methylpyrimidin-2-ylamino)benzyl|piperazine-1-carboxylic acid (intermediate product 40):

Mn,

OM pe sh re |. bi

M M

H-40

Coo)

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.35 g, 2.4 mmol) and 4-(4-aminobenzyl)piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 2.8 mmol) in acetic acid (20 ml) was heated at a temperature of 70 "C for 1 day. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (30 ml) and neutralized with 10 95 Mahon solution to pH -0. The aqueous layer, which was formed, extracted with EIAs (2 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous Ma»5Ox4 and filtered. The filtrate was concentrated and the title compound was used in the next step without purification. M5 (EBz): t /2 399 (MAN).

Example 110. M'A-(1H-Indol-4-yl)-5-methyl-Me-(4-piperazin-1-ylmethylphenyl)pyrimidin-2,4-diamine (compound I XXIII): chi

MN

OM Z che pl

M M

N I.XXII

A mixture of intermediate 40 (0.78 g, 2.0 mmol), 4-bromo-1-triisopropylsilanyl-1H-indole (0.70 g, 2.0 mmol), Raz(ava)z (0.15 g, 0.16 mmol), xanthphos (0.19 g, 0.32 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (20 mL) and refluxed under argon for 4.5 hours After that, the reaction mixture was cooled to room temperature, filtered and the filtered solid was washed with OSM (30 ml).

The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: hexane to 30 95 EIOAc/hexane) to give the TIR5-protected precursor.

TEA (2 ml) was added to the above TIR5-protected precursor (0.10 g, 0.15 mmol) in OSM (8 ml). The mixture was stirred at room temperature for 2 hours, then concentrated. The residue was purified by NRI C-chromatography and the fractions processed in this way were combined and poured into a saturated solution of ManCO3 (30 ml). The aqueous layer was extracted

EOAc (2 x 30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag5O»x and filtered. The filtrate was concentrated and the solid was triturated in E(Ac/hexane (1/5, 30 mL). After filtration, the title compound was obtained as a white solid (25 mg, C 95 overall yield) .

IN NMR (500 MHz, OM5O-av): 6 2.17 (in, ЗН), 2.20-2.30 (t, 4Н), 2.73 (I, 9-46 Hz, 4Н), 3, 28 (5, 2H), 6.41 (I, 90-2.2 Hz, 1H), 6.89 (y, U-8.5 Hz, 2H), 7.09 (I, 9U-7.8 Hz, 1H), 7.24 (a, 9-8.3 Hz, 1H). 7.27 (1. 9-28 Hz, 1H), 7.31 (y, 9-7.5 Hz, 1H), 7.44 (y, 9-8.5 Hz, 2H), 7.85 ( 5, 1H), 8.13(8, 1H), 8.77 (5, 1H), 11.10 (5, 1H) M5 (Ebuk): t/2 414 (МН).

Example 111. 5-Methyl-M-(7-methyl-1H-indol-4-yl)-Me-(4-(4-methylpiperazin-1-yl)/phenyl)pyrimidin-2,4-diamine (compound XX ):

Su

Hmmm

OHM

S, XX

M M and "АХХХ

A mixture of intermediate 32 (674 mg, 2.25 mmol), 4-bromo-7-methyl-1H-indole (522 mg, 2.48 mmol), Rag(ava)z (182 mg, 0.2 mmol), xanthophos (360 mg, 0.6 mmol) and cesium carbonate (2.6 g, 8 mmol) were suspended in dioxane (50 mL) and refluxed in an atmosphere

From argon for 20 hours. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to obtain the title compound (136 mg of NCI salt, 13 95) as a white solid. "H NMR (500 MHz, OM5O-dbv): 6 2.21 (v, ЗН), 2.55 (5, ЗН), 2.80 (а, 9-46 Hz, ЗН), 3.00-3 .05 (t, 2H), 3.10-3.16 (t, 2H), 3.45-3.48 (t, 2H), 3.64-3.66 (t, 2H), 6.33 -6.34 (t, 1H), 6.63 (bg, 2H), 6.92- 6.97 (t, 4H), 7.35 (I, 9-21 Hz, 1H), 7.83 ( 5, 1H), 10.04 (5, 1H), 10.24 (5, 1H), 11.08 (Bg 5, 1H), 11.34 (5, 1H), 12.12 (rg 5, 1H ). M5 (Eb-): t/2 428 (MAN).

Example 112. My-(7-Chloro-1H-indol-4-yl)-5-methyl-M2-(4-(4-methylpiperazin-1-yl)/phenyl)pyrimidin-2,4-diamine (compound IXXIM ): / MN and ; SI

NM What the heck

In, XX

M M

N I XXII

A mixture of intermediate 32 (298 mg, 1.0 mmol), 4-bromo-7-chloro-1H-indole (231 mg, 1.04 mmol), Raz(ava)z (92 mg, 0.1 mmol) , xanthophos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (50 ml) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title compound (251 mg NOSI salt, 51 95) as a white solid.

IN NMR (500 MHz, OM50-av): 6 2.21 (v, ЗН), 2.80 (y, 9-46 Hz, ЗН), 3.01-3.05 (t, 2Н), 3, 08-3.13 (t, 2H), 3.46-3.48 (t, 2H), 3.65-3.67 (t, 2H), 6.46-6.47 (t, 1H), 6.64 (Brie 5, 1H), 6.93 (y, 9U-8.9 Hz, 2H), 7.05 (9, 9-81 Gu, 2H), 7.25 (a, 9U-8, 0 Hz, 2H), 7.43-7.44 (t, 1H), 7.687 (5, 1H), 10.13 (5, 1H), 10.27 (5, 1H), 11.00 (re 5 , 1H), 11.70 (5, 1H), 12.23 (corner 5, H). M5 (Eb-k): t/2 448 (MaAAN)-.

Example 113. M2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-My-(7-methyl-TAU-indol-4-yl)pyrimidin-2,4-diamine ( compound GXXM):

K

NM about and 8

Sh. Zh

M M

N XXHM

A mixture of intermediate 38 (410 mg, 1.3 mmol), 4-bromo-7-methyl-1H-indole (275 mg, 1.3 mmol), Raz(ava)z (92 mg, 0.1 mmol) , xanthophos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (50 ml) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title compound (92 mg of NOSI salt, 15 95) as a white solid.

NMR NMR (500 MHz, OM50O-av): 6 1.88-1.90 (t, 2H), 1.93-2.02 (t, 2H), 2.21 (5, ЗН), 2 .55 (5, ZN), 3.06-3.10 (t, 2H), 3.51-3.54 (t, 4H), 4.26 (I, 2-4.9 Hz, 2H), 6.33-6.34 (t, 1H), 6.61 (Bg a, 2H), 6.93-6.95 (t, 2H), 7.03 (a, 9U-8.9 Hz, 2H ), 7.34 (I, 9-28 Hz, 1H), 7.85 (5, 1H), 10.07 (5, 1H), 10.33 (5, 1H), 10.91 (rgv, 1H ), 11.34(5, 1H), 12.15 (Bg5.H). M5 (Eb-k): t/2 443 (MAN).

Example 114. M2-(4(2-Pyrrolidin-1-yl)ethoxy)phenyl-5-methyl-M-(7-chloro-1H-indol-4-yl)upyrimidine-2,4-diamine (compound I ХХМИ): / МН and ; Si nm (in)

OM U

C XX

M M zo N LlIkhmI

A mixture of intermediate 38 (270 mg, 0.86 mmol), 4-bromo-7-chloro-1H-indole (198 mg, 0.86 mmol), Raz(ava)z (72 mg, 0.08 mmol), xanthophos (140 mg, 0.24 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (50 ml) and refluxed in an argon atmosphere for 20 h. The mixture was then filtered and the filtrate was concentrated in vacuo.

The residue was purified by NRI C-chromatography to give the title compound (33 mg of NOSI salt, 8 9o) as a white solid.

IN NMR (500 MHz, OM5O-av): 6 1.88-1.90 (t, 2H), 1.93-2.02 (t, 2H), 2.22 (5, ЗН), 3.06 -3.10 (t, 2H), 3.51-3.54 (t, 4H), 4.27 (Her, 9-4.9 Hz, 2H), 6.46-6.47 (t, 1H ), 6.63 (rg a, 2H), 6.95 (y, 9-8.2 Hz, 2H), 7.06 (a, 9-8.0 Hz, 1H), 7.25 (a, 9-8.0 Hz, 1H), 7.43 (I, 9-28 Hz, 1H), 7.90 (5, 1H), 10.13 (5, 1H), 10.40 (5, 1H) , 10.94 (horn 5, 1H), 11.70 (5, 1H), 12.33 (river, H). M5 (Eb-): t/2 463 (MaN)-.

Example 115. M2-(4-(2-(Pyrrolidin-1-yl)letoxy)phenyl)-5-methyl-My-(7-fluoro-1H-indol-4-yl)pyrimidin-2,4-diamine ( compound ГХХМИ): / МН су

NM

(in)

M MO, Vm Kh

M M

N IHHMI

A mixture of intermediate 38 (413 mg, 1.3 mmol), 4-bromo-7-fluoro-1H-indole (310 mg, 1.45 mmol), Raz(ava)z (92 mg, 0.1 mmol), xanthophos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (50 mL) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title compound (10 mg NOSI salt, 1.5 Fo) as a brown solid.

IN NMR (500 MHz, OM5O-av): 6 1.88-1.90 (t, 2H), 1.93-2.02 (t, 2H), 2.21 (5, ЗН), 3.06 -3.10 (t, 2H), 3.51-3.56 (t, 4H), 4.26 (I, 9-4.9 Hz, 2H), 6.42-6.43 (t, 1H ), 6.63 (rg a, 2H), 6.95-7.04 (t, ZN), 7.35 (0.9-8.9 Hu, 1H), 7.42 (I, 9-2 .8 Hz, 1H), 7.89 (5, 1H), 10.08 (5, 1H), 10.41 (5, 1H), 10.90 (Bg5, 1H), 11.85 (5, 1H ), 12.33 (corner 5, H). M5 (Eb-k): t/2447 (MAN):

Example 116. Me-(3-tert-butylphenyl-5-methyl-Me-(4-(4-methylpiperazin-yl/uphenyl)pyrimidine-2,4-diamine (compound GXXMI): ke ) and

OHM

S, Kh

M M

N HM

A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-tert-butyl-3-bromobenzene (256 mg, 1.2 mmol), Raz(ava)z (92 mg, 0.1 mmol), xanthophos ( 180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (50 mL) and refluxed in an argon atmosphere for 20 h. After that, the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title product

From the compound (27 mg of NSI salt, 6 95) as a white solid.

IN NMR (500 MHz, OM5O-av): 6 1.25 (5, 9H), 2.16 (5, ЗН), 2.80 (а, 9-46 Hz, ЗН), 3.04-3, 16 (t,

AN), 3.47-3.49 (t, 2H), 3.65-3.67 (t, 2H), 6.90 (y, 9-8.9 Hz, 2H), 7.26 (a , 9-9.0 Hz, 2H), 7.28-7.35 (t, 2H), 7.45 (Her, U-1.68 Hz, 1H), 7.50 (a, 9U-7, 8 Hz, 1H), 7.86 (5, 1H), 9.70 (5, 1H), 1037 (5, 1H), 11.01 (Bg5, 1H), 12.34 (Bg5, H). M5 (E5-k): t/2431. (MAN).

Example 117. M-(3-Tert-butylphenyl)-2-chloro-5-methylpyrimidin-4-amine (intermediate product 41):

NM" in

J

Me

A mixture of 2-chloro-5-methylpyrimidin-4-amine (670 mg, 4.7 mmol), 1-tert-butyl-3-bromobenzene (1.5 g, 7 mmol), Raz(ava)z (366 mg, 0.4 mmol), xanthophos (695 mg, 1.2 mmol) and cesium carbonate (6.2 g, 19 mmol) were suspended in dioxane (150 mL) and refluxed under an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EOAc (10 mL) and hexane (100 mL) was added to the solution. The solid was collected by filtration and washed with hexane to afford the crude title compound (1.2 g, 99 95) as a yellow solid.

Example 118. M'-(3-Tert-butylphenyl)-5-methyl-Me-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (compound I XXIX): nm" and (o ) tm

ХХ in

M M

N "I XXIX

A mixture of intermediate 41 (740 mg, 2.68 mmol) and tert-butyl-4-(4-aminophenoxy)piperidine-1-carboxylate (500 mg, 1.71 mmol) was suspended in acetic acid (10 mL) and heated at at a temperature of 100 "C for 4 h. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH-7. The resulting solution was extracted with EAsC (30 ml), and the organic layer was separated. The organic layer was then washed with brine, dried over Ma5O5, and filtered. The filtrate was concentrated in vacuo. This crude product was purified by HRI C chromatography to give the title compound (276 mg NOI salt, 35 95 ), which was a yellow solid.

NMR NMR (500 MHz, OM50-av): 6 1.22 (5, 9H), 1.77-1.81 (t, 2H), 2.03-2.07 (t, 2H), 2 ,14 (5, ZN), 3.00-3.04 (t, 2H), 3.18 (Bg 5, 2H), 4.56-4.57 (t, 1H), 6.86 (a, 9-8.9 Hz, 2H), 7.26-7.31 (t, 4H), 7.40 (5, 1), 7.44 (a, 2-7.5 Hz, 1H), 7, 84 (5, 1H), 8.93 (horn 5, 1H), 8.99 (Bg 5, 1H), 9.67 (5, 1H), 10.91 (5, 1H). M5 (Eb-) : t/2 432 (M.N).

Example 119. Tert-butyl-4-(4-(4-amino-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-carboxylate (intermediate product 42):

Coo)

Mn, (c)

OHM

- re MVos

M M

N "42

A mixture of 2-chloro-5-methylpyrimidine-4-amine (540 mg, 3.7 mmol) and tert-butyl-4-(4-aminophenoxy)piperidine-1-carboxylate (1.1 g, 3.7 mmol) was suspended in acetic acid (20 ml) and heated at a temperature of 70 "C for 1 hour. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH- 7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer was separated.Further, the organic layer was washed with brine, dried over

Lubricate and filter. The filtrate was concentrated in vacuo to give the title compound (1.4 g, 95 95) as a yellow solid.

Example 120. M-(1H-Indazol-yl)-5-methyl-M2-(4-piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (compound G XXX):

Lk re (c)

OM m XX M

M M

N XXX

A mixture of intermediate 42 (480 mg, 1.2 mmol), 4-bromo-1H-indazole (236 mg, 1.2 mmol),

Rag(ava)z (92 mg, 0.1 mmol), xanthophos (180 mg, 0.3 mmol), and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (50 mL) and refluxed refrigerator in an argon atmosphere for 20 hours. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by NRI C-chromatography to give the title compound (4 mg of the HCl salt, 1.2 95), which was a yellow solid.

NMR NMR (500 MHz, OM5O- av): 5 1.75-1.80 (t, 2H), 2.02-2.07 (t, 2H), 2.24 (5, ЗН), 3 .05-3.09 (gl, 2H), 3.17-3.21 (t, 2H), 4.52 (Brg 5, 1H), 6.63 (y, U-8.6 Hz, 2H) , 7.01 (a, 9-8.6 Hz, 2H), 7.14 (a, 9-7.3

Hz, 2H), 7.38-7.44 (t, 2H), 7.62 (y, 9-8.9 Hz, 2H), 7.92 (5, 1H), 8.02 (5, 1H ), 9.00 (rg5, 1H), 9.04 (Bg5, 1H), 10.20 (5, 1H), 10.33 (5, 1H). M5 (Ebuzh): tp/2 416 (Ma-N)".

Example 121. Tert-butyl ester of 4-13-(4-(4-chloro-3-methoxyphenylamino)-5-methylpyrimidin-2-ylamino|benzyl)piperazine-1-carboxylic acid (intermediate product 43): сх 7о МНо Whatever it is

M M and 43

A mixture of intermediate 31 (0.092 g, 0.33 mmol), tert-butyl ester 4-(3-

Co)aminobenzyl)piperazine-1-carboxylic acid (0.11 g, 0.39 mmol), Rag(ara)z (0.03 g, 0.033 mmol), xanthophos (0.038 g, 0.065 mmol) and cesium carbonate (0 .32 g, 0.98 mmol) was suspended in dioxane (5 ml) and heated by microwave irradiation at a temperature of 160 "C for 15 min.

After that, the reaction mixture was cooled to room temperature and spun in a centrifuge.

The reaction mixture was decanted and the organic phase was concentrated in vacuo. The residue was purified by NRI C-chromatography to give the title compound (0.075 g, 43 90) as a brown solid.

Example 122. My-(4-Chloro-3-methoxyphenyl)-5-methyl-M2-(3-piperazin-1-ylmethylphenyl)pyrimidin-2,4-diamine (compound I XXXI):

and 7o MN

Om ge

Sh r schu

M M

N LI.XXXI

A solution of intermediate 43 (0.075 g, 0.14 mmol) in OSM (8 mL) was mixed with TEA (2 mL). After 2 hours of stirring, the solvents were removed, and the resulting residue was triturated with diethyl ether to give a white hygroscopic powder (0.05 g, 82 95).

IN NMR (500 MHz, OM50O-av): 5 2.17 (5, ZN), 2.89 (horn 5, AN), 3.2 (bg 5, 4H), 3.68 (5, AN), 3.82 (bi 5, ZN), 7.16-7.19 (t, 2H), 7.28 (I, 97.9 Gu, 1H), 7.33 (y, 9-2.3 Hz, 1H), 7.39 (5, 1H), 7.43 (a, 9U-8.5

Hz, 1), 7.49 (a, 8.6 Hz, 1H), 7.98 (5, 1H), 8.8 (Bg 5, 2H), 9.78 (Bg 5, 1H), 10, 57 (g 5, 1H). M5 (E5yu): t/2 439 (MAN).

Example 123. My-(4-Chloro-3-methoxyphenyl)-5-methyl-Me-(4-(piperidin-4-yloxy)phenyl|pyrimidine-2,4-diamine (compound I XXXIII): si c | " MN

Ge) tm cho re MN

М M и ХХХИЙ

A mixture of intermediate 31 (0.66 g, 2.3 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.88 mg, 3.0 mmol) in acetic acid (15 mL) ) was heated by microwave irradiation at a temperature of 160 "С for 15 min. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml), and the mixture was neutralized with 10 95 Mahon solution until until a solid precipitate formed After filtration followed by column chromatography, the title compound was obtained as a beige solid (0.51 g, 50 vol).

IN NMR (500 MHz, OM5O-av): 6 1.37-1.44 (t, 2H), 1.86-1.89 (t, 2H), 2.09 (5, ЗН), 2.50 -2.56 (t, 2H), 2.91-2.95 (t, 2H), 3.16 (5, ЗН), 3.32 (Bbg 5, ЗН), 3.72 (5, ЗН) , 4.09 (Bg 5, 1H), 4.21-4.26 (t, 1H), 6.77 (a, 9-9 Hu, 2H), 7.27 (a, 9-8.5 Hu , 1H), 7.40-7.42 (t, 1H), 7.46-7.49 (t, ЗН), 7.687 (5, 1H), 8.31 (5, 1H), 8.78 ( 5, 1H). M5 (Eb-yu): t/72 440 (M.N).

Example 124. 4-(3-I4-(4-Chloro-3-methoxyphenylamino)-5-methylpyrimidin-2-ylamino|phenyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate product 44):

SI sh - "MN

Ohm

M M M

: still sich

About "A

A mixture of intermediate 31 (0.13 g, 0.46 mmol) and 4-(3-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester (0.19 mg, 0.68 mmol) in acetic acid (8 mL ) was heated at a temperature of 80 "C for 15 h. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml), and the mixture was neutralized with a 1095 MaO solution. After that, it was extracted ethyl acetate, washed with brine, and evaporated to an oily residue Purification of this product on column chromatography afforded the title compound as a white solid (0.12 g, 48 Vol).

Example 125. M'(4-Chloro-3-methoxyphenyl)-5-methyl-Me-(3-piperazin-1-yl-phenyl)pyrimidin-2,4-diamine (compound I XXXIII): si sh - "MH

Ohm

X, XX

M M M more

Y. mn .- XXX

A solution of intermediate 44 (0.11 g, 0.21 mmol) in OSM (8 mL) was mixed with TEA (1 mL). After three hours of stirring, the solvents were removed, and the resulting residue was taken up in ethyl acetate and washed with 1095% sodium bicarbonate solution. After that, the organic phase was dried over sodium sulfate, filtered and evaporated to a white powder. This product was diluted with OSM (5 mL) and mixed with 4M HCl in dioxane (0.5 mL). The solvents were immediately removed to give the NCI salt of the title compound as a white solid (0.06 g, 67 U).

IN NMR (500 MHz, OM5O-abv): 6 2.18 (5, ZN), 3.12 (Bg 5, 4H), 3.22 (Bg 5, 4H), 3.65 (5, ZE), 6.80 (y, 98.1 Hu, 1H), 6.95 (5, 2H), 7.14 (I, 9-82 Hu, 1H), 7.23 (y, 9-7.0 Hz, 1H), 7.37-7.40 (t, 2H), 7.95 (v, 1H), 9.33 (Bg 5, 2H), 9.88 (5, 1H), 10.62 (5, 1H). M5 (Eb-k): t/2 425 (MaAN)".

Example 126. 244-(3-Bromophenyl)piperidin-1-yl|ethanol (intermediate product 45):

And about

Methane 45 4-(3-Bromophenyl)piperidine (1.2 g, 4.8 mmol) and 2-bromomethanol (0.72 ml, 10 mmol) were diluted

of OME (20 mL) and mixed with potassium carbonate (2.7 g, 20 mmol). The mixture was stirred at ambient temperature for 18 hours and then poured into water and extracted with ethyl acetate. After that, the organic phase was washed with saline solution, dried over sodium sulfate, filtered and evaporated to obtain a light oil (0.6 g, 44 g).

Example 127. 2-(4-(3-(5-Methyl-2-(4-(4-methylpiperazin-1-yl)/uphenylaminopyrimidin-4-ylamino)phenyl)piperidin-1-yl|ethanol (compound I XXIII ): o. i

M schu no7 I m

S Zh

M M and "I XXIII

A mixture of intermediate 32 (0.11 g, 0.38 mmol), intermediate 45 (0.21 g, 0.75 mmol), Raz(abba)z (0.034 g, 0.037 mmol), xanthophos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) were suspended in dioxane (10 ml) and heated with microwave radiation at a temperature of 160 "C for 15 min. After that, the reaction mixture was cooled to room temperature and spun in a centrifuge. the mixture was decanted and the organic phase was concentrated in vacuo.The residue was purified by HRI C chromatography to afford the title compound (0.075 g, 43 95) as a purple solid (0.02 g, 11 95).

IN NMR (500 MHz, OM5o-av): 5 1.60-1.67 (t, 2H), 1.73 (y, 9-11.3 Hz, 2H), 2.02-2.07 (t , 2H), 2.08 (5, ЗН), 2.21 (5, ЗН), 2.39-2.45 (t, 7Н), 2.95 (y, 9-11.4 Hz, 2Н) . (0, 9-8.5 Hz, 1H), 7.22 (I, 9-7, Hz, 1H), 7.45-7.49 (t, ЗН), 7.66 (а, 9-7 ,7 Hz, 1H)» 7.82 (5, 1H), 8.09 (in, 1H), 8.67 (5, 1H). M5 (Eb-k): t/2 502 (MAN).

Example 128. Tert-butyl ester of 4-(3-bromobenzenesulfonylamino)piperidine-1-carboxylic acid (intermediate product 46):

Sat Sat in d)

G. I

97 I; at 46

3-Bromobenzenesulfonyl chloride (2.2 g, 8.7 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2 g, 10 mmol) were combined and diluted with OSM (50 mL) and TEA (3 .6 ml, 26 mmol). After 16 hours, the reaction mixture was poured into a separatory funnel and washed with water. After that, the organic phase was washed with saline solution, dried over sodium sulfate, filtered and evaporated to give a light oil, which solidified on standing (3.6 g, 98 b).

Example 129. Tert-butyl ester of 4-(3-15-methyl-2-(4-(4-methylpiperazin-1-yl/phenylamino|pyrimidin-4-ylamino|Ibenzenesulfonylamino)piperidine-1-carboxylic acid (intermediate product 47 ):

M Сх in МН m 07 M o) M o schu xx i : X more

M M

N "47

Zo A mixture of intermediate 32 (0.15 g, 0.518 mmol), intermediate 46 (0.28 g, 0.67 mmol), Raz(ava)z (0.024 g, 0.026 mmol), xanthophos (0.03 g, 0.052 mmol) and cesium carbonate (0.34 g, 1 mmol) were suspended in dioxane (10 ml) and heated with microwave radiation at a temperature of 160 C for 15 min. After that, the reaction mixture was cooled to room temperature and spun in a centrifuge. Then the mixture was decanted on ice. The resulting precipitate was dried and subjected to deprotection (0.2 g).

Example 130. 3-(5-Methyl-2-(4-(4-methylpiperazin-1-yl/uphenylamino|pyrimidin-4-ylamino)-M-piperidin-4-yl-benzenesulfonamide (compound I XXXM):

ve MN i and nm o o schu

ОМ сх ХМ гу

M M and I XXXXM

Intermediate 47 (0.2 g, 0.32 mmol) was diluted with OSM (10 mL) and mixed with TEA (0.3 mL).

After 3 hours, the solvents of the reaction mixture were removed and the precipitate formed was purified by HRI C-chromatography (0.01 g, 6 Vol).

NMR (500 MHz, OM50-av): 6 1.30-1.35 (t, 2H), 1.56-1.58 (t, 2H), 1.98 (5, 2H), 2 ,11 (5, ZN), 2.21 (5, ZN), 2.43-2.45 (t, AN), 2.84-2.87 (t, 2H), 3.02 (I, 9 -46 Hz, 2H), 6.680 (a, 9-9 Hz, 2H), 7.45-7.51 (t, 4H), 7.78 (Bg 5, 1H), 7.88 (5, 1H) , 8.05 (5, 1H), 8.20 (a, 9-7.6 Hz, 1H), 8.53 (5, 1H), 8.71 (c, 1H). M5 (Eb-): t/2 537 (MAN).

Example /- 131. My-(4-"Trifluoromethyl)-3-methylphenyl)-5-methyl-M2-(4-(4-methylpiperazin-1-yl)/phenyl)pyrimidin-2,4-diamine hydrochloride (compound I XXXMI):

MN ki what

ОМ сх Х

M M

N I XXVII

A suspension of intermediate 32 (0.12 g, 0.40 mmol), 1-bromo-3-(trifluoromethyl)-2-methylbenzene (0.14 g, 0.59 mmol), Raz(ava)z (37 mg, 0.04 mmol), xanthophos (47 mg, 0.08 mmol) and cesium carbonate (0.39 g, 1.20 mmol) in dioxane (20 mL) were degassed with argon for 2 min and then refluxed in a hermetically sealed tube overnight. After cooling to room temperature, the solvent was removed by rotary evaporation, and the resulting mixture was purified by silica gel eluting with a mixture of 10 95 CH2ZON/CHNS |» to give the title compound as a white solid.

This product was dissolved in CHCl3 (30 mL) and titrated with 2 M HCl in dioxane to pH 1. The solvent was removed by rotary evaporation and the solid product was recrystallized from acetone (25

MG, 13 Ob).

IN NMR (500 MHz, OM5O-av): 6 2.20 (v, ЗН), 2.26 (5, ЗН), 2.77 (y, 9У-4.5 Hz, ЗН), 3.00- 3.20 (t,

AN), 3.45 (a, 9-11.6 Hz, 2H), 3.63 (y, U-12.2 Hz, 2H), 6.71 (a, 9-81 Hz, 2H), 7 .05 (a, 9-9.0 Hz, 2H), 7.55 (i, 9-7.9 Hz, 1 H) 7.63 (a, 9-7.8 Hz, 1H), 7, 77 (y, 9U-7.77 Hz, 1H), 7.94 (5, 1H), 10.13 (5, 1H), 10.60 (5, 1H), 11.28 (5, 1H). M5 (Ebzh): t/2 457 (MN).

Example 132. 5-Methyl-M2-(4-(4-methylpiperazine-1-iluphenyl|-My-(3-

Zo (methylsulfonyl)phenyl)pyrimidine-2,4-diamine (compound I XXXMI!Y):

ХХ and МН and o) schu

OM o, Kh

M M

N XXXMI

A suspension of intermediate 32 (0.13 g, 0.44 mmol), 1-bromo-3-(methylsulfonyl)benzene (0.24 g, 1.0 mmol), Raz(ava)z (40 mg, 0.04 mmol), xanthophos (50 mg, 0.08 mmol) and cesium carbonate (0.43 g, 1.32 mmol) in dioxane (50 mL) was degassed with argon for 2 min, then refluxed overnight. After cooling to room temperature, the solvent was removed by rotary evaporation, and the resulting mixture was purified by silica gel eluting with a mixture of 30 95 CH2OnH/CHCl3 to give the title compound as a pale yellow solid (35 mg, 15 95 .

IN NMR (500 MHz, OM50O-av): 6 2.11 (in, ЗН), 2.23 (in, ЗН), 2.46 (рі 5, 4Н), 3.03 (і, 9-44 Hz . .6 (t, 2H), 7.91 (5, 1H), 8.05 (5, 1H), 8.36 (a, 9-6.7 Hz, 1H), 8.60 (5, 1H) , 8.77 (5, 1H). M5 (Eb-k): t/2 453 (MAN).

Example 133. 1-Bromo-3-(propylsulfonyl)benzene (intermediate product 48): (c)

DI

- ITV Vg

DI at 48

To a solution of 3-bromobenzenethiol (0.50 g, 2.6 mmol) in dioxane (50 mL) was added 1-iodopropane (1.1 g, 6.5 mmol) and cesium carbonate (2.2 g, 6.8 mmol ). This mixture was stirred at reflux until all the 3-bromobenzenethiol reacted. The reaction was quenched with a saturated solution of Ma!I-ISO3 (25 mL) and the mixture was extracted with CH3 (60 mL). The resulting product was refluxed in CHCl3 with TSRBA (2.9 g, 13 mmol) until all the starting material had reacted. The organic layer was washed with 2M Mahon, removing excess teSRBA, dried over Mag505 and filtered. The filtrate was concentrated and the crude product was purified on a silica gel column with 1:11 hexane/CHCl3 as eluent to give a colorless oil (0.30 g, 43 95 over 2 steps).

IN NMR (500 MHz, OM5O-av): 0.92 (I, 9U-7.4 Hz, ZN), 1.52-1.60 (t, 2H), 3.35-3.38 (t, 2H), 7.63 (i, usch-8.0 Hz, 1H), 7.88-7.91 (t, 1H), 7.95-7.98 (t, 1H), 8.04 (I , U-1.8 Hz, 1H).

Example 134. 5-Methyl-M2-(4-(4-methylpiperazine-1-iluphenyl)-My-(3-(propylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride (compound GXXXHMI):

ХХ в МН соте (in) DK schu

Residential complex

M M

N LAHHHMIY

Zo

A suspension of intermediate 32 (0.25 g, 0.84 mmol), intermediate 48 (0.26 g, 1. mmol), Raz(ava)z (8 mg, 0.01 mmol), xanthophos (16 mg, 0.03 mmol) and cesium carbonate (0.82 g, 2.52 mmol) in dioxane (50 mL) was degassed with argon for 2 minutes, then refluxed overnight. After cooling to room temperature, the solvent was removed by rotary evaporation, and the resulting mixture was purified by silica gel with an eluent of 10 95 CH2OnH/CHCl3Z to give the title compound as a white solid. This material was dissolved in HCl (30 mL) and titrated to pH 1 by addition of 2 M HCl in dioxane. The solvent was removed by rotary evaporation, and the solid was recrystallized from methanol (65 mg, 15 vol).

IN NMR (500 MHz, OM5O-av): 0.90 (i, 9-74 Hz, ЗН), 1.50-1.60 (t, 2Н), 2.18 (5, ЗН), 2.81 (in, ZN), 3.00-3.13 (t, 4H), 3.27 (Her, 9-7.7 Hz, 2H), 3.48 (y, 9-10.9 Hz, 2H) . .64 (I, U-8.0 Hz, 1H), 7.73 (a, 9-7.8 Hz, 1H), 7.93 (5, 1H), 8.00 (5, 1H), 8 .07 (5, 1H), 9.92 (in, 1H), 10.36 (5, 1H), 10.99 (5, 1H). M5 (Eb-): t/2 481 (MANU.

Example 135. 3-"Morpholinemethyl)benzolamine (intermediate product 49):

oh shit

Nm 49

To a solution of 3-nitrobenzaldehyde (5.9 g, 39.02 mmol), morpholine (3.4 g, 39.02 mmol), sodium cyanoborohydride (2.7 g, 43 mmol) in methanol (50 ml) at room temperature zinc chloride (0.1 g, 0.73 mmol) was added. The solution prepared in this way was refluxed for 1 hour. After cooling, the reaction was quenched with water (2 mL) and methanol was removed from the mixture by rotary evaporation. The resulting crude product was dissolved in 2M MOH (50 mL) and extracted with CHCl, dried over Mg5Ox and filtered.

The filtrate was concentrated under vacuum.

The thus obtained crude product in methanol (200 ml) was reduced with Raney nickel (Capeau) and hydrazine at room temperature. The reaction mixture was monitored using thin-layer chromatography (TLC) in ethyl acetate. After all the starting material had reacted, the methanol was removed by rotary evaporation. The resulting crude product was purified with ethyl acetate on silica gel to give the final product as a white solid (1.5 g, 50 95 over 2 stages).

IN NMR (500 MHz, OM5O-av): 2.31 (5, 4H), 3.28 (5, 2H), 3.56 (Y, 9-4.6 Hz, 4H), 4.97 (5 , 2H), 6.40-6.45 (t, 2H), 6.53 (I, 9U-1.8 Hz, 1H), 6.93 (i, 9-7.7 Hz, 1H).

Example 136 5-Methyl-M2-(3-"morpholinomethyl)phenyl)pyrimidine-2,4-diamine (intermediate 50):

Mn, with WHAT. in schu

M M

N BO

A mixture of 2-chloro-5-methylpyrimidin-4-amine (0.17 g, 1.17 mmol) and intermediate 49 (0.25 g, 1.30 mmol) was suspended in acetic acid (10 mL) and heated at 100 C for 2 hours. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH-8. The resulting solution was extracted with CHCl (100 ml), and the organic layer. The organic layer was then irradiated with brine, dried over NaCl, and filtered. The filtrate was concentrated in vacuo and this crude product was purified on

From a silica gel column with an eluent from a mixture of 10 96 CH3ZOH/EHUAc, the title compound was obtained as an oil (0.15 g, 43 Vol).

IN NMR (500 MHz, OM5O-av): 1.91 (in, ЗН), 2.35 (5, 4Н); 3.17 (in, 2H), 3.57(1, 9-44 Hz, 4H), 6.37 (5, 2H), 6.78 (a, 9-7.5 Hz, 1H), 7, 13 (1, 9-7.8 Hz, 1H), 7.59 (5, 1H), 7.69 (5, 1H), 7.74 (a, 2-93 Hz, 1H), 8.68 ( 5, 1H).

Example 137. M-tert-butyl-3-(5-methyl-2-(3-morpholin-4-ylmethyl-phenylamino)pyrimidin-4-ylamino|1-benzenesulfonamide hydrochloride (compound I XXXIX):

Fe

M

In MN

DI

(c) with schu; - what

M M

N L.XXXIxX

A suspension of intermediate 50 (1.0 g, 3.42 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.28 g, 4.28 mmol), Raz(abva)z (30 mg, 0, 03 mmol), xanthophos (40 mg, 0.07 mmol) and cesium carbonate (3.34 g, 10.24 mmol) in dioxane (50 mL) were degassed with argon for 2 minutes, then refluxed overnight . After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting mixture was purified by silica gel with an eluent from a mixture of 10 95 CH3ZON/CHCl3 to give the title compound as a white solid. This substance was dissolved in hot dioxane (150 ml) and titrated to pH 1 by adding 2 M NOSI in dioxane.

The solvent was removed by rotary evaporation, and the solid product (0.15 g, 8 U) was recrystallized from methanol.

NMR NMR (500 MHz, OM5O-a6): 1.08 (5, 9H), 2.20 (5, ЗН), 3.0-3.2 (t, 4Н), 3.7-4, 0 (t, 4H), 4.23 (v, 10.2H), 7.33 (Y, U-7.9 Hu, 1H), 7.38 (y, 9U-7.7 Hu, 1H), 7.48 (5, 1H), 7.55-7.65 (t, ЗН), 7.71 (y, i - 7.9Hz, 1H), 7.90 (а, 9-7.4 Hz, 1H), 8.01 (5, 1H), 9.96 (rg5, 1H), 10.61 (Bbg5, 1H), 11.31 (Bg 5, 1H). M5 (E5yu): t/2 511 ( M-AAS)".

Example 138. 2-Chloro-5-methyl-N-(3,5-dimethylphenyl)pyrimidin-4-amine (intermediate product 51):

What

J

M SI VI

A mixture of 1-bromo-3,5-dimethylbenzene (104 μl, 0.77 mmol), 2-chloro-5-methylpyrimidin-4-ylamine (104 mg, 0.72 mmol), RF(OAS)" (15 mg, 0.07 mmol), xanthophos (83 mg, 0.14 mmol) and potassium tert-butoxide (159 mg, 1.42 mmol) in dioxane (8 ml) were heated with microwave radiation at a temperature of 160 "C for 20 min. After that the reaction mixture was cooled to room temperature and filtered, rinsing with OSM and methanol.The filtrate was concentrated and purified by gradient flash chromatography (0-100 90 ethyl acetate in hexane) to give the title compound as a yellow oil (89 mg, 50 95 M5 (Eb-): t/2 248 (MAN).

Example 139. 5-Methyl-My-(3,5-dimethylphenyl)-M2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (compound XO): ray

Same MN

M M

N -khs

zo A mixture of intermediate 51 (89 mg, 0.36 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (139 mg, 0.47 mmol) in acetic acid was stirred at room temperature for 16 hours, and then heated at 95 "C for 2 hours. Then, the reaction mixture was concentrated in vacuo and purified by preparative NRI C chromatography. This product was made alkaline by adding MansSoOz (aqueous solution) (10 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine (5 mL), dried (Ma»5O4) and concentrated. The free base formed was taken up in Meon (5 mL) and concentrated HCl (5 drops) and concentrated in vacuo for 2 minutes in the presence of OSM and hexane , resulting in the NSI salt of the title compound in the form of an off-white solid (63 mg, 40 9).

1H NMR (500 MHz, OM5O-av): 5 1.72-1.83 (t, 2H), 2.02-2.08 (t, 2H), 2.14 (a, 2-06 Hu , ЗН), 2.24 (5, 6Н), 3.04-3.15 (t, 2Н), 3.21-3.31 (t, 2Н), 4.57-4.60 (t, 1Н ), 6.85 (5, 1H), 6.91 (a, 9U-8.9 Hz, 2H), 7.20 (5, 2H), 7.37 (y, 9-8.9 Hz, 2H ), 7.85 (5, 1H), 8.50 (Bg 5, 1H), 8.56 (Brg 5, 1H), 9.36 (rg5, 1H), 10.10 (Bg5, 1H). M5 (Eb:): t/2 404 (MAN).

Example 140. 2-Chloro-M-(3,5-dimethoxyphenyl)-5-methylpyrimidin-4-amine (intermediate product 52):

M

(in)

unit

Shit

J

M SI in

A mixture of 1-bromo-3,5-dimethoxybenzene (436 mg, 2.01 mmol), 2-chloro-5-methylpyrimidin-4-ylamine (287 mg, 2.00 mmol), RI(OAS)" (44 mg, 0.20 mmol), xanthphos (237 mg, 0.41 mmol) and potassium tert-butoxide (448 mg, 3.99 mmol) in dioxane (15 ml) and OME (5 ml) were heated by microwave radiation at a temperature of 160 C for 20 min. After that, the reaction mixture was cooled to room temperature and filtered, rinsing with OSM and methanol.

The filtrate was concentrated and purified by gradient flash chromatography (0-100 95 ethyl acetate in hexane) to afford the title compound as a yellow solid (182 mg, 33 95).

NMR NMR (500 MHz, OM5O-av): 6 2.17 (5, ЗН), 3.74 (5, 6Н), 6.27 (I, 9-22 Gu, 1Н), 6.99 ( and, 9-22

Hu, 2H), 8.06 (5, 1H), 8.71 (5, 1H). M5 (Eb): t/2 280 (MAN).

Example 141. M-(3,5-Dimethoxyphenyl)-5-methyl-M2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,A4-diamine (compound XCI):

M

(c) 7o MN

Same MN

M M

N.xSI

A mixture of intermediate 52 (100 mg, 0.36 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.36 mmol) in acetic acid was heated at a temperature of 95°C for 2 hours After that, the reaction mixture was concentrated in vacuo and

Zo was purified by preparative NRI-C chromatography to give the title trifluoroacetic acid salt as a yellow-brown solid (75 mg, 39 95).

NMR NMR (500 MHz, OM5O-av): 6 1.74-1.83 (t, 2H), 2.03-2.11 (t, 2H), 2.15 (5, ЗН), 3 .06-3.15 (t, 2H), 3.21-3.30 (t, 2H), 3.69 (5, 6H), 4.57-4.60 (t, 1H), 6.39 (Her, 9-2.2 Hz, 1H), 6.680 (a, 9-22 Hz, 2H), 6.89 (a, 9-8.9 Hz, 2H), 7.37 (a, 99.0 Hz, 2H), 7.86 (5, 1H), 8.53 (Big 5, 1H), 8.58 (Bg 5, 1H), 9.49 (ru 5, 1H), 10.24 (horn 5 , 1H). M5 (Eb-k): t/2 436 (MAN).

Example 142. 5-Methyl-M2-(4-(4-methylpiperazin-1-iluphenyl)-My-(3-(piperidin-1-yl)uphenyl)pyrimidin-2,4-diamine (compound XCII): o. t schu

Shit

J

M M

N . Khsi

A mixture of 1-(3-bromophenyl)piperidine (91 mg, 0.38 mmol), intermediate 32 (99 mg, 0.33 mmol), Raz(ava)z (15 mg, 0.02 mmol), xanthophos (24 mg, 0.04 mmol) and cesium carbonate (219 mg, 0.67 mmol) in dioxane (4 ml) were heated by microwave radiation at a temperature of 160 C for 15 min. After that, the reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in methanol, and filtered, rinsing with OSM and methanol. The filtrate was concentrated and purified by preparative NRI C-chromatography, yielding the title trifluoroacetic acid salt as an off-white solid (14 mg, 8 95).

IN NMR (500 MHz, OM5O-av): 6 1.47-1.53 (t, 2H), 1.56-1.61 (t, 4H), 2.07 (5, ЗН), 2.21 (5, ZN), 15...2.44 (I, U-4.9 Hz, 4H), 3.01 (1, 2-4.9 Hz, 4H), 3.08 (Y, U -5.4 Hz, 4H), 6.63 (ai, U-8.2, 2.3 Hz, 1H), 6.76 (90, 9-9.0 Hz, 2H), 7.12 (1 , 9U-8.3 Hz, 1H), 7.14 (5, 1H), 7.27 (a, 9-76 Hz, 1H), 7.50 (j, 9-9.0 Hz, 2H), 7.81 (5, 1H), 8.00 (5, 1H), 8.67 (5, 1H). M5 (EbB-k): t/7 458 (MN).

Example 143. MY-(3-"1H-Pyrrole-1-iluphenyl)-5-methyl-M2-(4-(4-methylpiperazin-1-yl)/phenyl)pyrimidin-2,4-diamine (HSP compound) : you, I nt,

M schu

UNTIL

M M

N . HO

A mixture of 1-(3-bromophenyl)-1H-pyrrole (86 mg, 0.39 mmol), intermediate 32 (99 mg, 0.33 mmol), Raz(ava)z (16 mg, 0.02 mmol), xanthophos (26 mg, 0.05 mmol) and cesium carbonate (215 mg, 0.66 mmol) in dioxane (4 ml) were heated by microwave radiation at a temperature of 160 C for 15 min. After that, the reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in methanol, and filtered with a rinse of OSM and methanol.

The substance is not completely white in color (32 mg, 18 Ob).

IN NMR (500 MHz, OM5O-av): 6 2.11 (in, ЗН), 2.21 (in, ЗН), 2.42 (I, 9-4.9 Hz, 4Н), 2.95 ( I, 9-49

Hz, 4H), 6.24 (I, 9-22 Hz, 2H), 6.58 (y, U-8.9 Hz, 2H), 7.23 (yes, 9U-7.8, 1.8 Hz, 1H), 7.31 (i, 9-22 Hz, 2H), 7.37 (1, 9-81 Hz, 1H), 7.43 (a, U-9.0 Hz, 2H), 7 .60 (a, 9-8.8 Gu, 1H), 7.86 (I, 9-22 Hz, 1H), 7.87 (5, 1H), 8.30 (5, 1H), 8.74 (5, 1H). M5 (Ebzh): those 440 (MAN).

Example 144. Tert-butyl ester //5-2-I4-(1-tert-butoxycarbonylpiperidin-4-yloxy)phenylamino|-5-methylpyrimidine-4-ylamino|indole-1-carboxylic acid (intermediate product 53):

(c) Physics of the MN

F (c)

M M o 53

A mixture of tert-butyl-5-bromo-1H-indole-1-carboxylate (161 mg, 0.54 mmol), intermediate 42 (202 mg, 0.50 mmol), Raz(abva)z (29 mg, 0, 03 mmol), xanthophos (36 mg, 0.07 mmol) and cesium carbonate (321 mg, 0.98 mmol) in dioxane (5 ml) was heated by microwave radiation at a temperature of 160 "C for 20 min. After that, the reaction mixture was cooled to at room temperature and filtered with a rinse of 100 mL of HSO.The filtrate was concentrated and purified by gradient flash chromatography (0-20,956 MeoN in LSO) to afford the title compound as a light brown solid (290 mg, 94 FU) M5 (Eb-): t/2 615 (Man).

Example 145. MA(1H-Indol-5-yl)-5-methyl-Me-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (compound XCM):

N zo

MN

SHHI and ra MN

M M

N. KhkhsiM

Intermediate 53 (290 mg, 0.47 mmol) was added to a solution of acetyl chloride (670 μL, 9.42 mmol) in methanol (22 mL), and the reaction mixture was heated at 60 °C for 4 hours.

The mixture was then concentrated in vacuo and purified by preparative HRIS chromatography to give the title trifluoroacetic acid salt as a brown solid (6 mg, 2 95).

IN NMR (500 MHz, OM5O-av): 6 1.70-1.78 (t, 2H), 1.98-2.07 (t, 2H), 2.16 (5, ЗН), 3.02 -3.11 (t, 2H), 3.21-3.30 (t, 2H), 4.44-4.53 (t, 1H), 6.43 (5, 1H), 6.75 (9 , 9-8.2 Hz, 2H), 7.16 (a, ./ - 8.4 Hz, 1H), 7.31 (9, 9-8.7 Hz, 2H), 7.40-7, 42 (t, 2H), 7.71 (5, 1H), 7.78 (5, 1H), 8.48 (Bg5, 1H), 8.54 (rg5, 1H), 9.65 (Bbgv, 1H ), 9.99 (ru 5, 1H), 11.18 (5, 1H). M5 (Eb-): t/2415 (M.AN)".

Example 146. My-(4-Chloro-3-methoxyphenyl)-5-methyl-Me-(b-piperazin-1-ylpyridin-3-yl)upyrimidine-2,4-diamine (compound KOM):

SI p. "Mn shk schu

F g

J. M

M M Zh

N.-khSM

A mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(5-aminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.10 g, 0.36 mmol), Rag(aba)z (30 mg, 0.033 mmol), xanthophos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in a mixture of dioxane/o ME (3/1.4 ml ) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 170 C for 30 min. After cooling to room temperature, the lid of the test tube was removed and the resulting mixture was filtered.

The filtered solid was washed with SOHC and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane to EtOAc) to obtain the tert-butoxycarbonyl (Boc)-protected precursor. TEA (3 ml) was added to a solution of this precursor in OCM (5 ml). The mixture was stirred at room temperature for 30 minutes, concentrated, and the residue was purified by NRI C-chromatography. The treated fractions were combined and poured into a saturated solution of ManCO3 (30 ml). The combined aqueous layers were extracted with EOAc (2 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous Mag25O:4 and filtered. The filtrate was concentrated and the resulting solid was triturated in a mixture of hexane/ETOAc (10/1, 55 ml). After filtration, the title compound was obtained as a white solid (20 mg, 13 Vol).

IN NMR (500 MHz, OM5O-av): 6 2.09 (in, ЗН), 2.81 (i, 9-5.0 Hz, 4Н), 3.29-3.31 (t, 4Н), 3.73 (in,

ЗН), 6.70 (а, 9-91 Hz, 1Н), 7.26 (а, 9-86 Hz, 1Н), 7.42 (9, 9-9.1 Hz, 1Н), 7.49 (a, 9-2.2 Hz, 1H), 7.76 (ad, 9-91, 2.6 Gu, 1H), 7.86 (5, 1H), 8.29 (5, 1H), 8 .31 (y, 9-26 Gu, 1H), 8.71 (5, 1H). M5 (Ebzh): t/2 426 (MAN).

Example 147. Tert-butyl ester of 4-(4-amino-2-methoxycarbonylphenyl)piperazine-1-carboxylic acid (intermediate product 54):

I will remember him. 54

To a solution of tert-butyl ester of 4-(2-methoxycarbonyl-4-nitrophenyl)piperazine-1-carboxylic acid (1.0 g, 2.7 mmol) in MeOnH (30 ml) was added 10 95 (wt.) Ra/cС (0.1 equiv. (wt.)) in

From an argon atmosphere. The mixture was evacuated and then backfilled with hydrogen (C cycles) and stirred at room temperature for 2 h. This heterogeneous reaction mixture was filtered through a pad of celite, washed with Meon, and concentrated in vacuo. The resulting crude amine compound was used in the next step without purification. M5 (E5H-): t/2 336 (MN).

Example 148. Methyl ester of 5-I4-(4-chloro-3-methoxyphenylamino)-5-methylpyrimidin-2-ylamino|-2-piperazin-1-yl-benzoic acid (compound XMI):

SI

S Y (c) (c) 7o MN Mk no FI -

J

M M live"

N . HOM

A mixture of intermediate 31 (0.10 g, 0.35 mmol), intermediate 54 (0.14 g, 0.42 mmol), Raz(ava)z (30 mg, 0.033 mmol), xanthophos (35 mg, 0 .06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) were suspended in dioxane (15 mL) and refluxed in an argon atmosphere for 2.5 h. After that, the reaction mixture was cooled to room temperature and diluted with OSM (30 ml). Then the mixture was filtered and the filtrate was concentrated.

The residue was purified by flash chromatography on silica gel (eluent: hexane to 60 96 E(OAc/hexane), obtaining the Bos-protected precursor. To a solution of this precursor in

TEA (2 ml) was added to OSM (5 ml). The mixture was stirred at room temperature for 1 hour, concentrated, and the residue was purified by HRIS chromatography. processed

In this way, the fractions were combined and poured into a saturated solution of Manso»z (30 ml). The combined aqueous layers were extracted with EtOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag50O" and filtered. The filtrate was concentrated and then collected in the minimum amount of EIOAc. Hexane was added to the solution until a solid precipitate formed.

After filtration, the title compound was obtained as a white solid (40 mg, 24 9b).

IN NMR (500 MHz, OM50O-av): 5 2.11 (v, ЗН), 2.80-2.90 (t, 8Н), 3.73 (5, ЗН), 3.74 (5, ЗН ), 6.98 (94, 9-8.9 Gu, 1H), 7.25 (y, 9-8.5 Hz, 1H), 7.40-7.48 (t, 2H), 7.69 (aa, U-8,9,2,6 Hz, 1), 7:90 (а, 9-26 Hz, 1Н), 7.91 (5, 1Н), 8.36 (в, 1Н), 9 ,04 (5, 1H). M5 (Eb-): t/:2 483 (MAN).

Example 149. Methyl ester of 5-amino-2-(2-pyrrolidin-1-ylethoxy)benzoic acid (intermediate product 55): og bu (0, pk 55

A suspension of 5-amino-2-hydroxybenzoic acid methyl ester (1.0 g, 6.0 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (1.2 g, 7.1 mmol) and cesium carbonate (5.0 g , 15 mmol) in OME (40 ml) was heated at a temperature of 60 "C for 17 h. After that, the mixture was allowed to cool to room temperature, poured into water (60 ml) and extracted with EtOAc (2 x 50 ml). the extracts were washed with saline solution, dried over anhydrous Mag5O5: and filtered.

The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: 100 mL to 30,960 MEOH/mL) to afford the title compound (0.2 g, 13 Uo) as a light brown solid. M5 (Eq): t/2 265 (MN).

Example 150. Methyl ester of 5-(4-(benzo|1,3Z|dioxol-4-ylamino)-5o--methylpyrimidin-2-ylamino|-2-(2-pyrrolidin-1-ylethoxy)benzoic acid (compound XMII ): (c)

With Fr

MN no Sg a

MM zhi" from N. Khsmi

A mixture of intermediate 30 (0.15 g, 0.57 mmol), intermediate 55 (0.20 g, 0.75 mmol), Raz(ava)z (50 mg, 0.055 mmol), xanthophos (60 mg, 0 .10 mmol) and cesium carbonate (0.30 g, 0.92 mmol) in a mixture of dioxane/UME (3/1, 4 ml) were hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 min. After after cooling to room temperature, the cap of the test tube was removed and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and the residue was purified by NRI C chromatography. The fractions treated in this way were combined and poured into a saturated solution of ManHsSoOz (30 mL) The combined aqueous layers were extracted

EtOAc (2 x 30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as an off-white solid (30 mg, 11 b).

NMR NMR (500 MHz, OM5O-av): 6 1.65-1.72 (t, 4H), 2.07 (5, ЗН), 2.50-2.62 (t, 4H), 2 .75 2.85 (t, 2H), 3.73 (5, ЗН), 4.02 (I, 9-5.8 Hz, 2H), 5.88 (5, 2H), 6.78-6 .88 (t, ZN), 6.92 (aa, 9U-8,0,2,1 Hu, 1H), 7.75-7.80 (t, 2H), 7.83 (5, 1H), 8.22 (in, 1H), 8.89 (5, 1H). M5 (Eb-): t/2 492 (MH).

Example 151. M-Tert-butyl-3--5-methyl-2-(4-(piperidin-4-yloxy)phenylamino|pyrimidin-4-ylamino)benzenesulfonamide (compound XMI!): z - re МН оо о о

Zh "MN

M M

N . HSMII

A mixture of intermediate 33 (0.15 g, 0.42 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.51 mmol) in acetic acid (3 mL ) was hermetically sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 150 C for 20 min. After cooling to room temperature, the lid of the tube was removed and the mixture was concentrated. The residue was taken up in water (20 mL) and adjusted to pH 10 95 with Mahon's solution until a solid precipitate formed. This solid was filtered and then purified by HRIS chromatography. The fractions treated in this way were combined, poured into a saturated solution of Manso" (30 ml) and extracted with ethyl acetate EtOAc (2x30 ml).

The combined extracts were washed with saline, dried over anhydrous NaOH and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (20 mg, 9 Vol).

NMR NMR (500 MHz, OM50-av): 6 1.12 (5, 9H), 1.65-1.73 (t, 2H), 1.95-2.05 (t, 2H), 2 ,12 (5, ZN), 2.89-2.95 (t, 2H), 3.10-3.20 (gl, 2H), 4.40-4.45 (gp, 1H), 6.84 (a, 9-91 Hz, 2H), 7.45-7.60 (t, 6H), 7.90 (5, 1H), 8.10-8.15 (t, 2H), 8.55 ( 5, 1H), 8.81 (5, 1H). M5 (Eb-): t/250 (MAN).

Example 152. 2-(5-Aminopyridin-2-yloxy)ethanol (intermediate product 56): o d i | on "DYA pam 56

Coo)

To a solution of 2-(5-nitropyridin-2-yloxy)ethanol (1.0 g, 5.4 mmol) in MeOnH (30 ml) under an argon atmosphere was added 10 9o(wt.) Ra/C (0.1 equiv. (mass)). The mixture was evacuated and then backfilled with hydrogen (C cycles) and stirred at room temperature for 1 hour. This heterogeneous reaction mixture was filtered through a pad of celite, washed with Meon, and concentrated in vacuo. The resulting crude amine compound was used in the next step without purification. M5 (EBzh): t/2 155 (MAN).

Example 153. 2-15-(4-(Benzo/1,3|dioxol-4-ylamino)-5-methylpyrimidin-2-ylamino|pyridin-2-yloxy)ethanol (compound XCIX): (c) che

MN te r "I MN y . Khsikh

A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 56 (0.10 g, 0.65 mmol), Raz(ava)z (30 mg, 0.033 mmol), xanthophos (35 mg, 0 .06 mmol) and cesium carbonate (0.26 g, 0.80 mmol) in a mixture of dioxane/ioME (3/1.4 ml) were hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 min. After after cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and the residue was purified by NRI C chromatography. The fractions treated in this way were combined and poured into a saturated solution of ).The combined aqueous layers were extracted

EtOAc (2 x 30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as an off-white solid (50 mg, 35 b).

IN NMR (500 MHz, OM5O-av): 6 2.06 (5, ZN), 3.66 (d, U-5.4 Hz, 2H), 4.15 (I, 9U-5.2 Hz, 2H), 4.77 (Her, 95.5 Hz, 2H), 5.91 (5, 2H), 6.52 (y, 9-9.0 Hz, 1H), 6.78-6.90 ( hl, ZN), 7.82 (5, 1H), 7.96 (aa, U-8.9, 2.7 Hz, 1H), 8.22 (0, 9-26 Hz, 1H), 8, 27 (5, 1H), 8.84 (5, 1H). M5 (EbB-k): t/:2 382 (MN).

Example 154. 1-(2-(2-Methoxy-4-nitrophenoxy)ethyl|pyrrolidine (intermediate product 57): - hole

Yes, but 57

A suspension of potassium 2-methoxy-4-nitrophenolate (2.0 g, 9.7 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (2.0 g, 12 mmol) and cesium carbonate (7.0, 22 mmol) in OME (35 ml) was heated at a temperature of 80 C for 16 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with saline, dried over anhydrous Mag5O5 and filtered.

The filtrate was concentrated and used in the next step without purification. M5 (Ebzh): t/2 267 (MaAN)".

Example 155. 3-Methoxy-4-(2-pyrrolidin-1-ylethoxy)phenylamine (intermediate 58):

Koo) - Fr

Io, d. 58

To a solution of intermediate 57 (1.7 g, 6.4 mmol) in Meon (30 mL) under an argon atmosphere was added 10 9o(wt) Ra/C (0.1 equiv (wt)). The mixture was evacuated and then backfilled with hydrogen (C cycles) and stirred at room temperature for 1 hour. This heterogeneous reaction mixture was filtered through a pad of celite, washed with Meon, and concentrated in vacuo.

The resulting crude amine compound was used in the next step without purification. MO (Eb-yu): t/2 237 (MEN).

Example 156. /M'-Benzo|1,3|dioxol-4-yl-M2-(3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl|-5-methylpyrimidine-2,4-diamine ( compound C):

(c) ch

MH work,

J

M M live"

N. p

A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 58 (0.11 g, 0.46 mmol), Raz(ava)z (30 mg, 0.033 mmol), xanthophos (35 mg, 0 .06 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in a mixture of dioxane/UME (3/1.4 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 20 min. After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OCM, the filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions processed in this way were combined and poured into a saturated solution of NaHSOO (30 ml). The combined aqueous layers were extracted

EAs (2 x 30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (50 mg, 28 Vol).

IN NMR (500 MHz, OM5O-av): 6 1.65-1.72 (t, 4H), 2.06 (5, ZN), 2.50-2.62 (t, AN), 2.75 -2.85 (t, 2H), 3.50 (5, ЗН), 3.94 (I, 9-61 Hz, 2H), 5.84 (5, 2H), 6.67 (a, U- 8.8 Hz, 1H), 6.78 (ad, U-7.8, 1.1 Hz, 1H), 6.83 (her, 9-7.9 Hz, 1H), 6.92 (yes, 9-8.1, 1.1 Hu, 1H), 7.14 (yes, 9-8.7, 2.4 Hu, 1H), 7.23 (y, 9-24

Hz, 1H), 7.83 (5, 1H), 8.21 (5, 1H), 8.69 (5, 1H). M5 (Ebzh): t/2 464 (M--NU.

Example 157. M-Tert-butyl-3-(2-(4-imidazol-1-yl-phenylamino)-5-methylpyrimidin-4-ylamino|1benzenesulfonamide (compound SI): rai in МН с-м 7 соо 17 vd

J

M M Fats"

N More

A mixture of intermediate 33 (0.40 g, 1.1 mmol), 4-imidazol-1-yl-phenylamine (0.20 g, 1.3 mmol), Rag(ava)z (0.10 g, 0, 11 mmol), xanthophos (0.12 g, 0.21 mmol) and cesium carbonate (0.80 g, 2.5 mmol) in a mixture of dioxane/oME (3/1, 8 ml) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 30 min. After cooling to room temperature, the lid of the tube was removed, and the resulting mixture

It was filtered. The filtered solid was washed with OCM, the filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions treated in this way were combined and poured into a saturated solution of MansSoOz (40 ml). The combined aqueous layers were extracted

EAs (2x40 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as an off-white solid (0.15 g, 28 9).

"H NMR (500 MHz, OM5o-av): 6 1.12 (5, 9H), 2.15 (5, ЗН), 7.07 (5, 1H), 7.43 (a, 9U-9, 0 Hz, 2H), 7.50-7.60 (t, ЗН), 7.61 (5, 1H), 7.79 (а, У-9.0 Hz, 2H), 7.98 (5, 1H), 8.08-8.13 (t, ZN), 8.64 (5, 1H), 9.19 (5, 1H). M5 (Ebzh): t/2 478 (MAN)".

Example 158. M-Tert-butyl-3-(2-(4-imidazol-1-ylmethylphenylamino)-5-methylpyrimidin-4-ylamino|benzenesulfonamide (compound SI): - 8 МН и ра m - | МЙ, рр,

M M

H - SI

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-imidazol-1-ylmethylphenylamine (60 mg, 0.35 mmol), Rag(aba)z (25 mg, 0.027 mmol), xanthophos (30 mg . after cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and the residue was purified by NRI C chromatography. The fractions treated in this way were combined and poured into a saturated solution of ManHsSoOz (30 ml ).The combined aqueous layers were extracted

EOAc (2 x 30 ml), and the combined organic layers were washed with saline, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (40 mg, 29 b). "H NMR (500 MHz, OM50-av): 6 1.12 (5, 9Н), 2.13 (5, НН), 5.07 (5, 2Н), 6.89 (5, 1Н), 7 .12 (a, 98.6 Hz, 2H), 7.15 (5, 1H), 7.46 (I, 90-7.9 Gu, 1H), 7.49-7.52 (t, 1H) , 7.56 (5, 1H), 7.63 (y, U-8.6 Hz, 2H), 7.72 (5, 1H), 7.94 (5, 1H), 8.09 (5, 1H), 8.14 (a, 9U-8.1 Hz, 1H), 8.60 (5, 1H), 9.02 (5, 1H). M5 (Eb-yu): t/2492 (MAN) :

Example 159. 2-(4-Aminophenoxy)ethanol (intermediate product 59): nara

Du

Us .5U

Zo A solution of 2-(4-nitrophenoxy)ethanol (2.1 g, 12 mmol) in MeonH (30 mL) was purged with argon and 10 9o(w/w) Ra/C (0.1 eq. (w/w) ). Air from the mixture was pumped out under a vacuum cap, and then the mixture was again filled with hydrogen from a cylinder. Then this cycle was repeated, and the resulting mixture was stirred at room temperature for 2 h. This heterogeneous reaction mixture was filtered through a pad of celite, washed with Meon, and concentrated in vacuo to afford the title compound (1.8 g, 99 95) as a brown solid. M5 (EbBzh): t/2 154 (MAN).

Example 160. M-Tert-butyl-3-2-(4-(2-hydroxyethoxy)phenylamino|-5-methylpyrimidin-4-ylaminobphenzolsulfonamide (compound SI): - rai A MH o (c)

M. Va

J

M M and SI

A mixture of intermediate 33 (0.10 g, 0.28 mmol), intermediate 59 (55 mg, 0.36 mmol), Rag(ava)z (25 mg, 0.027 mmol), xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in a mixture of dioxane/ioME (3/1.4 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 minutes. After cooling to room temperature The tube was capped, and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and the residue was purified by HRI C chromatography. The fractions treated in this way were combined and poured into a saturated solution of MnSO 2 (30 mL). Vol' the combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (15 mg, 11 b).

NMR NMR (500 MHz, OM50O-av): 6 1.12 (5, 9H), 2.12 (5, ЗН), 3.69 (ad, 9-5.2 Hz, 2Н), 3, 91 (i, 9-51

Gu, 2H), 4.82 (I, U-5.5 Hz, 2H), 6.680 (a, 9-9.1 Hz, 2H), 7.45-7.50 (t, 2H), 7, 52 (y, 9-9.0 Hz, 2H), 7.55 (5, 1H), 7.90 (5, 1H), 8.08-8.15 (t, 2H), 8.53 (5 , 1H), 8.77 (5, 1H). M5 (Eb-): t/z AIII (MAN).

Example 161. M'-(4-Chloro-3-methoxyphenyl)-5-methyl-Me-piperazin-1-ylmethylphenyl)pyrimidin-2,A4-diamine (compound SIM): ve 7o МН ооо

The same many

M M

H seven

A mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(4-aminobenzyl)piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol), Raz(ara)z (30 mg, 0.033 mmol), xanthophos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in a mixture of dioxane/o ME (3/1.4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 20 min. After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered.

The filtered solid was washed with OCM and the filtrate was concentrated.

Zo The residue was purified by flash chromatography on silica gel (eluent: from hexane to 60 96 E(OAc/hexane), obtaining the Bos-protected precursor. To a solution of this precursor in

TEA (3 ml) was added to OSM (5 ml). The mixture was stirred at room temperature for 1 hour, concentrated, and the residue was purified by HRIS chromatography. The fractions processed in this way were combined and poured into a saturated solution of NaHSOO (30 ml). The combined aqueous layers were extracted with VIOAc (2 x 30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mg50O and filtered. The filtrate was concentrated, and then collected in the minimum amount of EIOAc. Hexane was added to the solution until a solid precipitate formed.

After filtration, the title compound was obtained as a white solid (13 mg, 9 Vol).

IN NMR (500 MHz, OM5O-av): 6 2.11 (in, ЗН), 2.30-2.40 (t, 4Н), 2.83 (I, 9-48 Hz, 4Н), 3, 37 (5, 2H), 3.75 (5, ЗН), 7.08 (y, U-8.6 Hz, 2H), 7.29 (a, 9-86 Hz, 1H), 7.43 ( aa, 9-86, 2.2 Hz, 1H), 7.47 (a, 9sh2.2 Gu, 1H), 7.59 (y, 9-8.6 Hz, 2H), 7.91 (5, 1H), 8.37 (5, 1H), 8.99 (5, 1H). M5 (Ebzh): t/2 439 (MAN).

Example 162. M-Tert-butyl-3-yl5-methyl-2-(4-(2-methylimidazol-1-yl)phenylamino|pyrimidin-4-ylaminophenazolesulfonamide (compound SM):

rai 78 MN in mk oo 17

M

M M

N She,

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(2-methylimidazol-1-yl/phenylamine (60 mg, 0.35 mmol), Raz(abba)z (25 mg, 0.027 mmol) , xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in a mixture of dioxane/o ME (3/1.4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 " C for 20 min. After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and the residue was purified by NRI C chromatography. The fractions treated in this way were combined and poured into saturated MnSO 2 solution (30 mL).The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (30 mg, 22 b).

IN NMR (500 MHz, OM5O-av): 6 1.11 (5, 9H), 2.15 (5, ЗН), 2.24 (5, ЗН), 6.87 (0, 9-1.2 Hz, 1H), 7.18 (a, 9-1.3 Hz, 1H), 7.22 (a, 9-8.9 Hz, 2H), 7.50-7.55 (t, 2H), 7.56 (5, 1H), 7.79 (a, 9-8.9 Hz, 2H), 7.98 (5, 1H), 8.07-8.10 (t, 2H), 8.65 (5, 1H), 9.26 (5, 1H). M5 (Eb.yu): t/2 492 (MN).

Example 163. M-Tert-butyl-3-y5-methyl-2-(4-(2-methylimidazol-1-ylmethyl)phenylamino|pyrimidin-4-ylaminobenzenesulfonamide (compound CM): ra Zv MH / oi X, ze -

M M

; A. go - y

M M

N. SM

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(2-methylimidazol-1-ylmethyl)phenylamine (65 mg, 0.35 mmol), Raz(ava)z (25 mg, 0.027 mmol) , xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in a mixture of dioxane/oME (3/1, 4 ml) were hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "С for 20 min. After cooling to room temperature, the tube was capped, and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and

The residue was purified by NRI C-chromatography. The fractions processed in this way were combined and poured into a saturated solution of MansSoOz (30 ml). The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (30 mg, 21 Vol).

IN NMR (500 MHz, OM5O-av): 6 1.12 (5, 9H), 2.13 (5, ЗН), 2.24 (5, ЗН), 5.01 (5, 2Н), 6, 73 (th,

U-1.2 Hu, 1H), 7.01 (a, 9-86 Hz, 2H), 7.07 (a, 9-11 Hu, 1H), 7.44 (her, 9U-7.9 Hz , 1H), 7.48-7.51 (t, 1H), 7.56 (5, 1H), 7.62 (a, U-8.6 Hz, 2H), 7.94 (5, 1H) , 8.08 (5, 1H), 8.12 (a, 9-8.1 Hu, 1H), 8.60 (5, 1H), 9.02 (5, 1H). M5 (Ebu): t/2 506 (MN).

Example 164. M-tert-butyl-3-(5-methyl-2-(4-pyridin-4-ylmethylphenylamino)pyrimidin-4-ylamino|1benzenesulfonamide (compound SMI): - rai re MH o o

Gebode

J

M M DY

N . SM

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-pyridin-4-ylmethylphenylamine (65 mg, 0.35 mmol), Rag(aba)z (25 mg, 0.027 mmol), xanthophos (30 mg . after cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and the residue was purified by NRI C chromatography. The fractions treated in this way were combined and poured into a saturated solution of ).The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (45 mg, 32 b). "H NMR (500 MHz, OM5o-av): 6 1.11 (5, 9H), 2.13 (5, ЗН), 3.87 (5, 2Н), 7.07 (y, 9-8, 6 Hz, 2H), 7.22 (a, 9-6.0 Hz, 2H), 7.43 (I, 9-7.9 Hz, 1H), 7.47-7.50 (t, 1H) , 7.56 (y, U-6.3 Hz, 2H), 7.58 (5, 1H), 7.93 (5, 1H), 8.09 (5, 1H), 8.13 (9, 9U-8.0 Gu, 1H), 8.44 (a, 9-5.8 Gu, 2H), 8.58 (5, 1H), 8.94 (5, 1H). M5 (Eb-yu) : t/2 503 (M-AN)".

Example 165. M-Tert-butyl-3-(5-methyl-2-(4-morpholin-4-yl-phenylamino)pyrimidin-4-ylamino|Ybenzenesulfonamide (compound SM): rai in МН he and o, schu

M

UNTIL

M M

N SUP

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-morpholin-4-ylphenylamine (60 mg, 0.34 mmol), Rag(ava)z (25 mg, 0.027 mmol), xanthophos (30 mg , 0.052 mmol) and cesium carbonate (0.20 g,

Zo 0.61 mmol) in a mixture of dioxane/O ME (3/1, 4 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 20 min. After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OCM, the filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions processed in this way were combined and poured into a saturated solution of MansSoOz (30 ml). The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a gray solid (45 mg, 32 95).

IN NMR (500 MHz, ОМ50О-ав): 6 1.12 (5, 9Н), 2.12 (5, ЗН), 3.00 (И, 9-48 Hz, 4Н), 3.73 (и, 9-48 Hz,

AN), 6.82 (y, 9-91 Gu, 2H), 7.45-7.52 (t, 4H), 7.56 (5, 1H), 7.89 (5, 1H), 8, 10-8.17 (t, 2H), 8.52 (5, 1H), 8.73 (5, 1H). M5 (EbB-k): t/2 497 (MEN).

Example 166. M-Tert-butyl-3-(5-methyl-2-(4-(1,2,4)griazol-1-ylmethylphenylamino)pyrimidin-4-ylamino|benzenesulfonamide (compound SIX): - rai p MH (c) in! M

M Mt U

Z Y-k

M M

N. Sikh

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-11,2,4)griazol-1-ylmethylphenylamine (60 mg, 0.34 mmol), Raz(abba)z (25 mg, 0.027 mmol ), xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 20 min. After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OCM, the filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions processed in this way were combined and poured into a saturated solution of MansSoOz (30 ml). The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (37 mg, 27 b).

IN NMR (500 MHz, OM5o-av): 6 1.17 (5, 9Н), 2.13 (5, ЗН), 5.29 (5, 2Н), 7.14 (а, 9-86 Hz, 2H), 7.46 (I, 97.68 Hu, 1H), 7.48-7.51 (t, 1H), 7.56 (5, 1H), 7.63 (a, 9-86 Hu, 2H), 7.94 (5, 1H), 7.95 (5, 1H), 8.08 (5, 1H), 8.13 (9, 9-8.0 Hz, 1H), 8.59 ( 5, 1H), 8.60 (5, 1H), 9.04 (5, 1H). M5 (Eb-):t/2493(М-Н):

Example 167. M-Tert-butyl-3-y5-methyl-2-(4-(4-methylimidazol-1-yl/phenylamino|pyrimidin-4-ylaminobenzenesulfonamide) (compound СХ): ра в МН - m тоо 0о-

M

M M

N.sh

Zo

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-methylimidazol-1-yl)/phenylamine (60 mg, 0.35 mmol), Rag(aba)z (25 mg, 0.027 mmol ), xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 min.

After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with SOCM, the filtrate was concentrated, and the residue was purified by NRI C chromatography. The fractions processed in this way were combined and poured into a saturated solution of ManHsCO3 (30 ml). The combined aqueous layers were extracted with EOAc (2x30 ml), and the combined organic layers were washed with brine, dried over anhydrous Mag50O and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed.

After filtration, the title compound was obtained as an off-white solid (20 mg, 15 95).

IN NMR (500 MHz, OM5O-av): 6 1.12 (5, 9H), 2.15 (5, ЗН), 2.16 (в, ЗН), 7.30 (в, 1Н), 7, 38 (a, 9-96 Hz, 2H), 7.50-7.56 (t, 2H), 7.57 (5, 1H), 7.76 (a, U-9.0 Hz, 2H), 7.96 (5, 1H), 7.97 (5, 1H), 8.09-8.13 (t, 2H), 8.63 (5, 1H), 9.16 (5, 1H). M5 (EBzh): t/: 492 (MAN).

Example 168. M-Tert-butyl-3-(5-methyl-2-(4-(1,2,4|griazol-1-yl-phenylamino)pyrimidin-4-ylamino|1-benzenesulfonamide (compound CXI):

N

M ro rai re MN and (c) is! M M

ZM

J

M M

N . SH

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(11,2,4)triazol-1-yl-phenylamine (55 mg, 0.34 mmol), Rag(ava)z (25 mg . After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered.

The filtered solid was washed with OCM, the filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions treated in this way were combined and poured into a saturated solution of MansCO3 (30 ml). The combined aqueous layers were extracted with EIAs (2x30 ml), and the combined organic layers were washed with saline solution and dried over anhydrous Mag250Ox. and filtered. The filtrate was concentrated, and then collected in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (40 mg, 29 Vol). "H NMR (500 MHz, OM50o-av): 6 1.12 (5, 9H), 2.15 (5, ZN), 7.50-7.58 (t, ZN), 7.63 (a, 9-91 Hz, 2H), 7.83 (9, 9-9.0 Hz, 2H), 7.99 (5, 1H), 8.09 (5, 1H), 8.10-8.15 ( t, 1H), 8.17 (5, 1H), 8.66 (5, 1H), 9.12 (5, 1H), 9.27 (5, 1H). M5 (Eb); t/2 479 (MN).

Example 169. M-Tert-butyl-3-15-methyl-2-I3-(1H-tetrazol-5-yl)phenylamino|pyrimidin-4-ylaminophenzolsulfonamide (compound SHII): word МН ик лк о nm

what"

J

M M

N . CIS

Zo

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 3-(1H-tetrazol-5-yl)/phenylamine (55 mg, 0.34 mmol), Rag(aba)z (25 mg, 0.027 mmol) ), xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 °C for 20 min. After cooling to room temperature, the lid of the test tube was removed, and the resulting mixture was filtered.

The filtered solid was washed with OCM, the filtrate was concentrated, and the residue was purified by NRI C-chromatography. The fractions treated in this way were combined and poured into a saturated solution of MansCO3 (30 ml). The combined aqueous layers were extracted with EtOAc (2x30 ml), and the combined organic layers were washed with saline solution and dried over anhydrous Mag250Ox. and filtered. The filtrate was concentrated, and then collected in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (15 mg, 11 Vol).

IN NMR (500 MHz, OM5O-av): 6 1.13 (5, 9H), 2.15 (5, ЗН), 7.26 (I, 9-7.9 Hz, 1Н), 7.38 ( th, 9U-8.0

Hz, 1H), 7.44 (yes, U-7.9, 1.1 Hz, 1H), 7.50 (a, 9-7.6 Hz, 1H), 7.58 (5, 1H), 7.79 (ai, U-8,1,1,4 Hz, 1H), 7.98 (5, 1H), 8.16 (5, 1H), 8.22 (5, 1H), 8.27 (0.9-7.8 Hz, 1H), 8.57 (5, 1H), 9.08 (5, 1H), M5 (Eq): t/2480 (MAN).

Example 170. 4-"1H-Tetrazol-5-yl)phenylamine (intermediate product 60): nm

M she / du de vo

To a solution of 5-(4-nitrophenyl)-1H-tetrazole (1.0 g, 5.2 mmol) in MeOH (30 mL) was added 10 Fo (wt) Ra/C (0.1 equiv (wt) ) in an argon atmosphere. The mixture was evacuated, filled again with hydrogen (3 cycles) and stirred at room temperature for 1.5 h. This heterogeneous reaction mixture was filtered through a pad of celite, washed with Meon, and concentrated in vacuo. The resulting crude amine compound was used in the next step without purification. M5 (Evzh): t/2 162 (MAN)

Example 171. M-Tert-butyl-3-15-methyl-2-(4-(1H-tetrazol-5-yl)phenylamino|Ipyrimidinylaminobenzenesulfonamide (compound SHIII):

MN and in oo nm

what"

J

M M

N SH

A mixture of intermediate 33 (0.10 g, 0.28 mmol), intermediate 60 (60 mg, 0.37 mmol), Rag(abba)z (25 mg, 0.027 mmol), xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in a mixture of dioxane/ioME (3/1; 4 ml) was hermetically closed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 min. After cooling to room temperature The tube was capped, and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and the residue was purified by HRI C chromatography. The fractions treated in this way were combined and poured into a saturated solution of MnSO 2 (30 mL). Vol' the combined aqueous layers were extracted

of EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (15 mg, 11 b).

IN NMR (500 MHz, OM50O-av): 5 1.13 (5, 9Н), 2.16 (5, ЗН), 7.52-7.56 (t, 2Н), 7.57 (5, 1Н ), 7.83 (5, 4H), 8.01 (5, 1H), 8.08 (5, 1H), 8.13-8.19 (t, 1H), 8.69 (5, 1H) , 9.34 (5.1H). MO(E5Z Yu): t/2 480 (MAN).

Example 172. 3-(2-(4-(4-Acetylpiperazin-1-yl)/phenylamino|-5-methylpyrimidin-4-ylamino)-M-tert-butylbenzenesulfonamide (compound SHIM):

and | (at);

МН ух МН ХМ хх г ох, shuch

M

J

M M n. SCHEME

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 1-I(4-(4-aminophenyl)piperazin-1-yl|Istanone (80 mg, 0.36 mmol), Raz(aba)z ( 25 mg, 0.027 mmol), xanthophos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 "C for 20 min. After cooling to room temperature, the cap of the test tube was removed, and the resulting mixture was filtered. The filtered solid was washed with OSM, the filtrate was concentrated, and the residue was purified by NRI C chromatography. The fractions treated in this way were combined and poured into a saturated solution NaOH (30 mL) The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as an off-white solid (55 mg, 37 b).

IN NMR (500 MHz, OM5O-av): 6 1.12 (5, 9H), 2.04 (5, ЗН), 2.12 (5, ЗН), 2.97 (I, 9-52 Hz, 2H), 3.03 (Her, 95.1 Hz, 2H), 3.57 (ad, 95.4 Gu, 4H), 6.85 (a, 9U-9.0 Hz, 2H), 7.46 -7.52 (t, 4H), 7.56 (5, 1H), 7.90 (5, 1H), 8.10-8.17 (t, 2H), 8.52 (5, 1H), 8.75 (5.1H). M5 (E.Yu): t/2 538 (MN).

Example 173. M-Tert-butyl-3--5-methyl-2-|1-morpholin-4-ylethyl)/phenylamino|pyrimidin-4-ylaminobfbenzenesulfonamide (compound СХМ):

MN and o o no Z

AJ U

M M

H Also,

A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(1-morpholin-4-ylethyl/phenylamine (80 mg, 0.39 mmol), Raz(aba)z (30 mg, 0.033 mmol) , xanthophos (35 mg, 0.061 mmol) and cesium carbonate (0.26 g, 0.80 mmol) in dioxane (4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at a temperature of 160 C for 20 min. After cooling to room temperature temperature, the cap of the test tube was removed, and the resulting mixture was filtered.

The residue was purified by NRI C-chromatography. The fractions processed in this way were combined and poured into a saturated solution of MansSoOz (30 ml). The combined aqueous layers were extracted

EtOAc (2x30 ml), and the combined organic layers were washed with saline solution, dried over anhydrous Mag50" and filtered. The filtrate was concentrated, and then taken up in a minimum amount of EtOAc. Hexane was added to the solution until a solid precipitate formed. After filtration, the title compound was obtained as a white solid (40 mg, 27 b).

IN NMR (500 MHz, OM5o-av): 6 1.12 (5, 9Н), 1.25 (а, 9-6.6 Hz, ЗН), 2.13 (5, ЗН), 2.20- 2.30 (t, 2H), 2.30-2.40 (t, 2H), 3.24 (d, 9U-6.6 Hz, 1H), 3.54 (I, 2-44 Gu, 4H ), 7.10 (a, 90-8.5 Hz, 2H), 7.45-7.52 (t, 2H), 7.55 (5, 1H), 7.57 (a, U-8, 5 Hz, 2H), 7.93 (5, 1H), 8.09 (5, 1H), 8.15 (a, U-7.7 Hz, 1H), 8.57 (5, 1H), 8 ,92 (5, 1H). M5 (Ebzh): t/72 525 (MN).

Example 174. M'A-(1H-Indol-4-yl)-5-methyl-M2-(4-(4-methylpiperazin-1-yl/phenyl)pyrimidin-2,4-diamine (compound SHMI): chi

MN ki

M schu

J

M M

N . SHMI

A mixture of intermediate 32 (270 mg, 0.9 mmol), 4-bromo-1H-indole (196 mg, 0.9 mmol),

Rag(aura)z (91 mg, 0.09 mmol), xanthophos (157 mg, 0.27 mmol) and cesium carbonate (1.2 g, 3.6 mmol) were suspended in dioxane (100 mL) and boiled with a reflux condenser in an argon atmosphere for 20 hours. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title compound (55 mg NOSI salt, 14 95) as a white solid.

IN NMR (500 MHz, OM50-av): 6 2.22 (v, ЗН), 2.79 (y, 9-43 Hz, ЗН), 2.98-3.03 (t, 2Н), 3, 08-3.14 (t, 2H), 3.46-3.48 (t, 2H), 3.64-3.66 (t, 2H), 6.35-6.36 (t, 1H), 6.63 (Bg a, U-8.0 Gu, 1H), 6.98 (a, 95-91 Hz, 2H), 7.05 (a, 9-74 Hz, 1H), 7.16 (i , 9-76 Hz, 1H), 7.36 (i, 9-2.8 Hz, 2H), 7.43 (a, U-8.0 Hz, 1H), 7.86 (5, 1H), 10.07 (5, 1H), 10.27 (5, 1H), 11.00 (reg 5, 1H), 11.38 (5, 1H), 12.16 (Bg 5, H). M5 (Eb-yu): t/2 414 (MAN).

Example 175. 2-Chloro-5-methyl-N-(2,3-dimethylphenyl)pyrimidin-4-amine (intermediate product 61):

Co

Fi

M SI 61

A mixture of 2-chloro-5-methylpyrimidin-4-amine (143.6 mg, 1 mmol), 1-bromo-2,3-dimethylbenzene (222 mg, 1.2 mmol), Rag(aba)z (92 mg, 0.1 mmol), xanthophos (174 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (150 mL) and refluxed under an argon atmosphere for 20 h. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and hexane (100 mL) was added to the solution. The solid was collected by filtration and washed with hexane to afford the crude title compound as a yellow solid.

Example 176. 5-Methyl-M"-(2,3-dimethylphenyl)-M2-(4-piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (compound SCHMI):

Zo s s (c)

Same MN

M M

N . SHMI

A mixture of intermediate 61 (1.0 mmol) and tert-butyl-4-(4-aminophenoxy)piperidine-i-carboxylate (292.4 mg, 1.0 mmol) was suspended in acetic acid (10 mL) and heated at 100 C for 4 hours. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH-7. The resulting solution was extracted with EOAc (30 mL), and the organic layer was separated. Next, the organic layer was washed with a saline solution, dried over

Ma5o" and filtered. The filtrate was concentrated in vacuo and this crude product was purified by HRI C-chromatography to give the title compound (105 mg of NS salt, 24 95) as a yellow solid.

IN NMR (500 MHz, OM50O-av): 6 1.76-1.83 (t, 2H), 2.03 (5, ЗН), 2.05-2.09 (t, 2H), 2.17 (5, ZN), 2.30 (5, ZN), 3.02-3.05 (t, 2H), 3.18 (Bg 5, 2H), 4.53-4.56 (t, 1H) , 6.72 (а, 9-8.5 Hz, 2Н), 7.11-7.14 (gl, ЗН), 7.19-7.24 (gl, 2Н), 7.87 (5, 1Н ), 9.06 (Brg 5, 1H), 9.13 (Bg 5, 1H), 9.92 (5, 1H), 10.43 (5, 1H).

M5 (Eb-k): t/2 404 (M.N).

Example 177. My-(4-Chloro-3,5-dimethylphenyl)-5-methyl-M2-(4-(4-methylpiperazin-1-yl)uphenyl)pyrimidin-2,4-diamine (compound CHMII):

SI

In F MN I sleep

J

M M

N SH

A mixture of intermediate 32 (240 mg, 0.8 mmol), 5-bromo-2-chloro-1,3-dimethylbenzene (212 mg, 0.96 mmol), Raz(ava)z (92 mg, 0.1 mmol ), xanthphos (170 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by NRI C-chromatography to give the title compound (63 mg NOSI salt, 17 95) as a white solid.

IN NMR (500 MHz, OM5o-av): 6 2.15 (5, ZN), 2.17 (5, ZN), 2.80 (y, 9-4.5 Hz, ZN), 3.06- 3.14 (t,

AN), 3.48-3.52 (gl, 2H), 3.75-3.77 (gl, 2H), 6.93 (y, 9-8.9 Hz, 2H), 7.29 (a , 9-8.9 Hz, 2H), 7.46 (5, 2H), 7.90 (5, 1H), 9.65 (5, 1H), 10.49 (5, 1H), 11.13 (rg 5, 2H). M5 (Eb-k): t/2 437 (MAN):

Example 178. M2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-M-(3-tert-butylphenyl|-5-

Zo methylpyrimidine-2,4-diamine (compound ХХХ):

AND

(in)

M MO,

J

M M

N.SHIhX

A mixture of intermediate 41 (365 mg, 1.32 mmol) and 4-(2-(pyrrolidin-1-yl)/ethoxy)benzeneamine (410 mg, 1.98 mmol) was suspended in acetic acid (20 mL) and heated at at a temperature of 100 C for 4 hours. After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH-7. The resulting solution was extracted with EtOAc (30 mL), and the organic layer was separated.

Next, the organic layer was washed with saline solution, dried over Moa5O»4 and filtered.

The filtrate was concentrated in vacuo and the crude product was purified by HRIS chromatography to give the title compound (127 mg HCl salt, 20 Fo) as a white solid.

NMR NMR (500 MHz, OM5O-av): 6 1.89-1.91 (t, 2H), 1.98-2.02 (t, 2H), 2.17 (5, ЗН), 3 .07-3.12 (t, 2H), 3.52-3.57 (t, 4H), 4.32 (I, 93-48 Hz, 2H), 6.90 (a, U-8.9 Hz, 2H), 7.29-7.38 (t, 4H), 743-744 (t, 1H), 7.48 (a, 9U-7.9 Hz, 1H), 7.89 (5, 1H ), 9.75 (5, 1H), 10.51 (5, 1H), 11.07 (Bg, 1H). M5 (EBI zhk): t/7 446 (MAN).

Example 179. M2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-My-(4-(3-tert-butylphenylamino)-5-methylpyrimidin-2-yl)-5o-methylpyrimidin-2 ,4-diamine (compound CXX):

H

(c) I MO, rivers

M M M M

Н N .сХХ

A mixture of intermediate 41 (210 mg, 0.67 mmol), intermediate 38 (185 mg, 0.67 mmol), Rag(ava)z (55 mg, 0.06 mmol), xanthophos (104 mg, 0.18 mmol) and cesium carbonate (782 g, 2.4 mmol) were suspended in dioxane (50 ml) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title compound (94 mg of the NCI salt, 24 95), which was a yellow solid.

IN NMR (500 MHz, OM50O-av): 6 1.29 (5, 9H), 1.84-1.88 (t, 2H), 1.94-2.01 (t, 2H), 2.14 (5, ZN), 2.27 (v, ZN), 3.06-3.10 (t, 2H), 3.51-3.56 (t, 4H), 4.29 (I, 9-4 ,9 Hz, 2H), 6.97 (y, 9-91 Hz, 2H), 7.27 (a, 9-8.6 Hz, 2H), 7.34 (I, 7-7.9 Hz, 2H), 7.57 (I, U-1.9 Hz, 2H), 7.65 (y, 9-91 Hz, 1H), 7.72 (a, 9U-8.6

Hz, 2H), 8.15 (5, 1H), 8.39 (5, 1H), 9.82 (5, 1H), 10.21 (Bg 5, 1H), 10.68 (Bg5, 1H) , 10.93 (Bbg 5, 1H). M5 (Eb-yu): t/2 553 (MN).

Example 180. 5-Methyl-M2-I4-(4-methylpiperazine-1-iluphenyl|-MU-I(3-(piperidine-1-sulfonyl)phenylpyrimidine-2,4-diamine) (compound XXHI): --M y i schu y du r

M M zo N . ХХХХ

A mixture of intermediate 32 (150 mg, 0.5 mmol), 1-(3-bromobenzenesulfonyl)piperidine (152 mg, 0.5 mmol), Rag(aba)z (46 mg, 0.05 mmol), xanthophos (87 mg, 0.15 mmol) and cesium carbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by HRIS chromatography to give the title compound (84 mg NOSI salt, 37 95), which was a white solid.

IN NMR (500 MHz, OM50-av): 6 1.30-1.34 (t, 2H), 1.50-1.55 (t, 4H), 2.17 (5, ЗН), 2.81 (y, 9-45

Gu, ZN), 2.88 (I, 9-53 Hz, 4H), 3.04-3.16 (t, 4H), 3.47-3.51 (t, 2H), 3.75-3 .77 (t, 2H), 6.33-6.34 (t, 1H), 6.95 (a, U-9.0 Hz, 2H), 7.25 (a, 9U-9.0 Hz, 2H), 7.56-7.63 (t, 2H), 7.83 (Her, 9-1.7H4, 1H), 7.92 (5, 1H), 8.05 (a, 9U-9, 3 Gu, 1H), 9.94 (5, 1H), 10.38 (5, 1H), 10.88 (Bg5, 1H). M5 (Eb-k): t/2 522 (MANU.

Example 181. 5-Methyl-M2-I4-(4-methylpiperazine-1-iluphenyl|-M'-(3-(2-methylpiperidine-1-sulfonyl)phenyl|pyrimidine-2,4-diamine (compound SXXII): and (in)

Zh8--M "MN i schu no g -

M M

N . ХХХХ!

A mixture of intermediate 32 (161 mg, 0.54 mmol), 1-(3-bromobenzenesulfonyl)-2-methylpiperidine (172 mg, 0.54 mmol), Rag(aba)z (46 mg, 0.05 mmol), xanthophos (87 mg, 0.15 mmol) and cesium carbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and refluxed in an argon atmosphere for 20 h. After that, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by HRIS chromatography to give the title compound (10 mg of NCI salt, C 95), which was a white solid. "H NMR (500 MHz, OM5O-av): 6 0.98 (a, 9-6.9 Hz, ЗН), 1.15-1.21 (t, 1Н), 1.36-1.40 ( hl, ЗН), 1.47-1.53 (t, 2Н), 2.18 (5, ЗН), 2.80 (y, 9-4.5 Hz, ЗН), 2.94-2.99 (t, 1H), 3.05-3.16 (t, 4H), 3.47-3.49 (t, 2H), 3.59-3.61 (t, 2H), 3.73-3 .76 (t, 2H), 4.08-4.10 (gl, 1H), 6.93 (y, 9U-8.9 Gu, 2H), 7.25 (a, U-8.9

Hz, 2H), 7.58 (, U-8.0 Hz, 1H), 7.65 (a, 9-8.0 Hu, 1H), 7.92 (a, 9-71 Hu, 2H), 7.96 (Bbg, 1H), 9.95 (5, 1H), 10.45 (5, 1H), 11.00 (Bg 5, 1H). M5 (Ebzh): t/2 536 (MN).

Example 182. M-Cyclopentyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl/uphenylamino|pyrimidin-4-ylaminobphenzolsulfonamide) (compound CXXIP)):

And in (c) in--M vi

МН и щ и г и-

M M

N . ХХХХ

A mixture of intermediate 32 (229 mg, 0.78 mmol), 3-bromo-M-cyclopentyl-

From benzenesulfonamide (280 mg, 0.92 mmol), Raz(ava)z (92 mg, 0.1 mmol), xanthophos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (100 ml) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by HRIS-chromatography to give the title compound (130 mg HCI salt, 25 95), which was a white solid.

IN NMR (500 MHz, OM50-av): 6 1.27-1.36 (t, 4H), 1.36-1.58 (t, 4H), 2.18 (5, ЗН), 2.80 (a, 9-46

Hz, ZN), 3.05-3.15 (gl, AN), 3.36-3.42 (gl, 1H), 3.47-3.49 (t, 2H), 3.74-3, 76 (t, 2H), 6.94 (a, 9U-8.7 Hz, 2H), 7.26 (a, 9-8.9 Hz, 2H), 7.59 (I, 9-8.0 Hz, 1H), 7.68 (a, 9U-8.0 Gu, 1H), 7.75 (a, 9-71 Hz, 2H), 7.92 (B, 2H), 7.93 (Bg, 1H), 9.96 (5, 1H), 10.45 (v, 1H), 11.98 (rg 5, 1H). M5 (Eb-k): t/2 522 (MEN).

Example 183. 5-Methyl-M2-(4-(4-methylpiperazin-1-yl)uphenyl|-M-I(3-(pyrrolidine-1-sulfonyl)phenyl|pyrimidine-2,4-diamine) (compound SXXIM) : (c) --a

So Ya

U ah du y-

M M

N . SKKHIM

A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-(3-bromobenzenesulfonyl)pyrrolidine (360 mg, 1.24 mmol), Raz(ava)z (92 mg, 0.1 mmol), xanthophos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by NRI C-chromatography to give the title compound (200 mg NOSI salt, 37 95) as a white solid. "H NMR (500 MHz, OM5O-dv): 6 1.61-1.65 (t, 4H), 2.19 (5, ZN), 2.80 (Bg, ZN), 3.06-3, 16 (t, 1OH), 3.74-3.77 (rg, 2H), 6.94 (a, 9-9.0 Hz, 2H), 7.26 (a, 9-9.0 Gu, 2H ), 7.60 (i, 9-8.0 Hz, 1H), 7.65 (a, 9U-8.0 Hz, 1H), 7.91 (I, 9-1.7 Hz, 1H), 7.93 (5, 1H), 8.05 (y, 9U-7.5 Hz, 1H), 9.95 (5, 1H), 10.43 (5, 1H), 11.07 (Bg 5, 1H). M5 (EbBzh): t/2 508 (M--H)".

Example 184. MA-I3-(2,5-Dimethylpyrrolidine-1-sulfonyl)phenyl-5-methyl-Me-(4-(4-methylpiperazin-1-yl)phenyl|pyrimidine-2,4-diamine (compound CXXH ): about (c)

MN i schu ah du y-

M M

N. СХХУ

A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-(3-bromobenzenesulfonyl)-2,5-dimethylpyrrolidine (318 mg, 1.0 mmol), Raz(ara)z (92 mg, 0.1 mmol ), xanthophos (180 mg, 0.3

zo mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by HRIS chromatography to give the title compound (100 mg HCI salt, 17 95), which was a white solid.

IN NMR (500 MHz, OM50O-av): 6 1.26 (v, ЗН), 1.27 (5, ЗН), 1.45-1.48 (t, 4Н), 2.19 (5, ЗН ), 2.80 (9, 9-46 Hz, ЗН), 3.06-3.15 (t, 4Н), 3.47-3.50 (t, 2Н), 3.60-3.64 ( t, 2H), 3.74-3.76 (t, 2H), 6.94 (y, 9-9.0 Gu, 2H), 7.25 (y, 9-9.0 Hz, 2H), 7.59 (Her, 9-8.0 Hz, 1H), 7.68 (a, U-7.6 Hz, 1H), 7.93 (bg, 2H), 8.02 (B, 1H), 9.97 (5, 1H), 10.47 (in, 1H), 11.07 (rg 5, 1H). M5 (Eb-k): t/2 530 (MaN)".

Example 185. M-tert-butyl-3-(5-methyl-2-(4-piperazin-1-yl-phenylamino)pyrimidin-4-ylamino|benzenesulfonamide (compound SXXMI): (9)

IN

"ah DU -

M M

N . SHHMI

A mixture of intermediate 33 (355 mg, 1.0 mmol), tert-butyl-4-(4-aminophenyl)piperazine-1-carboxylate (278 mg, 1.0 mmol), Raz(ava)z (92 mg, 0 .1 mmol), xanthophos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in SiOCl (10 ml) and trifluoroacetic acid (2 ml) was added to the solution. The mixture was stirred for 4 hours at room temperature, after which 10 95 Mahon was added to it. The organic layer was separated, and the aqueous layer was extracted with SNeSi" (10 ml x 2). The combined organic layers were dried (Mag2504). The solvent was removed in vacuo. The residue was purified by HRIS chromatography to give the title compound (62 mg, 12 95) as a white solid. "H NMR (500 MHz, OM50O-av): 6 1.10 (5, 9H), 2.18 (5, ЗН), 3.20 (bg, 4Н), 3.33 (g, 4Н), 6 .94 (a, 9-9.0 Hz, 2H), 7.25 (y, U-9.0 Hz, 2H), 7.57 (I, U-8.0 Gu, 1H), 7.63 (5, 1H), 7.71 (a, 9-81 Hu, 1H), 7.87 (re, tn), 7.92 (rt, 1), 7.96 (Bg, 1H), 9.30 (Bg, 1H), 9.96 (5, 1H), 10.46 (5, 1H). M5 (Eb-): t/2 496 (MAN).

Example 186. M-tert-butyl-3-(2-4-14-(2-hydroxyethyl)piperazin-1-yl)uphenylamino)-(5-methylpyrimidin-4-ylamino)benzenesulfonamide (compound SXXMII):

Ge) (c)

B MN

MN schu i g y

M M

N . SHHMI

The above-described compound SXXMI (31 mg, 0.06 mmol) was dissolved in OME (10 mL) and 2-bromoethanol (16 mg, 0.13 mmol) and diisopropylethylamine (33 mg, 0.25 mmol) were added to the solution. The mixture was stirred for 48 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in EtOAc (20 mL). The solution was washed with saturated NaOH and saline. The combined organic layers were dried, concentrated to 2 ml of solution and ESO (20 ml) was added to the residue. The solid phase was collected by centrifugation and converted to its NCI salt (10.7 mg, 30 Or).

IN NMR (500 MHz, OM50O-av): 6 1.09 (5, 9H), 2.17 (5, ЗН), 3.12-3.23 (t, 4Н), 3.56-3.60 (t, 2H), 3.69-3.74 (t, 2H), 3.83 (Bbg, 2H), 4.13 (Bg, 2H), 6.94 (a, U-9.0 Hz, 2H), 7.25 (a, 9-9.0 Hz, 2H), 7.57 (Her, 9U-8.0 Hz, 1H), 7.63 (5, 1H), 7.71 (a, 9-81 Gu, 1H), 7.87 (bg, 1H), 7.93 (Bg, 1H), 7.95 (Brg, 1H), 9.98 (5, 1H), 10.53 (5, 1H), 10.75 (Bg, 1H). M5 (Ebzh): t/2 540 (MAN).

Example 187. M-tert-butyl-3-(5-methyl-2-(3-piperazin-1-yl-phenylamino)pyrimidin-4-ylamino|1benzenesulfonamide (compound SXXMII): ой, ВА-МН

WITH

-x -

And more. SKKHMP

A mixture of intermediate 33 (240 mg, 0.67 mmol), tert-butyl-4-(3-aminophenyl)piperazine-1-carboxylate (166 mg, 0.6 mmol), Rag(dva)z (55 mg, 0 .06 mmol), xanthophos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and refluxed under an argon atmosphere for 20 h. After that, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in SNeoSi" (10 ml) and trifluoroacetic acid (2 ml) was added to the solution. The mixture was stirred for 4 hours at room temperature, after which 10 95 Mahon was added to it. The organic layer was separated, and the aqueous layer was extracted with SiOCl (10 ml x 2). The combined organic layers were dried (Mag25O4). The solvent was removed in vacuo. The residue was purified by HRIS chromatography to give the title compound (18 mg, 6 95) as a white solid.

IN NMR (500 MHz, OM5O-av): 5 1.10 (5, 9H), 2.19 (5, ZH), 3.17 (bg, 4H), 3.27-3.29 (t, AN ), 6.80 (ad, 9-8.1 Gu, 1H), 6.87 (Bg, 1H), 6.96 (a, 9-81 Hz, 1H), 7.16 (I, 9-81 Hu, 1H), 7.53 (I, 9-8.3 Hz, 1H), 7.81 (5, 1H), 7.70 (a, U-7.8 Hu, 1H), 7.94 ( Bg, ZN), 9.19 (rg, 2H), 9.93 (5, 1H), 10.48 (5, 1H). M5 (Ek): t/2 496 (M--H)".

Example 188. M-Tert-butyl-3-(2-13-I4-(2-hydroxyethyl)piperazin-1-yl|phenylamino)-(5-methylpyrimidin-4-ylamino|Ibenzenesulfonamide (compound CXXIX): o (in ) in MN

So eh - chi

A tone of shhh

The above-described compound SXXMI (12 mg, 0.024 mmol) was dissolved in OME (10 mL) and 2-bromoethanol (6.1 mg, 0.048 mmol) and diisopropylethylamine (12 mg, 0.092 mmol) were added to the solution. The mixture was stirred for 48 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in EtOAc (20 mL). The solution was washed with saturated NaOH and saline. The combined organic layers were dried, concentrated to 2 ml of solution and ESO (20 ml) was added to the residue. The solid phase was collected by centrifugation and converted into its NSI salt (7 mg, 51 965).56 1.09 (5, 9H), 2.19 (5, ЗН), 3.1-2-3.22 (t, 4H), 3.56-3.60 (t, 2H), 3.69-3.74 (t, 2H), 3.81 (bg, 2H), 4.12 (Bg, 2H), 6.80 (Bg, 1H), 6.88 (Bg, 1H), 6.96 (Bg, 1H), 7.16 (Bg, 1H), 7.57 (Bg, 1H), 7.60 (5, 1H) , 7.69 (y, 9-7.68 Hz, 1H), 7.94 (Bg, ЗН), 9.94 (5, 1H), 10.49 (5, 1H). M5 (Ebzh): t/2 540 (MAN).

Example 189. /Me-(4-(1H-Pyrazol-1-yl)uphenyl-M-3-tert-butylphenyl)-5-methylpyrimidine-2,4-diamine (compound CXXX): a, F; and with -

M M

N. хХХ

A mixture of intermediate 41 (580 mg, 2.1 mmol) apa 4-(1H-pyrazol-1-yl)/benzeneamine (335 mg, 2.1 mmol) was suspended in acetic acid (10 mL) and heated at 100 C for 4 hours. The mixture was then allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 mL) and neutralized to pH--7.

The resulting solution was extracted with EAs (30 ml) and the organic layer was separated.

The organic layer was washed with saline, dried over Mo5Ox and filtered. The filtrate was concentrated in vacuo and the crude product was purified by HRI C chromatography to give the title compound (31 mg, 4 95) as a yellow solid.

IN NMR (500 MHz, OM5O-av): 6 1.24 (5, 9H), 2.18 (5, ЗН), 6.53 (I, U-2.0 Hz, 1Н), 7.33( a, U-8.0 Gu, 1H), 7.38 (i, 9U-7.9 Hz, 1H), 7.44 (5, 1H), 7.47 (a, 9-8.2 Hz, 1H), 7.50 (a, 9U-8.9 Hz, 2H), 7.67 (a, 9-8.9 Hz, 2H), 7.73 (5, 1H), 7.95 (5, 1H), 8.43 (y, 9-2.4 Gu, 1H), 9.81 (bBrg 5, 1H), 10.67 (5, 1H). M5 (Eb-k): t/2 399 (M.N).

Example 190. MY-(7-Chloro-1H-indol-4-yl)-5-methyl-M2-(4-((piperazin-1-yl)umethyl)phenyl)pyrimidin-2,4-diamine (compound CXXXI ): nm su, | IN

MN works

same day

M M

N . XXXI

Coo)

A mixture of intermediate 40 (150 mg, 0.37 mmol), 4-bromo-7-chloro-1H-indole (87 mg, 0.37 mmol), Raz(ava)z (38 mg, 0.04 mmol) , xanthophos (76 mg, 0.12 mmol) and cesium carbonate (521 mg, 1.6 mmol) were suspended in dioxane (50 mL) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was dissolved in NaCl (10 ml) and trifluoroacetic acid (2 ml) was added to the solution. The mixture was stirred for 4 hours at room temperature, after which 10 95

Mahon. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (10 ml x 2). The combined organic layers were dried (Ma25O4). The solvent was removed in vacuo. The residue was purified by NRI C chromatography to give the title compound (26 mg, 15 95) as a white solid.

NMR NMR (500 MHz, OM50O-av): 6 2.21 (in, 3H), 3.30 (bg, 4H), 3.50 (bg, 4H), 4.42 (rg, 2H), 6.91 (in, 1H), 7.11 (a, U-8.3 Hz, 1H), 7.40 (a, 9-7.5 Hz, 1H), 7.42 (i, U-2 .7 Hz, 1H), 7.70 (bg, 4H), 8.03 (5, 1H), 9.87 (Big, 1H), 9.95 (v, 1H), 10.64 (5, 1H ), 11.64 (5, 1H). M5 (Eb-): t/2 448 (M.H).

Example 191. My-(3-tert-butylphenyl)-5-methyl-M2-(4-(2-methyl-1H-imidazol-1-yl)uphenyl)pyrimidin-2,4-diamine (compound CXXXIII) : worthy

J

M M

N . ХХХХХХХХХХХХХХХ

A mixture of intermediate 41 (180 mg, 0.5 mmol) and 4-(2-methyl-1H-imidazol-1-yl)benzeneamine (113 mg, 0.65 mmol), Raz(aba)z (55 mg, 0 .06 mmol), xanthophos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and refluxed under an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by NRI C-chromatography to give the title compound (78 mg of NCI salt, 27 95), which was a white solid.

IN NMR (500 MHz, OM5O-av): 5 1.26 (5, 9H), 2.21 (5, ЗН), 2.50 (5, ЗН), 7.31-7.36 (t, 1Н ), 7.40 (i, 9U7.6 Hu, 1H), 7.44 (a, 9-8.9 Hz, 2H), 7.47 (a, 9-8.0 Hu, 2H), 7, 65 (a, 9U-8.9 Hz, 2H), 7.75 (y, 9-21 Hz, 1H), 7.79 (9, 9-21 Hz, 2H), 8.03 (5, 1H) , 10.02 (5, 1H), 11.26 (5, 1H). M5 (Eb-):t/2413(MaN)".

Example 192. 4-(4-Methyl-1H-imidazol-1-yl)benzolamine (intermediate 62):

M s ) died 62

To a solution of 1-fluoro-4-nitrobenzene (1.7 g, 12 mmol) in OME (100 ml) was added 4-methyl-1H-imidazole (0.82 g, 10 mmol) and K»CO3 (11 g, 80 mmol). The mixture was refluxed in an argon atmosphere for 20 hours. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with saline (100 mL x 2). The organic layer was dried and concentrated. The solid phase was dissolved in Men and

Z was bubbled with argon for 2 min., after which 10 95 Ra-S was added. Hydrogenation was completed after 4 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give the title compound (1.5 g, 87 95) as a brown solid.

Example 193. My-(3-tert-butylphenyl)-5-methyl-Me-(4-(4-methyl-1H-imidazol-1-yl)/phenyl)pyrimidin-2,4-diamine (compound CHXXIII):

-, g and S. Y

J

M M

N . ХХХХХХХХХХХХХХХ

A mixture of intermediate 41 (318 mg, 1.15 mmol), intermediate 62 (200 mg, 1.15 mmol), Raz(ava)z (92 mg, 0.1 mmol), xanthophos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 ml) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title compound (66 mg of the NCI salt, 20 95), which was a white solid, "H NMR (500 MHz, OM50-av): 6 1.26 (5.9Н ), 2.19 (5, ЗН), 2.36 (5, ЗН), 7.30 (а, 9-7.9 Hz, 1Н), 7.А1 (а, 9-7.9 Hz, 1Н ), 7.44 (I, 90-1.8 Hu, 1H), 7.54 (a, 90-7.9 Hu, 1H), 7.59 (a, 9-9.0 Hu, 2H), 7.68 (a, 9U-9.0 Hz, 2H), 7.94 (5, 1H), 7.99 (5, 1H), 9.53 (j, U --1.3 Hz, 1H) , 9.72 (horn 5, 1H), 10.81 (Bg 5, 1H). M5 (Eb-yu): t/2 413 (MAN):

Example 194. Tert-butyl-4-(4-aminophenyl|piperidine-1-carboxylate (intermediate 63): pom 63

To a solution of 4-(4-nitrophenyl)piperidine (412 mg, 2 mmol) in CH2Cl3 (100 mL) was added di-tert-butyl carbonate (480 mg, 2.2 mmol) and M,M-dimethylpyridin-4-amine ( 50 mg, 0.4 mmol). The mixture was stirred for 20 hours at room temperature. To the mixture was added a saturated solution of Manso»z (100 ml). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (50 ml x 2). The combined organic solution was dried and concentrated in vacuo. The residue was dissolved in Maine and bubbled with argon for 2 min., after which 10 95

Ra-sS. Hydrogenation was completed after 4 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to afford the title compound (460 mg, 83 95) as a white solid.

Example 195. M'-(3-Tert-butylphenyl)-5-methyl-M2-(4-(piperidin-4-yl)uphenyl)pyrimidin-2,4-diamine (compound CXXXIM): -Щ,, МН нд

J

M M

N . ХХХИМ

Zo

A mixture of intermediate 41 (170 mg, 0.6 mmol) and intermediate 63 (170 mg, 0.6 mmol) was suspended in acetic acid (10 mL) and heated at 100 °C for 4 h.

After that, the mixture was allowed to cool to room temperature, and acetic acid was removed from it under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH-7. The resulting solution was extracted with EOAc (30 ml) and the organic layer was separated. Next, the organic layer was washed with saline, dried over Mo93O and filtered. The filtrate was concentrated in vacuo and the crude product was purified by HRI C chromatography to afford the title compound (8 mg, C 95) as a white solid.

IN NMR (500 MHz, OM50-av): 6 1.26 (5, 9H), 1.76-1.88 (t, 4H), 2.17 (5, ЗН), 2.76-2.81 (t, 1H), 2.93-3.00 (t, 2H), 3.36-3.40 (t, 2H), 7.07 (a, 9-8.5 Hz, 1H), 7, 30-7.36 (t, 4H), 7.44 (5, 1H), 7.46 (a, 3U-8.7 Hz, 1H), 7.91 (5, 1H), 8.84 (Bg 5, 1H), 8.92 (Bg 5, 1H), 9.73 (5, 1H), 10.45 (5, 1H). MO(E5-):t/2

A16(MN)x.

Example 196. M'-(3-Tert-butylphenyl)-5-methyl-M2-(4-(1-morpholineethyl)phenyl)pyrimidine-2,4-diamine (compound CXXXM): -,,

Still GT

And about

M M

N. СХХХМ

A mixture of intermediate 41 (276 mg, 1.0 mmol) and 4-(1-morpholineethyl)benzeneamine (210 mg, 1.0 mmol), Rag(abba)z (92 mg, 0.1 mmol), xanthophos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and refluxed in an argon atmosphere for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title compound (17 mg NOSI salt, 4 95), which was a yellow solid.

NMR NMR (500 MHz, OM5O-av): 5 1.26 (5, 9H), 1.66 (a, U-6.8 Hz, ZN), 2.19 (5, ZN), 2, 79 (g, 2H), 2.92 (BI, 1H), 3.61-3.64 (t, 2H), 3.7 7-3.82 (t, 2H), 3.94-3.99 (t, 2H), 7.32 (0, 97.8 Hz, 1H), 7.42 (y, 9U1.9 Hu, 1H), 7.43 (y, 9-7.8 Hu, 1), 7.46-7.52 (t, 5H), 7.97 (5, 1H), 9.86 (5, 1H), 10.78 (5, 1H), 11.72 (Bg 5, 1H). M5 (EbBzh): t/2 446 (MAN).

Example 197. 5-Bromo-2-methylbenzenesulfonyl chloride (intermediate product 64): si xx v Vg 7 oo . 64

The bromide (1.99 g, 11.61 mmol) was stirred vigorously and mixed with chlorosulfonic acid (1.55 mL, 23.22 mmol). Upon completion of the addition, the resulting red syrup was heated at

From a temperature of 60 C. After 10 min. Ti C-chromatography showed the absence of starting material, and the reaction was quenched by pouring the mixture onto ice. The reaction product was extracted by washing with EOAc (2x150 ml). The organic phase was dried over Mag25O4, filtered and evaporated to a yellow oil (2.2 g, 70 Fo).

Example 198. 5-Bromo-2M-dimethylbenzenesulfonamide (intermediate product 65): vera ry Vg o o . 85

A stirred suspension of intermediate 64 (0.43 g, 1.58 mmol) in OSM (5 mL) was treated with a 2.0 M solution of methylamine in TNE (2.4 mL, 4.8 mmol). After 16 hours of reaction, the solvents were removed, and the resulting residue was diluted with EtOAc (150 mL) and washed with water. The organic phase was dried over Mag250O54, filtered and evaporated to give the product as a white solid (0.37 g, 89 9).

Example 199. 2M-Dimethyl-5-/5-methyl-2-I(4-(2-pyrrolidin-1-ylethoxy)phenylamino|pyrimidin-4-ylaminobenzenesulfonamide (compound СХХХМИ): ve uk x MH (c) (c ) about ra

M M

N . ХХХМІ

A mixture of intermediate 65 (0.14 g, 0.52 mmol), intermediate 38 (0.14 g, 0.43 mmol), Raz(abba)z (0.040 g, 0.043 mmol), xanthophos (0.050 g, 0.087 mmol) and cesium carbonate (0.43 g, 1.3 mmol) were suspended in dioxane (10 ml), hermetically closed in a microwave reaction tube and heated with microwave radiation at a temperature of 160 °C for a minute. After that, the reaction mixture was cooled to room temperature and centrifuged. The reaction mixture was decanted and the organic phase was concentrated in vacuo. The residue was purified by HRI C chromatography to afford the title compound as a white solid (0.052 g, 24 b).

NMR NMR (500 MHz, OM50O-av): 6 1.66-1.70 (t, 4H), 2.08 (5, ЗН), 2.43 (а, 9У-4.9 Hz, ЗН ), 2.5 (Bg 5,

AN), 2.78, (Y, 95.7 Gy), 4.00 (1, 9-5.9 GP), 6.79 (a, 9U-9.0 Hz, 2H), 7.31 ( y, 9-9.7 Hz, 1H), 7.42 (4, 9-9.8 Hz, 1H), 7.49 (a, 9-9.0 Gu, 1H), 7.87 (5, 1H), 7.97 (a, 9U-2.3 Hu, 1H), 8.07-8.09 (t, 1H), 8.49 (v, 1H), 8.75 (5, 1H). M5 (Eb-k): t/2 497 (MAN).

Example 200. 5-Bromo-M-tert-butyl-2-methylbenzenesulfonamide (intermediate product 66): 1 - p yx y (c) (c) . 66

A stirred suspension of intermediate 64 (1.22 g, 4.5 mmol) in OCM (25 mL) was mixed with tert-butylamine (1.4 mL, 13.6 mmol). After 16 hours of reaction, the solvents were removed, and the resulting solids were ground into a powder with water. The resulting solid was dried under vacuum overnight (1.3 g, 94 9b).

Example 201. M-Tert-butyl-5-(2-chloro-5-methylpyrimidin-4-ylamino)-2-methylbenzenesulfonamide (intermediate 67):

Co., Ltd. ve - r MN (c) (c)

OM xx H

M SI 67

A mixture of intermediate 66 (0.90 g, 2.96 mmol), 2-chloro-5-methylpyrimidin-4-ylamine (0.33 g, 2.28 mmol), Rag(ava)z (0.21 g, 0.23 mmol), xanthphos (0.264 g, 0.46 mmol) and cesium carbonate (22 g, 6.8 mmol) were suspended in dioxane (15 mL), sealed in a microwave reaction tube and heated with microwave radiation at a temperature of 160 " With during

15 min. After that, the reaction mixture was cooled to room temperature and spun in a centrifuge. The reaction mixture was decanted and the organic phase was concentrated in vacuo. The residue was purified on a silica gel column to give the title compound as a white solid (0.12 g, 14 Vol).

Example 202 M-tert-butyl-5-(2-(4-imidazol-1-yl-phenylamino)-5-methylpyrimidin-4-ylamino|-2-methylbenzenesulfonamide (compound CHXXMHII): - and re MH g (c) (in)

M m

M cha XX

M M

N . ХХХМІ

A mixture of intermediate 67 (0.113 g, 0.31 mmol), 4-imidazol-1-yl-phenylamine (0.059 g, 0.37 mmol), Raz(ava)z (0.028 g, 0.03 mmol), xanthophos ( 0.036 g, 0.06 mmol and cesium carbonate (0.3 g, 0.92 mmol) were suspended in dioxane (b ml), hermetically closed in a microwave reaction tube and heated with microwave radiation at a temperature of 160 "C for 15 min.

The reaction mixture was decanted and the organic phase was concentrated in vacuo. The residue was purified by NRI C-chromatography to give the title compound as a white solid (0.052 g, 24 Vol).

NMR NMR (500 MHz, OM5O-av): 6 1.11 (5, 9H), 2.13 (5, ЗН), 2.58 (5, ЗН), 7.07 (5, 1Н), 7.34 (y, 3-8.5 Hz, 1H), 7.42 (a, U-8.9 Hz, 2H), 7.48 (5, 1H), 7.60 (5, 1H), 7.78 (y, 9-8.9 Hz, 2H), 7.94 (5, 1H), 7.98-8.00 (t, 1H), 8.09 (v, 1H), 8.12 (y, 9-2.3 Hu, 1H), 8.56 (5, 1H), 9.16 (5, 1H). M5 (Eb-): t/2 492(МН)".

Example 203. M-Tert-butyl-3-yl5-methyl-2-(4-(pyrrolidine-1-carbonyl)phenylamino|pyrimidin-4-ylaminophenzolsulfonamide (compound CHXXMI!): -- and rec MH o (c) ( c) hu Kh

M M

N . ХХХМИЙ

A mixture of intermediate 33 (0.11 g, 0.32 mmol), (4-aminophenyl)pyrrolidin-1-yl-methanone (0.072 g, 0.38 mmol), Rag(ara)z (0.029 g, 0.032 mmol) , xanthophos (0.037 g, 0.063 mmol) and cesium carbonate (0.3 g, 0.95 mmol) were suspended in dioxane (b ml), sealed in a microwave reaction tube and heated with microwave radiation at a temperature

From 160 "C for 15 min. The reaction mixture was decanted, and the organic phase was concentrated in a vacuum.

The residue was purified by HRIS chromatography to give the title compound as a white solid (0.040 g, 25 g).

NMR NMR (500 MHz, OM5O-av): 5 1.11 (5, 9H), 1.8 (Brg 5, 4H), 2.14 (5, ЗН), 3.44 (I, 92- 66 Hu, 4H), 7.38 (9, 9-9.0 Hz, 2H), 7.52-7.54 (t, 2H), 7.56 (5, 1H), 7.70 (y, 9-9.68 Hz, 2H), 7.98 (5, 1H), 8.08-8.10 (t, 2H), 8.60 (Brg 5, 1H), 9.24 (5, 1H) M5 (Eb-k): t/2 509.

Example 204. M-Tert-butyl-3-(5-methyl-2-I(I4-(morpholine-4-carbonyl)phenylamino|pyrimidin-4-ylaminobenzenesulfonamide) (compound CXXXIX):

- y re MN o (c) (c) ve FI

M M

N . ХХХХ

A mixture of intermediate 33 (0.13 g, 0.37 mmol), (4-aminophenyl)-morpholin-4-yl-methanone (0.092 g, 0.45 mmol), Rag(ara)z (0.034 g, 0.037 mmol ), xanthophos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) were suspended in dioxane (b ml), hermetically closed in a microwave reaction tube and heated with microwave radiation at a temperature of 160 "C for 15 min The reaction mixture was decanted and the organic phase was concentrated in vacuo.

The residue was purified by HRIS chromatography to give the title compound as a white solid (0.065 g, 33 Vol).

IN NMR (500 MHz, OM5O-av): 6 1.11 (5, 9H), 2.14 (5, ЗН), 3.49 (corner 5, 4Н), 3.59 (corner 5, 4Н), 5.75 (5, 1H), 7.25 (9, 9-9.0 Hz, 2H), 7.52-7.54 (t, 2H), 7.56 (5, 1H), 7.71 (9, 99.0 Hz, 2H), 7.98 (5, 1H), 8.06-8.08 (t, 2H), 8.65 (rg 5, 1H), 9.26 (5, 1H ). M5 (Eb-): t/2 525 (MANU.

Example 205. M-Tert-butyl-3-(5-methyl-2-(4-(piperazine-1-carbonyl)phenylamino|pyrimidin-4-ylaminophenzolsulfonamide (compound CX): - rai 78X MH o (c) (c )

Om le ho De Ii. days

M M

N Hee.

A mixture of intermediate 33 (0.12 g, 0.33 mmol), 4-(4-aminobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.45 mmol), Rag(aba)z (0.030 g, 0.037 mmol), xanthophos (0.038 g, 0.075 mmol) and cesium carbonate (0.33 g, 1.1 mmol) were suspended in dioxane (b ml), sealed in a microwave reaction tube and heated with microwave radiation at a temperature 160 "C for 15 min. The reaction mixture was decanted, and the organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (25 956-100 95 EAs in hexane). Next, the product was treated with 20 ml of 20 95 TEA solution in OSM. After that solvents were removed by rotary evaporation.The remaining material was purified by HRIS chromatography to afford the title compound as a white solid (0.045 g, 26 b).

1H NMR (500 MHz, OM5O- av): δ 1.11 (5, 9H), 2.14 (5, ЗН), 2.82 (Lg 5, 4H), 3.48 (Bg 5, 4H), 7.24 (a, 99.0 Hu, 2H), 7.51-7.53 (t, 2H), 7.55 (5, 1H), 7.71 (j, 9U-9.0 Hu, 2H), 7.94 (5, 1H), 8.06-8.08 (t, 2H),

Koo) 8.65 (horn 5, 1H), 9.25 (5, 1H). M5 (Eb-): t/2 524 (MAN).

Example 206. Tert-butyl-4-(4-(4-(3-methoxyphenylamino)-o-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-carboxylate (intermediate 68):

OA c) but so

And

M M "vVos

N . 88

A mixture of 1-bromo-3Z-methoxybenzene (69.5 μL, 0.56 mmol), intermediate 42 (205 mg, 0.51 mmol), Raz(ava)z (23 mg, 0.03 mmol), xanthophos ( 33 mg, 0.06 mmol) and cesium carbonate (359 mg, 1.10 mmol) in dioxane (3 ml) were heated by microwave radiation at a temperature of 160 "C for 20 min. After that, the reaction mixture was cooled to room temperature, filtered, and the filtrate was washed with OSM and Meon The combined liquids were concentrated in vacuo and purified by gradient flash chromatography (0-100 90 ethyl acetate in hexane) to afford the title compound as a beige solid (215 mg, 83 ).

Example 207. 3-(2-(4-(Piperidin-4-yloxy)phenylamino)-5--methylpyrimidin-4-ylamino)phenol (compound СХ): but and МН (c)

M

Same MN

M M

N.shY

To a mixture of intermediate 68 (215 mg, 0.42 mmol) in OCM (4 mL) was added VGiz (120 mL, 1.27 mmol) and the mixture was stirred at room temperature for 64 h. The reaction was quenched by the addition of Meon and the mixture was concentrated in vacuo. The residue was purified by preparative method

NRI C-chromatography and the collected fractions were concentrated in vacuo to give the title salt of trifluoroacetic acid (116 mg, 56 95). The trifluoroacetic acid salt was taken from MeonN and passed through 5PE RI-HSOz MP-Kezip cartridges, concentrated in vacuo, triturated with ether and filtered to give the title compound as a white solid (31 mg, 69 95 recovery ).

IN NMR (500 MHz, OM5O-av): 6 1.51-1.60 (t, 2H), 1.90-1.98 (t, 2H), 2.07 (5, ЗН), 2.70 -2.78 (t, 2H), 3.02-3.09 (t, 2H), 4.28-4.36 (t, 1H), 6.48 (ad, 9U-8,1,2, 2 Hz, 1), 6.79 (a, 9-91 Hz, 2H), 7.06-7.11 (t, 2H), 7.16 (a, 9-8.5 Hz, 1H), 7 .57 (a, 7-91 Hz, 2H), 7.82 (5, 1H), 8.08 (5, 1H), 8.73 (5, 1H), 9.27 (Bg 5, 1H). M5 (EbBuzh): t/2 392 (MAN) ».

Example 208. (2-Chloro-5-methylpyrimidin-4-yl)(4-fluoro-3-methoxyphenyl)amine (intermediate 69):

XX

7 o MN

SHI

Zh zo M SI, 69

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (1.2 g, 8.1 mmol), 4-bromo-1-fluoro-2-methoxybenzene (1.8 g, 8.9 mmol), Raz (aba)z (0.74 g, 0.81 mmol), xanthophos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g, 24.2 mmol) were suspended in dioxane (60 mL) and refluxed in an argon atmosphere for 5 hours. After that, the reaction mixture was cooled to room temperature and diluted with USM (30 ml). Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give the title compound (0.3 g, 14 95) as a beige solid.

Example 209. My-(4-Fluoro-3-methoxyphenyl)-5-methyl-Me-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-diamine (compound CXI I):

Fi 7o MN (in) but et

UNTIL

M M

N ShP

A mixture of intermediate 69 (0.1 g, 0.37 mmol) and 4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.16 g, 0.75 mmol) was suspended in acetic acid (10 mL) and heated at at a temperature of 110 C for 16 hours. After that, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by NRI C-chromatography to give the title compound (0.03 g, 17 95) as green solid particles. "H NMR (500 MHz, OM5O-av): 5 1.88 (Bg 5, 2H), 2.0 (rg 5, 2H), 2.15 (5, ЗН), 3.08 (rg 5, 2H ), 3.55 (Run 5, 4H), 3.7 (5, ЗН), 4.32 (horn 5, 2H), 6.9 (a, 9-7.9 Hz, 2H), 7.13 (Bvg 5, 1H), 7.21-7.25 (t, 1H), 7.32-7.34 (t, ZH), 7.89 (5, 1H), 9.78 (horn 5, 1H ), 10.48 (rg 5, 1H), 10.92 (Big 5, 1H). M5 (Eb-k): t/2 438 (MaH)-.

Example 210. (2-Chloropyrimidin-4-yl)(3-methoxy-2-methylphenyl)amine (intermediate 70):

ZK

SHI

J

M with 70

A mixture of 3-methoxy-2-methylphenylamine (0.68 g, 5 mmol) and 2,4-dichloropyrimidine (0.74 g, 5 mmol) was suspended in ethyl alcohol (10 mL) and stirred at room temperature for 20 h. After that, the reaction mixture was diluted with UCS (50 ml), filtered and concentrated in vacuo. The residue was purified on a silica gel chromatography column to give the title compound (0.085 g, 7 9o) as yellow solids.

Example 211. M'-(3-Methoxy-2-methylphenyl)-Me2-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,A4-diamine (compound СХИ PI):

ZK, (c)

SI about

AND

M M

N SH

A mixture of intermediate 70 (0.08 g, 0.32 mmol) and 4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.13 g, 0.64 mmol) was suspended in acetic acid (10 mL) and heated at at a temperature of 80 C for 16 hours. After that, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by NRI C-chromatography, obtaining

From the title compound (0.03 g, 17 Fo) in the form of gray solid particles.

IN NMR (500 MHz, OM50O-av): 5 1.89 (rg 5, 2H), 2.0 (Bg 5, 4H), 3.08 (rg 5, 2H), 3.4 (Bg 5, 4H ), 3.54 (rg 5, AN), 3.83 (in, ZN), 4.91 (horn 5, 2H), 6.86 (Big 5, 2H), 6.97 (a, 9-81 Hz, 2H), 7.26 (I, 9-81 Hz, 1H),

7.34 (ri 5, 2H), 7.89 (v, 1H), 9.73 (horn 5, 1H), 10.62 (Bg 5, 2H), 11.01 (re 5, 1H). M5 (Eb-k): t/2 420 (MAN.

Example 212. Tert-butyl ester of 4-(4-acetylaminobenzenesulfonyl)piperidine-1-carboxylic acid (intermediate product 71): in! (c) h// min (c) re M o

M

M and o 7

A mixture of 4-(4-bromo-benzenesulfonyl)piperidine-1-carboxylic acid tert-butyl ester (4 g, 9.92 mmol), acetamide (0.88 g, 14.9 mmol), Raz(abva)z (0 .46 g, 0.49 mmol), xanthophos (0.56 g, 0.99 mmol) and cesium carbonate (9.7 g, 29.8 mmol) were suspended in dioxane (60 mL) and refluxed in an argon atmosphere for 4 hours. After that, the reaction mixture was cooled to room temperature and poured onto ice. The yellow solid particles formed were collected by filtration and dried. The crude product was purified by silica gel flash chromatography to afford the title compound as a beige solid (3.12 g, 82 Vol).

Example 213. Tert-butyl ester of 4-(4-aminobenzenesulfonyl)piperidine-1-carboxylic acid (intermediate product 72): in! (c) x// min nm My o'clock 72

A suspension of intermediate 71 (2.6 g, 6.7 mmol) was diluted with 60 ml of Claisen's alkali (Claisep) (88 g of KOH, dissolved in 63 ml of H2H0 and diluted with Meon to 250 ml) and heated at a temperature of 90 "С. For 2 hours, the reaction mixture was removed from the heating device, cooled to room temperature, and diluted with water (50 mL).The gray solids were collected by suction filtration, washed with water, and dried overnight (2.2 g, 97 rpm).

Example 214. M'-(4-Chloro-3-methoxyphenyl|-5-methyl-M2-(4-(piperidine-4-sulfonyl)phenyl|pyrimidine-2,4-diamine) (compound СХИ IM): 7о and МН o o "9

From 1

OM hu re MN

M M

N.ShyM

Zo

A mixture of intermediate 31 (0.14 g, 0.51 mmol), intermediate 72 (0.19 g, 0.56 mmol), Rag(ava)z (0.046 g, 0.051 mmol), xanthophos (0.59 g , 0.1 mmol) and cesium carbonate (0.5 g, 1.52 mmol) were suspended in dioxane (8 ml) and heated with microwave radiation at a temperature of 160 C for 15 min. After that, the reaction mixture was cooled to room temperature and spun in a centrifuge. Solvents were decanted and evaporated.

The resulting residue was purified by flash chromatography on silica gel to give

M-protected precursor of the title compound. These solid particles were mixed with 20 95 TEA in OSM solution and the mixture was immediately subjected to evaporation. The residue was dissolved in a minimal amount

KODAs and an excess of diethyl ether was added dropwise to the solution. The resulting light yellow powder was collected by filtration and dried (0.16 g, 55 95).

NMR NMR (500 MHz, OM50O-av): 5 1.61-1.69 (t, 2H), 1.98-2.01 (t, 2H), 2.16 (5, ЗН), 2 ,86 (ad, 9-12

Hu, 2H), 3.35 (a, U-12.6 Hz, 2H), 3.64 (ShK, 9U-11.7 Hu, 9U-3.8 Hz, 1H), 3.79 (5, ZN), 7.34 (aa, U-8.7 Hz, 92.0 Gu, 1H), 7.39-7.41 (t, 2H), 7.6 (a, 9-8.9 Hz, 2H), 7.91 (a, 9U-8.9 Hz, 2H), 8.02 (5, 1H), 8.19-8.21 (t, 1H), 8.6-8.63 (t , 1H), 8.89 (Bg 5, 1H). M5 (Eb-k): t/2488 (M.N).

Example 215. (4-Chloro-3-methylphenyl)(2-chloro-5-methylpyrimidin-4-yl)amine (intermediate 73):

In

MN

Ohm

Sh. Zh

M SI 73

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.34 g, 2.34 mmol), 4-bromo-1-chloro-2-methylbenzene (0.58 g, 2.8 mmol), Raz(ava ) with (0.21 g, 0.23 mmol), xanthophos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g, 7 mmol) were suspended in dioxane (9 ml) and heated by microwave radiation at at a temperature of 160 C for 20 min. After that, the reaction mixture was cooled to room temperature and spun in a centrifuge. Solvents were decanted and evaporated. The resulting residue was purified by flash chromatography on silica gel to give the title compound as a yellow solid (0.24 g, 38 95).

Example 216. M'-(4-Chloro-3-methylphenyl)-5-methyl-M2-(4-(piperidin-4-yloxy)phenyl|pyrimidine-2,A-diamine (compound CXI M):

In

MN

(in)

OM hu ra MN

M M

N.-sKHIM

A mixture of intermediate 73 (0.071 g, 0.27 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) was diluted with NOAS (5 mL) and heated microwave radiation at a temperature of 150 C for 15 min. After that, the solvents were removed, and the resulting residue was purified by HRI C-chromatography.

After separation, the title compound was obtained in the form of white solid particles (0.025 g, 22 Vol).

IN NMR (500 MHz, OM50O-av): 6 1.76-1.83 (t, 2H), 2.05-2.09 (t, 2H), 2.13 (5, ЗН), 2.27 (5, ZN), 3.10 (re 5, 2H), 3.16 (horn 5, 2H), 4.58-4.61 (t, 1H), 6.93 (a, 9-9 Hz, 2H), 7.34-7.39 (t, ЗН), 7.43-7.45 (t, 1H), 7.59 (in, 1H), 7.87 (5, 1H), 8.51 (Bi 5, 1H), 8.55 (ri 5, 1H), 9.38 (Big 5, 1H), 10.0 (rg 5, 1H). M5 (EB): t/2 424 (MAN):

Example 217. M-(3-Bromophenyl)acetamide (intermediate product 74):

Y u ra Vg n 74

A solution of 3-bromophenylamine (1.04 g, b mmol) was mixed with OIEA (2.3 ml, 13.3 mmol) and cooled to 0 °C. Acetyl chloride (0.47 ml, 6 .7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was then poured onto water and washed once. The organic phase was evaporated to give beige solids (1.25 g, 98 Vol).

Example 218. M-IZ3--2-Chloro-5-methylpyrimidin-4-ylamino)phenyl|Iacetamide (intermediate product 75):

Y g r MN

N

OHM

Shh Kh

M SI 75

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.71 g, 4.9 mmol), intermediate 74 (1.25 g, 5.9 mmol), Rag(ava)z (0.45 g, 0.49 mmol), xanthophos (0.57 g, 0.98 mmol) and cesium carbonate (4.8 g, 14.7 mmol) were suspended in dioxane (40 mL) and refluxed for 18 h. After that, the reaction mixture was cooled to room temperature, filtered and the solvents were evaporated. The resulting residue was purified by flash chromatography on silica gel to give the title compound as a white solid (0.44, 32 95).

Example 219. M-(3--5-Methyl-2-(4-(piperidin-4-yloxy)phenylamino|pyrimidin-4-ylamino)phenyl)acetamide (compound СХИ MI):

Y Fe ra MN

N

(in)

OHM

HU Where MN

M M

N. SHIMI

A mixture of intermediate 75 (0.074 g, 0.27 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) was diluted with SOAP (5 mL) and heated by microwave irradiation at a temperature of 150 "C for 15 min. After that, the solvents were removed, and the resulting residue was purified using HRI C-chromatography.

After separation, the title compound was obtained as white solid particles

From the color (0.072 g, 62 U).

IN NMR (500 MHz, OM50-av): 6 1.74-1.81 (t, 2H), 2.03-2.07 (t, 5H), 2.15 (5, ЗН), 3.09 (Bg 5, 2H), 3.24 (ri 5, 2H), 4.54-4.57 (t, 1H), 6.85 (y, 9-8.8 Hz, 2H), 7.22 ( y, 9-7.7 Hz, 2H), 7.29-7.39 (t,

AN), 7.77 (5, 1H), 7.687 (5, 1H), 8.55 (ri 5, 1H), 8.60 (rg 5, 1H), 9.67 (5, 1H), 10, 0 (Bg 5, 1H), 10.2 (horn 5, 1H). M5 (Eb-): t/2 433 (M.N).

Example 220. M-(3-Bromo-2-methylphenyl)acetamide (intermediate product 76):

І ІХ ra Vg

N

. 76

A solution of 3-bromo-2-methylphenylamine (4.1 g, 21.9 mmol) was mixed with OIEA (8.4 mL, 48 mmol) and cooled to 0 °C. Acetyl chloride (1.7 mL) was added dropwise using a syringe , 241 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was then poured into water and washed once. The organic phase was evaporated, leaving off-white solids. After trituration of this material in powder with hexane obtained the title compound in the form of white solid particles (4.4 g, 89 Vol).

Example 221. M-(3--2-Chloro-5-methylpyrimidin-4-ylamino)-2-methyl-phenyl|acetamide (intermediate product 77):

Khzh. / "MN

N

OHM

XX, X

M SI 77

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.86 g, 5.9 mmol), intermediate 76 (1.6 g, 7.1 mmol), Rah(ava)z (0.55 g, 0.59 mmol), xanthophos (0.69 g, 1.2 mmol) and cesium carbonate (5.8 g, 17.8 mmol) were suspended in dioxane (40 mL) and refluxed for 16 h. After that, the reaction mixture was cooled to room temperature, filtered and the solvents were evaporated. The resulting residue was purified by flash chromatography on silica gel to afford the title compound as a white solid (0.56 g, 32 g).

Example 222. M-(2-Methyl-3-(5-methyl-2-(4-(piperidin-4-yloxy)phenylamino|pyrimidin-4-ylamino)phenyl)acetamide (compound СХИ MI):

І ІХ ra MN

N

(in)

OM hu Where MN

M M

N. SHIMI

A mixture of intermediate 77 (0.15 g, 0.5 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.65 mmol) was diluted with HOAc (5 mL) and heated with microwave irradiation at a temperature of 150 C for 15 min. After that

Solvents were removed, and the resulting residue was purified by NRI C-chromatography.

After separation, the title compound was obtained as a white solid (0.091 g, 41 Urv).

NMR NMR (500 MHz, OM5O-av): 6 1.71-1.78 (t, 2H), 2.02-2.08 (t, 8H), 2.16 (5, ЗН), 3 .09 (Bg 5, 2H), 3.24 (rg 5, 2H), 4.50-4.52 (t, 1H), 6.77 (a, 9-8.4 Gu, 2H), 7, 09-7.15 (t, ZN), 7.27 (Ii, 97.9 Hz, 1H), 7.49 (0, 9-81 Gu, 1H), 7.86 (5, 1H), 8, 54 (horn 5, 1H), 8.59 (Big 5, 1H), 9.45 (5, 1H), 9.84 (horn 5, 1H), 10.34 (re 5, 1H). M5 (Eb -k): t/2 447 (M.N).

Example 223. 5-Methyl-M2-(4-(4-methylpiperazine-1-iluphenyl)-M--(3-nitrophenyl)pyrimidine-2,4-diamine (intermediate product 78): ож".

OHM

- H

M M

H 78

A mixture of 1-bromo-3-nitrobenzene (0.77 g, 3.8 mmol), intermediate 32 (0.95 g, 3.2 mmol),

Rag(ava)z (0.29 g, 0.32 mmol), xanthophos (0.37 g, 0.64 mmol) and cesium carbonate (3.1 g, 9.6 mmol) were suspended in dioxane (40 mL) and refluxed for 16 hours. After that, the reaction mixture was cooled to room temperature, filtered and the solvents were evaporated. The resulting residue was purified by flash chromatography on silica gel to afford the title compound as a white solid (0.53 g, 40 95).

Example 224. My-(3-Aminophenyl)-5-methyl-M2-(4-(4-methylpiperazin-1-yl)phenyl|pyrimidin-2,4-diamine (intermediate 79):

ON "I'm sorry

Om vh re

M M

H 79

A suspension of intermediate 78 (0.23 g, 0.54 mmol) in MeOH (25 mL) was purged with argon and mixed with Ra/C 10 95 (wt) (0.18 g). The normal atmosphere of the reaction mixture was replaced by hydrogen and stirred for 4 h. After that, the balloon hydrogen was removed, the reaction mixture was purged with argon, and then filtered through celite. The solvents were evaporated to leave a pale brown solid (0.17 g, 83 9).

Example 225. 1-(3--5-Methyl-2-(4-(4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylamino)phenyl)-3-phenylurea (compound СХИ MI): va MH I

N N

IN

OHM

XX X

M M

Н СХ M

A suspension of intermediate 79 (0.17 g, 0.45 mmol) in OCM (10 mL) was mixed with phenyl isocyanate (0.058 mL, 0.54 mmol) and stirred for 1 h. After that with

Solvents were removed from the reaction mixture, and the resulting residue was purified by NRI C-

chromatography, obtaining the title compound in the form of white solid particles (0.075 g, 33 Ov).

IN NMR (500 MHz, OM50-av): 6 2.09 (5, ZN), 2.15 (5, ZN), 2.30-2.32 (t, AN), 2.92-2.94 (t, 4H), 6.74 (a, 9-8.4 Hz, 2H), 6.94-6.97 (t, 1H), 7.19-7.28 (t, 5H), 7, 45 (a, U-8.8 Hz, 2H), 7.53 (a, 9-9.0 Hz, 2H), 7.73 (Bbg 5, 1H), 7.83 (5, 1H), 8 .23 (5, 1H), 8.68 (5, 1H), 8.74 (5, 1H), 8.78 (5, 1H). M5 (Ebzh): t/2 509 (M.N).

Example 226. 1-(3--5-Methyl-2-(4-(4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylamino)phenyl)-3-(3-trifluoromethylphenyl)urea (compound CX IX): ovo

ES Zh, MN me

N N I don't know

Oh I am H

М M y -СХХХx

A suspension of intermediate 79 (0.1 g, 0.26 mmol) in OCM (8 mL) was mixed with 1-isocyanate-3-trifluoromethylbenzene (0.043 mL, 0.31 mmol) and stirred for 1 h. After that, the solvents were removed from the reaction mixture, and the resulting residue was purified by HPLC chromatography to give the title compound as a white solid (0.039 g, 26 Vol).

IN NMR (500 MHz, OM5O- av): 6 2.16 (5, ЗН), 2.82 (5, ЗН), 2.86 (Bg 5, 2Н), 3.08 (Bg 5, 2Н) , 3.42 (Bg 5, 2H), 3.69 (rg 5, 2H), 6.88 (y, 9U-8.4 Hz, 2H), 7.20 (Bg 5, 1H), 7.29 -7.33 (t, 5H), 7.52 (I, 9-7.9 Hz, 1H), 7.57 (9, 9-8.5 Hz, 1H), 7.77 (5, 1H) , 7.84 (5, 1H), 8.09 (5, 1H), 9.42 (5, 1H), 9.66 (5, 1H), 9.71 (Bi 5,1H), 101 (bg 5, 1H). M5 (EB): t/2 577 (MAN):

Example 221. (2-Chloro-5-methylpyrimidin-4-yl)(2-methyl-3-trifluoromethylphenyl)amine (intermediate 80):

Es U "MN ie chi

MC 80

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.18 g, 5.9 mmol), 1-bromo-2-methyl-3-trifluoromethylbenzene (0.33 g, 1.4 mmol), Rag(ava ) with (0.12 g, 0.13 mmol), xanthophos (0.15 g, 0.25 mmol) and cesium carbonate (1.23 g, 3.8 mmol) were suspended in dioxane (8 mL) and heated in a microwave radiation at a temperature of 160 "C for 18 min. After that

The reaction vessel was spun in a centrifuge and decanted. The solvents were evaporated and the resulting precipitate was purified by flash chromatography on silica gel to afford the title compound as a white solid (0.095 g, 25 95).

Example 228. 5-Methyl-M"-(2-methyl-3-trifluoromethylphenyl)-M2-(4-(piperidin-4-yloxy)phenyl|pyrimidine-2,4-diamine (compound SI): "A, ( o) pastures

M M

N "S

A mixture of intermediate 80 (0.058 g, 0.2 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.073 g, 0.25 mmol) was diluted with HOASc (5 mL) and heated with microwave radiation at a temperature of 150 "C for 15 min. After that, the solvents were removed, and the resulting residue was purified using NRI C-chromatography.

After separation, the title compound was obtained as white solid particles (0.025 g, 30 Urv).

NMR NMR (500 MHz, OM50-av): 6 1.71-1.78 (t, 2H), 2.00-2.04 (t, 2H), 2.18 (5, ЗН), 2 .25 (5, ZN), 3.08 (horn 5, 2H), 3.22 (ri 5, 2H), 4.50-4.52 (t, 1H), 6.70 (a, 9-8 .3 Hz, 2H), 7.10 (a, 9-8.9 Hz, 2H), 7.54 (y, 9U-7.8, 1H), 7.62 (y, 97.7 Hz, 1H ), 7.75 (a, 957.8 Hz, 1H), 7.91 (5, 1H), 8.54 (rg 5, 1H), 8.61 (Bri 5, 1H), 9.88 (5 , 1H), 10.34 (Bg 5, 1H). M5 (Eb-k): t/2 458 (MAN).

Example 229. (3-Bromophenyl)pyrrolidin-1-yl-methanone (intermediate 81): sg

Vg o Vi

A solution of 3-bromobenzoyl chloride (2.7 g, 12 mmol) in OCM (40 mL) was cooled to 0 °C and mixed with pyrrolidine (3 mL, 36.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h After that, the mixture was poured into water and washed once.

The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give an amber oil (3.1 g, 100 Vol).

Example 230. 13-(2-Chloro-5-methylpyrimidin-4-ylamino)phenyl|pyrrolidin-1-ylmethanone (intermediate product 82): c "K (c)

OHM

Fi

M SI V?

A mixture of 2-chloro-5-methylpyrimidin-4-ylamine (0.22 g, 1.5 mmol), intermediate 81 (0.46 g, 1.8 mmol), Raz(ava)z (0.14 g, 0.15 mmol), xanthophos (0.17 g, 0.3 mmol) and cesium carbonate (1.5 g, 4.5 mmol) were suspended in dioxane (8 ml) and heated with microwave radiation at a temperature of 160 "C for 18 min. After that, the reaction vessel was rotated on a centrifuge and

They decanted. The solvents were evaporated and the precipitate was purified by flash chromatography on silica gel to afford the title compound as a white solid (0.25 g, 53 95).

Example 231. (3--5-Methyl-2-(4-(piperidin-4-yloxy)phenylamino|pyrimidin-4-ylamino)phenyl)pyrrolidin-1-yl-methanone (compound SI I): c 59e (in ) (c)

TM

M M

You are

A mixture of intermediate 82 (0.1 g, 0.32 mmol) and 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) was diluted with HOAc (6 mL) and heated with microwave radiation at a temperature of 150 "C for 15 min. After that, the solvents were removed, and the resulting residue was purified using HRI C-chromatography.

After separation, the title compound was obtained as white solid particles (0.005 g, C Y).

1H NMR (500 MHz, OM5O-av): 6 1.74-1.81 (t, 4H), 1.83-1.88 (t, 2H), 2.05-2.09 (t, 2H), 2.16 (in,

ZN), 2.25 (5, ZN), 3.25 (horn 5, 2H), 3.34 (I, 9-6.5 Hz, 2H), 3.46 (I, U-6.9 Hz , 2H), 4.45-4.59 (t, 1H), 6.91 (a, 9-8.8 Hz, 2H), 7.32 (a, 9-8.9 Hz, 2H), 7 .36 (y, 9U-7.7 Hu, 1H), 7.43 (1, 2-7.8, 1H), 7.67 (a, 9-7.9 Hu, 1H), 7.70 ( 5, 1H), 7.89 (in, 1H), 8.50 (Brg 5, 1H), 8.56 (horn 5, 1H), 9.64 (Big 5, 1H), 10.21 (Bg 5 , 1H). M5 (EB): t/2 473 (MAN):

Example 232. 3-Bromo-M-isopropylbenzamide (intermediate 83): nH

Mt "KA, o - 83

A solution of 3-bromobenzoyl chloride (0.83 g, 3.86 mmol) in SOCM (40 mL) was cooled to 0 s and mixed with isopropylamine (0.96 mL, 11.32 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. After that, the mixture was poured into water and washed once. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give the product as white solid particles (0.6 g, 66 95).

Example 233. M-Isopropyl-3-yl5-methyl-2-(4-4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-ylamino|benzamide (compound SI PI):

M t MN ki o schu

Ohm

S Kh

M M and "SP

A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 83 (0.13 g, 0.54 mmol), Raz(aba)z (0.031 g, 0.034 mmol), xanthophos (0.039 g, 0.067 mmol) and cesium carbonate

Zo (0.33 g, 1 mmol) was suspended in dioxane (8 ml) and heated with microwave radiation at a temperature of 160 "C for 15 min. After that, the reaction vessel was spun in a centrifuge and decanted. The solvents were evaporated, and the precipitate formed was purified by NRI C -chromatography, resulting in the title compound in the form of white solid particles (0.011 g, 7 Vol).

NMR NMR (500 MHz, OM5Oav): 6 1.14 (a, 9U-6.7 Hz, 6H), 2.16 (5, 4H), 2.87 (5, 4H), 3.10 ( Bbg 5, 2H), 3.51 (5, 2H), 4.22 (t, 1H), 6.85 (y, 9-8.8 Hz, 2H), 7.30-7.32 (t, 2H), 7.45 (I, 9-7.8 Hz, 1H), 7.69-7.70 (t, 2H), 7.90 (5, 1H), 7.99 (in, 1H), 8.24 (a, 9-7.7 Hz, 1H), 9.70 (Bg 5, 1H), 9.94 (horn 5, 1H), 10.2 (Bri 5, 1H). M5(B5- ): t/2 460 (M.N).

Example 234. 3-Bromo-M-tert-butylbenzamide (intermediate 84): nn

M re "KA, shchi . 84

A solution of 3-bromobenzoyl chloride (0.83 g, 3.86 mmol) in OCM (10 mL) was cooled to 0°C and mixed with tert-butylamine (1.2 mL, 11.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. After that, the mixture was poured into water and washed once. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give an amber oil (0.9 g, 94 Vol).

Example 235. M-Tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)-phenylamino|pyrimidin-4-ylamino)benzamide (compound SI):

Mas MN Ya o schu

OHM

Phi HU

M M

N "SO

A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 84 (0.1 g, 0.4 mmol),

Rag(ava)z (0.031 g, 0.034 mmol), xanthophos (0.039 g, 0.067 mmol) and cesium carbonate (0.33 g, 1 mmol) were suspended in dioxane (8 ml) and heated with microwave radiation at a temperature of 160 "C for 15 min. The reaction vessel was then centrifuged and decanted. The solvents were evaporated and the precipitate was purified by HRIS chromatography to afford the title compound as a white solid (0.055 g, 35 95).

NMR NMR (500 MHz, OM5O-av): 6 1.36 (5, 9H), 2.09 (5, ЗН), 2.21 (5, ЗН), 2.43 (I, 2-28 Hz, 4H), 3.00 (I, 9-2.8 Hu, 4H), 6.74 (a, 9-91 Hu, 2H), 7.35 (I, 9-7.9 Hz, 1H) , 7.44-7.48 (t, ЗН), 7.67 (5, 1Н), 7.85 (5, 1Н), 7.88-7.92 (t, 2Н), 8.36 (5 , 1H), 8.74 (5, 1H). M5 (Ebzh): t/2 474 (MANU.

Example 236. 5-Methyl-M2-(4-(4-methylpiperazin-1-yl)-phenyl|-M"-(3-piperidin-4-yl-phenyl)pyrimidine-2,4-diamine (compound SG IM ): o. shchi

NM I'm sorry

OHM

Phi HU

M M

N SIM

A mixture of intermediate 32 (0.08 g, 0.27 mmol), 4-(3-bromophenyl)piperidine (0.084 g, 0.35 mmol), Raz(abba)z (0.025 g, 0.027 mmol), xanthophos (0.031 g, 0.054 mmol) and cesium carbonate (0.26 g, 0.81 mmol) were suspended in dioxane (8 ml) and heated with microwave radiation at a temperature of 160 "C for 15 min. After that, the reaction vessel was spun in a centrifuge and

They decanted. The solvents were evaporated and the resulting precipitate was purified by HRIS chromatography to afford the title compound as a white solid (0.007 g, 6 Vol).

NMR NMR (500 MHz, OM5O-av): 6 1.74-1.79 (t, ZN), 2.09 (5, ZN), 2.21 (5, ZN), 2.43 (I , 9-28 Gu,

AN), 3.00 (I, U-2.8 Hz, 4H), 6.76 (a, 9-91 Hz, 2H), 6.90 (y, 9-7.7 Hz, 1H), 7 .24 (1, 2-7.9 Hz, 1H), 7.47-7.53 (t, ЗН), 7.68 (9, 9-8.2 Hz, 1H), 7.82 (5, 1H), 8.18 (5, 1H), 8.67 (5, 1H). M5 (Eb-): t/2 458 (MAN.

Example 237. Benzyl ester of 4-(3-15-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino|pyrimidin-4-ylaminobenzenesulfonyl)piperidine-1-carboxylic acid (intermediate product 85):

(c) zhav Sh rai 28 MN g (c) (c) schu pashi

Sh, H

M M

H 85

A mixture of intermediate 32 (0.17 g, 0.58 mmol), 4-(3-bromobenzenesulfonyl)piperidine-1-carboxylic acid benzyl ester (0.28 g, 0.64 mmol), Raz(abba)z (0.053 g, 0.058 mmol), xanthophos (0.067 g, 0.12 mmol) and cesium carbonate (0.57 g, 1.74 mmol) were suspended in dioxane (8 ml) and heated with microwave radiation at a temperature of 160 "C for 15 min. After that, the reaction vessel was spun in a centrifuge and decanted on ice.

The remaining yellow solids were collected, dried and used without further purification (0.4 g, 100 Fo).

Example 238. 5-Methyl-M2-I4-(4-methylpiperazin-1-iluphenyl|-MU-I(3-(piperidine-4-sulfonyl)phenyl|pyrimidine-2,4-diamine) (compound SIM):

Fe Fe paradise river MN shE (c) (c) shchu

OHM

5 X

M M

N Sim

A stirred solution of intermediate 85 (0.17 g, 0.26 mmol) in OSM (15 mL) was mixed with 1 M VViz in OSM (2 mL, 2 mmol). After 4 hours, the reaction was quenched by the slow addition of MeOH (4 mL), after which the solvents were removed. The residue was purified by NRI C-chromatography to give the title compound as a purple powder (0.008 g, 6 Vol).

IN NMR (500 MHz, OM50O-av): 5 1.31-1.40 (t, 2H), 1.75 (a, 9U-10.8 Hz, 2H), 2.12 (5, ЗН), 2.21 (5,

ЗН), 2.36-2.А41 (t, 2Н), 2.44 (y, 90-4.9 Hz, 4Н), 2.95 (y, 9-12.5 Hz, 2Н), 3, 02 (u, 9U-4.9 Hz, 4H), 3.24 (H, u11.7 Hz, U3.8 Hu, 1H), 6.81 (9, 9-9.0 Hu, 2H), 7 .44 (t, ZN), 7.56 (I, 9-8.0 Hz, 1H), 7.90-7.91 (t, 2H), 8.49 (0.9-7.6 Hz, 1H), 8.60 (5, 1H), 8.74 (5, 1H). M5 (Ebuzh): t/2 522 (MAN).

Example 239. Tert-butyl-4-(4-(4-(1H-indol-4-ylamino)-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-carboxylate (intermediate 86): bu

MN

(in)

BU no di

M M i z h o . 86

A mixture of 4-bromo-1H-indole (41 μl, 0.33 mmol), intermediate 42 (131 mg, 0.33 mmol),

Rag(ava)z (30 mg, 0.03 mmol), xanthophos (60 mg, 0.10 mmol) and cesium carbonate (428 mg, 1.31 mmol) in dioxane (3 ml) were heated with microwave radiation at a temperature of 160 " s for 20 min. After that, the reaction mixture was cooled to room temperature and filtered, rinsing with 100 mL of SOHC. The filtrate was concentrated and purified by gradient flash chromatography (0-15 96 MeoN in SOHC) to afford the title compound as a solid white (30 mg, 17 95).

Example 240. MA(1H-Indol-4-yl)-5-methyl-Me-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (compound SI MI): chi

MN

(in)

M no Dt FI

M M

N SIM

A mixture of intermediate 86 (27 mg, 0.05 mmol) in 30 96 TEA/USM (1 mL) was stirred for 3 hours. The reaction mixture was concentrated in vacuo and purified by preparative methods

NRI C-chromatography. The resulting fractions were concentrated in vacuo to give the title trifluoroacetic acid salt as a yellow-brown solid (11 mg, 43 Vol).

IN NMR (500 MHz, OM5O-av): 6 1.71-1.77 (t, 2H), 1.98-2.06 (t, 2H), 2.22 (5, ЗН), 3.03 -3.12 (t, 2H), 3.19-3.27 (t, 2H), 4.44-4.53 (t, 1H), 6.34-6.37 (t, 1H), 6 .64 (Bg yes, U-8.3 Hz, 2H), 7.08 (i, 9-72

Hz, ZN), 7.14 (1, 9-7.8 Hz, 1H), 7.36 (i, U-2.7 Hz, 1H), 7.39 (a, 9-81 Hz, 1H) , 7.84 (5, 1H), 8.48 (bg 5, 1H), 8.55 (ry 5, 1H), 9.85 (horn 5, 1H), 9.98 (ry 5, 1H), 11.27 (5, 1H).

Example 241, 2-Chloro-M-12-I4-(2-pyrrolidin-1-ylethoxy)phenylamino|pyrimidin-5-yl)-5-(3-trifluoromethylbenzoylamino)benzamide (compound SI MI):

Wow

M. iy

MN

(c) not o

S, Kh

M M

N "SIM

A mixture of 3-bromopyridine (379 mg, 2.4 mmol), 4-amino-2-chloro-5-methylpyrimidine (287 mg, 2.0 mmol), Raz(ava)z (18 mg, 0.02 mmol) , xanthophos (23 mg, 0.04 mmol) and cesium carbonate (975 mg, 3.0 mmol) in dioxane (15 mL) were refluxed for 1 hour in

From an argon atmosphere. The solvent was removed and the residue was purified by HRIS chromatography to give the intermediate, 2-chloro-5-methyl-N-(pyridin-3-yl)/pyrimidin-4-amine, as a yellow solid (252 mg, 57 95). In the second part of the experiment, a mixture of 2-chloro-5-methyl-N-(pyridin-3-yl)/pyrimidin-4-amine (80 mg, 0.36 mmol), 4-(2-(pyrrolidin-1-yl) ethoxy)benzeneamine (74 mg, 0.34 mmol), Raz(adba)z (3.2 mg, 0.003 mmol), xanthophos (4.2 mg, 0.007 mmol) and cesium carbonate (234 mg, 0.72 mmol) in dioxane (5 ml) was refluxed for 1 hour in an argon atmosphere. Purification of the crude reaction mixture by NRI C-chromatography afforded the title compound as a light brown solid (28 mg, 20 Vol).

IN NMR (500 MHz, OM50O-av): 5 1.85-1.95 (t, 2H), 2.0-2.09 (t, 2H), 2.18 (5, ЗН), 3.09 -3.18 (t, 2H), 3.55-3.65 (t, 4H), 4.27 (ad, 9-5.2, 4.7 Hz, 2H), 6.94 (a, U -8.9 Hz, 2H), 7.35 (a, 9-8.9 Hz, 2H), 7.50 (yes, U-8.2,4.68 Hz, 1H), 7.92-7 .96 (t, 1H), 8.08-8.15 (t, 1H), 8.45 (ad, 9U-4.8, 1.4, 1H), 8.84, 9.75, 9, 85, 10,24 (4 rg 5, IN each). M5 (EbB w): t/2 329 (M.N).

Example 242. Me 4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-M-(3-(trifluoromethoxy)phenyl)pyrimidine-2,4-diamine (compound SI MI):

Es Fe

Hundred MN nora 5th her g M and;

S, Kh

M M

N "SM

A mixture of 1-bromo-3-(trifluoromethoxy)benzene (241 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Raz(ava)z (9 mg , 0.01 mmol), xanthophos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane (15 mL) was refluxed for 10 hours under an argon atmosphere. The solvent was removed and the residue was purified by

NRI C-chromatography, obtaining the intermediate product, 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine as a brown solid (260 mg, 85 90). A mixture of this intermediate (100 mg, 0.33 mmol) and 4-(2-(pyrrolidin-1-yl/ethoxy)benzeneamine (67 mg, 0.33 mmol) in glacial acetic acid (5 mL) was refluxed with under reflux for 3 hours under an argon atmosphere. Purification of this crude reaction mixture by NRI C chromatography afforded the title compound as a white solid (11

MG, 7 U).

IN NMR (500 MHz, OM50O-av): 5 1.65-1.72 (t, 4H), 2.11 (5, ЗН), 2.51-2.55 (t, 2Н, superimposed on the peak solvent), 2.75 (i, 95.9 Hz, 2H), 3.25-3.34 (t, 2H superimposed on the water peak), 3.99 (i, 9-5.9

Hz, 2H), 6.79 (a, U-8.9 Hz, 2H), 6.98 (a, 9U-8.0 Hz, 1H), 7.40 (aa, O-7.6, 7 .4 Gu, 1H), 7.50 (a, 9-8.9 Hz, 2H), 7.76 (Bg 5, 1H), 7.87 (a, U-8.4 1H), 7.90 , 8.31, 8.41, 8.84 (4 5, 1IN each). M5 (Ebzh): t/2 474 (MaAN)".

Example 243. Me-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-M-(4-chloro-3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine (compound SI IH): shko. MN (o) nF Ma i;

Shh Kh

M M

N sih

Zo

A mixture of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (259 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Raz(ava) of (9 mg, 0.01 mmol), xanthophos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane (15 mL) were refluxed for 10 h under atmosphere argon The solvent was removed and the residue was purified by

NRI C-chromatography, obtaining the intermediate product 2-chloro-M-(4-chloro-3-(trifluoromethyl)phenyl)-

B-methylpyrimidine-4-amine as a brown solid (200 mg, 62 95). A mixture of this intermediate (161 mg, 0.5 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzeneamine (103 mg, 0.5 mmol) in glacial acetic acid (5 mL) was refluxed with reflux for 3 hours in an argon atmosphere. Purification of this crude reaction mixture by HRIS chromatography afforded the title compound as a brown solid (75 mg, 31 b).

IN NMR (500 MHz, OM50O-av): 5 1.65-1.72 (t, 4H), 2.10 (5, ЗН), 2.51-2.55 (t, 4H, superimposed on the peak solvent), 2.75 (Yi, 9U-6.0 Hz, 2H), 4.0 (I, 2-5.9 Hz, 2H), 6.79 (a, 9U-8.5 Gu, 2H) , 7.47 (a, 9U-9.0

Hz, 2H), 7.58 (y, 9-9.0 Hz, 2H), 7.93 (5, 1H), 8.01 (y, 9U-2.5 Hz, 1H), 8.22 ( and, U-8.5 Hz, 2H), 8.60, 8.88 (2 5, IN each). M5 (Ebuzh): t/2 492 (M.N).

Example 244. Determination of the ISzo value for Chak2-kinase

The values of concentration of ISvo compounds were determined by their luminescence tests on kinases and, in particular, on the recombinant kinase CHAK2, obtained from the base of cell signaling solutions Orziaye Seyi Zidpipe Zoishiop5. All tests were performed simultaneously in white flat-bottomed 96-well plates (Mips) at room temperature with a final volume of 50 μl. Each well contained 40 μl of a buffer solution consisting of 40 mM Tris buffer, pH 7.4, which contained 50 mM Masi, 800 μM ESTA, 350 μM Triop X-100, 2 mM p-mercaptoethanol, 100 μM peptide substrate. (ROKIIde; Oreiage Seii! Zidpaiipud boiIsiop5) and the corresponding amount

UACag (75-25 ng/well); the tests took place in a linear mode for 60 minutes. a touch of time.

The final concentrations of TagdeSep compounds for determining the value of IC were in the range from 1000 to 0.01 μM and were adjusted by adding the appropriate amount of the compound in 2.5 μl of dimethylsulfoxide (OM50O); the amount of OM5O in all tests was constant and was 595. The reaction was initiated by adding 10 μl of adenosine triphosphate (ATP) to the final concentration of 3 μM of the tests. After 60 min. during the reaction time, 50 μl of the reagent was added

Kipaze-SiIo (Rgoteda) for its completion. After this, the solution was allowed to work for another 10 minutes. to maximize the luminescence response.

Luminescence values were measured using the Shmyga 384 device (Tesap). Among them, two control reactions were carried out: in one of them, the medium did not contain the tested compound, and in the other it did not contain either an inhibitor or a peptide substrate. The ISvo values were calculated from the experimental data using the non-linear approximation program Rgizt (Megviop 4;

SgarpRaaid boimage). The obtained results are presented in Table. 1.

Table 1

Compounds of the present invention and their IC values when applied to Chuak2-kinase

CHUAK2

SI SI

OD 4-(2,4-dichloro-5-methoxyphenylamino)-2-|4- (2-pyrrolidine-1-6240 mes 5 ylethoxy)phenylamino|pyrimidine-5-

And carbonitrile

M M nN

SI SI

OD 4-(2,4-dichloro-5-methoxyphenylamino)-2-|3- (2-pyrrolidine-1- 10500 mo s ilethoxy)phenylamino|pyrimidine-5-

Z t carbonitrile

MU M 7 ve 7o MN Ma4-(2,4-dichloro-5-methoxy-phenyl)-5-

Me methyl-M2-I3-(2-pyrrolidine-1-2040

Ж r Я, iletoxy)phenyl|pyrimidine-2,4-diamine

M m 7

Continuation of table 1

OK Ma2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-MaA- o (3-methoxyphenyl)-5-methylpyrimidine-2,4- 52.68 s su - A diamine hydrochloride

M Y om y "MH M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-o methyl-Ma4-(3-nitrophenyl)pyrimidine-2,4- 61.1 s gu - -zt diamine hydrochloride

Dignity

Oh

МН М4-(4-methoxyphenyl)-М2-(4-(2-pyrrolidin-1-oylethoxy)phenyl|pyrimidine-2,4- 4330

C g - diamine trifluoroacetate

M Y she

MH What 4-(4-(4-methoxyphenylamino)pyrimidine-2-

M ilamino|-M-(2-pyrrolidine-1-10700

C diylethyl)benzenesulfonamide trifluoroacetate

M them

OK 9 sh 4-(4-(3-Methoxyphenylamino)pyrimidine-2-8Mylamino|-M-(2-pyrrolidine-1-638)

C for ylethyl)benzenesulfonamide trifluoroacetate

M their ss o MH M4-benzo|1,Z|dioxol-5-yl-5-methyl-M2-I(4- o (2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine- 87.2 s g U 2 ,4-diaminetrifluoroacetate 2, sh

Mn? 4-(I4-(4-Hydroxyphenylamino)pyrimidine-2-in M ylamino|-M-(2-pyrrolidine-1-) 9740

SI du ylethyl)benzenesulfonamide

M M

Continuation of Table 1 no" and "MH 3-(2-(4-(2-(pyrrolidin-1-oyl)ethoxy)phenylamino)-5-methylpyrimidine-203zogut 4-ylamino)phenol hydrochloride

Se ve b o, 4-I4-(3-hydroxyphenylamino)pyrimidine-2-

M ilamino|-M-(2-pyrrolidine-1- 3620

Soyylethyl)benzenesulfonamide trifluoroacetate

M. Y

M o, t AX M-methyl-3-(5-methyl-2-I(4-(2-pyrrolidin-1-oylethoxy)phenylamino|pyrimidine-4-257 and sutoylamino)benzamide

M

SI

"MA, M4-(4-chloro-3-methoxyphenyl)-5-methyl-M2- o o I4-(2-pyrrolidine-1-7.96 nF g m; yletoxy)phenyl|pyrimidine-2,4-diamine

XX, Vol

МН M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-

Ma4-(isoquinolin-1-yl)-o-methylpyrimidin-2,4-| 1050 s ud wa diamine and another s;

M. Y

UK, М4-(3-dimethylalippo-phenyl)-5-methyl-Ma- o 14-(2-pyrrolidin-1-19,7 nog ma yletoxy)phenyl|pyrimidine-2,4-diamine

A, 8

Asi MH 4-(2-(4-(2-(pyrrolidin-1-rya yl)ethoxy)phenylamino)-o-methylpyrimidine- 67.5 tem g X | 4-ylamino)-2-chlorobenzonitrile hydrochloride

Dignity

Continuation of table 1 vol

So, M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-o methyl-Ma4-(naphthalen-1-yl)pyrimidin-2,4- 20

Kf SK U diamine hydrochloride

Se i i si MH M4-(3,4-dichlorophenyl)-5-methyl-M2-I|4-(2-o pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-| 25.7 drops and 7 7o MH Ma4-(4-chloro-3-methoxyphenyl)-5-methyl-Ma-(3-piperazin-1-ylmethylphenyl)pyrimidin- 15.8 ak ko 2,A-diamine 9 s M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-MA-zh o (IN-indol-4-yl)-5-methylpyrimidin-2,4- 192 s su t diamine hydrochloride

ME Y

M-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-4- 702.0 s uva benzylpyrimidin-2-amine 00000

Sa si vo M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-MaA- (4-chloro-3-methoxyphenyl)-Ma4,5- 4900 s and dimethylpyrimidine-2,4- yav X / diamine trifluoroacetate - juice and

Mn M4-(4-chlorophenyl)-5-methyl-M2-I4-(2-o pyrrolidin-1-ylethoxy)phenyl|-pyrimidine- 182 nF g m; 2,A-diaminetrifluoroacetate

Dignity

Continuation of tables 1

SI

АХ and t 2-(4-I4-(4-chloro-3-methoxyphenylamino)-5- | 344 sodium methylpyrimidin-2-ylamino|phenoxy)ethanol and

IN,

WITH

B-methyl-MA-phenyl-M2-I(4-(2-pyrrolidin-1-167 c gylethoxy)phenyl|pyrimidine-2,4-diamine "

AND

M M

H and MH M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-o methyl-M4-p-tolylpyrimidine-2,4-35,7 y du Ma y | diamine hydrochloride

Dignity

Her and

МН M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-MaA- o (4-chloro-3-methylphenyl)-5-methylpyrimidine-| 12.4 no UV M » |2.4-diamine hydrochloride

San and i

E MH Ma4-(4-chloro-3-fluorophenyl)-5-methyl-M2-(4- o (2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-40,1 and UV Ma y |2.4-diamine

Se and 7o MH Ma4-(4-chloro-3-methoxyphenyl)-5-methyl-Ma-(4-morpholin-4-ylmethylphenyl)pyrimidin-13,3 and C 2,4-diaminetrifluoroacetate

Z TO the village

H

MH M4-benzo|bithiophen-5-yl-o-methyl-M2-(4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-| 28.5 and 0;

M and

Continuation of table 1 of - M4-benzo|bithiophene-3-yl-5-methyl-M2-(4-(2-

MH pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-| 124

Кк ве M4-(3-chlorophenyl)-5-methyl-M2-14-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-| 20.8 no du / diamine. menlleia still

M Y t also 2-chloro-M-(2-I(4-(2-pyrrolidin-1-oylethoxy)phenylamino|pyrimidin-5-yl)-5-(3- 304 y and g my; trifluoromethylbenzoylamino)benzamide you

E vo Ma-(4-fluoro-3-methoxyphenyl)-5-methyl-M2-o I4-(2-pyrrolidin-1-14,8-suto ylethoxy)phenyl|pyrimidine-2,4-diamine (in )

Fe M4-benzo|1,Z|dioxol-4-yl-5-methyl-M2-I|4- nn (2-pyrrolidin-1-ylethoxy)phenyl|Ipyrimidine- | 16.9 si purely 2,4-diamine ra

N

SI M and C M4-(4-chloro-3-methoxyphenyl)-5-methyl-M2-(3-piperazin-1-yl-phenyl)pyrimidin-2,4- 9.52 at diamine in

N ko o "MH M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-MaA- o I3-strifluoromethyl)phenyl)-5- 17.6 z o g m, methylpyrimidine-2,4- diamine

That's it

Continuation of table 1 sho

МН M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-MaA- o (4-«"«trifluoromethyl)phenyl)-5- 39.8 s g U methylpyrimidine-2,4-diamine hydrochloride

EX,

H y i bo MH Ma4-(4-chloro-3-methoxyphenyl)-5-methyl-Ma-(4-pyrazol-1-ylmethylphenyl)pyrimidin-2,4-| 18.9

Om k-x diamine cha shchi,

M M

Na M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-Ma4-(3- 207

SG, nF sh- och (trifluoromethoxy)phenyl)pyrimidine-2,4- " g 7" diamine in nH and and

Es MH M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-MaA- o (4-chloro-3-«(trifluoromethyl)phenyl)-5- 23.4 nd g m, methylpyrimidine- 2,4-diamine in

N

2, M4-(3-methoxy-2-methylphenyl)-M2-|4-(2-pyrrolidin-1-ylethoxy)phenyl|pyrimidine-2,4-| 371 is Sto diamine phenylpyr

N y i bo MH o o Ma4-(4-chloro-3-methoxyphenyl)-5-methyl-Ma- 8 (4-(piperidin-4-13 - iv sulfonyl)phenyl|pyrimidine-2,4-diamine k , chn

N

СИ со МН Yak M4-(4-chloro-3-methoxyphent)-5-methyl-Maschu I4-(4-methylpiperazine-1-5.5mgyl)phenyl|pyrimidine-2,4-diamine

Nn

Continuation of table 1 si s y "MH ge M4-(4-chloro-3-methoxyphenyl)-5-methyl-Ma2- schu (4-morpholin-4-yl-phenyl)pyrimidine-2,4- 130

M g diamine ra n

СИ с и "МН М- М4-(4-chloro-3-methoxyphenyl)-5-methyl-Ма2-

What; (4-pyrazol-1-yl-phenyl)pyrimidine-2,4- 35.3 mg diamine trifluoroacetate

KA nH and i 7o Mn Ma4-(4-chloro-3-methoxyphenyl)-5-methyl-Ma-

M (4-piperidin-1-yl-phenyl)pyrimidine-2,4- 35.3

M g of diamine

ХК н и 7о МН Ма4-(4-chloro-3-methoxyphenyl)-5-methyl-Ма-

I4-(4-methylpiperazin-1-12 m 73 ylmethyl)phenyl|pyrimidin-2,4-diamine vOvshF m M B:

N nm

Xra M4-(1H-indol-4-yl)-5-methyl-M2-(4-(4-

МН g methylpiperazin-1-yl)phenyl)pyrimidin-2,4-| 9.53% diamine hydrochloride in water

In, n

СИ со "МН ге Ma-(4-chloro-3-methoxyphenyl)-5-methyl-M2- schu (4-piperazin-1-yl-phenyl)pyrimidin-2,4- 615 m gu diamine

EC,

N y i bo MH Ma4-(4-chloro-3-methoxyphenyl)-5-methyl-Ma-ya o Bu dpiperiding i yloxy)phenylpyrimidine" 4.14

M "4-diamine yet!

M M

N

Continuation of Table 1 and "UK, and 3-H15-methyl-2-I4-(4-methylpiperazin-1-yl)/phenylamino|-pyrimidin-4- 23 temylamino)benzamide (6)

Fe r. 5 MH g of 3-(5-methyl-2-I4-(4-methylpiperazine-1-

SHI k il)/phenylamino|pyrimidine-4- 13.6

Zhylamino)dbenzenesulfonamide

M. Y

her

MH Ma4-(4-chloro-3-methylphenyl)-5-methyl-Ma- o I(4-(piperidin-4-yloxy)phenyl|pyrimidin-8,41-y UV IF 2,A-diamine hy MH

She re

Kh. MH M-(3-(5-methyl-2-I4-(piperidin-4-oyloxy)phenylamino|pyrimidin-4-ylamino)- 137

Om enyl)lacetamide

OO urn and (6) sura M4-benzo|1,Z|dioxol-4-yl-5-methyl-M2-I|4-

MH g (d4-methylpiperazin-1-yl)phenyl|pyrimidin-14,2-no and 2,4-diamine

Ov

Dignity

SI and o "MH M4-(4-chloro-3-trifluoromethylphenyl)-5-o methyl-M2-(4-(piperidin-4-114 tem g IF yloxy)phenyl|pyrimidine-2,4-diamine

San Mnyu

SI ury M4-(7-chloro-1H-indol-4-yl)-5-methyl-Ma-(4-n i (4-methylpiperazin-1-yl)phenyl)pyrimidin- | 5.36 si su 2,4-diamine

AH,

Continuation of table 1 va

M-(2-methyl-3-y5-methyl-2-(4-(piperidin-4-yloxy)phenylamino|pyrimidin-4- 146

MH ylamino)phenyl)acetamide in dO vei nH ss B-methyl-M4-(2,3-dimethylphenyl)-M2-(4-

MH (piperidin-4-yloxy)phenyl)pyrimidine-2,4-| 4.38 no (c) diamine hydrochloride di UF IF r MH nn uv B-methyl-M4-(3,5-dimethylphenyl)-M2-(4-

MH (piperidin-4-yloxy)phenyl)pyrimidine-2,4-| 37.2 but (c) diamine hydrochloride

ZHAGO r MN nN

Зв мом мн м77 | 1-(3--5-methyl-2-I(4-(4-methylpiperazin-1-yl)/phenylamino|pyrimidin-4-63.6-ylamino)phenyl)-3-phenylurea

ZK

M M

N

СИ ра Ma4-(4-chloro-3,5-dimethylphenyl)-5-methyl-chno M2-(4-(4-methylpiperazin-1-38 cyl)/phenyl)pyrimidine-2,4-diamine hydrochloride in ra

N rai m B "MH i M4-(3-tert-butylphent)-5-methyl-M2-(4-(4- i s u gyplperazine pl)phenyl)pyrimidine" 4.7

M "4-diamine hydrochloride

S X g

M M nN

Continuation of table 1 no o m77 | M-methyl-3-(5-methyl-2-|4-(4-

II g of methylpiperazine-1-161 o s: schuyl/uphenylamino|pyrimidin-4-' ylaminobbenzenesulfonamid ra nH o ro m M, M-dimethyl-3-(5-methyl-2-|4-(4-

II g methylpiperazine-1-95 o s schu yl/uphenylamino|pyrimidin-4-' ylaminobbenzenesulfonamide

N nm

X ra B-methyl-M4-(7-methyl-1H-indol-4-yl)-M2-

MH g (4-(4-methylpiperazin-1-3,84-yl)/phenyl)pyrimidine-2,4-diamine hydrochloride

M rev nN

X M4-(3-tert-butylphenyl)-5-methyl-M2-(4-

MH (piperidin-4-yloxy)phenyl)pyrimidine-2,4-| 2.73 but diamine hydrochloride

M vrOvshF r MN nN bo

Ko g М4-(3,5-dimethoxyphenyl)-5-methyl-Ма2-(4-(c) МН (piperidin-4-yloxy)phenyl)pyrimidine-2,4-| 137 no M diamine trifluoroacetate in OvaF

San MH in Y Fe vs Z, Mn Yak 1-(3-(5-methyl-2-(4-(4-methyl piperazin-1- schuyl)/phenylamino|pyrimidin-4-ylamino)phenyl)-i 126 3-(3-trifluoromethylphenyl)urea,

M

Continuation of Table 1 (c) present ethyl ester of 2-methyl-3-15-methyl-2-|4- (4-methylpiperazin-1-yl/uphenylamino|pyrimidin-4- 21.8 s sulylaminodobenzoic acids in

M M

Nn

ON (c)

Xo 2-methyl-3-(5-methyl-2-(4-(4-

MH t methylpiperazin-1-yl)-26.2 containing phenylamino|pyrimidin-4-ylamino)benzamide

M du a

N nm

X salt M4-(1H-indol-4-yl)-5-methyl-M2-(4-chn (piperidin-4-yloxy)phenyl)pyrimidine-2,4-| 427 si (in diaminetrifluoroacetic acid hydrogen Mn

N

X M2-(4-(2-(pyrrolidin-1-t)ethoxy)phenyl)-Ma-

MH (3-tert-butylphenyl)-5-methylpyrimidine- 6.71 2,A-diamine hydrochloride ooo,

AND,

M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-

M4-(4-(3-tert-butylphenylamino)-5-methylpyrimidin-2-yl)-5-methylpyrimidiniso-2,A-diamine hydrochloride

AKI,

SE,

Co b-methyl-M4-(2-methyl-3- pn trifluoromethylphenyl)-M2-|(4-(piperidin-4-| 52.9 ne (c) yloxy)phenyl|pyrimidine-2,4-diamine

Her KO s r MN nN

Continuation of table 1 on g p. and MH 3-(5-methyl-2-I4-(2-pyrrolidin-1-oylethoxy)phenylamino|pyrimidine-4-722

C g U ylaminosbbenzenesulfonamide

M. V. Va

SK m77 | Misopropyl-3-(5-methyl-2-I4-(4-

HER g methylpiperazine-1-11 8 o s schu yl)phenylamino)|pyrimidin-4-ylamino)- and benzenesulfonamide

J

Phi dl |MaA-tert-butyl-3-(5-methyl-2-14-(4-

MN M and

I g methylpiperazine-1- (c) schuyl)/phenylamino|pyrimidine-4-

Zhylamino)dbenzenesulfonamide

I love her

Osivy m )

B-methyl-M2-(4-(4-methylpiperazin-1-rayl)phenyl|-Im4-|3-(piperidine-1 - 248

МН g sulfonyl)phenyl|pyrimidine-2,4-' schu diamine hydrochloride all ogive m ) b-methyl-M2-(4-(4-methylpiperazin-1-yl phenyl)|-M4-|3-(2-methyl- piperidine-1-335

MH Mk sulfonyl)phenyl|pyrimidine-2,4-'

F diamine hydrochloride se (c)

ШО в МН Я М4-(3-methanesulfonyl-4-methylphenyl)-5-

I schu methyl-Ma-(4-(4-methylpterazin-1-160 mg hyluphenyl|pyrimidine-2,4-diamine)

Sa

Continuation of table 1 no

Fe | M-cyclohexyl-3-15-methyl-2-(4-(4-

SU Y ti ha methylpiperazine-1-394 o zsi yl)uphenylamino|pyrimidine-4-' gylamino)dbenzenesulfonamide

AND,

M ve MH ge M, M-diethyl-3-(5-methyl-2-|4-(4-methyl).

Piperazin-1-yl/uphenylamino|pyrimidin-4-60.3 gylaminobenzenesulfonamide

We are M

Se, sr ra Ma4-(3-trifluoromethyl)-2-methylphenyl)-5-pn g methyl-M2-(4-(4-methylpiperazine-1-87.1 s in yl)uphenyl)pyrimidine-2,4 -diamine hydrochloride

A, nN

O.A, (3-(B-methyl-2-(4-(piperidin-4-oyloxy)phenylamino|pyrimidine-4- 113

Ov IF ilamino)phenyl)pyrrolidin-1-yl-methanone o M Mn (in o A

N

M-cyclopentyl-3-(5-methyl-2-(4-(4- methylpiperazine-1-19 8)

MH, yl)phenylamino|pyrimidin-4-'one ylaminophenzol sulfonamide hydrochloride in

EC,

N

(9)

Ost M u

B-methyl-M2-(4-(4-methylpiperazin-1- ryl)uphenyl|-M4-3-(pyrrolidin-1-171 sulfonyl)phenyl|pyrimidine-2,4- diamine hydrochloride bucket

N

Continuation of table 1

Bough. (c) ki MH As 5-methyl-M2-(4-(4-methylpiperazine-1-

And yl)uphenyl|-M4-(3-(morpholine-4-20.7p sulfonyl)phenyl|pyrimidine-2,4-diamine

M. Y

N . . "A, ki M-isopropyl-3-(5-methyl-2-(4-(4-methylpiperazine-1- BA!) ipsrenitaminoipyrimidine-ya ylamino)benzami ki, and

N o-o-o

B-methyl-M2-(4-(4-methylpiperazin-1-pyrilophenyl)-M4-(3- 215

МН g (methylsulfonyl)phenyl)pyrimidine-2,4-no schu diamine vd

That's it

N

A, ky M-tert-butyl-3-(5-methyl-2-|4-(4-methylpiperazin-1-890 iv; DK and gophenipamino)pyrimidine-yatlamino); enzymes, i

No. 85

B-methyl-M2-(4-(4-methylpiperazin-1-iluphenyl)-M4-(3- p (propylsulfonyl)phenyl)pyrimidine-2,4-

MN ho diamine no du

Sa mn ge v-methyl-M2-I4-(4-methylpiperazine-1-

Nm yl)uphenyl|-M4-(3-piperidin-4-yl- 42.5 s; phenyl)pyrimidine-2,4-diamine

Continuation of Table 1 that nm MH Ma-tert-butyl-3-N5-methyl-2-(4-morpholine-

HER 4-ylmethylphenylamino)pyrimidine-4- 12.5 o i dO ylamino|benzenesulfonamide

A, 4 (c) o-v-Mn no

Phi M-tert-butyl-3-(5-methyl-2-(4-piperazine-

MH co 1-yl-phenylamino)pyrimidine-4- 7.59 no schu ylamino|benzenesulfonamide hydrochloride vd

With Mr

Ma4-(3-(2,5-dimethylpyrrolidine-1-sulfonyl)phenyl|-5-methyl-M2-(4-(4- 18.8

MH ky methylpiperazin-1-yl)/phenyl|pyrimidin-2,4-"no F diamine hydrochloride

M

I C san (c) r vi M-tert-butyl-3-(2-(4-I4-(2-ra hydroxyethyl)piperazine-1-ilyphenylamino)- chn g (b-methylpyrimidin-4-1,09zo su ylamino|Ybenzenesulfonamide hydrochloride

A, their and more

II K yl-phenylamino)pyrimidine-4-19 o | with ylamino|benzenesulfonamid ra nH y

SK tn M-tert-butyl-3-(5-methyl-2-(6-piperazine-

II F 1-ylpyridin-3-ylamino)pyrimidine-4- 10 o | s and ylamino|)benzenesulfonamide

San school

Continuation of table 1 c As 2-I4-(3-15-methyl-2-(4-(4-methylpiperazin-1-mMM Myl)/phenylamino|pyrimidine-4-8,46 7 ne x | y ylamino) phenyl)piperidin-1-yl|ethanol or vk o. MN

M-tert-butyl-3-(5-methyl-2-(3-morpholin-4-ylmethylphenylamino)pyrimidine-4- 7.06

MH ilamino|Ybenzenesulfonamid no p

Sa schu village nm MH M-tert-butyl-3-(5-methyl-2-(4-pyrazol-1-ylmethylphenylamino)pyrimidin-4- 18.6 o | hm more ylaminosbbenzenesulfonamide

See them and nm. HER Fe

HER MH N-tert-butyl-3-(5-methyl-2-3-(piperidinyl)1-sulfonyl)phenylamino|pyrimidine-4- 316 tem oylamino)dbenzenesulfonamide

Uh, this is her father. M-tert-butyl-3-((5-methyl-2-(14-((4-

And МН methylpiperazine-1-298 (c) syl)umethyl|Ifenyl)amino)pyrimidine-4-y and also ilyaminodbenzenesulfonamide sh-y M p. M-tert-butyl-3-((5-methyl-2-C4-piperazine-

Mn SE, Hn 1-il-3-

I schu (trifluoromethyl)phenyl|amino)pyrimidine-4- 22.5

Zyl)amino|ybenzenesulfonamide

We are M

Continuation of table 1 i o nm. HER p 3-(2-C4-(4-acetylpiperazin-1-yl)-3-

Her MN Se, go (trifluoromethyl)phenyl|amino)-5- 357 (c) with methylpyrimidin-4-yl)amino|-M-tert-

J. butylbenzenesulfonamide

M-tert-butyl-3-(5-methyl-2-(3-piperazin-1-ylphenylamino)pyrimidin-4-18isoglyamino]benzenesulfonamide hydrochloride

J

M m 773

Y. plural (9) sk

Cx M-tert-butyl-3-(2-13-(4-(2-

MH hydroxyethyl)piperazin-1-yl|-phenylamino)- 40 5 (b-methylpyrimidine-4- "

Z Feylamino|Ybenzenesulfonamide hydrochloride

MU M 77 or in nm MH M-tert-butyl-3-C5-methyl-2-((3-((4-

HER methylpiperazin-1-65BO ozoFekyyl)usulfonylI|phenyl)amino)pyrimidine-4- (c)yl||dzminobbenzenesulfonamide

CA

And sx M-tert-butyl-3-((5-methyl-2-A- in MH:

І (piperazin-1-46(c)ylmethyl)phenylamino)pyrimidine-4-

Also il)amino|Ibenzenesulfonamide

M i Mn (9)

As B-methyl-M2-(4-(4-methylpiperazine-1-

KI and - OP. MY Top (c) M yl)uphenyl|-M4-|(3-(piperidine-4 198 nm ve gu sulfonyl)phenyl|pyrimidine-2,4-diamine si

Continuation of table 1

M" and "MH is B-methyl-M2-(4-(4-methylpiperazin-1-yl)uphenyl)-M4-(3-(piperidin-1-46.3 m gylulophenyl)pyrimidine-2,4 -diamine and

N y Z As Ma4-(3-(1H-pyrrol-1-yl)phenyl)-5-methyl-M2- shsh- schu (4-(4-methylpiperazine-1- 33.8 m udilophenyl)pyrimidine-2 ,4-diamine ra nH in

With MN m7 | 3-(5-methyl-2-I(4-(4-methylpiperazin-1-yl)-su g phenylamino|pyrimidin-4-ylamino)-M- 543

Ov piperidin-4-yl-benzenesulfonamide and M and nM--M ich

M4-(1H-indazol-4-yl)-5-methyl-M2-(4-

MH (piperidin-4-yloxy)phenyl)pyrimidine-2,4-zo ss diamine hydrochloride p Mn

H nM--M

AND

M4-(1H-indol-4-yl)-5-methyl-M2-(4-chn morpholin-4-ylmethylphenyl)pyrimidin-2,4-| 7.42 pedestrians more:

H nM--M

H

M4-(1H-indol-4-yl)-5-methyl-M2-(4-

МН piperazin-1-ylmethylphenyl)pyrimidin-2,4-| 10.1 November

AK, M. pl

N o M-tert-butyl-3-(5-methyl-2-|4-(2- and 07 Kho pyrrolidine-1- 125

Fo sho iletoxy)phenylamino|pyrimidine-4- "

Ov X / ylaminozbbenzenesulfonamide

Continuation of Table 1 according to tn 3-(2-(4-(piperidin-4-yloxy)phenylamino)-

MN

/ si

M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-

Night Ma-(7-chloro-1H-indol-4-yl)-5- 1.16 sec methylpyrimidine-2,4-diamine hydrochloride

ZhK 0;

M M nn

MN

/

M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-

Night methyl-M4-(7-methyl-1H-indole-4-6,98 si stryl)pyrimidine-2,4-diamine hydrochloride - uk Y

KA nN

MN

/

IS

M2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-

Night Ma4-(7-fluoro-1H-indol-4-yl)-5-9,28 si to methylpyrimidine-2,4-diamine hydrochloride y i nH i i bo MH Hn M4-(4-chloro-3-methoxyphenyl) -5-methyl-M2- (b-piperazin-1-ylpyridin-3-yl)pyrimidine- 121

Zm g 2, A-diamine

Let's live

M M

N

SI

OD o o M methyl ester of 5-I4-(4-chloro-3-hymethoxyphenylamino)-5-methyl-pyrimidin-512siI 2-ylamino|-2-piperazin-1-yl-benzoic acid ra nH

Continuation of Table 1.

МН 4-ylamino)-5-methylpyrimidin-2-ylamino)|-2-164 o (2-pyrrolidin-1-ylethoxy)benzoic acid

N

Ul, M-tert-butyl-3-(5-methyl-2-|(4-(piperidin-o o o o 4-yloxy)phenylamino|pyrimidine-4- 7,3 vvi IF ylaminozdbenzenesulfonamide)

ME m MN

N nm

M4-(1H-indol-5-yl)-5-methyl-M2-(4-

MH (piperidin-4-yloxy)phenyl|pyrimidine-2,4-zo still diamine p MH

N

(c) nt 2-15-I(I4-(benzo|1,Z|dioxol-4-ylamino)-5-

МН methylpyrimidin-2-ylamino|pyridine-2-116 si DY yloxy)ethanol

Ech i nH a (vra M4-benzo|1,Z|dioxol-4-yl-M2-I|Z-methoxy- 4-(2-pyrrolidin-1-ylethoxy)phenyl|-5- 9.34 si and aka methylpyrimidine-2,4-diamine a

N n

Moore Mo. p re MH g M-tert-butyl-3-(2-(4-imidazol-1-o o M / ylphenylamino)-5-methylpyrimidine-4- 12.3 mg gylamino|1-benzenesulfonamide

Kk

N

Continuation of table 1 g

M gr rech mn M-tert-butyl-3-(2-(4-imidazol-1-oylmethylphenylamino)-5-methylpyrimidine-4-| 8.42 "em mM | ylamino|1benzenesulfonamide

S Duet r p

M M

N

M... g M-tert-butyl-3-(2-I4-(2- p o? With her hydroxyethoxy)phenylamino|-5- 203 s o ot o c methylpyrimidine-4- | ;

EC, ylaminophenzolsulfonamide

M

ОИ in

M-tert-butyl-3-(5-methyl-2-|4-(4-oxymorpholin-4-486ylmethyl)phenylamino|pyrimidin-4-ylamino)benzenesulfonamide

BU M vrOvshe se S

SI

Fo "MH Ma4-(4-chloro-3-methoxyphenyl)-5-methyl-Ma-(4-piperazin-1-ylmethylphenyl)pyrimidin- 152

Substitute 77 2, A-diamine

Still!

N-tert-butyl-3-(5-methyl-2-|4-(2- oi Kho ), methylimidazole-1-343 s M il/phenylamino|pyrimidin-4-' ylaminobbenzenesulfonamide

IN

N

M. g M-tert-butyl-3-(5-methyl-2-|4-(2- 2r tn methylimidazole-1- 219

Zm - ylmethyl) phenylamino|pyrimidine-4-th vOOshka; ylaminobenzenesulfonamide nH v rok Mn M-tert-butyl-3-(B-methyl-2-(4-pyridin-4-oo ylmethylphenylamino)pyrimidine-4- 80.7 tem 7 |ylamino|benzenesulfonamide

Al

Continuation of table 1 c

M y re MH ge M-tert-butyl-3-(5-methyl-2-(4-morpholin- /x . . . . oso y 4-ylphenylamino)pyrimidine-4- 121 m duylamino|Ibenzenesulfonamide 2 that o; M2-(4-(1H-pyrazol-1-iluphenyl)-M4-(3-tert-| 53

Fo g butylphenyl)-5-methylpyrimidine-2,4-diamine

Se nm si u

M4-(7-chloro-1H-indol-4-yl)-5-methyl-Ma-(4-

MH ((piperazin-1-yl)umethyl)phenyl)pyrimidin-694no 2,A-diamine hydrochloride

M ueshe se M. pl

A, va M4-(3-tert-butylphenyl)-5-methyl-M2-(4-7 (2-methyl-1H-imidazol-1-38.4 s Ya pyl)phenyl)pyrimidine-2,4- diamine hydrochloride

ХХ, -7,, t M4-(3-tert-butylphenyl)-5-methyl-M2-(4-

H- (2-methyl-1H-imidazol-1-94 2 Ya p yl) phenyl) pyrimidine-2,4-diamine hydrochloride ve o M-tert-butyl-3-(5-methyl-2-(4- Ho P,2,4griazol-1- zva

Zm m--7 ylmethylphenylamino)pyrimidine-4-y

Zh g IS U ylamino|benzenesulfonamide

M M s-m

N a M M-tert-butyl-3-(5-methyl-2-|4-(4- i o Zo t methylimidazol-1-417 s M iluphenylamino|pyrimidine-4-);

Zhylamino)benzenesulfonamide

Continuation of table 1 n vva -k 2,M-dimethyl-5-(5-methyl-2-(4-(2- 07 Kho g pyrrolidine-1- 127 s M m iletoxy)phenylamino|pyrimidine-4-

Zhylaminophenzolsulfonamide

M m

M. ve M-tert-butyl-2-methyl-5-(5-methyl-2-|4-(2- gyn pyrrolidine-1-444

Where is ylethoxy)phenylamino|pyrimidine-4-' sh re ud Sh, ylaminobbenzenesulfonamide

M M n

From MN mom | M-tert-butyl-3-|(5-methyl-2-(4-y | M : . A . . o o M-Y P1,2,4)griazol-1-ylphenylamino)pyrimidine- | 41.4 g of 4-ylamino|benzenesulfonamide

M M nN

He Fe

In pn M-tert-butyl-3-(5-methyl-2-13-(1H-oso): p. A. with tetrazol-5-yl/uphenylamino|pyrimidin-4-55,9 ylaminobphenzolsulfonamide

J. M

М М Ом и нн вы ре МН ГЕ M-tert-butyl-5-(2-(4-imidazol-1-l Y - - - - oo ylphenylamino)-5-methylpyrimidine-4- 88.2

Fe ud ilamino|-2-methylbenzenesulfonamide hu

М М нН и ре МН о M-tert-butyl-3-(5-methyl-2-|(4-(pyrrolidine-oo 1-carbonyl)phenylamino|pyrimidine-4- 33.5 s and I;ylamino)dbenzenesulfonamide va 2 r: MH o M-tert-butyl-3-(5-methyl-2-I4-(morpholine-oo 4-carbonyl)phenylamino|-pyrimidine-4- 32.9 7 and Zylaminobenzenesulfonamide

AK what

N

Continuation of table 1 n

A, o M-tert-butyl-3-(5-methyl-2-I4-(piperazine-oo 1-carbonyl)-phenylamino|pyrimidine-4-tmylaminobbenzenesulfonamide

Phew! ) Ulf

M M nn nN

LC of them M p r: M -tert-butyl-3-(5-methyl-2-IA-(1H- o 0 - / | tetrazol-5-yl)uphenylamino|pyrimidin-4- 96.7 m mo |ylamino )benzenesulfonamide

In m, M4-(3-tert-butylphenyl)-5-methyl-M2-4-(1-morpholinethyl)phenyl)pyrimidine-2,4- 19.9 m 7 diamine hydrochloride ve and "in (c)

3-(2-I4-(4-Acetylpiperazine-1-yl)phenylamino|-5-methylpyrimidine-4-ylamino)-N-tert-butyl-

And benzenesulfonamide

N

And "МН МН М4-(3-tert-butylphenyl)-5-methyl-М2-(4-(piperidin-4-yl)uphenyl)pyrimidin-2,4- 20.9

Om diamine hydrochloride

AK

M. g M-tert-butyl-3-15-methyl-2-|4-(1- p: Mn i i oi Kho morpholin-4 297

Zm 7 ylethyl)phenylamino|pyrimidine-4-y

Z FI ylaminobenzenesulfonamide - (c)

Feto |B-methyl-M4-(2,3-dimethylphenyl)-M2-(4-(4-

MH and methylpiperazin-1-yl)phenyl)pyrimidine-2,4-16 diamine hydrochloride

What

J

M M nN

Continuation of table 1

SI

Fe,

МН g М4-(4-chloro-2-methylphenyl)-5-methyl-М2-(4-mono(4-methylpiperazin-1-yl)phenyl)pyrimidin- 15.9

M 2,4-diamine hydrochloride

M M

N

Fi yhl | 5-methyl-M4-(3,4-dimethylphenyl)-M2-(4-(4-

MH is methylpiperazin-1-yl)phenyl)pyrimidin-2,4-| 16.6% diamine hydrochloride

M j su

M M

N

Example 245. Determination of the effectiveness of selected compounds

The HER, STI1-2, and normal human dermal fibroblast cells (MNOE: poptai! pitap aegtai! Yargobriaviv5) used in these experiments were obtained from the American Tissue Culture Collection (Ategisap Tizvuie Siyige SoPesiop, Rockville, MD), and Wag/Z- cells were obtained from the Center for Cancer Research (OKE2, Heidelberg, Germany).

Vayeg/z3, NEG and MNOE cells were grown in nutrient medium KRMI 1640 (sirso VK,

Sainetzrygud, st. Maryland), supplemented with penicillin, streptomycin, l-glutamine and 10 95 fetal bovine serum (EB5). STI 1-2 cells were grown in the same medium supplemented, in addition, with 20 U/ml recombinant 1-2 (Noyipapi-I aVospe, Msheu, New York). Plasmid containing the sequence encoding human CHAK2 was purchased from Ipmigodep (Madison, WI). CHAK2Ue"i cDNA was created by the method of site-directed mutagenesis with the introduction of the M617RE mutation in the sequence encoding human UACZ, and subsequent verification by means of sequencing in two directions. Next, this cDNA was subcloned into a retroviral vector and transferred into Wag/3 cells. Permanently transduced

Vag/Z cells expressing ЧАК2Уе"t were selected and received 1 mg/ml 418. These cells were injected with SER by lentiviral transduction using ri epiib-SER (Ipmigodep), after which cells were selected using blasticidin and confirmed through the expression of SER

EAS5 analysis (fluorescent cell sorting).

Cell proliferation assays were performed using the XTT (Cell Proliferation) kit according to the manufacturer's instructions (Cospe, Aiateda, CA). The methodology of these tests consisted in the fact that three samples of approximately 2.5x103 cells each were seeded into the wells of a microplate with 100 μl of KRMI culture medium plus various doses of the compound Mo CHIM. During 72 hours of incubation, twenty microliters of HIT was added to the wells and the incubation process continued for another 4-6 hours. The colored formazan product that was formed was measured by spectrophotometry using a Mtakh spectrophotometer (MoiIesshiag

Remise5, ZippumaIe, pcs. California) at 450 nm with a correction of 650 nm. IS values were determined with the help of the SgarpRay Rgist 4.0 program (San Diego, California); such

In this way, the obtained values of the optical density (003) were plotted on the Y-axis (on a linear scale), and the concentration (mM) on the X-axis (on a logarithmic scale). The obtained data were subjected to mathematical analysis with approximation by the method of non-linear regression, and the ISvo values expressed the concentration that inhibited 50 95 cell proliferation.

Proliferation of ES5O0

NES-270 nm

Vai3: CHAK2M61 7E-297 nm

Control data: I--2-induced "AKZ-dependent proliferation - 3395 nm

Control data: normal human dermal fibroblasts - 6487 nm

Apoptosis test

Wag/3-UAKUe cells! 7 - cultured in the ERMI nutrient medium containing 10 95 ЕВ5, 1 mg/ml 0418 and 10 mg/ml blasticidin, were treated with the KHIM compound at concentrations of 1, 3 and 10 µM for 24 hours. After collecting the cells by centrifugation with a relative force of 890 KSE (heIaime sepigtidayop iogse) for 5 min. genomic DNA was separated from cellular debris using a DNA isolation kit (Rygedep, Spipo, CA). From each sample, 5 μg of genomic DNA was subjected to electrophoresis in a 1.295 agarose gel, thus revealing the fragmentation of genomic DNA (DNA ladder analysis). Adjacent normal human dermal fibroblasts (MNOBE: pogta! pitap degtai! prgobiavzi5) were grown as control samples in a nutrient medium (Satrbekh, UMaiKegemiShe, MO) with 60-95 confluency, which were treated with KIM compounds as described above. After 2 washes with ice-cooled physiological solution (PB5), buffered with phosphate, genomic DNA was separated from

MNOR cells for electrophoresis on agarose gel.

Immunoblotting

Vag/3-CHAKUv!"" cells, which were treated with the KHIM compound and the vehicle (control), were centrifuged, washed twice with ice-cooled PB5 solution and lysed with buffer for radioimmunoprecipitation analysis (RIPA). By the BSA method (Riegse, Koskoga,

IU) protein concentration was determined and 100 μg of the total cellular protein of each sample in 1x Laemmli buffer (IGaetti) was analyzed by Western blotting. The white spot was probed with an antibody against phospho-5TATb (Tugb94/699) (Orziage Viotesppoidou, SpagiocevsmiPe, Virginia), then subjected to stripping and again probed with an antibody against 5TAT5 (Sei! Bidpaiipud Thesppo!odu,

Oapmege, st. Minnesota). Phospho-Z5TATb and 5TAT5 proteins were visualized by the enhanced chemiluminescence method (Riegse). In a similar way, research was carried out on ip mimo for signal transmission. The methodology of these studies consisted in the fact that on the 11th day after the injection of cells, experimental animals of one group were orally administered a carrier, and the other - 100 mg/kg of the KIM compound.

Seven hours after the administration of these drugs, spleens were harvested and rapidly homogenized in a RaziRger rapid preparation unit (ObBiodep, Igmipe, CA). 100 μg of each spleen homogenate was subjected to Western blotting. The white spot was probed with an antibody against phospho-517АТ5 (Tugb94/699), and then with an antibody against 5ТАТ?5 and visualized by the enhanced

From chemiluminescence.

Analysis by fluorescent sorting method (HAS5) of the tumor load in the blood circulation

On the 11th day after the injection of Vag/3-UAKa2Uv'" cell suspension in a mouse that received a vehicle, 1 ml of blood was collected from the limbs by cardiac bleeding, and 10 mice from each of the three groups receiving, respectively, 10, ZO and 100 100 mg/kg of KHIM compounds, 0.1 ml of blood was taken by non-lethal retroorbital method and distributed by dosage groups. Mononuclear blood cells were separated by centrifugation in a Ficol gradient (RisoI) (Zidta-

Ayagispy, St. Louis, st. Missouri) (relative strength 600 KSE, duration 30 minutes). Separated cells were subjected to BASbZ analysis and thus determined the percentage of CEP-positive cells

Wag/3zakaUe "-cells. The obtained results are presented in the diagram below.

The orally administered KIM compound reduces the number of UAK2Uv""-tumor cells in the blood circulation in a dose-dependent manner. what 0 ate

B

Ko from Dn ; : in the sword of Mpyaek Zbniuk te

To the Hundred:

Study of tumors in blood circulation on experimental animals

Intravenous injections of Vag/3 cells expressing ZAKO and SE

XM compounds were administered orally in the indicated doses, starting from the 3rd day and ending on the 20th day after the injection. On the 11th day, blood samples were taken from the animals of each group and subjected to BASb analysis to determine the percentage of cells in the blood circulation that were SERP-positive. Parallel studies were also conducted in which animals were treated in the same way, except that they were given a single dose of 100 mg/kg of the drug on day 11 and sacrificed 4 hours later and assayed for TZAT5 phosphorylation in enlarged tumor-bearing spleens . The obtained results are presented in the diagram below.

Results of studies of the action of the compound XI Mip mimo on the model of tumors in the bloodstream

I Sat 7 zdo Kir rose with soda koya: same | E s i ei ii sh- in: nannies

With the same m with as "kzhechyaaetyi: THEY ARE MISAK. "Death due to tracheal aspiration during oral feeding

Medicines were administered orally twice a day, starting from day 3 after tumor injection

Oauw: Days

RO, bBia: Orally, twice a day

Eye administration and performance data

Tests of the proposed compounds were conducted when they were administered as eye drops with a dose of 0.1 95.

For local administration of compounds in preparations with 0.1 95 doses in a mixture of 0.2 9o tyloxapol/1 95

NRMS/A4 95 mannitol exposure levels detected in the posterior part of mouse eye tissues are shown at two different time points, namely at 2 h. and 7 o'clock Data on the effectiveness of the tested compounds are given in Table. 2.

Table 2

Concentration (nM) in the eye tissues of the mouse after bilateral local instillation of 0.1 96 of the drug ОХХ1 11111111 Concentration of nM///ССГО in the eye preparation 1111111171116 1 351 | .-KHGBR./ 2970. 17 3780 11111117 | goy | 777711 of 4800,777777 | 18600 11111111 gbbov 11117132 |7111111zivo11111 11111117 | 592 | 11171711 225071 45400 1111171 2vo | 77777111 7350777777717171 172

Example 246. Compound KhMII in studies of ocular efficacy in the model of oxygen-induced retinopathy (SIK: ohudep-ipdiseai heiporaipu)

Tests of the HM compound were conducted on experimental mice models of oxygen-induced retinopathy (OIC), in which retinal neovascularization was induced by cycling the oxygen content in the tissues of newborn mice from a normal level to an elevated level and back to a normal level. Broods of C57VI/6 mice were transferred to an environment with increased oxygen content (70 95 Ohm), starting from the 7th day after birth (P 7). After 5 days, the broods were placed in an environment with a normal oxygen level (21 95 О2), where they were kept for 5 days, receiving during this period by local administration the compound CHMII, and the control individuals - the appropriate carrier. At the end of this period, total retinal preparations were prepared and stained with fluorescently labeled lectin (B5I.I), which recognized mouse endothelium. And finally, by means of fluorescence microscopy, digital images were obtained, which were analyzed with the help of an image analysis program, and based on the results of this analysis, a quantitative assessment of the vascular surface was carried out. In one group of these experiments, where animals were injected with 0.195 of the preparation of the compound HMI! twice a day (fight), there was a 29 95 decrease in the vascular surface compared to control animals that received the carrier (Р«0.05, n-11-15); in the other group, a 22 95 decrease was observed (Р«0.02, n-6b). The obtained results are summarized in

Table 3.

Table C

Group Surface of blood vessels (mm, mean of Change relative to controls

Research Mo RU r ud "average of x individuals that received treatments root mean square deviation) carrier biv-ob4 Carrier (| 77777777 Yam Her 11111 zom! 77777711 35506771 Y7111111111leo1

SIV-007 Nosii (| 77777777 83508 |! we ZH LU ATII PO SEU Ko OO 5

It is quite clear that the description of the invention presented here with explanations on some Examples of its practical implementation does not limit the possibilities of creating various other modifications and variants of it, which lie within the framework of its idea and scope, outlined in the appended below

The formula of the invention.

Claims (3)

FORMULA OF THE INVENTION 1. Compound of formula 32: MN, I fear horror or M M H 32 or its salt. 2. The method of obtaining the compound of the formula CHM: : Fi M y te chi t v) schu Shchi ra M M N HM in which the interaction of 3-bromo-M-tert-butylbenzenesulfonamide is carried out with the compound of the formula Za: y i schu Shchi a M M H 32. 3. The method according to claim 2, in which the crude product obtained at the stage of interaction of the compound of formula 32 with 3-bromo-N-tert-butylbenzenesulfonamide is additionally purified.