Pyrimidine derivatives and a method of inhibiting of jak pathway

UKRAINE ₍₁₉₎ iA (11) 106975 (s) C2

(51) IPC

007ч 401/12 (2006.01)

007 till 403/14 (2006.01)

007y 413/12 (2006.01)

007? 413/14 (2006.01)

007 to 417/14 (2006.01)

007 ÷ 451/02 (2006.01)

007 ÷ 471/04 (2006.01)

007 ^ 471/08 (2006.01)

007 ^ 491/08 (2006.01)

007 to 498/04 (2006.01)

Α61Κ 31/506 (2006.01)

Α61Κ 31/5377 (2006.01)

Α61Κ 31/538 (2006.01)

Α61Κ 31/5383 (2006.01)

Α61Κ 31/54 (2006.01)

STATE SERVICE BANITELECTUAL PROPERTY IN UKRAINE

(12) DESCRIPTION TO THE INVENTORY PATENT

(21) Application number:

(22) Date of application:

(24) Date from which the valid law for the invention:

(31) Number of the previous application in accordance with the Paris Convention:

(32) Date of submission of a preliminary application in accordance with the Paris Convention:

(33) Code of the State party to the Paris Convention, to which a previous application has been filed:

(41) Publication of information about the application:

(46) Publication of information on the issuance of a patent:

(86) Number and date

submission of an international application filed in accordance with the PCT Agreement

and 2011 10139

22.01.2010

10.11.2014

61 / 241,630,

61 / 147,059

09/11/2009

01/23/2009

υδ,

υδ

10.10.2011, Bull No. 19

10.11.2014, Bulletin No. 21

PCT / 5252/021856,

22.01.2010

(72)

(73)

(74)

Inventor (s):

Lee Guy (ΘΝ / δδ),

Hekrodt Tilo J. (JE / S)

Chen Yang (ΘΝ / δδ),

McMurtley Darren John (CA / υδ),

Taylor Vanessa (ΟΒ / υδ),

Singh Rajinder (υδ / υδ),

Ding Pingy (SICH / υδ),

Thoth Sambayah (υδ / υδ),

Yen Rose (υδ / υδ)

Owner (s):

RAJDEL PHARMACEUTICALS, INC.,

1180 Wieigape Voiheuigs, Zoeia Zapragatsesio, SaiiTogpia 94080, Ipiiye Ziyaye otategis (IZ)

Representative:

Osharova Irina Aleksandrovna, registry number 9

List of documents taken into accountexpertise:

OTO 2008/118822 A1; 10/02/2008

I_iо C. its ai .: "ipIiIiOGe oT bAKe / zTAATe avСIIіііііііііііііієєєєє: а роееіЬєе пем сіаєєгг ОТ Сгієд" // Огід Сісеуегу їоСау: Віоеіісіо, 2004, уоі. 9, ICO 6, pp. 268-275.

υΑ 106975 C2

(54) DIRECT PYRIMIDINE AND THE INJECTION OF SIGNAL WAY 6AK

iA 106975 C2

(57) Summary:

The present invention describes compounds of Formula I, compositions containing such compounds, and methods for the use of compounds and compositions in the treatment of conditions in which the modulation of the signal pathway of CAC or inhibition of CAC kinases, especially CAC2 and CAC3, is therapeutically useful.

iA 106975 C2

SWITCH LINKS FOR FAMILY APPLICATIONS

This application claims the priority of previous applications of the United States No. 61/241 630 filed on September 11, 2009 and # 61/147 059, filed January 23, 2009, the contents of which are incorporated herein for any purposes as a reference.

The branch of technology

The present invention provides chemical compounds and methods for their use in modulating the signal path of AAF, inhibition of one or more AAC kinases, and also in the treatment of states in which modulation of the signal path of AAF or inhibition of A? K kinases, in particular A? K?, Is therapeutically justified.

The level of technology

Janus (^ Aη5) -kinase (or ΑΑΚ) is a family of cytoplasmic tyrosine kinase proteins, which includes AAC1, CA2, AA3, and THCH2. Each of AAC-kinases selectively acts on the receptors of certain cytokines, with individual cytokines or signaling pathways having an effect on several αΑκ kinases. Studies indicate that AAC3 binds to conventional gamma chains (UCs) of different cytokine receptors. In particular, AAC3 selectively binds to the receptors and is part of the signal path of the cytokines for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. ΑΚΙ-kinase interacts with other receptors of cytokines IL-2, IL-4, IL-7, IL-9 and IL-21, while ΑΝΑΚ 2-kinase interacts, among other things, with receptors IL-9 and TNF-α. When binding certain cytokines with their own receptors (eg, IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), there is an oligomerization receptors that, in turn, leads to the formation of close cytoplasmic end segments of bound AAC-kinases, which facilitates the transphosphorylation of tyrosine residues on the AAC kinase. Such transphosphorylation leads to activation of Ακκ kinase.

Phosphorylated AAC-kinases bind a variety of protein-carrier signals and transcription activators (8THA (PTAT)). Such PCT (8THA) proteins, which are DNA-binding proteins, which are activated by phosphorylation of the tyrosine residues, act as signaling molecules and transcription factors, and eventually bind to specific DNA sequences present in promoters of genes sensitive to cytokines (Beopagba and et al., (2000), A.A.I.Egdu Sip.IttipoI.105: 877-888). The signal pathway AAC / δΤΑΤ is involved in the mediation of many pathologic immune responses, for example allergies, asthma, autoimmune diseases, for example, transplant rejection (allograft), rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as solid and hematological newities, including leukemia and lymphomas. An overview of the pharmaceutical significance of the signaling path ΔΑΚ / δΤΑΤ is presented by Rogal, (1999), My. Meb 5: 432: 456 and ZeebeI et al., (2000), Opsodep 19: 2645-2656.

In particular, AAC3 is involved in a number of biological processes. For example, it has been shown that proliferation and survival of mast cell mice, induced by IL-4 and IL-9, depended on the signal path of the AAc3- and gamma-chain (Zygiki et al., (2000), Vioob 96: 2172-2180). By playing a critical role in the degradation of mast cell mediated by the IDE receptor (Mayaeoia et al., 1999, ViOse, Vioruus Res., Sottip., 257: 807-813), inhibition of the √ΑΚ 3-kinase, as already been reported, prevents hypersensitivity reactions of Type I , including anaphylaxis (Mayaeoia et al., (1999), A. Viola, SIT 274: 27028-27038). It has also been shown that inhibition of √ΑΚ3 leads to immunological suppression of rejection of allograft (κκκι, (2001), TgaprrI, Pgos 33: 3268-3270). The kinases, in particular, of the ^ Aβ kinase involved in the mechanism, which is observed in the early and late stages of rheumatoid arthritis (MIiyeg-Babpeg et al., (2000), A. Ittipoi, 164: 3894-3901), hereditary amyotrophic lateral sclerosis, nee et al. (2000), VioSiTe ViOrius. Rez.Sottyp 267: 22-25); leukemia (Zybesc et al., (1999), Sip. Sapseg Res. 5: 1569-1582), mushroom-like mycosis, forms of T-cell lymphoma (Meizep et al., (1997), Rhasa Nisea Asab. ІІAA 94: 6764-6769); and an abnormal growth of cells (Yu et al., (1997), A. Ittipoi, 159: 5206-5210; Saiiii-Raisope et al., (1999), Ittipius 10: 105-115). ІІAA 94: 6764-6769); and an abnormal growth of cells (Yu et al., (1997), A. Ittipoi, 159: 5206-5210; Saiiii-Raisope et al., (1999), Ittipius 10: 105-115). ІІAA 94: 6764-6769); and an abnormal growth of cells (Yu et al., (1997), A. Ittipoi, 159: 5206-5210; Saiiii-Raisope et al., (1999), Ittipius 10: 105-115).

6AK kinases, including AAC3, are expressed in large numbers by primary leukemic cells in children with acute lymphoblastic leukemia, the most common form of cancer in children, with the study establishing the relationship between activation of 3ΤAT in certain cells with signals that regulate apoptosis (Eotyipi et al. (1996), Mine, Seven Wonders, 16: 4710-6, Biblical Etiquences, (1997), Vio. 89: 4146-52, Capeco et al., (1997), Cypriot Exodus 109: 185-193; Pharmacodynamics (1996), A.V.O.I., Sit., 271: 19483-8). It is also known that such kinases play an important role in the differentiation of lymphocytes, their functioning and survival. In particular, AAC3 plays an essential role in the functioning of lymphocytes, macrophages and mast cells. Taking into account the importance of ΑΑκ-kinases, in particular, ΑΑΚ3, compounds modulating the signal path of ΑΑΚ, including the selective signaling pathways of ΑΑΚ3,

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ee ai., (2004) At. à Tgapzriap 4: 51-57; Sibelius (2003) Session 302: 875-878). The states in which the involvement of the AAG signaling pathway or the modulation of the ΑΑκ kinases, in particular, ΑΑΚ3, involves therapeutically useful therapies including leukemia, lymphoma, transplant rejection (e.g., rejection of transplanted pancreatic islet cells, bone marrow transplant rejection (e.g., transplant versus host) ), autoimmune diseases (such as diabetes) and inflammation (eg, asthma, allergic reactions). Stages that can benefit from the inhibition of AAc3 are discussed in more detail below.

Taking into account the numerous states for which successful treatment is envisaged through the modulation of the ΑΑΚ signaling pathway, it immediately becomes apparent that new compounds modulating the ΑΑΚ signaling pathways and methods of using such compounds should provide significant therapeutic benefits for a number of patients. The present invention describes novel compounds 2, 4-pyrimidindamine for use in the treatment of conditions in which the use of the signaling pathway ΑΑΚ or inhibition of ΑΑκ kinases, in particular, αΑκ3, is therapeutically useful.

EVIDENCE OF INVENTORY

In one embodiment, the compounds, prodrugs and methods of use of such compounds and prodrugs in the treatment of states in which modulation of the signal path of AAC or inhibition of AAC kinases, in particular, AA2, CA3, or both, is found to be therapeutically useful.

One embodiment of the invention describes compounds of the formula, a salt thereof or a pharmaceutical composition comprising the following compound:

Where:

X and Y are O, 8, 8 (0), 8O₂ or ΝΡ;

every P¹ independently represented by H, and may be substituted by C._1-6alkyl, C (O) -C_1-6alkyl, CO₂- WITH_1-6alkyl or p⁵⁰;

every P⁵⁰ represented by -S (P⁹) 2-A-P¹⁰, where A represents O or 8; every P⁹independently represented by H, and may be substituted with C1-6alkyl substituted by C6-10aryl or substituted by C7-16arylalkyl; or vice versa, two P⁹, together with carbon, to which compounds are attached, form a substituted C3-8cycloalkyl group or heteroalicyclil having from 3 to 8 members in some cases; P is represented by P or -P (O) (OR) 2; Each P is independently represented by P^and or a monovalent cationic group; or two P¹¹, together with the atoms to which they are attached, form a cyclophosphate group of 4-8 members, or two P¹¹ together represent a bivalent cationic group;

ring A represented by C._6-10aryl or heteroaryl of from 5 to 10 members;

every P² independently represented by H, P^is, P^ı, P^is replaced by one or more of the same or other R^and and / or R^ı, -OR^is substituted with one or more of the same or other P^and

and / or R^ı, -8R^is substituted with one or more of the same or other P^and and / or R^and, -C (O) P^issubstituted with one or more of the same or other P^and and / or R^ı, -Y (R^andR)^is, where R^is substituted by one or more of the same or other P^and and / or R^ı, -8 (O) 2P^is substituted with one or several of the same or other R^and and / or R^ı, -Y (R^and) - 8 (O) 2P^is, where R^is substituted with one or several of the same or other R^and and / or R^ı, -B (OR^and) 2, -B (N (P^with) 2)₂, - (C (P^and) 2) t-P^ı, -O- (C (P^and) 2) t-P^ı, -8- (C (P^and) 2) t-P^ı, -O- (C (P^ı) 2) t-P^and, -H (P^and) - (C (P^and) 2) t-P^ı, -O- (CH 2) t -CH ((CH 3)₂) tP^BR)^ı,

-C (O) H (P^and) - (C (P^and) 2) t-P^ı, -O- (C (P^and) 2) t-C (0) H (P^and) - (C (P^and) 2) t-P^ı, -N ((C (P^and) 2) tP^ı)₂,

-8- (C (P^and) 2) t-C (O) I \ I (P^and) - (C (P^and) 2) t-P^ı, -Y (R^and) -C (O) -Y (P^and) - (C (P^and) 2) t-P^B,

-Y (R^and) -C (O) - (C (P^and) 2) t-C (p^and) (P.^B) 2 or -Y (P^and) - (C (P^and) 2) t-C (O) -Y (P^and) - (C (P^and) 2) t-P^B;

every P^and independently represented by H, deuterium, C1-6alkyl, C3-8cycloalkyl, C_4-11cycloalkylalkyl, C._{6- 10}aryl, c_{7- 16}arylalkyl, heteroalkyl of 2-6 members, heteroalicyclil of from 3 to 10 members, heteroalicycloalkyl of 4-11 members, heteroaryl of 5-15 members, or heteroarylalkyl of 6 to 16 members;

every P^ı represented independently = O, -OR^and, -O- (C (P^and) 2) t-OR^and, haloC1-3alkyloxy, = 8, -8P^and, = IР^and, = YOU^and, -Y (R^with) 2, halogen, -SRe, -Si, -NO, -OSY, -80N, -YO, -YO₂, = N2, -N3, -8 (O) P^and, -8 (O) 2P^and, -8O3P^and, -8 (O) N (P^with) 2, -8 (O) 2Y (P^with) 2, -O8 (O) P^and, -O8 (O) 2P^and, -O8O3P^and, -O8 (O) 2Y (P^with) 2, -C (O) P^and, -SO2P^and, -C (O) N (P^with) 2, -C (YY^and) -Y (R^with) 2, -C (CH2) -P^and, -C (CH) -Y (P^with) 2,

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-OC (O) P^and, -OC (O) OR^and, -OC (O) N (P^with) 2, -OC (NH) -Y (P^with) 2, -OC (IRL^and) -Y (R^with) 2, -Y (P^and) -Z (O) 2H, - [N (P^and) C (O)] p^and, - [ı (P^and) C (O)] POR^and, - [ı (P^and) C (O)] n (R^with) 2 or - [N (P^and) C (IRL^and)] p-i (p^with) 2;

every P^with independently represented by R^and or, conversely, two P^with containing nitrogen with which they are bonded to form heteroalicyclils of from 3 to 10 members or heteroaryl of from 5 to 10 members, which may in some cases include one or more identical or different additional heteroatoms, and which may optionally be substituted with one or more identical or different P^and and / or R^and groups;

every P^and represented = O, -OR^and, haloC1-3alkyloxy, C1-6alkyl, = 3, -ZR^and, = IР^and, = YOU^and, -Y (R^and) 2, halogen, -SR₃, -O, -NO, -YOU, -SOY, -YOU, -YO₂, = N₂, -N₃, -Z (O) P^and, -Z (O2) P^and, -ZO3P^and, -Z (O) N (P^and) 2, -Z (O) 2Y (P^and) 2, -OZ (O) P^and, -OZ (O) 2P^and, -OZO3R^and, -OS (O) 2Y (P^and) 2, -C (O) P^and, -SO2P^and, -C (O) N (P^and) 2, -C (YY^and) I (P^and) 2, -C (CH) P^and, -C (CH) N (P^and) 2, -THE₂R^and, -OC (O) N (P^and) 2, -OC (IRL^and) I (P^and) 2, - [N (P^and) C (O)] p^and, - (C (P^and) 2)_p-Or^and, -Y (R^and) -Z (O) 2P^and, -C (O) -C1-6 haloalkyl, -Z (O)₂WITH_1-6haloalkyl, -OC (O) P^and, -O (C (P^and) 2) t-OR^and, -Z (C (P^and) 2)_t-Or^and, -Y (R^and) C-6-halogenalkyl, -P (O) (OR^and) 2, -Y (P^and) - (C (P^and) 2) t-OR^and, - [ı (P^and) C (O)] POR^and, - [ı (P^and) C (O)] n (R^and) 2, - [N (P^and) C (IRL^and)] ny (p^and) 2 chi-y (p^and) C (O) C1_-6halogenalk; two P^and, taken together with the atom or atoms to which they are attached, are combined with the formation of a partially or fully saturated mono-orcyclical ring of 3-10 members, which may in some cases include one or more heteroatoms and in some cases, be substituted by one or more P^and;

every P^is represented independently by C._1-6alkyl, c_3-8cycloalkyl, C._4-iicycloalkylalkyl, c_{6- 10}aryl, c_{7- 16}arylalkyl, heteroalkyl of 2-6 members,

heteroalicyclic having from 3 to 10 members, heteroalicycloalkyl of 4-11 members, heteroaryl of 5-15 members, or heteroarylalkyl of 6 to 16 members;

p is represented by 0, 1,2, 3 or 4, each t is represented by 1,2 or 3; each η is represented by 0, 1,2 or 3;

two groups of P²taken together with the atom or atoms to which they are attached are combined to form a partially or completely saturated mono- or di-cyclic ring of 4-10 members, which in some cases may include one or more heteroatoms and may in some cases be substituted by one or a few p^and and / or R^ı;

Z¹ and Z² Independently represented by CH, SR² or N;

R³ represented by H, in some cases replaced by C._1-6alkyl or p⁵⁰;

R⁴ represented by H, in some cases replaced by C._1-6alkyl or p⁵⁰; and

R⁵ represented by halogen, -CO2 is in some cases substituted with C1-6alkyl, alkynyl, hydroxy, in some cases substituted C1-6alkoxy, nitro, -N (P^and) 2, -C (O) N (P^and)₂, -SO₂R^andor -C (O) P^and groups

Another embodiment of the invention is a method of inhibiting the activity of AβK-kinase, including contact of a α-kinase kinase with an effective amount of a compound sufficient to inhibit the activity of ακ-kinase, wherein the compound is of Formula I, as described herein in the Invention. In one embodiment of the invention, the contact is carried out in the form of a nylon, in another embodiment of the invention, the contact is carried out in the form of a vinyl.

Another embodiment of the invention is a method for treating an autoimmune disease mediated by T cells, which comprises administering to a patient suffering from a type of autoimmune disease an amount of a compound effective for treating an autoimmune disease, wherein the compound is as defined in Formula I as described herein.

Another embodiment of the invention is a method of treating retransmission of an allograft to a recipient of a graft, including administering to the recipient of the transplant a quantity of a compound effective for preventing rejection, wherein the compound corresponds to Formula I as described in this application for the invention. In this context, the administration may include contacting a transplantation organ with a compound or pharmaceutical composition described in the present application for the invention, before transplantation and / or with the administration of the transplant to the recipient.

Another embodiment of the invention is a method of treating an IV hypersensitivity reaction, including administering to a patient an amount of a compound effective to prevent or reduce the hypersensitivity reaction, wherein the compound is in accordance with Formula I as described in the present application for the invention.

Another embodiment of the invention is a method of treating an eye disease or disorder, including administering to a patient an amount of a compound effective for preventing or treating an eye disease or disorder, the compound of formula I being as herein described in the present application.

Another embodiment of the invention is a method of inhibiting a cascade of a signal

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a transduction in which 6DK3-kinase plays a role, including the contact of a cell expressing a receptor involved in such a signaling cascade with a compound, the compound of which corresponds to Formula I, as described in this application for the invention.

Another embodiment of the invention is a method of treating a disease mediated by the ακ-kinase, including administering to a patient a quantity of a compound effective for preventing or treating the mediated anti-HK-kinase disease, wherein the compound corresponds to Formula I, as described in the present application for the invention.

Another embodiment of the invention describes a pharmaceutical composition, including compounds of Formula I, as described in the present application for the invention. The method of treatment using the compounds of the 2,4-pyrimidinedinamine and the pharmaceutical compositions described herein for the invention may be used as a monotherapy or in combination, or as an additional therapy for pre-immunosuppressive therapy.

Another embodiment of the invention describes a kit comprising a compound of formula I as described herein in the present application for the invention, a prodrug thereof, or a pharmaceutical composition, the inclusion of the described compound, packaging and instructions for use.

Another embodiment of the invention describes a unit of a dosage composition comprising a compound of Formula I as described herein with the present invention, its prodrugs, or a pharmaceutical composition, including a compound of Formula I as described.

Other embodiments of the invention include methods for using a compound for screening other agents that are used to treat or prophylaxis diseases mediated by AβK-kinase.

Below is a more detailed description of the presented and other embodiments of the inventions.

DETAILED DESCRIPTION OF THE INVENTION

Review

The invention describes compounds of formula I, as well as compositions and methods of using such compounds in the treatment of conditions in which modulation of the signal pathway of CAg or inhibition of the ακ-kinases, in particular, HaCl3, is therapeutically useful. Also described are compositions, methods of use as agents for screening and other methods of use.

Terms

As used herein, the following words and phrases will be listed below, except when the context in which they are used will assume a different meaning or it will be clearly stated that the words or phrases have a different meaning.

The symbol "-" denotes a single bond, the symbol "^ =" denotes a double bond, and the symbol "^ =" denotes a triple bond. The symbol "^ \ l" refers to the group, which is connected by double bond and which occupies the extreme position with the presence of a double bond, to which the symbol is attached; that is, the geometry of the E- or Z-double bond is ambiguous, suggesting the inclusion of both isomers. When a group is depicted removed from its initial formulas, the symbol "^^" will be used at the end of the communication, which was theoretically split up to separate the group from its original structural formula.

When chemical structures are depicted or described, unless otherwise noted, it is assumed that all carbon atoms have substitutions in the position of hydrogen atoms for the verification of valency 4. For example, in the structure of the left side (see below), it is assumed that there are nine hydrogen atoms. Nine hydrogen atoms are depicted on the structure on the right side. Sometimes, a single atom in the structure is described in the textform as having hydrogen, or substituted hydrogen atoms (clearly indicated hydrogen atoms), for example, -CH₂CH₂-. An expert in this field of science will understand that the above described descriptive methods are common in chemical science, ensuring the simplicity and simplicity of describing complex structures.

With this application, some ring structures are depicted in the general form and will be described by the text. For example, in the scheme below, if ring A is used for the phenyl description, such ring A contains no more than four hydrogen atoms (with P not H).

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If the group P on the ring is depicted as "floating" in the ring system, as in the group, for example:

then, unless otherwise noted, the substituting P may be located on any atom of a fused two-ring system of the ring, with the exception of an atom that binds to the symbol "^ - ^" and forms a stable structure. In the example given, the group P may be located on any atom in a ring of 5 or 6 members of the system of the indole ring.

If more than one similar "floating" group is depicted, as, for example, in the following formula:

K or

NN

, or

where there are two groups, in particular, P, and a link indicating joining the original structure, and unless otherwise noted, "floating" groups can be located in any atomic ring of the ring, again assuming that each substitution of the image, the suspect or clearly the expressed hydrogen in the ring system and a chemically stable compound will be formed by a similarcondition.

If the group P on the ring is depicted in the ring existing in the system, containing saturated atoms of carbohydrate, as, for example, in the formula:

where u may be greater than one, suggesting the replacement of the indicated, predicted or clearly expressed hydrogen atom in the ring, therefore, unless otherwise noted, two P may be located on the same carbon atom. A simple example when represented by a methyl group; The carbon of the indicated ring ("ring" carbon) maybe attached dimethyl. In yet another example, two P's on the same carbon atom can form a ring, thus creating a spirocyclical ring structure (which includes a "spirocyclical" group). Using the preceding example, it turns out that the two Rutile, for example, the piperidine ring in the spirocyclical structure together with the cyclohexane, as represented, for example, by the following formula:

"Alkil" in its broadest sense includes linear, branched or cyclic structureshydrocarbon compounds and their combinations. Alkyl groups can be completely saturated or include one or more unsaturated units, but do not include an aromatic ring. AsGenerally, the alkyl groups are determined by a subordinate index represented in the form of a whole number or a range of integers. For example, "S.₈alkyl "includes η-octyl, iso-octyl, 3-octinyl, cyclohexenelethyl, cyclohexyleneethyl, and the like, while the subscript" 8 "denotes that all groups that are defined by the term have a fixed number of carbon atoms equal to eight. In another example, the term "C._1-6alkyl "refers to alkyl groups having from one to

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six carbon atoms and, depending on the saturation, branching and / or rings, the required number of hydrogen atoms. Examples of C._1-6alkyl groups include methyl, ethyl, vinyl, propyl, isopropyl, butyl, 5-butyl, t-butyl, isobutyl, isobuthenyl, pentyl, pentynyl, hexyl, cyclohexyl, hexenyl, and the like. When the alkyl residue with a specific number of carbon atoms is indicated in general, all geometric isomers having the same number of atoms of carbon should be taken into account. For example, "propyl" or "c₃alkyl "can include η-propyl, c-propyl, propenyl, propynyl and isopropyl. Cycloalkyl is a substituent of alkyl and includes cyclic hydrocarbon groups containing from three to thirteen carbon atoms. Examples of cycloalkyl groups include c-propyl, c-mutant, c-pentyl, norbornyl, norbornenyl, c-hexenyl, adamantyl, and the like. As already noted, alkyl refers to the residues of alkanyls, alkenyls and alkynyls (and their combinations) and includes, for example, cyclohexylmethyl, vinyl, allil, isophenyl, and the like. Alkyl with a certain number of carbon can be called using a more specific but still general name for geometric communication, for example, "C_3-6cycloalkyl "means only cycloalkyl having 3-6 carbon atoms. Unless otherwise indicated, alkyl groups independently or in part of another group, for example, -C (O) alkyl, contain from one to twenty atoms of carbon, representing in the form C_{1- 20}alkyl In the example of "-C (O) alkyl", which does not specify the boundary number of carbon atoms, the carbonyl bond -C (O) alkyl is not included in the calculation of carbon atoms, ie "alkyl" is indicated as a whole. But if a certain limit number of carbon atoms is indicated, for example, in the term "C_{1- 20}alkyl containing in some cases, replacements, "where such substitutions include" oxidation, "the carbon of any carbonyl bond, formed by a similar" oxidative "substitution, is included in the calculation of carbon atoms, ie, such carbon atoms are part of the original limiting number of carbon atoms. However, in returning to "C._{1- 20}alkyl containing in some cases a substitution ", if such a substitution includes a group of fixed carbon numbers, for example -CH₂CO₂H, two carbon atoms in suchgroup are not included in the limiting number of carbon atoms C_1-20alkyl

When indicating the number of carbon atoms at the beginning of the term, consisting of two terms, the limiting amount of carbon atoms is understood to be included in both terms. For example, for the term "S._{7- 14}arylalkyl ", when calculating the carbon atoms, both the terms" aryl "and" alkyl "(in this case, a maximum of 14 atoms) are taken into account, but additional substitutions are not included in the count of the number of atoms until they affect the carbon atom from the group of atoms used for counting the total number of carbon atoms, as in the example with the "oxidative" group above. Similarly, when a reduced number of carbon atoms, for example, "heteroarylalkyl from 6 to 14 members", when calculating a limited number of carbon atoms, both the terms "heteroaryl" and "alkyl" are taken into account, while additional substitutions are not included in the count of the number of atoms until they do not belong to the carbon atom used to calculate the number of atoms. In another example, "S._{4- 10}cycloalkylalkyl "refers to cycloalkyl, linked to the primary structure by means of alkylene, alkylidene or alkylidine; in this example, the group is limited to 10 carbon atoms, including the atoms of the substitutions of alkylene, alkylidene or alkylidine. As another example: an "alkaline" site, for example, "C._{7- 14}arylalkyl "should include alkylene, alkylidenabo alkylidine, unless otherwise indicated, for example in the terms" C7-14arylalkylene "or" C6-10aryl-CH2CH2- ".

"Alkylene" refers to direct, branched and cyclic (and combinations thereof) of a bivalent radical consisting exclusively of carbon and hydrogen atoms, unsaturated bonds, having from 1 to 10 carbon atoms, for example, methylene, ethylene, propylene, η-butylene etc. Alkylene-like to alkyl refers to the same residue as alkyl, but has two sections of accession and, in particular, is completely saturated. Examples of alkylene include ethylene (-CH₂CH₂-), propylene (- CH₂CH₂CH₂-), dimethylpropylene (-CH₂C (CH₃)₂CH₂-), cyclohexane-1,4-diethyl, etc.

" Alkylidene" refers to direct, branched and cyclic (and combinations thereof) of an unsaturated bivalent radical consisting exclusively of carbon and hydrogen atoms of 2 to 10 carbon atoms, for example, ethylides, propylidenes, η-butylides, and the like. Alkilidene is similar to alkyl, refers to the same residue as alkyl, but has two attachment sites and, in particular, at least one unsaturated double bond. Examples of alkylidenes include vinylidene (-CH = CH-), cyclohexylvinylidene (-CH = C (C₆N₁₃) -), cyclohexene-1,4-diyl, and the like.

"Alkilidine" refers to direct, branched and cyclic (and combinations thereof) of an unsaturated bivalent radical consisting exclusively of carbon and hydrogen atoms of 2 to 10 carbon atoms, for example, propylidine-2-inyl, butylid-1-inlyl and t .p Alkilidine is similar to alkyl, refers to the same residue as alkyl, but has two attachment sites and, in particular, as the least one unsaturated triple bond.

Each of the aforementioned radicals ("alkyl", "alkylidenes" and "alkylidines"), when introduced

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iA 106975 C2

any substituting group may contain substitution groups in the alkyl residues containing the unsaturated bonds themselves. For example, 2- (2-phenylethinyl-but-3-enyl) -naphthalene (the name given to IRIAS) contains a p-butylid-3-inyl radical with a vinyl group in the 2-position of the radical. So way, the combination of alkyl and carbon-containing substitutions are limited to 30 carbon atoms.

"Alcoxy" refers to the group -O-alkyl, where the alkyl corresponds to the above definition. Alcoxy includes, for example, methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy, I-butoxy, ze-butoxy, p-pentoxy, cyclohexyloxy, cyclopropylmethyloxy, and the like.

"Halogenalkyloxy" refers to the group -O-alkyl, wherein the alkyl is as defined above, and, moreover, contains a substitution by one or two halogen atoms. For example, the group is "halogen"_1-3Alkyloxy "includes -OSE₃, -THE₂N, -External₂, -OSH₂CH₂Vr, -OCh₂CH₂CH₂I, -OC (CH₃)₂Vr, -OCh₂SI etc.

"Acyl" refers to the groups -C (O) H, -C (O) alkyl, -C (O) aryl, and -C (O) heterocyclyl.

? Α-amino acids "refer to the presented in nature and the market α-amino acids and their optical isomers. Typical and α-amino acids present on the market include glycine, alanine, serine, homoserine, threonine, valine, norvalin, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, octopus, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine , homophenylalanine, phenylglycine, orto-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. The "side chain of the α-amino acid" refers to the radical of the α-carbon atom of the α-amino acid (as defined above), for example, hydrogen (for glycine), methyl (for allynine), benzyl (for phenylalanine), and so on. d.

"Amino" belongs to the group -YN₂.

"Amid" refers to the group -C (O) NN₂ or -Y (H) acyl.

"Aryl" (sometimes referred to as "Ag") refers to a monovalent aromatic carboxylic group, consisting of, unless otherwise indicated, from 6 to 15 carbon atoms forming a single ring (eg, phenyl) or several condensed rings (for example, naphthylabo anthryl) ; such condensed rings may be aromatic or nonaromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H) -one-7-yl, 9,10-dihydrophenanthrenyl, indanyl, tetralinyl, fluorenyl, and the like. ), and the site of accession includes an atom of the aromaticstructure of the aryl group, with the aromatic structure in the area of ​​accession contains only carbon atoms of the aromatic ring. If any portion of the aromatic ring contains a heteroatoma, the group is heteroaryl and is not aryl. Aryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic. "Arilen" refers to Daril which has at least two groups attached to it. For example, "propylene" refers to the prevalent radical of the phenyl ring. Thus, phenylene may contain more than two joined groups, but is determined by at least two attached groups (other than hydrogen).

"Alkylaryl" refers to the residue in which the aryl radical is attached to the original structure using the following radicals: alkylene, alkylidene or alkylidine. Examples include benzyl, phenylethyl, phenylvinyl, phenylalyl, and the like. When this "substitution in some cases", this means that in some cases, the corresponding atoms in groups of alkylene, alkylidene or alkylidine of the alkylaryl group may be substituted. For example, "C7-11arylalkyl" refers to arylalkyl, limited to eleven carbon atoms, for example, phenyleneethyl, phenylvinyl, phenylpentyl and naphthylmethyl are examples of "C7-11 arylalkyl" groups.

"Aryloxy" refers to the group -O-aryl, wherein the aryl is determined in accordance with the definition herein, including, for example, phenoxy, naphthoxy, etc. groups

Carboxyl, carboxy or carboxylate refers to -CO2H or its salts.

"Ether of carboxylic acid" or "ether" refers to the group -CO₂alkyl, -CO₂aryl or -CO2heterocyclyl.

"Carbonate" refers to the group -OCO2 alkyl, -OCO2aryl or -OSO2heterocyclyl.

"Karbamat" refers to the group -OC (O) NN₂, -Y (H) carboxyl or -H (H) ester of a carboxylic acid.

"Cyano" or "nitrile" refers to the group -SY.

"Formyl" refers to a specific acyl group -S (O) H.

"Halo-" or "halogen" refers to fluorine, chlorine, bromine and iodine groups.

"Halogenalkyl" or "halogenaryl" as a whole refers to aryl and alkyl radicals containing one or more substituted halogen atoms. For example, "digalogranaril", "digalogenalkyl", "trihalogenaril", and the like. refer to aryl and alkyl radicals with a substitution of several halogen atoms, but not necessarily halogens; In this way, 4-chloro-3-fluorophenyl is included in the digalogenaryl group.

"Heteroalkyl" refers to alkyl, in which one or more but not all carbon atoms

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substituted heteroatoms. The heteroalkyl group has a linear or branched geometry. For example, "heteroalkyl of 2-6 members" is represented by a group that can contain no more than 5 carbon atoms, since at least one of at most 6 atoms must be represented by a heteroatom, with the group linear or branched. In addition, for the purposes of the present invention, the heteroalkyl group always begins with a carbon atom, however, although the heterocyclo may contain one or more heteroatoms, the site of attachment to the parent molecule is not a heteroatom. A heteroalkyl group of 2-6 members includes, for example, -CH₂CHF₃, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -C (CH2) 2CH2CH2CH2, and the like, wherein X is represented by O, NH, NH_ν6alkyl and 8 (O)_0-2.

"Pergalo" as a modifier indicates that the group, modified in such a way that all present hydrogen atoms are replaced by halogen atoms. An example is "pergaloalkyl." Pergalalkyls include -SR₃, -SR₂SR₃, perchlorethylene, etc.

"Hydroxy" or "hydroxyl" refers to the group -OH.

"Heteroatom" refers to O, 8, N or R.

"Heterocyclyl" in its broadest sense includes systems with aromatic and non-aromatic ring, and, more specifically, refers to a stable radical ring of 13-15 members, which includes carbon atoms and 1-5 heteroatoms. For purposes of the present invention, the heterocyclic radical may be a monocyclic, bicyclic or tricyclic ring system, which may include ringed or bridged cells, as well as spirocyclic systems; Atoms of nitrogen, phosphorus, carbon or copper in a heterocyclic radical may in some cases be oxidized to various oxidative states. As an example: group -3 (O)_0-2- refers to -3- (sulfide), -3 (O) - (sulfoxide) and -3O₂- (sulfonium) for bonds. For ease of nitrogen in particular, but non-exclusive, nitrogen included in the aromatic ring is designed to include relevant Ν-oxide form, although it is not obviously expressed in this particular example. Thus, for a compound containing, for example, a pyridyl ring, the presence of an appropriate pyridyl-H-oxide means the possibility of inclusion in the invention described herein for the compound. In addition, the included ring of nitrogen atoms may in some cases be represented in quaternary form. "Heterocycle" includes heteroaryl and heterocyclyl, so the heterocyclic ring can be partially or fully saturated or aromatic. Thus, the term "heterocycloalkyl" includes heteroalicycloalkyl and heteroarylalkyl. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioksanyl, bezofuranyl, karbazolil, tsynnolinyl, dioksolanyl, indolizynil, naftyridynil, perhidroazepinyl, fenazinyl, fenotiazinyl, fenoksazinyl, ftalazinyl, pterydinyl, purinyl, hinazolinyl, hinoksalinyl, hinolinyl, izohinolinyl, tetrazoyil, tetrahidroizohinolinyl, piperydinyl, piperazinyl, 2-oksopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pirazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridine, tetrahydropyridinyl, pyridinyl, pyrazine , Pirymidinyl, pirydazinyl, oxazolyl, oksazolinyl, oksazolidinyl, triazolil, isoxazolyl, izoksazolidinyl, morfolinyl, thiazolyl, tiazolinyl, tiazolidinyl, isothiazolyl, hinuklidinyl, izotiazolidinyl, indolyl, izoindolil, indolinyl, izoindolinyl, oktahidroindolil, oktahidroizoindolil, quinolyl, izohinolil,

"Heteroaryl" refers to an aromatic group with 1-10 inclusions in the ring of atoms of carbon and 1 to 4 ring hetero atoms in the ring. Heteroaryl groups have in their composition at least one aromatic ring, while they can be completely or partially saturated. If in any aromatic ring of the group there is a heteroatom, then the group is a heteroaryl, even if, for example, another ring in the group does not contain heteroatoms. For example, 2H-pyrido [3,2-b] [1,4] oxazine-3 (4H) -on-7-yl, indolyl and benzimidazolyl are "heteroaryl". The heteroaryl groups may have one ring (eg pyridinyl, imidazolyl or furyl) or multiple condensed rings (for example, indolizinyl, quinolinyl, benzomidazolyl, benzothienyl), and such fused rings can be aromatic / nonaromatic and / or contain a heteroatom, and the site of attachment to the parent molecule is represented by the atom of the aromatic ring heteroaryl group. In one embodiment of the invention, the nitrogen atoms and / or sulfur atoms included in the ring of the heteroaryl group may in some cases be oxidized to form an N-oxide (N2O), sulfinil or sulfonyl. The compounds described in this application for the invention and those containing phosphorus, whether or not incorporated into a heterocycle, include oxidized forms of phosphorus. Heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic. whether or not included in the heterocycle, include oxidized forms of phosphorus. Heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic. whether or not included in the heterocycle, include oxidized forms of phosphorus. Heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic.

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"Heteroaryloxy" refers to -O-heteroaryl.

"Heteroarylene" in general refers to any heteroaryl having at least two groups attached to it. For example, "pyridylene" refers to a bivalent radical pyridyl ring. Thus, pyridylene may contain more than two attached groups, but determined by at least two attached groups (other than hydrogen).

"Heteroalicyclic" refers to a non-aromatic heterocyclic radical. The heteroalicyclic radical may contain unsaturated bonds, but not aromatic. As already noted, aryls and heteroaryls are joined to the original structure with the aromatic ring. Thus, for example, 2H-1,4-benzoxazine-3 (4H) -one-4-yl is a heteroalicyclic, while 2H-1,4-benzoxazine-3 (4H) -one-7-yl is aryl. In another example, 2H-pyrido [3,2-b] [1,4] oksazyn-3 (4H) -one-4-yl is heteroalitsyklichnym, while 2H-pyrido [3,2-b] [1 , 4] oxazine-3 (4H) -one-7-yl is heteroaryl.

"Heterocycloalkyl" refers to a heterocyclic group attached to the parent molecular by means of, for example, linker alkylene, for example, (tetrahydrofuran-3-yl) methyl or (pyridin-4-yl) methyl.

.0

or

"Heterocycloxyl" refers to -O-heterocyclyl.

Nitro belongs to the group -NO₂.

"Okso" refers to a radical in which the oxygen atom is connected by a double bond.

"Oxy" refers to the radical -O · (which is also denoted as -►O), which is a radical of a single bond of oxygen joining. For example, nitrogen oxides are represented by nitrogen atoms carrying an oxy-radical.

If it is indicated that the group and its bearing structure are attached to two partners, this is indicated by the bivalent radical, for example, -OSN₂-, it is understood that each of the two partners can be associated with a separate group at one end, and the other partner must be necessarily linked to the other end of the bivalent group, unless otherwise specified by a clearly defined form. In other words, divalent radicals should not be interpreted as limited to the indicated orientation, for example, "-OSH2-" denotes not only the group "-OSH2-", depicted in the picture, but also "- CH2O-".

"In some cases" or "optionally" indicates that the phenomenon or circumstance described below may or may not arise, and the description includes examples where the phenomenon or circumstance arises, and also examples when they do not arise. One skilled in the art will appreciate that any suitable synthetic compounds for any of the described molecules containing one or more optional substituents must be taken into account. "Replaced in some cases (optionally)" refers to all subsequent modifications that are included in the term, for example, in the term "replaced in some cases aryl_1-8alkyl "in some cases may optionally represent fragment" Ci_-8alkyl "and" aryl "fragment of aryl_1-8an alkyl group. In addition, for example, substituted in some cases, alkyl includes, in some cases, substituted cycloalkyl groups. The term "substituted" when used to modify a particular group or radical indicates that one or more hydrogen atoms of said group or radical independently of one another are replaced by the same or by different substitution groups (see below). Thus, when a group is indicated as "substituted in some cases," this definition means that the groups are replaced by one or more radicals (see below).

Substituting groups to replace one or more hydrogen atoms (any two atoms of a water atom on a carbon atom may be replaced by = O, = NR⁷⁰, = N-PO⁷⁰, = N₂ or = 3) of saturated carbon atoms in said group or radical are represented by the following: I⁶⁰, halogen, = O, -OI⁷⁰, -What⁷⁰, -N (H)⁸⁰) 2, perhaloalkyl, -O, -OCH -SOCH-NO, -NO2, = N2, -N3, -CO2J⁷⁰, -ZO3^_M⁺, -ZO3Ya⁷⁰, -OZO2Ya⁷⁰, -OO3^-M +, -OSO3Ya⁷⁰, -Ya (O) (O ") 2 (M⁺) 2, -Y (O) (O ") 2M²⁺, -Ya (O) (THERE⁷⁰) O "M +, -P (O) (OI⁷⁰) 2, -C (O) I⁷⁰, -C (C) I⁷⁰, -C ^ H ^ H⁷⁰, -CO2^-M +, -CO2J⁷⁰, -С (З) ОЯ⁷⁰, -SSO ^ I⁸⁰^, - C ^ I ^ XY⁸⁰'^, -OC (O) I⁷⁰, -OC (C) I⁷⁰, -CO2^-M +, -OSO2Ya⁷⁰, -OC (C) THERE⁷⁰,

^ I ^ C ^ I, -NY⁷⁰СО2^_М+, ^Я^^Я⁷⁰, ^^^^^^^^^^^^⁷⁰, -NYa⁷⁰C (O) N (I⁸⁰) 2, ^⁷^^⁷¼⁷⁰ and-NJ⁷⁰C (NI⁷⁰) N (I⁸⁰) 2 where I am⁶⁰ represented by C1-6alkyl, heterocyclyl of from 3 to 10 members, heterocyclyl_1-6an alkyl of 3-10 members, c_6-10aryl or c_6-10aryl_1-6alkyl; with each I am⁷⁰independently H and I⁶⁰, every I am⁸⁰ Independently, I am⁷⁰ or vice versa, two of me⁸⁰, taken together with the nitrogen atom to which they are attached, form heteroalicycliles of from 3 to 10 members, which in some cases may comprise 1 to 4 identical or different additional heteroatoms selected from

9

υΑ 106975 C2

O, N and 8, with N in some cases may contain H or C.₁-WITH₃alkyl substitution; each M + is an oppositely charged ion with a single positive charge. Each M + is represented independently, for example, by an alkali metal ion, for example, K +, N +, L +, ammonium ions, for example, + N (H⁶⁰) 4 or an alkaline earth metal ion, for example [Ca²+] 0.₅, [Md²+] 0.5 or [Va²+] 0.₅(the subscript index "0.5" indicates that one of the oppositely charged ions for such a doubly-valent alkaline earth metal ion can be represented in an ionized form of the compounds of the present invention, while another typical reciprocally charged ion, for example, chlorine ion, or two ionized compounds can serve as an opposite charged ion for such ions two-suspended alkaline earth metals, or twice the ionized compounds can serve as an optionally charged ion for such divalent alkaline earth metal ions). An individual example: it is indicated that -N (H⁸⁰)₂ includes -NH₂, -NH-alkyl, -NH pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4-methyl-piperazin-1-yl, N-morpholinyl, and the like.

Substituent groups for substitution of hydrogen atoms with carbon atoms with unsaturated bonds in groups containing unsaturated carbon atoms are, if not indicated, other, as follows: -H⁶⁰, halogen, -O^-M +, -OH⁷⁰, -ZN⁷⁰, -Z^-M +, -N (H⁸⁰)₂, perhaloalkyl, -O, -O-N-MSO-NO, -NO 2, -N 3, -ZO 2 NH⁷⁰, -ZOZ^-M +, -ZO3H⁷⁰, -OZO2N⁷⁰, -OZZ^-M +, -OSO3H⁷⁰, -YaOz^-2(M + b-Ros)^-2M²+, -Ya (O) (OH⁷⁰) O "M +, -P (O) (OH⁷⁰) 2, -C (O) H⁷⁰, -C (C) H⁷⁰, -O (NN⁷⁰) Η⁷⁰, -CO2^-M +, -CO2H⁷⁰-S (Z) OH⁷⁰, -C (O ^ N⁸⁰N⁸⁰, -O (NN⁷⁰) N (H⁸⁰) 2, -OC (O) H⁷⁰, -OC (C) H⁷⁰, -CO2^-M +, -OSO2N⁷⁰-OC (C) OH⁷⁰, ^ N⁷⁰SLEEP⁷⁰, ^ N⁷⁰C (C) H⁷⁰, ^ N⁷° СО2^_M +, -NH SO.T, ^ N⁷⁰C (O) OH⁷⁰-NOHMMM, -NH⁷⁰O (NN⁷⁰) Η⁷⁰ and -NH⁷⁰O (NN⁷⁰) N (H⁸⁰) 2 where I am⁶⁰, N⁷⁰, N⁸⁰ and M + are presented in accordance with the foregoing definitions provided that in the case of substituted alkenomabo alkyn, the substituent groups are not represented -O^-M +, -OH⁷⁰, -ZN⁷⁰ or -Z^-M +.

Substituent groups for replacing hydrogen atoms on nitrogen atoms in groups containing similar nitrogen atoms are represented by the following (unless otherwise noted): -N⁶⁰, -O^-M⁺, -OH⁷⁰-ZN⁷⁰, -Z^-M +, -N (H⁸⁰) 2, perhaloalkyl, -O, -NO, -O, -O2, -Z (O) 2N⁷⁰, -ZO3^-M +, -ZO3H⁷⁰, -OZ (O) 2H⁷⁰-OZ3^-M +, -OSO3H⁷, -RO3^2-(M +)₂, -RO3^2-M²+, -P (O) (OH⁷⁰)AT^-M +, -P (O) (OH⁷⁰) (OH⁷0), -C (O) H⁷⁰-C (C) H⁷⁰, -O (NN⁷⁰) Η⁷⁰, -SO2N⁷⁰, -C (C) OH⁷⁰, -C (O ^ N⁸⁰N⁸⁰, -O (NN⁷⁰) NN⁸⁰Η⁸⁰, -OC (O) N⁷⁰, -OC (C) H⁷⁰^ N⁷⁰C (O) OH⁷⁰

70

^ N⁷⁰SLEEP⁷⁰, 'An⁷⁰C (C) H⁷⁰'

^ n^{/ 0}c (o) ^ n⁸⁰) 2, -νη^{/ 0}ο (νη^{/ N}) η⁷⁰ and -νη⁷⁰ο (νη⁷⁰) N (η⁸⁰) 2 where I am⁶⁰

NN ^^ H⁷⁰,

-SO2N⁷⁰, -OC (C) OH

N⁷⁰, N⁸⁰ and M⁺ presented

in accordance with the definition above.

In one embodiment of the invention, the replacement group may contain 1,2, 3 or 4 substitutions, 1,2 or 3 substitutions, 1 or 2 substitutions, or 1 substitution.

It is to be understood that the present invention does not include compounds in which all substitutable groups contain polymers that have arisen in determining the alternates of further derivatives relative to themselves (for example, substituted aryl has a substituted aryl group as a substituent which is itself substituted by a substituted aryl group, the latter hereinafter substituted by a substituted aryl group, etc.). In this case, when a large number of substitutions is allowed, the maximum number of such iterations replaces three.

"Sulfonamide" refers to the group -ZO ^ N₂, -CHN) ZO₂H, ^ (H) ZO₂alkyl, -rN) ZO₂aryl or ((H) CO)₂heterocyclyl.

"Sulfonyl" belongs to the group -ZO₂H, -ZO₂alkyl, -ZO₂aryl or -ZO₂heterocyclyl.

"Sulphanil" refers to the group -ZN, -Z-alkyl, -Z-aryl, or -Z-heterocyclyl.

"Sulfinyl" refers to the group -Z (O) H, -8 (O) alkyl, -8 (O) aryl or -8 (O) heterocyclyl.

"Suitable substitute group" is determined according to the traditional value for a specialist in this field of science; such a group is attached to carbon, and when the reaction is formed a new relationship, carbon loses the group when the formation of a new connection. A typical example of a suitable substituent group is a nucleophilic substitution reaction, for example,³-hybridizedcarbons (8N₂ or 8N₁), for example, the substituent group is represented by the halide, i.e. bromide, the reactant must be represented by bromine benzyl. Another typical exemplary reaction is represented by the reaction of the nucleophilic aromatic substitution (8Ngγ). Another example is the inclusion reaction (for example, transition metal) in the relationship between the partner with the aromatic ring bearing the substituting group, followed by restoration of the binding. "Suitable substitute group" is not limited to such restrictionsmechanisms of the reaction. Examples of suitable substitutable groups include halogens, in some cases, substituted aryl or alkyl sulfonates, phosphonates, azides, and -Z (O) 0-2 Ya, while may be in some cases represented by substituted alkyl, in some cases, substituted by the malachite or in some cases substituted heteroaryl.

"Stereoisomer" and "stereoisomers" refer to compounds having the same order of accession of atoms, but different location of atoms in space. Stereoisomers include cis-

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trans isomers, E and Z isomers, enantiomers and deesterioms. The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, and therefore may contain enantiomers, diastereomers, and other stereoisomeric forms that may be defined as stero-chemistry in the form of (P) or (8) - or (I) or (b) for amino acids. The present invention includes all such possible isomers, as well as their racemates and optically pure forms. Optical active (+) and (-), (P) - and (8) -, or (i) - and (b) - isomers can be obtained using chiral synthones, chiral reagents or using a standard for example, the formation of diastereoisomeric salts or complexes that can be separated, for example, by crystallization; the formation of diastereoisomeric derivatives that can be separated, for example by crystallization; a selective reaction of one enantiomer with an enantiomer-specific reagent, for example, by enzymatic oxidation or reduction by a large division of modified and unmodified enantiomers; gas-liquid or liquid chromatography in a chiral medium, for example, on a chiral substrate (silicon), by coupling a chiral ligand or in the presence of a chiral solvent. If the required enantiomer is converted to another chemical molecule using one of the above-described separation procedures, additional actions may be required to isolate the desired formyl enantiomer. On the other hand, a specific enantiomer can be synthesized by pathosymmetric synthesis using optically active reagents, substrates, a catalyst, or solvents, or by converting the enantiomer into another enantiomer of a method of metasymmetric transformation. In a mixture of enantiomers containing a large number of separate enantiomers, the main enantiomer can be further enriched (with concomitant loss of yield) by recrystallization.

If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise noted, it is meant that the compounds include E and Z geometric isomers.

"Tautomer" refers to alternative forms of a molecule that differ only in the electron-binding of atoms and / or the location of protons, for example, enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing a ring arrangement of atoms -Y = C H) -YN-, for example, pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles. One skilled in the art recognizes that in the present invention it is possible and foreseen the presence of other tautomeric forms of the arrangement of atoms in the ring.

In the concepts of the present invention, the term "steam" refers to the location of the substituent on the naphenyl radical or the 6-membered heteroaryl ring relative to another substitute in the ring; this relative position of the substitute is represented by the provisions of 1.4. That is, starting from one adder connected to the first atom of the 6-membered ring, and considering the atoms, including the first atom, the other substitute is located on 4 atoms of the 6-membered ring; At the same time, the relative orientation of the alternates in the 6-membered ring is denoted as a "pair". For example, the lower compound is shown and has a methyl group in the "vapor" position relative to N2 pyrimidinediamine; The compound also has a methyl group in the "bet" position.

"Patient" or "object of research" refers to mammals and other animals, in particular human beings. Thus, the methods of application include both human treatment, and in the field of veterinary medicine. In one embodiment, the patient or participant is represented by a mammal. In another embodiment, the patient or participant is represented by a human being.

"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of compounds that have been obtained using a variety of organic and inorganic anti-charged ions well known in science and include, for example, only sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. .; the molecule having the basic functionality, contains salts of organic or inorganic acids, for example, hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. Pharmaceutically acceptable salts obtained by attaching acids are salts having a biological efficacy of the free bases along with the meaning of lipid partners that are not biologically undesirable, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, orthophosphoric acid, etc. etc., as well as organic acids,

11

iA 106975 C2

acid, malonic acid, succinic acid, fumaric acid, grapetic acid, citric acid, benzoic acid, cinnamic acid, alcoholic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable salts obtained with the addition of The bases include salts of derivatives of inorganic bases, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Typical salts are represented by salts of ammonium, potassium, sodium, calcium of magnesium. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including substituted naturally occurring amines, cycloamines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine , triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histoidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglyucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamide resins, etc. Typicalorganic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, for example, 3. M. Wegde, et al., "Rationale of Israel," March 3, 1977; 66: 1-19 (Included in this document by reference)). Typicalorganic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, for example, 3. M. Wegde, et al., "Rationale of Israel," March 3, 1977; 66: 1-19 (Included in this document by reference)). Typicalorganic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, for example, 3. M. Wegde, et al., "Rationale of Israel," March 3, 1977; 66: 1-19 (Included in this document by reference)).

"Pharmaceutically effective amount" and "therapeutically effective amount" refers to the amount of compound sufficient to treat said disorder or disease, or one or more symptoms, and / or to prevent the onset of the disease or disorder. The number ofcompounds, which is a "therapeutically effective amount," will vary depending oncompounds, the state of the disease and its weight, the age of the patient undergoing treatment, etc. Therapeutically effective amount can be determined by a specialist in the field of sciencestandard methods.

Prodrugs refer to compounds that have been transformed in conditions of an νίνο to obtain an output compound, for example by hydrolysis in the stomach or enzymatic conversion in the blood. Typical examples include, but are not limited to, the ethers and amide forms of the compound, the active form of which contains a carboxylic acid molecule. Examples of pharmaceutically acceptable esters of the compounds of the present invention include, but are not limited to, alkyl esters (for example, 1 to 6 carbon atoms), with the alkyl group having a straight or branched chain. Suitable esters also include cycloalkyl ethers and arylalkyl esters, such as benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present invention include, but are not limited to, primary amides, secondary and tertiary alkylamides (for example, 1-6 carbon atoms). The amides of yethers of the compounds of the present invention can be obtained using standard methods. A detailed discussion of prodrugs is presented in T. Nidissi and V. V. Ziyiyah, "Rho-bhidz az ΝονοίσεheShegu Zuziets," Volume 14 AS.Z. Zoutrozit Segeiz, and in Vio ^ ee ^ ziye Saggiehz ip Ogid Oezdip, Ebt. Ebtagb V. RosIe, Ategisap RIagtasseiisiAsia Azzosiaiiiop Apb Regditop Rgez, 1987 (Included is a submitted document for any purpose via the link).

"Metabolite" refers to a split or end product of a compound or its salt in result of a metabolism or biotransformation in an organism of an animal or human, for example, by biotransformation into a more polar molecule by oxidation, reduction or hydrolysis, or the formation of a conjugate (see Report of the Pharmacy Sitape, Tie Rigtasoiodisia Vaziz otiiyeegareiiisz "8 ™ Eb., Regditop Rgez, Syitaep et al. (Eds), 1990 (included in this document using the link)). The metabolite of the compound described herein or a salt thereof can itself be a bio-active compound in the body. While the prodrugs described herein must correspond to a criterion for the formation of a biologically active starting compound under the conditions of ipνννο, the "metabolite" includescompounds which are not provided for prodrugs and include all compounds, formed in the conditions of the νίνο ip conjugate administration of the compound of the invention with said biological activity. One aspect of the invention describes compounds of 2,4-pyrimidinediamine, which is a specific metabolite of the compound described herein. For example, a biologically active metabolite manifests itself in a happy coincidence of circumstances that is not foreseeable for any progeny regge. In other words, biologically active compounds are defined as a result of practical methods of application of the invention presented and described in this application. "Silvat" refers to a complex formed by the combination of solvent molecules with molecules or ions of soluble matter. The solvent may be an organic compound, an inorganic compound, or a mixture thereof. Some examples of solvents include, but are not limited to, methanol, N, N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide and water. The compounds described herein may exist in an unleaded and sialivated form, together with solvents that are or are not pharmaceutically acceptable, for example, water, ethanol, and the like. The activated forms of the compounds herein are considered and described by the invention at least in general terms.

12

iA 106975 C2

"Treatment" in the context of the present invention encompasses the treatment of a disease or condition of a vestibular, preferred person having a condition or disease, and includes the following:

(i) preventing the onset of a disease or condition in a mammal, especially in a mammal that is susceptible to the condition but not yet diagnosed;

(ii) inhibiting the disease or condition, for example, by relieving or retarding its development;

(iii) a weakening of the disease or condition, for example, caused by a decrease in the disease or condition, or their symptoms;

(ίν) stabilization of the disease or condition.

As used herein, the terms "disease" and "state" may be applied interchangeably or may differ in the presence of a pathogen state or in the absence of an illness (with an unclear etiology), which, consequently, can not be considered a disease, but only undesirable a condition or a syndrome, thus doctors can define only separate asymptoms.

It is understood in the same way that the above definitions do not include unacceptable substitutions (for example, methyl substituted with 5-fluorine groups). Such unacceptable substitutions may be readily detected by a person skilled in the art.

Compounds and compositions

The present application describes novel compounds 2,4-pyridinediamine, prodrugs of the compound, methods for the preparation of the compound, and methods of using such compounds in the treatment of conditions in which the use of the signaling pathway, or the modulation, including inhibition of anti-HK kinases, in particular, HaCl3, is therapeutically justified. Such conditions include, but are not limited to, leukemia, lymphoma, transplant rejection (e.g., rejection of an islet pancreatic transplant, rejection of the graft, rejection of the kidney transplant, rejection of the liver transplant, rejection of the lung graft), bone marrow transplantation (e.g. graft versus host disease), autoimmune diseases (for example, diabetes) and inflammation (for example, asthma, allergic reactions, visual disturbances). Taking into account the severity and prevalence of such diseases and conditions,

Connections

The compounds herein and their salts are, as a rule, pyrimidine-2,4-diamine, which is substituted in 5 positions by various groups; substituted in the 2nd position in different and in some cases substituted aromatic groups; and substituted in the 4th position with the following: aminobenzo [b] oxazol-2 (3H) -one, 1H-benzo [b] imidazol-2 (3H) -one, benzo [b] thiazol-2 (3H) -one, benzo [b] [1,3] dithiol-2-one, benzo [b] [1,3] oxatiol-2-one, benzo [b] [1,3] dioxol-2-one, [1,3] oxazolino [4,5-b] pyridin-2-one, thiazolo [5,4-b] pyridine-2 (1 H) -one, oxazolo [5,4-b] pyridin-2 (1 H) -one, [1 3] oxathiolo [5,4-b] pyridin-2-one, thiazolo [4,5- b] pyridin-2 (3H) -one, oxazolo [4,5- b] pyridine-2 (3H) -one ,

[1,3] dioxolo [4,5-b] pyridin-2-one, [1,3] dithiolo [4,5-b] pyridin-2-one, 1 H -imidazo [4,5- b] pyridin- 2 (3H) -one, [1,3] oxathiolo [4,5-b] pyrazin-2-one, thiazolo [5,4-b] pyrazin-2 (3H) -one, oxazolo [5,4-b] ] pyrazine-2 (3H) -one, [1,3] dioxolo [4,5-b] pyrazin-2-one, [1,3] dithiolo [4,5- b] pyrazin-2-one and 1H- imidazo [4,5-b] pyrazine-2 (3H) -one; in each case, each compound has one or more substituted groups, including prodrug molecules, as described in the present application for the invention. In addition to the above-described groups, the N2- and N4-amines of the pyrimidindinamine system may also in some cases contain a substitution of alkyl groups and / or prodrug groups.

In particular, the typical compounds described are represented by formula I:

I

Where:

X and Y are O, 8, 3 (0), 5O₂ or ΝΡ;

every P¹ independently represented by H, and may be substituted by C._1-6alkyl, C (O) -C_1-6alkyl, CO₂- WITH_1-6alkyl or p⁵⁰;

every P⁵⁰ represented by -S (P⁹)₂-A-P¹⁰, where A represents O or 5; every P⁹independently represented by H, and may be substituted with C1-6alkyl substituted by C6-10aryl or substituted by C7-16arylalkyl; or vice versa, two P⁹, along with the carbon to which

13

iA 106975 C2

they join, form optionally replaced by C.₃_₈a cycloalkyl group or a heteroalicyclil

10

with 3-8 members;

represented by P or -P (O) (OR)₂;

everyone

11

R in an independent manner

represented by R^and or a monovalent cationic group; or two P '¹, together with the atoms to which they are attached, form a cyclophosphate group of 4-8 members, or two P¹¹ together represent a bivalent cationic group;

Ring A represented by C._6-10aryl or heteroaryl of from 5 to 10 members;

every P² independently represented by H, P^is, P^ı, P^is replaced by one or more of the same or other R^and and / or R^ı, -OR^is substituted with one or more of the same or other P^andand / or R^ı, -8R^is substituted with one or more of the same or other P^and and / or R^ı, -C (O) P^issubstituted with one or more of the same or other P^and and / or R^ı, -Y (R^andR)^is, where R^is replaced8 (O)₂R^is replaced by one or

one or more of the same or other P^and and / or R^ı

and / or R^ı, -Y (R^and) - 8 (O) 2P^is, where R^is replaced by one or-B (IR (P.^WITH) 2)₂, - (C (P^andB) t-p^ı, -O- (C (P^andB) t-p^B, -8- (C (P^and) 2) t-P^ı, -O- (CH 2) t -CH ((CH 2)_tR^ıR)^ı, -С (О) ИЧ (Р.^and) - (C (P^and)₂) t-P^ı,

-Y ((C (P^and) 2) tP^ı) 2, -8- (C (P^and) 2) т-С (О) ИЧ (Р^and) - (C (P^and) 2) t-P^B,

-Y (R^and) -C (O) - (C (P^and) 2) t-C (p^and) (P.^ú) 2 oz

₆alkyl, c_3-8cycloalkyl,

_Rand

and

several of the same or different number of the same or R^ı, -B (OR^and)₂,

-O- (C (P^ı) 2) t-P^and, -M (P.^and) - (C (P^and) 2) t-P^ı,

-O- (C (P^and) 2) t-C (O) I \ I (P^and) - (C (P^and) 2) t-P^B,

-Y (R^and) -C (O) -Y (P^and) - (C (P^and)₂) t-P^ı,

-Y (R^and) - (C (P^and) 2) t-C (O) -Y (P^and) - (C (P^and) 2) t-P^B;

every P^and Independently represented by H, deuterium, С1С_4-11cycloalkylalkyl, C._{6- 10}aryl, c_{7- 16}arylalkyl, heteroalkyl of 2-6 members, heteroalicyclile of 3 to 10 members, heteroalicycloalkyl of 4-11 members, heteroaryl of 5-15 members, or heteroarylalkyl of 6 to 16 members;

halogen C1-80N, -NΘ,

-O- (C (P^and) 2) t-OR^and

Each P is independently represented = O, -OR₃alkyloxyl, = 8, -8P^and, = NR^and, = NOR^and, ^ (P.^WITH)₂, halogen, -SH₃, -CH2-N6 -OC2

-NΘ₂, = N₂, -N₃, -8 (O) P^and, -8 (O) 2P^and, -8O3P^and, -8 (O) ^ P^WITH) 2, -8 (0) ^ (P^WITH) 2, -O8 (O) P^and, -O8 (O) 2P^and, -O8O3P^and, -O8 (O) ^ (P^with) 2, -C (O) P^and, -SO2P^and, -C (O) ^ P^WITH) 2, -S ^ P^and) ^ (P^WITH) 2, -CH2OH) -P^and, -CHO OH) - ^ P^WITH) 2, -OC (O) P^and, -OC (O) OR^and, -OC (O) ^ P^WITH) 2, -OC ^ H) ^ (P^with) 2, -OC ^ P^and) ^ (P^WITH) 2, ^ (P^and) -8 (O) 2 H, - ^ (P^and) C (O)] p^and, - ^ (P.^and) C (O)] POR^and, - ^ (P.^and) C (O)] ^ (P^WITH) 2 or - ^ (P^and) C ^ P^and)] n ^ {P^WITH) 2;

every P^WITH represented independently by P^and, or, conversely, two P^WITH contain a mixture of nitrogen to which they are bonded to form heteroalicycliles of from 3 to 10 members, or heteroaryl of from 5 to 10 members, optionally containing one or more identical or different additional heteroatoms, and which optionally may be optionally substituted with one or more identical or different P^and and / or R³ groups;

every P³ represented = O, -OR^and, haloC1-3alkyloxy, C1-6alkyl, = 8, -8P^and, = NR^and, = NOR^and, ^ (P.^and) 2, halogen, -SH₃, -CH2-N6-SO6 -8C2-N4, -Nθ₂, = N₂, -N₃, -8 (O) P^and, -8 (O2) P^and, -8O3P^and, -8 (O) ^ P^and) 2, ^ (OB ^ RU, -O8 (O) P)^and, -O8 (O) 2P^and, -O8O3P^and, -OZO ^ SRO -S (O) P^and, -SO2P^and, -S ^^ RU, -S ^ P ^^ RU, -C ^ OH) P^and, -CH2OH, -Pr -OCO2P^and, -OC ^^ Pr -OS ^ P ^^ RU - ^ (P ^ CCO)] ^³, - (C (P^and) 2)_p-Or^and, ^ (P.^and) -8 (O) 2P^and, -C (O) -C1-6 haloalkyl, -8 (O)₂WITH_1-6haloalkyl, -OC (O) P^and, -O (C (P^and) 2) t-OR^and, -8 (C (P^and) 2)_t-Or^and, - ^ P ^ C-₆haloalkyl, -

P (O) (OR^and) 2, -N (P^and) - (C (P^and) 2) t-OR^and, - ^ (P ^ C ^^ pORa - ^ (P ^ C ^ L ^ PU,^and) C (O) C_1-6haloalkyl; two P³, taken together with the atom or atoms to which they are attached, are combined with the formation of a partially or completely saturated mono-orcyclical ring of 3-10 members, optionally containing one or more heteroatoms and may optionally be substituted by one or more P^and;

every P^and independently represented by cycloalkylalkyl, C6-10aryl, C7-16arylalkyl,

heteroalicyclic having 3-10 members, heteroalicycloalkyl groups or heteroarylalkyl of 6 to 16 members;

p is represented by 0, 1,2, 3 or 4, each t is represented by 1,2 or 3; each η is represented by 0, 1,2 or 3;

two groups of P²taken together with the atom or atoms to which they are attached are combined with the formation of a partially or completely saturated mono- or di-cyclic ring of 4-10 members, which in some cases may include one or more heteroatoms and may in some cases be replaced by one or a few p^and and / or R^ı;

Z¹ and Z² represented independently by CH, SR² or N;

R³ represented by H, in some cases replaced by C._1-6alkyl or p⁵⁰;

R⁴ represented by H, in some cases replaced by C._1-6alkyl or p⁵⁰; and

R⁵ represented by halogen, -CO2 is in some cases substituted with C1-6alkyl, alkynyl, hydroxy, in some cases substituted C1-6alkoxy, nitro, ^ (P^and) 2, -C (O) p^and)₂, -SO₂R^andor -C (O) P^and groups

WITH_1-6alkyl, c_3-8cycloalkyl, C._4-heteroalkyl of 2-6 members, 4-11 members, heteroaryl 5-15

14

iA 106975 C2

In one embodiment, the compounds of structural formula I are compounds wherein the ring A is phenyl or pyridyl substituted with one or more groups. In one embodiment of the invention, the ring A is represented by phenyl with at least one group in the position of a para-N4 pyrimidinediamine. In another embodiment of the invention, Ring A is represented by a pyridyl with at least one group in the position of a pair relative to N4 pyrimidinediamine. In a more specific embodiment of the invention, ring A is represented by pyridine-3-yl (wherein N4 pyrimidindinam is in the 3-yl position) with at least one group in the position of a para-related N4 pyrimidinediamine. In a more specific embodiment of the invention, the ring A is represented by pyridine-2-yl (wherein N4 pyrimidindinam is in the 2-yl position) as a minimal group in the position of the vapor relative to N4 pyrimidinediamine. In other embodiments, the derivation of the group in the target state may replace or complement the groups in the position of the pair in the above embodiments of the invention. In all of the above embodiments, the invention of a group in the positions of a pair and / or a meth may include nitrogen, for example, substituted in some cases an amine directly attached to the ring A, or in some embodiments of the invention, binds to ring A through alkylene. Such substituted in some cases amines include amines, determined by -CH (I In other embodiments, the derivation of the group in the target state may replace or complement the groups in the position of the pair in the above embodiments of the invention. In all of the above embodiments, the invention of a group in the positions of a pair and / or a meth may include nitrogen, for example, substituted in some cases an amine directly attached to the ring A, or in some embodiments of the invention, binds to ring A through alkylene. Such substituted in some cases amines include amines, determined by -CH (I In other embodiments, the derivation of the group in the target state may replace or complement the groups in the position of the pair in the above embodiments of the invention. In all of the above embodiments, the invention of a group in the positions of a pair and / or a meth may include nitrogen, for example, substituted in some cases an amine directly attached to the ring A, or in some embodiments of the invention, binds to ring A through alkylene. Such substituted in some cases amines include amines, determined by -CH (I^with) 2 relative to Formula I. In a specific embodiment, the invention is substituted in some cases by the amine attached to the ring A by a C1-6 alkylene. In more specific embodiments of the invention, in some cases, the amine is attached to the ring A by means of C1-3alkylene and the amine -CH (Y^with) 2 relative to the formula I itself is replaced by the group -CH (I^with)₂.

As already noted, certain compounds described herein have the structural formula I, wherein ring A is represented by phenyl substituted with one or more of Y² groups Thus, in one embodiment, the compounds described herein have the formula: A:

where the variables are represented in accordance with the description for formula I, and in addition: X and Y are independently represented by O or NJ¹; every I¹ represented by H, in some cases substituted by C1-6alkyl or I⁵⁰; every I^2a, I^2b, I^2s and I²⁰ independently represented by me²; and I⁵represented by halogen, -CH with the substitution in some cases of C1-6alkyl, nitro group, -CH (Y^and) 2, -C (O) C (I^and) 2, -CO₂I^and or -C (O) I^and.

One embodiment of the invention is represented by a compound having the structural formula! A, wherein Xi Y is independently represented by NI¹. In a more specific embodiment of the invention, Xi Y are independently represented by NH or N-C 1-6 alkyl. In an even more specific embodiment of the invention, X and Y are independently H or N 3. In one embodiment of the invention, wherein X and Y are defined more specifically in accordance with the above, I⁵represented by halogen or C1-6alkyl; Z¹ represented by C-H, C-halo, or C, substituted in some cases by C 1-6 alkyl; and Z² represented by CH In a more specific embodiment of the Invention, I^2s and I²⁰ represented by H; and I⁵ represented by I or CH3. In an even more specific embodiment of the invention, each I^2a and I^2b independently represented by H, C._1-

₆alkyl-oh^and, -OSG3, -5J^and, ^ (I^with) 2, halogen, -OH₂H, -OCh₂G, -SG₃, -SCH, -3 (O) ^ (I^with) 2, -5 (O) 2Y^and,-SOY^and, -SO2Ya^and, -C (O) C (I^with) 2, -CH (I^and) -5 (O) 2Y^and or - [Ch (I^and) C (O)] n^and; and every I am^2a and I^2b is not N. The only embodiment of the invention of each I^2a and I^2b represented independently by H, -CH (I^with) 2, halogen, -CH3₃, -SCH, -5 (O)₂H (ya^with) 2, -5 (O) 2Y^and, -C (O) I^and, -SO2Ya^and, -C (O) C (I^with) 2 or -CH (I^and) -5 (O) 2Y^and. This is a specific embodiment of the invention of each I^2a represented by H, by halogen or by a subgroup; every I^2b represented by halogen, -SH3, -SCH, -5 (O) 2C (I^with) 2, -5 (O)₂I^and, -C (O) I^and, -SO₂I^and, -C (O) C (I^with) 2 or -CH (I^and) -5 (O) 2Y^and. In another specific embodiment of the invention, I^2arepresented by halogen, -SH₃, -SCH, -5 (O)₂H (ya^with) 2, -z (O) 2Y^and, -C (O) I^and, -SO2Ya^and, -C (O) C (I^with) 2 or-Ch (I^and) -5 (O) 2Y^and; and I^2b represented by H, halogen or cyano group.

In another embodiment of the invention, the compound is described in accordance with a structural formula aA, with one X and Y represented by O, and the other are NN¹. In a specific embodiment of the invention, the compound is represented by the formula IA1 or IA2:

15

iA 106975 C2

where R^2s represented by H; R⁵ represented by halogen or C1-6alkyl; Z¹ representing TH, C-Halo or C, in some cases substituted with C1-6alkyl; and Z² represented by CH

Another embodiment of the invention is represented by a compound having the structural formulas IA1 or IA2, wherein P⁵ represented by E or CH3. In a more specific embodiment of the invention, each P, P and P is independently represented by C1-6alkyl, -OR, -OCE3, -ZR, -N (P) 2, halogen, -OCE2N, -OSH2E, -CE3, -CH3 ( O) 2N (P °) 2, -Z (O) 2P^and, -C (O) P^and, -SO2P^and, -C (O) CH (P^with) 2, - (C (P^and) 2)_t-R^ı, -Ч (Р.^and) -Z (O) 2P^and or - [Ch (P.^and) C (O)] p^and. In another, more specific

2b

2s

the embodiment of the invention^2a, P^{2 and} and R^2s independently represented by C1-6alkyl, -OR^and, -OCE2, halogen, -EU₃ or -You. In one embodiment of the invention, P^2a represented by CH3; R^2brepresented by halogen; and R^2s represented by CH3. In another embodiment of the invention, R^2arepresented by CH3; R^2b represented by CH3; and R^2s represented by a halogen. In another embodiment, the embodiment of the invention^2a represented by CH3; R^2b represented by CH3; and R^2s represented by CH3. In a more specific embodiment of the invention, P^2a represented by CH3; R^2b representations of CH3; and R^2s represented by CH3, P⁵ submitted by sn₃.

In another embodiment of the invention, compounds with the structural formula IA1, deR are described⁵ represented by CH³, every P^2a, P²⁰ and R^2s independently represented by C1-6alkyl, halo1-6alkyl, -OR^and, -OSE3, -ZR^and, -Ч (Р.^with) 2, halogen, -OSE2N, -OCN2E, -SCH, -Z (O) 2C (P^with) 2, -Z (O)₂R^and, -C (O) P^and, -SO2P^and, -C (O) CH (P^with) 2, - (C (P^and)₂)_t-R^ı, -Ч (Р.^and) -Z (O) 2P^and or - [Ch (P.^and) C (O)] p^and. This is a more specific embodiment of the invention^2a, P^2b and R^2s represented independently by C._1-6alkyl, -OR^and, -OSE3, halogen, -EE3, or -CH. In one embodiment of the invention, R^2a represented by CH3; R^2b represented by halogen; and R^2s represented by CH3. In another embodiment of the invention, R^2a represented by CH3; R^2b represented by CH3; and R^2s represented byhalogen. In another embodiment of the invention, each P^2a, P^2b and R^2s independently represented by C1-6alkyl or halo1-6alkyl. In another embodiment of the invention, each P is^2a, P^2b and R^2s independently represented by C1-6alkyl. In a more specific embodiment of the invention, R^2a represented by CH3; R^2b represented by CH3; and R^2s submitted by the CNN

Another embodiment of the invention is represented by compounds with the structural formulas IA1 or IA2, wherein P^2b represented by H; R⁵ represented by E or CH3. In an even more specific embodiment of the invention, each R^2a and R^2s independently represented by H, C1 -6alkyl, -OR^and, -OSE3, -ZR^and, -Ч (Р.^with) 2, halogen, -OCE2H, -OCN2E, -SE3, -CH5, -Z (O) 2C (P^with) 2, -Z (O)₂R^and, -C (O) P^and, -SO2P^and, -C (O) CH (P^with) 2, -CH (P^and) -Z (O) 2P^and, -С (Р.^and) 2-h (p^with) 2 or - [Ch (P^and) C (O)] p^and; and every R^2a and R^2sis not H. In another embodiment of the invention, each R^2a and R^2s independently represented by H, C1-6alkyl, -OR^and, -OCE3, halogen, -EU₃, -С (Р.^and) 2-h (p^with) 2 or -YOU. In another embodiment, the invention of the invention^2a represented - СЕ3 or СН3; and R^2s represented by halogen or -CH3. In another embodiment of the invention, R^2a represented by H, -CH3, -CE3, -OR^and or -OSE3; and R^2srepresented by -S (P^and) 2- CH (P^with) 2.

Another embodiment of the invention is represented by compounds with the structural formulas IA1 or IA2, wherein P^2s represented by H; R⁵ represented by E or CH3. In one particular embodiment of the invention, each P^2a and R^2b independently represented by H, C1-6 alkyl, -OR^and, -OSE2N, -OCN2E, -OSE3, -ZP^and, -Ч (Р.^with) 2, halogen, -CE₃, -CH, -Z (O)₂H (p^with) 2, -Z (O) 2P^and, -C (O) P^and, -SO2P^and, -C (O) CH (P^with)₂, -Ч (Р.^and) -Z (O) 2P^and, -С (Р.^and) 2-h (p^with) 2 or - [Ch (P^and) C (O)] p^and; and every R^2a and R^2b is not N. The only embodiment of the invention is each R^2a and R^2b represented by H, C._1-6alkyl, -OR^and, -OSez, halogen, -CH (P^with)₂, -EU₃, -С (Р.^and) 2-h (p^with) 2 or -YOU. In another embodiment of the invention, R^2brepresented by - СЕ3 or -СН3; and R^2a represented by halogen or -CH3. In another embodiment, the embodiment of the invention P is H, -CH₃, -EU₃, -OR or -OSE₃; and R is represented by -CH (P)₂or -C (P^and) 2- CH (P^with) 2. In yet another embodiment of the invention, R^2a represented by -CH (P^with)₂ or-C (P.^and) 2- CH (P^with) 2; and R²° representations of H, -CH₃, -EU₃, -OR^and or -THE₃.

Another embodiment of the invention describes compounds having the structural formula IA1 or IA2, wherein P^2s and R^2s represented by H, and R⁵ represented by E or CH₃; R^2a and R^2b are kept together with carbon deposits to which they are attached, with the formation of partially or completely saturated

16

iA 106975 C2

mono- or bicyclic ring having from 4 to 10 members, which in some cases may contain one or more heteroatoms and in some cases include the substitution of one or more of Ya^and and / or Ya^ı. In one embodiment of the invention, it is represented by a 5-membered ring, and in a more specific embodiment, the 5-membered ring is represented by cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine or tetrahydrofuran; In some cases, one or more of them may be included^and and / or I^ı, substituting. In a specific embodiment of the invention, the 5-membered ring is represented by pyrrolidine, and in more specific embodiments of the invention, the compounds have a structural formula that corresponds to the formula IA3:

where am I^ı represented by OH, C1-6alkyl, -CO2C1-6alkyl, -C (O) C1-6alkyl or -8 (O) 2C1-6alkyl. In another embodiment, the invention^2a and I^2b are held together with the carbon atoms to which they are attached to form partially or completely saturated monocyclic rings of 6, 7 or 8 members, which may in some cases include one or more heteroatoms, and may in some cases be substituted with one or more of Y^and and / or I^ı. In one embodiment of the invention, in the case of a 6-membered ring, such ring is represented by cyclohexane, morpholin, piperidine, dioxane, oxathiazinamine or piperazine, and in some cases may contain one or more of Y^and and / or I^ı , substituting. In another embodiment of the invention in the case of a 7-membered ring, such a ring is represented by cyclopentane, cyclohepten, azepan, tetrahydroazepine or diazepane, and in some cases may contain one or a few substituents of Y^and and / or I^ı. In another embodiment of the invention in the case of an 8-membered ring, such a ring is represented by cyclooctane, cyclooctane, azocane, hexahydroazotine, diazocane or hexahydrodiazocine, and in some cases may contain one or more of the ions^and and / or I^ı. For each of the above embodiments of the invention, wherein I am^2a and I^2b containing together with the carbon atoms to which they are attached form 5-, 6-, 7-, or 8-membered, partially or fully saturated monocyclic rings, and there is a more specific embodiment of the invention in which 0, 1, 2 or 3 is present.^and and I^ı, and I^and represented by C1-6alkyl, each I^ı independently represented = O, -YY^and, haloC1-3alkyloxyl, -8J^and, -C (I^WITH) 2, halogen, -SR, -SH, -8 (O)₂H (ya^WITH) 2, -8 (O) 2Y^and, -C (O) I^and, -SO2Ya^and, -C (O) C (I^WITH) 2, -CH (I^and) -8 (O) 2Y^and or-C (I^and) 2-I (I^WITH) 2. For example, in one embodiment of the invention there is at least one I^ı, represented = O; and in some cases I may be present^and, which in some cases maybe replaced by C._1-6alkyl Separate examples of compounds according to Formula IA3 include, but are not limited to, compounds such as IV-2, IV-10, IV-14-IU-16, IU-18-IU-34 and IU-50 (see Table IV).

Some embodiments of the invention include compounds in which the ring A is represented by a different radical, except for phenyl. In a specific embodiment of the invention, ring A is represented by pyridine or pyridazine. As shown in formula I, and with respect to such an embodiment of the invention, pyridine or pyridazine may have several region-specific configurations and attachment sites for a leaving molecule. One embodiment of the invention of compounds of structural formula I describescompounds according to the formula IV:

1 2

where the variables are determined in the same way as the variables for formula I; in addition: O and Independently represented N or CH², provided that at least one O¹ and o² represented by N; X and Y are independently represented by O or NH¹; every I¹ represented by an independentH, in some cases, may be substituted with C1-6alkyl or Y.⁵⁰; p is represented by 0, 1,2 or 3; and I⁵ represented by halogen, -CH in some cases substituted with C1-6alkyl, nitro, -CH (Y^and) 2, -C (O) C (I^and) 2, -CO₂I^and or -C (O) I^and.

17

iA 106975 C2

One embodiment of the invention that describes compounds represented by a compound having the structural formula IV1 or IV2:

structural

the formula

Iw

One embodiment of the invention describes compounds having the structural formula IV1 or IV2, wherein X and Y are independently represented as NR¹. In a more specific embodiment of the invention, Xi Y are independently represented by NH or NR1-6alkyl. In an even more specific embodiment of the invention, X and Y are independently NR or NHOH. In one embodiment, a compound of the invention, wherein X and Y are as defined in the above information; R⁵represented by halogen or C1-6alkyl; Z¹ represented by CH, C-Halo or C, in some cases, substituted by C1-6alkyl; and Z² represented by CH In another embodiment of the invention, R^2a and R^{2s |} represented by H; and R⁵ represented by B or CH3. In another embodiment, the invention

2s

every P^2b and R^2s independently represented by H, C1-6alkyl, -OR^and, -OSN2V, -SAV₃, -3P^and,

-Y (R^with) 2, halogen, -OSV2N, -SV3, -CH3, (O) 2Y (P^with) 2,

3 (O)₂R^and, -C (O) P^and, -SO2P^and, -C (O) N (P^with) 2,

2b; g., 2s

-Y (P) -3 (O)₂P, -C (P)₂-Y (P)₂ or - [Y (P) C (O)]_pP; and each P and P are not H. In another such embodiment, each R is^2b and R^2s independently represented by H, C1-6alkyl, -Y (P.^with) 2, halogen, -SO₃, -SY, -3 (O)₂I (P.^with)₂-3 (O)₂R^and, -C (O) P^and, -SO2P^and, -C (O) N (P^with) 2, -C (P^and)₂-Y (R^with) 2 or -Y (P^and) -3 (O) 2P^and. In another embodiment of the invention, R^2b represented by H, halogen, -SO3, -On, or -CH3; and^2s represented by -Y (P.^with) 2, -3 (O)₂I (P.^with) 2, -3 (O) 2P^and, -C (O) N (P^with) 2 or -C (P^and) 2- N (P^with) 2.

Another embodiment of the invention describes compounds having the structural formula IV1 or IV2, wherein Xi Y are represented as O and Y is represented as NR¹. In one embodiment of the invention, P⁵represented by halogen or C1-6alkyl; Z¹ represented by CH, C-Halo or C, in some cases, substituted by C1-6alkyl; and Z² represented by CH In another embodiment of the invention, R^2a and R^2s represented by H; and R⁵ represented by B or CH3. In an even more specific embodiment of the invention, each R^2b and R^2s represented independently H, C_1-6alkyl, -OR^and, -

ERUs₃, -3P^and, -Y (R^with) 2, halogen, -OSV2N, -OCN2B, -SV3, -Si, -3 (O) 2Y (P^with) 2, -3 (O)₂R^and, -C (O) P^and, -SO2P^and, -C (O) N (P^with) 2, -Y (P^and) -3 (O)₂R^and, -С (Р.^and) 2- N (P^with) 2 or - [N (P^and) C (O)]_pR^and; and one with R^2b and R^2s is not H. The only embodiment of the invention is each R^2y and R^2s independently represented by H, C1-6alkyl, -Y (R.^with) 2, halogen, -SO₃, -SY, -3 (O)₂I (P.^with) 2, -3 (O) 2P^and, -C (O) P^and, -SO2P^and, -C (O) N (P^with) o, -c (p^and) 2- N (P^with) 2 or -Y (P^and) -3 (O) 2P^and. In a more specific embodiment of the invention, P is represented by H, halogen, -SO3, -N, or -CH₃; and R^2s represented by -Y (P.^with) 2, -3 (O) 2Y (P^with) 2, -3 (O)₂R^and, -C (O) N (P^with)₂ or -C (P^and) 2- N (P^with) 2. In another embodiment of the invention, R^2brepresented by H, halogen, -SV₃, ^ N or -CH₃; and R^2s represented by -Y (P.^with)₂ or -C (P^and) 2- N (P^with) 2.

Another embodiment of the invention describes compounds having the structural formula IV1 or IV2, wherein X is represented by O; Υ represented by NR¹; Z¹ represented by CH, C-Halo or C, in some cases, substituted by C1-6alkyl; Z² represented by CH; R^2a and R^2s represented by H; and R⁵ represented by Vabo CH3, P^2b and R^2s are held together with the carbon atoms to which they are attached to form a 4-10 membered partially or completely saturated mono- or bicyclic ring, which in some cases may contain one or more heteroatoms, and in some cases may include substituting one or more P^and and / or R^ı. In one embodiment of the invention, the ring is represented by a 5-, 6-, 7-, or 8-membered, partially or completely saturated, monocyclic ring, which may in some cases contain a substitution of one or more P^and and / or R^ı. In an aqueous embodiment of the invention, the 5-, 6-, 7-, or 8-membered, partially or fully saturated, monocyclic ring is represented by cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazinamine, piperazine, cycloheptane, cyclohepten, azepan, tetrahydroazepine, diazepane, cyclooctane, cyclooctane, azocane, hexahydroazoton, diazocane or hexahydrodiazocine; in some cases, may contain substitution of one or a few^and and / or R^ı. For each of the above embodiments of the invention, wherein R^2b ip^2s are held together with the carbon atoms to which they are attached form a 5-, 6-, 7-, or 8-

18

iA 106975 C2

partially or fully saturated monocyclic rings. There are more specific embodiments of the invention in which 0, 1, 2 or 3 P is present^and and R^ı, and R^and represented by C1-6alkyl, each P^ı independently represented = O, -OR^and, haloC1-3alkyloxyl, -3R^and, -Ч (Р.^with)₂, halogen, -SR3, -CH, -3 (O) CH (P^with) 2, -3 (O) 2P^and, -C (O) P^and, -SO2P^and, -C (O) CH (P% -CH (P^and) -3 (O) 2P^and or-C (P.^and) 2-h (p^with) 2. For example, in one embodiment of the invention, at least one P is present^ı, represented = O; in some embodiments of the invention^and in some cases may be replaced by C._1-6alkyl In such an embodiment of the invention, compounds such as An-45, An-46 and An-47 are described (see Table IV).

Another embodiment of the invention, which describes compounds having a structural formula IV, is represented by the compound having the structural formula IV3:

? 2s

2a

where every P

One embodiment of the invention describes a compound having the structural formula IV3, wherein X is represented as O and Y, represented as IR¹. In one embodiment of the invention, P⁵represented by halogen or C1-6alkyl; Z¹ represented by CH, C-Halo or C, in some cases, substituted by C1-6alkyl; and Z² represented by CH In another embodiment of the invention, R^2a represented by H; and R⁵ represented by P or CH3. In an even more specific embodiment of the invention, each P and P is independently represented by H, C1-6alkyl, -OR, -OCR3, -8R, -CH (P% halogen, -SR2N, -OCN2P, -SR3, -CH2, -3 ( О) 2Ч (Р.^with) 2, -3 (ODP^and, -C (O) P^and, -SO2P^and, -C (O) CH (P^with) 2, -CH (P^and) -3 (O) 2P^and, -С (Р.^and) 2-h (p^with) 2 or - [Ch (P^and) C (O)] p^and; and one with R^2y and R^2s is not H. In another embodiment of the invention, each R^2b and R^2s independently represented by H, C1-6alkyl, -CH (R.^with) 2, halogen, -SR 3, -CH, -3 (O) 2C (P^with) 2, -3 (O)₂R^and, -C (O) P^and, -SO2P^and, -C (O) CH (P^with) 2, -C (P^and) 2-h (p^with) 2 or -CH (P^and) -3 (O) 2P^and. In a more specific embodiment of the invention, R^2b represented by H, halogen, -SR3, -CH3, or -CH₃; and R^2s represented by -CH (P^with) 2, -3 (0) 2C (P^with) 2, -3 (O)₂R^and, -C (O) CH (P^with)₂or -C (P^and) 2- CH (P^with) 2. In another embodiment of the invention, R^2b represented by H, halogen, -SR₃, -SY, or -CH₃; and R^2s represented by -CH (P^with)₂ or -C (P^and) 2- CH (P^with) 2.

Another embodiment of the invention describes compounds having the structural formula IV3, wherein X is represented by O; Υ is represented by ır¹; Z¹ represented by CH, C-halo or C, in some cases replaced by C._1-6alkyl; Z² represented by CH; R^2s and R^{2s |} represented by H; and R⁵ represented by P or

2s

CH₃, P^2b and R^2s are held together with the carbon atoms to which they are attached to form a 10-membered, partially or completely saturated mono- or bicyclic ring, which in some cases may contain one or more heteroatoms, and in some cases may include substituting one or more P^and and / or R^ı. In one embodiment of the invention, the ring is represented by a 5-, 6-, 7-, or 8-membered, partially or completely saturated, monocyclic ring, which may in some cases contain a substitution of one or more P^and and / or R^ı. In an aqueous embodiment of the invention, the 5-, 6-, 7-, or 8-membered, partially or fully saturated, monocyclic ring is represented by cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane , oxathiazine, piperazine , cycloheptane, cyclohepten, azepan, tetrahydroazepine, diazepane, cyclooctane, cyclooctane, azocane, hexahydroazotine, diazocane or hexahydrodiozocine; in some cases, may contain substitution of one or a few^and and / or R^ı. For each of the above embodiments of the invention, wherein R^2b ip^2s containing, together with the carbon atoms to which they are attached, form a 5-, 6-, 7- or 8-membered, partially or fully saturated monocyclic ring, there is a more specific embodiment of the invention in which 0, 1, 2 or 3 P^and and R^ı, and R^and represented by C1-6alkyl, each P^ı represented independently = O, -OR^and, halo-3-alkoxy-3R^and, -Ч (Р.^with)₂, halogen, -SR3, -CH, -3 (O) CH (P^with) 2, -3 (O) 2P^and, -C (O) P^and, -SO2P^and, -C (O) CH (P% -CH (P^and) -3 (O) 2P^and or-C (P.^and) 2- CH (P^with) 2.

Another embodiment of the invention describes compounds having the structural formula I, wherein the ring is represented by indazole, benzoxazole, pyrazolopyridine or isoxosulopyridine; X represented by O; Υ is represented by ır¹; R⁵ represented by halogen or C1-6alkyl; Z¹Representative CH, C-Halo or C, substituted in some cases by C 1-6 alkyl; Z² represented

19th

iA 106975 C2

CH; and every R² independently represented by H, C1-6alkyl, -OR^and, -OSV3, -3R^and, -N (P °) 2, halogen, -OSV2N, -OCN2B, -SV3, -SCH -3 (O) 2C (P^with) 2, -3 (O)₂R^and, -C (O) P^and, -SO2P^and, -C (O) CH (P^with) 2, -N (P^α) -8 (o)₂P^α or - [Ch (P.^and) C (O)] p^and.

Another embodiment of the invention that describes compounds of the structural formula I is represented by the compound of the structural formula II:

II

₂

where the variables are determined in the same way as the variables for formula I; in addition: two Hold together with the formation of the ring B; the ring B together with the two atoms of the phenyl ring to which it is attached forms a 5-, 6- or 7-membered ring, which in some cases may include 1, 2 or 3 heteroatoms independently selected from IR (P^with), O and 8; R^and represented by C 1-6 alkyl; and every R^ı independently = O, -OR^and, haloC1-3alkyloxy, -8P^and, -Ч (Р.^with) 2, halogen, -CH3, -CH, -3 (O) CH (P^with) 2, -3 (O) 2P^and, -C (O) P^and, -SO2P^and, -C (O) CH (P^with)?, -CH (P^and) -3 (O) 2P^and or-C (P.^and) 2-h (p^with) 2. In one more specific embodiment of the invention, Z¹ represented by CH, C-Halo or C, in some cases substituted by C._1-6alkyl For the purpose of furthering the description of the ring B, examples of the ring B include the following (regardless of the presence of unsaturated bond between the two phenyl ring atoms and in order to simplify the nomenclature): cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazine, piperazine, cycloheptane, cyclohepten, azepan, tetrahydroazepine, diazepane, cyclooctane, cyclooctane, azocane, hexahydroazocine, diazocanabo, hexahydrodiazocine. For example, if ring B is represented by cyclohexane, then the compound will have a structure according to the formula Na:

Another example: if ring B is represented by cyclohepten, then the compound will have a structure corresponding to the formulas H3, Ne, iib or Ne:

20

iA 106975 C2

10

15

20

iiC

yee

Another embodiment of the invention describes a compound of formula IA1, wherein K is represented by H, K⁵ represented by halogen or C1-6alkyl; Z¹ represented by CH, C-Halo or C, is substituted in some cases by C1-6alkyl; Z is represented by CH; and each K, K and K represented independently of C._1-6alkyl, -OK^and, -OSG3, -ZK^and, -Y (K^with) 2, halogen, -OH₂H, -OCh₂G, -SG₃, -SY, -Z (O)₂I \ I (K.^with) 2, -Z (O) 2K^and, -C (O) K^and, -SO2K^and, -C (O) I \ I (K.^with) 2, - (C (K^and) 2) t-K^ı, -I \ І (К.^and) -Z (O) 2K^and or- [Y (K^and) c (O)] pC^and, provided that one of K.^2a, K.^2b and K.^2s represented by -Y (K.^with) 2, -C (O) N (K^with) 2 or (C (K^and) 2) t-K^ı. In a more specific embodiment of the invention, K⁵ represented by P or CH3.

, 2b

2s

In another embodiment, one of the embodiments of the invention^2a, K.^{2 and} and K.^2s represented by -N (K) 2. In another embodiment of the invention one of the K^2a, K.^2b and K.^2s represented by - (C (K^and) 2)_t- K.^ı. In a more specific embodiment of the invention, K⁵ represented by G or CH3. In a more specific embodiment of the invention one K^2a, K.^2b and K.^2s represented by -Y (K.^with) 2, that is:

Υ> σO O

1^_νΥ^νη

μ "N / -O> -O 1-^νY ° ^ζ~^νΥ^νη

-NH Α^νΥ ΖΥ

νη He CU

or

-N

in some cases there may be one or more identical or different groups that are substituted by Ka and / or Kb. In a more specific embodiment of the invention, one of^2a, K.^2y and K.^2s

25 representations - (С (К.^and) 2) t-K^ı, and, in particular, -С (К.^and) 2- N (K^with)₂. In an even more specific way

2 I 2 No 2 about me

one embodiment of the invention, K, K and K is represented by -C (K)₂- N (K)₂ , ie:

21

iA 106975 C2

N ^

Αν-

'N' VV or

N '

Ã^ζ

^to Η ^to ι

RI

N '

Η

Ύν

kk

in some cases there may be one or more identical or different groups that are substituted by Ra and / or Pb.

In one embodiment, at least one P group² is represented by a group that increases solubility, that is, a group having hydrophilic properties, sufficient to improve or increase the solubility of the compound in which it is contained, compared with the analoguecompany that does not include such a group. Hydrophilic nature can be achieved, for example, by the inclusion of functional groups having the property of ionization under conditions of use, with the formation of charged molecules (for example, carboxylic acids, sulfonic acids and salts, phosphoric acids and salts, amines, etc.), as well as by the inclusion of groups with a non-replaceable charge (eg, quaternary ammonium groups) and / or heteroatoms or heteroatomic groups. For example, -O- (C (P^and) 2) t-P^ı, -3- (C (p^and) 2)_t-R^ı, -O- (C (P^ı) 2) t-P^and, -H (P^and) - (C (P^and) 2) t-P^ı, -O- (CH2) t -CH ((CH2) t * Z, -C (O) H (P^and) - (C (P^and) 2) t-P^B and -N ((C (P^and) 2) tK^B) 2. More specific examples include -O-C1-6alkylene-P^ı, -3-C1-6alkylene-P^ı, -O- C 1-6 alkylene-R^and, where R^and represented by a heterocyclic radical, -H (R.^and) - C1-6alkylene-P^ı, -O-C1-6alkylene-CH ((CH2) and-2P^ıR)^ı, -C (O) H (P^and) - C1-6alkylene-P^ı and -N ((C (P^and) 2) 1-3P^ı) 2. More specific examples include -O-S_1-4alkylene-p^ı, -3-C1-4alkylene-R^ı, -O-C1-4alkylene-R^and, where R^and represented by a heterocyclic radical, -H (R.^and) - C1-4alkylene-P^ı, -O-C1-4alkylene-CH ((CH₂)_1-2R^BR)^B, -C (O) H (P^and)- WITH_1-4alkylene-P^ı and -N ((C (P^and) 2) 1-3P^ı) 2. In another specific example, in accordance with the above formula for groups that increase solubility in water, such groups are represented by an amino acid linked to the molecule by means of nitrogen of the amino acid. In a more specific example, the water-soluble group is represented by the α-amino acid or its derivatives attached to the original ring, for example, the ring A and / or Z¹or Z², using nitrogen of the α-amino acid, for example, -H (H) C (P^and)₂- R^ı, where R^ı represented by СО2Р^and or -C (O) H (P^with) 2. In another specific embodiment of the invention, the group raising the solubility in water is represented by the following: morpholine, piperidinyl, N-Cycloalkylpiperidinyl, piperazinyl, N-Cycloalkylpiperazinyl, pyrrolidinyl, N-Cycloalkylpyrrolidinyl, diazepinyl, N-C - ^₆alkyl azepinyl, homopiperazinyl, N-C18 alkyl homopiperazinyl, imidazoyl, and the like. In another example, the group that increases the solubility in water, is represented by one of the above rings, attached to the parent molecule with the help of alkylene, alkylidene or alkylidine as an alkaline. In a more specific embodiment of the invention, the group that increases the solubility of the wastewater, is represented by one of the aforementioned rings attached to the parent molecule using C_1-6alkylene, wherein one or two alkyl carbon atoms are independently substituted with one O, 8 or NH, but not at the site of the linker linkage of the two above heteroatoms linker. Other groups that increase water solubility are widely known and include, for example, such hydroxy groups as alkyl and heteroalicycliles substituted with one or more amines, alcohol, carboxylic acid, phosphoric acid, sulfoxide, carbohydrate, sugar alcohol, amino acid, thiol, polyol, ether, thioether and quaternary ammonium salts.

For each of the above embodiments of the invention that describes compounds with the structural Formulas I, IA, IA1, IA2, IA3, IV, IV1, IV2, IV3 and II, there is another embodiment of the invention where P¹ represented by H or P⁵⁰; R⁵⁰ represented by -CH2OR (O) (OR¹¹) 2; and every R¹¹represented independently by P^and or a monovalent cationic group; or two P¹¹, together with the atoms to which they are attached, form an 8-membered cyclic phosphate group, or two P¹¹together represent a bivalent cationic group. In addition, for each of these embodiments, there is a more specific embodiment of the invention, wherein each P¹¹is independently represented by H, t-butyl or a pharmaceutically acceptable cation, for example, HOC₂CH₂N (CH₃)₃⁺, + +, + +, Or +.

As already noted, compounds 2, 4-pyrimidindamine and prodrugs, as well as their salts, can

22

iA 106975 C2

One embodiment of the invention is represented by the pharmaceutically acceptable salt of the compound of Formula I. The pharmaceutically acceptable salts of the present invention may be formulated using conventional methods, for example, in the reaction of a free base with one or several equivalents of the corresponding acid in a solvent or medium in which such a salt is soluble, or in a solvent, for example, in water, with the reaction product being removed by means of a vacuum meters, freeze-drying or exchange anions present in inshymanionom salt with a suitable ion exchange resin. The present invention includes the production of compounds 2, 4-pyrimidinediamine, as well as their salts and hydrates, for example, hydrated formiates.

In another embodiment of the invention, the compounds represented in Tables I-II, orstereoisomer, tautomer, prodrugs, saltwater, or a pharmaceutically acceptable salt thereof are described. The compounds described herein are represented in the original form and in the form of salt (at least). Some specifics obtained according to their designation in Tables I to IV include calcium salt: Compounds I-517; Monoclonal salt: Compounds I-414; bis-choline salt: Compounds I-531; formate: Compounds I-7 - 1-10, 1-43, 1-46, 1-47, 1-49, 1-50, 1-51, 1-53, 1-54, 1-56, 1-127 , 1-128, 1-132, 1-134, 1-137, I-138, 1-140, 1-153-1-158, 1-165-1-169, 1-172-1-190, 1 -201 - 1-239, 1-241, 1-271, 1-272, 1-423, 1-433, I-438 - 1-442, 1-445, 1-446, 1-455 - 1-457 , 1-460, 1-463-1-468, 1-470, 1-473, 1-486, 1-487, 1-494, 1-498, 1-499

- 1-504, 1-513 - 1-515, 1-518, 1-519, 1-527, 1-530, 11-4, 11-5, 11-6, 11-8, 11-9, 11 -11, 11-12, 11-42, 11-43, 11-48, II-49, ІІ-53, ІІ-55 - ІІ-70, ІІ-78, ІІ-79, ІІ-151, ІІІ-12 , I-14, М-3, М-10, М-11, М-14, М-17, М-18, М-19, IV-21, М-31, М-32 and Иν-60 - and -62; diformate: Compounds ΙΙ-3, γ-46, γ-47, γ-51, Ι-52 and ΙΙ-54; monotrifluoroacetate: compounds I-11-and-16, and-27, and-28, and-30- and-32, and-34-and-38, and-52, and-55, and-57-and-95, and-104

- and-109, and-115, and-129, and-130, and-131, and-135, and-136, and-141, and-142, and-145, and-149 and -159, and -160 - and-164, and-171, I-191, and-192, and-193, and-195-and-200, and-242-and-254, and-256-and-262, and-264 - and-269, and-273, and-274, and-403, and-404, I-419, and-422, and-427, and-432, and-447, and-449, and -452, and -454, and -458, and -469, and -474, and -477, and -488, and -492, and -507, and -508, and -520, and -521, and -529, and -535 , I-7, М-12, М-13, М-15, М-16, М-22 - М-30, М-33, М-34, М-51, М-52, М-53, М -54, M-59 and Ιν-64; Difluoroacetate: Compounds I-120 - and-123, and-255, and-263, and-270, and-426, and-459, II-17, and -19, and-38, and-45, and-71 , ii-74, ii-76, ii-77, ii-87, ii-93, ii-100, ii-101, ii-102, ii-150 and i-20-benzenesulfonic acid: compounds I-393; p-toluenesulfonic acid salt: Compounds I-409; sulfuric acid salt: Compounds I-411; Hydrochloric acid salt: compounds I-133 and I-412; dihydrochloride: compounds II-44; disodium salt: Compounds I-33, and-358, and-407, and-451, and-528, and-536 and I-538, magnesium salt: Compounds I-526; mesylate salt: Compounds I-410; and mono-sodium salt: Compounds I-413, I-436 and I-437.

As will be appreciated by a specialist in the field of sciences, the presented formulas include other salts, in addition to those described. Similarly, one skilled in the art will appreciate that the present formulas include and grow, for example, hydrates.

Table Ι

R^2a

<tr><td><p>Compound</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>tT</p></td><td><p>R⁵</p></td><td><p>R^2a</p></td><td><p>R²⁰</p></td><td><p>R^2s</p></td><td><p>R²³</p></td></tr><tr><td><p>and-1</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SLEEP</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>and-2</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) CHN2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>and-3</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>C (O) CHN2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>and-4</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>SLEEP</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>and-5</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>&gt; -X</p><p>&gt; -N) N-</p><p>Xⁱⁿ</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>and-6</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>R</p></td><td><p>&gt; -N&gt; N-</p><p>Xⁱⁿ</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>and-7</p></td><td><p>AT</p></td><td><p>Ch- (n-propyl)</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>5 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>and-8</p></td><td><p>AT</p></td><td><p>Ch- (n-propyl)</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>H (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>and-9</p></td><td><p>AT</p></td><td><p>Ch- (isopropyl)</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>5 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr>

23

iA 106975 C2

? 2a

R^2b

R^2s

P^2a

<tr><td><p>I-10</p></td><td><p>AT</p></td><td><p>N- (isopropyl)</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-11</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-12</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-13</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-14</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-15</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-16</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-17</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-18</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-19</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-20</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-21</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-22</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-23</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-24</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2YH2</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-25</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2Y (H) -1 -We</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-26</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>YOU</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-27</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>YOU</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-28</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>YOU</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-29</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>YOU</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-30</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>AT</p><p>&gt; -δ-N ⁴E</p><p>^ς at</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-31</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>About GA</p><p>&gt; -δ-NO^ς at</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-32</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>about Mr.</p><p>&gt; -δ-NO^ς at</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-33</p></td><td><p>AT</p></td><td><p>HEADING (O) (OH) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-34</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-35</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-36</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-37</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-38</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-39</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-40</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-41</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>3 (O) 2Me</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-42</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-43</p></td><td><p>Hyss3</p></td><td><p>Hyss3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-44</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>YOU</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-45</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>YOU</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-46</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-47</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-48</p></td><td><p>In</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-49</p></td><td><p>Hyss3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-50</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-51</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-52</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-53</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-54</p></td><td><p>In</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-55</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-56</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N (H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-57</p></td><td><p>Hyss3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>3 (O) 2YH2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr>

24

iA 106975 C2

R^2a

Table I

<tr><td><p></p></td><td><p>-58</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-59</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>5 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-60</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-61</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-62</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-63</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-64</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-65</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-66</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-67</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-68</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-69</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-70</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-71</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-72</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-73</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-74</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-75</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-76</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-77</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-78</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-79</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-80</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-81</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-82</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-83</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-84</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-85</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-86</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-87</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-88</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-89</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-90</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-91</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-92</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-93</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-94</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-95</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-96</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>CH3) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-97</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>CH3) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-98</p></td><td><p>N4</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-99</p></td><td><p>N4</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-100</p></td><td><p>N4</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-101</p></td><td><p>N4</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-102</p></td><td><p>N4</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-103</p></td><td><p>N4</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-104</p></td><td><p>N4</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-105</p></td><td><p>N4</p></td><td><p>AT</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>^ H) 3 (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-106</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SRP3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-107</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>SRP3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-108</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>SRP3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p></p></td><td><p>-109</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>SRP3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-110</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p></p></td><td><p>N</p></td><td><p>N</p></td></tr>

25

iA 106975 C2

? 2a

R^2b

R^2s

P^2a

<tr><td><p>1-111</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>Λ0^Ν-</p><p>to</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-112</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>B ^ N ^^ -VII</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-113</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>B ^ N ^^ -VII</p></td><td><p>SI:</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-114</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>° X</p><p>&gt; -5-NN</p><p>AT</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-115</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>g</p></td><td><p>OS ^</p></td><td><p>OS ^</p></td><td><p>OS ^</p></td><td><p>Η</p></td></tr><tr><td><p>1-116</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>ΘΟΡ2Η</p></td><td><p>OS ^</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-117</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>5 (O) 2SGa</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-118</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>5 (O) 2SGa</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-119</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>OS ^</p></td><td><p>OS ^</p></td><td><p>OS ^</p></td><td><p>Η</p></td></tr><tr><td><p>1-120</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>SI ^</p></td><td><p>Αθ</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-121</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>-L®</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-122</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>SI ^</p></td><td><p>_xwith</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-123</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>0®</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-124</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>morpholin-4-yl</p></td><td><p>OSG3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-125</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>СО2 ^ 3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-126</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>garden</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-127</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>° A</p><p>N</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-128</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>AI&gt; €</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-129</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>C (O) C ^</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-130</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>C (O) C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-131</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>SN</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-132</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>sjuzhs ^ ъ</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-133</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>^) N (H ^ H3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-134</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>^to N</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-135</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>SUMMER</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-136</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>pyrrolidine-1-yl</p></td><td><p>C (OZH2</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>1-137</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>SI ^</p></td><td><p>Η</p></td><td><p>C ^ M ^ C ^^</p></td><td><p>Η</p></td><td><p>Η</p></td></tr>

26

iA 106975 C2

R^2a

Table I

<tr><td><p>1-138</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>AT</p><p>ΛνΛ</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-139</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>About 1</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-140</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>AA</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-141</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>C (o) NIN2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-142</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>AA</p><p>^to N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-143</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>Yes</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-144</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>Du</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-145</p></td><td><p>at</p></td><td><p>HY (o) CH2CH3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>C (o) NIN2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-146</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (o-1-</p><p>You) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>C (o) NIN2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-147</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (OH) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>C (o) NIN2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-148</p></td><td><p>at</p></td><td><p>HYCH2OOR (o) (oAa) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>C (o) NIN2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-149</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>AMU</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-150</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (OH) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>AMU</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-151</p></td><td><p>at</p></td><td><p>HYCH2OOR (o) (oAa) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-152</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (o-1-</p><p>You)₂</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>Du</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-153</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-154</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-155</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>5SH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-156</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p></p></td><td><p>C (o) NIN2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-157</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>hh</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-158</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-159</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>Co2CN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-160</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-161</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>OSB3</p></td><td><p>N</p></td><td><p>N</p></td></tr>

27

iA 106975 C2

I^2a

Table I

<tr><td><p>I-162</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>CP3</p></td><td><p>Η</p></td></tr><tr><td><p>I-163</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SRP3</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-164</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>CP3</p></td><td><p>SI3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-165</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>CP3</p></td><td><p>OS ^ C ^ OS ^</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-166</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SIA</p></td><td><p>isopropyl</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-167</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI</p></td><td><p>CP3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-168</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>CP3</p></td><td><p>OSI-SI;</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-169</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>CP3</p></td><td><p>Η</p></td><td><p>CP3</p></td><td><p>Η</p></td></tr><tr><td><p>I-170</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI3</p></td><td><p>СО2І</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-171</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI3</p></td><td><p>O (Θ) N (H) ΟΗ2ΟΗ₃</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-172</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-173</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-174</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-175</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Hr</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-176</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI3</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>SI3</p></td></tr><tr><td><p>I-177</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>CP3</p></td><td><p>N (H) O (Θ) ΟΗ₃</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-178</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI3</p></td><td><p>SI3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-179</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>CP3</p></td><td><p>OS-cyclohexyl</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-180</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SRP3</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-181</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>OSI ^</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-182</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>OSI-SI;</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-183</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>OSI ^</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-184</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>SI</p></td><td><p>Η</p></td></tr><tr><td><p>I-185</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Hr</p></td><td><p>Η</p></td><td><p>SI</p></td><td><p>Η</p></td></tr><tr><td><p>I-186</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>R</p></td><td><p>Η</p></td></tr><tr><td><p>I-187</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI</p></td><td><p>Η</p></td><td><p>SN</p></td><td><p>Η</p></td></tr><tr><td><p>I-188</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>CP3</p></td><td><p>Hr</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-189</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Hr</p></td><td><p>Η</p></td><td><p>CP3</p></td><td><p>Η</p></td></tr><tr><td><p>I-190</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI3</p></td><td><p>Al</p><p>⁴ Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-191</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI</p></td><td><p>γ</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-192</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>Α</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-193</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>OSI ^</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>R</p></td></tr><tr><td><p>I-194</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI</p></td><td><p>OSI-SI;</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-195</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>OS-cyclobutyl</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-196</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>OS-isopropyl</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-197</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>OSH2SH2-isopropyl</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-198</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>SI</p></td><td><p>CP3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-199</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>SI3</p></td><td><p>Η</p></td></tr><tr><td><p>I-200</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>R</p></td><td><p>OSIa</p></td><td><p>R</p></td></tr><tr><td><p>I-201</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>Az</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-202</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>AA</p><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-203</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SIA</p></td><td><p>Η</p></td><td><p>-L_ο</p></td><td><p>Η</p></td><td><p>Η</p></td></tr>

28

iA 106975 C2

R^2a

Table I

<tr><td><p>! -204</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>To</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -205</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>-Do</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -206</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>1 ^ri-This</p><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -207</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>-Ra</p><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -208</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>Υ</p><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -209</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -210</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>· 2'ν^Δ</p><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -211</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>Dr.</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -212</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>L.</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -213</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>I RI</p><p>dt</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -214</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>-D &lt;</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -215</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>L.</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -216</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>to</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>-217</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>■ D '</p><p>To</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr>

29

iA 106975 C2

I^2a

Table I

<tr><td><p>1-218</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>O / ---</p><p>pp</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-219</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>SOMYUR</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-220</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>pp</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-221</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>C (OCHN) Pb</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-222</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>СО2Н</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-223</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>pp</p><p>⁴ N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-224</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OCH2CH (CH3) 2</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-225</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OCH2-cyclopropyl</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-226</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>O-cyclobutyl</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-227</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OCH2-cyclobutyl</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-228</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSII3</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-229</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) CH 3</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-230</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>R</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-231</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>ArA</p><p>N</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-232</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>p</p><p>N</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-233</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>-RP</p><p>N</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-234</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-235</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p></p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-236</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>AND"</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-237</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>SR2N</p></td><td><p>N</p></td></tr><tr><td><p>1-238</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH2R</p></td><td><p>N</p></td></tr><tr><td><p>1-239</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) 2CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-240</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td><td><p>R</p></td><td><p>N</p></td></tr><tr><td><p>1-241</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>Α^Ν\ /^ν~</p></td><td><p>N</p></td><td><p>R</p></td><td><p>N</p></td></tr><tr><td><p>1-242</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-243</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>C (O ^ N2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-244</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>C (O) 2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-245</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>C (O) 2CH3</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr>

30

iA 106975 C2

<tr><td><p>I-246</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>SI</p></td><td><p>SI-3</p></td><td><p>AND</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-247</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>SI</p></td><td><p>SI-3</p></td><td><p>Η</p></td><td><p>AND</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-248</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>SR</p></td><td><p>S3</p></td><td><p>3 (O ^ І-І2</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-249</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>SR</p></td><td><p>SI-3</p></td><td><p>5 (O) 2SY3</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-250</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>SR</p></td><td><p>SI-3</p></td><td><p>5 (O) 2SY3</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-251</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>SR</p></td><td><p>SI-3</p></td><td><p>OSI-3</p></td><td><p>Η</p></td><td><p>CP3</p></td><td><p>Η</p></td></tr><tr><td><p>I-252</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SI-3</p></td><td><p>С (ОМСИ-І3) 2</p></td><td><p>Η</p></td><td><p>OS-3</p></td><td><p>Η</p></td></tr><tr><td><p>I-253</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SI-3</p></td><td><p>AND</p></td><td><p>Η</p></td><td><p>OS-3</p></td><td><p>Η</p></td></tr><tr><td><p>I-254</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SI-3</p></td><td><p>AT</p><p>Aa</p></td><td><p>Η</p></td><td><p>OS-3</p></td><td><p>Η</p></td></tr><tr><td><p>I-255</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SI-3</p></td><td><p>at</p><p>Αν ν-A</p></td><td><p>Η</p></td><td><p>OS-3</p></td><td><p>Η</p></td></tr><tr><td><p>I-256</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>SI-3</p></td><td><p>AT</p><p>Aa</p><p>^ 0</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-257</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>Η</p></td><td><p>0</p><p>Aa</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-258</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>SI-3</p></td><td><p>OS-3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-259</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>OSI-3</p></td><td><p>Η</p></td><td><p>Pda</p></td><td><p>Η</p></td></tr><tr><td><p>I-260</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>С (ОМСИ-І3) 2</p></td><td><p>OS-3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-261</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>AND</p></td><td><p>OS-3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-262</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>at</p><p>Aa</p><p>^ 0</p></td><td><p>OS-3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-263</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>at</p><p>^ А ^ _уч-</p></td><td><p>OS-3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-264</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>SI-3</p></td><td><p>OSII3</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>I-265</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>SI</p></td><td><p>OS-3</p></td><td><p>Pda</p></td><td><p>Η</p></td></tr><tr><td><p>I-266</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>OSII3</p></td><td><p>Η</p></td><td><p>Pda</p></td><td><p>Η</p></td></tr><tr><td><p>I-267</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ΘΗ</p></td><td><p>SI-3</p></td><td><p>OSI-3</p></td><td><p>C (OMS-3) 2</p></td><td><p>Η</p></td><td><p>Η</p></td></tr>

31

iA 106975 C2

R^2a

Table I

<tr><td><p>1-268</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p></p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-269</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>AT</p><p>To</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-270</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>AT</p><p>Κν Ν-</p><p>d</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-271</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SR2N</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-272</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-273</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>SR2N</p></td><td><p>N</p></td></tr><tr><td><p>1-274</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CH2R</p></td><td><p>N</p></td></tr><tr><td><p>1-275</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>R</p></td><td><p>CD</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-276</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>them</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-277</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>them</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-278</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>D ^_Z^Ν^ \</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-279</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CD</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-280</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-281</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>R</p></td><td><p>Dg / \ v-</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-282</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>R</p></td><td><p>Di / \ ι-</p></td><td><p>R</p></td><td><p>N</p></td></tr><tr><td><p>1-283</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>DN^Z</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-284</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>&gt;</p><p>? -N, N-</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-285</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>D ^ _N-y</p></td><td><p>CP3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-286</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>oxazole-5-yl</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-287</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>Hr</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-288</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>Hr</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-289</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>pyridine-4-yl</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-290</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>pyridine-3-yl</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-291</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>pyridine-3-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-292</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OCN2CH2OSN3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr>

32

iA 106975 C2

I^2a

Table I

<tr><td><p>I-293</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>UL</p><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-294</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>MH</p></td><td><p>g</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-295</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>MH</p></td><td><p>pyrrolidine-1-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-296</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>SG3</p></td><td><p>N</p></td></tr><tr><td><p>I-297</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SG3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-298</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>■&gt; A "</p><p>(-0 ^{4 = 7}</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-299</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>(-0 \ = Ν</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-300</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>\</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>І-301</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SG3</p></td><td><p>N</p></td><td><p>SG3</p></td><td><p>N</p></td></tr><tr><td><p>I-302</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>I-303</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SG3</p></td><td><p>MH</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-304</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH (OH) SG3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-305</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>ОСН2СО2СН3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-306</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>AT</p><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-307</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>ОСН2С (О) ЧН2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-308</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>H (H) C (O) RI</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-309</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH (CH3) C (O) CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-310</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>MH</p></td><td><p>pyrrolidine-1-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-311</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OCR2N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-312</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSG2N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-313</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>ОСН2СН3</p></td><td><p>OCR2N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-314</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>OCR2N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-315</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>И-316</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) CHN2</p></td><td><p>Ν^Z \and-</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-317</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>O ι</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-318</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>at_h</p><p>Clever</p><p>("NN")</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-319</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>ОСН2С (О) ЧН2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>I-320</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>■ yU</p><p>Co</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr>

33

iA 106975 C2

R^2a

Table I

<tr><td><p>1-321</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>About us</p><p>p-</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-322</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>Oh, - \</p><p>_Y-</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-323</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) NIN2</p></td><td><p>AT</p><p>CHNN-</p><p>WITH</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-324</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OS (CH3) 2C (O) NH2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-325</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Hn</p><p>D ° qA_at</p></td><td><p>CH3</p></td></tr><tr><td><p>1-326</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OCN2C (O) N (CH3) 2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-327</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>YOU</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-328</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>CH3</p></td></tr><tr><td><p>1-329</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>pyridine-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-330</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SG3</p></td><td><p>pyridine-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-331</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH2OH</p></td><td><p></p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-332</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>piperazine-1-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-333</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>/ -_h \ other</p><p>XX</p><p>'-' oh</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-334</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OS (CH3) 2SY</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-335</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2C (O) NH2</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-336</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>СО2СН3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-337</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-338</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-339</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>YOU</p></td><td><p>thiomorpholin-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-340</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p></p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-341</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>YOU</p></td><td><p></p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-342</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2SY</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-343</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>xxx</p><p>'-' oh</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-344</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>/ - \</p><p>X- N- (</p><p>'-' oh</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-345</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>xxx</p><p>⁴- 'Oh</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-346</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>/ - \ 'o</p><p>'-' Oh</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-347</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>g</p></td><td><p>OCR2N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-348</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>OCR2N</p></td><td><p>SI</p></td><td><p>N</p></td></tr>

34

iA 106975 C2

R^2a

Table I

<tr><td><p>1-349</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-350</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-351</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-352</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-353</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CB3</p></td><td><p>N</p></td><td><p>OSV2N</p></td><td><p>N</p></td></tr><tr><td><p>1-354</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>CB3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-355</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>1-butyl</p></td><td><p>N</p></td><td><p>1-butyl</p></td><td><p>N</p></td></tr><tr><td><p>1-356</p></td><td><p>AT</p></td><td><p>YSSNOOR (O) (O-1-</p><p>You) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CB3</p></td><td><p>N</p></td></tr><tr><td><p>1-357</p></td><td><p>AT</p></td><td><p>HEADING (O) (OH) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CB3</p></td><td><p>N</p></td></tr><tr><td><p>1-358</p></td><td><p>AT</p></td><td><p>HEAD (O) (OAA) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CB3</p></td><td><p>N</p></td></tr><tr><td><p>1-359</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>IN</p></td><td><p>N</p></td></tr><tr><td><p>1-360</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>CB3</p></td><td><p>N</p></td></tr><tr><td><p>1-361</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CB3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-362</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-363</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-364</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-365</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-366</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>OSV3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-367</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>3СВ3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-368</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-369</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-370</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) NIN2</p></td><td><p>N</p></td><td><p>CB3</p></td><td><p>N</p></td></tr><tr><td><p>1-371</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>isopropyl</p></td><td><p>OSN3</p></td><td><p>isopropyl</p></td><td><p>N</p></td></tr><tr><td><p>1-372</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>O-isopropyl</p></td><td><p>N</p></td><td><p>CB3</p></td><td><p>N</p></td></tr><tr><td><p>1-373</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>YOU</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-374</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-375</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSV3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-376</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>OSV3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-377</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSV3</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-378</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>OSV3</p></td><td><p>N</p></td></tr><tr><td><p>1-379</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OSV3</p></td><td><p>N</p></td></tr><tr><td><p>1-380</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>YOU</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-381</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>OSN3</p></td><td><p>IN</p></td><td><p>N</p></td></tr><tr><td><p>1-382</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p></p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-383</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>YOU</p></td><td><p>SI</p></td><td><p>CH2CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-384</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OCN2CH2OSN3</p></td><td><p>N</p></td><td><p>CB3</p></td><td><p>N</p></td></tr><tr><td><p>1-385</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>OSV2N</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-386</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2C (O) NH2</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-387</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>OSV2N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-388</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>OSV2N</p></td><td><p>IN</p></td><td><p>N</p></td></tr><tr><td><p>1-389</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2C (O) NH2</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-390</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSV2N</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-391</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2C (O) NH2</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-392</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2C (O) NH2</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-393</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CB3</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-394</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-395</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>OS (CH3) 2C (O) NH2</p></td><td><p>IN</p></td><td><p>N</p></td></tr><tr><td><p>1-396</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH (OSN3) CB3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-397</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2SY</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-398</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-399</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>SI</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-400</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-401</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>N</p></td><td><p>OSV2N</p></td><td><p>N</p></td></tr>

35

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Table I

<tr><td><p>1-402</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2C (O) CHN2</p></td><td><p>N</p></td><td><p>R</p></td><td><p>N</p></td></tr><tr><td><p>1-403</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>A-404</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CP3</p></td><td><p>_ζ° -</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-405</p></td><td><p>AT</p></td><td><p>CHSNOOR (O) (O-1-</p><p>You) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-406</p></td><td><p>AT</p></td><td><p>CHSNOR (O) (OH) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-407</p></td><td><p>AT</p></td><td><p>CHSNOR (O) (OCHA) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-408</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>R</p></td><td><p>R</p></td><td><p>R</p></td><td><p>N</p></td></tr><tr><td><p>1-409</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>R</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-410</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>R</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-411</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>R</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-412</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>R</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-413</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>R</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-414</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>R</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-415</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>R</p></td><td><p>CP3</p></td><td><p>R</p></td><td><p>N</p></td></tr><tr><td><p>1-416</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2SCH</p></td><td><p>N</p></td><td><p>R</p></td><td><p>N</p></td></tr><tr><td><p>1-417</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OS (CH3) 2SCH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-418</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OCR2N</p></td><td><p>C1</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-419</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>isopropyl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-420</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>1-butyl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-421</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-422</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH2O-isopropyl</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-423</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>lLon</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-424</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OH</p></td><td><p>SI</p></td><td><p>N</p></td></tr><tr><td><p>1-425</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OH</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-426</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>Ż N</p><p>⁴ \</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-427</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-428</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-429</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-430</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SR</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-431</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SR</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-432</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>R</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-433</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OCR2N</p></td><td><p>CH2R</p></td><td><p>N</p></td></tr><tr><td><p>1-434</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>MH</p></td><td><p>OCR2N</p></td><td><p>N</p></td></tr><tr><td><p>1-435</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>OCR2N</p></td><td><p>N</p></td></tr><tr><td><p>1-436</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-437</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>R</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-438</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>SR2N</p></td><td><p>N</p></td></tr><tr><td><p>1-439</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>CH2R</p></td><td><p>N</p></td></tr><tr><td><p>1-440</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-441</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OSCS</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-442</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OCR2N</p></td><td><p>SR2N</p></td><td><p>N</p></td></tr><tr><td><p>1-443</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>pyridine-4-yl</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-444</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>pyridine-3-yl</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-445</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) CH 3</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-446</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>lLon</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>N</p></td></tr><tr><td><p>1-447</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OSCS</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-448</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OSCS</p></td><td><p>SI</p></td><td><p>N</p></td></tr>

36

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R^2a

Table I

<tr><td><p>! -449</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p></p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -450</p></td><td><p>AT</p></td><td><p>CHN₂OR (O) (O-1-</p><p>You) 2</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>CHs</p></td><td><p>R</p></td><td><p>CHs</p></td><td><p>N</p></td></tr><tr><td><p>-451</p></td><td><p>AT</p></td><td><p>CHN₂OR (O) (OCA)₂</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>CHs</p></td><td><p>R</p></td><td><p>CHs</p></td><td><p>N</p></td></tr><tr><td><p>-452</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>Bodies</p></td><td><p>Bodies</p></td><td><p>CHs</p></td><td><p>N</p></td></tr><tr><td><p>! -45s</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SSC</p></td><td><p>CHs</p></td><td><p>Bodies</p></td><td><p>Bodies</p></td><td><p>CHs</p></td><td><p>N</p></td></tr><tr><td><p>! -454</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SR</p></td><td><p>CHs</p></td><td><p>Bodies</p></td><td><p>Bodies</p></td><td><p>CHs</p></td><td><p>N</p></td></tr><tr><td><p>-455</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>-, αΛ⁷</p></td><td><p>SI</p></td><td><p>N</p></td></tr><tr><td><p>-456</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>R</p></td><td><p>N</p></td><td><p>R</p></td></tr><tr><td><p>-457</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>-RD</p><p>N</p></td><td><p>N</p></td><td><p>SZ</p></td><td><p>N</p></td></tr><tr><td><p>! -458</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>Bodies</p></td><td><p>Bodies</p></td><td><p>SI</p></td><td><p>N</p></td></tr><tr><td><p>! -459</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>CHs</p></td><td><p>A&gt;</p></td><td><p>CHs</p></td><td><p>N</p></td></tr><tr><td><p>! -460</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>Υ</p><p>N</p></td><td><p>N</p></td><td><p>SZ</p></td><td><p>N</p></td></tr><tr><td><p>-461</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>-dl</p><p>N</p></td><td><p>N</p></td><td><p>SZ</p></td><td><p>N</p></td></tr><tr><td><p>-462</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>-trm ^</p><p>N</p></td><td><p>N</p></td><td><p>SZ</p></td><td><p>N</p></td></tr><tr><td><p>! -46s</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p></p></td><td><p>N</p></td><td><p>SZ</p></td><td><p>N</p></td></tr><tr><td><p>! -464</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p></p></td><td><p>N</p></td><td><p>SZ</p></td><td><p>N</p></td></tr><tr><td><p>! -465</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>N</p></td><td><p>SZ</p></td><td><p>N</p></td></tr><tr><td><p>! -466</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td><td><p>R</p></td></tr><tr><td><p>-467</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>N</p></td><td><p>R</p></td><td><p>R</p></td></tr><tr><td><p>! -468</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>R</p></td></tr><tr><td><p>! -469</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>DL</p><p>N</p></td><td><p>N</p></td><td><p>SZ</p></td><td><p>N</p></td></tr><tr><td><p>! -470</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>N</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -471</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>pyridine-4-yl</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>! -472</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CHs</p></td><td><p>pyridine-on-yl</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td></tr>

с7

iA 106975 C2

R^2a

Table I

<tr><td><p>1-473</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>ρΑνΑ</p><p>N</p></td><td><p>N</p></td><td><p>CE3</p></td><td><p>N</p></td></tr><tr><td><p>1-474</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-475</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-476</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>IS</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-477</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IS</p></td><td><p>IS</p></td><td><p>IS</p></td><td><p>IS</p></td></tr><tr><td><p>1-478</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>MH</p></td><td><p>N</p></td><td><p>OSE₂N</p></td><td><p>N</p></td></tr><tr><td><p>1-479</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CE3</p></td><td><p>N</p></td></tr><tr><td><p>1-480</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IS</p></td><td><p>N</p></td><td><p>IS</p></td><td><p>IS</p></td></tr><tr><td><p>1-481</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IS</p></td><td><p>IS</p></td><td><p>N</p></td><td><p>IS</p></td></tr><tr><td><p>1-482</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>pyridine-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-483</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>pyridine-3-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-484</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IS</p></td><td><p>pyridine-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-485</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CE3</p></td><td><p>OSN3</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-486</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>pyridine-4-yl</p></td><td><p>pyridyl-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-487</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>pyridine-3-yl</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-488</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SE</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-489</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SE</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-490</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SE</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>IS</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-491</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>IS</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-492</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SE</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>IS</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-493</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>IS</p></td></tr><tr><td><p>1-494</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>pyridine-4-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-495</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSE₂N</p></td><td><p>N</p></td><td><p>SI</p></td><td><p>N</p></td></tr><tr><td><p>1-496</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>OSN3</p></td><td><p>SI</p></td><td><p>N</p></td></tr><tr><td><p>1-497</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CE3</p></td><td><p>N</p></td><td><p>SI</p></td><td><p>N</p></td></tr><tr><td><p>1-498</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CE3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>OSN3</p></td></tr><tr><td><p>1-499</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>CH3</p></td></tr><tr><td><p>1-500</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>CH3</p></td></tr><tr><td><p>1-501</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>CH3</p></td></tr><tr><td><p>1-502</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Ei</p></td></tr><tr><td><p>1-503</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH2CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-504</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH2CH3</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-505</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>IS</p></td><td><p>pyridine-3-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-506</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>pyridine-3-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-507</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>IS</p></td><td><p>OSN3</p></td><td><p>IS</p></td></tr><tr><td><p>1-508</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SE</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>IS</p></td><td><p>OSN3</p></td><td><p>IS</p></td></tr><tr><td><p>1-509</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>6-CI-pyridine-3-yl</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-510</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p></p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-511</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N-N</p><p>\</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-512</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>^ AAAA °</p><p>N \ - /</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>1-513</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>IS</p></td></tr><tr><td><p>1-514</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>IS</p></td></tr><tr><td><p>1-515</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>IS</p></td></tr><tr><td><p>1-516</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSE₂N</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-517</p></td><td><p>AT</p></td><td><p>CHN₂OR (O) (OH)₂</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-518</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>CE3</p></td><td><p>CH3</p></td></tr><tr><td><p>1-519</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>C (O) CH 3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>IS</p></td></tr><tr><td><p>1-520</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>SI</p></td></tr>

38

iA 106975 C2

R^2a

Table I

<tr><td><p>1-521</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>SI</p></td></tr><tr><td><p>1-522</p></td><td><p>at</p></td><td><p>In</p></td><td><p>SRI</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>SI</p></td></tr><tr><td><p>1-523</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>ahon</p></td><td><p>N</p></td><td><p>N</p></td><td><p>IN</p></td></tr><tr><td><p>1-524</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (o-1-</p><p>You) 2</p></td><td><p>SRI</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-525</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (OH) 2</p></td><td><p>SRI</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-526</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (OH) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-527</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>I</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-528</p></td><td><p>at</p></td><td><p>HYCH2OOR (o) (oAa) 2</p></td><td><p>SRI</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-529</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td></tr><tr><td><p>1-530</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>IN</p></td></tr><tr><td><p>1-531</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (OH) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-532</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>CB3</p></td><td><p>IN</p></td></tr><tr><td><p>1-533</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>IN</p></td></tr><tr><td><p>1-534</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>IN</p></td></tr><tr><td><p>1-535</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-536</p></td><td><p>at</p></td><td><p>HYCH2Or (o) (OH) 2</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>N</p></td></tr><tr><td><p>1-537</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>IN</p></td><td><p>N</p></td></tr><tr><td><p>1-538</p></td><td><p>at</p></td><td><p>HYCH2OOR (o) (oAa) 2</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>OSN3</p></td><td><p>IN</p></td><td><p>CH3</p></td><td><p>N</p></td></tr>

<tr><td><p>Table II</p><p>R^2b</p><p>X / Z¹. R⁵ R^2a , P^2s</p><p>Ż "1 ΧΧϊ and</p><p>^{Mr. N} and-</p></td></tr><tr><td><p>Wed</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>R⁵</p></td><td><p>R^2a</p></td><td><p>p2b</p></td><td><p>R^2s</p></td><td><p>R^{2s |}</p></td></tr><tr><td><p>11-1</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>-Y (CH 3) 2</p></td><td><p>N</p></td></tr><tr><td><p>11-2</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Ha</p><p>to</p></td><td><p>N</p></td></tr><tr><td><p>11-3</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>1-methyl-1,4-diazepan-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-4</p></td><td><p>at</p></td><td><p>Y- (n-propt)</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-5</p></td><td><p>at</p></td><td><p>Y- (n-propt)</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>^ -NN- /</p><p>O '</p></td><td><p>N</p></td></tr><tr><td><p>11-6</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>4-methylpiperidin-1-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-7</p></td><td><p>at</p></td><td><p>H- (isopropyl)</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-8</p></td><td><p>at</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>/ - \ o</p><p>) -N Ng</p><p>SR₃</p></td><td><p>N</p></td></tr>

39

iA 106975 C2

<tr><td><p>Table II</p><p>K^2b</p><p>_x , ζ¹. ΥΑζ²⁰</p><p>° αX1 ΧΧΥΥ "</p><p>υΥ₍/ ιΛ_νΥ^ν</p><p>^ΗΗ</p></td></tr><tr><td><p>СрС</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>K⁵</p></td><td><p>K^2a</p></td><td><p>K^2b</p></td><td><p>K^2s</p></td><td><p>K^2C</p></td></tr><tr><td><p>ii-9</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>Ooh₃</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>/ - \ o</p><p>&gt; M</p><p>^xo</p></td><td><p>Η</p></td></tr><tr><td><p>i-10</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>Ooh₃</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>piperazine-1-yl</p></td><td><p>Η</p></td></tr><tr><td><p>i-11</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>Ooh₃</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>x / x l °</p><p>2-NNY; /</p></td><td><p>Η</p></td></tr><tr><td><p>i-12</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>Ooh₃</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>¢ -N ^ _</p></td><td><p>Η</p></td></tr><tr><td><p>ii-13</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-14</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-15</p></td><td><p>NN</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-16</p></td><td><p>NN</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-17</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>morpholin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-18</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>morpholin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-19</p></td><td><p>NN</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>morpholin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-20</p></td><td><p>N ^ 3</p></td><td><p>N ^ 3</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-21</p></td><td><p>N ^ 3</p></td><td><p>N ^ 3</p></td><td><p>Ooh</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-22</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-23</p></td><td><p>N ^ 3</p></td><td><p>AT</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-24</p></td><td><p>AT</p></td><td><p>N ^ 3</p></td><td><p>Ooh</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-25</p></td><td><p>NN</p></td><td><p>AT</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-26</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>C ^</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-27</p></td><td><p>NN</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>C ^</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr><tr><td><p>ii-28</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>C ^</p></td><td><p>I</p></td><td><p>Η</p></td></tr><tr><td><p>ii-29</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Ooh₃</p></td><td><p>ΥΥ</p><p>I</p></td><td><p>Η</p></td></tr><tr><td><p>iy-30</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>Ooh</p></td><td><p>R</p></td><td><p>Η</p></td><td><p>Ooh₃</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>Η</p></td></tr>

40

υΑ 106975 Ο2

<tr><td><p>Table II</p><p>I^2b</p><p>x, ζ¹. SAl²⁰</p><p>_atts ίπ ΧΧΥΥ "</p><p>^{Mr. N.} R-</p></td></tr><tr><td><p>СрС</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>N⁵</p></td><td><p>N^2a</p></td><td><p>N^2b</p></td><td><p>N^2s</p></td><td><p>N^2s</p></td></tr><tr><td><p>11-31</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>5</p></td><td><p>N</p></td></tr><tr><td><p>11-32</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>tt</p><p>I</p></td><td><p>N</p></td></tr><tr><td><p>11-33</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td><td><p>I</p></td><td><p>N</p></td></tr><tr><td><p>11-34</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>R</p></td><td><p>N</p></td><td><p>N</p></td><td><p>I</p></td><td><p>N</p></td></tr><tr><td><p>11-35</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>-R n) -1 -methylpiperidin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-36</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>-RN) -piperidine-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-37</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p></p></td><td><p>N</p></td></tr><tr><td><p>11-38</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>τθ</p></td><td><p>N</p></td></tr><tr><td><p>11-39</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-40</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>5</p></td><td><p>N</p></td></tr><tr><td><p>11-41</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>5?</p><p>/ - \ o</p><p>A NN- /</p><p>O &lt;γ</p></td><td><p>N</p></td></tr><tr><td><p>11-42</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>11-43</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>C (o)₂CH3</p></td><td><p>N</p></td></tr><tr><td><p>11-44</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>5?</p><p>\ h</p></td><td><p>N</p></td></tr><tr><td><p>11-45</p></td><td><p>AT</p></td><td><p>NJ</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>-C (O) -piperazin-1-yl</p></td><td><p>N</p></td></tr>

41

iA 106975 C2

<tr><td><p>Table II</p><p>R^2b</p><p>y, Z¹. p5 P²θ .Р^2s</p><p>° CU1 "YY Y"</p><p>^{Mr. N.} R-</p></td></tr><tr><td><p>Wed</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>R⁵</p></td><td><p>R^2a</p></td><td><p>p2b</p></td><td><p>R^2s</p></td><td><p>R^{2s |}</p></td></tr><tr><td><p>11-46</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>0 gm</p><p>MNN-N</p></td><td><p>N</p></td></tr><tr><td><p>11-47</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>O / - \</p><p>NN ^.</p><p>to ^{7 7} )</p></td><td><p>N</p></td></tr><tr><td><p>11-48</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>IN</p></td><td><p>N</p></td></tr><tr><td><p>11-49</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p></p></td><td><p>N</p></td></tr><tr><td><p>11-50</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>ήΟΟ^η</p></td><td><p>N</p></td></tr><tr><td><p>11-51</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>&gt; -^ν0^νη</p></td><td><p>N</p></td></tr><tr><td><p>11-52</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>■ "-so- _ν</p></td><td><p>N</p></td></tr><tr><td><p>11-53</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>io ^</p></td><td><p>N</p></td></tr><tr><td><p>11-54</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>'-^ΝO^Ν~_ν</p></td><td><p>N</p></td></tr><tr><td><p>11-55</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>ΉνΑ-</p></td><td><p>N</p></td></tr><tr><td><p>11-56</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>&gt; Λ</p><p>¢ -N</p></td><td><p>N</p></td></tr><tr><td><p>11-57</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>h / o λ °</p><p>&gt; -N-N-</p><p>SR₃</p></td><td><p>N</p></td></tr>

42

iA 106975 C2

<tr><td><p></p></td><td><p>Table II</p></td></tr><tr><td><p>Υ</p></td><td><p>1</p></td><td><p>ΝΓ</p><p>N</p></td><td><p>I</p><p>N</p></td><td><p>R^2b</p><p>2a 1 o2s</p><p>'Yeah</p><p>Χγ^Ν</p><p>⁴ R²³</p></td></tr><tr><td><p>Wed 3</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>R⁵</p></td><td><p>R^2a</p></td><td><p>R^2b</p></td><td><p>R^2C</p></td><td><p>R²³</p></td></tr><tr><td><p>11-58</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>to</p><p>0 = 0--0</p><p>XX</p><p>1</p></td><td><p>N</p></td></tr><tr><td><p>11-59</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>4,4-difluoropiperidin-1-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-60</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>4,4-dimethylpiperidin-1-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-61</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p></p></td><td><p>N</p></td></tr><tr><td><p>11-62</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p></p></td><td><p>N</p></td></tr><tr><td><p>11-63</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>KH</p></td><td><p>N</p></td></tr><tr><td><p>11-64</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>ρ_Νρ_Ν-</p></td><td><p>N</p></td></tr><tr><td><p>11-65</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>KMU</p></td><td><p>N</p></td></tr><tr><td><p>11-66</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p></p></td><td><p>N</p></td></tr><tr><td><p>11-67</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>kr</p></td><td><p>N</p></td></tr><tr><td><p>11-68</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>KM-</p></td><td><p>N</p></td></tr><tr><td><p>11-69</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>M,</p></td><td><p>N</p></td></tr><tr><td><p>11-70</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>&gt; n - /</p></td><td><p>N</p></td></tr><tr><td><p>11-71</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>pyrrolidine-1-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-72</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr>

43

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<tr><td><p>Table ΙΙ</p><p>R^2b</p><p>χ, ζ¹. K²\ X \ / K^2C</p><p>Γ1 Ρϊ Υ "</p><p>γΓΓΧΧγ</p><p>^{Mr. N.} R-</p></td></tr><tr><td><p>Wed</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>R⁵</p></td><td><p>R^2a</p></td><td><p>p2b</p></td><td><p>R^2s</p></td><td><p>R²³</p></td></tr><tr><td><p>ii-73</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>ССН3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>ii-74</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>-CH (H) CH₂-cyclopropyl</p></td><td><p>N</p></td></tr><tr><td><p>ii-75</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SR</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>ii-76</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>SR</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>morpholin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>ii-77</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>Hr</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>ii-78</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>-CH (H) 5 (O)₂CH3</p></td><td><p>N</p></td></tr><tr><td><p>ii-79</p></td><td><p>AT</p></td><td><p>CHSN3</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>-CH (H) 5 (O)₂CH3</p></td><td><p>N</p></td></tr><tr><td><p>ii-80</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>\</p><p>N-</p><p>tCG</p></td><td><p>N</p></td></tr><tr><td><p>ii-81</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>ii-82</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p></p></td><td><p>N</p></td></tr><tr><td><p>iy-83</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Η</p><p>CH₃</p><p>g-σ t</p></td><td><p>N</p></td></tr><tr><td><p>ii-84</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>0</p></td><td><p>N</p></td></tr><tr><td><p>ii-85</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CP3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>ii-86</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Η</p><p>¿v</p></td><td><p>N</p></td></tr><tr><td><p>ii-87</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Γ^νX / chi</p></td><td><p>N</p></td></tr><tr><td><p>iy-88</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>LF-</p></td><td><p>N</p></td></tr>

44

iA 106975 C2

<tr><td><p>Table II</p><p>R^2b</p><p>y, ζ¹. I⁵. p^2a / X / I^2s</p><p>_atts Ά ΊΑϊΥΥ</p><p>^{Mr. N}</p></td></tr><tr><td><p>Wed</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>I⁵</p></td><td><p>I^2a</p></td><td><p>I^2b</p></td><td><p>I^2s</p></td><td><p>I^{2s |}</p></td></tr><tr><td><p>11-89</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>\</p><p>oh</p></td><td><p>N</p></td></tr><tr><td><p>11-90</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>\</p><p>kA</p></td><td><p>N</p></td></tr><tr><td><p>11-91</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>P, h</p><p>AND</p></td><td><p>N</p></td></tr><tr><td><p>11-92</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>HN-</p></td><td><p>N</p></td></tr><tr><td><p>11-93</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>HN-SOUND</p><p>RA</p></td><td><p>N</p></td></tr><tr><td><p>11-94</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>HN ^</p><p>ί-σ Υ</p></td><td><p>N</p></td></tr><tr><td><p>11-95</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Ha</p><p>'-^Z RI</p></td><td><p>N</p></td></tr><tr><td><p>11-96</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>ΗΗ</p><p>Ν.</p><p>ρ Α ί t</p></td><td><p>N</p></td></tr><tr><td><p>11-97</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>ΗΗ</p><p>NN /</p><p>&lt;- "Υ ϊ</p></td><td><p>N</p></td></tr><tr><td><p>11-98</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>HHNX. / N. / PII</p><p>&gt; - &lt;ϊϊ</p></td><td><p>N</p></td></tr><tr><td><p>11-99</p></td><td><p>AT</p></td><td><p>N4</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>) -NH</p><p>P</p><p>⁴- 'Ρή</p></td><td><p>N</p></td></tr>

45

iA 106975 C2

<tr><td><p>Table II</p><p>R^2b</p><p>Γ1 ΧΧχχ</p><p>SSSAS^{Mr. N.} WITH</p></td></tr><tr><td><p>Wed</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>R⁵</p></td><td><p>R^2a</p></td><td><p>p2b</p></td><td><p>R^2s</p></td><td><p>ρ2ά</p></td></tr><tr><td><p>11-100</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>shh</p></td><td><p>Η</p></td></tr><tr><td><p>11-101</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>ss</p></td><td><p>Η</p></td></tr><tr><td><p>11-102</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>ss</p></td><td><p>Η</p></td></tr><tr><td><p>11-103</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>with</p><p>AT</p></td><td><p>Η</p></td></tr><tr><td><p>11-104</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>®NH</p></td><td><p>Η</p></td></tr><tr><td><p>11-105</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>) -NH</p><p>WITH</p></td><td><p>Η</p></td></tr><tr><td><p>11-106</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>* X</p><p>⁴- 'RI</p></td><td><p>Η</p></td></tr><tr><td><p>11-107</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>) -NH</p><p>X</p></td><td><p>Η</p></td></tr><tr><td><p>11-108</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>Η</p></td><td><p>'WITH</p></td><td><p>Η</p></td></tr><tr><td><p>11-109</p></td><td><p>AT</p></td><td><p>NN</p></td><td><p></p></td><td><p>C ^</p></td><td><p>Η</p></td><td><p>SRe</p></td><td><p>/ -N0 "</p><p>5</p></td><td><p>Η</p></td></tr>

46

iA 106975 C2

<tr><td><p>Table II</p><p>R^2b</p><p>X, Z¹. p5 P^2a D \ .P^2s</p><p>Γ1 Υϊ η</p><p>^ΗΗ P-</p></td></tr><tr><td><p>Wed</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>R⁵</p></td><td><p>R^2a</p></td><td><p>R^2y</p></td><td><p>R^2s</p></td><td><p>R^{2s |}</p></td></tr><tr><td><p>11-110</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>SNea</p></td><td><p>N</p></td><td><p>Wed 3</p></td><td><p>1-ethylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-111</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>SNea</p></td><td><p>N</p></td><td><p>R</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-112</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>&gt; d</p></td><td><p>N</p></td></tr><tr><td><p>11-113</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>N</p><p>\ / k \ 1</p><p>(-</p></td><td><p>N</p></td></tr><tr><td><p>11-114</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>1-ethylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-115</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>YOU</p></td><td><p>HELL-</p><p>5</p></td><td><p>N</p></td></tr><tr><td><p>11-116</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>SI</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>11-117</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>&gt; d</p><p>) -N&gt; N-</p></td><td><p>N</p></td></tr><tr><td><p>11-118</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>SI</p></td><td><p></p></td><td><p>N</p></td></tr><tr><td><p>11-119</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>I-SD</p></td><td><p>N</p></td></tr><tr><td><p>11-120</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>ADA</p></td><td><p>N</p></td></tr><tr><td><p>11-121</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>ASO</p></td><td><p>N</p></td></tr><tr><td><p>11-122</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>SI</p></td><td><p>ASO</p></td><td><p>N</p></td></tr><tr><td><p>11-123</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>-OSN₃</p></td><td><p>N</p></td></tr><tr><td><p>11-124</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CP3</p></td><td><p>&gt; D</p><p>(-N)</p></td><td><p>N</p></td></tr><tr><td><p>11-125</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>R</p></td><td><p>Αθ</p></td><td><p>N</p></td></tr>

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<tr><td><p>Table II</p><p>R^2b</p><p>X, Z¹. R ® P²θ / Λ / Ρ^2s</p><p>° xX1 "Àϊ Υ"</p><p>ν^ΛM_ΝΑ_ΝX_ΝΛγΝ^{Mr. N}</p></td></tr><tr><td><p>Wed</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>R⁵</p></td><td><p>R^2a</p></td><td><p>p2b</p></td><td><p>R^2s</p></td><td><p>ρ2ά</p></td></tr><tr><td><p>ІІ-126</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>he is</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-127</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>&gt;</p><p>? -You-</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-128</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>&gt; -o</p><p>mind ı-⁷</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-129</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>&gt; -G</p><p>(-I \ _ / Y-</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-130</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>&gt; -g</p><p>yyyyyy</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-131</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>)</p><p>? -S ın</p><p>h</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-132</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Η γ.</p><p>\ / ~ k \ 1</p><p>(-Y_</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-133</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>mSH</p><p>[student</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-134</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p></p></td><td><p>N</p></td></tr><tr><td><p>ІІ-135</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>m \ 2 °</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-136</p></td><td><p>AT</p></td><td><p>In</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>1-isopropylpiperazin-4-yl</p></td><td><p>N</p></td></tr>

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<tr><td><p>Table II</p><p>I^2b</p><p>χ, Z¹. U / X P²θ xk .Ya²°</p><p>_atts Ά ΊΑϊ Υ "</p><p>^{Mr. N.} R-</p></td></tr><tr><td><p>Wed</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>Z¹</p></td><td><p>I⁵</p></td><td><p>I^2a</p></td><td><p>I^2b</p></td><td><p>I^2s</p></td><td><p>I²⁰</p></td></tr><tr><td><p>ІІ-137</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>eUn</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-138</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>&gt; -You</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-139</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>to</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-140</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>BOS₃</p></td><td><p>BOS₃</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-141</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>BOS₃</p></td><td><p>BOS₃</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-142</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>BOS₂CH₂OH</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-143</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>1-methylpiperazin-4-yl</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-144</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>BOS (CH₃)₂</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-145</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>BOS₂CH₂BOS₃</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-146</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>OS (CH₃)₂C (O) CHN₂</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-147</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>SG3</p></td><td><p>BOS₃</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-148</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>BOS₂CH₂CH₂OH</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-149</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>BOS₂CH₂CH₂BOS₃</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-150</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>SI</p></td><td><p>ζθ</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-151</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-152</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>BOS₃</p></td><td><p>N</p></td><td><p>N</p></td></tr><tr><td><p>ІІ-153</p></td><td><p>AT</p></td><td><p>ChN</p></td><td><p>CH</p></td><td><p>CH3</p></td><td><p>N</p></td><td><p>CH3</p></td><td><p>CH3</p></td><td><p>N</p></td></tr>

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<tr><td><p>Table III</p></td></tr><tr><td><p></p></td><td><p>A XX</p><p>R³</p></td><td><p>AND</p><p>ı</p></td><td><p>Λ</p><p>1</p></td><td><p>T ^ 2 / | -P^and(oh^ı)</p></td></tr><tr><td><p>Compound</p></td><td><p>Υ</p></td><td><p>R³</p></td><td><p>R^andor Rⁱⁿ</p></td></tr><tr><td><p>III-1</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>Η</p></td></tr><tr><td><p>ІІІ-2</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>AT-</p></td></tr><tr><td><p>ІІІ-3</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>CO₂-And you</p></td></tr><tr><td><p>ІІІ-4</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>Ooh₈</p></td></tr><tr><td><p>ІІІ-5</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>Ooh₂ΟΗβ</p></td></tr><tr><td><p>ІІІ-6</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>n-propyl</p></td></tr><tr><td><p>ІІІ-7</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>WITH-₂-cyclopropyl</p></td></tr><tr><td><p>ІІІ-8</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>G-isopropyl</p></td></tr><tr><td><p>ІІІ-9</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>HH₂-SH₂isopropyl</p></td></tr><tr><td><p>ІІІ-10</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>WITH-₂-cyclopentyl</p></td></tr><tr><td><p>ІІІ-11</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>HH₂- (bicyclo [2.2.1] hept-5-en-2-yl)</p></td></tr><tr><td><p>ІІІ-12</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>Ο ^ ΟΗβ</p></td></tr><tr><td><p>ІІІ-13</p></td><td><p>MS (O) -i-You</p></td><td><p>C (O) -i-You</p></td><td><p>C (O) -i-You</p></td></tr><tr><td><p>ІІІ-14</p></td><td><p>NN</p></td><td><p>Η</p></td><td><p>δ ^ ΟΗβ</p></td></tr>

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<tr><td><p>Table IV</p><p>dd dd</p></td></tr><tr><td><p>Clap</p><p>uka</p></td><td><p></p></td></tr><tr><td><p>IV-1</p></td><td><p>DDD</p></td></tr><tr><td><p>No. 2</p></td><td><p>Α9</p><p>0</p></td></tr><tr><td><p>i-n</p></td><td><p>Yes</p><p>Λν · -^ν</p></td></tr><tr><td><p>ІУ-4</p></td><td><p>Χϊ&gt;</p><p>DD</p></td></tr><tr><td><p>№5</p></td><td><p>DD</p></td></tr><tr><td><p>ν- &lt;5</p></td><td><p>Χι '·</p></td></tr><tr><td><p>No. 7</p></td><td><p>DD</p><p>Dmn</p></td></tr><tr><td><p>IU-8</p></td><td><p>DL</p><p>Λά</p></td></tr><tr><td><p>-9</p></td><td><p>Haha</p></td></tr><tr><td><p>No. 10</p></td><td><p></p></td></tr>

<tr><td><p>Table IV</p><p>DD DD</p></td></tr><tr><td><p>Clap</p><p>uka</p></td><td><p>«Х ·</p></td></tr><tr><td><p>№1 1</p></td><td><p>Χλ</p><p>R</p></td></tr><tr><td><p>No. 12</p></td><td><p>X</p></td></tr><tr><td><p>IV-η</p></td><td><p>XX&gt;</p><p>-X</p><p>t</p></td></tr><tr><td><p>№14</p></td><td><p>hr</p></td></tr><tr><td><p>№15</p></td><td><p>DAY "</p></td></tr><tr><td><p>No. 16</p></td><td><p>PD</p></td></tr><tr><td><p>№17</p></td><td><p>DD</p></td></tr><tr><td><p>No. 18</p></td><td><p>d</p></td></tr>

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<tr><td><p>Table IV</p><p>^{o =}&lt;° ХХХl аР^{2) p}</p><p>Mr. N</p></td></tr><tr><td><p>Clap</p><p>uka</p></td><td><p></p></td></tr><tr><td><p>Jan-19</p></td><td><p></p></td></tr><tr><td><p>20</p></td><td><p></p></td></tr><tr><td><p>ı-21</p></td><td><p>Λ "</p></td></tr><tr><td><p>IU-22</p></td><td><p>&lt;- H</p></td></tr><tr><td><p>-23</p></td><td><p>Ж &lt;"</p><p>H o</p></td></tr><tr><td><p>ı-24</p></td><td><p>γΧΧΧο</p><p>Η</p></td></tr><tr><td><p>-25</p></td><td><p>Η</p></td></tr><tr><td><p>-26</p></td><td><p>~ αΑ °</p><p>ο Η</p></td></tr><tr><td><p>ı-27</p></td><td><p>ΑΑ</p></td></tr><tr><td><p>IU-28</p></td><td><p>/</p><p>3νΝ</p><p>tg λ λ °</p></td></tr>

<tr><td><p>Table IV</p></td></tr><tr><td><p>0</p><p>ο &lt;</p><p>Ν</p><p>Η</p></td><td><p>Αιι ΛΑ^ν</p><p>AaDlC</p><p>ΗΗ</p></td><td><p></p></td></tr><tr><td><p>Clap</p><p>uka</p></td><td><p>Α</p></td><td><p>&lt;K²) ρ</p></td></tr><tr><td><p>GU-29</p></td><td><p>Α *</p></td><td><p>-N</p><p>'Ν</p><p>Η</p></td></tr><tr><td><p>1U-30</p></td><td><p>Α *</p></td><td><p>Λ</p></td></tr><tr><td><p>ı-31</p></td><td><p>Α</p></td><td><p>IN</p></td></tr><tr><td><p>À-32</p></td><td><p>αΑ °</p></td></tr><tr><td><p>-33</p></td><td><p>Α</p></td><td><p>Η</p><p>Νχ.Ο</p></td></tr><tr><td><p>À-34</p></td><td><p>Α</p></td><td><p>\ ρ</p></td></tr><tr><td><p>-35</p></td><td><p>Α</p></td><td><p>Ε °&gt;</p><p>ο</p></td></tr><tr><td><p>ı-36</p></td><td><p>Α ^ οΛ</p></td></tr><tr><td><p>-37</p></td><td><p>Α</p></td><td><p>O</p><p>TG</p></td></tr><tr><td><p>ı-38</p></td><td><p>αχ</p></td></tr>

52

iA 106975 C2

<tr><td><p>Table IV</p><p>_οχ ° ΤΐΟΟ AA^{2) p}</p></td></tr><tr><td><p>Ν</p><p>Η</p></td><td><p>^ν NNN</p><p>ΗΗ</p></td></tr><tr><td><p>Clap</p><p>uka</p></td><td><p>Χ&gt; "^{ΒΙ |}&gt;</p></td></tr><tr><td><p>IU-39</p></td><td><p>χχ:&gt; ο</p></td></tr><tr><td><p>-40</p></td><td><p>ΑΑ</p></td></tr><tr><td><p>À-41</p></td><td><p>Αοο^with \</p></td></tr><tr><td><p>-42</p></td><td><p>/</p><p>Χτ^Ν-</p><p>χχ</p></td></tr><tr><td><p>À-43</p></td><td><p>ΑΑ</p></td></tr><tr><td><p>ı-44</p></td><td><p>ΑΑ</p></td></tr><tr><td><p>À-45</p></td><td><p>"° Α</p></td></tr><tr><td><p>À-46</p></td><td><p>Η</p><p>-N. .N ^ .0</p><p>-XV</p></td></tr><tr><td><p>ı-47</p></td><td><p>-XV</p><p>Η</p></td></tr><tr><td><p>ı-48</p></td><td><p>e) 3</p><p>&lt;H</p></td></tr>

<tr><td><p></p></td><td><p>Table IV</p></td><td><p></p></td></tr><tr><td><p>0-</p><p>° = &lt;</p><p>Ν</p><p>Η</p></td><td><p>χΑ Ύν</p><p>ΑΑ Λ λ χ</p><p>Ν NN</p><p>ΗΗ</p></td><td><p>SA^{(p2) p}</p></td></tr><tr><td><p>Clap</p><p>uka</p></td><td><p>V</p></td><td><p>®^{(ρ2) ρ}</p></td></tr><tr><td><p>GU-49</p></td><td><p></p></td><td><p>α</p></td><td><p>N</p><p>N</p><p>&lt;</p></td></tr><tr><td><p>ν-50</p></td><td><p>AU</p></td><td><p>AND</p></td></tr><tr><td><p>ı-51</p></td><td><p>X</p></td><td><p>-0</p></td><td><p></p></td></tr><tr><td><p>-52</p></td><td><p>X</p></td><td><p>-0</p></td><td><p>V</p></td></tr><tr><td><p>vi-53</p></td><td><p>Α</p></td><td><p>OS</p></td><td><p></p></td></tr><tr><td><p>À-54</p></td><td><p>X '</p></td><td><p>Os</p></td><td><p>γχ</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>ο^χ</p></td><td><p></p></td></tr><tr><td><p>GU-55</p></td><td><p></p></td><td><p>γΎ</p></td><td><p>Χχ.</p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>kA</p></td><td><p></p></td></tr><tr><td><p></p></td><td><p></p></td><td><p>he is</p></td><td><p></p></td></tr><tr><td><p>ı-56</p></td><td><p>V</p></td><td><p>AND</p></td><td><p>and</p></td></tr><tr><td><p>À-57</p></td><td><p>Α</p></td><td><p>os</p></td><td><p></p></td></tr><tr><td><p>vi-58</p></td><td><p>η</p><p>~ Α ^ '</p></td><td><p>0 ^</p></td></tr>

53

iA 106975 C2

<tr><td><p>Table IV</p><p>o = &lt;° Ye A</p><p>η Η Η</p></td></tr><tr><td><p>Clap</p><p>uka</p></td><td><p></p></td></tr><tr><td><p>59</p></td><td><p>Α</p><p>P</p></td></tr><tr><td><p>ı-60</p></td><td><p>Α</p></td></tr><tr><td><p>À-61</p></td><td><p>Α</p></td></tr><tr><td><p>-62</p></td><td><p>Α</p><p>P</p></td></tr>

<tr><td><p>Table IV</p><p>νΥ^χν^Λν^Λν^Λ-⁷</p><p>η Η Η</p></td></tr><tr><td><p>Clap</p><p>uka</p></td><td><p></p></td></tr><tr><td><p>-v 63</p></td><td><p>Υ "Ν</p><p>νΥ</p><p>P</p></td></tr><tr><td><p>IV-64</p></td><td><p>ΥΥ</p><p>νΥ</p><p>ρ · ΤΡΑ</p></td></tr>

Prolixes

One skilled in the art will appreciate that the compounds 2,4-pyrimidinediamine described herein may include functional groups that may be masked by groups with the subsequent formation of prodrugs. Such prodrugs, of course, but not necessarily, are pharmacologically inactive ditches until they are converted to the active form of the drug. Indeed, many of the described inventions of compounds 2, 4-pyrimidindamine include molecules that are hydrolyzed or split in a different way under conditions of use. For example, the ether groups usuallyare acid-catalysed hydrolysis to obtain the original carboxylic acid influences of the acidic environment of the stomach or hydrolysis with the base catalyze under the influence of the main environments of urine or blood. Thus, when administered orally to a patient, a compound of 2,4-pyrimidinediamine, comprising an ether molecule,

The mechanism of metabolism of the progroup (progroup) is not critical and can be triggered, for example, by hydrolysis in the acidic conditions of the stomach as described above and / or enzymes present in the digestive tract and / or tissues or organs of the body. In addition, it is possible to selectivelymove into groups by metabolism in certain parts of the body. For example, a large number of esters is cleaved in acidic conditions of the stomach. Prodrugs, which, as it has been developed, undergo chemical degradation in the stomach to form active 2,4-pyrimidinediamine, may include progroups, including such esters. On the other hand, progroups can be developed for metabolism in the presence of enzymes such as esterase, amidase, lipolase and phosphatase, including ATPase and kinase, etc. Progroups, as well as ligaments that are capable of metabolizing in the hypnosis of νίνο, are well known to science, and are presented, for example, but not limited to, esters, thioethers, silyl esters, silyl-thioethers, esters, complex thioethers, carbonates, thiocarbonates, carbamates, thiocarbamates, urea, thiourea and carboxamides. In some cases, a "precursor" group, which is oxidized by oxidative enzymes, such as, for example, cytochrome P₄₅₀ liver, in a group subjected to a further metabolism.

In prodrugs, any available functional molecule can be masked bygroup forproduction. Functional groups included in the compounds 2, 4-pyrimidinediamine are masked by groups for inclusion in the molecule, represented by the following (without limitation): amines (primary and secondary), hydroxyl groups, sulfanil groups (thiols) and carboxyl groups. Science is known for a wide variety of progroups, as well as the resulting molecules that are suitable for masking the functional groups in the active compounds of 2,4-pyrimidindamine to produce prodrugs. For example, a hydroxyl functional group can

54

iA 106975 C2

to be disguised as a molecule of sulfonate, ether or carbonate, which further undergoes hydrolysis under the conditions of ip ν ^ ο with the formation of a hydroxyl group. A functional amino group can be masked in the form of a promoter of amide, carbamate, imine, urea, phosphonil, phosphoryl or sulfenil, followed by hydrolysis in the conditions of ip ν ^ ο on the formation of a mamunogroups. The carboxyl group may be disguised as an ether moiety (including silyl ethers and thioethers), amide or hydrazide, followed by hydrolysis under ipMnO to form a carboxyl group. Those skilled in the art will be aware of other specific examples of suitable progroups and their respective molecules. All these groups, alone or in combination, may be included in pro-drugs.

In some embodiments of the invention describing compounds 2, 4-pyrimidindamine and methods of using such compounds, the progroup (s) can be attached to any available primary or secondary amine, including, for example, a nitrogen atom of N2 2, 4-pyrimidinediamine, an atom nitrogen N4 2, 4-pyrimidindinamine and / or a primary or secondary nitrogen atom, a group included, substituted 2,4-pyrimidinediamine.

As already noted above, the identity of the progroup is not critical, provided that the progroup can undergo a metabolism in the specified conditions of application, for example, in the acidic gastric environment and / or enzymes present in the conditions of the ip v2, in order to obtain a biologically active group, for example, 2,4-pyrimidindamine as described herein in the invention. Thus, a skilled person in the art will appreciate that the progroup may include virtually any known or recently discovered hydroxyl, amino or thiol protecting group. Non-limiting examples of suitable protecting groups are presented, for example, in the Examination of Suggestions and Principles of Interaction, Sagepe &amp; Shiis, 2^pb Еб., ύοΗπ Шііеу &amp; 3οпз, Υοι% 1991

(pages 10 through 142 (alcohols, 277-308 (thiols) and 309-405 (amines) are included in this document with the help of the link, hereinafter referred to as "Sagep &amp; Shiis").

A separate, suitable group for use in the typical compounds described is represented by the CN₂OR (OH)₂, as well as esters, mixed acid esters and their salts. In some embodiments, the progrup is -CH₂OR (OH)₂ is joined by the atom atom, which is included or not included in the ring structure of the parent molecule. The compound may include more than one such group. Thus, one embodiment of the invention is described

I

or its saltwater, where A, X, Y, Z¹, Z², P², P³, P⁴, P⁵ and p are presented in accordance with the above description of the description, and at least one P¹ (if present), P³ and R⁴ represented by R⁵⁰; where R⁵⁰represented by -CH2OR (O) (OR¹¹) 2; every P¹¹ independently represented by H, C._1-6alkyl or monovalent cationic group, or two R¹¹, together with the atoms to which they are attached, form an 8-membered cyclic phosphate group

55

where every R⁵⁵ independently represented by H, which in some cases may be substituted with C1-6alkyl, in some cases substituted by a 3-8 membered heteroalicyclic, in some cases replaced by C_6-14aryl, in some cases replaced by C.₇_₂₀arylalkyl, in some cases substituted with 5-14-membered heteroaryl or in some cases substituted by 6-15-membered heteroarylalkyl; ζ representing 0, 1, 2 or 3; or two P¹¹ together represent a divalent organic or inorganic cationic group, while typical inorganic divalent cationic groups include Ba²⁺, You²⁺, Sa²+, C²⁺, Md²⁺, N0 3g²+ and Ζη²+

Another embodiment of the invention described herein includes compounds of

55

iA 106975 C2

formula aa

or his village, where A, Z¹, Z², P², P³, P⁴, P⁵ and p are represented in accordance with the above description, and at least one P1, P³ and R⁴ represented by R⁵⁰; where R⁵⁰ represented by -CH2OR (O) (OR¹¹) 2; every P¹¹ independently represented by H, C1-6alkyl ormonovalent cationic group, or two P¹¹, together with the atoms to which they are attached, form a 6-membered cyclic phosphate group, wherein -CH2OR (O) (OR¹¹)₂ represented

or

AT

p.o.-r

at

or two P¹¹ together represent a pharmaceutically acceptable bivalent cationic group, for example Ca²⁺, Md²⁺ or Zz²⁺.

Another embodiment of the invention describes a compound of formula IV

or his village, where A, Z¹, Z², P², P⁵ and p are represented in accordance with the above description, IR is represented by -CH₂OR (O) (OR)₂; Each P is independently represented by H, C_1-6alkyl, I_i +, K +, NOSN₂CH₂H (CH₃)₃+, Cha +, or ın₄+; or two P¹¹ together represent a divalent cationic group selected from Ca²⁺, Md²⁺ and Ζη²⁺.

Another embodiment of the invention describes a compound of formula V

OK¹¹

V

or his village, where A, Z¹, Z², P², P⁵ and p are represented in accordance with the above description, and the same P¹¹ independently represented by H, t-butyl, bis +, NOSH₂CH₂H (CH₃)₃+, +, +, Or +

56

iA 106975 C2

NN₄+; or two K¹¹ together represent a divalent cationic group selected from Ca²⁺, Md²⁺ and Ζη²⁺. Although it is not expected to bind to any particular mechanism

work, it is assumed that the group -С ^ ОР ^ NОК¹¹^, for example, according to formula V, are converted to the active compounds by means of the appropriate hydroxy methylamine intermediate below:

It is known that such compounds of hydroxymethylamine, despite the possibility of their isolation under controlled conditions, are unstable under physiological conditions and in various pH ranges, in which they undergo hydrolysis of uiuo with the formation of formaldehyde and active active substance. Based on this observation, the compounds of the present invention include progrouphydroxymethyl, which can metabolize yippo, for example, in the acidic environment of the stomach / or enzymes present in the digestive tract or other organs and / or tissues or liquidsorganism, the formation of active substance 2, 4 pirymidyndiaminu.

Moreover, it is expected that the amino- and thio-analogues of such hydroxymethyl amines will be similar to these unstable under physiological conditions and also undergo hydrolysis of uiuo with the formation of the active drug 2,4-pyrimidindinamine. Accordingly, the compounds of the present invention include such suitable primary amino and thiol compounds. In addition, the invention includes compounds in which the groups of primary amine, thiol and hydroxyl are masked with "protective" groups, which are removed under physiological conditions of use with the formation of corresponding hydroxymethyl, thiomethyl and aminomethyl compounds, which essentially makes similar compounds with "protecting groups" similar proliques

The suitability of any particular group for the desired route of administration can be confirmed in the course of biochemical analyzes. For example, if prodrugs need to be injected into a separate tissue or organ, and there are known data on the different expressing tissues or organs of the enzymes, certain prodrugs can be tested for metabolism during biochemical analyzes with isolated enzyme (s). Conversely, certain prodrugs can be tested for metabolism in relation to the active compound 2,4-pyrimidindiamine together with the tissue / organ extract. The use of tissue and / or organ extracts can be particularly convenient in the absence of data on the expression of individual enzymes in the specified tissues or organs or in cases where isolated enzymes are not available. An expert in this area of ​​science will be able to easily select groups, which have metabolic properties (for example, kinetics), which are suitable for certain types of applications, using similar immunization tests. Specific proliners can also be tested for the appropriate metabolism using animal models in vitro.

Compounds of the present invention carrying the pro-group -CO-ORSONOC¹¹^ can be synthesized, thus, for example, represented for compounds of formula V.

Typically, an ion proton in the oxazolidinone ring can be selectively alkylated with a phosphonate reagent, where bc is a corresponding substituting group to form the compounds of the present invention, in this case the formulas V. The following description of the preparation of the progroup formulas -CH2OR (O) (OK¹¹) 2 is specifically disclosed in US Patent No. 449,458 entitled "Pyrimidindinamic Proliferations and Their Application" (incorporated herein by reference in their entirety).

57

iA 106975 C2

One skilled in the art will appreciate that the compounds of the invention may have a tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, the compounds and prodrugs of the invention may comprise one or more chiral centers and / or double bonds and, as a result, may exist in the form of stereoisomers, for example, double-bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, for example , racemate. Another example: the compounds of the invention may exist in several tautomeric forms, including the enol form, keto-form and mixtures thereof. Since the various names of the compound, the formula and the structure of the compounds within the scope of this specification and the claims of the invention may represent only one of the possible tautomeric, conformationally isomeric, optically isomeric or geometrically isomeric forms, that the invention includes any tautomeric, conformational isomeric, optically isomeric and / or geometrically isomeric forms of the compounds described herein, as well as mixtures of such different isomeric forms. In cases with limited rotation, i.e. around the center of the structure of 2,4-pyrimidinediamine, there may be atropisomers, which are also specifically included in the compounds of the invention. It is to be understood that the compounds described herein, except for isomeric forms, are chemically stable and can be isolated.

As will be apparent to one skilled in the art, in more than one isotropic form, a certain amount of atoms is maintained. For example, hydrogen can be represented in the form

protium (¹H), deuterium (²H) and tritium (³H), and carbon in nature is found in the form of three different

12 13 14

isotopes: C, C and C. Thus, the formulas described herein include compounds having one or a number of different isotopic forms of certain elements, including hydrogen and carbon. In one embodiment of the invention, the compounds described are in the form of isotopes. As a particular example, the compounds of formula I are enriched substantially with deuterium relative to the reaction.

In nature, deuterium is represented in the amount of 0,015%. Accordingly, about one ounce of 6,500 hydrogen atoms, represented in nature, has one atom of deuterium. Herepresented compounds containing deuterium in one or more positions. Thus, compounds of the deuterium of this specification contain deuterium in one or more positions (in each particular case) with a frequency of occurrence of more than 0.015%.

In one embodiment of the invention, the compounds of formula (I) in a position which, according to determinations, should contain deuterium, have a minimum isotope enrichment ratio of 2000 (30% deuterium content) in each atom, which according to the designations must contain deuterium, or the minimum isotope enrichment factor of 3000 (45% of deuterium content).

In another embodiment of the invention, the compound of formula (I) has an isotope enrichment coefficient for each deuterium atom 3500 (deuterium content of 52.5% for each atom containing deuterium), 4000 (deuterium content 60%), 4500 (deuterium content 67.5%) , 5000 (deuterium content 75%), 5500 (deuterium content 82.5%), 6000 (deuterium content 90%), 6333.3 (deuterium content 95%), 6466.7 (deuterium content 97%), 6600 (deuterium content 99%) or 6633.3 (deuterium content 99.5%).

Pharmaceutical compositions

Another embodiment of the invention describes a pharmaceutical composition, including a compound as described in each of the embodiments of the invention presented above. The pharmaceutical compositions described herein can be prepared by standard mixing, dissolving, granulating, cooking pellets, crushing into powder, emulsifying, cooking capsules, capping or lyophilization. The composition of the compositions may be formulated in a standard manner using one or more physiologically acceptable carriers, solvents, auxiliaries, or additional agents facilitating the transformation of active active compounds into preparations that may be used in pharmacy.

The composition of the compound 2,4-pyrimidinediamine may be formulated for the preparation of pharmaceutical compositions regge or in the form of a hydrate, a saltwater, a N-oxide or a pharmaceutically acceptable salt, as described herein. Typically, such salts have a greater solubility in water solutions than the corresponding unbound acids and bases, but salts with lower solubility may also be formed than the corresponding unbound acids and bases.

One embodiment of the invention describes a pharmaceutical composition, including a compound of Formula I, as described herein, and at least one pharmaceutically acceptable auxiliary, solvent, preservative, stabilizer, or a mixture thereof.

The compounds can be presented in the form of a number of formulations and dosages. The compounds may be presented in a pharmaceutically acceptable form, including pharmaceutical compositions regge, or in the form of a hydrate, a saltwater, a N-oxide or a pharmaceutically acceptable salt, as described herein. Typically, such salts have a higher solubility in water solutions than the corresponding unbound acids and bases, but salts can also be formed with a higher solubility than the corresponding unbound acids and bases. It is to be understood that the reference to compounds 2, 4-pyrimidinediamine or "active compounds" during the discussion

58

iA 106975 C2

compositions are also included, where appropriate, as well as the formulation of the prodrugs of compounds 2, 4-pyrimidinediamine.

In one embodiment, the compounds are presented as non-toxic pharmaceutically acceptable salts, as previously noted. Suitable pharmaceutically acceptable salts of the compounds described herein include acid addition salts, for example, salts formed with hydrochloric acid, fumaric acid, p-toluenesulfonic acid, maleic acid, amber acid, acetic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Amino group salts may also include quaternary ammonium salts in which the nitrogen atom of the amino group carries a suitable organic group, for example, alkyl, alkenyl, alkynyl or substituted alkyl molecule. In addition, if the compounds described herein carry an acidic portion, suitable pharmaceutically acceptable salts thereof may include salts of metals, for example alkali metal salts (potassium or sodium),

Pharmaceutical compositions for the administration of compounds 2,4-pyrimidinediamine may be for convenience in the form of a dosage form and to be prepared using any known pharmaceutical method. Pharmaceutical compositions can be prepared, for example, by the homogeneous and direct reaction of the active active ingredient together with a carrier vehicle, a finely divided solid carrier or both carriers, and then, if necessary, forming the product in the desired dosage form. The pharmaceutical composition of the active active substance contains a sufficient amount of such substance to produce the necessary therapeutic effect.

Compounds 2,4-pyrimidinediamine can be administered orally, parenterally (intravenously, intraperitoneally, intravenously, intracerebral, intracysterically or by infusion, subcutaneous injection or implantation), in the form of nasal spray for inhalation, vaginal, rectal, sublingual, urethral (for example , urethral suppositories) or place (for example, gel, ointment, cream, aerosol, etc.), and may be presented alone or together in the form of an appropriate dosage form containing standard non-toxic pharmaceuticals acceptable carriers, adjuvants, auxiliary agents and bases suitable for each route of administration. In addition to treating warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats and monkeys, the compounds described herein may be effective for humans.

The administration of the compounds described herein, or pharmaceutically acceptable salts thereof, in a pure form or in the form of an appropriate pharmaceutical composition can be accomplished by using any of the embodied methods of administration or agents serving for these purposes. Thus, administration may be, for example, oral, nasal, parenteral (intravenous, intramuscular or subcutaneous), local, percutaneous, intravaginal, intravascular, intracysterinal or rectal, in the form of a solid, semi-solid dosage form, lyophilized powder or liquid, for example, in the form of tablets, suppository, pills, soft elastic and solid gelatin capsules, powders, solutions, suspensions or aerosols, or the like, preferably in a dosage form suitable for the simple administration of precise doses.

For local application, ΑΑΚ-exemplary compounds or prodrugs can be presented in the form of well known science solutions, gels, ointments, creams, suspensions, and the like. Such dosage forms may be included in bandages or other transdermal delivery systems, or drugs, for example, the composition of ingredients was specifically designed as an auxiliary agent for transporting the compound through the skin to other tissues in the body.

System formulations include formulations designed to be administered by injection (e.g., subcutaneous, intravenous, intramuscular, intranasal or intraperitoneal), as well as for transdermal, transmucosal, oral or pulmonary administration.

Drugs used and administered by injection include sterile suspensions, solutions or emulsions of the active active ingredient (s) on an aqueous or oily basis. Compositions may also contain suspending, stabilizing, and / or dispersing agents. Inject formulations may be presented in the form of a dosage form, for example, in the form of ampoules or in multi-dose containers, and may include added preservatives.

On the other hand, injectable drugs may be presented in the form of a powder for reconstitution before using a suitable carrier, including, but not limited to, sterile pyrogen-free water, a buffer, and a dextrose solution. For this purpose, the active substance (s) can be dried by any known science, for example, lyophilization, followed by recovery before use.

When transmucosal administration in the formulation penetrating penetration is used

59

υΑ 106975 Ο2

through the appropriate barrier. Such penetrants are known to science.

For oral administration, the pharmaceutical compositions may be presented in form, e.g., lollipops, tablets or capsules made using standard methods, and include pharmaceutically acceptable excipients, such as binding agents (eg, pregelatinised corn starch, polyvinylpyrrolidone or hydroxypropylmethyl cellulose), fillers (e.g. , lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (for example, magnesium stearate, talc or silicon), disintegrators (for example form, potato starch or sodium starch glycollate) or moisturizing agents (for example, sodium lauryl sulfate). Pills may be coated with known science methods, for example, sugars, films, or intestinal solvent. In addition, pharmaceutical compositions containing 2, The 4-substituted pyrimidindamine as an active agent or prodrug thereof, in a form suitable for oral administration, may also include, for example, lozenges, lollipops, suspensions on a water or oily basis, dispersing powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions for oral administration can be made in accordance with any known art methods for the production of pharmaceutical compositions, and such compositions may contain one or more agents, including schuvachy, flavors, dyes ykonservanty to provide pharmaceutically acceptable taste. The tablets contain active active ingredient (including drug and / or prodrug) in admixture with non-toxic and pharmaceutically acceptable auxiliaries suitable for the production of tablets. Such auxiliaries can be represented, for example, by inert solvents (for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulated and disintegrating agents (for example, corn starch or alginic acid), which bind to agents ( such as starch, gelatin or camiddy) and lubricants (for example, magnesium stearate, stearic acid or talc). Tablets may be left uncovered or they can be coated with known methods to slow down Disintegration and absorption in the gastrointestinal tract, thus providing a long lasting effect for a longer period. For example, can use such "slow down time" as glycerol monostearate or glyceryl distearate. Tablets can also be coated using methods, described U.S. Pat. Nos. 4,256,104, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for release control. The pharmaceutical compositions described herein may also be presented in the form of a water-based emulsion.

Liquid oral dosage forms may be presented, for example, elixirs, solutions, syrups or suspensions, or they can be presented as a dry product for reconstitution with water or other suitable carrier prior to use. Such liquid dosage forms can be prepared using standard methods and pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hygogenized edible fats), emulsifiers (e.g., lecithin or gum), non-aqueous bases (for example, almond oil, fatty esters, ethanol, cremofor ™ or fractional vegetable fats) and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Compositions can also contain buffer salts, preservatives, dyes, flavors and sweeteners (if necessary).

Oral formulations may contain an appropriate formulation to provide controlled release of the active active ingredient.

For buccal administration, the composition can be presented in the form of tablets or candy tablets with the appropriate formulation.

For nasal administration or administration by inhaling or fuming, the active compound (s) or prodrugs may be presented in the form of an aerosol spray in packages with pressure or in the form of a nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon oxide, or other suitable gas). In the case of a pressurized aerosol, the dose is determined by means of a valve for the measurement of the required amount. Capsules and cartridges for use in inhalers or insufflators (e.g., capsules and cartridges containing gelatin) may in their composition contain a powder mixture of the compound and a powder suitable for the base, for example, lactose or starch.

Pharmaceutical compositions may be presented in sterile form and administered by injection of aqueous or oily suspensions. Such a suspension may be formulated in accordance with known dispersing or wetting agents, as well as by said super-suspending agents. A sterile drug and an injectable one

60

iA 106975 C2

may also be presented as sterile and administered by injection with a solution or suspension in a non-toxic and parenterally-acceptable solvent or diluent. Among acceptable carriers and solvents that can be used, water, a solution of a ringer and an isotonic solution of sodium chloride are presented. Compounds 2,4-pyrimidinediamine can also be administered in the form of rectal or urethral suppositories. For rectal and vaginal routes of administration, the active compound can be presented as solutions (for containing the cluster), suppositories or ointments containing traditional bases, such as cocoa butter or other glycerides. In certain embodiments, the compounds can be presented as an enteric suppository, for example, for use in the treatment of fertility states, in particular, in men (for example,

Described compounds 2, 4-pyrimidinediamine can be used to produce a formulation or drug, including medicaments suitable for rectal or enteral administration. In addition, the present application describes methods of producing compositions, including the described compounds 2, 4-pyrimidinediamine, in a form suitable for urethral or rectal administration, including suppositories.

For local application, creams, ointments, jellies, gels, solutions, suspensions, etc. containing 2,4-pyrimidindamine can be used. In certain embodiments, the compounds 2, 4-pyrimidinediamine may be formulated for topical application together with polyethylene glycol (PEG). Such formulations may in some cases include additional pharmaceutically acceptable ingredients, such as solvents, stabilizers and / or adjuvants. In certain embodiments, the formulations for local application are designed for the treatment of allergic conditions and / or skin conditions, including psoriasis, contact dermatitis and atopic dermatitis, among all other indications described herein.

Described compounds 2, 4-pyrimidinediamine can be used to produce a formulation or drug, including medicines suitable for local application. Accordingly, methods for the production of compositions, including compounds 2, 4-pyrimidinediamine in a form suitable for local application, are presented separately.

The compounds 2, 4-pyrimidinediamine described herein can also be delivered using device for inhalation and methods known in the art, including, for example, U.S. Patent No. 6,241969; U.S. Patent No. 6,060,069; U.S. Patent No. 6,388,647; U.S. Patent No. 6,335,316; US Pat. No. 5,364,838; U.S. Patent No. 5,672,581; No. 096/32149; No. 95/24183; U.S. Patent No. 5,654,047; U.S. Patent No. 5,040,487; U.S. Patent No. 5,672,581; U.S. Patent No. 5,443,250; Patent USA N ° 419 315; U.S. Patent No. 5,558,085; No.98 / 33480; U.S. Patent No. 5,364,833; US Patent No. 320 094; U.S. Patent No. 5,780,014; U.S. Patent No. 5,658,878; 5,518,998; No. 5,506,203; U.S. Patent No. 5,661,130; U.S. Patent No. 5,565,523; U.S. Patent No. 5,645,051; U.S. Patent No. 5,282,166; U.S. Patent No. 5,777,497; U.S. Patent No. 5,992,112; U.S. Patent No. 5,327,883; U.S. Patent No. 5,277,195; US Patent Application N °. 20010041190; US Patent Application No. 20020006901; U.S. Patent Application Ser. No..20020034477.

Among the devices that may be used for the administration of certain compounds 2,4-pyrimidinediamine, known compounds are known to science, for example, inhalers with measurable dosages, liquid nebulisers, dry powder inhalers, sprays, thermal evaporators, and the like. Another suitable technology for the introduction of certain compounds of 2,4-pyrimidindamine includes electrohydrodynamic aerosols.

In addition, the device for inhalation is mainly practical in terms of ease of use, rather small and convenient size, the ability to enter multiple doses and reliability. Some okremipryklady on the market inhalation devices include ΤυΦοΜαίΘΐ "(Aziha, №iItipdyiop, YE) RoyiaYaIeh (SIaho, RezeahsY Thiapdie Rahk, ûñ) Yuizkyz (SIaho, RezeahsY ThiapdieRahk, ΝΟ) yiyihaueli nebulizer (ΜαΙΙϊποΚΓοόί) nebulizer Αθογπ II (Meghizia MebisI Rhubisis, Toiot, Nv), an inhaler with measured doses of νθπίοΐϊπ (Οίχχ, ResteagSi Thiogipedia Ragk, N0), etc. In an aqueous embodiment of the invention of compound 2, 4-pyrimidinediamine can be delivered by means of a dry powder inhaler or a spray.

One skilled in the art will see that the formulation of compounds 2,4-pyrimidinediamine, the amount of dasg delivered and the duration of administration of a single dose depends on the type of used inhalation device and other factors. For some aerosol delivery systems, such as nebulisers, the frequency of administration and the duration of time during which the system is activated will depend largely on the concentration of compounds 2, 4-pyrimidindamine verazole. For example, in a nebuliser solution, more short periods of administration may be used at a higher concentration of compound 2, 4-pyrimidinediamine. In some embodiments, devices such as metered dose inhalers may provide

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iA 106975 C2

higher concentrations of aerosol and function in shorter periods for delivery of the required amount of compound 2, 4-pyrimidinediamine. Devices such as dry powder inhalers deliver an active active substance until a given charge is present in the device. In inhalers of this type, the amount of compound 2, 4-pyrimidinediamine, represented by a given amount in the form of a powder, determines the dose for single administration. Formulation of 2,4-pyrimidindamine is selected to obtain particles of the desired size in the selected inhalation device.

Formulations of compounds 2,4-pyrimidinediamine for administration with a dry powder inhaler can generally include a finely divided dry powder containing compounds of 2,4-pyrimidinediamine, but the powder itself may comprise a bulking agent, a buffer, a carrier, auxiliary, another auxiliary substance, etc. Excipients may be included in the dry powder formulation of compounds 2, 4-pyrimidinediamine, for example, for proper dilution of the powder, followed by delivery by a separate dry powder inhaler, to facilitate the preparation of the formulation, to provide preferred powder properties, to facilitate dispersion of the powder from the inhalation device to stabilize the formulation. (for example, buffers or antioxidants) to provide a taste of the drug or the like. Typical substituents include mono-, di- and polysaccharides, sugar alcohols and other polyols,

Examples of the compounds 2, 4-pyrimidinediamine described herein are also suitable for the introduction of methodomaginalization. For example, the described compounds 2, 4-pyrimidinediamine can be used for the manufacture of a formulation or a preparation, including medicines suitable for injection by inhalation. Accordingly, the present application for an invention describes methods for producing compositions, including the compounds 2,4-pyrimidinediamine presented herein, in a form suitable for administration, including administration by inhalation method. For example, a dry powder can be made in various ways using standard methods, for example, described in each of the above publications included in this document using a link, and, for example, Wakeg et al., U.S. Patent US. 5,700,904 (incorporated herein by reference in its entirety). The sizes of the particles vary accordingly for maximum compliance with the lower respiratory tract and are achieved by the method of fine fractionation, grinding, and the like. The liquid dosage form can be prepared by dissolving one or more of the described compounds 2, 4-pyrimidinediamine in a suitable solvent, for example, water, at an appropriate pH level, including buffers or other auxiliary agents.

For intravenous administration of compound 2, 4-pyrimidinediamine or prodrugs can be developed in the form of a solution, emulsion, suspension, etc., suitable for injection into the eye. Eye contact is usually carried out with the help of local influence, but also includes others. eye contact (if necessary). Science is known for a number of foundations that are suitable forcompounds for intraocular application. Certain and non-limiting examples are described in the United States Patent No.. 6,261,547; US patent Νο. 6 197 934; US patent Νο. 6,056,950; US patent Νο. 5,800,807; US patent Νο. 5,776,445; US patent Νο. 5,698,219; US patent Νο. 5,521,222; Patent USA Nο. 5,403,841; US patent Νο. 5 077 033; US patent Νο. 4 882 150; and US Patent No. 4738 851.

Typical preparations for intravenous administration contain a pharmaceutically effective amount of the compound 2,4-pyrimidinediamine described herein, for example from 0.0001% to about 1.0% by weight (v / v). In certain formulations, the pharmaceutically effective amount of the compound is from 0.0003% to 0.1% (v / v), from 0.003% to 0.5% (v / v), or from 0.01% to 0.03% (in /in).

In certain examples, formulations of the formulation containing the compounds described herein 2,4-pyrimidinediamine include the regulatory tonicity of the substance, the buffer, or both of these substances. For certain examples of compositions for eye application, the regulatory tonicity of the agent is represented by simple hydrocarbon or sugar alcohol. As it is known to a specialist in this area of ​​science, agents regulating tonicity, can be used in these compositions to bring the tonicity of the composition to normal values. Examples of suitable and regulatory tonicity of agents include, but are not limited to, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, hydrocarbons such as dextrose, fructose, galactose, polyols, for example, sugar alcohols, including, for example, mannitol, sorbitol, xylitol, lactitol , isomalt, maltolol and their combinations. Compositions containing a buffer

In one aspect of the invention, compositions for eye treatment containing the compounds 2,4-pyrimidindamine described herein may in some cases contain a stabilizing surfactant

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iA 106975 C2

polymer or both substances. Surfactants are used in some compositions to facilitate the delivery of high concentrations of the administered compound, 2,4-pyrimidinediamine. Such surfactantscan promote the dissolution of the compound. Typical surfactants include polysorbate, poloxamer, polyisil 40 stearate, polyoxyl, castor oil, tuloxapole, triplet and sorbitan monolaurate. In certain embodiments of the invention surfactant is selected from Triton X114, tyloxapole and their combinations. In yet another embodiment of the invention, the compositions for eye application include a stabilizing polymer represented by a carbomer 974r.

For prolonged delivery of a compound or prodrug, 2,4-pyrimidinediamine may bepresented in the form of depot preparations for administration by implantation or intramuscular injection. The active agent can be presented together with suitable polymeric orhydrophobic materials (e.g., in the form of an emulsion in a suitable oil) or ion-exchange resins, or as thinner soluble derivatives (for example, in soluble salt salts). On the other hand, cutter delivery systems can be used, made in the form of an adhesive disk or a patch that provide a slow release of the active active substance (-n) for cross-absorption. In this case, also can be used amplifiers to facilitate cross-penetration active active substance (-n). Suitable cross-plasters are described, for example, in the United States Patent No.. 5 407 713 .; US patent Νο. 5,352,456; U.S. Patent No. 5,332,213; US patent Νο. 5 336168; US patent Νο. 5,290,561; US patent Νο. 5,254,346; US patent Νο. 5,164,189; Patent USA Nο. 5,163,899; US patent Νο. 5,088,977; US patent Νο. 5 087 240; US patent Νο. 5008 110; and the US patent Νο. 4,921,475.

On the other hand, other pharmaceutical delivery systems can be used. The liposome emulsion is a well-known example of the bases used to deliver drugs that can be used to deliver the active active substance (s) or prodrugs. Certain organic solvents, such as dimethylsulfoxide (DMSO), can also be used, however, as generally, they have a higher toxicity.

If desired, the pharmaceutical compositions may be presented as packaging or dispenser, which may contain one or more dosage units with active active substance (s). The packaging may include, for example, metal or plastic foil, for example, to be presented in blister packs. Packing or device dispenser may be accompanied by instructions for use.

Another embodiment of the invention describes a kit including compounds, prodrugs, or pharmaceutical composition presented above in each of the embodiments of the invention. The following is a more detailed description of a set of one embodiment of the invention.

Ways

The present invention describes compounds 2,4-pyrimidindamine, prodrugs and pharmaceutical compositions for use in the treatment of the conditions described herein. The present invention further describes the use of the compounds of the present invention in the manufacture of a medicament for treating conditions in which therapeutically justified exposure to the signaling pathway of 6AC or inhibition of 6AC kinases, in particular, 6AC 3-kinases. Such conditions include cases of lymphocyte, macrophage or cellular damage. Conditions in which the involvement of the 6AK signaling pathway or inhibition of 6AC-kinases, in particular 6AC3, is supposed to be therapeutically justifiable, include leukemia, lymphoma, transplant rejection (e.g., rejection of transplanted islet cells of the pancreas, rejection of bone marrow transplants (e.g., transplant response the host)

In another embodiment of the invention, the methods presented herein may be used in the practice as a method of treating the conditions described herein. Thus, in a specific embodiment of the invention, the compound 2, 3-pyrimidindamine (and various forms described herein, including pharmaceutical compositions comprising compounds (in various forms)) may be used to treat the conditions described herein in animals, including humans. Methods include administering to the patient a quantity of the compound or salt, prodrug, hydrate, or N-oxide described herein, effective for treating the condition. In one embodiment, the invention is presented by a mammal (other than human), including, but not limited to, representatives of cattle, horses, cats, dogs, rodents or primates. In another embodiment of the invention, the patient is represented by a person.

As already noted earlier, numerous states can be treated with the use of compounds 2, 4-pyrimidinediamine and their prodrugs, and methods of treatment are described in this application. As already mentioned earlier in the text, "treatment" of a patient's disease is to (1) prevent the onset of a disease in a patient with a tendency or absence of symptoms

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disease; (2) inhibition of disease or repression of its development, or (3) mitigating or causing regression of the disease. As is well known in science, "treatment" is an approach for obtaining predominant or desired results, including clinical results. For the purposes of the present invention, preferred or desired results may include one or more (but not limited to) the following indicators: mitigation or elimination of one or several symptoms, reduction of the degree of severity of the condition, including disease, stabilized (that is, not degraded) condition, including disease, preventing the spread of the disease, slowing down or delaying the condition, including disease, progression, weakening or temporary relief of the condition, including the disease, proceed to remission (partial or complete), mo exposed and undetectable.

The compounds described herein are potent and selective inhibitors of ΑΑκ-kinases, and in particular, are selective for signaling pathways for cytokines containing HaG3. As a consequence of such activity, the compounds may be used in a variety of methods, for example, methods and methods for regulating or inactivating the activity of the ακ-kinase, a signaling pathway cascade involving the α-kinase, as well as a biological response, under the influence of such signaling cascades. For example, in one embodiment of the invention, the compounds can be used to inhibit the κα kinase in vitro and in vivo, virtually in any cells expressing ακ-kinase, for example, in hematopoietic cells, for example, which are expressed, for example, as HaCl3. They can also be used to regulate signal transmission cascades in which the alpha kinase, in particular, AAc3, plays an important role. Such signaling cascade signaling cascades include, but are not limited to, signaling cascades of cytokine receptors, include a generalgamma chain, for example, signaling cascades of IL-4, IL-7, IL-5, IL-9, IL-15 and IL-21 receptors , or IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. The compounds can also be used in conjunction with or in conjunction with Μνο for regulating, in particular, for inhibition, cellular or biological responses, upon which similar cascade of signaling pathway dependent on ABC is affected. Such cellular or biological responses include, but are not limited to, an increase in the expression of IL-4 / cells of gated CU23 and IL-2-mediated T cell proliferation. It is important that the compounds may be used to inhibit HaG-kinases under the conditions of yiwu as a therapeutic approach for the treatment or prevention of diseases, mediated entirely or partly by the activity of 6AC kinases (these diseases are referred to as &amp; quot; mediated HaC-kinase diseases &amp; quot;). Non-limiting examples of Haagin-kinase-mediated diseases that may be curable or prevented by the compounds described herein include, but are not limited to: allergies; asthma; autoimmune diseases including systematic autoimmune disorders, transplant rejection (eg, kidneys, heart, lungs, liver, pancreas, skin, graft versus host transplant reaction and transplant versus host disease), rheumatoid arthritis, amyotrophic lateral sclerosis; T-cell mediated autism-related diseases, such as multiple sclerosis, psoriasis, and Sjogren's syndrome; inflammatory diseases of type II, such as vascular inflammation (including vasculitis, arteritis, atherosclerosis and coronary artery disease); diseases of the central nervous system such as stroke; lung diseases such as obliterative bronchitis and primary pulmonary hypertension; steady-state retarded hypersensitivity reactions of type Ιν; hematologic malignant neoplasms, such as leukemia and lymphomas.

One embodiment of the invention is a method as described below, comprising the compounds of formula I; In a more specific embodiment of the invention, the compound is described in accordance with Formulas IA, IIA1, IA2, IA3, IΒ, IΒ1, I B2, IΒ3 and / or II. For the purpose of brevity, the methods described below mean the use of a compound of formula I, but also refers to the use of appropriate methods according to various compounds of the sub-species and species composition.

One embodiment of the invention is a method of inhibiting the activity of Ακκ kinase, including the contact of ΑΚ kinase with an effective amount of a compound sufficient to inhibit the activation of the Ακκ kinase, with the compound of formula I:

and

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iA 106975 02

or its salt, where:

X and Y are O, 8, 8 (O), 8O₂ or NZ

every P¹ represented independently by H, and may be substituted by C._1-6alkyl, C (O) -C_1-6alkyl, CO₂- WITH_1-6alkyl or p⁵⁰;

every P⁵⁰ represented by -S (P⁹) 2-A-P¹⁰, where A represents O or 8; every P⁹independently represented by H, and may be substituted with C1-6alkyl substituted by C6-10aryl or substituted by C7-16arylalkyl; or vice versa, two P⁹, together with carbon, to which they are attached, form optionally substituted C3-8cycloalkyl group or heteroalicycliles of 3-8 members; P is represented by P or -P (O) (OR) 2; Each P is represented by an independent line P^and or a monovalent cationic group; or two P¹¹, together with the atoms to which they are

11

attached, form a cyclophosphate group of 4-8 members, or two Ribivalent cationic group;

Ring A represented by C._6-10aryl or heteroaryl of from 5 to 10 members;

together are the ones

Each P is represented independently by H, P, P, P substituted by one or more

the same or other R^and and / or R^ı, -OR^is substituted with one or more of the same or other P^andand / or R^ı, -8R^is substituted with one or more of the same or other P^and and / or R^ı, -C (O) P^issubstituted with one or more of the same or other P

same or other Re / or R.^ı, -N (P³) P⁶

one or more of the same or other P^and and / or R^ı, -8 (O) 2P^is substituted substitutions of the same or other P^and and / or. R^ı, - ^ P^and) - 8 (O) 2P^is, where R^is replaced

several similar or other R^and and / or R^ı, -B (OR^and) 2, -V ^^ UU - (C (P^and) 2)_t-R

where P is replaced by one orone

, B

-8- (C (P^and) 2) t-P "

-O- (C (P^B) 2) t-P^and

yr^and) - (C (P^and) 2) t-P^B

o-sssr ^

-O- (CH2) t -CH ((CH2) tR^BR)

-O- (C (P^and) 2) t-C (O) N (P^and) - (C (P^and) 2) t-P^B

_tR

^ (C ^^ tP ^,

-SOEFPrS ^ Ut-P,

^ - (C ^ Ut-SOE ^ RUS ^ Pt-P¹'.....

^ {RU \ OMIS ^ BUT-C ^ CROU ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

independently cycloalkylalkyl, heteroalicyclil of from 3 to 10 members, heteroalicycloalkyl moieties, or heteroarylalkyl of 6 to 16 members;

every

Alkyloxy,

represented by C6-10aryl,

independent

aa

way

and

N,

C7-

deuterium, C1-16 arylalkyl,

_Rand

Alkyl, C3-8cycloalkyl, C4 heteroalkyl of 2-6 members,

4-11 members, heteroaryl from 5 to 15

_RB

= 8, -8P^and, = NR^and, = ΝΟΡ '

Represented = O, ^ (P^WITH)₂, halogen, -SR

-Or^and,

, -0N,

-O- (C (P^and) 2) t-OR^and, -NO, -XO 2 N, -80 N,

halogen C1-N, -NO2,

= N₂, -N₃, -8 (O) P^and, -8 (O) 2P^and, -8O3P^and, -8 (O) ^ P^WITH) 2, ^ (OB ^ P ^, -O8 (O) P^and, -O8 (O) 2P^and, -O8O3P^and, -O8 (O) 2N (P, -C (O) P)^and, -SO2P^and, -S ^^ RU, -S ^ RU ^ RU, -S ^ OH) -P^and, -O (NOK) -N (P ^ 2, -OC (O) P^and, -OC (O) OR^and, -O (O) N (P R, -O 0 (NK) -N (P 2, -O 0 (N p³) -N (P ^ 2, yP^and) -8 (O)₂N,

In (p^and) C (O)] p^and, - [N (P³) 0 (o)] pPP³, - ^ (Р ^ С ^^^ РУ or - ^ (Р ^ С ^ Р ^ Л- ^ РУ;

every P^WITH represented independently by P^and, or, conversely, two P^WITH contain a mixture of nitrogen to which they are bonded to form heteroalicycliles of from 3 to 10 members, or heteroaryl of from 5 to 10 members, optionally containing one or more identical or different additional heteroatoms, and which optionally may be optionally substituted with one or more identical or different P^and and / or R³ groups;

every P³ represented = O, -OR^and, haloC1-3alkyloxy, C1-6alkyl, = 8, -8P^and, = NR^and, = NOR^and, ^ (P.^and) 2, halogen, -SR 3, -NO 2, -NO 2, -NO 2, -NO 2, -NO 2, -NO 2, = N 2, -N₃, -8 (O) P^and, -8 (O2) P^and, -8O3P^and, ^ (O ^^ V, ^ (OB ^ RU, -O8 (O) P)^and, -O8 (O) 2P^and, -O8O3P^and, -OS ^^ RU-C (O) P^and, -SO2P^and, -S ^^ RU, -S ^ P ^^ P0, -0 (NOK) P³, -0 (NOK) N (P³)₂, -THE₂R^and, -OC ^^ RU -osw ^ u ^^

- ^ (P ^ C ^ HnP ^

6haloalkyl,

- (C (P^and) 2) p-OR^and

-C (O) -C1-6 haloalkyl, -8 (O) 2C1-

p (O) (OR^and) 2, - ^ ro ^ ruu

and

-OC (O) P^and, -O (C (P^and) 2) t-OR^and, -8 (C (P^and) 2)_t-Or^and, urU- * haloalkyl,

OR^and, Y (P.^and) C (O)]_pOR^and, - ^ (^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _³, taken together with the atom or atoms to which they are attached, are combined with the formation of a partially or completely saturated mono-orcyclical ring of 3-10 members, optionally containing one or more heteroatoms and may optionally be substituted by one or more P^and;

every P^and independently represented by C1-6alkyl, C3-8cycloalkyl, C4-11cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, heteroalkyl of 2-6 members,

heteroalicyclic having from 3 to 10 members, heteroalicycloalkyl of 4-11 members, heteroaryl of 5-15 members, or heteroarylalkyl of 6 to 16 members;

p is represented by 0, 1, 2, 3, or 4; each t is represented by 1, 2 or 3; each η is represented by 0, 1, 2 or 3;

two groups of P², taken together with the atom or atoms to which they are attached, are combined with the formation of a partially or completely saturated mono- or di-cyclic ring of 4-10 members, which,

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iA 106975 C2

in some cases, may include one or more heteroatoms and may in some cases be replaced by one or more I^and and / or I^ı;

Z¹ and Z² Independently represented by CH, CH² or N

I³ represented by H, in some cases replaced by C._1-6alkyl or me⁵⁰;

I⁴ represented by H, in some cases replaced by C._1-6alkyl or me⁵⁰; and

I⁵ represented by halogen, -SCH, in some cases substituted with C 1-6 alkyl, alkynyl, hydroxy, in some cases substituted by C 1-6 alkoxy, nitro, -CH (Y^and) 2, -C (O) C (I^and) 2, -CO2J^andor -C (O) I^and groups

Another embodiment of the invention is a method for inhibiting the activity of the betaKinase kinase, including the contact of a bAC kinase with an effective amount of a compound sufficient to inhibit the activity of the betaKinase kinase, with the compound of Formula I as described herein in the Invention. In certain embodiments, the methods described herein are carried out under the conditions of ipνίνο.

Another embodiment of the invention is a method of inhibiting the activity of the betaKinase kinase, including the contact of bactan kinase with an effective amount of a compound sufficient to inhibit the activity of the baccinate, with the compound of formula I as described in the present application.

In a specific embodiment of the invention, the compounds may be used for the treatment and / or prevention of rejection of organ and / or tissue transplant recipients (i.e., for the treatment and / or prevention of rejection of the allograft) in recipients. Allotransplants may be separated during the cell-mediated or humoral immune response of the recipient against the antigens of the graft (histocompatibility) present on the donor cell membranes. Strongantigens are regulated by a complex of genetic locus of human leukocyte antigens of group A (HLA). Together with antigens in the blood group ABO, they are the major antigen of human transplantation.

As a rule, rejection after transplantation can be divided into three categories: hypertension that occurs within several hours-days after transplantation; acute, which occurs after a few days - months after transplantation; chronic, which occurs a few months -years after transplantation.

Excessive rejection is caused mainly by the production of host antibodies that attack the transplant tissue. During a high-intensity reaction, the rejection of the antibody very quicklybecomes in the transplant vessels after transplantation. Shortly thereafter, thrombosis of the vessels occurs, leading to ischemia, which can lead to necrosis and death. Transplant infarction does not respond to known methods of immunosuppressive therapy. Considering the fact that antigens NI-A can be determined by the nature of the virus, a significant reduction in hyperactivity rejection involves screening before transplantation. As a result of screening, the high-level rejection is currently relatively infrequent.

Acute rejection occurs through mediation by the accumulation of antigen-specific cells in the graft tissue. T cell-mediated immune response against antigens (e.g., PCTT or PTCA) is the main mechanism of acute rejection. Accumulation of such cells leads to damage to the tissue of the graft. It is believed that T-cells of СО4 + helper and СО8 + cytotoxic T-cells are involved in the process, and the antigen is present in cells as a donor, and in the host dendritic cells. СО4 + T-helper helps to activate other effector cells, such as macrophages and eosinophils, against the transplant. Also included is an estimate of the activation of the cascade of signal transmission by T-cells (for example, cascades CO28, CO40b and CO2).

Cell-mediated acute rejection in many cases can be reversible with the help of intensive immunotherapy. After a successful stopping of rejection, the severely damaged elements of the graft are healed by fibrosis, and the remaining part of the graft remains normal. After solving the problem of acute rejection, dosage-stimulating drugs can be reduced to very low levels.

Chronic rejection, which is a separate problem for renal transplants, often propagates in an insidious way despite increased immunosuppression. It is believed that this occurs mainly due to cell-mediated hypersensitivity of type IV. The pathologic profile differs from such profile in acute rejection. Endothelialarteria is mainly involved in extensive proliferation, which can gradually cause occlusion of the prostate of the vessel, resulting in ischemia, fibrosis, intestinal stroma and arteriosclerotic changes. Chronic rejection occurs mainly due to the progressive obliteration of the vascular transplant system, which resembles a slow process of vasculitis.

With the hypersensitivity of type IV, cytotoxic CO 8 T cells and СО4 T-helperies recognize the synthesized intra-or extracellular antigen when found in a complex with

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GCGS molecules of class I or II, respectively. Macrophages act as antigen-bearing cells and release IL-1, which promotes the proliferation of T-helper cells. T-helper cells release interferon gamma IL-2, which together regulate delayed hyperactivity reactions mediated by activation of the macrophages and the immune response mediated by T cells. In the case of organ transplantation, cytotoxic T cells destroy contact graft cells.

Since beta kinases play a critical role in the activation of T cells, compounds 2,4-pyrimidindiamine, described herein, can be used to treat and / or prevent many aspects of transplant rejection, and are particularly useful in treating / preventing rejection reactions that are are caused, at least in part, by T-cells of PRHPT or PTHH. Compounds 2,4-pyrimidinediamine can also be used for the treatment / prevention of chronic rejection in recipients of transplants and, in particular, in recipients of kidney transplants. The compounds can also be administered to the organ or tissue of the transplant recipient prior to transplantation.

Another embodiment of the invention is a method of treating an autoimmune disease-mediated T-cell, including administering to a patient suffering from an autoimmune disease, an amount effective to treat an autoimmune disease, wherein the compound is in accordance with Formula I as described herein. In certain embodiments, the methods described relate to autoimmune diseases, namely, multiple sclerosis (MS) or Sjogren's syndrome.

Treatment using compounds 2,4-pyrimidinediamine described in the present application for the invention can be used as a monotherapy or in combination, or as an additional therapy for pre-immunosuppressive therapy, for example mercaptopurine; corticosteroids (for example, prednisone); methylprednisolone and prednisone; alkylating agents (for example, cyclophosphamide); inhibitors of calneurine (eg, cyclosporine, sirolimus and takrolimus); inhibitors of inosin monophosphate dehydrogenase (IMPDG) (eg, mycophenolate, mycophenolate tamlophosphate and azathioprine); means designed to suppress the cellular immunity, leaving the recipient intolerable to the intolerance of the intolerance to the intramuscular immunological response, including various antibodies (e.g., anti-lymphocyte globulin (ATO), anti-myccycular globulin (ATO), monoclonal antibody T-cells (OCT3)) and irradiation. Such various agents may be used in accordance with their standard or total dosage, as indicated in the destination information accompanying the form of the dasgs presented on the market (see also the information on the appointment in the Physician Reference Guide 2006 (included in this document using the link).) Azatioprin in At present, the company is represented by Zaich RiagtasiIisais, MS. trading name AZASAN; mercaptopurine is currently represented by OiairiagtaceiIisase, MS. under the trade name PURINETOL; prednisone and prednisolone presently presented by the company Yaohapa Lagoaohogez, Ms .; Methylprednisolone is currentlypresented by the company RTigheg; Sirolimus (rapamycin) is currently represented by the company NumeM-AuegZI under the trade name RAPAMUN; tacrolimus is currently presented by Eimisam under the trade name PROGRAM; Ciclosporin is presently represented by the company ΝονθΓίϊδ under the trade name SANDIMMUN, as well asAlboro company under the trade name GENGRAF; inhibitors of IMFDG, such as mycophenolate tamil and mikofenol acid, are currently represented by YaOSIe under the trade name of SELLSEPT and the Nova ™ brand under the trade name MIFORTIC; azathioprine is currently presented by OIhao ZitiM KIiPe under the trade name IMURAN; Antibodies at that time are represented by OgMo BioIesI under the trade name ORTOCLON, by the company Viagra under the trade name SYMULEKT (basiliximab) and by the company YaOSIe under the trade name ZENAPAKS (daklyzumab). Ciclosporin is presently represented by the company ΝονθΓίϊδ under the trade name SANDIMMUN, as well asAlboro company under the trade name GENGRAF; inhibitors of IMFDG, such as mycophenolate tamil and mikofenol acid, are currently represented by YaOSIe under the trade name of SELLSEPT and the Nova ™ brand under the trade name MIFORTIC; azathioprine is currently presented by OIhao ZitiM KIiPe under the trade name IMURAN; Antibodies at that time are represented by OgMo BioIesI under the trade name ORTOCLON, by the company Viagra under the trade name SYMULEKT (basiliximab) and by the company YaOSIe under the trade name ZENAPAKS (daklyzumab). Ciclosporin is presently represented by the company ΝονθΓίϊδ under the trade name SANDIMMUN, as well asAlboro company under the trade name GENGRAF; inhibitors of IMFDG, such as mycophenolate tamil and mikofenol acid, are currently represented by YaOSIe under the trade name of SELLSEPT and the Nova ™ brand under the trade name MIFORTIC; azathioprine is currently presented by OIhao ZitiM KIiPe under the trade name IMURAN; Antibodies at that time are represented by OgMo BioIesI under the trade name ORTOCLON, by the company Viagra under the trade name SYMULEKT (basiliximab) and by the company YaOSIe under the trade name ZENAPAKS (daklyzumab). currently represented by YaOSIe under the trade name of SELLSEPT and the company Novaia under the trade name MIFORTIC; Azatioprin is currently represented by the OIhao ZitiM KIiPe under the trade name IMURAN; Antibodies at that time are represented by OgMo BioIesI under the trade name ORTOCLON, by the company Viagra under the trade name SYMULEKT (basiliximab) and by the company YaOSIe under the trade name ZENAPAKS (daklyzumab). currently represented by YaOSIe under the trade name of SELLSEPT and the company Novaia under the trade name MIFORTIC; Azatioprin is currently represented by the OIhao ZitiM KIiPe under the trade name IMURAN; Antibodies at that time are represented by OgMo BioIesI under the trade name ORTOCLON, by the company Viagra under the trade name SYMULEKT (basiliximab) and by the company YaOSIe under the trade name ZENAPAKS (daklyzumab).

In another embodiment, the compound 2, 4-pyrimidinediamine may be administered incombination or adjuvant with a Zuc kinase inhibitor. Zuk kinase is a tyrosine kinase, which is known to play a critical role in signaling through the receptor of the Rs, as well as in other cascades of the signal transmission, for example, cascades involving the signaling of the receptor by B cells (Tithe et al., (2000), Ittipoioda Tobau 21: 148-154) apibei episode Iii (1), laia (2), apbiea (3) andPpeiIgoriIiz (Moszaui et al., (2002), Ittipius 16: 547-558). For example, GCC-kinase plays bazovurol in vysokoaffinniy receptor signaling in mast cells that leads doaktyvatsiyi and the subsequent release of multiple chemical mediators that trigger napadyalerhiyi. However, unlike the tank kinases, which help regulate signaling pathways involved vupovilnenyh or cell-mediated hypersensitivity reaction type IV, GCC-kinazadopomahaye regulate signaling pathways involved in immediate and ^ -oposeredkovanyh reaktsiyahhiperchutlyvosti I type. Certain compounds that affect the Zuk signaling pathway can also / do not affect the signaling paths 6AK.

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Suitable compounds for inhibiting Zuk are described, for example, in serial N0. 10/355 543 dated January 31, 2003 (publication ηο 2004/0029902); SH 03/063794; serial nokia. 10/631 029 dated 29 July

2003 (publication ηο.2007 / 0060603); SHO 2004/014382; serial nokia. 10/903 263 of July 30

2004 (publication ηο.2005 / 0234049); PCT / ІІZ2004 / 24716 of July 30, 2004 (ШО005 / 016893); serial Nо. 10/903 870 of July 30, 2004 (publication ηο 2005/0209224); PCT / iZ2004 / 24920of July 30, 2004; serial nokia. 60/630 808 of November 24, 2004; serial nokia. 60/645424 dated January 19, 2005; and serial nokia. 60/654 620, dated February 18, 2005 (included in the genuine document using the link). Described are compounds 2, 4 and pirymidyndiaminu GCC compound inhibitors can be used alone or in combination with one or dekilkomastandartnymy transplant rejection treatments, as described above.

In a specific embodiment of the invention, compound 2, 4-pyrimidinediamine may be used to treat or prevent such diseases in patients who have not been (consistently) responded to treatment or have become resistant to treatment of Duct inhibitors by one or another of the treatments used to treat a particular disease. , 4-pyrimidinediamine can also be used in combination with Zuck's inhibitor compounds in patients who are resistant to treatment or who do not respond to treatment with Zuk compounds. Suitable coupling agents Zuc, together with 2,4-pyrimidinediamine compounds, may be administered in accordance with the description above.

In one embodiment, the invention provides a method of treating T-cell-mediated autoimmune disease, including administering to a patient suffering from an autoimmune disease, an amount of a compound of formula I adjuvanted by a compound that inhibits zucchiniasis with an IC50 index of at least 10 μmol , which is effective for the treatment of autoimmune disease.

In another embodiment, the method of treating retransmission of an allograft, acute or chronic, in a recipient of a graft, including administering to the recipient of a graft a quantity of a compound of formula I, effective for treating or preventing rejection, is described. In still another embodiment of the invention, the compound can also be administered to the organ or tissue of the graft recipient before or together with the transplantation. In another embodiment, the compound is introduced into a tissue or organ to a patient. In a specific embodiment of the invention, the rejection of the allergotransplant is mediated by RHPT or PTHH. In another embodiment, the organ for allotransplantation is a kidney, heart, liver or lung. In another embodiment of the invention, in which the organ for allotransplantation is the kidney, heart, liver or allele, The compound is administered in conjunction with or adjuvant with other immunosuppressants. In a more specific embodiment of the invention, the immunosuppressant is represented by cyclosporine, tacrolimus, serolimus, an inhibitor of IMDGH, mycophenolate mofetil, an antibody to T cells or OCT3.

The compounds 2, 4-pyrimidia diamine described herein are moderators of the IL-4 signaling pathway. As a result, compounds 2, 4-pyrimidinediamine may be characterized by response to reactions of type I hypersensitivity. Thus, in a specific embodiment of the invention, 2,4-pyrimidinediamine can be used to treat such reactions and, consequently, diseases mediated or caused by similar hypersensitivity reactions (eg allergies) and for prophylactic purposes. For example, the one who suffers from allergies can take one or more selective and described compounds 6AC before the expected effects of allergens in order to slow down the onset or progression, or elimination of allergic responses.

When used for the treatment or prevention of such diseases, compounds 2, 4-pyrimidinediamine can be taken as monotherapy, mixtures of one or more compounds of 2,4-pyrimidinediamine, or in a mixture, or in combination with other agents used to treat such diseases and / or symptoms associated with suchdisease. Compounds 2,4-pyrimidinediamine can also be taken in a mixture or in combination with agents used to treat other disorders or malaise, for example, steroids, membrane stabilizers, 5-lipoxygenase inhibitors (5LOs), leukotriene and receptor synthesis inhibitors, isotype switch inhibitors Go eitherSynthesis EidE, inhibitors of switching to Isotype IDS or synthesis of IdS, β-agonists, inhibitors of tryptase, aspirin, cyclooxygenase inhibitors (COX), methotrexate, anti-TNF preparations, rituximab, P4 inhibitors, p38 inhibitors, PY44 inhibitors and antihistamines. Compounds 2, 4-pyrimidinediamine may be taken in the form of prodrugs or pharmaceutical compositions, including the active ingredient.

Another embodiment of the invention is a method for treating a hypersensitivity reaction

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The mite, including administering to the patient an amount of a compound effective to prevent or reduce the hypersensitivity reaction, wherein the compound is of the formula I as described in the present application for the invention. In one embodiment, the methods are used for prophylactic purposes. In some embodiments, the compound is administered to an allergen pre-effect.

Another embodiment of the invention is a method of inhibiting a signal transduction cascade in which AAc 3-kinase plays a role, including the contact of a cell expressing a receptor involved in such a signaling cascade with a compound, wherein the compound is in accordance with Formula I, as described herein invention.

Another embodiment of the invention is a method of treating an AHK-kinase-mediated disease, including administering to a patient a quantity of a compound effective for preventing or treating an α-kinase-mediated disease, wherein the compound corresponds to Formula I, as described herein.

Another embodiment of the invention is a method of treating an AHK-kinase-mediated disease, in which the disease is represented by PCTT or PTCA, including administration to the patient of an amount of a compound effective for preventing or treating a mediated aK-kinase disease, wherein the compound is as defined in formula I as described in this application for invention.

In another embodiment of the invention, eye disorders are treated using an effective amount of a compound of formula I as described herein. In one aspect of the invention, the described method for treating eye disorders involving the administration of one or more of the compounds 2, 4-pyrimidinediamine, presented herein is effective in increasing the volume of tear production compared with such an indication in the absence of treatment, thereby reducing the symptoms of the dry eye syndrome. In one aspect of the invention, the volume of tear production increases for five days, less than four days or, in some cases, less than the back of the day. In one embodiment of the invention, the amount of tear production increases by at least 25% relative to the baseline tear production during two days of primary treatment of the compound 2, 4-pyrimidindamine described herein. In one embodiment of the invention, the development of a dilution is increased by at least 30%, at least 50% relative to the initial tear production for less than two days. Increased tear production with the introduction of the compounds described here leads, in some cases, to the volume of tear produced in relation to normal production of schizoids. Typically, the described compounds, when used for local treatment of eye disorders, are administered at least once a day, but usually two times a day.

As already mentioned, another embodiment of the invention describes a method of treating a disease and / or eye disorders and includes administering to the patient an amount of a compound effective for treating the disease and / or eye disorders, wherein the compound has the formula I as described in the application. Diseases and eye disorders include, but are not limited to, dryhihchi syndrome, uveitis, allergic conjunctivitis, glaucoma and rosacea in the eye. Dry eye syndrome (CTC), also known as dry keratoconjunctivitis, dry keratitis or xerophthalmia, is a disease of mucus caused by decreased tear production or increased vaginal discharge of the lacrimal film, and is often found in humans and some animals. Whether or iridocyclitis is inflammation of the medial layer ("vascular envelope of the eye"), and in typical cases, can be represented by any inflammatory process that covers the internal structures of the eye. Allergic conjunctivitis is an inflammation of the conjunctiva (a membrane that covers the proteins of the eye) caused by allergies. Glaucoma is a group of diseases that affect the optic nerve and lead to the loss of mesh ganglion cells in a characteristic manner, that is, this type of optical neuropathy. Increased intraocular pressure is a significant risk factor for the development of glaucoma (above 22 mm Hg or 2.9 KPa) and inflammatory processes, such as uveitis, which can lead to such an increase in intraocular pressure. Rosacea is a chronic inflammatory condition characterized by erythema of the face with a loss of eyes. As already noted, the compounds described herein can be used to treat inflammatory reactions. Unwilling to establish a relationship with the theory, the compounds described herein are considered to be effective methods of treating such ocular disorders, due to, at least in part, their inhibitory activity of AAC.

Typically, the active compounds described herein inhibit the signal path AAC / δίαί. The activity of a specific compound as an inhibitor of Ακκ kinase can be evaluated either in vivo or in vivo. In some embodiments of the invention, the activity of a single compound can be tested by cell assay. Suitable assays include analyzes that determine inhibition of phosphorylation activity or ATPase ATC kinase activity. Thus, it is said that the compoundinhibits the activity of ΑΑκ-kinase in the event that it inhibits the phosphorylation or activity of the ACCase kinase ATPase with the IC index₅₀ 20 μmol or less.

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"Violation of cell proliferation" refers to a disorder characterized by an anomalous proliferation of cells. Violation of proliferation does not imply any restriction on the rate of cell growth, but simply indicates the loss of normal control of growth and distribution of cells. Thus, in some embodiments of the invention, cells with proliferative disorder may have the same rates of distribution as the cells of the health, but do not respond to signals that limit such growth. In the term "proliferation of cells" also included tumors and tumors, representing an abnormal growth of tissue. Cancer refers to each of the malignant neoplasms, which is characterized by proliferation of cells that have the ability to capture environment and / or metastasize into new colonization sites.

"Hematopoietic neoplasms" refers to the violation of cell proliferation, which occurred at the level of hematopoietic cells. As a rule, hematopoiesis is a physiological process, when undifferentiated cells or stem cells develop into different cells that occur in peripheral blood. At the initial stage of development, hematopoietic stem cells, which are usually in the bone marrow, are subjected to a series of cell distributions by the formation of multipotent precursor cells, which then develop in one of two ways with the formation of the lymphoid line of cells and the myeloid line of cells. The precursors of the myeloid precursors are differentiated into three main subgroups, including erythroid, megakaryocytic granulocytic / monocytic pathways of development. An additional path of development leads to the formation of dendritic cells involved in the presentation of antigen. The erythroid cell line leads to the growth of red blood cells, and megakaryocytic thrombocytes. Cells of the granulocyte / monocyte line are on the way of development of granulocytes or monocytes, while the first path leads to the formation of neutrophils, eosinophils and basophils, and the second way leads to the formation of monocytic blood and macrophages.

The precursor cells of the lymphoid cell line develop in the course of the B cell pathway, the T cell path or the path not associated with T / B cells. Like the myeloid line of cells, the additional lymphoid pathway leads to the formation of dendritic cells involved in antigenicity. The predecessors of B-cells develop in a pre-B cell (pre-B), which differentiates into B cells that are responsible for the production of immunoglobulins. T-cell precursors are differentiated into pre-T cells (pre-T), which, based on the effects of certain cytokines, develop into cytotoxic cells or T-helper / suppressors involved in cell-mediated immunity. Cells that do not belong to T / B cells result in the generation of natural killers (NK-cells). Neoplasms from hematopoietic cells can engage cells at any stage of hematopoiesis, including hematopoietic stem cells, multipotent precursor cells, oligopotent precursor cells, pre-cells and breeding differentiated cells. Categories of hematopoietic neoplasms may correspond to descriptions of and diagnostic criteria used by a specialist in this field of science (see, for example, the International Classification of Diseases and Related Health Problems (ICD 10), World Health Organization (2003)). Hematopoietic tumors can also be characterized at the molecular level, for example, by means of markers on the cell surface of gene expression profiles, cellular phenotypes, determined by aberrant cells, and / or chromosomal aberrations (eg deletions, translocations, insertions, etc.), characteristic for certain hematopoietic neoplasms, such as the chromosome RIiAberiIa, which is manifested in chronic myelogenous leukemia. Other classifications include classifications of the active formulations of the National Cancer Research Institute (Sapsig, 1982, 49: 2112-2135) and the revised Classification of lymphoma in European-American society (ΡΕΑΙ).

"Lymphoid neoplasia" refers to a proliferative disorder, and includes cells of the lymphoid line of hematopoiesis. Lymphoid neoplasms can arise from cells in the form hematopoetychnyhstovburnyh lymphoid progenitor cells, pre-cell and end chynomdyferentsiyovanyh cells. Such tumors can be subdivided on the basis of phenotypic signs of aberrant cells or differentiated state, which resulted in anomalous cells. Such subgroups include, among other things, B-cell neoplasms, T-cell neoplasms, NK-cellular tumors and Hodgkin's lymphoma.

"Myeloid neoplasm" refers to a proliferative disorder, and includes cells myeloid line hematopoiesis. Neoplasms may arise from hematopoietic stem cells in the form of myeloid precursor cells, pre-cells and ultimately differentiatedcells. Myeloid tumors can be subdivided on the basis of phenotypic marker cells or differentiated state, which resulted in anomalous cells. Such subgroups include, among other things, myeloproliferative disorders, myelodysplastic / myeloproliferative diseases, myelodysplastic syndromes, acute

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myeloid leukemia and acute biphenotipic leukemia.

General disorders of the proliferation of treated cells are described here

compounds, refers to any disorder characterized by proliferation of aberrant cells. _They They include various tumors and types of cancer, malignant and benign, metastatic or nonmetastatic. Using the methods described herein can be subject to the specific properties of cancer, such as tissue invasiveness or metastasis. Violations of cell proliferation include a number of cancers, for example, breast cancer, cancerous cells, kidney cancer, gastrointestinal cancer, gall bladder cancer, pancreatic cancer, squamous cell carcinoma of the lung and adenocarcinoma. More specifically, for certain tissues, organs or parts of the body: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell,

gastrointestinal tract: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancer (carcinoma, lymphoma, leiomyosarcoma), gastrointestinal cancer ), cancer of the pancreas (proctovary adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, and VIPoma), cancer of the small intestine (adenocarcinoma, lymphoma, carcinoid, sarcoma Kaposi, leiomyoma, hemangioma, lipoma, neurofiber urea, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, gammatoma, leiomyoma), urogenital pathways: kidney cancer (adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, leukemia), bladder and ureteral cancer (squamous cell carcinoma, transition cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); cranberry hemorrhoids: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,

angiosarcoma, hepatocellular adenoma, hemangioma; bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, hihantoklitynnahordoma, bone and cartilaginous exostosis, benign chondroma, hondroblastoma, hondromiksofibroma, osteoyidnaosteoma and giant cell tumors ; nervous system: the skull (osteoma, hemangioma, granuloma, xanthoma, deforming osteitis), brain membrane (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], multivariate glioblastoma, oligodendroglioma, neurenoma, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, meningioma, glioma, sarcoma); female genital organs: uterine cancer (endometrial cancer), cervical cancer (cervical cancer, pre-tumor dysplasia of the cervix), ovarian carcinoma (ovarian carcinoma, serum cystic anesthetic carcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosotecan cell carcinoma, tumor of sertol-leydig cells, dysgerminoma, malignant teratoma), vulval cancer (squamous cell carcinoma , intraepithelial cancer, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (cell lung cancer, squamous cell carcinoma, botulinum sarcoma (embryonal rhabdomyosarcoma), cancers of the fallopian tubes (carcinoma), cornea Gonorrhea system: blood cancer (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma], skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus syndrome, lipoma, angioma, dermatofibroma, keloids, psoriasis; adrenal gland: neuroblastoma. The term "cancer cell" in the context of a given inoculation includes a cell present in each of the above conditions. In some embodiments of the invention, the violation of cell proliferation is represented by a hematopoietic new formation characterized by aberrant growth of the cells of the hematopoietic system. Haematopoietic malignant tumors may originate from pluripotent stem cells, multipotent precursor cells, oligopotant precursor cells, pre-cells and end-differentiated cells that participate in hematopoiesis Some hematologic malignant tumors are believed to have arisen from hematopoietic stem cells that have the ability to self-healing. Example, cells are capable of developing specific subtypes of acute myeloid leukemia (GML) during transplantation, including superficial cellular markerhematopoietic stem cells, and such stem cells become a source of leukemiccells. Blast cells that do not possess the characteristic marker of stem cell hematopoietic cells are not able to give rise to a tumor during transplantation (VIAEGE et al., 1997,

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Vioos 89: 3104-3112). The origin of stem cells of certain hematopoietic malignant neoplasms also finds its support in observing that in healthy cells of the blood-forming line, as well as leukemic blast cells, there are specific chromosomal anomalies associated with certain types of leukemias. For example, reciprocal translocation (9? 34; 22y11), associated with about 95% of chronic myeloid leukemia, is present in cells of the myeloid, erythroid and lymphoid lines, indicating that in the hematopoietic stem cells there is chromosomal aberration. The subgroup of cells in certain types of CML has a phenotype marker of cells of the hematopoietic line of stem cells.

Despite the fact that haematopoietic tumors often originate from protruding cells, the precursor cell count or more end-differentiatedcells at a certain stage of development may also be the source of some leukemias. For example, the enhanced expression of the fusion protein Vsg / Ay (associated with chronic myeloid leukemia) of conventional myeloid precursor cells or granulocytic / macrophage precursor cells leads to a condition similar to leukemia. In addition, some chromosomal aberrations associated with subtypes of leukemia have not been detected in the cell population with the phenotype of marker haematopoietic stem cells, but are found in a cell population that has markers of a more differentiated state of the hematopoietic pathway (Tigiras et al., 1995, ViooS85: 2154- 2161). So,

In some embodiments, the hematopoietic tumor undergoing treatment is represented by a lymphoid tumor, in which abnormal cells originated from and / or a typical phenotype of the lymphoid cell lines. Lymphoid tumors can be divided into B cell neoplasms, T- and NK-cell tumors, as well as Hodgkin's lymphoma. In the future, B cell neoplasms can be divided into neoplasms of the predecessor B cells and neoplasms of mature / peripheral B cells. Typical B cell neoplasms are represented by B-lymphoblastic leukemia / lymphoma of their precursor cells (B-cell acute lymphoblastic leukemia from precursor cells), whereas the typical maturation / maturation of peripheral B cells is represented by chronic lymphocytic B cell leukemia / small cell lymphocytic lymphoma , B-cell prolimfotsytarnymleykozom, limfoplazmatsytarnoyu lymphoma, splenic lymphoma marginal zone, hairy cell leukemia, plazmaklitynnoyu myeloma / plazmatsytomoyu, extranodal B-cell lymphoma marginal zone MAT-type nodalnoyu B-cell limfomoyumarhinalnoyi zone, follicular lymphoma, lymphoma of cells mantle zone of diffuse B -microcellular lymphoma, mediastinal diffuse B-cerebral lymphoma, primaryexsudative lymphoma and lymphoma / leukemia Burkitta. The compounds disclosed herein are particularly useful in the treatment of T-cell and NK-cell tumors, which are further subdivided by nano-formation from T-lymphocyte precursors and tumors of peripheral (mature) T-lymphocytes. Typical tumors of T-lymphocytic precursors are represented by T-lymphoblastic lymphoma / leukemia from precursor cells (T-cell acute lymphoblastic leukemia and precursor precursors), while typical tumors of peripheral (mature) T-lymphocytes are represented by T-cell prolymphocytic leukemia, T cell leukemia from major granular lymphocytes, aggressive NK-cell leukemia, T-cell lymphoma / leukemiasis (NTU-1), extranodal NK / T-cell lymphoma, nasal type, T cell lymphoma associated with ene tetanus, tetanus, hepatolytic T cell lymphoma, T-cell pancinnitate lymphoma of subcutaneous tissue, fungal mycosis / Sezar syndrome, anaplastic large cell lymphoma, T / 0-cellular, with primary skin lesions, peripheral T-cell lymphoma, unspecified, angioimmunoblast T-cell lymphoma, anaplastic large cell lymphoma, T / 0-cell, with a primary systemic lesion. The third group of lymphoid neoplasms is represented by lymphoma of Hodgkin, also called Hodgkin's disease. Typical diagnoses of this kind that can be treated with these compounds include, among others, Hodgkin's noodular lymphoma with a lymphoid superiority, as well as various classical forms of Hodgkin's disease, typical of which is classical Hodgkin's lymphoma with nodular sclerosis (grade 1 and 2), classical Hodgkin's lymphoma with more lymphocytes, classical lymphoma, Hodgkin's mixed-cell variant, as well as classical lymphoma, Hodgkin with depletion of lymphoid tissue. In various embodiments of the invention, each of the lymphoid tumors associated with aberrant activity of 6AC,

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inhibitors of 6Ακ.

In some embodiments, the inventions of the hematopoietic tumors undergoing treatment are represented by myeloid tumors. This group includes a large class of violations of cell proliferation, including or reflecting the characteristic phenotype of cells of the myeloid line. Myeloid neoplasms can be subdivided into myeloproliferative diseases, myelodysplastic / myeloproliferative diseases, myelodysplastic syndromes and acute myeloid leukemia. Typical myeloproliferative diseases are leukemia hronichnymymiyelohennymy (such positivity in chromosome RYiIabeyirYia (1 (9; 22) (yats34; ya11)), chronic neutrophilic leukemia, chronic eosinophilic leukemia / hipereozynofilnymsyndromom, chronic idiopathic myelofibrosis, polycythemia vera and idiopatychnoyutrombotsytopeniyeyu. Typical myelodysplastic / myeloproliferative diseases are represented by chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, and myovomental myelomonocytic leukemia. Typical myelodysplastic syndromes are represented by refractory anemia with / without ring-like sideroblasts, refractory cytopenia (myelodysplastic syndrome) with multiple-dysplasia, refractory anemia (myelodysplastic syndrome) with excess blast cells, 5-syndrome, and myelodysplastic syndrome. In various embodiments of the invention, each of the myeloid formations associated with aberrant activity of 6KC can be treated with 6KC inhibitor compounds. Typical myelodysplastic syndromes are represented by refractory anemia with / without ring-like sideroblasts, refractory cytopenia (myelodysplastic syndrome) with multiple-dysplasia, refractory anemia (myelodysplastic syndrome) with excess blast cells, 5-syndrome, and myelodysplastic syndrome. In various embodiments of the invention, each of the myeloid formations associated with aberrant activity of 6KC can be treated with 6KC inhibitor compounds. Typical myelodysplastic syndromes are represented by refractory anemia with / without ring-like sideroblasts, refractory cytopenia (myelodysplastic syndrome) with multiple-dysplasia, refractory anemia (myelodysplastic syndrome) with excess blast cells, 5-syndrome, and myelodysplastic syndrome. In various embodiments of the invention, each of the myeloid formations associated with aberrant activity of 6KC can be treated with 6KC inhibitor compounds.

In some embodiments, the 6KC inhibitor compounds may be used for the treatment of acute myeloid leukemia (GML), which is a large class of myeloid lesions having their own subunit in accordance with the disorders. Such units include, among other things, GML with recurrent cytogenetic translocations, GML withmultilinear dysplasia and other unspecified GMLs. Typical GMLs with relapsing cytogenetic translocations include, among others, GML with pathologies (8; 21) (22, 22), GML1 (SVH-alpha) / ETO, acute myeloid leukemia (GML with 1 (15; 17) (22; -12) and variants of progressive multifocal leukoencephalopathy / alpha receptors to retinoic acid), GML with abnormal bone marrow eosinophils (eg (16) (p13ts22) orI (16; 16) (p13; l11), SVR / MUN11H), and GML Pathology 11c23 (MLL). Typical GMLs with multilinternal dysplasia are represented by diseases with / without a myelodysplastic syndrome before. Other types of unspecified acute myeloid leukemia within any defined group include the minimally differentiated GML, GML without signs of ripening of the cells, acute myelomonocytic leukemia, acute monocytic leukemia, leukemia, acute basophilic leukemia and acute panmiliosis with myelofibrosis.

One of the methods for analyzing such inhibition is to determine the effect of compounds 2, 4-pyrimidindinamene on increasing the expression of gene products that regulate the subsequent linksignal cascade. In the course of the analysis, Katoz / IL-4 B cells are stimulated by interleukin-4 (IL-4), resulting in the activation of the signal path of AAC / ZIA by phosphorylation of the kinase family 6ΑΚ (6ΑΚ1 and 6ΑΚ3), which in turn leads to phosphorylation and activation of transcription factor 8yay-6. One of the genes whose expression is influenced by the activation of 8yay-6 is a receptor of IdE with a low affinity (CU23). To investigate the effect of inhibitors (for example, described herein with 2,4-substituted pyrimidinediamine compounds) on the kinase 6Ακ1 and 6Ακ3, human K-cell cathosis is stimulated by human IL-4. 20-24 hours after stimulation, cells are colored to detect elevated expression of CU23 and analyzed using ESA8 analysis. Reducing the amount of CU23 present in comparison with the control states indicates that the test compound actively inhibits the signaling pathway of 6CK kinase. Typical analysis of a similar kind is described in detail in Example 2.

The activity of the compounds described herein can be further characterized by analyzing the effects of the compounds described herein 2,4-pyrimidindiamine on the proliferation of human primary T cells. In this analysis, human primary T cells, derived from peripheral blood and activated by stimulation of the T cell receptor and CU28, are proliferated in culture in response to cytokine interleukin-2 (IL-2). Such a proliferative response depends on the activation of the tyrosine kinase 6Ακ1 and 6Ακ3, which phosphorylate and activate the transcription factor 8ya-5. Primary T cells of the man are incubated with compounds of 2,4-pyrimidinediamine in the presence of IL-2 for 72 hours, and intracellular ATP concentrations acting as the endpoint of the assay, are measured to assess the viability of cells.

The activity of the compounds described herein may further be characterized by analyzing the effect of the compounds 2,4-pyrimidindinamine described herein on the epithelial cells of the lung A549 and cells of 937.

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The epithelial cells of the lung A549 and cells and937 overexpress ICAM-1 (SU54) on their surface in response to various stimuli. Thus, the use of the expression ISAM-1 that the indicator allows to assess the effect of the compounds studied on signaling pathways for the cell of the same type. Stimulation of IL-1β with IL-1r receptor is susceptible to the signaling TRAE6 / NECKa pathway, which results in increased expression of ISAM-1. IFN Indicates Increased Expression by Activating the Signaling Path and EXPOSURE. The elevated expression of ICAM-1 can be quantified by flow cytometry, along with the calculation of the dosing curve and the values ​​of the EU₅₀.

The active compounds described herein usually inhibit the signaling pathway of the iKK kinase with the values ​​of IC₅₀ in the range of 1 mmol or less, as can be measured in the analyzes described herein. It is understood that a skilled person will estimate that compounds having lower IC values₅₀(eg 100 μmol, 75 μmol, 50 μmol, 40 μmol, 30 μmol, 20 μmol, 15 μmol, 10 μmol, 5 μmol, 1 μmol, 500 nmol, 100 nmol, 10 nmol, 1 nmoland even lower) may be especially useful for therapeutic purposes. In the case when necessary activity, specific for a specific cell type, the compound can be evaluated on the subject of activity relative to the required type of cells and subjected to screening for lack ofactivity for cells of another type. Desired degree of "inactivity" in the course of screening ornecessary ratio of activity relative to inactivity may vary for different situations andcan be selected by the user.

The active compounds of 2,4-pyrimidindinamine also typically inhibit the expression of CO23 in B cells stimulated with IL-4, with an IC value₅₀ in the range of 20 μmol or less, usually in the range of 10 μmol, 1 μmol, 500 nmol, 100 nmol, 10 nmol, 1 nmol or even less. Suitable analyzes that can be used are described in Example 2, "Analysis of the Patov line of β-stimulated IL-4 cells." In certain embodiments of the invention, the active compounds 2,4-pyrimidinediamine have an IC value₅₀ less than or equal to 5 μmol, greater than 5 μmol, but less than 20 μmol, more than 20 μmol, or greater than 20 μmol, but less than 50 μmol (the analysis is described in Appendix 2).

In addition, the active compounds of 2,4-pyrimidindamine typically inhibit the activity of human primary T cells with an IC value₅₀ in the range of 20 μmol or less, usually in the range of 10 μmol, 1 μmol, 500 nmol, 100 nmol, 10 nmol, 1 nmol or even less. The value of the IC₅₀ for primary human T cells can be determined during a standard analysis of human T cells of the first instance. A suitable analysis that can be used is presented by "the primary analysis of proliferation of human T-cells stimulated by IL-2." In certain embodiments, the active compounds of 2,4-pyrimidinediamine have an IC value.₅₀less than or equal to 5 μmol, more than 5 μmol, but less than 20 μmol, greater than 20 μmol, or more than 20 μmol, but less than 50 μmol.

The active compounds of 2,4-pyrimidindinamine also typically inhibit the expression of ICAM1 (SU54), induced by Influencing IFN in cells of 937 or A549, with an IC value₅₀ in the range of 20 μmol or less, usually in the range of 10 μmol, 1 μmol, 500 nmol, 100 nmol, 10 nmol, 1 nmol or even less. The value of the IC₅₀ for the expression of ICAM (CY54) in cells stimulated by IFN may be determined during a functional cell assay with an isolated line of cells A549 or v937. The active compounds of 2,4-pyrimidinediamine have an essentially IP value₅₀ less than or equal to 20 μmol more than 20 μmol, or more than 20 μmol, but less than 50 μmol.

Use of compounds as research tools

One skilled in the art will understand that certain crystalline protein complexes with a ligand, in particular, complexes of iAc-ligand, and their corresponding X-ray structural coordinates may be used to identify new structural information that may be useful for understanding the biological activity of the kinases described herein. In addition, the structural characteristics of the aforementioned proteins, in particular, the form of the ligand binding site, can be used in methods for the development or identification of electoral modulators of kinases, as well as in solving structures of other proteins with similar characteristics. Similar protein-ligand complexes that include the compounds described herein as a ligand component are one aspect of the invention.

In addition, a person skilled in the art will appreciate that such crystals having a corresponding radiographic quality can be used as a method for identifying a candidate agent that is capable of binding and modulating the activity of the kinases. Such methods may be characterized by the following aspects: a) the introduction into the corresponding computer program of information determining the domain of a ligand for binding to the ligand in conformation (for example, by means of a coordinate radiological structure obtained using suitable three-dimensional crystal structures described above), while A computer program creates a model of a three-dimensional structure domain of binding to a ligand; b) introduction of the model of the three-dimensional structure of the binding domain with

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ligand; c) overlaying the model of the candidate agent on the domain binding model of the ligand; d) estimation of the spatial conformity of the candidate agent model with the ligand binding domain. Aspects a-g do not necessarily have to be fulfilled in the specified order. Such methods cancause the following: the rational development of the drug with a model of three-dimensionalstructure, as well as the choice of potential candidate-candidate in accordance with computer modeling.

In addition, one skilled in the art will appreciate that such methods may lead to the following: the involvement of a candidate agent identified as the appropriate ligand binding domain, a biological activity vanusal for kinase modulation, and a determination of modulation of the kinase activity of said candidate agent during the assay. Such methods may also include administering a candidate agent for modulating the activity of a kinase to a mammal suffering from a condition appropriate to the modulation of kinase according to the description described above.

In addition, the person skilled in the art will appreciate that the compounds described herein may be used in a method for assessing the ability of the test agent to be associated with a molecule or molecular complex, including the kinase binding domain of the ligand. Such a method can be characterized by the following aspects: a) the creation of a computer model of the connecting "pocket" of the ligand using the structural coordinates obtained for the corresponding crystals with ligature radiographs; b) the use of computer algorithms to perform operations to determine the correspondence between the investigated agents and computer model interconnect "pocket"; c) analysis of the results of the operation for determining conformity for the quantitative determination of association between the investigated agent and the computer model connecting "pockets".

Use of compounds as screening agents

To attract the compounds described herein in the screening method for candidate agents that bind, for example, the protein AAC, the protein binds to the substrate, and the compound described herein is added to the input of the assay. In addition, the compound described herein binds to the substrate, for example, with a linker that does not exert an excessive effect on biological activity, after which a protein is fed. Classes of candidate agents, including the search for binding agents, include specific antibodies, synthetic binding agents identified during screening, chemical libraries, peptide analogues, etc. Of particular interest are screening tests for the identification of candidate agents that have low toxicity for human cells. For this purpose, a number of analyzes can be used, including assays for the identification of labeled proteins,

Determination of binding of the candidate agent, for example, with the protein AAC, can be carried out in several ways. In one example, the candidate agent (the compound described herein) is labeled, for example, as fluorescing or a radioactive molecule, after which binding is determined directly. For example, this can be done by adding all or a portion of the ΑΑβ protein to a solid substrate, adding a labeled agent (for example, the compound described herein, in which at least one atom is substituted by an isotope), the excess liquid is washed out, and the amount of the label is present in the substrate . Different ways of blocking and flushing can be used. By "label" it is understood that the compound is directly or indirectly labeled "agent", which provides a conditioned signal, for example, a radioisotope that fluoresces the label, the enzyme, antibodies, particles, for example, by magnetic particles, chemiluminescent labels orspecific binding molecules, and the like. Specific binding molecules include pairs, for example, biotin and streptavidin, digoxin and antidiogoxine, etc. For specific binding agents, the complementary member will usually be labeled with a molecule favorable to the determination according to known procedures. The label can directly or indirectly provide a conditioned signal.

In some embodiments of the invention, only one component is indicated. For example, the antibiotic AIC may be labeled with the use of tyrosine¹²⁵And either with the help of fluorophores. On the other hand, different labels can be used to label more than one component; example,¹²⁵And it can be used for proteins, and fluorophores - for candidate agents.

The compounds described herein can also be used as competitors for the screening of additional candidate products. The "candidate bioactive agent" or "candidate drug", or their grammatical equivalents used in this text, describe any molecule, for example, a protein, an oligopeptide, a small organic molecule, a polysaccharide, a polynucleotide, etc., which are to be tested for biological activity . They may have

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the ability to directly or indirectly change the phenotype of cell proliferation or expression of the sequence of cell proliferation, including sequences of nucleic acids and sequences of proteins. In other cases, the change in the binding of proteins to cell proliferation and / or activity should be screened. In the case of screening for binding or protein activity, some embodiments of the invention exclude molecules that are known to bind to a single protein. Typical embodiments of the invention include analyzes involving the use of candidate agents that do not bind to the target protein in its endogenous native state and are referred to as "exogenous" agents. In one example, exogenous agents will henceforth exclude antibodies to the ΑΑΚ protein.

Candidate agents may include compounds from many chemical classes, however, as a rule, they are represented by organic molecules with a molecular weight of more than 100 Daltons and less than 2500 Daltons. The candidate agents include the functional groups necessary for the structural interaction with the proteins, in particular for the binding of hydrogen and lipophilic groups, and include, as a general rule, at least an amine, carbonyl, hydroxyl, ether or carboxyl groups, for example, at least two functional chemical groups. Candidate agents often include cyclic carbon or heterocyclic structures and / or aromatic or polyaromatic structures substituted by one or more of the above-mentioned functional groups. Candidate agents are also found among biomolecules, including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives,

Candidate agents receive from a variety of sources, including libraries of synthetic or natural compounds. For example, for the random and directed synthesis of a number of organiccompounds and biomolecules, including the expression of randomized oligonucleotides, is a number of ways. On the other hand, there are or produced libraries of natural compounds in the form of extracts of bacteria, fungi, plants and animals. In addition, with the help of standard chemical, physical and biological means, natural or synthetically derived libraries and compounds are modified. The known pharmacological agents can be subjected to direct or random chemical modification, for example, acylation, alkylation, esterification, amidification, for obtaining structural analogues.

In one example, the binding agent of the candidate agent is determined using the competitive binding assays. In this case, the competitor is represented by a molecule that is known to bind to the ΑΑΚ protein, for example, an antibody, a peptide that is linked to a partner, a ligand, etc. Under certain circumstances, a candidate binding agent and a binding molecule may have a competitive binding in which the binding molecule replaces the candidate agent.

In some embodiments, the candidate agent is labeled. To ensure sufficient binding, the first (for example, the ΑΑΚ protein) is added a candidate agent, competitor or both substances. Incubation can be carried out with any temperature that provides optimal activity, usually in the range of 4 ° C to 40 ° C. Periodic carbations are selected for optimal activity, but can also be optimized to facilitate rapid and highly effective screening. The excess of the reagent is usuallydetermined or washed away. Then a second component is added, after which the binding is determined in the presence or absence of the labeled component.

In one example, the competitor is first added, then the candidate agent. Replacement competitor is a sign of binding of the candidate agent to the protein AAC and indicates the ability to bind and potentially modulate the activity of the AAC protein. In such an embodiment, the invention may be marked with any component. Thus, in the case of a label of the competitor, the presence of the label in the solution after washing indicates the substitution by the agent. On the other hand, in the case of a candidate agent label, the presence of a label in the substrate indicates replacement.

In an alternative embodiment of the invention, a candidate agent is first added, followed by incubation and washing, and then a competitor is added. The lack of binding to the competitor may indicate that the candidate agent is associated with a high affinity affinity protein. Thus, in the case of labeling of the candidate protein, the presence of the label in the substrate, along with the lack of binding of the competitor, may indicate that the candidate agent is able to bind the ABC protein.

This can be particularly useful for identifying a CAAC protein binding site. This can be done by several methods. In one embodiment of the invention, after detecting the binding of the ΑΑκ protein with the candidate agent, the ΑΑΚ protein is fragmented or modified, and analyzes are repeated to identify the components required for binding.

The modulation is tested by the screening of candidate agents capable of modulating the activity of the ΑΑκ protein, including the steps of a combination of the candidate agent with the ΑΑκ protein as defined above, as well as the determination of the change in the biological activity of the ΑΑκ protein. So, at

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such an embodiment of the invention, the candidate agent must bind (even if it is not necessary) and change its biological or biochemical activity. The methods include the screening of cells in the nythia and ip vnio for the presence of changes in viability, morphology and other cellular characteristics.

On the other hand, differential screening can be used to detect candidique drugs that bind to the native 6AK protein but can not bind to the 6AB modified protein.

Various reagents may be included in screening tests. They include such reagents as salts, neutral proteins, such as albumin, detergents, etc., which can be used to facilitate optimal binding of protein-protein and / or lower nonspecific orphanic interactions. In addition, reagents that improve the analytical efficiency, such as protease inhibitors, nuclease inhibitors, antibacterial agents, etc. can be used. A mixture of components can be added in any order that provides the necessary binding.

Input methods

The compounds of the present invention, 2,4-pyrimidindinamine or prodrugs, or the compositions thereof, will be used, as a rule, in an amount effective to achieve the intended result, for example, in an amount effective for treating or preventing a separate appropriate treatment of the condition. Compound (s) may be administered with therapeutic purpose for achieving therapeutic benefit or for the purpose of prevention to achieve a preventive effect. The therapeutic benefit is understood as the elimination or reduction of the underlying disease corresponding to the treatment and / or reduction of symptoms and / or the elimination of one or several symptoms associated with the underlying disease, thus the patient reports on the improvement of health despite the fact that the patient may still be under action of the underlying disease. For example, administration of a compound to a patient suffering from allergies, provides therapeutic benefits not only in terms of improving or eliminating the main allergic response, but also in terms of reducing the weight or duration of symptoms associated with allergy after exposure to the allergen. Another example: the therapeutic benefit in the context of asthmaincludes improved breathing after an asthmatic attack or a decrease in the incidence or weight of asthma attacks. Another specific example: the therapeutic benefit of a transplant rejection context involves the ability to reduce the acute exacerbation episode, for example, PTHH or RHPT, or the ability to prolong the time between the occurrence of acute episodes of rejection and / or the emergence of chronic rejection. Therapeutic benefit also includes stopping or slowing progression of the disease, regardless of the availability of improvement.

The amount of compound administered will depend on various factors, including, for example, a separate direction for treatment status, route of administration, weight of the disease, appropriate treatment, age and weight of the patient, bioavailability of the individual active compound. Determination of effective dose is a duty of a specialist in the field of sciences.

As is known to a specialist, the desired dose of compound of 2,4-pyrimidinediamine will also depend on age, weight, general health and weight of the disease, appropriate treatment of the patient. Perhaps the dose will be adjusted for the patient's gender and / or lung function if the patient needs to be administered by inhalation. The dose can also be adjusted in patients suffering from more than one condition, or patients with additional conditions that affect the function of the lungs and the ability to breathe normally, such as emphysema, bronchitis, pneumonia, and respiratory infections. The dose and frequency of administration of compounds or their prodrugs will also depend on the fact that such compounds have been developed for the treatment of acute state attacks or with the purpose of preventing the disorder. For example, acute attacks of allergic conditions, including due to allergy to asthma, transplant rejection, etc. An expert in the field will be able to determine the optimal dose for an individual patient.

For prophylactic administration, the compound can be administered to a patient having a risk of developing one of the conditions described above. For example, it is unknown whether the patient has an allergy to a single drug; in this case, the compound may be administered prior to the administration of the drug, which will avoid or reduce the allergic reaction to the drug. On the other hand, a prophylactic injection may be used, which will avoid the appearance of symptoms of a patient with a diagnosed major illness. For example, a compound may be administered to a patient suffering from an allergy to the expected antigen exposure. Compounds can also be administered in preventive health care to patients who are repeatedly exposed to agents that can cause one of the disorders described above, which will prevent the development of the disease. For example, compounds can be introduced to a healthy patient

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Repeated exposure to the antigen, as known, can cause allergies, such as latex, to prevent the development of allergy in such a patient. On the other hand, the compound may be given to a patient suffering from asthma before performing their activities, which contributes to the development of asthma attacks, which will reduce the severity of such attacks or to avoid the onset of asthma.

In the context of transplant rejection, the compound may be administered at a time when the patient does not have an acute rejection reaction to prevent rejection and / or to the clinical signs of chronic rejection. The compound can be administered to the patient systematically, as well as into the tissue or organ before tissue transplantation or organ to the patient.

The amount of the compound administered will depend on various factors, including, for example, the individual indicative treatment, the route of administration, the purpose of administration (treatment or prophylaxis), the weight of the disease, the treatment, the age and weight of the patient, the bioavailability of the individual active compound. Determination of the effective dose is a duty of a specialist in this area of ​​science.

Effective doses can be pre-determined in the course of yiyugo tests. For example, the primary dose for use in animals may be designed to achieve suchconcentration of the active compound in a circulating blood or serum that is at or above the Yueo value of a single compound measured during the iipi analysis. When calculating the dosage to achieve such a concentration in circulating blood or serum, the bioavailability of a single compound is taken into account. As a guide, the reader can use the Hypodermic &amp; Nutrition, "Septhe and the Gypsy Scriptures," and "A Comparative Study of Psychiatric Psychiatry", Chapter 1, p. 1-46, the last edition, as well as sources quoted here.

Initial dosages can also be evaluated on the basis of data from the uiouo, for example, data model of animals. Animal models that can be used to test the efficacy of the compounds for treating or preventing the various compounds described above are well known in the art. Applicable animal models for hypersensitivity or allergic reactions are described in (1995) AIIgegdu50 (218irrI): 6-9, discussion 34-38. and Titase et al., (2001), à. AIiygdu Shiip. Identity.107 (6): 1025-1033. Suitable animal models for allergic rhinitis are described in Z2eIepui et al., (2000), Aggrepiatiiyiyogyziiiypd 50 (11): 1037-42; Catadias et al., (1994), Shiip. Exh. AIIgundu 24 (3): 238-244 apb8iditoeio ai., (2000), IttiporiIagtasoiod 48 (1): 1-7. Suitable animal models for allergic conjunctivitis are described by Saggegaz et al., (1993), Vg. à OrMiaits 77 (8): 509-514; 8aida ee ai., (1992), OrIiIatis Res.24 (1): 45-50; Apib Kipegei her ai., (2001), Impossible. OrIiIiIoI. Wiz 8s 42 (11): 2483-2489. Suitable animal models for systemic mastocytosis are described by O'Carey et al., (1987), A.A. Ipejpeg Meb 1 (2): 75-80. Verap-Kipibzep et al., (1989), Wye. Raion 26 (1): 90-92. Suitable animal models for hypersexpression syndrome are described by CIATAP ey ai., (1990), Sip. Identity.IttyporaIoI. 56 (1): 46-53. Suitable animal models for B-cell lymphomas are described by Hellenicia et al. (1998), Pgoss. №I Asab 8s &amp; amp; 8A 95: 13853-13858 &amp; quot; she et al., (1996) &amp; quot ;. IttipoI.157 (12): 5503-5511. Suitable animal models for atopic disorders, for example, atopic dermatitis, atopic eczema, and atopic asthma, are described by CIAP et al., (2001), à. Jouez OeghtaM.117 (4): 977-983 apib. 8iio et al., (1999), Ipi. AgsI AIiyehdu Ittipoi. 120 (8ir1 of 1): 70-75. Suitable animal models for transplant rejection, for example, the PTHC model, are described by O'Shea et al. (2004), Neue Reuiemz Yugid Uyizsoeuu 3: 555-564; Seikois-SigI) e &amp; Tiibeiz, (2004), Sighepyriyataeiiisaya Yezidp 10: 1767-1784; (2003), vol. 302: 875-878. A specialist in the field can easily adapt such information to determine the dosages for the introduction of a person.

The dose will be in the range of 0.0001 or 0.001, or 0.01 mg / kg / day to 10 mg / kg / day, but may be higher or lower, depending on, among other things, the activity of the compound, its bioavailability, route of administration and various other factors presented above. The value of the doses and the interval of their administration can be adjusted individually, providing sufficient concentrations of the compound in plasma to support the therapeutic or prophylactic effect. For example, compounds may be taken once a week, several times a week (for example, every other day), once a day, or several times a day, depending inter alia, on the route of administration, specific indications treated and the doctor's decision, thatsigns. In the case of local input or electoral absorption, for example, with local application, the effective local concentration of the active compound (-k) may not be interconnected with plasma concentration. A specialist in this area will be able to optimize the effectiveness of local findings without unnecessary experiments.

Compound (s) will preferably provide therapeutic or prophylactic benefits without causing significant toxicity. The toxicity of the compound (-k) can be determined using standard

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pharmaceutical procedures. The dose ratio between the toxic and therapeutic (orprophylactic) effect is a therapeutic index. It is more advantageous to use compound (s) with increased therapeutic indices.

The preliminary provision on dose requirements for compounds 2, 4-pyrimidindinamine is valid for excipients provided (as obviously to the skilled specialist) that the amount of administered prodrugs will also depend on a number of factors, including, for example, the bioavailability of individual drugs, the rate of conversion, and the conversion efficiency to the active drug compound at selected input path. Determination of the effective dose of prodrugs for individual use and the route of administration is within the framework of a specialist in the field.

Effective doses can be evaluated initially by means of an analysis of the activity of metabolism. For example, the primary dose of prodrugs for use in animals may be developed to achieve such an active compound concentration in circulating blood or serum that exceeds or is at the level of the value of IC₅₀ a single compound measured at the input of the in-vivo assay, for example, an ICPM or VMSM, and other hybrid analyzes described in the U.S. Patent Application Serial No. 10/355 543 dated January 31, 2003 (υ32004 / 0029902Α1), International Application Serial No. PCT / 503/03022 dated January 31, 2003 (UTO 03/063794), US Patent Application Serial No. 10/631 029 dated July 29, 2003, International Application Serial No. РСТ / и503 / 24087 (ОТО2004 / 014382), application US Patent Serial No. 10/903 263 dated July 30, 2004, and the International Application Serial No. PCT / 2006/24716 (OTO005 / 016893). When calculating the dose for achieving such concentrations in circulating blood or serum, a specialist in this area takes into account the bioavailability of certain prodrugs administered in the established way. As a guide, the reader can use RipDi &amp; oToBuyu, "SepeGiI RigpsiRez," Yep: from TIE RIgtaSeIiAsAi Vaziz oi TIeGareIiIs, Section 1, p. 1-46, last edition, Radatopop Rgez, as well as references to sources here.

In addition, the present application describes sets for the administration of 2,4-pyrimidindamine, its prodrugs or pharmaceutical compositions, including compounds, which may include a dose of both a minimal compound of 2,4-pyrimidindamine or a composition comprising at least one compound 2, 4 -pyrimidine diamine. Sets also include appropriate packaging and / or instructions for the use of the compound. Sets may also include means for delivering at least one compound of 2,4-pyrimidinediamine or compositions comprising at least one compound 2, 4-pyrimidinediamine, for example, an inhaler, a spray dispenser (e.g., nasal spray), a syringe for injections or pressurized packaging for capsules, tablets, candles, or other device as described herein. The kit also contains compounds and reagents for preparing the composition for administration. The composition may be presented in a dry or dried sublimation form, or in the form of a solution, in particular, a sterile solution. If the composition is in a dry form, the reagent may include a pharmaceutically acceptable diluent for preparing a liquid composition. The kit may comprise a device for entering or measuring compositions, including, but not limited to, a syringe, pipette, trench band, or an inhaler.

Sets may include other therapeutic compounds for use in conjunction with the compounds described herein. In one embodiment, the therapeutic agents are immunosuppressant or antiallergic compounds. Such compounds may be presented in a separate form or mixed with the compounds of the present invention.

The sets will include the appropriate instructions for cooking and entering the composition, side effects of the composition, and other relevant information. Instructions may be presented in any suitable format, including, but not limited to, printed text, videotape, computer readable disc or optical disc.

One embodiment of the invention includes a compound of formula I or a prodrug thereof, a package and instructions for use.

In another embodiment latter describes a set that includes farmatsevtychnukompozytsiyu consisting of compounds of formula I or prodrug thereof, and at least odnohofarmatsevtychno appropriate adjuvant, solvents, preservatives, stabilizers abosumishi, packaging and instructions for use.

Another embodiment of the invention describes a kit for treating a single patient suffering from or susceptible to the condition described herein; Such a set includes a container with a dose of 2, 4-pyrimidinediamine or composition (according to the presented descriptions) and instructions for use. The container can be used by each of the well-known science, but it must meet the requirements for storage and delivery of oral, local, rectal, urethral or inhalant compositions.

Kits containing a sufficient dosage of 2,4-pyrimidinediamine or compositions for effective treatment of the patient for a long time may also be provided

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for example, for a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, or more.

One skilled in the art will appreciate that the generalized embodiments of the invention can be used in conjunction with any suitable combination for obtaining additional embodiments of the invention not presented above, and such embodiments of the invention are to be considered as part of the present invention.

Synthesis of compounds

Described herein compounds 2,4-pyrimidindinamy can be synthesized by a series of methods of synthesis using the raw materials presented in the market and / or raw materials obtained by standard synthesis methods. Suitable standard methods can be adapted for the synthesis of compounds 2, 4-pyrimidindamine and prodrugs described herein and described in US Pat. No. 0. 5,958,935 (incorporated herein by reference). Specific examples describing the synthesis of numerous compounds 2,4-pyrimidindamine and prodrugs, as well as their intermediates, are described in US patent application serial No. 10/355 543 of 31 January 2003 (i32004 / 0029902A1, incorporated herein by reference). Appropriate standard methods that can be used in a conventional manner and / or adapted for the synthesis of active compounds of 2,4-pyrimidinediamine, can also be presented in an international application serial N0. PCT / 303/03022 dated January 31, 2003 (Sho 03/063794), US Patent Application Serial No. 10/631 029 dated July 29, 2003, the international patent application serial N0.RST / and303 / 24087 (SHO2004 / 014382), the US patent application serial N0. 10/903 263, and an international patent application serial N0. PCT / 32004/24716 (SHO005 / 016893) (Included in the actual document using the link). All the compounds described herein (including prodrugs) can be obtained by the usual adaptation of such methods. and an international patent application for serial N0. PCT / 32004/24716 (SHO005 / 016893) (Included in the actual document using the link). All the compounds described herein (including prodrugs) can be obtained by the usual adaptation of such methods. and an international patent application for serial N0. PCT / 32004/24716 (SHO005 / 016893) (Included in the actual document using the link). All the compounds described herein (including prodrugs) can be obtained by the usual adaptation of such methods.

Specific typical synthesis methods of the 2,4-substituted pyrimidine diamine compounds described herein are also described in Example 1 below. An expert in the field will be able to easily adapt such examples for the synthesis of additional 2, 4-substituted pyrimidinediamine compounds.

On the Schemes 0) - (νΝ) below is a series of typical synthesis routes that can be used to synthesize the compounds 2, 4-pyrimidinediamine described herein. Such methods may conveniently be adapted to synthesize the compounds 2, 4-pyrimidinediamine described herein. After each reaction step, the product can be purified or, depending on the nature of the chemical, be used in the next step without purification.

For example, the compounds can be synthesized from substituted or unsubstituted uracil, as shown in Scheme (I) below. On Scheme (I), ring A, I⁵, (I²) p, X, Y, Z¹ and Z² presented in accordance with the description given in the application. In accordance with Scheme (I), uracil A-1 has two substituted atoms in positions 2 and 4 (substituted with halogenation agents, for example, ROSI3, or any other standard halogenating agent) under standard conditions, containing 2,4-dichloropyrimidine A -2 Depending on the deputy I⁵, in the compound A-2pirimidindiamine chlorine in the C4 position is more reactive to nucleophiles than the chlorine position of C2. This different reactivity can be used to synthesize 2,4-pyrimidindiamines I by the first reaction with 2,4-dichloropyrimidine A-2 with one equivalent of A-3 to give 4-substituted 2-chloro-4-pyrimidindamine A-4, and then and an amine A-5 containing a 2,4-pyrimidinediamine of the formula A-6 (compounds of the formula I, wherein each I³ and I⁴represented by H). Compounds of formula I wherein one or two groups of NH at the positions of C2 and C4 are pyrimidine substituted may be obtained, for example, by alkylation of NH groups.

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iA 106975 C2

As a rule, C4 halide is more reactive to nucleophiles, as shown in Scheme. However, as it will be recognized by a specialist in the field, the identity of the Deputy R⁵ canchange such a reactive ability. For example, if P⁵ represented by trifluoromethyl, will be a mixture of 4 N-substituted 4-pyrimidindinamine A-4 and the corresponding 2N-substituted 2-pyrimidinediamine with respect to 50:50. The regioselectivity of the reaction can also be controlled by adjusting the solvent and other conditions of synthesis (for example, temperature), which is well known to science.

The reactions represented in Scheme (I) may proceed more rapidly if the reaction mixture was heated by means of a microwave oven. When heated in a similar way, the following conditions may be used: heating to 175 ° C in ethanol for 5-20 minutes in a Smith reactor (ReChina, Syringe, Zmep) in a sealed test tube (at a pressure of 20 bar).

Raw materials presented by uracil A-1 can be purchased commercial sources or be obtained using standard methods of organic chemistry. Presented in the uracil market, which can be used as raw materials for the Scheme (I), include, for example, the following (without limitation): uracil (AIBgisI # 13,078-8; registration number CAS3 66-22-8); 5-bromuracil (AIBgisI # 85,247-3; number in the register of the CAC 51-20-7; 5-fluorouracil (AIBgisI # 85,847-1; registry code SAZ 51-21-8); 5-ioduracil (AIBgisI # 85,785-8 ; the registration number of the SAZ 696-07-1); 5- intratracyl (AIBgisI # 85,276-7; registration number of the SAZ 611-08-5); 5- (trifluoromethyl) -uracil (AIBgISI # 22,327-1; SAZ registry number 54-20-6). In addition, the 5-substituted aryls are represented by Sepegha Ipihegtebiaez from Sapaba, ips., ΕόττιοηΙοη, CA and / or IppIgesSiit, Sebeh, France, or can be obtained using standard methods. Below is a series of references that contain suitable synthesis methods.

Amines A-3 and A-5 can be purchased from commercial sources or synthesized using standard methods. For example, suitable amines can be synthesized from nitrogen compounds using standard chemical methods. Specific typical reactionsrepresented in the chapter of the examples. See also VideI, 1989, Rghisiasai Ağdapis Síteiz, ÁbbisopShezieu Lopdtap, Ib. apib boip Shiyuu &amp; oopz, Ips.

Those skilled in the art recognize that, in some cases, amines A-3 and A-5 and / or subunits for uracil A-1 may include functional groups requiring protection under clocking. The exact identity of any protective group (-pn) will depend on the identity of the protected functional group, which will become apparent to a specialist in this field of science. The guidance for choosing the appropriate protective group, as well as the synthesis strategies for their adherence and removal, are presented, for example, in Sherep &amp; Shiis

Thus, the protective group belongs to a group of atoms, which, when they are attached to the reactive functional group in the molecule, mask, reduce or prevent the reactivity of the functional group. As a rule, a protective group can be selectively removed for

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iA 106975 C2

desire for synthesis. Examples of protective groups are presented in Oheep &amp; Shiiz and in Naggizopahi., Sotrepbiate οί ZupiIeis Ağdapis MeiIobz, Tom. Representative amine-protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (BOC), tert-butoxycarbonyl (BOC), trimethylsilyl ( TMS), trimethylsilyl-ethanesulfonyl (TES), tritilated and substituted tri-alkyl groups, allolocarbonyl, 9-fluoronylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NMVOC) and the like. Representative hydroxyl protecting groups include, but are not limited to, hydroxyl groups acylated with the formation of acetic and benzoic acid esters, or alkylated with the formation of benzyl and triple esters, as well as alkyl ethers, tetrahydroxypyranyl ester, trialkylsilyl esters (e.g.,

A Specific Embodiment of the Invention The scheme (I) using 5-fluorouracil (AI6γ ^ N # 32,937-1) as a feedstock is presented in Scheme (Ia) below. On the Tsa circuit, ring A, (P²) p, X, Y, Z¹ and Z² presented in accordance with the description given in Scheme (I). Compound A-10-2F, 4C-di-substituted -5-fluoro-2,4-pyrimidindamine - can be obtained by reacting 2,4-dichloro-5-fluoropyrimidine A-8 (presented on the market and obtained from A-7, for example , based on uracil dehydrohalogenation using, for example, ROSI3) with an equivalent of amine A-3 containing 2-chloro-4-substituted-5-fluoro-4-pyrimidindamine A-9 followed by reaction with one or several amino acids A-5 ( as a rule, 1.1 equivalents A-5 and 2 equivalents A-5).

Although the majority of the synthesis schemes discussed above do not indicate the use of protecting groups, a specialist in the field recognizes that in some cases certain substitutions, for example, P² and / or other groups may include functional specification required zahyst.Tochna protecting group used will depend on, among other things, the identity of the functional group is protected and the reaction conditions used in the synthesis okremiyshemi that will be apparent to those skilled in the art. A guide for choosing protective groups, joining and deleting them for a separate application is presented, for example, in the OEEP &amp; SHIEL.

The prodrugs described herein can be obtained with the usual modification of the abovementioned methods. On the other hand, such prodrugs can be prepared by the method of the reaction of a properly protected 2,4-pyrimidindamine with a suitable reagent to obtain the desired progroup. The conditions for such reactions and the removal of the protection from the product for the preparation of prodrugs are well known.

There are a number of references to literary sources that contain methods that can be used for the synthesis of pyrimidines in general, as well as raw materials described in Schemes (I) - (νΙΙ). In particular, for the receipt of individual recommendations, the reader is recommended to address ΒΓον / η, ŋ. Å., "ThE Rugitbyshez", in Thie Sietis à Ĩ Neegosussis Sotroppz, Vioit 16 (SchaezzOegdeg, A., Eb.), 1962, ipeizzepes RioIizIges, (A UMuzup, οί Boip Shiieu &amp; Zopz), Chet Yoi-k

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("Vogp I"); Vogp, B. B., "TIE Rugitibitez", inTieto Sietizigo, Neihegosussis Sotropis, Viote 16,3irrinthe I (Oteizizhegdeg, A.A.A. Tauiog, E.S., ES.), 1970, OTiyevu-ipIeGsSePse (AUmzIOp oO BIOpOTiiEu &amp; 5opz), Yet Yoi-k (Vogotp II "); Vogitp, B. B., "Tie RugitibiPes", and the Tie Sitiizigo οίNeiososusіs SotropіsS, Vіοііte 16, 3іrrііtepі II (OTezizhegdeg, A.App Taуіог, Е.S., ES.), 1985, Αη Ιπιγερίεςς Πίσιος &amp; Πουρ ), Yet Yoo ^ k ("Vogotp III"); Vogitp, B. B., "Tie RugitibiPes" and TIe Sietizigo, Neihegosussis SotropiS, Vioit 52 (OTeizizhegdeg, A.A.A. Tauiog, E.S., ES.), 1994, BOIP OTiyuu &amp; 3opz, Is., Chet Wohk, pp. 1-1509 (Vogotp ^ "); ^ ppeg, S. ot. Pharmacy, A., in Neihegosussis Sotropis, Vioitte 6, (EISeggyes, R. S., ES.), 1957, oipiyuu, Chet Wagk, Chapter 7 (pyrimidine); Rayayeye, b. Α., Gipsirisio MosSegp Neihegosussis Sietizigu, 1968, OT. A.Vepiatip, Ips., Yet Yo ^ k, p. 1 - 401 (Uracil synthesis, pp. 313, 315; pyrimidindinamine synthesis, pp. 313-316; synthesis of aminopyrimidindinamine, p. 315); Boyie, b. A., Mizi, K. Pharmacy ZTIII, S.R., NeihegosussisCityzigu, 3^gC Ebiyip, 1995, SIRATAP APB NANI, LOPBOP, UC, p. 1 - 516; VO ^ B ^ D, N., ap., RI-RoIІєп2, С., НапСооок οί ЧисИеозиСе 3упіIезіз, боИп ОТієуу &amp; 5опз, Ыет Υο ^ к, 2001, с. 1-631 (protection of pyrimidines by acylation from pp. 90-91; pyrimidine silicion pp. 91-93); Boyie, b. A., MIIZ, K. ApS 3tiiiI, S.R., Neihegosusiz Sietizigu, 4^iI ESIiOP, 2000, VIAstekIIi 3syepse, ShS, Ohshb, υΚ, p.1 - 589; and SotrgeIepzma Agdapis 3upiIeziz, State University 1-9 (Tgozi, V.M. apS Ritepd, I., ES.), 1991, Reghtotop Rgez, OhhgS, IR.

EXAMPLES

In the following, the invention refers to the following non-limiting examples. The scope of the invention includes any synthesis methods that are functionally equivalent. Various modifications to the embodiments of the invention described herein will become apparent to a person skilled in the art from the description below and accompanying figures. Such modifications are included in the scope of the appended claims.

One embodiment of the invention is represented by a compound according to Formula I, as described in the Examples below.

In the examples below, as well as in the application of the invention, the following abbreviations have the following meanings. Unless stated otherwise, the terms have a common meaning for them.

<tr><td><p>TFA</p></td><td><p>=</p></td><td><p>trifluoroacetic acid</p></td><td><p>mmoles</p></td><td><p>=</p></td><td><p>millimil</p></td></tr><tr><td><p>MeOH</p></td><td><p>=</p></td><td><p>methanol</p></td><td><p>nmol</p></td><td><p>=</p></td><td><p>nanomolar</p></td></tr><tr><td><p>ETOAs</p></td><td><p>=</p></td><td><p>ethyl acetate</p></td><td><p>DMSO</p></td><td><p>=</p></td><td><p>dimethyl sulfoxide</p></td></tr><tr><td><p>and-RgON</p></td><td><p>=</p></td><td><p>isopropanol</p></td><td><p>ml</p></td><td><p>=</p></td><td><p>milliliter</p></td></tr><tr><td><p>Eion</p></td><td><p>=</p></td><td><p>ethanol</p></td><td><p>mg</p></td><td><p>=</p></td><td><p>milligram</p></td></tr><tr><td><p>with</p></td><td><p>=</p></td><td><p>sglelet</p></td><td><p>pound / inch2</p></td><td><p>=</p></td><td><p>pound per inch²</p></td></tr><tr><td><p>WITH</p></td><td><p>=</p></td><td><p>doublet</p></td><td><p>H</p></td><td><p>=</p></td><td><p>norm</p></td></tr><tr><td><p>and</p></td><td><p>=</p></td><td><p>triplet</p></td><td><p>μmol</p></td><td><p>=</p></td><td><p>micromolar</p></td></tr><tr><td><p>I</p></td><td><p>=</p></td><td><p>quartet</p></td><td><p>rpm</p></td><td><p>=</p></td><td><p>revolutions / minute</p></td></tr><tr><td><p>t</p></td><td><p>=</p></td><td><p>multiplet</p></td><td><p>gi</p></td><td><p>=</p></td><td><p>room temperature</p></td></tr><tr><td><p>SS</p></td><td><p>=</p></td><td><p>doublet or doublet</p></td><td><p>and I.</p></td><td><p>=</p></td><td><p>water</p></td></tr><tr><td><p>Lg</p></td><td><p>=</p></td><td><p>wide</p></td><td><p>μl</p></td><td><p>=</p></td><td><p>microliter</p></td></tr><tr><td><p>M3</p></td><td><p>=</p></td><td><p>mass spectrum</p></td><td><p>EBS</p></td><td><p>=</p></td><td><p>embryonal bovine</p><p>serum</p></td></tr><tr><td><p>M3 (E3)</p></td><td><p>=</p></td><td><p>mass spectrometry (electro-sputtering) turned-phase</p></td><td><p>І_СМ3</p></td><td><p>=</p></td><td><p>mass spectrometer with liquid chromatography</p></td></tr><tr><td><p>OF-HPLC</p></td><td><p>=</p></td><td><p>Highly effective</p></td><td><p>PAC3</p></td><td><p>=</p></td><td><p>flow cytometry</p></td></tr>

liquid chromatography

Example 1: Synthesis of pyrimidine-2,4-diamines

Synthesis of 5- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one:

In a 5-amino-benzo [C] oxazole-2 (3H) -one (300.1 mg, 2.0 mmol) and 2,4-dichloro-5-

methyl pyrimidine (423.8 mg, 2.6 mmol) was added MeOH (8 mL) and H2O (2 mL). Viscous liquid was stirred at room temperature for 64 h. The precipitate of the reaction mixture was collected by filtration, washed with EtOAc (3 ml x 2) and further dried in vacuo. 5- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one was obtained as a dirty-white solid: 394 mg (71% yield);¹H NMR (300 MHz, DMSO)? 11.68 (bs, 1H), 8.62 (s, 1H), 7.94 (C, b = 0.8, 1H), 6.97 (C, b = 2.0, 1H), 6.82 (C, b = 8.1, 1H), 6.74 (Cs, b = 2.0, 8.1, 1H), 2.15 (s, 3H) ; I_SM3 (M +) t / z 277.10.

Synthesis of H4- (benzo [S] oxazol-2 (3H) -on-5-yl) -CH2- (3-methylsulfonyl) phenyl) -5-methylpyrimidin-

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υΑ 106975 Ο2

2,4-diamine: (1-16)

In a test tube of 5- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one (138.3 mg, 0.5 mmol) and 3- (methylsulfonyl) benzamide hydrochloride (207 , 7 mg, 1.0 mmol) was added i-RgON (10 mL), then TFA (μl, 1.5 mmol). The test tube was tightly closed, and the reaction mixture was stirred at a temperature of 85-90 ° C. for 40 hours. The solvent was removed by the mind, and the crude product was purified by the ON-EHR method. N4- (benzo [S] oxazol-2 (3H) -on-5-yl) -N- (3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine was obtained as mono-trifluoroacetate: white color, 129 mg (49% yield);¹H NMR (300 MHz, DMSO)? 11.60 (5.1H), 9.43 (5, 1H), 8.43 (5, 1H), 8.20 (5, 1H), 8.11 (bg C, b = 7.5, 1H), 7.96 (C, b = 0.8, 1H), 7.49 - 7.33 (t, 4H), 7.27 (C, b = 8.5 , 1H), 3.13 (5, 3H), 2.16 (5, 3H); I_SMZ (M +) t / ζ 412.47.

Synthesis of 5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [C] imidazole-2 (3H) -one:

In a 5-amino-1 H -benzo [C] oxazole-2 (3H) -one (298.3 mg, 2.0 mmol) and 2,4-dichloro-5-fluoropyrimidine (434.1 mg, 2, 6 mmol) was added MeOH (8 mL) and H2O (2 mL). The viscous solution was subjected to stirring at room temperature for 3 days. The precipitate of the reaction mixture was collected by filtration, washed with EDAs (3 ml x 2) and further dried in vacuo. 5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [S] oxazol-2 (3H) -one was obtained as a dirty white solid: 390.3 mg (70% yield);¹H NMR (300 MHz, DMSO)? 10.69 (5, 1H), 10.63 (5.1H), 9.87 (5, 1H), 8.27 (C, b = 3.6, 1H) , 7.35 (C, b = 1.9, 1 H), 7.18 (Cs, b = 1.9, 8.3, 1 H), 6.93 (C, b = 8.3, 1 H); I_SMZ (M +) t / ζ 279.80.

Synthesis of 4- (5-nitropyridin-2-yl) morpholine:

2-bromo-5-nitropyridine (5 g, 24.6 mmol) and morpholine (5.4 ml, 61.5 mmol) were added in a round-bottom flask with dichloromethane (125 ml) solution. The reaction proceeded for 4 hours, then the mixture was cooled at room temperature. Subsequently, the solution was washed with saturated water solution of sodium bicarbonate and saline solution. The organic layer was dried (No.₂ZO₄), filtered, and the solvent was removed in vacuum. 4- (5-nitropyridin-2-yl) morpholine was obtained as a yellow solid: 4.9d (95% yield);¹H NMR (300 MHz, DMSO)? 8.95 (b, b = 2.7, 1H), 8.22 (C?, B = 2.7, 9.6, 1H), 6.92 (C, b = 9.6, 1H), 3.74-3.65 (t, 8H); I_SMZ (M +) m / z 210.34.

Synthesis of 6-morpholinopyridine-3-amine:

4- (5-nitropyridin-2-yl) morpholine (4.9 g, 23.4 mmol) and 10% Pb on activated carbon (500 mg) were added to a solution of EUN (250 ml). Hydrogenation was carried out in Parra flask at room temperature and 40 psi² for 2 g. Solids were filtered, filtrate collected. The solvent was removed in vacuo. 6-morpholinopyridine-3-amine isombed in the form of a solid of purple color: 3.7d (88% yield);¹H NMR (300 MHz, DMSO)? 7.64 (b, b = 2.7, 1H), 6.96 (s, b = 2.7, 8.8, 1H), 6.65 (C, b = 8.8, 1H), 4.63 (5, 2H), 3.72-3.69 (t, 8H); 3.21-3.18 (t, 4H); I_SMZ (M +) t / ζ 180.08.

Synthesis No. (benzimidazolin-2-one-5-yl) -2 - ((2-morpholinyl) pyridin-5-yl) -5-fluoropyrimidine-2,4-diamine: (11-19)

In a test tube of 5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [C] imidazole-2 (3H) -one (27.6 mg, 0.1 mmol) and 6-morpholinopyridin-3 -amine (35.8 mg, 0.2 mmol) was added i-RgON (2 ml) followed by TFA (10 μl, 0.13 mmol). The test tube was tightly closed, and the viscous solution was subjected to stirring at 95 ° C for 2 days. The solvent was removed in vacuo, and the crude product was purified by the ON-HPLC method. N- (benzimidazolin-2-one-5-yl) -2 - ((2-morpholinyl) pyridin-5-yl) -5-fluoropyrimidine-2,4-diamine was obtained as a solid of a light orange color (di- trifluoroacetate): 51.1 mg (79% yield);¹H NMR (300 MHz, DMSO)? 10.61 (5, 2H), 9.79 (bg, 5, 1H), 9.55 (bg, 5, 1H), 8.31 (5, 1H), 8.13 (C, b = 4.4, 1H), 7.92 (bg C, b = 8.8, 1H), 7.22 (C, b = 8.1, 1H), 7.18 (5, 1H ), 7.10 (bg C, b = 8.8, 1H), 6.89 (C, b = 8.1, 1H), 3.78-3.75 (t, 4H), 3.50 - 3.47 (t, 4H); I_SMZ (M +) t / ζ 423.00.

Synthesis of 6- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one:

The (6-amino-benzo [C] oxazol-2 (3H) -one (1.0 g, 6.7 mmol) and 2,4-dichloro-5-methylpyrimidine (1.4 g, 8.7 mmol) MeOH (20 mL) and H2O (5 mL) were added. The viscous liquid was stirred at room temperature for 2 days. The precipitate of the reaction mixture was collected by a filtration method, washed by N.₂O (3 ml of χ 2) and ESA (3 ml of χ 2), and further dried in vacuo. 6- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one was obtained as a solids of light reddish color: 1.59 g (86% yield);¹H NMR (300 MHz, DMSO)? 11.59 (5.1H), 8.87 (5, 1H), 7.99 (5, 1H), 7.56 (5, 1H), 7.28 (C , b = 8.3, 1H), 7.06 (C, b = 8.3, 1H), 2.14 (5, 3H).

Synthesis of N- (benzo [S] oxazol-2 (3H) -on-6-yl) -2- (3-morpholinyl) phenyl) -5-methylpyrimidine-2,4-

diamina: (1-48)

In a test tube containing 6- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one (27.73 mg, 0.1 mmol) and 3-morpholinobenzamine (26.7 mg, 0.15 mmol) was added i-RgON (2 mL), then TFA (10 mL)

84

iA 106975 C2

ll, 0.13 mmol). The test tube was tightly closed, and the solution was blended at a temperature of 95 ° C for 2 days. The solvent was removed in vacuo, and the crude product was purified by the ON-HPLC method. K4- (benzo [b] oxazole-2 (3H) -one-6-yl) ^ 2 (3-morpholinyl) phenyl) -5-metylpirymidyn-2,4-diamine was obtained as a solid red light color : 32.9 mg (78% yield);¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.90 (s, 1H), 7.81 (from , 1H), 7.37 (b, b = 8.3, 1H), 7.27 (s, 1H), 7.14 (b, b = 8.3, 1H), 7.07-7.01 (t, 2H), 6.58-6.50 (t, 1H), 3.68-3.65 (t, 4H), 2.95-2.92 (t, 4H), 2.14 (s , 3H); I_SM3 (M +) t / z 419.03.

Synthesis of K4- (benzoxazolinin-2-one-5-yl) -2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-

methyl pyrimidine-2,4-diamine: (11-13)

In a test tube of 5- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [b] oxazol-2 (3H) -one (27.7 mg, 0.5 mmol) and 6- (4-methylpiperazin-1- yl) pyridine-3-amine (38.4 mg, 1.0 mmol) was added i-RgON (2 mL), then TFA (10 μl, 0.13 mmol). The test tube was tightly closed, and the reaction mixture was stirred at 85 ° C. for 2 days. The solvents were removed by the ignorance, and the crude product was purified by the ON-HPLC method. The purified compound in the form of trifluoroacetate was dissolved in MeOH-H₂O (1: 4, 2 ml) and passed through the Pb-NSO column₃-MR-ZRE, washed with the same solvents (1 ml). The filtrate was collected, and the solvent was removed by lyophilization. K4- (benzoxazosinin-2-one-5-yl) -2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine was obtained as a solid propellant color: 23.1 mg (53% yield);¹H NMR (300 MHz, DMSO)? 11.57 (s, 1H), 8.73 (s, 1H), 8.30 - 8.28 (t, 2H), 7.87 - 7.84 (t, 2H), 7.46-7.28 (t, 2H), 7.22 (b, b = 8.5, 1H), 6.71 (b, b = 9.1.1H), 3.40 - 3.37 (t, 4H, overlapping with N₂O), 2.44-2.41 (t, 4H), 2.25 (s, 3H), 2.11 (s, 3H), I_SM3 (M +) m / z 433.52.

Synthesis of K4- (benzidimidazolin-2-one 5-yl) -2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-

fluoropyrimidine-2,4-diamine: (11-16)

In a test tube of 5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [b] imidazole-2 (3H) -one (28.0 mg, 0.1 mmol) and 6- methyl piperazin-1-yl) pyridine-3-amine (38.4 mg, 0.2 mmol) was added i-RgON (2 ml), then TFA (10 μl, 0.13 mmol). The tube was tight closed, and the solution was subjected to stirring at a temperature of 85? C for 2 days. The solvent was removed in vacuo, and the crude product was purified by the ON-HPLC method. The purified compound in the form of trifluoroacetate was dissolved in MeOH-H₂O (1: 4, 2 ml) and passed through the Pb-NSO column₃-MR-ZRE, washed the same solvents (1 ml). The filtrate was collected and the solvent was removed by lyophilization. K4- (benzidimidazolin-2-one 5-yl) -2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-

fluoropyrimidine-2,4-diamine was obtained as a solid of purple color: ¹NMSO (300 MHz, DMSO)? 10.56 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.27 (bg b , b = 2.3, 1 H), 8.00 (bb, b, 3.8, 1 H), 7.84 (bb, b = 2.3, 9.1, 1 H), 7.30 (bb , b = 1.7, 8.2, 1H), 7.17 (b, b = 1.7, 1 H), 6.86 (b, b = 8.2, 1 H), 6.73 (b, b = 9.1, 1 H), 3.40-3.37 (t, 4H, overlapping with H₂O), 2.44-2.41 (t, 4H), 2.25 (s, 3H); I_SM3 (M +) t / ζ 436.50.

Synthesis of 6- (5-methyl-2- (6- (4-methylpiperazin-1-yl) pyridine-3-ilamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one: (11-25)

In a test tube of 5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [b] imidazole-2 (3H) -one (28.0 mg, 0.1 mmol) and 6- methyl piperazin-1-yl) pyridine-3-amine (38.4 mg, 0.2 mmol). The tube was sealed and the solution was stirred at 85 ° C. for 2 days. The solvent was removed in vacuo, and the crude product was purified by the ON-HPLC method. The purified compound in the form of trifluoroacetate was dissolved in MeOH-H2O (1: 4, 2 ml) and passed through the Pb-NSO column₃-MR-ZRE, washed with the same solvents (1 ml). The filtrate was collected, and the solvent was removed by lyophilization. 6- (5-methyl-piperazin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [b] oxazol-2 (3H) -one was

obtained in the form of a solid of purple color: 26.2 mg (60% yield); ¹H NMR (300 MHz, DMSO)? 11.70 (s, 1H), 9.97 (s, 1H), 9.49 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1 H), 7.65 (b, b = 11.7.2H), 7.21 (b, b = 8.8, 1H), 7.05 (b, b = 8.4, 1H), 6 , 89 (b, b = 8.9, 1H), 4.34-4.31 (t, 4H), 3.09-3.07 (t, 4H), 2.85 (s, 3H), 2 , 13 (s, 3H).

The following compounds were obtained in the same manner as the above examples, or by methods described in the text of this application or known to a person skilled in the art.

1-1: N- (benzo [b] oxazol-2 (3H) -on-5-yl) -2- (3-formylphenyl) -5-methylpyrimidine-2,4-diamine

M3 (E3) 363.02 (M + H), 361.18 (M-H); ¹H NMR (300 MHz, DMSO) δ 10.47 (s, 1H), 9.75 (s, 1H), 7.94 (br, 6.33, 2H), 7.70 (t, 3H) , 7.55 (b, b = 7.5, 1H), 7.41 (b, b = 7.9, 3H), 7.24 (b, b = 7.9, 1H), 2.16 ( s, 3H) ppm

2- (3-aminocarbonylphenyl) -5-methylpyrimidine-2,4-dichlorophenyl)

diamin

85

iA 106975 C2

M3 (EH) 376.99 (M + H), 375.11 (M-H); ¹H NMR (300 MHz, DMSO)? 11.66 (5, 1H), 10.36 (5, 1H), 9.61 (5, 1H), 7.93 (t, 2H), 7.76 (5 , 1H), 7.63 (b, b = 7.9, 1H), 7.54 (b, b = 7.6, 1H), 7.42 (t, 1H), 7.25 (bb, b = 7.4, 14.7, 1H), 2.14 (5, 3H) ppm

1-3: H4- (benzo [b] oxazol-2 (3H) -on-5-yl) -N2- (4-aminocarbonylphenyl) -5-methylpyrimidine-2,4-

diamin

MH (ES) 377.12 (M + H), 375.04 (M-H); ¹H NMR (300 MHz, DMSO) δ 11.78 (5, 1H), 10.40 (5, 1H), 9.61 (5, 1H), 7.94 (5, 1H), 7.85 (5 , 1H), 7.70 (b, b = 8.6, 2H), 7.51 (b, b = 8.6, 2H), 7.33 (5, 1H), 2.14 (5, 3H ) md

1-4: H4- (benzo [b] oxazol-2 (3H) -on-5-yl) -N2- (4-formylphenyl) -5-methylpyrimidine-2,4-diamine

M3 (EI) 363.02 (M + H), 361.01 (M-H); ¹H NMR (300 MHz, DMSO)? 10.27 (5, 1H), 9.43 (5, 1H), 8.04-7.85 (t, 2H), 7.73 (I, b = 9, 6, 1H), 7.57 (b, br = 8.7, 2H), 7.31 (5, 1H), 7.24 (5, 1H), 2.16 (5, 3H) ppm.

1- (5-

diazabicyclo [3.3.1] nonan-3-yl) phenyl) -5-methylpyrimidine-2,4-diamine

M3 (EH) 514.25 (M + H), 512.32 (M-H); ¹H NMR (300 MHz, DMSO)? 8.92 (5, 1H), 8.32 (5, 1H), 7.84 (5, 1H), 7.61-7.37 (t, 3H), 7 , 7.36 (5, 1H), 6.94 (5, 1H), 3.50 (t, 3H), 7.40 (5H, 2.97 (t, 4H), 2.77 (b, b = 5.0, 4H), 2.59 (b, b = 11.9, 2H), 2.26 (5, 3H), 2, 12 (5, 3H), 2.07 (t, 2H), 1.48 (t, 2H), 0.92 (b, b = 8.0, 9H) ppm

1-6: N4- (benzo [b] oxazol-2 (3H) -on-5-t) -N2- (3-fluoro-4- (1,5,7-trimethyl-3,7-

diazabicyclo [3.3.1] nonan-3-yl) phenyl) -5-methylpyrimidine-2,4-diamine

MH (ES) 518.22 (M + H), 516.30 (M-H); ¹H NMR (300 MHz, DMSO)? 9.20 (5, 1H), 9.14 (t, 1H), 8.40 (5, 1H), 7.85 (5, 2H), 7.63 (5 , 2H), 7.42-7.25 (t, 1H), 7.14 (t, 1H), 7.06-6.81 (t, 1H), 3.51 -3.04 (t, 4H) ), 2.67 (b, b = 27.5, 4H), 2.08 (t, 6H), 1.41 (t, 2H), 0.91 (b, b = 5.2, 9H) m .d

1-7: N4- (3-p -propentbenzo [b] oxazol-2 (3H) -one 5-t) -N2 - ((3-methylsulfonyl) fent) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.41 (5, NH), 8.50 (5, NH), 8.14 (5, 1H), 8.09-7.86 (t, 2H), 7 , 64.67 (m, 6H), 3.68 (1H, b = 4.7, 2H), 3.07 (5, 3H), 2.11 (5, 3H), 1.63 (Ις , b = 4.4, 9.8, 2H), 0.81 (I, b = 7.6, 3H).

1-8: N4- (3-p -proptenbenzo [b] oxazol-2 (3H) -one 5-t) -N2 - ((4-methylsulfonyl) fent) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.29 (5, NH), 8.99 (5, NH), 8.40 (5, OH), 7.86 (5, 1H), 7.54 (b , b =

12.1, 3H), 7.37 (b, b = 8.4, 1H), 7.27 (b, b = 7.2, 1H), 7.06-6.87 (t, 2H), 3.72 (1, b = 10.9, 2H), 2.84 (5, 3H), 2.08 (5, 3H), 1.63 (1ц, b = 12.2, 17.8, 2H ), 0.81 (I, b = 9.4, 3H).

1-9: N4- (3Z-propo-benzo [b] oxazol-2 (3H) -on-5-t) -N2 - ((3-methylsulfonyl) fent) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.39 (5, OH), 8.43 (5, OH), 8.13 (t, 2H), 8.07-7.85 (t, 2H), 7 (T, 2H), 7.42 - 7.17 (t, 2H), 4.43-4.34 (t, 1H), 3.05 (5, 3H), 2.11 (5, 3H ), 1.39 (b, b = 6.9, 6H).

1-10: N4- (3Z-propo-benzo [b] oxazol-2 (3H) -one 5-t) -N2 - ((4-methylsulfonyl) fent) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.27 (5, NCH), 8.97 (5, NH), 8.35 (5, OH), 8.12 (5, 1H), 7.86 (5 , 1H), 7.52 (t, 3H), 7.25 (b, b = 9.2, 1H), 6.95 (b, b = 8.9, 2H), 4.50-4.31 (t, 1H), 2.84 (5, 3H), 2.09 (5.3H), 1.40 (b, b = 6.9, 6H).

1-11: N4- (benzimidazolin-2-one-5-yl) -N2 - ((3-aminosulfonyl) phenyl) -5-methylpyrimidine-2,4-

diamin

I.SMZ (M +) m / z 411.95; ¹H NMR (300 MHz, DMSO)? 10.72 (5, 1H), 10.68 (5, 1H), 10.11 (bg, 5.1H), 9.53 (bg, 5, 1H), 7.88 (Bg, 5, 2H), 7.75 (5, 1H), 7.47 (5, 1H), 7.37 (bg, 5, 2H), 7.28 (b, b = 8.2, 1H), 7.13 - 7.08 (t, 2H), 6.96 (b, b = 8.2, 1H), 2.19 (5, 3H).

1-12: N4- (benzimidazolin-2-on-5-yl) -N2 - ((4-aminosulfonyl) phenyl) -5-methylpyrimidine-2,4-

diamin

I.SMZ (M +) m / z 411.95; ¹H NMR (300 MHz, DMSO)? 10.75 (5, 1H), 10.72 (5, 1H), 10.40 (5, 1H), 9.63 (5, 1H), 7.89 (5 , 1H), 7.57 (bb, b = 8.9, 8.9, 4H), 7.21 (bg, 5, 1H), 7.03-6.89 (t, 4H), 2.15 ( 5, 3 H).

1-13: 5- (5-Fluoro-2- (4-aminosulfonyl-phenylamino) pyrimidin-4-ylamino) -1H-benzo [b] imidazole-

2 (3H) -one

I.SMZ (M +) m / z 415.92; ¹H NMR (300 MHz, DMSO)? 10.67 (5, 1H), 10.61 (5, 1H), 9.64 (bgb, b =

6.8, 1H), 9.42 (bb, b = 9.1, 1H), 8.14 (bb, b = 2.3, 3.8, 1 H), 7.82 (bg b, b = 8 , 9.2H), 7.61 (bg, b, b =

8.9, 2H), 7.31 (bgb, b = 8.2, 1H), 7.17 - 7.15 (t, 3H), 6.94 (b, b = 8.2, 1 H).

1-14: N4- (benzo [b] oxazol-2 (3H) -on-5-t) -N2- (3-aminosulfonyl) phentene) -5-methyl-prime matter-2,4-diamine

I.SMZ (M +) t / z 430.42; ¹H NMR (300 MHz, DMSO)? 11.60 (5, 1H), 9.34 (5, 1H), 8.39 (5, 1H), 8.10 (5, 1H), 8.03 (bg 5, 1H), 7.94 (5, 1H), 7.45 (bb, b = 8.6, 1H), 7.38 (b, b = 1.7, 1H), 7.33 - 7 , 31

86

iA 106975 C2

(t, 2H), 7.28 - 7.25 (t, 3H), 2.16 (5, 3H).

1-15: N4- (benzo [b] oxazol-2 (3H) -on-5-t) -N2- (4-aminosulfonyl) fent) -5-methylprimeshin-2,4-diamine

I.S.M. (M +) m / z 412.93; ¹H NMR (300 MHz, DMSO)? 11.77 (5, 1H), 10.00 (bg, 5, 1H), 9.26 (bg, 5.1H), 7.96 (s, 1H), 7.71 - 7.61 (t, 4H), 7.34 (bg, 5, 2H), 7.34 - 7.24 (t, 3H), 2.19 (5, 3H).

1-16: N2 - ((3-methylsulfonyl) phent) -N4- (2-oxo-2,3-diprobenzo [b] oxazol-6-t) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.50 (5, 1H), 9.40 (5, 1H), 8.39 (5, 1H), 8.17 (5, 1H), 8.05 (b , b =

7.5, 1H), 7.91 (5, 1H), 7.82 (s, 1H), 7.38-7.32 (t, 3H), 7.02 (b, b = 8.4, 1H), 3.10 (5, 3H), 2.11 (5, 3H).

1-17: N4- (benzo [b] oxazol-2 (3H) -on-5-t) -N2- (4-methylsulfonyl) fent) -5-methylprimeshin-2,4-diamine

I.SM8 (M +) m / z 411.95; ¹H NMR (300 MHz, DMSO)? 11.76 (5, 1H), 10.05 (bg, 5, 1H), 9.20 (bp, 5.1H), 7.98 (s, 1H), 7.80 (b, b = 9.0, 2H), 7.71 (b, b = 9.0, 2H), 7.37 (b, b = 9.0, 1H), 7.31 -7.28 ( t, 2H),

3.16 (5, 3H), 2.20 (5, 3H).

1-18: N4- (benzo [b] oxazol-2 (3H) -one 5-t) -N2- (3-aminosulfonyl) fent) -5-fluoroprims-2,4-diamine

I.S.M. (M +) m / z 416.89; ¹H NMR (300 MHz, DMSO)? 11.63 (5, 1H), 9.58 (5, 1H), 9.46 (5, 1H),

8.16 (b, b = 3.7, 1H), 8.13 (5, 1H), 7.97 (bb, b, 7.7, 1H), 7.57 (bb, b = 2.1, 8.7, 1H), 7.46-7.33 (t, 3H), 7.33-7.23 (t, 3H).

1-19: N4- (benzo [b] oxazol-2 (3H) -one 5-t) -N2- (4-aminosulfonyl) fent) -5-fluoroprimchin-2,4-diamine

I.S.M. (M +) m / z 416.94; ¹H NMR (300 MHz, DMSO)? 11.70 (5, 1H), 9.69 (5, 1H), 9.52 (5, 1H),

8.19 (b, b = 3.7, 1H), 7.83 (b, b = 8.9, 2H), 7.65 (b, b = 8.9, 2H), 7.51 (bg b, b = 8.7, 1H), 7.38 (b, b = 1.7, 1H), 7.30 (b, b = 8.7, 1H), 7.16 (bg, 5, 2H).

1-20: N4- (benzo [b] oxazol-2 (3H) -one 5-t) -N2- (3-methylsulfonyl) fent) -5-fluoroprims-2,4-diamine

I.S.M. (M +) m / z 416.37; ¹H NMR (300 MHz, DMSO)? 11.68 (bg, 5, 1H), 9.66 (5, 1H), 9.45 (5, 1H), 8.23 ​​(5, 1H), 8.18 ( b, b = 3.7, 1 H), 8.08 (b, b = 9.1, 1 H), 7.54 - 7.37 (t, 4 H), 7.24 (b, b = 8.6 , 1H), 3.16 (5, 3H).

1-21: N4- (benzo [b] oxazol-2 (3H) -one 5-t) -N2- (4-methylsulfonyl) fent) -5-fluoroprims-2,4-diamine

I.S.M. (M +) m / z 415.92; ¹H NMR (300 MHz, DMSO)? 11.70 (5, 1H), 9.84 (5, 1H), 9.56 (5, 1H), 8.21 (b, b = 3.4, 1 H) , 7.92 (b, b = 8.9, 2H), 7.73 (b, b = 8.9, 2H), 7.47 (bgb, b = 8.6, lH), 7.41 (Bg, 5.1H), 7.33 (b, b = 8.6, 1H), 3.16 (5, 3H).

1-22: N4- (benzimidazolin-2-one-5-yl) -N2- (3-methylsulfonyl) phenyl-5-methylpyrimidine-2,4-diamine

I.S.M.sub.8 (M +) m / z 411.04; ¹H NMR (300 MHz, DMSO)? 10.71 (5, 1H), 10.67 (5, 1H), 10.18 (bg, 5.1H), 9.46 (bg, 5, 1H), 8.02 7.82 (t, 3H), 7.57 (b, b = 7.0, 1H), 7.39 (bb, b = 8.0, 8.0, 1H), 7.17 - 7, 02 (t, 2H), 6.96 (b, b = 8.0, 1H), 3.14 (5, 3H), 2.19 (5, 3H).

1-23: N4- (benzimidazolin-2-one-5-yl) -N2- (4-methylsulfonyl) phenyl-5-fluoropyrimidine-2,4-diamine

I.S.M. (M +) m / z 414.94; ¹H NMR (300 MHz, DMSO)? 10.69 (5, 1H), 10.63 (5, 1H), 9.79 (5, 1H),

9.49 (5, 1H), 8.15 (b, b = 3.8, 1H), 7.89 (b, b = 8.5, 2H), 7.68 (b, b = 8.5, 2H ), 7.27 (b, b = 8.2, 1 H),

7.19 (5, 1H), 6.96 (b, b = 8.2, 1H), 3.14 (5, 3H).

1-24: N4- (benzo [b] oxazol-2 (3H) -one 5-t) -N2 - ((3-aminosulfonyl-4-methyl) fent) -5-

methyl pyrimidine-2,4-diamine

I.S.M. (M +) m / z 427.02; ¹H NMR (300 MHz, DMSO)? 11.71 (5, 1H), 10.05 (bg, 5, 1H), 9.42 (bg, 5.1H), 7.89 (s, 1H), 7.84 (Bg, 5, 1H), 7.74 (bb, b, 6.8, 1H), 7.36 - 3.26 (t, 5H), 7.20 (b, b = 8.2, 1H) ,

3.49 (5, 3H, overlapping with H₂O), 2.19 (5, 3H).

1-25: N4- (benzo [b] oxazol-2 (3H) -one 5-t) -N2 - ((3-tertiary-buttnamensulfonyl) fent) -5-

methyl pyrimidine-2,4-diamine

I.S.M. (M +) m / z 469.05; ¹H NMR (300 MHz, DMSO)? 11.70 (5, 1H), 10.03 (bg, 5, 1H), 9.35 (bg, 5.1H), 7.93 (5, 1H), 7.89 - 7.85 (t, 2H), 7.58 - 7.19 (t, 6H), 2.20 (5, 3H), 1.12 (5, 9H).

1-26: N4- (benzo [b] oxazol-2 (3H) -on-5-t) -N2- (3-cyanophen) -5-methylpropylamino-2,4 -amino

I.S.M. (M +) m / z 359.06; ¹H NMR (300 MHz, DMSO)? 11.64 (5, 1H), 10.07 (bg, 5, 1H), 9.34 (bg, 5.1H), 8.10 (5, 1H), 7.97 (T, 2H), 7.69-7.66 (t, 1H), 7.51-7.38 (t, 2H), 7.33 (b, b = 8.3, 1H), 7.28 -

7.16 (t, 2H), 2.19 (5, 3H).

1-27: N4- (benzo [b] oxazol-2 (3H) -one 5-t) -N2- (4-cyanophen) -5-methylpropylamino-2,4-dimethylamino

I.S.M. (M +) m / z 359.47; ¹H NMR (300 MHz, DMSO)? 11.09 (bg, 5, 1H), 9.64 (5, 1H), 8.51 (5, 1H), 8.30 (5, 1H), 7.98 ( 7.58 (b, b = 8.8, 2 H), 7.38 (5, 1 H), 7.32 (5, 1 H), 7.88 (b, b = 8.8, 2 H) 1H), 2.16 (5, 3H).

1-28: N4- (benzimidazolin-2-on-5-yl) -N2- (3-cyanophenyl) -5-methylpyrimidine-2,4-diamine

87

iA 106975 C2

I.S.M.S (M +) m / z 358.02; ¹NMR (300 MHz, DMSO) δ 10.67 (5, 2H), 10.43 (5, 1H), 9.55 (5, 1H), 7.97 (b, &amp; lt; RTI ID = 11.6, 2H) , 7.71 (b, J = 8.1, 1H), 7.47 - 7.36 (t, 2H), 7.18 - 6.92 (t, 3H), 2.19 (5, 3H) .

1-29: H4- (benzimidazolin-2-on-5-yl) -N2- (4-cyanophenyl) -5-methylpyrimidine-2,4-diamine

I_SM3 (M +) t / z 358.50; ¹1H NMR (300 MHz, DMSO)? 10.75 (5, 1H), 10.68 (5, 1H), 10.08 (bg, 5.1H), 9.24 (bg, 5, 1H), 7.93 (T, 2H), 7.73 (b, J = 8.7, 2H), 7.55 (b, J = 8.7, 2H), 7.10-7.08 , 00 (b, δ = 8.7, 1H), 2.18 (5, 3H).

1-30: H4- (benzo [b] oxazol-2 (3H) -on-5-yl) -H2- (3- (morpholinosulfonyl) phenyl) -5-

methyl pyrimidine-2,4-diamine

I_SM3 (M +) m / z 482.98; ¹NMR (300 MHz, DMSO)? 11.70 (5, 1H), 10.05 (bg, 5, 1H), 9.26 (bg, 5.1H), 8.02 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.0 = 1H), 7.96 (5, 1H), 7.81 (5, 1H), 7.47 (bb, A = 8.0, 8.0, 2H), 7.41 - 7.23 (t, 3H), 3.64-3.62 (t, 4H), 2.85-2.83 (t, 4H), 2.19 (5, 3H).

1-31: H4- (benzo [b] oxazol-2 (3H) -on-5-yl) -H2- (3- (morpholinosulfonyl) phenyl) -5-

fluoropyrimidine-2,4-diamine

I_SM3 (M +) t / z 486.93; ¹NMR (300 MHz, DMSO)? 11.65 (5, 1H), 9.68 (5, 1H), 9.54 (5, 1H),

8.19 (b, &amp; lt; / RTI &amp; gt; 3.7, 1H), 8.14 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 9.2, 1H), 8.03 (bg, 5, 1H), 7.49 (bb, 8.0, 2H), 7.42 (5, 1H), 7.26 (bb, A = 9.2, 9.2, 2H), 3.66-3.64 (t, 4H), 2, 88 - 2.86 (t, 4H).

1-32: H4- (benzimidazolin-2-on-5-yl) -H2- (3- (morpholinosulfonyl) phenyl) -5-fluoropyrimidine-2,4-diamine

I_SM3 (M +) t / z 486.04; ¹NMR (300 MHz, DMSO)? 10.63 (5, 1H), 10.58 (5, 1H), 9.63 (5, 1H), 9.45 (5, 1H), 8.17 - 8 , 14 (t, 2H), 7.97 (5, 1H), 7.44 (bb, A = 7.8, 8.0, 1H), 7.31 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.2, 1H) , 7.24 (b, J = 7.8, 1 H), 7.20 (5, 1 H), 6.92 (b, J = 8.2, 1 H), 3.66 - 3.64 (t, 4H), 2.88-2.86 (t, 4H).

1-33: H4- (3-phosphorylmethylbenzo [b] oxazol-2 (3H) -on-5-yl) -H2 - ((3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine

I_SM3 (M +) t / ζ 522.40; ¹NMR (300 MHz, Yu₂O) δ 7.68 (bg, 5H, 2H), 7.59 (bb, br = 6.7, lH), 7.40 -7.21 (t, 4H), 7.06 (b, δ = 8.5, 1H), 5.38 (b, J = 5.7, 2H), 3.06 (5, 3H), 2.01 (5, 3H).

1-34: H4- (1,3-dimethylbenzimidazolin-2-on-5-yl) -N2 - ((3-aminosulfonyl) phenyl) -5-

methyl pyrimidine-2,4-diamine

I_SM3 (M +) t / z 440.03; ¹NMR (300 MHz, DMSO)? 10.15 (bg, 5, 1H), 9.51 (bg, 5, 1H), 7.92 (5.1H), 7.87 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.3, 1H), 7.78 (5, 1H), 7.47 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 7.9, 1H), 7.38-7.36 (t, 2H), 7.28-7.23 (t, 2H),

7.20 (b, J = 8.3, 1H), 3.40 (5, 3H), 3.27 (5, 3H), 2.21 (5, 3H).

1-35: H4- (1,3-dimethylbenzimidazolin-2-on-5-yl) -N2 - ((4-aminosulfonyl) phenyl) -5-

methyl pyrimidine-2,4-diamine

I_SM3 (M +) t / z 440.03; ¹NMR (300 MHz, DMSO)? 10.20 (bg, 5, 1H), 9.54 (bg, 5, 1H), 7.95 (5.1H), 7.65 (b,? 8.8, 2H), 7.57 (b, δ = 8.8, 2H), 7.40 (5, 1H), 7.26 - 7.20 (t, 3H), 3.41 (5, 3H), 3 , 31 (5.3H), 2.21 (5, 3H).

1-36: H4- (1,3-dimethylbenzimidazolin-2-on-5-yl) -N 2 - ((3-methylsulfonyl) phenyl) -5-

methyl pyrimidine-2,4-diamine

I_SM3 (M +) t / z 439.01; ¹NMR (300 MHz, DMSO) δ 10.37 (bg, 5, 1H), 9.62 (bg, 5, 1H), 7.95-7.90 (t, 3H), 7.56 (b, &amp; lt; RTI ID = 7.6, 1H), 7.34-7.39 (t, 2H), 7.25 - 7.18 (t, 2H), 3.40 (5, 3H), 3.26 (5, 3H) , 3.09 (5, 3H), 2.21 (5, 3H).

1-37: H4- (1,3-dimethylbenzimidazolin-2-on-5-yl) -N2 - ((3-methylsulfonyl) phenyl) -5-

methyl pyrimidine-2,4-diamine

I_SM3 (M +) t / z 454.00; ¹NMR (300 MHz, DMSO)? 10.33 (5, 1H), 9.89 (5, 1H), 9.82 (5, 1H), 7.88 (5, 1H), 7.36 (5 , 1H), 7.32 (b, J = 8.1, 1H), 7.20 (bg, 5, 2H), 7.12 (bg, 5, 1H), 7.07 (bb, A = 8.1 , 8.19), 6.94 (bg, b, J = 7.8, 1H), 3.40 (5, 3H), 3.27 (5, 3H), 2.97 (5, 3H) , 2.22 (5, 3H).

1-38: H4- (1,3-dimethylbenzimidazolin-2-on-5-yl) -N2 - ((4-methylsulfonyl) phenyl) -5-

methyl pyrimidine-2,4-diamine

I_SM3 (M +) t / z 454.02; ¹NMR (300 MHz, DMSO)? 10.23 (5, 1H), 9.89 (5, 1H), 9.72 (5, 1H), 7.87 (5, 1H), 7.38-7 , 3.51 (5, 3H), 3.31 (5, 3H), 35 (t, 3H), 7.20 (5, 2H), 7.03 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.7, 2H) 2.93 (5.3H), 2.21 (5, 3H).

1-39: H4- (1,3-dimethylbenzimidazolin-2-on-5-yl) -H2 - ((3-aminosulfonyl) phenyl) -5-

fluoropyrimidine-2,4-diamine

I_SM3 (M +) t / z 443.99; ¹NMR (300 MHz, DMSO)? 9.52 (5, 1H), 9.41 (5, 1H), 8.13 (b,? = 3.6.1H), 8.10 (5, 1H) , 8.03-7.99 (t, 1H), 7.62 (bg, 5, 1H), 7.42-7.34 (t, 3H), 7.29 (bg, 5, 2H), 7.14 (Bg b, δ = 8.4, 1 H), 3.37 (5, 3 H, overlapped with H-O), 3.33 (5, 3 H).

1-40: H4- (i, 3-dimethylbenzimidazolin-2-on-5-yl) -N2 - ((4-aminosulfonyl) phenyl) -5-

fluoropyrimidine-2,4-diamine

I_SM3 (M +) t / z 443.99; ¹NMR (300 MHz, DMSO)? 9.65 (5, 1H), 9.47 (5, 1H), 8.16 (b,? = 3.6.1H), 7.83 (b, &amp; lt; RTI ID = 8.7, 2H), 7.62-7.59 (t, 3H), 7.34 (b,? = 8.7, 1H), 7.17 - 7.15 (t, 3H), 3, 38 (5, 3H, overlapping with HU), 3.32 (5, 3 H).

88

iA 106975 C2

1-41: H4- (1,3-dimethylbenzimidazolin-2-on-5-yl) -H2 - ((3-methylsulfonyl) phenyl) -5-

fluoropyrimidine-2,4-diamine

I.S.M.sub.3 (M +) m / z 442.95; ¹H NMR (300 MHz, DMSO)? 9.60 (s, 1H), 9.44 (s, 1H), 8.20 (s, 1H), 8.16 (C, α = 3.7, 1 H) , 8.09 (bg C, δ = 6.0, 1H), 7.57 (s, 1H), 7.46-7.42 (t, 2H), 7.38 (bg C, δ = 8, 3, 1H), 7.14 (C, δ = 8.3, 1H), 3.38 (s, 3H), 3.32 (s, 3H), 3.13 (s, 3H).

1-42: H4- (1,3-Dimethylbenzimidazolin-2-on-5-yl) -H2 - ((3-methylsulfonyl) phenyl) -5-

fluoropyrimidine-2,4-diamine

I_SM3 (M +) t / z 457.96; ¹H NMR (300 MHz, DMSO)? 9.59 (bs, 1H), 9.34 (s, 1H), 9.25 (s, 1H), 8.09 (C,? = 3.7, 1H ), 7.61 (s, 1H), 7.56 (C, δ = 8.4, 1H), 7.45 (s, 1H), 7.40 (C, δ = 8.4, 1H), 7.15 - 7.08 (t, 2H), 6.75 (C, Y = 8.0, 1H), 3.37 (s, 3H, partially overlapping with H₂O), 3.31 (s, 3H), 2.98 (s, 3H).

1-43: H4- (1,3-dimethylbenzimidazolin-2-on-5-yl) -N 2 - ((4-methylsulfonyl) phenyl) -5-

fluoropyrimidine-2,4-diamine

I_SM3 (M +) t / z 458.02; ¹H NMR (300 MHz, DMSO)? 9.38 (s, 1H), 9.34 (s, 1H), 9.20 (s, 1H), 8.08 (C, Å = 3.8, 1 H) , 7.63 (s, 1H), 7.60-7.58 (t, 2H), 7.31 (bg C, δ = 8.3, 1H), 7.13 (C, δ = 8.3 , 1H), 7.02 (C, ia = 8.8, 2H), 3.38 (s, 3H, partially overlapped with N₂O), 3.31 (s, 3H), 2.91 (s, 3H).

1-44: H4- (benzo [S] oxazol-2 (3H) -on-5-yl) -N2- (3-cyanophenyl) -5-fluoropyrimidine-2,4-diamine

I_SM3 (M +) t / z 362.96; ¹H NMR (300 MHz, DMSO)? 9.72 (s, 1H), 9.70 (bs, 1H), 9.51 (s, 1H), 8.27 (s, 1H), 8.19 ( C, Å = 3.8, 1H), 7.81 (C, Å = 9.4, 1H), 7.47 - 7.21 (t, 5H).

1-45: H4- (benzo [S] oxazol-2 (3H) -on-5-yl) -N2- (4-cyanophenyl) -5-fluoropyrimidine-2,4-diamine

I_SM3 (M +) t / z 362.95; ¹H NMR (300 MHz, DMSO)? 11.84 (bd, s, 1H), 9.86 (s, 1H), 9.55 (s, 1H),

8.20 (C, J = 3.7, 1H), 7.88 (C, J = 8.8, 2H), 7.65 (C, J = 8.8, 2H), 7.44-7 , 41 (t, 2H), 7.31 (C, δ = 8.4.1H).

1-46: H4- (benzo [S] oxazol-2 (3H) -on-5-yl) -H2 - ((3-morpholinyl) phenyl) -5-methylpyrimidine-2,4-

diamin

I_SM3 (M +) t / z 419.10; ¹H NMR (300 MHz, DMSO)? 11.62 (bd, s, 1H), 8.87 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 7.91 ( s, 1H), 7.38 - 7.34 (t, 2H), 7.24 (C, J = 8.2, 1H), 7.16 (C, J = 8.2, 1H), 7, 01 (Cs, δ = 8.2, 8.2, 1H), 6.47 (C, δ = 8.2, 1H), 3.65-3.62 (t, 4H), 2.91-2 , 88 (t, 4H), 2.13 (s, 3H).

1-47: H4- (benzo [S] oxazol-2 (3H) -on-5-yl) -H2 - ((3-morpholinyl) phenyl) -5-fluoropyrimidine-2,4-

diamin

I_SM3 (M +) t / z 423.07; ¹H NMR (300 MHz, DMSO)? 11.92 (bs, 1H), 9.39 (s, 1H), 9.12 (s, 1H), 8.12 (C,? = 3.7, 1H ), 7.47 - 7.45 (t, 2H), 7.29 - 7.23 (t, 2H), 7.18 (C, δ = 8.1, 1H), 7.06 (Cs, α = 8.1,

8.1, 1 H), 6.52 (C, J = 8.2, 1H), 3.68 - 3.65 (t, 4H), 2.97-2.94 (t, 4H).

1-48: H4- (benzo [S] oxazol-2 (3H) -on-6-yl) -H2 - ((3-morpholinyl) phenyl) -5-methylpyrimidin-2,4-

diamin

¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.90 (s, 1H), 7.81 (from , 1H), 7.37 (C, δ = 8.3, 1H), 7.27 (s, 1H), 7.14 (C, δ = 8.3, 1H), 7.07-7.01 (t, 2H), 6.58 - 6.50 (t, 1H), 3.68-3.65 (t, 4H), 2.95-2.92 (t, 4H), 2.14 (from , 3H); I_SM3 (M +) t / z 419.03.

1-49: H4- (3-Methylbenzo [S] oxazol-2 (3H) -on-6-yl) -H2 - ((3-morpholinyl) phenyl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.00 (bs, 1H), 8.50 (bs, 1H), 8.90 (s, 1H), 7.88 (s, 1H), 7.44 (C, δ = 8.2, 1H), 7.25-7.22 (t, 2H), 7.15 (C, δ = 8.2, 1H), 7.05 (Cs, α = 8, 2, 8.2, 1H), 6.58 - 6.51 (t, 1H), 3.67 - 3.64 (t, 4H), 3.39 (s, 3H), 2.93 - 2, 90 (t, 4H), 2.15 (s, 3H); I_SM3 (M +) t / ζ 433.11.

1-50: H2- (4- (methylsulfonyl) phenyl) -N4- (1H-benzo [C] imidazol-2 (3H) -on-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.52 (s, 1H), 10.48 (s, 1H), 9.23 (s, 1H), 8.87 (s, 1H), 8.19 (from , 1H), 7.79 (s, 1H), 7.57 (C, δ = 8.8, 2H), 7.14 (C, δ = 8.2, 1H), 7.09 (s, 1H ), 6.93 (C, J = 8.8, 2H), 6.85 (C, J =

8.2, 1 H), 2.85 (s, 3 H), 2.06 (s, 3 H).

1-51: H2- (4- (methylsulfonyl) phenyl) -N4- (1H-benzo [C] imidazol-2 (3H) -on-5-yl) -5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.52 (C,? = 9.6, 2H), 9.29 (s, 1H), 9.17 (s, 1H), 9.08 (s, 1H) , 8.00 (s, 1H), 7.57 (C, J = 7.8, 2H), 7.25 (C, δ = 8.3, 1H), 7.14 (s, 1H), 6 , 99 (C, Å = 7.8, 2H), 6.84 (C, Å = 8.3.1H), 2.86 (s, 3H).

1-52: H4- (benzo [S] oxazol-2 (3H) -on-5-yl) -N2- (4-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.57 (s, 1H), 9.29 (s, 1H), 9.03 (s, 1H), 8.43 (s, 1H), 8.10 (with , 1H), 7.84 (s, 1H), 7.55 (C, δ = 8.6, 2H), 7.30 (C, δ = 8.6, 2H), 7.20 (C, = 8.2, 1H), 6.97 (C, J = 8.2, 2H), 2.86 (s, 3H), 2.08 (s, 3H).

1-53: H4- (benzo [S] oxazol-2 (3H) -on-5-yl) -N2- (4-methylsulfonyl) phenyl) -5-fluoropyrimidine-2,4-diamine

89

iA 106975 C2

¹H NMR (300 MHz, DMSO)? 11.57 (bs, 1H), 9.34-9.30 (t, 2H), 9.18 (s, 1H), 8.05 (b, b = 3 , 5.16 (b, b = 8.6, 2H), 7.44 (b, b = 8.6, 1H), 7.35 (s, 1H), 7.20 (b , b = 8.6, 1 H), 7.02 (b, b = 8.6, 2 H), 2.87 (s, 3 H).

I-54: N2- (3- (methylsulfonyl) phenyl) -N4- (1H-benzo [b] imidazol-2 (3H) -on-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.53 (s, 1H), 10.46 (s, 1H), 9.50 (s, 1H), 8.89 (s, 1H), 8.15 (b , b =

7.6, 1H), 7.79 (s, 1H), 7.59 (b, b = 8.2, 1H), 7.35 (s, 1H), 7.21 (b, b = 10, 1H, 6.98 (bs, b = 8.2, 1 H), 6.85 (b, b = 8.2, 1 H), 6.64 (b, 1 H) b = 6.9, 1H), 2.94 (s, 3H), 2.07 (s, 3H).

I-55: N4- (benzo [b] oxazol-2 (3H) -on-5-yl) -N2- (3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diaminformioate

¹H NMR (300 MHz, DMSO)? 11.56 (s, 1H), 9.53 (s, 1H), 9.04 (s, 1H), 8.34 (s, 1H), 7.85 (from , 1H), 7.56 (b, b = 8.7, 1H), 7.40 (b, b = 6.2, 1H), 7.39 (s, 1H), 7.34 (s, 1H ), 7.20 (b, b = 8.6, 1 H), 7.05 (b, b = 8.1, 1 H), 6.67 (b, b = 8.3, lH), 2.95 (s, 3H), 2.08 (b, b = 8.8, 4H).

I-56: N4- (benzo [b] oxazol-2 (3H) -on-5-yl) -N2- (3-methylsulfonyl) phenyl) -5-fluoropyrimidine-2,4-

diamin

¹H NMR (300 MHz, DMSO)? 11.63 (bs, 1H), 9.57 (s, 1H), 9.33 (s, 1H), 9.25 (s, 1H), 8.06 ( b, b =

3.6, 1H), 7.55-7.50 (t, 2H), 7.42-7.40 (t, 2H), 7.21 (b, b = 8.6, 1H), 7, 11 (bb, b = 8.1, 8.1, 1H), 6.71 (b, b = 8.2, 1H), 2.95 (s, 3H).

I-57: N2 - ((3-aminosulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.64 (s, 1H), 9.58 (s, 1H), 8.13 (b, b = 3.8, 1H), 8.07 (s, 1H) , 8.01 (s, 1H), 7.92 (b, b = 7.3, 1H), 7.50 (b, b = 10.4, 1H), 7.41-7.36 (t, b = 7.5, 2H), 7.26 (s, 2H), 7.19 (b, b = 8.5, 1H), 3.33 (s, 3H).

I-58: N2- (4-aminosulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.63 (s, 1H), 9.51 (s, 1H), 8.14 (b, b = 3.6, 1H), 7.97 (s, 1H) , 7.92 (b, b = 8.8, 2H), 7.62 (b, b = 8.8, 2H), 7.49 (b, b = 8.4, 1H), 7.20 ( b, b = 8.4, 1H), 7.11 (s, 2H), 3.35 (s, 3H).

I-59: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.66 (s, 1H), 9.53 (s, 1H), 8.19 (s, 1H), 8.15 (b, b = 3.7, 1H) , 8.02 (b, b = 8.8, 1H), 7.99 (s, 1H), 7.54-7.36 (t, 3H), 7.19 (b, b = 8.5, 1H), 3.34 (s, 3H), 3.12 (s, 3H).

I-60: N2- (4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.79 (s, 1H), 9.56 (s, 1H), 8.16 (b, b = 3.7, 1H), 7.97 (s, 1H) , 7.88 (b, b = 8.9, 2H), 7.70 (b, b = 8.8, 2H), 7.45 (s, 1H), 7.22 (b, b = 8, 5, 1H), 3.34 (s, 3H), 3.12 (s, 3H).

I-61: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.61 (s, 1H), 9.58 (s, 1H), 9.43 (s, 1H), 8.09 (b, b = 3.9, 1H) , 7.99 (s, 1H), 7.50 (bs, b = 9.9, 2H), 7.40 (s, 1H), 7.16 (bb, b = 8.2, 15.3, 2H), 6.76 (b, b = 5.6, 1H), 3.33 (s, 3H), 2.96 (s, 3H).

I-62: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.70 (s, 1H), 9.44 (s, 2H), 8.10 (b, b = 4.0, 1H), 7.93 (s, 1H) , 7.51 (b, b = 8.8, 2H), 7.45 (b, b = 8.5, 1H), 7.18 (b, b = 8.5, 1H), 7.07 ( b, b = 8.8, 2H), 3.33 (s, 3H), 2.91 (s, 3H).

I-63: N2 - ((3-aminosulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.29 (s, 1H), 9.51 (s, 1H), 7.90 (s, 1H), 7.79 (b, b = 8.1, 1H) , 7.74 (s, 1H), 7.63 (s, 1H), 7.46 (b, b = 7.9, 1H), 7.39 - 7.28 (t, 4H), 7.22 (b, b = 8.4, 1 H), 3.35 (s, 3 H), 2.15 (s, 3 H).

I-64: N2 - ((4-aminosulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.22 (s, 1H), 9.45 (s, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.60 (s , 4H), 7.37 (bb, b = 1.9, 8.4, 1H), 7.26 (b, b = 8.4, 1H), 7.20 (s, 2H), 3.37 (s, 3H), 2.15 (s, 3H).

I-65: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.09 (s, 1H), 9.34 (s, 1H), 7.94-7.87 (t, b = 10.1.3H), 7.66 ( 7.51 (b, b = 7.8, 1H), 7.43 (b, J = 7.8, 1 H), 7.34 (b, b = 10.1, 1 H), 7.22 (b, b = 8.4, 1H), 3.35 (s, 3H), 3.09 (s, 3H), 2.15 (s, 3H).

90

iA 106975 C2

and-66: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.24 (s, 1H), 9.35 (s, 1H), 7.95 (s, 1H), 7.82- 7.61 (t, 5H), 7 , 35 (C, b = 8.3, 1H), 7.27 (C, b = 8.3, 1H), 3.36 (s, 3H), 3.13 (s, 3H), 2.16 (δ, 3H).

(3-aminosulfonyl) phenyl) -M- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.13 (δ, 1 H), 9.42 (δ, 1 H), 7.92 (δ, 1 H), 7.77 (C, δ = 9.3, 2 H) , 7.43 (C, b = 6.6, 2H), 7.35 - 7.23 (t, 5H), 3.21 (s, 3H), 2.16 (s, 3H).

i-68: N - ((4-aminosulfonyl) phenyl) -M- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.06 (δ, 1 H), 9.33 (δ, 1 H), 7.94 (δ, 1 H), 7.65 (C, δ = 8.9, 2 H) , 7.57 (C, b = 8.9, 2H), 7.48 (s, 1H), 7.36 (C, b = 8.6, 1H), 7.29 (C, b = 8, 6, 1H), 7.20 (s, 2 H), 3.26 (s, 3 H),

2.16 (s, 3H).

and-69: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.23 (s, 1H), 9.44 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.84 (C , b = 8.2, 1 H), 7.51 (C, b = 7.7, 1 H), 7.44-7.39 (t, 2 H), 7.32 (C, b = 8.6, 1H), 7.23 (C, b = 8.6, 1H), 3.20 (s, 3H), 3.06 (s, 3H), 2.16 (s, 3H).

and -70: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.16 (s, 1H), 9.30 (s, 1H), 7.96 (s, 1H), 7.74 (C, b = 8.9, 2H) , 7.65 (C, b = 8.9, 2H), 7.48 (s, 1H), 7.38 (C, b = 8.6, 1H), 7.28 (C, b = 8, 6, 1 H), 3.25 (s, 3 H), 3.12 (s, 3 H),

2.16 (s, 3H).

and-71: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.10 (δ, 1H), 9.73 (s, 1H), 9.57 (s, 1H), 7.87 (s, 1H), 7.46 (δ , 1H), 7.34-7.25 (t, 3H), 7.16 (s, 1H), 7.10 (b, 8.0 = 1.0, 1H), 6.86 (C, b = 9 , 0, 1 H), 3.22 (s, 3 H), 2.93 (s, 3 H),

2.16 (s, 3H).

and-72: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO) δ 10.06 (δ, 1 H), 9.63 (δ, 2 H), 7.85 (δ, 1 H), 7.46 (δ, 1 H), 7.39 - 7. , 30.23 (s, 3H), 7.21 (C, b = 8.6, 1 H), 7.02 (C, B = 8.6, 2 H), 3.26 (s, 3 H), 2.90 (δ, 3H), 2.15 (s, 3H).

and-73: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.05 (s, 1H), 9.74 (s, 1H), 9.56 (s, 1H), 7.83 (s, 1H), 7.65 (δ 1H), 7.36 (C, b = 8.0, 1H), 7.29 (C, b = 8.2, 1 H), 7.23 (C, b = 8.2, 1 H), 7 , 14 (Cs, b = 8.0, 2H), 6.89 (C, b =

8.2, 1 H), 3.35 (s, 3 H), 2.95 (s, 3 H), 2.15 (s, 3 H).

and-74: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.97 (s, 1H), 9.64 (s, 1H), 9.57 (s, 1H), 7.82 (s, 1H), 7.65 (δ 1H), 7.33 (C, B = 8.5, 3H), 7.22 (C, B = 8.5, 1H), 7.05 (C, B = 8.5, 2H), 3 , 36 (δ, 3H), 2.92 (δ, 3H), 2.14 (δ, 3H).

(3-aminosulfonyl) phenyl) -M- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.60 (C, b = 4.2, 2 H), 8.14 (C, b = 4.2, 1 H), 8.05 (d, 1 H), 7, 89 (C, b = 7.0, 1H), 7.68 (s, 1H), 7.42-7.24 (t, 6H), 3.27 (s, 3H).

and-76: ^ - ((4-aminosulfonyl) phenyl) -M- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

fluoropyrimidine-2,4-diamine

H NMR (300 MHz, DMSO)? 9.65 (s, 1H), 9.55 (s, 1H), 8.16 (C, b = 3.6, 1 H), 7.77 (C, b = 8.7, 2H), 7.67 (s, 1H), 7.60 (C, b = 8.7, 2H), 7.38 (C, b = 8.7, 1H), 7.30 ( C, b = 8.7, 1 H), 7.13 (s, 2 H), 3.28 (s, 3 H).

i-77: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.64 (s, 1H), 9.56 (s, 1H), 8.16 (s, 2 H), 7.99 (C, b = 8.9, 1 H) , 7.65 (s, 1H), 7.51 - 7.33 (t, 3H), 7.28 (C, B = 8.8, 1H), 3.27 (s, 3H), 3, 09 (δ, 3H).

and -78: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

fluoropyrimidine-2,4-diamine

NMR (300 MHz, DMSO)? 9.80 (s, 1H), 9.59 (d, 1H), 8.18 (C, b = 3.6, 1 H), 7.86 (C, b = 8.8, 2H), 7.70 (s, 1 H), 7.66 (C, b = 6.3, 2 H), 7.39-7.30 (t, 2 H), 3.28 (δ , 3 H), 3.11 (s, 3 H).

and-79: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [S] oxazol-5-yl) -5-

91

iA 106975 C2

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.70 (5, 1H), 9.62 (5, 1H), 9.48 (5, 1H), 8.12 (b, b = 4.0, 1H) , 7.68 (5.1H), 7.45-7.37 (t, 3H), 7.27 (b, b = 8.6, 1H), 7.13 (t, b = 8.0, 1H), 6.77 (b, b = 8.0, 1H), 3.26 (5, 3H), 2.94 (5, 3H).

I-80: CH2 - ((4-methylsulfonyl) phenyl) -CH4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-5-yl) -5-

fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.72 (5, 1H), 9.43 (5, 2H), 8.12 (5, 1H), 7.65 (5, 1H), 7.52 (b , b = 8.7, 2H), 7.33 (b, b = 8.7, 1H), 7.27 (b, b = 8.7, 1H), 7.04 (b, b = 8, 7,2H), 3.26 (5, 3H), 2.88 (5, 3H).

I-81: CH2 - ((3-methylsulfonylamino-4-methyl) phenyl) -CH4- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-

yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.49 (5, 1H), 8.96 (5, 1H), 8.91 (5, 1H), 8.31 (5, 1H), 7.84 (5 , 2H), 7.60 (b, b = 8.3, 1H), 7.47 (5, 1H), 7.37 (b, b = 8.6, 1H), 7.00 (bb, b = 8.3, 12.6, 2H), 2.95 (5, 3H), 2.19 (5, 3H), 2.09 (5, 3H).

I-82: CH2 - ((3-methylsulfonylamino-4-methyl) phenyl) -CH4- (3-methyl-2-oxo-2,3-

dihydrobenzo [b] oxazol-5-yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.93 (5, 1H), 9.50 (5, 1H), 9.07 (5, 1H), 7.83 (5, 1H), 7.45 (5 1H), 7.37-7.20 (t, 4H), 7.04 (b, b = 8.3, 1H), 3.19 (5, 3H), 2.87 (5, 3H), 2.23 (5, 3H), 2.15 (5, 3H).

I-83: ​​CH2 - ((3-methylsulfonylamino-4-methyl) phenyl) -CH4- (3-methyl-2-oxo-2,3-

dihydrobenzo [b] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.99 (5, 1H), 9.53 (5, 1H), 9.04 (5, 1H), 7.81 (5, 1H), 7.63 (5 , 1H), 7.37-7.29 (t, 2H), 7.23 (b, b = 7.6, 2H), 7.08 (b, b = 8.3, 1H), 3.35 (5, 3H), 2.90 (5, 3H), 2.25 (5, 3H), 2.14 (5, 3H).

I-84: CH2 - ((3-methylsulfonylamino-4-methyl) phenyl) -CH4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-

yl) -5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.61 (5, 1H), 9.60 (5, 1H), 9.37 (5, 1H), 8.97 (5, 1H), 8.10 (b , b = 4.0, 1H), 7.50 (bb, b = 6.1, 14.8, 2H), 7.42 (5, 1H), 7.34 (5, 1H), 7.24 (b, b = 8.6, 1 H), 7.05 (b, b = 8.5, 1 H), 2.93 (5, 3 H), 2.21 (5, 3 H).

I-85: CH2 - ((3-methylsulfonylamino-4-methyl) phenyl) -CH4- (3-methyl-2-oxo-2,3-

dihydrobenzo [b] oxazol-5-yl) -5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.69 (5, 1H), 9.40 (5, 1H), 8.99 (5, 1H), 8.11 (b, b = 4.0, 1H) , 7.66 (5.1H), 7.54-7.33 (t, 3H), 7.29 (b, b = 8.6, 1H), 7.06 (b, b = 8.6, 1H), 3.23 (5, 3H), 2.90 (5, 3H), 2.22 (5.3H).

I-86: CH2 - ((3-methylsulfonylamino-4-methyl) phenyl) -CH4- (3-methyl-2-oxo-2,3-

dihydrobenzo [b] oxazol-6-yl) -5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.67 (5, 1H), 9.42 (5, 1H), 8.97 (5, 1H), 8.09 (b, b = 4.1, 1H) , 7.94 (5.1H), 7.51 (b, b = 8.4, 2H), 7.44 (5, 1H), 7.20 (b, b = 8.4, 1H), 7 , 08 (b, b = 8.4, 1 H), 3.34 (5, 3 H), 2.94 (5, 3 H), 2.23 (5, 3 H).

I-87: Ch2 - ((4-fluoro-3-methylsulfonyl) phenyl) -CH4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.68 (5, 1H), 10.00 (5, 1H), 9.65 (5, 1H), 9.50 (5, 1H), 7.83 (5 , 1H), 7.52 - 7.04 (t, 6H), 2.98 (5, 3H), 2.14 (5, 3H).

I-88: CH2 - ((4-fluoro-3-methylsulfonyl) phenyl) -CH4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-

5-yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.93 (5, 1H), 9.62 (5, 1H), 9.45 (5, 1H), 7.85 (5, 1H), 7.43-7 , 21 (t, 5H), 7.12 (bb, b = 9.3, 1H), 3.23 (5, 3H), 2.95 (5, 3H), 2.15 (5, 3H).

I-89: CH2 - ((4-fluoro-3-methylsulfonyl) phenyl) -CH4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-

6-yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.95 (5, 1H), 9.61 (5, 1H), 9.45 (5, 1H), 7.83 (5, 1H), 7.61 (5 , 1H), 7.45-7.31 (t, 3H), 7.23 (b, b = 8.4, 1H), 7.13 (bb, b = 9.6, 1H), 3.35 (5, 3H), 2.97 (5, 3H), 2.14 (5.3H).

I-90: CH2 - ((4-fluoro-3-methylsulfonyl) phenyl) -CH4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-yl) -5-

fluoropyrimidine-2,4-diamine

H NMR (300 MHz, DMSO)? 11.58 (5, 1H), 9.50 (5, 2H), 9.36 (5, 1H), 8.09 (b, b = 3.9, 1H) , 7.63-7.52 (t, 2H), 7.47 (b, b = 8.8, 1H), 7.35 (5, 1H), 7.23 (b, b = 8.8, 1H), 7.10 (bb, b = 8.8, 1H), 2.98 (5.3H).

I-91: CH2 - ((4-fluoro-3-methylsulfonyl) phenyl) -CH4- (3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-5-yl) -5-fluoropyrimidin-2 , 4-diamine

¹H NMR (300 MHz, DMSO)? 9.61 (5, 1H), 9.51 (5, 1H), 9.40 (5, 1H), 8.11 (b, b = 3.9, 1H) , 7.63 (5.1H), 7.58-7.47 (t, 2H), 7.39 (b, b = 8.6, 1H), 7.28 (b, b = 8.6, 1H), 7.12 (bb, b = 9.3, 1 H), 3.26 (5.3 H), 2.96 (5, 3 H).

92

iA 106975 C2

(3-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-fluoro-pyrimidine-2 &amp; lt; / RTI &amp; gt; , 4-diamine

¹H NMR (300 MHz, DMSO)? 9.64 (s, 1H), 9.51 (s, 1H), 9.46 (s, 1H), 8.10 (b,? = 3.9, 1 H) , 7.90 (s, 1H), 7.58-7.46 (t, 3H), 7.21-7.09 (t, 2H), 3.34 (s, 3H), 2.99 (s , 3 H).

I-93: ^ - ((4-methylsulfonylamethylamino) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-

yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.70 (s, 1 H), 9.99 (s, 1 H), 9.49 (s, 1 H), 7.86 (s, 1 H), 7.43 (b , à =

8.6, 2H), 7.32 - 7.14 (t, 5H), 3.17 (s, 3H), 2.88 (s, 3H), 2.14 (s, 3H).

I-94: ^ - ((4-methylsulfonylamethylamino) phenyl) -M- (3-methyl-2-oxo-2,3-

dihydrobenzo [b] oxazol-5-yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.12 (s, 1H), 9.59 (s, 1H), 7.90 (s, 1H), 7.46-7.43 (t, 3H), 7 , 36.85 (s, 3H), 3.16 (s, 3H), 2.88 (s, J = 8.6, 1H), 7.28-7.19 (t, 3H), 3.25 (s, 3H), 3.16 , 3H), 2.15 (s, 3H).

I-95: ^ - ((4-methylsulfonylamethylamino) phenyl) -M- (3-methyl-2-oxo-2,3-

dihydrobenzo [b] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 10.10 (s, 1H), 9.56 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 7.43 (b , à =

8.6, 2H), 7.34 (b, J = 8.1, 1H), 7.26-7.23 (t, 3H), 3.34 (s, 3H), 3.18 (s, 3H), 2.89 (s, 3H), 2.15 (s, 3H).

I-96: ^ - ((4-methylsulfonylamethylamino) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-

yl) -5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.61 (s, 1H), 9.59 (s, 1H), 9.47 (s, 1H), 8.11 (b,? = 3.9, 1H) , 7.60 (b, J = 8.6, 2 H), 7.43 (b, J = 8.6, 1 H), 7.34 (s, 1 H), 7.28 - 7.17 (t, 3H), 3.17 (s, 3H), 2.89 (s, 3H).

I-97: ^ - ((4-methylsulfonylamethylamino) phenyl) -M- (3-methyl-2-oxo-2,3-

dihydrobenzo [b] oxazol-6-yl) -5-fluoropyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 9.65 (s, 1H), 9.49 (s, 1H), 8.11 (b,? = 3.9, 1H), 7.95 (s, 1H) , 7.60 (b, δ = 8.8, 2H), 7.46 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.8, 1H), 7.25-7.18 (t, 3H), 3.33 (s, 3H), 3.18 (s, 3H), 2.90 (s, 3H).

I-98: ^ - ((3-aminosulfonyl) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.51 (s, 1H), 9.39 (s, 1H), 8.45 (s, 1H), 8.04 (from 1 H), 7.95 (s, 1H), 7.88-7.85 (t, 2H), 7.38-7.23 (t, 5H), 7.02 (b, 8 = 8.3, 1 H), 2.11 (from , 3 H).

I-99: ^ - ((4-aminosulfonyl) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.56 (s, 1H), 9.41 (s, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.83 - 7 (T, 3H), 7.55 (b, J = 8.7, 2H), 7.35 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.4, 1H), 7.14-7.00 (t, 3H) , 2.11 (s, 3H).

I-100:? - ((3-methylsulfonyl) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine;

I-101: ^ - ((4-methylsulfonyl) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine;

I-102: ^ - ((3-methylsulfonyl) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine;

I-103: ^ - ((4-methylsulfonyl) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-

methyl pyrimidine-2,4-diamine;

I-104: No. - ((3-methylsulfonylamino-4-methyl) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine ;

I-105: ^ - ((4-fluoro-3-methylsulfonyl) phenyl) -M- (2-oxo-2,3-dihydrobenzo [b] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine

¹H NMR (300 MHz, DMSO)? 11.50 (s, 1H), 9.47 (s, 1H), 9.08 (s, 1H), 8.35 (s, 1H), 7.85-8 , 83 (t, 2H), 7.68-7.64 (t, 1H), 7.58 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.5, 1H), 7.36 (b, &amp; lt; , 7.10-6.93 (t, 2H), 2.99 (s, 3H), 2.09 (s, 3H).

I-106: N- (benzoxazolin-2-on-5-yl) -2- (3-trifluoromethoxyphenyl) -5-methylpyrimidine-2,4-

diamine trifluoroacetate;

I-107: No.- (benzooxazolin-2-one-5-yl) -2- (3-trifluoromethoxyphenyl) -5-fluoropyrimidine-2,4-

diamine trifluoroacetate;

I-108: N- (benzoxazolin-2-one-5-yl) -2- (4-trifluoromethoxyphenyl) -5-methylpyrimidine-2,4-

diamine trifluoroacetate;

I-109: N4- (benzoxazolin-2-on-5-yl) -N2- (4-trifluoromethoxyphenyl) -5-fluoropyrimidine-2,4-

diamine trifluoroacetate;

2- (3-trifluoromethyl-4- (4-ethylpiperazin-1-yl) phenyl] -5-trifluoromethyl-1- (benzoxazolinin-2-on-5-yl)

methyl pyrimidine-2,4-diamine

BSM5 (t / z): 514 (M + H); ¹H NMR (DMSO ba, 300 MHz): δ 11.51 (s, 1H), 9.22 (s, 1H), 8.38 (s, 1H), 7.94 (s, 1H), 7.87 (t, 2H), 7.33-7.18 (t, 4H), 2.80 (s, 4H), 2.49 (bps, 6H), 2.09 (s, 3H), 1.04 (and, 3H, δ = 6.3 Hz).

93

iA 106975 C2

and-111: Ch4- (benzooxazolin-2-one 5-yl) -CH2- [5-methyl-4- (4-methylpiperazin-1-yl) phenyl] -5-

methyl pyrimidine-2,4-diamine

I_SM3 (t / z): 458 (M + H); ¹H NMR (DMSO 06.33 MHz):? 8.67 (s, 1H), 8.27 (s, 1H), 7.80 (s, 1H), 7, z1 (t, 4H), 7.19 (b, 1H, δ = 9, from 4Z), 6.69 (b, 1H, δ = 8.7, 4Z), s, 94 (s, 1H), s, 80 (s, 1H), s, z0 (b, 1H, &amp; lt; / RTI &amp; gt; = 10.2Hz), 3.21 (b, 1H, δ = 8.7Hz), 3.15 (s, 1H), 2.92b, 1H, δ = 10.5 Hz), 2.57 (s, 3H), 2.07 (s, 3H), 2.04 (b, 1H, &amp; lt; = 9.6Hz), 1.99 (b, 1H, &amp; lt; RTI ID = 10.8 &amp; gt; Hz), 2.00 (s, 3H), 1.88 (b, 1H, &amp; lt; / RTI &amp; gt; = 10.8 Hz).

N12: Ch4- (benzoxazolinin-2-on-5-yl) -CH2- [4-Ch- (1-butyl) aminosulfonylphenyl] -5-

methyl pyrimidine-2,4-diamine

I_SM3 (t / z): 469 (M + H); ¹H NMR (DMSO b₆, 300 MHz):? 11.80 (s, 1H), 10.59 (s, 1H), 9.81 (s, 1H), 7.94 (s, 1H), 7.60 (b, 2H, δ = 9.0Hz), 7.53 (b, 2H, δ = 8.7Hz), 7.40 (s, 1H), 7.32 (b, 1H, &amp; lt; = 9.0Hz), 7, 19 (t, 2H), 2.16 (s, 3H), 1.03 (s, 9H).

N1 of: Ch4- (benzoxazolinin-2-one-5-yl) -CH2- [4-methyl-sec-Ch- (1-butyl) aminosulfonylphenyl] -5-

methyl pyrimidine-2,4-diamine

I_SM3 (t / z): 48z (M + H); ¹H NMR (DMSO b₆, 300 MHz): δ 11.66 (s, 1H), 9.90 (s, 1H), 9.20 (s, 1H), 7.86 (s, 2H), 7.75 (b, 1H, δ = 6.9Hz), 7.42 (s, 1H), 7.26 (t, 3H), 7.13 (b, 1H, &amp; lt; / RTI &amp; gt; = 8.7Hz), 2.48 (s, 3H) , 2,1? (S, 1H), 1.07 (s, 9H).

N14: Ch4- (benzoxazolinin-2-one 5-yl) -CH2- [s-Ch- (i-propyl) aminosulfonylphenyl] -5-

methyl pyrimidine-2,4-diamine

I_SM3 (t / z): 455 (M + H); ¹H NMR (DMSO ba, 300 MHz): δ 11.72 (s, 1H), 10.42 (s, 1H), 9.68 (s, 1H), 7.91 (s, 1H), 8.10 (b, 1H, &amp; lt; / RTI &amp; gt; 7.8Hz), 7.68 (s, 1H), 7.58 (b, 1H, α = 7.2Hz), 7.44 (b, 1H, (T, 2H), 2.16 (s, 1H), 0.91 ( b, 6H, α = 6.3 Hz).

N15: Ch4- (benzooxazolin-2-one-5-yl) -CH2- (s, 4,5-trimethoxyphenyl) -5-fluoropyrimidine-2,4-diamine

I_SM3 (t / z): 428 (M + H); ¹H NMR (DMSO b₆, 300 MHz): δ 11.61 (s, 1H), 9.70 (s, 1H), 9.38 (s, 1H), 8.11 (b, 1H, &amp; lt; = 4.2 Hz), 7 , 44 (bb, 1H,? = 1.8 and 8.7 Hz), 7.34 (b, 1H,? = 1.8 Hz), 7.19 (b, 1H,? = 8.4Hz), ??? 6.93 (s, 2H), 3.58 (s, 3H), 3.57 (s, 6H).

N16: CH2- (S) - (difluoromethoxy) -4-methoxyphenyl) -CH4- (benzo [b] oxazol-2 (nH) -on-5-yl) -5-

methyl pyrimidine-2,4-diamine

I_SM3: purity: 96.68%; MS (t / e): 4? 0.24 (M + H);¹H NMR (300 MHz, DMSO)? 11.33 (b, 1H), 8.92 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.55 (s , 1H), 7.46 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.7, 1 H), 7, o0 (b, α = 8.7, 1H), 7.29 (s, 1H), 7.18 = 9.0, 1 H), 6.92 (b, δ = 8.7, 1 H), 6.81 (1, δ = 75, 1 H), c, 7 (c, n H), 2.08 (from , nH); ^19thRNMR (282 MHz, DMSO) δ = 96.44 (b, &amp; lt; RTI ID = 0.0 &amp; gt; = 7z).

(N, N-iso-5-yl) -CH2- (4-trifluoromethylsulfonyl) phenyl-5-

methyl pyrimidine-2,4-diamine

I_SM3: purity: 91.03%; MS (t / e): 466.14 (M + H);¹H NMR (300 MHz, DMSO)? 11.62 (s, 1H), 10.02 (s, 1H), 8.59 (s, 1H), 8.00 (b,? = 9.0, 2H) , 7.98 (b, J = 4.2, 1 H), 7.78 (b, J = 8.7, 2H), 7.28 (s, n H), 2,1 (c, n H); ^19thR NMR (282 MHz, DMSO)? -94.87.

(2H) -one-5-yl) -CH2- (trifluoromethylsulfonyl) phenyl-5-

methyl pyrimidine-2,4-diamine

I_SM3: cleanliness: 100%; MS (t / e): 466.14 (M + H);¹H NMR (300 MHz, DMSO)? 11.56 (s, 1H), 9.64 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8, z0 , δ = 7.2, 1H), 7.94 (s, 1H), 7.56 (I, δ = 7.8, 1H), 7.51 (I, α =

7.2, 1H), 7, 10 (t, 2H), 7.22 (b,? = 9.0, 1H), 2.11 (s, nH); ^19thR NMR (282 MHz, DMSO) δ - 94, s9.

N19: Ch4- (benzo [b] oxazol-2 (nH) -on-5-yl) -CH2- (s, 4,5-trimethoxy) phenyl-5-methylpyrimidine-2,4-diamine

I_SM3: purity: 99.98%; MS (t / e): 424.28 (M + H);¹H NMR (300 MHz, DMSO)? 11.56 (s, 1H), 9.07 (bg, 1H), 8.59 (bd, 1H), 7.84 (s, 1H), 7, z1 (b , δ = 9.1.2H), 7.18 (b, δ = 8.4, 1H), 6.95 (s, 2H), s, 56 (s, 1H), s, 52 (s, 6H ), 2.09 (s, nH).

(N- (4- (1,4-diaza-bicyclo [3.2.2] nonan-4-yl) -is-4- (benzo [b] oxazol-2 (nH) -one 5-yl)

methyl) phenyl) -5-methylpyrimidine-2,4-diamine

M3 (E3) 472.1z (M + H); ¹H NMR (300 MHz, ES), 8.37 (t, 2H), 7.78-6.95 (t, 7H), c, 59.6, 42 (t, 9H), 2.42-2.21 (t, 4H), 2,1z (s, nH), 2,11 (s, nH).

I21: 4- (8-methyl-8-azabicyclo [3.2.1] octan-5-yl)

ylamino) phenyl) -5-methylpyrimidine-2,4-diamine

M3 (E3) 472.12 (M + H); ¹H NMR (ES 300 MHz) 8.40 (t, 2H), 7.63-6.40 (t, 9H), c, 95-s, 5z (t, 4H), 2.81 (s, nH ), 2.66-2.15 (t, 7H), 2,1z (s, nH).

(2H) -benzoxazol-2 (nH) -one-5-yl) -CH2 - ((4- (dihydro-1H-pyrido [1,2-a] pyrazine-

2 (6H, 7H, 8H, 9H, 9aH) -yl) -is-methyl) phenyl) -5-methylpyrimidine-2,4-diamine;

M3 (E3) 486.17 (M + H); ¹H NMR (DMSO, 300 MHz) 8.35 (t, 2H), 7.71 (t, 1H), 7.298-6.85 (t, 6H), s, 48 ​​(t, nH), c, 25- 2.78 (t, 6H), 2.16 (s, 1H), 2.09 (s, 1H), 2.0az-1.51 (t, 6H).

2-nitrobenzo [b] oxazol-2 (nH) -one 5-yl) -CH2- (4- (8-methyl-2,8-diaza-bicyclo [3.2.1] octan-2-

yl) phenyl) -5-methylpyrimidine-2,4-diamine

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iA 106975 C2

MH (ES) 458.10 (M + H); ¹H NMR (CU₃O, 300 MHz) 8.41 (bs, 2H), 7.68 (s, 1H), 7.40-6.74 (t, 8H), 4.02 (bs, 2H), 3.59 (t , 2H), 3.17 (t, 2H), 2.87 (s, 3H), 2.29-2.15 (t, 4H), 2.13 (s, 3H).

5-yl) -5-methyl-CH2- [3- (morpholin-4-yl) -4-oxazolidin-2 (3H)

trifluoromethoxyphenyl] -2,4-pyrimidindamine

NMR (DMSO ba, 300 MHz): δ 11.53 (s, 1H), 9.10 (s, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 7.32-7.18 (t, 3H), 7.00 (b, 1H, &amp; lt; RTI ID = 0.0 &amp; gt; 8.7 Hz), 4.09 (q, 1H, &amp; lt; , 3.58 (s, 3H), 3.15 (b, 2H, α = 5.1 Hz), 2.69 (s, 3H), 2.08 (s, 3H); I_SM8 (t / z): 503 (M + H).

and-125: 4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-ylamino] -

methyl ester of benzoic acid

¹H NMR (DMSO, 300 MHz): δ 9.30 (s, 1H), 8.41 (s, 1H), 8.22 - 8.31 (t, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.67-7.78 (t, 2H), 7.54-7.65 (t, 1H), 7.30-7.40 (t, 2H), 7, 25 (b, &amp; amp; 8.3 Hz, 1H), 3.29-3.40 (t, 3H) 2.09 (s, 3H) ppm; M8 (E8) 392 (M + H).

and-126: 4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-ylamino] -

benzoic acid

¹H NMR (DMSO, 300 MHz):? 9.26 (s, 1H), 8.53 (b, &amp; lt; = 4.4 Hz, 1H), 8.41 (bs, 1H), 8.34 (b, δ = 8.3Hz, 2H), 8.14 (s, 1H), 7.90 (s, 1H), 7.68 (t, 2H), 7.44-7.52 (t, 1H), 7.27 - 7.38 (t, 1H), 2.04-2.15 (t, 3H) ppm; M8 (E8) 378 (M + H).

and-127: Ch- (2-diethylaminoethyl) -4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -

pyrimidine-2-ylamino] -benzamide

MZ (EZ) 476 (M + H)

and-128: 5- {2- [4- (3-diethylamino-pyrrolidine-1-carbonyl) -phenylamino] -5-methyl-pyrimidin-4-

ylamino} -3H-benzooxazol-2-one

MZ (EZ) 502 (M + H)

and-129: 5- [2- (4-Acetyl-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO-b₆) δ: 9.31 (s, 1H), 8.38 (s, 1H), 8.20-8.33 (t, 1H), 8.18 (s, 1H), 7.88 (s, 1H ), 7.66-7.79 (t, 2H), 7.52-7.69 (t, 1H), 7.32-7.42 (t, 2H), 7.25 (b, 8 = 8 , 2 Hz, 1H), 2.23 (s, 3H) 2.09 (s, 3H) ppm; M8 (E8) 376 (M + H);

and-130: 5- [2- (3-Acetylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.69 (s, 1H), 10.37 (0.09 sec, 1H), 9.60 (0.09 sec, 1H), 7.90 (b, = 7.4 Hz, 2H), 7.71 (b, J = 8.0 Hz, 1H), 7.62 (b, J = 7.7 Hz, 1H), 7.29 - 7.43 (t, 1H), 7.14-7.27 (t, 4H), 2.39 (s, 3H), 2.14 (s, 3H) ppm; M8 (EZ) 376 (M + H).

and-131: 2-methyl-5- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) -pyrimidin-2-ylamino] -benzonitrile

¹H NMR (DMSO, 300 MHz): δ 11.66 (s, 1H), 10.50 (0.09 sec, 1H), 9.66 (0.09 sec, 1H), 7.93 (b, = 3.6 Hz, 2H), 7.45 (bb, &amp; lt; = 8.5, 1.7 Hz, 1H), 7.30 (b, &amp; lt; / RTI &amp; gt; 8.3 Hz, 2H), 7.07-7, 22 (t, 2H), 2.35 (s, 3H), 2.13 (s, 3H) ppm; M8 (E8) 373 (M + H).

and-132: Ch, D-dimethyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide

MH (ES) 405 (M + H)

and-133: Ch-methyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide

¹H NMR (DMSO, 300 MHz): δ 11.92 (s, 1H), 10.90 (s, 1H), 10.03 (s, 1H), 8.52 - 8.28 (t, 1H), 7.95 (s, 1H) 7.67 (b, &amp; amp; 8.6, 2H) 7.45 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.6, 2H) 7.34 (s, 1H) 25 (s, 2H), 2.72 (s, 3H), 2.15 (s, 3H); md M8 (E8) 391 (M + H).

yl-4-

ilamino] -benzamide formate

and-135: 4- [5-methyl-4- (2-oxo-2,3-dihydrobenzooxazol-5-ylamino) -pyrimidin-2-ylamino] -CH-

phenylbenzamide

¹H NMR (DMSO, 300 MHz): δ 11.79 (s, 1H), 10.49 - 10.22 (t, 1H), 10.05 (s, 1H), 9.71 - 9.38 (t , 1H), 7.95 (s, 1H), 7.79 (b,? = 8.7, 1H), 7.73 (b,? = 7.6, 1H), 7.62 (b,? = 8.7, 1H), 7.39 - 7.22 (t, 5H), 7.12 - 7.02 (t, 1H), 2.15 (s, 3H) ppm; M8 (EZ) 453 (M + H).

and-136: 4- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) -pyrimidin-2-ylamino] -2-

pyrrolidine-1-yl-benzamide

¹H NMR (DMSO, 300 MHz): δ 11.73 (s, 1H), 10.29 (s, 1H), 9.62 (s, 1H), 7.97 (s, 1H), 7.73 ( s, 1H), 7.49 - 7.11 (t, 2H), 7.00 - 6.52 (t, 2H), 3.13-2.80 (t, 4H), 2.32 - 1, 97 (t, 3H), 1.85-1.54 (t, 4H) mdd; M8 (E8) 446 (M + H).

and-137: Ch-Ethyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzoxazol-5-ylamino) -pyrimidin-2-ylamino] -benzamide

¹H NMR (DMSO, 300 MHz): δ 11.64 (s, 1H), 9.32 (s, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 7.89 ( b, a =

9.8, 1 H), 7.70 (br, J = 8.8, 2H), 7.61 (b, J = 8.8, 2H), 7.45 - 7.15 (t, 3H), 3.30 - 3.18 (t, 2H), 2.10 (s,

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iA 106975 C2

3H), 1.08 (br d, b = 7.2, 2H) ppm; MH (ES) 405 (M + H).

I-138: N-cyclobutyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide formate

M3 (E3) 431 (M + H)

I-139: N-isopropyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide

¹H NMR (DMSO, 300 MHz): δ 11.64 (s, 1H), 9.31 (s, 1H), 8.47 (5, 1H), 7.91 (s, 2H), 7.66 ( bb, b =

8.8, 22.3, 4H), 7.33 (s, 1H), 7.29 - 7.21 (t, 2H), 4.18 - 3.93 (t, 1H), 2.10 ( s, 3 H), 1.12 (b, b = 6.6, 6 H) ppm; MH (ES) 419 (M + H).

I-140: N-cyclopropyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzoxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide formate

I-141: 2-Chloro-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-ylamino] -benzamide trifluoroacetate

¹H NMR (DMSO, 300 MHz): δ 11.89 - 11.38 (t, 1H), 10.43 - 10.06 (t, 1H), 9.77 - 9.20 (t, 1H), 7 , 93 (s, 1H), 7.67 (s, 1H), 7.58-7.36 (t, 1H), 7.29 (t, 2H), 7.20 (t, 2H), 2, 13 (s, 3H) md; MZ (EZ) 410/412 (M + H).

I-142: N-cyclopropyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide trifluoroacetate

I-143: N-cyclopropyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide

¹H NMR (DMSO, 300 MHz): δ 11.62 (s, 1H), 9.27 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.90 ( s, 1H), 7.65 (t, 3H), 7.29 (t, 3H), 3.33 (s, 3H), 2.87-2.61 (t, 1H), 0.59 (t , 4H) ppm; MH (EH) 417 (M + H).

I-144: N-cyclobutyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide;

I-145: 4- [5-methyl-4- (2-oxo-3-propionyl-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-

ilamino] -benzamide

M3 (E3) 433 (M + H)

I-146: di-tertiary butyl (5- (2- (4-carbamoyl-phenylamino) -5-methylpyrimidin-4-ylamino) -2-oxobenzo [b] oxazole-3 (2H) -yl) methylphosphate

¹H NMR (DMSO, 300 MHz): δ 9.38 (s, 1H), 8.50 (s, 1H), 8.31 (s, 1H), 7.95 (s, 1H), 7.76 ( bb, b =

8.7, 26.3, 5H), 7.36 (s, 2H), 7.12 (s, 1H), 5.63 (b, b = 11.1, 2H), 2.12 (s, 3H), 1.31 (s, 18H) ppm; MZ (E3) 599 (M + H).

I-147: (5- (2- (4-carbamoyl-phenylamino) -5-methylpyrimidin-4-ylamino) -2-oxobenzo [b] oxazol-

3 (2H) -yl) methyl dihydrogen phosphate

M3 (E3) 487 (M + H)

I-148: Sodium (5- (2- (4-carbamoyl-phenylamino) -5-methylpyrimidin-4-ylamino) -2-

oxobenzo [b] oxazol-3 (2H) -yl) methylphosphate

M3 (E3) 487 (M + H)

I-150: (5- (2- (4- (cyclobutylcarbamoyl) phenylamino) -5-methylpyrimidin-4-ylamino) -2-

oxobenzo [b] oxazol-3 (2H) -yl) methyl dihydrogen phosphate

M3 (E3) 541 (M + H)

I-151: Sodium (5- (2- (4- (cyclobutylcarbamoyl) phenylamino) -5-methylpyrimidin-4-ylamino) -2-

oxobenzo [b] oxazol-3 (2H) -yl) methylphosphate

M3 (E3) 541 (M + H)

I-152: di-tertiary butyl (5- (2- (4- (cyclobutylcarbamoyl) phenylamino) -5-methylpyrimidin-4-ylamino) -2-oxobenzo [b] oxazol-3 (2H) -yl) methylphosphate

M3 (E3) 653 (M + H).

I-153: 5- [2- (4-Chloro-3-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

¹H NMR (300 MHz, DMSO)? 9.49 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.92 (s , 2H), 7.42 (b, b = 8.8, 1H), 7.26 (t, 2H), 2.09 (s, 3H) ppm; MZ (EZ) 435/437 (M + H);

I-154: 5- [5-Methyl-2- (4-methyl-3-trifluoromethylphenylamino) -pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

¹H NMR (DMSO-d6) δ: 11.71 (s, 1H), 10.59 (bs, 1H), 9.68 (bs, 1H), 7.94 (s, 1H) , 7.72 (s, 1H), 7.53 (b, b = 8.3 Hz, 1H), 7.25 (b, b = 8.5 Hz, 2H), 7.08-7.20 ( t, 2H), 2.32 (bd, s, 3H), 2.13 (s, 3H) mdd; MZ (EZ) 416 (M + H);

I-155: 5- [5-Methyl-2- (4-methylsulfanyl-3-trifluoromethylphenylamino) -pyrimidin-4-ylamino] -

3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.35 (s, 1H), 8.42 (s, 1H), 8.05 (s, 1H), 7.90 (s, 2H), 7.32 ( s, 2H), 7.23 (b, b = 6.6, 2H), 2.43 (s, 3H), 2.08 (s, 3H) ppm; MH (EH) 448 (M + H).

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iA 106975 C2

I-156: 4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-ylamino] -2- (4-

methylpiperidine-1-yl) -benzamide

M8 (E8) 474 (M + H)

I-157: 5- [2- (3-cyclopentansulfonyl-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

¹(M, 2H), 7.90 t, 3H),

2.81 (t, 1H), 2.09 (s, 3H), 1.92 - 1.64 (t, 4H), 1.68-1.38 (t, 4H) ppm; MZ (EZ) 466 (M + H).

I-158: 5- [5-Methyl-2- (3-trifluoromethylphenylamino) -pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.38 (s, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.88 ( b,? = 16.6, 2H), 7.41 - 7.16 (t, 3H), 7.11 (s, 1H), 2.09 (s, 3H) ppm; MH (ES) 402 (M + H).

I-159: 2-Methyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -pyrimidin-2-ylamino] -methyl ether of benzoic acid

M8 (E8) 406 (M + H)

I-160: 5- [5-Methyl-2- (4-trifluoromethylphenylamino) -pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹1H NMR (DMSO-d6) δ: 11.75 (s, 1H), 10.16 (bs, 1H), 9.23-9.61 (t, 1H), 7.93 (s, 1H) ), 7.61-7.78 (t, 2H), 7.44-7.63 (t, 3H), 7.16-7.40 (t, 2H), 2.13 (s, 3H) m .d; MH (ES) 402 (M + H);

I-161: 5- [5-Methyl-2- (4-trifluoromethoxy-3-trifluoromethylphenylamino) -pyrimidin-4-ylamino] -3H-benzooxazol-2-one

M8 (E8) 486 (M + H)

I-162: 5- [2- (3-Fluoro-5-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one trifluoroacetate

¹H NMR (DMSO, 300 MHz): δ 11.65 (s, 1 H), 10.32 - 10.20 (t, 1 H), 9.40 - 9.28 (t, 1 H), 7.95 (from , 1H), 7.81 - 7.66 (b, 1H), 7.57 (s, 1H), 7.33 - 7.06 (t, 4H), 2.13 (s, 3H) md ; MH (ES) 420 (M + H).

I-163: 5- [2- (4-Fluoro-3-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

M8 (E8) 436 (M + H).

I-164: 5- [5-Methyl-2- (4-methyl-3-trifluoromethylphenylamino) -pyrimidin-4-ylamino] -3H-

benzooxazol-2-one trifluoroacetate

For ¹H NMR see I-154; M8 (E8) 413 (M + H).

I-165: 5- {2- [4- (2-Methoxy-ethoxy) -3-trifluoromethylphenylamino] -5-methyl-pyrimidin-4-ylamino} -

3-benzoxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.67 - 11.58 (t, 1H), 9.65 - 9.56 (t, 1H), 9.06-8.94 (t, 1H), 7 , 86 (t, 2 H), 7.23 (b, J = 8.0, 1 H), 7.19 - 7.05 (t, 1 H), 6.97 (b, J = 8.7, 2 H) , 6.83 (t, 1H), 4.10 -3.99 (t, 2H), 3.60 (t, 2H), 3.28 (s, 3H), 2.10 (s, 3H) m .d; MZ (EZ) 476 (M + H).

I-166: 5- [2- (4-isopropyl-3-methylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

M8 (E8) 390 (M + H)

I-167: 5- [2- (3-Chloro-4-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

¹H NMR (DMSO-d6) δ: 11.79 (s, 1H), 10.96 (bs, 1H), 9.73 (bd, s, 1H), 8.00 (s, 1H) , 7.87 (s, 1H), 7.61 (b, J = 8.8 Hz, 1H), 7.28 - 7.45 (t, 2H), 7.10 - 7.26 (t, 2H) ), 2.14 (s, 3H) ppm; MH (ES) 436 (M + H);

I-168: 5- [2- (4-Ethoxy-3-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

M8 (E8) 446 (M + H)

I-169: 5- [2- (3,5-bis-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

M8 (E8) 470 (M + H)

I-170: 2-methyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzoxazol-5-ylamino) -pyrimidin-2-ylamino] -benzoic acid

M8 (E8) 392 (M + H)

I-171: M -ethyl-2-methyl-4- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) -pyrimidin-2-ylamino] -benzamide

M8 (E8) 419 (M + H)

I-172: 5- [2- (4-Chloro-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.16 (s, 1H), 8.37 (s, 1H), 8.23 ​​(s, 1H), 7.87 (s, 1H), 7.67 ( b, J = 8.9.1 H), 7.43 - 7.20 (t, 2 H), 7.14 (b, J = 8.9, 1 H), 2.08 (s, 3 H) ppm ; MH (EH) 368 (M + H).

I-173: 5- [2- (3-Chloro-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3 H -benzooxazol-2-one

M8 (E8) 368 (M + H)

I-174: 5- (5-Methyl-2-phenylamino-pyrimidin-4-ylamino) -3H-benzooxazol-2-one

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iA 106975 C2

¹H NMR (DMSO-S₆) δ: 11.93 (5, 1H), 10.81 (5, 1H), 9.85 (5, 1H), 7.90 (5, 1H), 7.40 (C, δ = 8.0 Hz, 2H), 7.26 - 7.32 (t, 2H), 7.11 - 7.23 (t, 3H), 6.98 - 7.08 (t, 1H), 2.13 (5, 3H) m.d. MZ (EZ) 334 (M + H);

I-175: 5- [2- (3-Bromo-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

MZ (EZ) 412/414 (M + H)

I-176: 5- [2- (4-Chloro-2,5-dimethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

MZ (EZ) 396/398 (M + H)

I-177: Ch- {4- [5-Methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) -pyrimidin-2-ylamino] -2-

trifluoromethylphenyl} acetamide

MH (EH) 459 (M + H)

I-178: 5- [2- (3,4-dimethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO-S₆) δ: 11.78 (s, 1H), 10.11 (bd, s, 1H), 9.65 (bd, s, 1H), 7.84 (s, 1H), 7.26 - 7.36 (t, 1H), 7.15-7.24 (t, 3H), 6.90-7.13 (t, 2H), 2.12 (t, 6H), 1.97 (5, 3H) m .d; MS (E5) 362 (M + H);

I-179: 5- [2- (4-cyclohexylmethoxy-3-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.72 (s, 1H), 10.32 (s, 1H), 9.77 (s, 1H), 7.86 (s, 1H), 7.56 ( 2.37 (s, 2H), 7.32-7.02 (t, 3H), 2.48 (t, 2H), 2.13 (s, 3H), 1.73 (s, 5H), 1.37-0 , 90 (t, 6H) ppm; M5 (E5) 514 (M + H).

I-180: 5- [2- (4-Chloro-3-trifluoromethoxyphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

MZ (EZ) 452/454 (M + H)

I-181: 5- [2- (4-chloro-3-methoxyphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.72 (s, 1H), 10.01 (s, 1H), 9.40 (s, 1H), 7.87 (s, 1H), 7.22 ( C, A =

8.3, 3H), 7.17 - 7.01 (t, 1H), 3.55 (5, 3H), 2.12 (5, 3H) ppm; M5 (E5) 398/400 (M + H).

I-182: 5- [2- (4-chloro-3-ethoxy-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.76 (s, 1H), 10.24 (s, 1H), 9.56 (s, 1H), 7.90 (s, 1H), 7.24 ( t, 4H), 7.00 (C, δ = 10.6, 1H), 3.59 (t, 2H), 2.13 (s, 3H), 1.18 (I, δ = 6.9, 3H) m.d. M5 (E5) 412/414 (M + H).

I-183: 5- [2- (4-Fluoro-3-methoxyphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.75 (s, 1H), 10.25 - 10.08 (with bg, 1H), 9.63 - 9.49 (bg, 1H), 7.86 (5, 1H), 7.19 (t, 5H), 3.55 (5, 3H), 2.13 (5, 3H) ppm; M5 (E5) 382 (M + H);

I-184: 5- [2- (3,5-Dichloro-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

MZ (EZ) 402/404 (M + H)

I-185: 5- [2- (3-Bromo-5-chloro-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

MH (EH) 448 (M + H)

I-186: 5- [2- (3-chloro-5-fluorophenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO-S₆) δ: 11.69 (s, 1H), 10.25 (bs, 1H), 9.50 (bs, 1H), 7.94 (s, 1H), 7.23-7 , 44 (t, 3H), 7.06-7.23 (t, 2H), 6.93 (C, J = 8.3 Hz, 1H), 2.13 (5, 3H) ppm; M5 (E5) 386 (M + H);

I-187: 3-chloro-5- [5-methyl-4- (2-oxo-2,3-dihydrobenzoooxazol-5-ylamino) -pyrimidin-2-ylamino] -

benzonitrile

MZ (EZ) 393/395 (M + H)

I-188: 5- [2- (4-Bromo-3-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

MZ (EZ) 482/484 (M + H);

I-189: 5- [2- (3-Bromo-5-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one

MZ (EZ) 480/482 (M + H);

I-190: Ch-Cyclobutyl-2-methyl-4- [5-methyl-4- (2-oxo-2,3-dihydro-benzooxazol-5-ylamino) -

pyrimidine-2-ylamino] -benzamide

MH (ES) 445 (M + H);

I-191: 5- {2- [3-chloro-4- (2-morpholin-4-yl-ethoxy) -phenylamino] -5-methyl-pyrimidin-4-ylamino} -3H-

benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.57 (s, 1H), 9.02 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.84 ( C, A =

6.3, 1 H), 7.37 (C, δ = 9.1, 1 H), 7.30-7.19 (t, 1 H), 6.96 (C, δ = 9.1, 1 H), 6, 69 - 6.40 (t, 1H), 4.26-4.00 (t, 2H), 3.63 (t, 4H), 3.02-2.81 (t, 2H), 2.87 - 2.60 (t, 4H), 2.07 (5, 3H) ppm; MZ (EZ) 497/499 (M + H);

I-192: 5- {5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-ylamino} -3H-

benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 9.02 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.49 ( C, δ = 9.0.2H), 7.41 - 7.26 (t, 2H), 7.21 (C, δ = 8.5, 1H), 6.76 (C, δ = 9.0 , 2H), 4.09 (I, δ = 5.3, 2H), 3.76-3.59

98

iA 106975 C2

(t, 4H), 3.01 (t, J = 5.2, 2H), 2.81 (5, 4H), 2.07 (5, 3H) ppm; M8 (E8) 463 (M + H);

I-193: 5- [2- (2,4-Difluoro-5-methoxyphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹NMR (DMSO, 300 MHz): δ 11.70 (s, 1H), 9.82 (s, 1H), 9.54 (d, 1H), 7.84 (d, 1H), 7.45 ( t, a =

10.8: 1H), 7.32 - 7.21 (t, 1H), 7.18 (b,? = 5.1, 2H), 3.57 (5, 3H), 2.12 (5, 3H) m.d. MS (E8) 400 (M + H);

I-194: 5- [2- (3-Chloro-4-ethoxy-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.73 (s, 1H), 10.16 (s, 1H), 9.67 (s, 1H), 7.86 (s, 1H), 7.53 ( δ, 1 H), 7.22 (t, 3 H), 7.08-6.88 (t, 1 H), 4.10 - 3.82 (t, 2 H), 2.07 (s, 3 H), 1 , 44-1.06 (t, 3H) ppm; MS (E8) 412/414 (M + H);

I-195: 5- [2- (4-cyclobutylmethoxyphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.81 (s, 1H), 10.20 (s, 1H), 9.74 (s, 1H), 7.81 (s, 1H), 7.35 - 7.10 (t, 4H), 6.82 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.8, 2H), 3.87 (b, &amp; lt; RTI ID = 6.8, 2 H), 2.78 - 2.59 (t, H), 2.12 (s, 3 H), 2.09 - 1.96 (t, 2H), 1.85 (t, 4H) ppm; MS (E8) 418 (M + H);

I-196: 5- [2- (4-Isobutoxyphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.81 (s, 1H), 10.25 (s, 1H), 9.70 (s, 1H), 7.81 (s, 1H), 7.24 ( t, 3H),

6.81 (t, 2H), 3.66 (t, 2H), 2.10 (5, 3H), 1.97 (t, 1H), 0.94 (t, 6H) ppm; MS (E8) 406 (M + H);

I-197: 5- {5-methyl-2- [4- (3-methylbutoxy) -phenylamino] -pyrimidin-4-ylamino} -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.81 (s, 2 H), 10.19 (δ, 1 H), 9.69 (δ, 1 H), 7.82 (δ, 1 H), 7.35 - 7.14 (t, 4H), 6.82 (b, J = 8.9, 2H), 3.91 (t, J = 6.6, 2H), 2.11 (s, 3H), 1, 88-1.63 (t, 1H), 1.56 (ς, Å = 6.6.2H), 0.90 (b, Å = 6.6, 6H) ppm; MS (E8) 420 (M + H);

I-198: 5- [2- (3-Chloro-4-trifluoromethylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-

benzooxazol-2-one trifluoroacetate

¹H NMR (DMSO, 300 MHz): δ 11.80 (s, 1H), 11.07 (s, 1H), 9.81 (s, 1H), 7.98 (s, 1H), 7.83 ( δ, 1 H) 7.59 (b, δ = 8.8, 1 H) 7.43 - 7.25 (t, 2 H) 7.20 (d, 1 H) 7.12 (b, 8.5, 1 H), 2.13 (5, 3 H) ppm; MS (E8) 436/438 (M + H);

I-199: 5- [2- (3-Fluoro-5-methylphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO, 300 MHz): δ 11.74 (s, 1H), 10.32 (s, 1H), 9.70 (s, 1H), 7.92 (s, 1H), 7.31 b, δ = 8.5, 1 H), 7.18 (b, δ = 9.6, 2 H), 6.96 (d, 1 H), 6.62 (b, δ = 10.0, 1 H), 2.13 (5, 3H), 2.10 (5, 3H) ppm; MS (E8) 366 (M + H);

I-200: 5- [2- (2,4-Difluoro-3-methoxyphenylamino) -5-methyl-pyrimidin-4-ylamino] -3H-benzooxazol-2-one

¹H NMR (DMSO-b₆) δ: 11.84 (s, 1H), 10.33 (s, 1H), 9.77 (s, 1H), 7.89 (s, 1H), 7.55-6.94 (t, 5H ),

3.82 (5, 3H), 2.12 (5, 3H) ppm; MS (E8) 400 (M + H);

I-201: 5- (2- (4- (1- (azetidin-1-yl) ethyl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [b] oxazol-2 (3-one

C2zH24N6O2. MS (E8I) t / z 417.01 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.91 (s, 1H, NH), 8.30 (d, 1H, NH), 8.17 (s, 1H, NH), 7.75 (s, 1H, 7.6-7.52 (t, 2H, ArI), 7.38-7.27 (t, 2H, ArI), 7.22 (d, 1H, ArJ), 7.01 (t, δ = 8.3, 1 H, ArgA), 6.78 (b, J = 8.5, 1 H, Ar, Y), 3.63-2.85 (t, 5H, O, 204), 2.05 (δ , 3H, CU, 1.95-1.75 (t, 2H, MS), 1.05 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 6.6, 3H, OH2Z).

I-202: 5- (2- (4- (1- (cyclopropylamino) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

Сге ^^ MA. MS (E8I) t / z 417.03 (M + 1) +.

I-203: 5- (5-Methyl-2- (4- (1- (pyrrolidin-1-yl) ethyl) phenylamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

Cr MS (E8I) t / z 431.12 (M + 1) +.

I-204: 5- (5-Methyl-2- (4- (1-morpholinoethyl) phenylamino) pyrimidin-4-ylamino) benzo [b] oxazol-

2 (3 ^^

C24H26N6Oz. MS (E8I) t / z 447.13 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.80 (s, 1H, NH), 8.21 (s, 1H, NH), 8.12 (s, 1H, NH), 7.77 (s, 1H, 7.74 (b, J = 2.5, 1H, Br), 7.55 (b, 8 = 8.5, 2H, , 3.89 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.5, 2H, &amp; lt; / RTI &amp; gt; GaH), 6.79 (b, &amp; lt; = 8.6, 1 H, GaH), 3.63-3.23 t, 5H, MCH2), 2.31-2.18 (t, 4H, 2θ), 2.07 (s, 3H, CU, 1.22 (b, Å = 6.7, 3H, OC6 )

1- (3- (diethylamino) pyrrolidin-1-yl) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

С28Нз5N7О2. MS (E8I) t / z 502.19 (M + 1) +.

I-206: 5- (2- (4- (1- (benzylamino) ethyl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [b] oxazol-2 (3-chloro-

C27H26N6O2. MS (E8I) t / z 467.03 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.32 (δ, 1H, NH), 8.15 (s,

99

υΑ 106975 Ο2

1H, N, 7.33-7.15 (t, 13H, AZ), 4.22 (5, 2H, CH₂), 3.48 (t, 1H, CH), 1.84 (5, 3H, CH)₃), 1.22 (C, b =

6.6, 3H, CH3).

1-207: 5- (2- (4- (1- (isopropylamino) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

WITH₂3H₂6 ^ o₂. MS (E8I) t / z 419.04 (M + 1) +,¹H NMR (300 MHz, DMSO)? 9.13 (5, 1H, N2, 8.35 (5,1 H, N2, 8.27 (s, 1H, N, 7.86 (s, 1H, Aι), 7.65 (C, B = 8.4, 2H, AA), 7.42 (5, 1H, AZ), 7.32 (C, b =

8.7, 1H, AA), 7.27 - 7.16 (t, 3H, Asti), 4.16 (t, 1H, CH), 2.08 (5, 3H, OH3), 1.42 (t, 5H, 2SH₂, CH), 1.11 (C, b = 6.3, 3H, OH3).

1-208: 5- (5-Methyl-2- (3- (1- (propylamino) ethyl) phenylamino) pyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one

AT₂₃N₂₆^ O₂. MS (ESI) t / z 419.06 (M + 1) +,¹H NMR (300 MHz, DMSO)? 9.03 (5, 1H, N2, 8.33 (5.1H, N2, 8.24 (s, 1H, N, 7.86 (s, 1H, 7.67-7.53 (t, 2H, AA), 7.37 (C, b = 1.7, 1H, AA1), 7.31 (C5, b = 8.6, 2.1 , 1H, AA), 7.20 (C, B = 8.6, 1H, AA), 7.16 - 7.06 (t, 1H, AA), 6.88 (C, b = 7.5, 1H, AAi), 3.54 (t, 1H, CH), 2.34 (t, 2H, CH₂), 2.08 (5, 3H, CH)₃), 1.40 (t, 2H, CH2)₂), 1.27 (C, b = 6.6, 3H, OH3), 0.79 (I, b = 7.4, 3H, CH3).

I-209: 5- (2- (3- (1- (isopropylamino) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

WITH₂3H₂6 ^ o₂. MS (E8I) t / z 419.05 (M + 1) +.¹H NMR (300 MHz, DMSO)? 9.04 (5, 1H, N, 8.34 (5,1 H, N2, 8.24 (s, 1H, N, 7.86 (s, 1H, AAi), 7.67-7.48 (m , 2H), 7.42-7.03 (t, 4H, AAi), 6.90 (C, b = 7.6, 1H, AZ), 3.71 (t, 1H, CH), 2.66-2.42 (t, 1H, CH), 2.34 (t, 2H, CH2)₂), 2.08 (5, 3H, CH3), 1.27 (C, b = 6.6, 3H, CH2)₃), 0.95 (t, 6H, 2CH)₃)

I-210: 5- (2- (3- (1 - (isopropylamino) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₃N₂₄^ O₂. MS (E8I) t / z 417.04 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.92 (5, 1H, N2, 8.32 (5,1H, N2, 8.15 (s, 1H, N, 7.86 (s, 1H, 7,51 (C, b = 9.5, 2H, AA), 7.31 (C, B = 7.0, 2H, AA), 7.21 (C, b = 9.2, 1H , Αιη), 7.05 (δ, δ = 7.8, 1H, AA1), 6.83 (C, δ = 7.6, 1H, AA), 3.47 (t, 1H, CH2), 2 , 0.71 (t, 4H, &amp; lt; RTI ID = 0.0 &amp; gt; 2SN₂)

I-211: 5- (2- (3- (1- (azetidin-1-yl) ethyl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one

WITH₂3H₂4 ^ o₂. MS (E8I) t / z 417.03 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.94 (5, 1H, N, 8.33 (s, 1H, N, 8.18 (s, 1H, N, 7.85 (s, 1H, 7,54-7,43 (t, 2H, AZ), 7,31 (5,1H, AZ), 7,28-7,23 (t, 2H, DNH), 7,02 (1, b = 7.8, 1H, DNH), 6.74 (C, b = 7.5, 1H, DNH), 3.53 (t, 1H, CH), 2.98 (t, 4H, 2CH₂), 2.04 (5, 3H, CH)₃), 1.95-1.78 (t, 2H, CH2)₂), 0.95 (C, b = 6.6, 3H, CH)₃)

I-212: 5- (5-methyl-2- (3- (1- (pyrrolidin-1-yl) ethyl) phenylamino) pyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

WITH₂₃N₂₆^ O₂. MS (E8I) t / z 431.12 (M + 1) +,¹NMR (300 MHz, DMSO) δ 8.94 (s, 1H, N, 8.33 (s, 1H, N, 8.17 (s, 1H, N, 7.85 (s, 1H, AI), 7.50 (C, B = 8.3, 2H, Ai), 7.25-7.15 (t, 3H, Ai), 7.03 (I, b = 7.8, 1H, AZ ), 6.79 (C, b = 10.5, 1H, AA), 3.51 (t, 1H, CH), 2.98 (t, 4H, 2CH₂), 2.54-2.38 (t, 4H, 2CH)₂), 2.07 (5, 3H, CH3), 1.67-1.51 (t, 4H, 2CH)₂), 0.95 (C, b = 6.6, 3H, CH3).

I-213: 5- (2- (3- (1 - (Benylamino) ethyl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [S] oxazol-

2 (3H) -one

WITH₂7H₂6 ^ o₂. MS (E8I) t / z 467.04 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.99 (5, 1H, N, 8.31 (5.1H, N2, 8.19 (s, 1H, N, 7.86 (s, 1H, 7.61 (5, 1H, AA1), 7.55 (5, 1H, AA1), 7.35 (5, 1H, AA1), 7.31 - 7.20 (t, 5H, AA1) , 7.19 (t, 1H, AA), 7.15 (t, 1H, AAi), 7.09 (I, b = 7.9, 1H, AA), 6.89 (C, b = 7, 5, 1H, AAi), 3.58 (t, 1H, CH), 3.55 (5, 2H, CH₂), 2.08 (5, 3H, CH)₃), 1.23 (s, b = 6.6, 3H, CH)₃)

I-214: 5- (2- (3- (1- (3- (diethylamino) pyrrolidin-1-yl) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

WITH₂₈N₃₅^ O₂. MS (E8I) t / z 502.12 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.96 (5, 1H, N, 8.33 (s, 1H, N, 8.18 (s, 1H, N, 7.85 (s, 1H, AI), 7.53-7.44 (t, 2H, AAi), 7.33 (5, 1H, AAi), 7.26 (C, b =

1.8, 1H, AAi), 7.23 (5, 1H, AAi), 7.04 (1H, b = 7.9, 1H, AAi), 6.76 (C, b = 7.6, 1H, AAi ), 3.57-3.40 (t, 1H, CH), 2.76 (CC, b = 14.5, 7.3, 4H, 2CH₂), 2.35 (s, b = 5.8, 3H, CH)₂, CH2), 2.21 (C, B = 8.3, 1H, CH), 2.07 (5, 3H, CH3), 1.98-1.84 (t, 2H, CH₂), 1.78-1.62 (t, 1H, CH), 1.16 (C, b = 6.3, 3H, CH3), 1.01 (t, 6H, 2CH3).

I-215: 5- (5-Methyl-2- (3- (1- (piperidin-1-yl) ethyl) phenylamino) pyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

WITH₂₅N₂₃^ O₂. MS (E8I) t / z 444.95 (M + 1) +,¹H NMR (300 MHz, DMSO)? 9.22 (5, 1H, N2, 8.35 (5,1H, N2, 8.21 (s, 1H, N, 7.96 (C, b = 7.9, 1H, AAi), 7.89 (s, 1H, AAi), 7.46-7.38 (t, 2H, AAi), 7.37 -7.30 (t, 1H, AAi), 7.27 (C, B = 7.6, 1H, AAi), 7.22 (5, 1H, AAi), 7.18 (5, 1H, AAi), 3.57-3.45 (t, 1H , CH), 2.52-2.40 (t, 4H, 2CH)₂), 2.09 (5, 3H, CH3), 1.46-1.36 (t, 6H, 3CH)₂), 1.15 (C, b = 6.7, 3H, CH3).

I-216: 5- (2- (3- (1 - (diethylamino) ethyl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [S] oxazol-

100

iA 106975 C2

2 (3H) -one

₂₄N₂₈YES₆AT₂. MS (E30 t / z 433.07 (M + 1) +.

1-217: 5- (5-Methyl-2- (3- (1-morpholinethyl) phenylamino) pyrimidin-4-ylamino) benzo [b] oxazol-

2 (3H) -one

WITH₂4H₂6Y6Oh. MS (E30 t / z 447.06 (M + 1) +.

1-218: ^ cyclobutyl-4- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-ylamino) pyrimidin-2-

ylamino) -2- (trifluoromethyl) benzamide

WITH₂4H₂1EeY6O3. MS (E3I) t / z 499.07 (M + 1) +,¹H NMR (300 MHz, DMSO)? 11.66 (5, 1H, OH), 10.17 (5, 1H, OH), 8.54 (5, 1H, OH), 8.52 (5, 1H, NIN), 7.93 (5, 1H, AgN), 7.85 (5, 1H, AgN), 7.74 (b, &amp; lt; RTI ID =

9.9, 1 H, AgN), 7.29 (bb, A = 13.6, 8.1, 2H, AgN), 7.23-7.14 (t, 2H, AgN), 4.28 (t , 1H, CH), 2.16-2.09 (t, 2H, CH2)₂), 2.13 (5, 3H, CH2)₃), 2.02-1.82 (t, 2H, CH2)₂), 1.67-1.60 (t, 2H, CH2)₂)

1-219: 4- (5-Methyl-4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-ylamino) pyrimidin-2-ylamino)

phenyl-2- (trifluoromethyl) benzamide

WITH₂₆N_19thIS₃YES₆AT₃. MS (E30 t / z 521.10 (M + 1) +.

1-220: N-cycloprop-2-methoxy-4- (5-methyl-4- (2-oxo-2,3-diprobenzo [b] oxazol-5-

ylamino) pyrimidine-2-ilamino) benzamide

WITH₂₃N₂₂N6O4. MS (E30 t / z 446.46 (M + 1) +,¹1H NMR (300 MHz, DMSO)? 11.72 (5, 1H, OH), 10.06 (5, 1H, OH), 9.61 (5, 1H, OH), 7.87 (5, 1H, AgN), 7.33-6.99 (t, 4H, AgN), 6.93 (b, J = 8.2, 1H, AgN), 6.59 (b, A = 9.7, 1H, AgN ), 3.54 (t, 3H, CH)₃), 2.48 (t, 1H, CH), 2.12 (5, 3H, CH)₃), 1.37-1.20 (t, 4H, 2CH2).

1-221: 2-methoxy-4- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-ylamino) pyrimidin-2-

ylamino-phenylbenzamide

WITH₂₆N₂₂YES₆AT₄. MS (E30 t / z 482.49 (M + 1) +).

1-222: 4- (5-Methyl-4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-ylamino) pyrimidin-2-ylamino) -2-

(trifluoromethyl) benzoic acid

WITH₂₀N14E₃YES₅O4 MS (E30 t / z 446.01 (M + 1) +.

1-223: cyclopropyl-4- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-ylamino) pyrimidin-2-ylamino) -2- (trifluoromethyl) benzamide

WITH₂₃N19E₃N6O4. MS (E30 t / z 485.08 (M + 1) +.

1-224: - (2- (3-Isobutoxy-5- (trifluoromethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₃N₂₂IS₃YES₅AT₃. MS (E30 t / z 474.06 (M + 1) +,¹H NMR (300 MHz, DMSO)? 9.31 (5, 1H, OH), 8.40 (5, 1H, OH), 7.92 (5, 1H, OH), 7.61 (5, 1H, AgN), 7.54 (5, 1H, AgN), 7.34-7.22 (t, 2H, AgN), 7.18 (b, 8 = 4.2, 2H, AgN), 6.61 ( 5, 1H, AgN), 3.56 (b, &amp; lt; RTI ID = 0.0 &amp; gt; = 6.6, 2H, &amp; lt; / RTI &amp; gt;₂), 2.09 (5, 3H, CH)₃), 1.97-1.81 (t, 1H, CH), 0.87 (b,? = 6.6, 6H, 2CH₃)

1-225: 5- (2- (3- (cyclopropylmethoxy) -5- (trifluoromethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂3H₂₀E3Y₅O3 MS (E30 t / z 472.05 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.27 (5, 1H, OH), 8.13 (5, 1H, OH), 7.92 (5, 1H, OH), 7.60 (5, 1H, AgN), 7.53 (5, 1H, AgN), 7.31 - 7.21 (t, 2H, AgN), 6.72 (5.2H, AgN), 6.45-6.13 (t, 1H, AhN), 3.76-3.62 (t, 2H, CH2)₂), 2.48 (t, 1H, CH), 2.09 (5, 3H, CH3), 0.52 (b,? = 7.2, 2H, CH3), 0.22 (b,? = 5 , 9, 2H, CH2).

1-226: 5- (2- (3-cyclobutoxy-5- (trifluoromethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₃N₂₀IS₃YES₅AT₃. MS (E30 t / z 472.09 (M + 1) +.

1-227: 5- (2- (3- (cyclobutylmethoxy) -5- (trifluoromethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₄N₂₂IS₃YES₅AT₃. MS (E30 t / z 486.11 (M + 1) +.

1-228: 5- (2- (3-Deuterated methoxy-5- (trifluoromethyl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₀H13O3r3Y₅O3 MS (E30 t / z 435.13 (M + 1) +,¹H NMR (300 MHz, DMSO)? 8.42 (5, 1H, OH), 8.13 (5, 1H, OH), 7.91 (5, 1H, OH), 7.57 (b, &amp; lt; RTI ID = 7.1, 2H, AgN), 7.30-7.13 (t, 4H, AgN), 6.62 (5, 1H, AgN), 2.08 (5, 3H, CH3).

1-229: 5- (2- (3-Acetyl-5-methoxyphenylamino) -5-methylpyrimidin-4-ylamino) benzo [b] oxazol-

2 (3H) -one

WITH₂₁N_19thYES₅AT₄. MS (E30 t / z 406.12 (M + 1) +,¹H NMR (300 MHz, DMSO)? 9.19 (5, 1H, OH), 8.39 (5.1H, OH), 8.21 (5, 1H, OH), 7.90 (5, 1H, AgN), 7.75 (5, 1H, AgN), 7.66 (5, 1H, AgN), 7.33-7.26 (t, 2H, AgN), 7.19-7.16 (t, 1H, AhN), 6.90 (5, 1H, AhN), 3.64 (5, 3H, CH3), 2.37 (5, 3H, CH3), 2.08 (5, 3H, CH3).

1-230: 5- (2- (3-Chloro-4-fluoro-5- (trifluoromethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

101

iA 106975 C2

WITH_19thN₁₂C1_P4^ O₂. MS (ESI) t / z 453.96 (M + 1) +.

1-231: 5- (2- (3- (1 - (isopropylamino) ethyl) -5-methoxyphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

C24I-I28 ^ O3. MS (ESI) t / z 449.13 (M + 1) +.

1-232: 5- (2- (3-methoxy-5- (1- (propylamino) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

C24H28 ^ O3. MS (ESI) t / z 449.07 (M + 1) +.

1-233: 5- (2- (3- (1- (cyclopropylamino) ethyl) -5-methoxyanilamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₄N₂₆^ O₃. MS (ESI) t / z 447.20 (M + 1) +.

1-234: 5- (2- (3-methoxy-5- (1- (pyrrolidin-1-yl) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₅N₂₈^ O₃. MS (ESI) t / z 461.12 (M + 1) +,¹H NMR (300 MHz, DMSO)? 9.25 (s, 1H, N4), 8.30 (s, 1H, N4), 8.21 (s, 1H, N4), 7.90 (s, 1H, AgN), 7.33-7.11 (t, 2H, AgN), 6.99-6.69 (t, 3H, AgN), 6.47 (s, 1H, AgN), 3.79 (i, b = 7.7, 1H, CH), 3.71 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.54-2.06 (t, 8H, 4CH₂), 1.44 (s, 3H, CH3).

1-235: 5- (2- (3- (1- (azetidin-1-yl) ethyl) -5-methoxyphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂4H₂6 ^ O3. MS (ESI) t / z 447.42 (M + 1) +.

1-236: 5- (2- (3-Methoxy-5- (1- (methylamino) ethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₂N₂₄^ O₃. MS (ESI) t / z 421.14 (M + 1) +.

1-237: 5- (2- (3- (Difluoromethyl) -5-methylphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₀N₁₇R₂^ O₂. MS (ESI) t / z 398.08 (M + 1) +,¹H NMR (300 MHz, DMSO)? 9.17 (s, 1H, N4), 8.40 (s, 1H, N4), 8.11 (s, 1H, N4), 7.88 (s, 1H, AgN), 7.60 (b, b = 13.3, 2H, AgN), 7.30-7.20 (t, 3H, AgN),

6.78 (s, 1H, AgN), 6.71 (s, b = 61.7, 2H, CH), 2.10 (s, 3H, CH3), 2.08 (s, 3H, CH3).

1-238: 5- (2- (3- (fluoromethyl) -5-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [b] oxazol-2 (3H) -one

WITH₂₀H1₃™₅AT₂, MS (ESI) t / z 380.08 (M + 1) +, ¹H NMR (300 MHz, DMSO)? 9.04 (s, 1H, N4), 8.37 (s, 1H, N4), 8.11 (s, 1H, N4), 7.87 (s, 1H, AgN), 7.45 (b, b = 8.4, 2H, AgN), 7.34-7.18 (t, 3H, AgN), 6.65 (s, 1H, AgN), 5.12 ( b, b = 53.3, 2H, CH₂), 2.47 (s, 3H, CH)₃), 2.08 (s, 3H, CH)₃)

1-239: 5- (5-Methyl-2- (4-methyl-3- (methylsulfonyl) phenylamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.63 (s, 1H), 9.34 (s, 1H), 8.40 (s, 1H), 8.18 (b, b = 1.7, 1H) , 8.04 (bb, b = 8.4, 1.9, 1H), 7.93 (s, 1H), 7.44 (bb, b = 8.6, 1.9, 1H), 7, 39 (s, 1H), 7.26 (b, b = 8.6, 1H), 7.22 (b, b = 8.4, 1H), 3.16 (s, 3H), 2.56 ( s, 3H), 2.15 (s, 3H); I_RM3 (M +) t / z 426.01.

1-240: 5- (2- (3-Fluoro-5-morpholinophenylamino) -5-methylpyrimidin-4-ylamino) benzo [b] oxazol-

2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.60 (s, 1H), 9.09 (s, 1H), 8.47 (s, 1H), 7.92 (s, 1H), 7.32 (bg s, 1H),

7.26 - 7.23 (t, 2H), 7.16 (b, b = 12.1, 1H), 6.96 (s, 1H), 6.27 (b, b = 12.1, 1H ), 3.67-3.64 (t, 4H), 2.97-2.94 (t, 4H), 2.14 (s, 3H); I_RM3 (M +) t / z 437.05.

1-241: 5- (2- (3-Fluoro-5- (4-methylpiperazin-1-yl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.60 (s, 1H), 9.04 (s, 1H), 8.44 (s, 1H), 7.92 (s, 1H), 7.33 (s , 1H), 7.30-7.22 (t, 2H), 7.18 (b, b = 12.1, 1H), 6.95 (s, 1H), 6.27 (b, b = 12 (T, 4H), 2.56 - 2.53 (t, 4H, overlapping with DMSO peaks), 2.35 (s, 3H), 2.14 ( s, 3H); LMMZ (M +) t / z450.06.

1-242: 5- (2- (4-Fluoro-3- (methylsulfonyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.69 (s, 1H), 10.14 (s, 1H), 9.36 (s, 1H), 8.00 - 7.91 (t, 3H), 7 , 41 (bs, b = 9.3, 1H), 7.34 - 7.21 (t, 3H), 3.31 (s, 3H), 2.19 (s, 3H); I_RM3 (M +) t / z 429.99.

1-243: 3- (5-Methyl-4- (7-methyl-2-oxo-2,3-dihydrobenzo [b] oxazol-5-ylamino) pyrimidin-2-

ilamino) benzosulfonamide

¹H NMR (300 MHz, DMSO)? 11.65 (s, 1H), 10.09 (bs, 1H), 9.33 (bs, 1H), 7.93 - 7.91 (t, 2H) ,

7.78 (s, 1H), 7.48 (b, b = 7.6, 1H), 7.39 - 7.34 (t, 3H), 7.14 (s, 1H), 7.12 (s, 1H), 2.33 (s, 3H), 2.19 (s, 3H); I_RM3 (M +) t / z 426.94.

1-244: 7-methyl-5- (5-methyl-2- (3- (methylsulfonyl) phenylamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.63 (s, 1H), 10.01 (s, 1H), 9.18 (s, 1H), 8.01 (b, b = 7.3, 1H) , 7.96

102

iA 106975 C2

7.94 (t, 2H), 7.54 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 8.0, 1H), 7.44 (t, 8.0 = 1.0, 1H), 7.13 (bg, 5, 2H) 3.14 (5, 3H), 2.33 (5, 3H),

2.18 (5, 3H); I_RM3 (M +) t / z 426.01.

1-245: 5- (2- (4-Fluoro-3- (methylsulfonyl) phenylamino) -5-methylpyrimidin-4-ylamino) -7-

methylbenzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO)? 11.62 (5, 1H), 10.08 (bg, 5, 1H), 9.26 (bg, 5, 1H), 8.05-8.00 (t, 1H) , 7.93-7.90 (t, 2H), 7.37 (t, J = 9.3, 1H), 7.13 (5, 1H), 7.11 (5, 1H), 3.30 (5, 3H), 2.32 (5, 3H), 2.18 (5.3H); I_RM3 (M +) t / z 444.01.

1-246: 5- (5-Methyl-2- (3- (pyrrolidine-1-carbonyl) phenylamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO) δ 11.78 (5, 1H), 10.19 (5, 1H), 9.71 (5, 1H), 7.94 (5, 1H), 7.66 (5 , 1H), 7.50 (b, J = 8.7, 1H), 7.37 - 7.24 (t, 5H), 3.46 (t, J = 6.5, 2H), 3.26 (t, J = 6.5, 2H), 2.20 (5, 3H), 1.90

- 1.77 (t, 4H); I_RM3 (M +) t / z 431.06.

1-247: 5- (5-Methyl-2- (4- (pyrrolidine-1-carbonyl) phenylamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO)? 11.81 (5, 1H), 10.13 (5, 1H), 9.62 (5, 1H), 7.95 (5, 1H), 7.53-7 , 50 (t, 2H), 7.45-7.36 (t, 3H), 7.29 (bg, 5, 1H), 7.24 (bb, &amp; lt; RTI ID = 0.0 &amp; gt; 8.4, 2.0, 1H) 3.48 (t, J = 6.4, 2H), 3.39 (t, J = 6.4, 2H), 2.20 (5, 3H), 1.92-1.82 (t, 4H ); I_RM3 (M +) t / z 431.05.

1-248: 3- (4- (7-Fluoro-2-oxo-2,3-dihydrobenzo [b] oxazol-5-ylamino) -5-methylpyrimidin-2-

ilamino) benzosulfonamide

¹NMR (300 MHz, DMSO)? 12.04 (5, 1H), 10.03 (bg, 5, 1H), 9.23 (bg, 5, 1H), 7.99 (bg, 5, 1H), 7, 96

7.93 (t, 2H), 7.56-7.42 (t, 3H), 7.36 (bg, 5, 2H), 7.19 (b,? = 1.5, 1H), 2, 19 (5, 3H); I_RM3 (M +) t / z 431.02.

1-249: 7-Fluoro-5- (5-methyl-2- (3- (methylsulfonyl) phenylamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO)? 12.03 (5, 1H), 10.03 (bg, 5, 1H), 9.16 (bg, 5, 1H), 8.08 (5, 1H), 8.04 (T, 2H), 7.58 - 7.50 (t, 3H), 7.19 (b, J = 1.7, 1H), 3.17 (5, 3H), 2.19 (5, 3H); I_RM3 (M +) t / z430.03.

1-250: 7-Fluoro-5- (2- (4-fluoro-3- (methylsulfonyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO)? 12.01 (5, 1H), 10.06 (bg, 5, 1H), 9.20 (bg, 5, 1H), 8.05-8.00 (t, 3H) , 7.49 - 7.41 (t, 2H), 7.20 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 1.5, 1H), 3.31 (5, 3H), 2.18 (5, 3H); I_RM3 (M +) t / z 448.01.

1-251: 7-Fluoro-5- (2- (3-methoxy-5- (trifluoromethyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 12.03 (5, 1H), 10.00 (bg, 5, 1H), 9.31 (bg, 5, 1H), 8.01 (bg, 5, 1H), 7, 51 (5, 1H), 7.44 (5, 1H), 7.38 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 12.3, 1H), 7.15 (5, 1H), 6.86 (s, 1H), 3 , 76 (5, 3H), 2.18 (5, 3H); I_RM3 (M +) t / ζ 450.05.

1-252: 3-methoxy-N, N-dimethyl-5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [b] oxazol-5-

ylamino) pyrimidine-2-ilamino) benzamide

¹NMR (300 MHz, DMSO)? 11.75 (5, 1H), 10.18 (bg, 5, 1H), 9.71 (bg, 5, 1H), 7.95 (5, 1H), 7.31 (b, δ = 8.5, 1H), 7.24 (bg, 5, 1H), 7.21 (bb, b = 8.5, 1H), 7.10 (5, 1H), 7.05 (5, 1H), 6.64 (5, 1H), 3.68 (5.3H), 2.98 (5, 3H), 2.84 (5, 3H), 2.19 (5, 3H) ; I_RM3 (M +) t / z 435.04.

1-253: 5- (2- (3-methoxy-5- (pyrrolidine-1-carbonyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO)? 11.77 (5, 1H), 10.30 (bg, 5, 1H), 9.78 (bg, 5, 1H), 7.96 (5, 1H), 7.30 (b, δ = 8.4, 1H), 7.25 (bg, 5, 1H), 7.22 (bb, b = 8.4, 1H), 7.17 (5, 1H), 7.11 (B, 5, 1H), 6.76 (bg, 5, 1H), 3.69 (s, 3H), 3.45 (t, a = 6.5, 2H), 3.27 (t, a = 6 , 5, 2H), 2.20 (5, 3H), 1.91-1.75 (t, 4H); I_RM3 (M +) t / ζ461,09.

1-254: 5- (2- (3-Methoxy-5- (morpholin-4-carbonyl) -phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO)? 11.72 (5, 1H), 10.07 (bg, 5, 1H), 9.57 (bg, 5, 1H), 7.95 (5, 1H), 7.31 (b, δ = 8.4, 1H), 7.25 - 7.18 (t, 3H), 7.06 (5, 1H), 6.63 (5, 1H), 3.78 - 3.28 (t, 8H, overlapping), 3.68 (5, 3H, overlapped), 2.19 (5, 3H); LMM8 (M +) t / z 477.10.

1-255: 5- (2- (3-Methoxy-5- (4-methylpiperazine-1-carbonyl) -phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO) δ 11.75 (5, 1H), 10.42 (bg, 5, 1H), 10.07 (bg, 5, 1H), 9.64 (bg, 5, 1H), 8, 00 (5, 1H), 7.31 (b,? = 8.4, 1H), 7.25 - 7.21 (t, 3H), 7.06 (5, 1H), 6.68 (5, 1H), 4.01 - 3.01 (t, 8H, overlapped), 3.67 (5, 3H, overlapped), 2.86 (5, 3H), 2.19 (5, 3H); LMM8 (M +) m / z 490.10.

1-256: 5- (5-Methyl-2- (3- (morpholin-4-carbonyl) phenylamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹NMR (300 MHz, DMSO) δ 11.78 (5, 1H), 10.30 (5, 1H), 9.71 (5, 1H), 7.96 (5, 1H), 7.54-7 , 51

103

iA 106975 C2

(t, 2H), 7.37-7.31 (t, 2H), 7.25-7.23 (t, 2H), 7.12 (b, b = 7.6, 1H), 3.62 - 3.26 (t, 8H), 2.20 (5.3H); I. RPM (M +) m / z 447.09.

1-257: 5- (5-Methyl-2- (4- (morpholin-4-carbonyl) -phenylamino) pyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.83 (5, 1H), 10.38 (5, 1H), 9.71 (5, 1H), 7.98 (5, 1H), 7.55-7 , 7.23 (t, 2H), 7.39 (b, b = 8.5, 1H), 7.33 - 7.30 (t, 3H), 7.25 (bg b, b = 8.5, 1 H ), 3.63-3.51 (t, 8H), 2.20 (5, 3H); I.RMZ (M +) t / z 447.03.

1-258: 5- (2- (4-methoxy-3-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [b] oxazol-

2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.84 (5, 1H), 10.06 (5, 1H), 9.79 (5, 1H), 7.83 (5, 1H), 7.35 (b , b = 8.2, 1H), 7.27 - 7.23 (t, 2H), 7.17 - 7.14 (t, 2H), 6.91 (bbb, b = 8.2, 1 H ), 3.79 (5, 3H), 2.18 (5, 3H), 2.01 (5, 3H); I. RPM (M +) m / z 378.05.

1-259: 5- (2- (3-Methoxy-5-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [b] oxazol-

2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.72 (5, 1H), 9.85 (5, 1H), 9.39 (5, 1H), 8.15 (b, b = 4.4, 1 H) , 7.47 (bb, b = 8.6, 1.5, 1H), 7.39 - 7.27 (t, 4H), 6.87 (b, b = 8.6, 1H), 3, 78 (5, 3H), 2.06 (5, 3H); I. RPM (M +) m / z 378.05.

1-260: 2-methoxy-N, N-methyl-5- (5-methyl-4- (2-oxo-2,3-diprobenzo [b] oxazol-5-

ylamino) pyrimidine-2-ilamino) benzamide

¹H NMR (300 MHz, DMSO)? 11.80 (5, 1H), 9.99 (5, 1H), 9.68 (5, 1H), 7.87 (5, 1H), 7.38 (bg b, b =

8.9, 1H), 7.30 (b, b = 8.6, 1H), 7.25 - 7.20 (t, 3H), 7.06 (b, b = 8.9, 1H), 3.80 (5, 3H), 2.99 (5, 3H), 2.71 (5, 3H), 2.18 (5, 3H); I.RMZ (M +) t / z 435.11.

1-261: 5- (2- (4-methoxy-3- (pyrrolidine-1-carbonyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.82 (5, 1H), 9.81 (bg, 5, 1H), 9.50 (bg, 5, 1H), 7.87 (5, 1H), 7.40 (Bgb, b = 8.8, 1H), 7.31 (b, b = 2.9, 1H), 7.27 - 7.22 (t, 3H), 7.05 (b, b = 8, 8.1H), 3.80 (5, 3H), 3.46 (1H, b = 6.6, 2H), 3.05 (1H, b = 6.6, 2H), 2.17 (5, 3H), 1.92-1.74 (t, 4H); I.RMZ (M +) t / ζ 461.11.

1-262: 5- (2- (4-methoxy-3- (morpholin-4-carbonyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.75 (5, 1H), 9.88 (bg, 5, 1H), 9.52 (bg, 5, 1H), 7.87 (5, 1H), 7.45 (bb, b = 8.7, 1.9, 1H), 7.33 - 7.22 (t, 4H), 7.04 (b, b = 8.7, 1H), 3.81 (5, 3H), 3.65-3.08 (t, 8H), 2.18 (5.3H); I.RMZ (M +) t / z 477.10.

1-263: 5- (2- (4-methoxy-3- (4-methylpiperazine-1-carbonyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.77 (5, 1H), 9.96 (bg, 5, 1H), 9.59 (bg, 5, 1H), 7.91 (5, 1H), 7.53 (Bgb, b = 8.7, 1H), 7.34 - 7.25 (t, 4H), 7.07 (b, b = 8.7, 1 H), 4.60 - 3.10 (t, 8H, overlapping), 3.83 (5, 3H, overlapped), 2.89 (bg, 5, 3H), 2.18 (5, 3H); I_RM5 (M +) t / z 490.10.

1-264: 5- (2- (3-Methyl-4-trimethylmethoxyphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.83 (5, 1H), 9.99 (5, 1H), 9.78 (5, 1H), 7.81 (5, 1H), 7.35 (b , 7.39 (t, 2H), 6.91 ), 2.18 (5, 3H), 2.02 (5, 3H); I. RPM (M +) m / z 381.10.

1-265: 5- (2- (3-Chloro-4-methoxy-5-methylphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.74 (5, 1H), 9.89 (bg, 5, 1H), 9.57 (bg, 5, 1H), 7.92 (5, 1H), 7.48 (5.1H), 7.36 (b, b = 8.3, 1H), 7.24-7.18 (t, 3H), 3.71 (5, 3H), 2.18 (5, 3H ), 2.14 (5, 3H); I. RPM (M +) t / z411,97.

1-266: 5- (2- (3-Methyl-5-trimethylmethoxyphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.77 (5, 1H), 9.93 (bg, 5, 1H), 9.72 (bg, 5, 1H), 7.90 (5, 1H), 7.35 (b, b = 8.3, 1H), 7.25 - 7.22 (t, 2H), 6.84 (5, 1H), 6.81 (5, 1H), 6.50 (5, 1H ), 3.43 (5, 3H), 2.19 (5, 3H), 2.12 (5, 3H); I. RPM (M +) t / z 381.10.

1-257: 2-methoxy-N, N-methyl-4- (5-methyl-4- (2-oxo-2,3-diprobenzo [b] oxazol-5-

ylamino) pyrimidine-2-ilamino) benzamide

¹H NMR (300 MHz, DMSO)? 11.75 (5, 1H), 10.49 (5, 1H), 9.74 (5, 1H), 7.92 (5, 1H), 7.30-7 , 7.33 (brs, 5H), 3.45 (5, 3H), 2.92 (5, 3H), 7.04 (b, , 2.70 (5, 3H), 2.14 (5, 3H).

1-268: 5- (2- (3-Methoxy-4- (pyrrolidine-1-carbonyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [b] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.74 (5, 1H), 10.33 (5, 1H), 9.66 (5, 1H), 7.90 (5, 1H), 7.30-7 (B, J = 5.9, 1H), 7.04 (br, 5H, 2H), 3.46 (s, 3H), 3.38 (s, 6.5, 2H), 3.03 (1H, b = 6.5, 2H),

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iA 106975 C2

2.14 (s, 3H), 1.79 (Ci, b = 18.9, 6.5, 4H).

k269: 5- (2- (3-methoxy-4- (morpholin-4-carbonyl) -phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.71 (s, 1H), 10.26 (s, 1H), 9.65 (s, 1H), 7.89 (s, 1H), 7.31 - 7 , 7.07 (br s, 2H), 3.57 (bs, 4H), 3.47 (bg, s, &amp; lt; RTI ID = 0.0 &amp; gt; 2H), 3.45 (s, 3H), 3.08 (bs, 2H), 2.14 (s, 3H).

L270: 5- (2- (3-methoxy-4- (4-methylpiperazine-1-carbonyl) phenylamino) -5-methylpyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.75 (s, 1H), 10.30 (s, 1H), 9.95 (s, 1H), 9.48 (s, 1H), 7.94 (s , 1H), 7.29 - 7.04 (t, 6H), 3.44 (s, 3H), 2.82 (s, 3H), 2.13 (s, 3H).

Bis71: 5- (2- (3- (difluoromethyl) -4-methoxyphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.59 (s, 1H), 9.16 (s, 1H), 8.54 (s, 1H), 7.84 (s, 1H), 7.71 (C , b = 11.0, 2H), 7.31 (C, b = 8.4, 1H), 7.31 (s, 1H), 7.20 (C, b = 8.4, 1H), 6 , 94 (bs, b = 55.4, 1H), 6.93 (s, 1H), 3.76 (s, 3H), 2.08 (s, 3H).

L272: 5- (2- (4-methoxyphenylamino) -5-methylpyrimidin-4-ylamino) benzo [S] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.61 (s, 1H), 8.93 (s, 1H), 8.49 (s, 1H), 7.80 (s, 1H), 7.46 (C , b =

8.9, 2H), 7.31 (C, b = 9.0, 2H), 7.30 (s, 1H), 7.21 (C, b = 9.0, 1H), 6.74 ( C, b = 8.9, 2H), 3.67 (s, 3H), 2.07 (s, 3H).

L273: 5- (2- (3- (Difluoromethyl) -5-methoxyphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.66 (s, 1H), 10.12 (s, 1H), 9.56 (s, 1H), 7.89 (s, 1H), 7.29 - 7 , 11 (t, 5H), 6.76 (bs, b = 55.9, 1H), 6.73 (s, 1H), 3.62 (s, 3H), 2.13 (s, 3H).

L274: 5- (2- (3- (fluoromethyl) -5-methoxyphenylamino) -5-methylpyrimidin-4-

ylamino) benzo [S] oxazol-2 (3H) -one

¹H NMR (300 MHz, DMSO)? 11.70 (s, 1H), 10.17 (s, 1H), 9.68 (s, 1H), 7.88 (s, 1H), 7.28 (C , b =

8.6, 1H), 7.18 (s, 1H), 7.16 (C, b = 8.6, 1H), 7.02 (s, 1H), 6.98 (s, 1H), 6 , 64 (s, 1H), 5.25 (s, 1H), 5.09 (s, 1H), 3.60 (s, 3H), 2.13 (s, 3H).

L275: Ch2- [4- (4,4-difluoropiperidinyl) -3-fluoro] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.56 (s, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.64 (C , b =

15.3, 1H), 7.25 (t, 3H), 7.18 (C, b = 10.8, 1H), 6.88 (br, i = 9.4, 1H), 2.99 ( and 4H), 2.08 (s, 3H), 2.08 (t, 4H); ^19thR NMR (282 MHz, DMSO)? -111.68, -138.03; I_SM3: purity: 97.23%; MS (t / e): 471.27 (M + H).

L276: Ch2- [4- (4,4-difluoropiperidinyl) -3-trifluoromethyl] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-

1,3-benzoxazol-5-yl) -2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.51 (s, 1H), 9.28 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.88 (s , 1H),

7.80 (s, 1H), 7.36 (C, b = 8.4, 1H), 7.27 (t, 2H), 7.19 (C, b = 9.3, 1H), 2, 88 (i, 4H), 2.09 (s, 3H), 2.03 (t, 4H); ^19thR NMR (282 MHz, DMSO) δ 75.78; I_SM3: purity: 89.60%; MS (t / e): 521.31 (M + H).

L277: Ch2- [3-chloro-4- (4,4-difluoropiperidinyl)] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.53 (s, 1H), 9.05 (s, 1H), 8.37 (s, 1H), 7.85 (t, 2H), 7.37 (C , b = 9.0, 1H), 7.23 (t, 3H), 6.99 (C, b = 9.0, 1H), 2.95 (s, b = 5.1, 4H), 2 , 08 (s, 3H), 2.08 (t, 4H); I_SM3: purity: 93.39%; MS (t / e): 487.23 (M + H).

L278: Ch2- [3-chloro-4- (4-ethylpiperazino)] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.55 (b, 1H), 9.02 (s, 1H), 8.37 (s, 1H), 7.83 (C, b = 6.6, 2H) , 7.37 (C, b = 9.0, 1H), 7.22 (t, 3H), 6.93 (C, b = 9.6, 1H), 2.87 (s, 4H), 2 , 08 (s, 3H), 1.03 (b, b = 6.9, 3H); I_SM3: purity: 89.90%; MS (t / e): 480.29 (M + H).

L279: Ch2- [4- (4,4-difluoropiperidinyl)] phenyl-5-methyl-Ch4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.58 (br, 1H), 8.73 (s, 1H), 8.25 (s, 1H), 7.80 (s, 1H), 7.46 (C (bd, 7.8, 2H), 7.32 (C, b = 9.9, 2H), 7.20 (C, b = 7.8, 1H), 6.79 (C, b = 8, 1, 2H), 3.16 (t, 4H), 2.06 (s, 3H), 2.03 (t, 4H); ^19thR NMR (282 MHz, DMSO)? 111.17; I_SM3: purity: 97.36%; MS (t / e): 453.23 (M + H).

L280: Ch2- (3,5-dimethoxy) phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.51 (s, 1H), 8.89 (s, 1H), 8.33 (s, 1H), 7.85 (s, 1H), 7.29 (s , 1H),

7.27 (C, b = 11.1, 1H), 7.17 (C, b = 9.3, 1H), 6.89 (C, b = 2.1, 2.2H), 5.96 (s , 1H), 3.56 (s, 6H), 2.08 (s, 3H); I_SM3: purity: 91.13%; MS (t / e): 394.24 (M + H).

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iA 106975 02

1-281: N2- [3-Fluoro-4- (4-methylpiperazino)] phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.65 (s, 1H), 9.57 (bg, 1H), 7.86 (s, 1H), 7.49 (3, 1H), 7.27 (3 , b = 7.2, 1H), 7.20 (t, 2H), 7.07 (3, 1H), 6.98 (1H, b = 9.0, 1H), 3.48 (3, b = 10.5, 2H), 3.34 (3, b = 12.0, 2 H), 3.20 (3, 2 H), 2.93 (3, b = 12.3, 2 H), 2.86 (s, 3H), 2.12 (s, 3H); I.SM8: purity: 82.99%; MS (t / e): 450.26 (M + H).

1-282: N2- [3,5-Difluoro-4- (4-methylpiperazino)] phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.62 (s, 1H), 9.77 (bd, 1H), 9.53 (bd, 1H), 9.03 (bg, 1H), 7.90 (s , 1H),

7.28 - 7.13 (t, 5H), 3.43 (3, b = 11.1, 2H), 3.24 (3, b = 12.3, 2H), 3.15 (bg, 4H) ), 2.84 (3, b = 3.6, 3H), 2.11 (s, 3H); I.SM8: purity: 92.64%; MS (t / e): 468.29 (M + H).

1-283: N2- [4-chloro-3- (4-ethylpiperazino)] phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 9.07 (s, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 7.51 (s , 1H), 7.35 - 7.18 (t, 4H), 7.08 (3, b = 9.0, 1H), 2.72 (bg, 4H), 2.42 (bg, 4H), 2.36 (q, b = 7.2, 2H), 2.09 (s, 3H), 1.02 (I, b = 7.2, 3H); I_SM8: purity: 94.40%; MS (t / e): 480.28 (M + H).

1-284: N2- [4-chloro-3- (3,4,5-trimethylpiperazino)] phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.57 (s, 1H), 9.05 (s, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.87 (from , 1H), 7.32 (t, 3H), 7.20 (3, b = 8.7, 1H), 7.13 (3, b = 8.4, 1H), 2.09 (s, 3H ), 1.23 (bg, 6H); I_SM8: cleanliness: 80.46%; MS (t / e): 494.32 (M + H).

1-2585: 5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- [3- (4-propylpiperazino) -4-

trifluoromethyl] phenyl-2,4-pyrimidinediamine

NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 9.28 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.88 (s , 2H),

7.29 (s, 3H), 1.60 (bg, 2H) , 0.90 (I, b = 7.2, 3H); ^19thHYAMP (282 MHz, DMSO) δ 75.43; I_SM8: cleanliness: 95.71%; MS (t / e): 528.37 (M + H).

1-286: 5-methyl-N2- [3- (1,3-oxazol-5-yl)] phenyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.57 (s, 1H), 10.03 (bg, 1H), 9.49 (bg, 1H), 8.32 (s, 1H), 7.88 (s , 1H), 7.80 (s, 1H), 7.40 (t, 2H), 7.32 (t, 2H), 7.22 (s, 2H), 7.12 (3, b = 9, 3, 1H), 2.15 (s, 3H); I_SM8: purity: 95.22%; MS (t / e): 401.23 (M + H).

1-287: N2- (3-Bromo) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.59 (s, 1H), 9.30 (s, 1H), 8.54 (s, 1H), 7.96 (s, 1H), 7.88 (from , 1H), 7.45 (3, b = 8.1, 1H), 7.23 (t, 2H), 7.05 (1H, b = 7.8, 1H), 6.96 (t, 2H) ), 2.10 (s, 3H); I_SM8: purity: 97.81%; MS (t / e): 412.11 (M + H).

1-288: N2- (4-Bromo) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.61 (s, 1H), 9.14 (s, 1H), 8.37 (s, 1H), 7.86 (s, 1H), 7.62 (3 , b = 9.0, 2H), 7.26 (t, 5H), 2.09 (s, 3H); I_SM8: purity: 98.23%; MS (t / e): 412.12 (M + H).

1-289: 5-Methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- [3- (pyridin-4-yl)] phenyl-2,4 -

pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.52 (s, 1H), 8.58 (3, 2H), 7.99 (b, 1H), 7.89 (s, 1H), 7.56 (t , 2H), 7.49 (t, 2H), 7.42 (3, 1H), 7.19 (t, 2H), 7.07 (3, 1H), 2.15 (s, 3H); I_SM8: purity: 94.63%; MS (t / e): 411.24 (M + H).

1-290: 5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- [3- (pyridin-3-yl)] phenyl-2,4 -

pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.54 (s, 1H), 8.62 (s, 1H), 8.53 (3, 1H), 7.84 (t, 3H), 7.39 (t , 4H),

7.18 (t, 2H), 7.01 (3, 1H), 2.15 (s, 3H); I_SM8: purity: 86.04%; MS (t / e): 411.24 (M + H).

1-291: 5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- [4- (pyridin-3-yl)] phenyl-2,4 -

pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.73 (s, 1H), 8.88 (s, 1H), 8.55 (3, 1H), 8.11 (3, 1H), 7.88 (from , 1H), 7.60 (t, 5H), 7.33 (3, 1H), 7.26 (t, 2H), 2.16 (s, 3H); I_SM8: purity: 94.74%; MS (t / e): 411.21 (M + H).

1-292: N2- [4-methoxy-3- (2-methoxyethoxy)] phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.52 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.31 (3 , b =

2.4, 3H), 7.17 (3, b = 9.3, 1 H), 7.13 (3, b = 8.1, 1 H), 6.72 (3, b = 9.0, 1 H ), 3.69 (1H, b = 4.8, 2H), 3.66 (s, 3H), 3.50 (3, b = 4.2, 2H), 3.26 (s, 3H), 2.07 (s, 3H); I_SM8: cleanliness: 95.38%; MS (t / e): 438.08 (M + H).

106

iA 106975 C2

1-293: N2- [3- (cycloproptanno-carbonomethoxy) -4-methoxy] phent-5-methyl-4-4- (2-oxo-2,3-

dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.69 (5, 1H), 9.86 (bd, 1H), 9.54 (bd, 1H), 7.92 (5, 1H), 7.75 (5 , 1H),

7.23 (5, 3H), 6.98 (b, 1H), 6.89 (b, b = 9.6, 2H), 4.26 (5, 2H), 3.74 (5, 3H), 2 , 64 (p, b = 3.9, 1 H), 2.13 (5, 3 H), 0.62 (b, J = 6.0, 2 H), 0.44 (br, 2.7, 2H); I.SM8: purity: 96.56%; MS (t / e): 477.28 (M + H).

1-294: N2- (3-cyano-4-fluoro) fent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.19 (bg, 1H), 9.42 (5, 1H), 8.47 (5, 1H), 8.25 (bb, b = 2.7, 5, 7, 1H), 7.90 (5, 1H), 7.72 (t, b = 4.5, 1H), 7.34 - 7.17 (t, 4H), 2.10 (5, 3H) ; ^19thR NMR (282 MHz, DMSO) δ -135.29; I.SM8: purity: 94.39%; MS (t / e): 377.18 (M + H).

1-295: N2- [3-cyano-4- (1H-pyrrol-1-t)] fent-5-methyl-4-oxo-2,3-dipro-1,3-benzoxazol-5- yl) -2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 9.54 (5, 1H), 8.49 (5, 1H), 8.33 (b, b = 2.4, 1 H), 7.93 (5, 1 H) , 7.79 (b, b = 8.7, lH), 7.36 (b, b = 8.7, lH), 7.28 (5, 1H), 7.25 (b, b = 8, 4, 1H), 7.20 (b, b = 9.6, 1H), 7.07 (5.2H), 6.25 (5, 2H), 2.11 (5, 3H); I.SM8: purity: 94.01%; MS (t / e): 424.23 (M + H).

1-296: N2- (3-methoxy-5-trifluoromethyl) fent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 9.30 (5, 1H), 8.41 (5, 1H), 7.90 (5, 1H), 7.58 (b, 2H), 7.24 (5 , 1H),

7.18 (t, 2H), 6.62 (5, 1H), 3.64 (5, 3H), 2.09 (5, 3H); ^19thR NMR (282 MHz, DMSO) δ - 77.41; I.SM8: purity: 95.05%; MS (t / e): 432.21 (M + H).

1-297: N2- (4-methoxy-3-trifluoromethyl) fent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.15 (bg, 1H), 9.04 (5, 1H), 8.33 (5, 1H), 7.90 (5, 1H), 7.85 (5 , 1H),

7.81 (b, b = 8.7, 1H), 7.28 (5, 1H), 7.27 (b, b = 6.3, 1H), 7.17 (b, b = 9.0 , 1H), 7.03 (b, b = 9.0, 1H), 3.78 (5, 3H), 2.08 (5, 3H); ^19thR NMR (282 MHz, DMSO) ?δ 76.81; I.SM8: purity: 96.38%; MS (t / e): 432.19 (M + H).

1-298: N2- {4-methoxy-3 - [(pyridin-4-one) methoxy]} phent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.51 (b, 1H), 8.76 (s, 1H), 8.52 (b, b = 6.0, 2H), 8.27 (5, 1H) , 7.82 (5, 1H), 7.43 (5, 1H), 7.33 (b, b = 8.4, 1H), 7.32 (5, 1H), 7.28 (b, b = 5.1, 2.2H), 7.16 (t, 2H), 6.78 (b, b =

8.7, 1 H), 4.81 (5, 2 H), 3.71 (5, 3 H), 2.07 (5, 3 H); I.SM8: purity: 93.03%; MS (t / e): 471.25 (M + H).

1-299: N2- {4-methoxy-3 - [(pyridin-3-t) methoxy]} phent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.52 (5, 1H), 8.81 (b, 1H), 8.51 (5, 1H), 8.50 (b, b = 7.2, 1H) , 7.83 (5, 1H), 7.72 (b, b = 7.5, 1H), 7.46 (5, 1H), 7.38 (b, b = 3.9, 1H), 7 , 6.78 (b, b = 8.7, 1 H), 4.80 (5, 2 H), 3.68 (s, 3 H) (5, 3H), 2.07 (5, 3H); I.SM8: purity: 91.60%; MS (t / e):

471.23 (M + H).

1-300: N2- {4-methoxy-3- [2- (dimetamino) ethoxy) phentet-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 8.72 (5, 1H), 8.25 (5, 1H), 7.82 (5, 1H), 7.33 (5, 2H), 7.31 (b , b = 10.2, 1H), 7.16 (b, b = 8.7, 1H), 7.13 (b, b = 11.1, 1H), 6.72 (b, b = 9, 0, 1 H), 3.74 (b, J = 5.7, 2H), 3.66 (5, 3H), 2.16 (5, 6H), 2.07 (5, 3H); I.SM8: purity: 98.92%; MS (t / e): 451.26 (M + H).

1-301: N2- [3,5-B (trifluoromethyl)] fent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-benzoxazol-5-yl) -2,4- pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.52 (5, 1H), 10.04 (bg, 1H), 8.99 (bg, 1H), 8.18 (5, 2H), 7.96 (5 , 1H), 7.48 (5, 1H), 7.20 (t, 3H), 2.14 (5, 3H); ^19thR NMR (282 MHz, DMSO)? -77.91; I.SM8: purity: 96.63%; MS (t / e): 470.18 (M + H).

1-302: N2- (3,5-methyl) phent-5-methyl-4-oxo-2-oxo-2,3-dipro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.71 (5, 1H), 9.79 (bd, 1H), 9.59 (bg, 1H), 7.83 (5, 1H), 7.30 (b , b =

9.6, 1 H), 7.20 (5, 2 H), 6.98 (5, 2 H), 6.65 (5, 1 H), 2.14 (5, 3 H), 2.05 (5, 6 H ); I.SM8: purity: 96.82%; MS (t / e): 362.17 (M + H).

1-303: N2- (4-Cyano-3-trifluoromethyl) fent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.55 (b, 1 H), 9.98 (5, 1 H), 8.56 (5, 1 H), 8.27 (5, 1 H), 8.03 , b =

8.1, 1H), 7.97 (5, 1H), 7.84 (b, b = 9.3, 1H), 7.26 (5, 1H), 7.23 (5, 2H), 2 , 12 (5, 3H); To NMR (282 MHz, DMSO)? -77.44; I.SM8: purity: 93.84%; MS (t / e): 427.16 (M + H).

1-304: N2- [3- (1-hydroxy-2,2,2-trifluoroethyl)] phent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO) δ 11.69 (5, 1H), 10.00 (bg, 1H), 9.49 (bg, 1H), 7.85 (5, 1H), 7.56 (b , b =

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iA 106975 C2

8.1, 1H), 7.41 (s, 1H), 7.29 - 7.12 (t, 4H), 6.81 (s, 1H), 4.92 (ς, 1H), 2.14 (s, 3H); ^19thH NMR (282 MHz, DMSO)? -92.60 (b, b = 6); ^ SM8: purity: 96.71%; MS (t / e): 432.14 (M + H).

I-305: H2- (3-methoxycarbonylmethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.54 (s, 1H), 8.98 (s, 1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.35 (s , 1H), 7.31 (s, 2H), 7.22 (s, 1H), 7.20 (b, b = 4.8, 1 H), 6.99 (br, s = 8.1, 1 H ), 6.35 (b, b = 8.1, 1H), 4.56 (s, 2H), 3.67 (s, 3H), 2.09 (s, 3H); ^ SM8: purity: 90.78%; MS (t / e): 422.18 (M + H).

I-306: 5-methyl-H2- (3-methylaminocarbonylmethoxy) phenyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 10.63 (bg, 1H), 8.99 (s, 1H), 8.30 (s, 1H), 7.89 (b, 1H), 7.86 (from , 1H), 7.39 (s, 1H), 7.33 (b, 2H), 7.24 (b, b = 8.1, 1H), 7.18 (b, b = 9.0, 1 H ), 7.01 (br d, b = 8.1, 1 H), 6.38 (b, b =

8.1, 1H), 4.26 (s, 2H), 2.63 (b, b = 4.5, 3H), 2.09 (s, 3H); ^ SM8: purity: 95.80%; MS (t / e): 421.21 (M + H).

I-307: H2- (4-aminocarbonylmethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO) δ 11.58 (br, 1H), 8.79 (s, 1H), 8.26 (s, 1H), 7.81 (s, 1H), 7.52 (b , b =

8.7, 2H), 7.45 (s, 1H), 7.35 (b, 2H), 7.31 (s, 1H), 7.20 (b, b = 8.4, 1H), 6 , 75 (b, b = 8.7, 2H), 4.31 (s, 2H), 2.07 (s, 3H); ^ SM8: purity: 90.97%; MS (t / e): 407.20 (M + H).

I-308: 5-methyl-4-4- (2-oxo-2,3-dipro-1,3-benzoxazol-5-t) -N2- (4-

phenylcarbonylamino) phenyl-2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 10.06 (s, 1H), 8.94 (s, 1H), 8.30 (s, 1H), 7.90 (b, b = 7.2, 2H) , 7.85 (s, 1H), 7.60 (b, b = 9.0, 2H), 7.51 (t, 6H), 7.36 (b, b = 8.4, 1H), 7 , 31 (s, 1H), 7.20 (b, b = 8.1, 1H), 2.09 (s, 3H); ^ SM8: purity: 98.33%; MS (t / e): 453.21 (M + H).

I-309: N2- [4- (N-acetyl-N-methyl) amino] fent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 10.93 (b, 1H), 9.11 (s, 1H), 8.34 (s, 1H), 7.86 (s, 1H), 7.67 (b , b =

8.4, 2H), 7.29 (b, 2H), 7.22 (b, b = 8.1, 1H), 7.04 (b, b = 8.7, 2H), 3.07 ( s, 3H), 2.09 (s, 3H), 1.72 (s, 3H); ^ SM8: purity: 95.99%; MS (t / e): 405.22 (M + H).

I-310: H2- [3-cyano-4- (pyrrolidin-1-yl)] phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 10.12 (bg, 1H), 8.86 (s, 1H), 8.30 (s, 1H), 7.83 (b, b = 6.0, 2H) , 7.52 (b, b = 9.0, 1H), 7.25 (s, 1H), 7.18 (br, s = 8.4, 2H), 6.64 (b, b = 9, 3, 1H), 3.40 (s, 4H), 2.07 (s, 3H), 1.90 (s, 4H); ^ SM8: purity: 96.09%; MS (t / e): 428.20 (M + H).

I-311: H2- (4-Difluoromethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 10.48 (b, 1H), 9.04 (s, 1H), 8.32 (s, 1H), 7.85 (s, 1H), 7.65 (b , b =

9.3, 2 H), 7.28 (b, 2H), 7.20 (b, b = 9.3, 1 H), 7.02 (br, b = 75, 1 H), 6.93 (b, b = 9.0, 2H), 2.08 (s, 3H); ^19thRNMR (282 MHz, DMSO) δ - 96.76 (b, b = 73); ^ SM8: purity: 97.82%; MS (t / e): 400.16 (M + H).

I-312: H2- (3-Difluoromethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 10.54 (b, 1H), 9.18 (s, 1H), 8.36 (s, 1H), 7.88 (s, 1H), 7.61 (s , 1H), 7.43 (b, b = 8.1, 1H), 7.27 (b, 2H), 7.18 (b, b = 8.7, 1 H), 7.12 (br, = 8.4, 1 H), 6.99 (br d, b = 75, 1 H), 6.58 (b, b = 9.0, 1 H), 2.09 (s, 3 H); ¹T NMR (282 MHz, DMSO)? 96.98 (b, b = 73); ^ SM8: purity: 97.94%; MS (t / e): 400.16 (M + H).

I-313: H2- (4-Difluoromethoxy-3-ethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 9.02 (s, 1H), 8.35 (s, 1H), 7.87 (s, 1H), 7.51 (s, 1H), 7.28 (b , 7.21 (s, 1H), 7.16 (b, b = 8.7, 1H), 6.90 (b, b = 9.0, 1H), 6 , 3.68 (s, 3H), 1.18 (br, s = 6.9, 3H) ; ^19thH NMR (282 MHz, DMSO) δ = 96.43 (b, b = 76); ^ SM8: purity: 96.55%; MS (t / e): 444.16 (M + H).

I-314: H2- (3-Chloro-4-difluoromethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 9.27 (s, 1H), 8.44 (s, 1H), 7.98 (b, b = 2.4, 1H), 7.88 (s, 1H) , 7.43 (b, b = 9.0, 1 H), 7.23 (s, 3 H), 7.11 (b, b = 9.0, 1 H), 7.03 (br d, 72 = 1H), 2.09 (s, 3H); ^19thH NMR (282 MHz, DMSO) δ = 97.27 (b, b = 73); ^ SM8: purity: 97.47%; MS (t / e): 434.12 (M + H).

I-315: H2- [3- (cyclopropylaminocarbonylmethoxy)] phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.66 (s, 1H), 9.82 (b, 1H), 9.48 (bd, 1H), 8.04 (b, b = 4.2, 1H) , 7.84 (s, 1H), 7.25 (s, 3H), 7.09 (b, b = 7.5, 1H), 7.05 (s, 2H), 6.56 (b, b = 9.0, 1H), 4.28 (s, 2H), 2.65 (p, b = 3.0, 1H), 2.14 (s, 3H), 0.62 (d, b = 4 , 8, 2H), 0.46 (d, b = 2.7, 2H); ^ SM8: purity: 91.36%; MS (t / e):

108

iA 106975 C2

447.23 (M + H).

I-316: Ch2- [3-aminocarbonyl-4- (4-methylpiperazino)] phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2 , 4-pyrimidindinamine

¹H NMR (300 MHz, DMSO)? 8.97 (5, 2H), 8.25 (5, 1H), 7.91 (5, 1H), 7.83 (t, b = 6.0, 2H) , 7.45 (5.1H), 7.36 (b, b = 8.4, 1H), 7.32 (5, 1H), 7.16 (b, b = 8.1, 1H), 7 , 03 (b, b = 8.4, 1H), 2.84 (t, 4H), 2.22 (5.3H), 2.08 (5, 3H); LSMS: purity: 92.35%; MS (t / e): 475.28 (M + H).

I-317: 2- [4- (isopropoxycarbonylmethoxy)] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.74 (5, 1H), 9.86 (b, 1H), 9.58 (b, 1H), 7.78 (5, 1H), 7.29-7 (T, 5H), 6.83 (b, b = 8.7, 2H), 4.97 (p, b = 6.9, 1 H), 4.68 (5, 2 H), 2.12 (5, 3H), 1.19 (b, b = 6.0, 6H); LSMS: purity: 76.08%; MS (t / e): 450.24 (M + H).

I-318: 2- [4- (ethylamino-carbonylamino)] phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.71 (5, 1H), 9.78 (bg, 1H), 9.54 (bp, 1H), 8.40 (5, 1H), 7.76 (5 , 1H),

7.26 (5, 7H), 6.07 (5, 1H), 3.07 (s, b = 6.6, 2H), 2.12 (5, 3H), 1.02 (t, b = 6.9, 3 H); LSMS: purity: 94.25%; MS (t / e): 420.24 (M + H).

I-319: CH2- [3- (aminocarbonylmethoxy)] phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine

1H NMR (300 MHz, DMSO)? 11.68 (5, 1H), 7.84 (5, 1H), 7.42 (5, 1H), 7.37 (5, 1H), 7.27 (5 , 3H), 7.10 (t, 3H), 6.61 (5, 1H), 4.29 (5, 2H), 2.13 (5, 3H); LSMS: purity: 91.03%; MS (t / e): 407.19 (M + H).

I-320: 5-methyl-2- [3- (morpholinocarbonylmethoxy)] phenyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.68 (5, 1H), 9.95 (bg, 1H), 9.58 (bp, 1H), 7.85 (5, 1H), 7.30 (b , b =

8.7, 1H), 7.23 (b, b = 6.6, 2H), 7.11 (t, b = 7.8, 1H), 6.99 (b, b = 9.6, 2H) ), 6.61 (b, b = 7.2, 1H), 4.69 (5.2H), 3.55 (5,4H), 3.41 (5,4H), 2.14 (5, 3H); LSMS: purity: 96.33%; MS (t / e): 477.25 (M + H).

I-321: 5-methyl-2- [3- (4-methylpiperazin-1-yl) carbonyl] phenyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.70 (5, 1H), 10.15 (b, 1H), 9.88 (bd, 1H), 9.43 (bd, 1H), 7.92 (5 , 1H), 7.58 (b, b = 7.8, 1H), 7.52 (5, 1H), 7.30-7.22 (t, 4H), 7.06 (b, b = 7 , 2, 1H), 3.40 (bg, 4H), 3.03 (bg, 4H), 2.80 (5, 3H), 2.13 (5, 3H); LSMS: purity: 95.46%; MS (t / e): 460.29 (M + H).

I-322: 5-methyl-2- [4- (4-methylpiperazin-1-yl) carbonyl] phenyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.71 (5, 1H), 9.83 (b, 1H), 7.93 (5, 1H), 7.61 (b, b = 9.0, 2H) , 7.33 (t, 5H), 3.39 (t, 2H), 3.23 (t, 2H), 3.06 (t, 2H), 2.81 (5, 3H), 2.13 ( 5, 3 H); I_SMZ: purity: 86.87%; MS (t / e): 460.30 (M + H).

I-323: 5-methyl-2- [3-methylaminocarbonyl-4- (4-methylpiperazino)] phenyl-4- (2-oxo-2,3-

dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.73 (5, 1H), 10.02 (bg, 1H), 9.64 (bd, 2H), 8.45 (b, 1H), 7.87 (5 1H), 7.58 (5, 1H), 7.48 (b, 1H), 7.21 (5, 3H), 7.03 (b, b = 8.4, 1H), 3.49 ( b, b = 9.3, 2H), 3.17 (t, b = 6.6.4H), 2.94 (b, 2H), 2.87 (5, 3H), 2.81 (b, b = 4.8, 3H), 2.13 (5, 3H); I_SMZ: purity: 93.72%; MS (t / e): 489.30 (M + H).

I-324: 2- [4- (1-aminocarbonyl-1-methyl) ethoxy] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 8.83 (5, 1H), 8.28 (5, 1H), 7.82 (5, 1H), 7.49 (b, b = 9.0, 2H) , 7.46 (5.1H), 7.34 (b, b = 9.6, 1H), 7.29 (5, 1H), 7.18 (b, b = 8.7, 2H), 6 , 72 (b, b = 9.0, 2H), 2.06 (5, 3H), 1.32 (5, 6H); I_SMZ: purity: 94.37%; MS (t / e): 435.21 (M + H).

I-325: 5-methyl-C2- (2-methyl-3-methylaminocarbonylmethoxy) pnevupI-C4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 8.15 (5, 1H), 8.06 (5, 1H), 7.83 (b, 1H), 7.76 (5, 1H), 7.39 (b , b =

9.3, 1H), 7.29 (5, 1H), 7.16 (b, b = 7.5, 1H), 7.04 (b, b = 8.1, 2 H), 6.58 ( b, b = 8.4, 1H), 4.42 (5, 2H), 2.65 (b, b = 4.5, 3H), 2.07 (5, 3H), 2.04 (5, 3H); I_SMZ: purity: 94.87%; MS (t / e): 435.26 (M + H).

I-326: CH2- (3-Dimethylaminocarbonylmethoxy) phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.30 (bg, 1H), 8.94 (5, 1H), 8.31 (5, 1H), 7.87 (5, 1H), 7.34 (b , b =

6.6, 3H), 7.21 (b, b = 9.0, 2H), 6.99 (t, b = 8.1, 1H), 6.37 (b, b = 8.4, 1 H ), 4.60 (5, 2H), 2.94 (5, 3H),

2.82 (5, 3H), 2.08 (5, 3H); I_SMZ: purity: 93.47%; MS (t / e): 435.22 (M + H)

I-327: Ch2- (3-cyano-4-morpholino) phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-

yl) -2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 7.41 (5, , 7.88

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iA 106975 C2

(s, 1H), 7.65 (b, J = 7.5, 1H), 7.24 (b, J = 8.1, 3 H), 7.02 (b, J = 9.0, 1 H) , 3.71 (br, 4H), 2.97 (br, 4H), 2.08 (s, 3H); I_SM8: purity: 93.52%; MS (t / e): 444.22 (M + H).

I-328: H2- (3-methoxy-2-methyl) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.70 (s, 1H), 9.70 (s, 1H), 9.55 (s, 1H), 7.71 (s, 1H), 7.22 (t , 3.19 (s, 3H), 7.16 (b,? = 8.1, 1H), 6.92 (d, J = 6.9, 2H), 3.78 (s, 3H), 2.11 (s, 3H ), 1.96 (s, 3H); I_SM8: purity: 94.95%; MS (t / e): 378.22 (M + H).

I-329: H2- [3-chloro-4- (pyridin-4-yl)] phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-

yl) -2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.72 (s, 1H), 9.55 (b,? = 7.8, 2 H), 9.38 (s, 1 H), 8.41 (s, 1 H) , 8.30 (b, J = 7.2, 2 H), 7.51 (b, J = 8.7, 1 H), 7.40 (s, 1 H), 7.34 (s, 2 H), 6 , 81 (s, 1H), 6.73 (b, 1H), 6.50 (bg, 1H), 2.31 (s, 3H); I_SM8: cleanliness: 68.83%; MS (t / e): 445.19 (M + H).

I-330: 5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- [4- (pyridin-4-yl) -3-

trifluoromethyl] phenyl-2,4-pyrimidinediamine

NMR (300 MHz, DMSO)? 11.74 (s, 1H), 9.65 (b,? = 7.2, 2 H), 9.40 (s, 1 H), 8.42 (s, 1 H) , 8.13 (b, J = 7.2, 2 H), 7.39 (s, 1 H), 7.34 (t, 3 H), 7.11 (s, 1 H), 6.93 (b, = 8.1, 1 H), 6.43 (bd, 1H), 2.32 (s, 3 H); ^19thH NMR (282 MHz, DMSO) δ - 70.12; I_SM8: purity: 86.84%; MS (t / e): 479.21 (M + H).

I-331: H2- [3-hydroxymethyl-4- (4-methylpiperazino)] phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2 , 4-pyrimidindinamine

¹H NMR (300 MHz, DMSO)? 11.70 (bg, 1H), 9.52 (bd, 1H), 7.82 (s, 1H), 7.37 (bd, 2H), 7.25 (s , 3.49 (s, 3H), 6.94 (b, 1H), 4.45 (s, 2H), 3.49 (bg, 4H), 3.14 (s, 3H), 2.86 (s, 4H), 2 , 12 (s, 3H); I_SM8: purity: 73.83%; MS (t / e): 462.30 (M + H).

I-332: 5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- (4-piperazino) phenyl-2,4-

pyrimidine diamine

¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 9.99 (bg, 1H), 9.64 (bg, 1H), 8.70 (bd, 2H), 7.81 (s , 1 H),

7.29 - 7.22 (t, 5H), 6.90 (b, J = 8.7, 2H), 3.24 (s, 8H), 2.12 (s, 3H); I_SM8: purity: 94.64%; MS (t / e): 418.24 (M + H).

I-333: H2- [4- (4-Ethylaminocarbonyl) piperazino] phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.75 (s, 1H), 9.88 (s, 1H), 9.69 (s, 1H), 7.74 (s, 1H), 7.30-7 , 6.89 (b, J = 7.8, 2H), 6.57 (s, 1H), 3.39 (s, 4H), 3.02 (s, 6H), 16 (t, 5H), 6.89 2.12 (s, 3H), 1.00 (d, J = 7.2, 3H); I_SM8: purity: 73.76%; MS (t / e): 489.28 (M + H).

I-334: H2- [4- (1-cyano-1-methyl) ethoxy] phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) - 2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.75 (s, 1H), 10.08 (s, 1H), 9.66 (s, 1H), 7.85 (s, 1H), 7.38 (b , à =

8.7, 2 H), 7.28 (b, J = 8.7, 1 H), 7.21 (s, 2 H), 7.03 (b, J = 9.0, 2 H), 2.13 ( c, 3 H), 1.63 (s, 6 H); I_SM8: purity: 97.92%; MS (t / e): 417.24 (M + H).

I-335: N2- [3- (1-aminocarbonyl-1-methyl) ethoxy] phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.72 (s, 1H), 9.97 (s, 1H), 9.54 (s, 1H), 7.86 (s, 1H), 7.38 (with , 1 H),

7.30 (b, J = 9.6, 1 H) 7.24 (b, J = 8.4, 3 H) 7.09 (b, &amp; lt; RTI ID = 4.5, 2 H) 6.98 (s, ), 6.53 (s, 1H), 2.13 (s, 3H), 1.35 (s, 6H); I_SM8: purity: 97.33%; MS (t / e): 435.25 (M + H).

I-336: H2- (3-methoxy-4-methoxycarbonyl) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 9.36 (s, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.51 (b,? = 8.4, 1H) , 7.48 (s, 1H), 7.36 (b,? = 6.6, 1H), 7.30 (b, 2H), 7.21 (b,? = 9.3, 1 H), 3 , 68 (s, 3H), 3.52 (s, 3H), 2.10 (s, 3H); I_SM8: purity: 85.55%; MS (t / e): 422.23 (M + H).

I-337: N2- (3-methoxy) fent-5-methyl-4-4- (2-oxo-2,3-dipro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹H NMR (300 MHz, DMSO) δ 11.55 (s, 1 H), 8.94 (s, 1 H), 8.33 (s, 1 H), 7.86 (s, 1 H), 7.31 , δ = 6.9.3 H), 7.18 (br, A = 8.12 H), 7.00 (br, J = 8.1, 1 H), 6.38 (b, δ = 7, 8.1H), 3.57 (s, 3H), 2.08 (s, 3H); I_SM8: purity: 94.08%; MS (t / e): 364.22 (M + H).

I-338: 5-methyl-H2- (4-morpholino) phenyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹NMR (300 MHz, DMSO) δ 11.74 (s, 1 H), 9.68 (s, 1 H), 7.74 (s, 1 H), 7.27 - 7.16 (t, 5 H), 6 , 88 (b, 2H), 3.71 (s, 4H), 3.04 (s, 4H), 2.12 (s, 3H); I_SM8: purity: 73.88%; MS (t / e): 419.18 (M + H).

I-339: H2- (3-cyano-4-thiomorpholino) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.34 (bg, 1H), 9.20 (s, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.88 (s (B, J = 9.6, 1H), 7.23 (b, J = 6.3, 3H), 7.03 (b, &amp; lt; RTI ID = 0.0 &amp; gt; 9.0, 1 H), 3 , 20 (e, 4H), 2.74 (s, 4H), 2.08 (s, 3H);

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iA 106975 C2

I.SMZ: purity: 84.84%; MS (t / e): 460.24 (M + H).

3-methoxy-4- (4-methylpiperazino)] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.73 (s, 1H), 10.12 (s, 1H), 9.66 (s, 2H), 7.83 (s, 1H), 7.26 (C , à =

9.3, 1H), 7.22 (C, 2H), 6.94 (C, Å = 9.6, 2H), 6.82 (C, Å = 8.4, 1H), 3.50 ( s, 3H), 3.45 (b, 4H), 3.18 (i, 2H), 2.85 (1H, 5H), 2.13 (s, 3H); I_SMZ: purity: 92.71%; MS (t / e): 462.25 (M + H).

I-341: Ch2- [3-cyano-4- (4-methylpiperazino)] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 9.18 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.63 (C , δ = 9.3.1H), 7.23 (C, J = 8.7, 3H), 6.99 (C, J = 9.0, 1H), 2.98 (1H, 4H), 2 , 21 (s, 3H), 2.07 (s, 3H); I_SMZ: purity: 91.59%; MS (t / e): 457.27 (M + H).

I-342: 2- [3- (1-cyano-1-methyl) ethoxy] phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) - 2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.71 (s, 1H), 9.98 (s, 1H), 9.48 (s, 1H), 7.88 (s, 1H), 7.31 - 7 , 18 (t, 6H), 6.83 (C, J = 7.8, 1H), 2.13 (s, 3H), 1.57 (s, 6H); I_SMZ: purity: 97.74%; MS (t / e): 417.27 (M + H).

I-343: 2- [4- (4-acetyl) piperazino] phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4- pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 8.73 (s, 1H), 8.25 (s, 1H), 7.81 (s, 1H), 7.48 (C, δ = 8.4, 2H) , 7.33 (C, J = 8.1, 1H), 7.30 (s, 1H), 7.20 (C, J = 8.1, 1 H), 6.76 (C, δ = 8, 7, 2H), 3.54 (s, 4H), 2.99 (1H, 2H), 2.92 (1H, 2H), 2.05 (s, 3H), 2.01 (s, 3H); I_SMZ: purity: 94.65%; MS (t / e): 460.28 (M + H).

I-344: 2- [4- (4-ethoxycarbonyl) piperazino] phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.01 (bg, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.47 (C , à =

8.7, 2H), 7.32 (C, J = 11.1, 2 H), 7.19 (C, δ = 8.7, 1 H), 6.75 (C, δ = 8.7, 2H), 4.03 (s, 3H), 2.05 (s, 3H), 4.03 (s, 3H), 3.46 (1, 4H), 2.94 17 (I, J = 7.2, 3H); I_SMZ: purity: 91.97%; MS (t / e):

490.26 (M + H).

I-345: 2- [3- (4-acetyl) piperazino] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4- pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.74 (s, 1H), 10.04 (s, 1H), 9.71 (s, 1H), 7.82 (s, 1H), 7.27 (C , à =

9.3, 1H), 7.22 (C, J = 6.6, 2H), 7.11 (1H, J = 8.1, 1H), 6.89 (s, 1H), 6.83 ( C, δ = 8.1, 1H), 6.74 (C, α = 8.1.1H), 3.45 (1H, 4H), 2.97 (1H, 2H), 2.84 (I, 2H), 2.14 (s, 3H), 2.01 (s, 3H); I_SMZ: cleanliness: 100%; MS (t / e): 460.08 (M + H).

I-346: 2- [3- (4-ethoxycarbonyl) piperazino] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.69 (s, 1H), 9.85 (bd, 1H), 9.52 (b, 1H), 7.81 (s, 1H), 7.24 (s , 3.09), 7.09 (1H, J = 8.1, 1H), 6.93 (s, 1H), 6.86 (C, J = 7.5, 1H), 6.69 (C, = 6.9, 1H), 4.04 (C, J = 7.2, 2H), 3.38 (s, 4H), 2.90 (s, 4H), 2.12 (s, 3H), 1.18 (1, Å = 6.9, 3H); I_SMZ: purity: 93.55%; MS (t / e): 490.32 (M + H).

I-347: Ch2- (4-Difluoromethoxy-3-fluoro) phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.63 (s, 1H), 9.61 (s, 1H), 8.89 (b, 1H), 7.88 (s, 1H), 7.75 (C , à =

14.4, 1H), 7.29 - 7.10 (t, 5H), 7.05 (I, δ = 74, 1H), 2.10 (s, 3H); ^19thE NMR (282 MHz, DMSO) δ = 97.45 (C, α = 73); I_SMZ: purity: 98.63%; MS (t / e): 418.21 (M + H).

I-348: Ch 2 - (3,5-dichloro-4-difluoromethoxy) phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.57 (s, 1H), 9.48 (s, 1H), 8.55 (s, 1H), 7.91 (s, 1H), 7.77 (s , 2H), 7.25 (C, J = 8.1, 1H), 7.20 (s, 1H), 7.16 (C, δ = 8.1, 1H), 6.96 (I,? = 73, 1H), 2.08 (s, 3H); ^19thE NMR (282 MHz, DMSO)? 95.79 (C,? = 73); I_SMZ: purity: 93.57%; MS (t / e): 468.13 (M + H).

I-349: Ch2- (4-fluoro-3-methoxy) phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.34 (b, 1H), 8.96 (s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.46 (C , à =

8.1, 1H), 7.31 (C, J = 5.4, 2H), 7.23 (C, J = 8.7, 1 H), 7.20 (C, δ = 9.3, 1 H ), 6.93 (1, α = 9.9, 1H), 3.55 (s, 3H), 2.07 (s, 3H); ^19thE NMR (282 MHz, DMSO) δ = 160.84; I_SMZ: cleanliness: 100%; MS (t / e): 382.03 (M + H).

I-350: 2- (3-fluoro-4-methoxy) phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.65 (s, 1H), 9.47 (bd, 1H), 9.05 (b, 1H), 7.83 (s, 1H), 7.52 (C , à =

14.7, 1H), 7.24 (s, 3H), 7.10 (C, 1H), 6.99 (I,? = 9.3, 1H), 3.74 (s, 3H), 2.10 (s, 3H); E NMR (282 MHz, DMSO) δ 149.86; I_SMZ: cleanliness: 100%; MS (t / e): 382.02 (M + H).

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I-351: N2- (3-methoxy-4-methyl) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.58 (s, 1H), 8.83 (s, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 7.35 (b , b =

10.5, 2H), 7.25 (s, 1H), 7.20 (b, J = 6.9, 2H), 6.84 (b, b = 8.4, 1H), 3.50 ( s, 3H), 2.07 (s, 3H), 2.01 (s, 3H); I_SMZ: purity: 90.74%; MS (t / e): 378.26 (M + H).

I-352: N2- (3-fluoro-5-methoxy) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

¹H NMR (300 MHz, DMSO)? 11.53 (s, 1H), 9.15 (s, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.26 (with , 1H),

7.20 (b, b = 8.1, 3H), 6.99 (s, 1H), 6.22 (b, b = 10.8, 1H), 3.60 (s, 3H), 2.08 ( s, 3H); ^19thR NMR (282MHz , DMSO) δ = 127.86; I_SMZ: purity: 96.96%; MS (t / e): 382.20 (M + H).

I-353: N2- (3-Difluoromethoxy-5-trifluoromethyl) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.56 (s, 1H), 9.97 (b, 1H), 9.10 (b, 1H), 7.94 (s, 1H), 7.74 (s , 1H), 7.69 (s, 1H), 7.20 (t, 3H), 7.19 (br, i = 73, 1H), 7.01 (s, 1H), 2.13 (s, 3H); ^19thR NMR (282 MHz, DMSO) δ - 77.31; I_SMZ: purity: 95.73%; MS (t / e): 468.21 (M + H).

I-354: N2- (3-methoxy-4-trifluoromethyl) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 11.67 (s, 1H), 9.88 (bd, 1H), 9.06 (b, 1H), 7.92 (s, 1H), 7.35 (b , b = 9.0, 2H), 7.28 (b, 4H), 3.57 (s, 3H), 2.13 (s, 3H); ^19thR NMR (282 MHz, DMSO) δ - 75.24; I_SMZ: cleanliness: 86.29%; MS (t / e): 432.23 (M + H).

I-355: (3,5-di-tertiary butyl) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4- pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.68 (s, 1H), 9.86 (s, 1H), 9.50 (s, 1H), 7.82 (s, 1H), 7.24 - 7 , 17 (t, 5H), 7.09 (s, 1H), 2.13 (s, 3H), 1.10 (s, 18H); I_SMZ: purity: 98.22%; MS (t / e): 446.35 (M + H).

I-356: N4- {3- [bis (1,1-dimethylethoxy)] phosphinoyloxymethyl-2-oxo-2,3-dihydro-1,3-

benzoxazol-4-yl] -methyl-methoxy-trifluoromethyl-enyl-methyl-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 9.37 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.78 (s , 1H), 7.60 (s, 1H), 7.32 (s, 2H), 6.68 (s, 1H), 5.62 (b, b = 10.8, 2H), 3.71 ( s, 3H), 2.12 (s, 3H), 1.30 (s, 18H);^19thR NMR (282 MHz, DMSO) ?δ 76.83; ³¹R NMR (121 MHz, DMSO)? 10.51; I_SMZ: purity: 95.06%; MS (t / e): 598.30.

I-357: N2- (3-methoxy-5-trifluoromethyl) phenyl-5-methyl-N4- [3- (phosphonoxy) methyl-2-oxo-2,3-

dihydro-1,3-benzoxazol-5-yl] -2,4-pyrimidinediamine

¹H NMR (300 MHz, DMSO)? 7.95 (s, 1H), 7.67 (s, 1H), 7.29 (s, 2H), 6.66 (s, 1H), 5.56 (b , 2H), 3.74 (s, 3H), 2.12 (s, 3H); ^19thR NMR (282 MHz, DMSO) δ: 76.80; I_SMZ: purity: 81,15%; MS (t / e): 542.16 (M + H).

I-358: N2- (3-methoxy-5-trifluoromethyl) phenyl-5-methyl-N4- [3- (phospho-oxy) methyl-2-oxo-2,3-

dihydro-1,3-benzoxazol-5-yl] -2,4-pyrimidindamine disodium salt

¹H NMR (300 MHz, DMSO)? 7.92 (s, 1H), 7.53 (b, 3H), 7.18 (s, 2H), 6.59 (bd, 2H), 5.44 (b , 2H), 3.79 (s, 3H), 2.12 (s, 3H); ^19thR NMR (282 MHz, DMSO) ?δ 76.53; I_SMZ: purity: 93.44%; MS (t / e):

542.20 (M + H).

I-359: N2- (3,5-Difluorophenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.61 (s, 1H), 9.61 (s, 1H), 8.78 (s, 1H), 7.91 (s, 1H), 7.30-7 , 15 (t, 5H), 6.59 (bs, b = 9.0, 1H), 2.10 (s, 3H); ^19thR NMR (282 MHz, DMSO) δ - 126.14; I_SMZ: purity: 96.57%; MS (t / e): 370.20 (M + H).

I-360: N2- (3-fluoro-5-trifluoromethyl) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.55 (s, 1H), 9.61 (s, 1H), 8.53 (s, 1H), 7.92 (b, b = 11.1, 2H) , 7.69 (s, 1H), 7.22 (t, 3H), 6.96 (b, b = 8.7, 1H), 2.10 (s, 3H); ^19thR NMR (282 MHz, DMSO) δ - 77.18, -125.92; I_SMZ: purity: 94.90%; MS (t / e): 420.22 (M + H).

I-361: N2- (4-fluoro-3-trifluoromethyl) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.54 (s, 1H), 9.35 (s, 1H), 8.42 (s, 1H), 8.08 (b, b = 5.7, 1H) , 7.90 (s, 1H), 7.85 (b, 1H), 7.30-7.19 (t, 4H), 2.08 (s, 3H); ^19thR NMR (282 MHz, DMSO) δ - 75.89, -142.78; I_SMZ: purity: 97.69%; MS (t / e): 420.21 (M + H).

I-362: N2- (4-fluoro-3-methyl) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

¹H NMR (300 MHz, DMSO)? 11.13 (b, 1H), 8.94 (s, 1H), 8.33 (s, 1H), 7.85 (s, 1H), 7.55 (b , b =

7.2, 1H), 7.35 (bb, b = 9.9, 5.4, 1H), 7.28 (t, 2H), 7.22 (b, b = 9.0, 1H), 6.88 (bs, b = 9.3, lH), 2.07 (s, 3H), 1.99 (s, 3H); ^19thR NMR (282 MHz, DMSO) δ - 143.48; I_SMZ: purity: 97.37%; MS (t / e): 366.22

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iA 106975 C2

(M + H).

1-363: H2- (3-Fluoro-4-methyl) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine

¹NMR (300 MHz, DMSO)? 11.58 (5, 1H), 9.11 (5, 1H), 8.39 (5, 1H), 7.87 (5, 1H), 7.62 (b , à =

13.5, 1H), 7.28 - 7.15 (t, 4H), 6.98 (t, J = 8.4, 1H), 2.08 (5, 6H); ^19thR NMR (282 MHz, DMSO) δ -132.82; I_SM3: purity: 98.10%; MS (t / e): 366.22 (M + H).

1-364: H2- (3-Chloro-4-methyl) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹NMR (300 MHz, DMSO) δ 11.33 (bg, 1H), 9.10 (5, 1H), 8.39 (5, 1H), 7.86 (b, J = 5.7, 2H) , 7.32 (b, δ = 8.1, 1H), 7.23 (b, 3H), 7.05 (b,? = 8.4, 1H), 2.17 (5, 3H), 2 , 07 (5, 3H); I_SM3: purity: 96.65%; MS (t / e): 382.20 (M + H).

1-365: H2- (3,4,5-trimethyl) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

¹NMR (300 MHz, DMSO)? 11.39 (b, 1H), 8.70 (5, 1H), 8.29 (5, 1H), 7.83 (5, 1H), 7.30 (b , à =

6.3, 2H), 7.21 (t, 3H), 2.06 (5, 3H), 1.99 (5, 6H), 1.98 (5, 3H); I_SM3: purity: 96.73%; MS (t / e):

376.27 (M + H).

1-366: H2- (3-Chloro-4-trifluoromethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

I_SM3: purity: 96.28%; MS (t / e): 452.19 (M + H).

1-367: H2- (4-trifluoromethylthio) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

I_SM3: cleanliness: 95.52%; MS (t / e): 434.16 (M + H).

1-368: H2- (3-fluoro) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-

pyrimidine diamine

I_SM3: cleanliness: 95.77%; MS (t / e): 352.20 (M + H).

1-369: H2- (3,5-dimethyl-4-methoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4 -pirimidindinamine

I_SM3: purity: 97.05%; MS (t / e): 392.28 (M + H).

1-370: H2- (3-Carboxamid-5-trifluoromethyl) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

I_SM3: purity: 95.87%; MS (t / e): 445.24 (M + H).

1-371: H2- (3,5-Diisopropyl-4-methoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4 -pirimidindinamine

I_SM3: purity: 98.88%; MS (t / e): 448.33 (M + H).

1-372: H2- (3-isopropoxy-5-trifluoromethyl) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

I_SM3: cleanliness: 100%; MS (t / e): 460.14 (M + H).

1-373: H2- (3-Cyano-4-methoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

I_SM3: purity: 94.66%; MS (t / e): 389.23 (M + H).

1-374: H2- (3,5-dimethyl-4-fluoro) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

¹NMR (300 MHz, DMSO) δ 11.43 (bg, 1H), 8.85 (5, 1H), 8.33 (5, 1H), 7.84 (5, 1H), 7.28 (b , à =

6.6, 4H), 7.21 (b, J = 9.0, 1H), 2.06 (5, 3H), 1.98 (5, 6H); ^19thR NMR (282 MHz, DMSO) δ - 147.89; I_SM3: purity: 97.65%; MS (t / e): 380.24 (M + H).

1-375: H2- (4-Fluoro-3-trifluoromethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

I_SM3: purity: 96.82%; MS (t / e): 436.21 (M + H).

1-376: H2- (3-Fluoro-4-trifluoromethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

I_SM3: purity: 97.88%; MS (t / e): 436.21 (M + H).

1-377: H2- (4-chloro-3-trifluoromethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidine diamine

I_SM3: purity: 95.28%; MS (t / e): 452.14 (M + H).

1-378: H2- (3-chloro-5-trifluoromethoxy) phenyl-5-methyl-H4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine

I_SM3: purity: 95.29%; MS (t / e): 452.19 (M + H).

1-379: 5-Methyl-H2- (3-methyl-5-trifluoromethoxy) phenyl-H4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

I_SM3: purity: 97.81%; MS (t / e): 432.24 (M + H).

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and-380: Ch2- (4-cyano-3-methoxy) phenyl-5-methyl-Ch4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

I.SMZ: purity: 97,08%; MS (t / e): 389.07 (M + H).

and-381: Ch2- (3,5-Difluoro-4-methoxy) phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-

yl) -2,4-pyrimidindamine

I.SMZ: purity: 100%; MS (t / e): 400.04 (M + H).

and-382: 5-methyl-CH2- (4-morpholinomethyl) phenyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -

2,4-pyrimidindamine

I.SMZ: purity: 85.62%; MS (t / e): 433.28 (M + H).

and-383: Ch2- (4-chloro-3-cyano-5-ethyl) phenyl-5-methyl-4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2 , 4-pyrimidindinamine

I.SMZ: purity: 90.90%; MS (t / e): 421.24 (M + H).

and-384: 2- [3- (2-methoxy) ethoxy-5-trifluoromethyl] phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

I.SMZ: purity: 86,68%; MS (t / e): 476.27 (M + H).

and-385: 2- (4-difluoromethoxy-3,5-dimethyl) phenyl-5-methyl-4-4- (2-oxo-2,3-dihydro-1,3-

benzooxazol-5-yl) -2,4-pyrimidinediamine

I.SMZ: purity: 96,79%; MS (t / e): 428.26 (M + H).

and-386: C2- [3- (1-aminocarbonyl-1-methyl) ethoxy-4-fluoro] phenyl-5-methyl-4- (2-oxo-2,3-dihydro-

1,3-benzoxazol-5-yl) -2,4-pyrimidindamine