EA038488B1 - Azolopyrimidine for the treatment of cancer-related disorders - Google Patents

Abstract

Compounds of formula I that are inhibitors of at least one of the A2A and A2B adenosine receptors, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by the adenosine A2A receptors and/or the adenosine A2B receptors is described.

Description

State of the art

Adenosine is one of the purine nucleosides, a compound containing a complex of adenine and a ribose sugar molecule (ribofuranose). Adenosine occurs naturally in mammals and plays an important role in several biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signaling (as cyclic adenosine monophosphate). Adenosine is also involved in processes associated with vasodilation, including vasodilation in the heart, and acts as a neuromodulator (for example, it is believed to be involved in enhancing sleep). Along with participation in these biochemical processes, adenosine is used as a therapeutic antiarrhythmic agent for the treatment of, for example, supraventricular tachycardia. As discussed below, tumors escape the host response by inhibiting immune function and enhancing tolerance, and adenosine has been shown to play an important role in allowing tumors to escape from the immune system. It has been found that adenosine signaling through the A2AR and A2BR receptors, which are expressed in various subpopulations of immune cells and endothelial cells, plays an important role in tissue protection during inflammatory responses. Moreover, under certain conditions, adenosine protects tumors from immune destruction (for example, see Fishman P. et al. (2009), Handb Exp. Pharmacol. 193: 399441).

Adenosine receptors are a class of G-protein coupled purinergic receptors, the endogenous ligand of which is adenosine. In humans, the four types of adenosine receptors are called A _b A2A, A _2B and A ₃ . _{A 1} modulation has been proposed for the management and treatment of, for example, neurological disorders, asthma, heart and kidney failure. A2A antagonists have been suggested for the management and treatment of, for example, Parkinson's disease; A2B modulation has been proposed for the management and treatment of, for example, chronic lung diseases, including asthma; and A ₃ modulation has been proposed for the management and treatment of, for example, asthma and chronic obstructive pulmonary disease, glaucoma, cancer and stroke.

Historically, adenosine receptor modulators have been indiscriminate. This is acceptable in certain indications when the endogenous agonist adenosine, which acts on all four adenosine receptors in cardiac tissue, is administered parenterally to treat severe tachycardia. However, the use of subtype-selective adenosine receptor agonists and antagonists makes it possible to obtain the desired results while minimizing or eliminating side effects.

Thus, there is a need in the art for subtype selective adenosine receptor agonists. The present invention addresses this problem and also provides additional benefits.

The essence of the invention

The present invention relates to compounds that modulate adenosine A _2A receptors (A2AR) and / or adenosine A _2B receptors (A _2B R), and compositions (eg, pharmaceutical compositions) containing these compounds. Such compounds, including their synthesis methods and compositions, are detailed below.

The present invention also relates to the use of such compounds and compositions for the treatment and / or prevention of various diseases, disorders and conditions mediated, in whole or in part, by adenosine A ₂ A receptors (A2AR) and / or adenosine A _2B receptors (A _2B R) ... Such diseases, disorders and conditions are detailed here. Unless otherwise indicated, when describing the use of the compounds of the present invention, it should be borne in mind that such compounds may be in the form of a composition (eg, a pharmaceutical composition).

As discussed below, although the compounds of the present invention are _{believed to exert their action by inhibiting adenosine A 2} A receptors (A2AR) and / or adenosine A _2B receptors (A _2B R), for the practice of the invention, an accurate understanding of the basic mechanism of action of the compounds not required. On the other hand, it is envisaged that the compounds can exercise their action by directly or indirectly inhibiting adenylate cyclase. It is also contemplated that the compounds may act by inhibiting both adenosine A ₂ A receptors (A2AR) and / or A _2B receptors (A2BR) and adenylate cyclase. Although the compounds of the present invention are generally referred to herein as inhibitors of adenosine A ₂ A receptors (A2AR) and / or adenosine A _2B receptors (A _2B R), it should be understood that the term A2AR / A2BR inhibitors encompasses compounds, which act individually by inhibiting A _2A R, A _2B R or adenylate cyclase; and / or compounds that act by inhibiting A2AR, A2BR and adenylate cyclase.

It is known that adenosine A2A and A _2B receptors on the cell surface are up-regulated in various tumor cells. Therefore, antagonists of adenosine A2A and / or A _2B receptors represent a new class of promising therapeutic agents for oncology.

Activation of adenosine A ₂ A receptors leads to inhibition of immune responses to tumors through suppression of the function of T-regulatory cells and inhibition of cytotoxicity of natural killer cells and tumor-specific activity of CD4 7CD8 'cells. Therefore, inhibition of this receptor subtype by specific antagonists can enhance the effect of immunotherapy in

- 1 038488 cancer treatment. Activation of adenosine _A2 receptors plays a role in the development of tumors by increasing the expression level of angiogenic factors in endothelial cells, microvascular (e.g., see P. Fishman et al, Handb Exp Pharmacol ( 2009) 193:.... 399-441). In addition, blockade of adenosine 2A receptors has been shown to increase the efficacy of anti-PD-1 antibodies by enhancing anti-tumor T cell responses (P. Beavis et al., Cancer Immunol. Res. DOI: 10.1158 / 2326-6066.CIR-140211 of February 11, 2015). A more detailed discussion of the role of A2AR and A _2B R is provided below.

Adenosine receptor 2A (A2AR).

A2AR (also called AdoRA _2A ) is a G-protein coupled receptor (GPCR) from a family of 7 transmembrane α-helices. Based on the crystallographic structure, A2AR contains a ligand-binding pocket that is different from that of other structurally defined GPCRs (for example, bbb ₂ -adrenergic receptors).

As already mentioned, adenosine is involved in ensuring that tumors evade the immune system. A _2A R plays a critical, non-redundant role in mediating adenosine-induced anti-inflammatory responses. A _2A R negatively regulates immune responses, and pharmacological inhibition of A2AR activation has been shown to be an important means of enhancing immunotherapy.

As noted above, the activation of A _2A R affects adaptive immunity, for example, A _2A R protects the body from excessive tissue destruction not only by dramatically suppressing the function of T cells, but also by enhancing the development of regulatory T cells. Since A2AR activation is a potent inhibitor of adaptive immunity, tumor-derived adenosine is thought to block anti-tumor immunity.

Along with other roles, A2AR was found to be involved in the selective upsurge of anti-inflammatory cytokines, promotes an increase in PD-1 and CTLA-4, promotes the formation of regulatory T cells LAG-3 and Foxp3 ^+, and mediates inhibition of regulatory T cells. PD-1, CTLA-4 and other immune checkpoints are discussed in detail below. Since all of these immunosuppressive properties have been identified as mechanisms by which tumors escape host immune responses, a cancer immunotherapy regimen that includes A2AR antagonists may lead to enhanced tumor immunotherapy (see generally Naganuma M. et al. (2006), J. Immunol. 177: 2765-769).

A _2A R antagonists may play an important role in chemotherapy and radiation therapy. Mechanistically, it was hypothesized that concomitant administration of A _2A R antagonists during chemotherapy or radiation therapy would lead to the expansion of tumor-specific T cells and, at the same time, prevent the induction of tumor-specific regulatory T cells. Moreover, it is believed that the combination of A _2A R antagonists with anticancer vaccines will provide at least an additive effect due to their different mechanisms of action. Finally, A2AR antagonists can be used most effectively in combination with cancer vaccines and other checkpoint blockers. For example, blocking PD-1 involvement as well as inhibition of A2AR could impair the ability of tumors to shut off tumor-specific effector T cells (eg see Fishman P. et al. (2009) Handb Exp. Pharmacol. 193: 399-441) ... Moreover, adenosine signaling through the A2AR receptor appeared to be a promising negative feedback loop, and preclinical studies have confirmed that blocking A _2A R activation can markedly enhance anti-tumor immunity (Sitkovsky MV et al. (2014) Cancer Immun. Res. 2 : 598-605).

Adenosine receptor 2B (A _2B R).

A _2B R (also called AdoRA _2B ) is a GPCR that occurs in many different cell types. It requires higher concentrations of adenosine for activation than other adenosine receptor subtypes (eg AiR, A _2A R and A ₃ R) (Fredholm BV et al. (2001) Biochem. Pharmacol. 61: 443-448) ... Such conditions have been observed, for example, in tumors, where hypoxia is usually observed. Unlike other adenosine receptor subtypes, A2BR may play an important role in pathophysiological conditions associated with massive adenosine release. However, selective blockade or stimulation of this subtype of adenosine receptors may not interfere with numerous important physiological functions of adenosine, mediated through other subtypes of adenosine receptors. However, the pathway leading to A _2B R mediated inhibition is not fully understood.

The key mechanism for tumor growth is angiogenesis. The process of angiogenesis is highly regulated by a variety of angiogenic factors and is triggered by adenosine under certain conditions associated with hypoxia. In humans, A _2B R is expressed in microvascular endothelial cells, where it plays an important role in the regulation of the expression of angiogenic factors such as vascular endothelial growth factor (VEGF). In some tumor types, hypoxia has been observed to induce an increase in A2BR expression, suggesting that A2BR receptors play a critical role in mediating the effects of adenosine on angiogenesis. Thus, blocking A2BR can restrict tumor growth by limiting oxygen supply to tumor cells. In addition, experiments on adenylate cyclase activation indicate that A2BR receptors are the only subtype of adenosine receptors in certain tumor cells, suggesting that A2BR antagonists may exert effects on certain types of tumors (for example, see Feoktistov I. et al. (2003) , Circ Res.

- 2 038488

92: 485-492).

Recent data make it difficult to understand the exact role of A _2B R modulators. As outlined above, the data support that A2BR receptors play an important role in mediating the effects of adenosine on tumor growth and progression. Indeed, inhibition of angiogenesis and inhibition of phosphorylation of ERK1 / 2 represent the most interesting effects for a potential anti-cancer therapy based on A2BR as a target. However, inhibition of angiogenesis requires the use of A _2B R antagonists, while inhibition of growth signaling through other clinically significant pathways (e.g., the MAP kinase pathway) can be accomplished by treatment with A2BR agonists (e.g., see Graham S. et al. (2001), Eur J. Pharmacol 420: 19-26). The results of additional experimentation could mean that both agonists and antagonists will constitute useful treatment options in combination with other therapeutic interventions when used at different stages of disease and treatment.

In one specific aspect, the present invention provides compounds of formula (I)

or their pharmaceutically acceptable salts, hydrates or solvates, where G ¹ means N or CR ^3a ;

G ² means N or CR ^3b ;

G ³ means N or CR ^3c ;

R ^3a , R ^3b and R ^3c are each independently H, deuterium or C _1-6 alkyl;

R ^1a and R ^{1b are} each independently selected from the group consisting of:

i) H or deuterium, ii) C _1-8 α-alkyl optionally substituted with 1-3 R ⁵ substituents, iii) -X ¹ -O-C _1-8 alkyl optionally substituted with 1-3 R ⁵ substituents, iv) -C (O) -R ⁶ ,

v) Y optionally substituted with 1-3 R ⁷ substituents, and vi) -X ¹ -Y optionally substituted with 1-3 R ⁷ substituents;

or R ^1a and R ^1b together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl ring optionally substituted with 1 to 3 R ⁸ substituents, wherein the heterocycloalkyl contains 02 additional ring-vertex heteroatoms selected from the group consisting of O , N and S;

each Y is C _3-8 cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 additional ring-vertex heteroatoms selected from the group consisting of O, N and S;

R ² and R ⁴ are each independently H, deuterium or C _1-3 alkyl;

Ar ¹ means 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R ⁹ ;

Ar ² means phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R ¹⁰ ;

wherein the 5-6 membered heteroaryl of Ar ¹ and Ar ² each independently contains 1-3 heteroatoms at the ring vertices selected from the group consisting of O, N, N + —O ^- and S;

each X ¹ means C _1-6 α-alkyl;

each R ^{5 is} independently selected from the group consisting of hydroxyl, C _3-8 cycloalkyl, phenyl, —O-phenyl, —C (O) OR ^a, and oxo;

each R ⁶ is C _1-8 alkyl or Y, each of which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, —O-phenyl, phenyl, and —OC _1-8 alkyl;

each R ^{7 is} independently selected from the group consisting of C _1-8 alkyl, hydroxyl, —OC _1-8 alkyl, oxo, and C (O) OR ^a ;

each R ^{8 is} independently selected from the group consisting of C _1-8 α-alkyl, hydroxyl, and oxo;

each R ^{9 is} independently selected from the group consisting of C1-8αalkyl, C1-8deuteroαalkyl, -O-C1-8αalkyl, -O-C1-8deuteroαalkyl, -X ¹ -O-C1-8alkyl, -OX ¹ O-C1-8αalkyl , -X ¹ O-X ¹ -O-C1-8 alkyl, -C (O) ORa, halogen, cyano, NR ^b R ^c , Y, -X ¹ -C3-8 cycloalkyl and -X2-Z, where X ² is selected from the group consisting of C1-6αalkylene, -C _1-6 αalkylene-O-, -C (O) - and -S (O) ₂ -, Z means 4-6 membered heterocycloalkyl containing 1-3 heteroatoms per ring vertices selected from the group consisting of O, N and S, each of said substituents R ⁹ optionally substituted with 1-3 R ¹¹ ;

each R ^{10 is} independently selected from the group consisting of C1-8 alkyl, C1-8 deuteroalkyl, halogen, cyano, —O — C1-8 alkyl, —O — C1-8 deuteroalkyl, —X ¹ —O — C1-8 alkyl, —O — X ¹ -O-C _1-8 alkyl, -S (O) ₂ -C _1-6 alkyl, -C (O) NR ^d R ^e and 4-6 membered heteroaryl containing 1-3 heteroatoms at the ring vertices selected from the group consisting of O, N and S, each of said R ¹⁰ substituents being optionally substituted by 1-3 R ¹² , or two R ¹⁰ on adjacent ring vertices of Ar ^{2 are} optionally connected to form a 5-membered heterocyclic ring, optionally substituted 1-2 halogens;

- 3038488 each R ^{11 is} independently selected from the group consisting of hydroxyl, halogen, cyano, —NR ^d R ^e , —C (O) OR ^a , phenyl, C _3-8 cycloalkyl, and C _1-4 alkyl optionally substituted with C (O) OR ^a ;

each R ^{12 is} independently selected from the group consisting of halogen, cyano, hydroxy, —C (O) OR ^a ;

each R ^a means H, deuterium or C _1-6 alkyl;

each R ^b and R ^{c is} independently selected from the group consisting of H, deuterium, C _1-8 alkyl,

-S (O) 2-C1-6alkyl, -C (O) OR ^a and -X1-C (O) OR ^a ;

each R ^d and R ^{e is} independently selected from the group consisting of H, deuterium, C _1-8 alkyl,

-S (O) ₂ -C _1-6 alkyl;

provided that when each G ¹ and G ² is N, G ³ is CH, R ² is CH3, and each R ^1a and R ^1b is H or deuterium, then Ar ² does not mean 2-thienyl, phenyl, 2-, 3- or 4-methoxyphenyl, 3- or 4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl, or 2- or 4-methylphenyl.

In a preferred aspect of the present invention, there is provided a compound of formula (I) p1 a p1 b

or a pharmaceutically acceptable salt thereof, wherein G ¹ is N or CR ^3a ;

G ² means N or CR ^3b ;

G ³ means N or CR ^3c ;

R ^3a , R ^3b and R ^3c are each independently H, deuterium or C _1-6 alkyl;

R ^1a and R ^{1b are} each independently selected from the group consisting of:

i) H or deuterium, ii) C _1-8 alkyl optionally substituted with 1-3 R ⁵ substituents, iii) -X ¹ -O-C _1-8 alkyl optionally substituted with 1-3 R ⁵ substituents, iv) -C (O) -R ⁶ ,

v) Y optionally substituted with 1-3 R ⁷ substituents and vi) -X1-Y optionally substituted with 1-3 R ⁷ substituents;

or R ^1a and R ^1b together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl ring optionally substituted with 1-3 R ⁸ substituents, the heterocycloalkyl containing 02 additional heteroatoms selected from the group consisting of O, N and S;

each Y is C _3-8 cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 additional heteroatoms selected from the group consisting of O, N and S;

R ² and R ⁴ are each independently H, deuterium or C _1-3 alkyl;

Ar ¹ means 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R ⁹ ;

Ar ² means phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R ¹⁰ ;

where the 5-6-membered heteroaryl at Ar ¹ and Ar ² each independently contains 1-3 heteroatoms selected from the group consisting of O, N, N + -O ^- and S;

each X ¹ means C _1-6 alkylene;

each R ^{5 is} independently selected from the group consisting of hydroxyl, C 3-8 cycloalkyl, phenyl, —O-phenyl, —C (O) OR ^a, and oxo;

each R ⁶ is C _1-8 alkyl or Y, each of which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, —O-phenyl, phenyl and —OC _1-8 alkyl;

each R ^{7 is} independently selected from the group consisting of C _1-8 alkyl, hydroxyl, —OC _1-8 alkyl, oxo, and C (O) OR ^a ;

each R ^{8 is} independently selected from the group consisting of C _1-8 alkyl, hydroxyl, and oxo;

each R ^{9 is} independently selected from the group consisting of C1-8 alkyl, C1-8 deuteroalkyl, —O — C1-8 alkyl, —O — C1-8 deuteroalkyl, —X ¹ —O — C1-8 alkyl, —OX ¹ —O — C1— 8alkyl, -X ¹ -O-X ¹ -O-C1-8alkyl, -C (O) ORa, halogen, cyano, NR ^b R ^c , Y, -X1-C3-8cycloalkyl and -X ² -Z, where X ^{2 is} selected from the group consisting of C1-6 _{alkylene, -C 1-6} alkylene-O-, -C (O) - and -S (O) ₂ -, Z means 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N and S, each of said substituents R ⁹ optionally substituted with 1-3 R ¹¹ ;

each R ^{10 is} independently selected from the group consisting of C1-8 alkyl, C1-8 deuteroalkyl, halogen, cyano, —O — C1-8 alkyl, —O — C1-8 deuteroalkyl, —X ¹ —O — C1-8 alkyl, —O — X ¹ -O-C _1-8 alkyl, -S (O) ₂ -C _1-6 alkyl, -C (O) NR ^d R ^e and 4-6-membered heteroaryl containing 1-3 heteroatoms selected from the group, consisting of O, N and S, each of said substituents R ¹⁰ optionally substituted with 1-3 R ¹² , or two R ¹⁰ on adjacent ring atoms of Ar ² optionally join to form a 5-membered heterocyclic ring, optionally substituted with 1-2 halogens ;

each R ^{11 is} independently selected from the group consisting of hydroxyl, halogen, cyano, —NR ^d R ^e ,

- 4 038488

- C (O) OR ^a , phenyl, C _3-8 cycloalkyl and C _1-4 α-alkyl optionally substituted with C (O) OR ^a ;

each R ^{12 is} independently selected from the group consisting of halogen, cyano, hydroxy, —C (O) OR ^a ;

each R ^a is H, deuterium or Cμ ₆ alkyl;

each R ^b and R ^{c is} independently selected from the group consisting of H, deuterium, C _1-8 α-alkyl,

- S (O) 2-C1-6 alkyl, -C (O) OR ^a and -X1-C (O) OR ^a ;

each R ^d and R ^{e is} independently selected from the group consisting of H, deuterium, C _1-8 α-alkyl,

- S (O) ₂ -C _1-6 alkyl;

provided that when each G ¹ and G ² is N, G ³ is CH, R ² is CH3, and each R ^1a and R ^1b is H or deuterium, then Ar ² does not mean 2-thienyl, phenyl, 2-, 3- or 4-methoxyphenyl, 3- or 4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl, or 2- or 4-methylphenyl.

In some embodiments of the present invention, a compound of formula is provided

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

As described below, Compound I is a potent antagonist of A _2A R and A2BR with potencies at both receptors of less than 10 nM.

In some embodiments, the present invention provides methods for treating or preventing cancer in subjects (e.g., humans) comprising administering to them a therapeutically effective amount of at least one A _2A R / A _2B R inhibitor described herein. In some embodiments, the present invention includes methods of treating or preventing cancer in subjects by administering at least one of the compounds described herein in an amount effective to regress or arrest the progression of A _2A R mediated immunosuppression. In some embodiments, A _2A R mediated immunosuppression is mediated by antigen presenting cells (APC).

Examples of cancers that can be treated with the compounds and compositions described herein include, but are not limited to, cancer of the prostate, colon, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovaries, testicles, head, neck, skin (including melanoma and basal cell carcinoma), mesothelial membrane, leukocytes (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including small cell lung cancer and non-small cell lung cancer), adrenal gland, thyroid gland , kidney or bone; glioblastoma, mesothelioma, renal cell carcinoma, stomach cancer, sarcoma, choriocarcinoma, basal cell carcinoma of the skin and seminal testis. In some embodiments of the present invention, the cancer is melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, sarcoma, ovarian cancer, head and neck cancer, cervical cancer, or sarcoma of Kaposi. Cancers that are candidates for treatment with the compounds and compositions of the present invention are discussed in detail below.

The present invention provides methods of treating a subject receiving a bone marrow transplant or a peripheral blood stem cell transplant by administering a therapeutically effective amount of an A2AR / A2BR inhibitor sufficient to enhance the delayed-type hypersensitivity response to a tumor antigen, slowing the time to recurrence of post-transplant malignancy, increasing the survival time without relapse after transplant; and / or improved long-term survival after transplant.

In some embodiments, the present invention provides methods of treating or preventing infectious diseases (e.g., viral infections) in subjects (e.g., humans) comprising administering to them a therapeutically effective amount of at least one A2AR / A2BR inhibitor (e.g., a novel inhibitor of the present invention). In some embodiments, the infectious disease is a viral infection (eg, a chronic viral infection), a bacterial infection, a fungal infection, or a parasitic infection. In some embodiments, the viral infection is a human immunodeficiency virus or cytomegalovirus.

In yet other embodiments, the present invention provides methods of treating or preventing immunological diseases, disorders, or conditions in subjects (eg, humans) comprising administering to them a therapeutically effective amount of at least one A2AR / A2BR inhibitor described herein. Examples of immunological diseases, disorders and conditions are described below.

Other diseases, disorders and conditions that can be treated or prevented, in whole or in part, by modulating A2AR / A2BR activity are potential indications for the A _2A R / A _{2B R inhibitor compounds of the present invention.}

The present invention also provides for the use of the A _2A R / A _2B R inhibitors described herein in combination with one or more additional agents. One or more

5,038488 additional agents may have some activity modulating adenosine A _2A receptors and / or adenosine A _2B receptors; on the other hand, they can function according to other mechanisms of action. In some embodiments, such agents include radiation therapy (eg, localized radiation therapy or whole body radiation therapy) and / or other non-pharmacological treatments. When using combination therapy, the compounds described herein and one of the additional agents can be in the form of one composition or several compositions, and the methods of treatment can be carried out simultaneously, sequentially, or in some other way. For example, the present invention provides a treatment regimen in which the irradiation phase is followed by the chemotherapy phase. Combination therapy can be additive or synergistic. Other benefits of combination therapy are described below.

In some embodiments, the present invention provides for the use of the A2AR / A2BR inhibitors described herein in combination with immune checkpoint inhibitors. It has been shown that blocking immune checkpoints, which leads to an increase in antigen-specific T-cell responses, is a promising approach to cancer therapy in humans. Examples of immune checkpoints (ligands and receptors) that are candidates for blocking, and some are selectively upregulated in various types of tumor cells, include PD1 (programmed cell death protein-1); PDL1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA4 (cytotoxic T-lymphocyte-associated antigen-4); TIM3 (T-cell membrane protein-3); LAG3 (lymphocyte activation gene 3); TIGIT (T-cell immunoreceptor with Ig and ITIM domains) and killer cell inhibitory receptors. Inhibitors of immune checkpoints and combination therapy with them are discussed in detail elsewhere here.

In other embodiments, the present invention provides methods of treating cancer in subjects comprising administering to them a therapeutically effective amount of at least one A2AR / A2BR inhibitor and at least one chemotherapeutic agent, such agents including, but not limited to, alkylating agents (e.g., nitrogen mustard gas analogs , such as chlorambucil, cyclophosphamide, isophamide, mechlorethamine, melphalan and uramustine; aziridines such as thiotepa; methanesulfonate esters such as busulfan; nucleoside analogs (such as gemcitabine); nitrosoureas such as carmustine, lomustine, and strepitrintozocinum inhibitor , platinum complexes such as cisplatin, carboplatin and oxaliplatin, bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); Anthracycline drugs (eg, doxorubicin, daunorubicin, epirubicin, and idarubicin); drugs that cause DNA strand breaks (such as bleomycin); topoisomerase II inhibitors (eg, amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); drugs that bind to the minor groove in DNA (for example, plicamycin); antimetabolites (e.g. folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacytidine, cytarabine and floxuridine; purine antagonists such as mercapto-lurabidine ribonucleotide reductase of the hydroxyurea type); drugs that interact with tubulin (for example, vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives and paclitaxel); hormonal drugs (eg, estrogens; conjugated estrogens; ethinylestradiol; diethylstilbestrol; chlorotrianisen; identifestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone, methylluoxymesterone) adrenal corticosteroids (eg, prednisone, dexamethasone, methylprednisolone, and prednisolone); luteinizing hormone releasing factors or gonadotropin-releasing hormone antagonists (eg, leuprolide acetate and goserelin acetate); antihormonal drugs (eg, tamoxifen, antiandrogen drugs such as flutamide; and antiadrenal drugs such as mitotane and aminoglutethimide). The present invention also provides for the use of A2AR / A2BR inhibitors in combination with other agents known in the art (eg arsenic trioxide) and other chemotherapeutic agents developed in the future.

In some embodiments related to methods of treating cancer, administration of a therapeutically effective amount of an A2AR / A2BR inhibitor described herein in combination with at least one chemotherapeutic agent results in cancer survival being higher than cancer survival observed with either the other one by one. In other embodiments relating to methods of treating cancer, administration of a therapeutically effective amount of an A2AR / A2BR inhibitor described herein in combination with at least one chemotherapeutic agent results in a greater reduction in tumor size or a greater inhibition of tumor growth than the reduction in tumor size or tumor growth observed with the introduction of only one remedy.

In other embodiments, the present invention provides methods for treating or preventing cancer in subjects comprising administering to them a therapeutically effective amount of at least one A2AR / A2BR inhibitor described herein and at least one signaling inhibitor (STI). In one specific embodiment, the at least one STI is selected from the group consisting of Bcr-Abl kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors,

- 6,038488 HER2 / neu receptor inhibitors and farnesyl transferase inhibitors (FTIs). Other potential STIs are listed elsewhere here.

The present invention also provides methods for enhancing tumor cell rejection in subjects, comprising administering an A ₂ AR / A _2B R inhibitor in combination with at least one chemotherapeutic agent and / or radiation therapy, resulting in greater tumor cell rejection than when administered alone. only an A2AR / A2BR inhibitor, a chemotherapeutic agent, or only with radiation therapy.

In other embodiments, the present invention provides methods of treating cancer in subjects comprising administering to them a therapeutically effective amount of at least one A2AR / A2BR inhibitor and at least one immunomodulator other than A2AR / A2BR inhibitors. In certain embodiments, at least one immunomodulator is selected from the group consisting of CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC / CCL19 , SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFN-a / -13, M-CSF, IL-3, GM-CSF, IL-13, anti- IL-10 and indolamine-2,3-dioxygenase 1 (ID01). Other potential immunomodulators are listed elsewhere here.

The present invention provides embodiments comprising methods of treating or preventing infectious diseases (e.g., viral infections) in subjects (e.g., humans) comprising administering to them a therapeutically effective amount of at least one A2AR / A2BR inhibitor described herein and a therapeutically effective amount of an anti-infective agent.

In some embodiments of the present invention, the additional therapeutic agent is a cytokine, including, for example, granulocyte macrophage colony stimulating factor (GM-CSF) or FLT3 ligand. The present invention also provides methods for the treatment or prevention of viral infections (e.g., chronic viral infections), including, but not limited to, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein Barr virus (EBV), chickenpox virus smallpox, Coxsackie virus and human immunodeficiency virus (HIV). The use of the compounds described herein for the treatment (alone or as part of a combination therapy) of infections is discussed in more detail below.

In additional embodiments, the treatment of infectious diseases is accomplished by co-administration of the vaccine in combination with the administration of a therapeutically effective amount of the A _2A R / A _2B R inhibitor of the present invention. In some embodiments, the vaccine is an antiviral vaccine, including, for example, an HIV vaccine. In other embodiments, the vaccine is effective against tuberculosis or malaria. In other embodiments, the vaccine is an anti-tumor vaccine (eg, a vaccine against melanoma); the anti-tumor vaccine may contain genetically modified tumor cells or cells of a genetically modified lineage, including genetically modified tumor cells or cells of a genetically modified lineage that have been transfected to express the granulocyte macrophage colony stimulating factor (GM-CSF). In certain embodiments, the vaccine comprises one or more immunogenic peptides and / or dendritic cells.

In some embodiments, the present invention provides methods of using the compounds described herein in combination with one or more antimicrobial agents.

In some embodiments relating to the treatment of infections by administering an A _2A R / A _2B R inhibitor and at least one additional therapeutic agent, the symptom of infection observed after administration of the A _2A R / A _2B R inhibitor and the additional therapeutic agent is improved over the same symptom of infection after the introduction of one or the other one by one. In some embodiments, the observed symptom of infection may be a decrease in viral load, an increase in the number of CD4 'T cells. a decrease in opportunistic infections, an increase in the duration of survival, the elimination of a chronic infection, or a combination of both.

Disclosure of the essence of the invention

Before describing the present invention further, it should be understood that the invention is not limited to the specific embodiments set forth herein, and that the terminology used herein is intended only to describe specific embodiments and not to limit it.

When a range of values is given, the invention is intended to cover each intermediate value, up to a tenth of a unit of the lower limit, unless the context clearly indicates otherwise, between the upper and lower limit of that range and any other specified or intermediate value in the specified range. The upper and lower limits of these smaller ranges may independently fall within the smaller ranges and are also encompassed by the invention, subject to any specifically excluded limits in the indicated range. If the specified range includes one or both of the limits, then ranges excluding one or both of these included limits are also included in the invention. Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art to which this invention belongs.

- 7 038488

In the present invention, the singular includes the plural, unless the context clearly dictates otherwise. It should also be noted that the claims may be drafted in such a way as to exclude any optional element. Moreover, such a statement should serve as a prior basis for the use of such exclusive terminology as exclusively, only, etc. in connection with the indication of the elements of the formula or using a negative constraint.

The publications discussed herein are incorporated solely for their disclosure prior to the filing date for this invention. In addition, the dates of publication provided may differ from the actual dates of publication, which may require independent confirmation.

General.

Provided herein are, for example, compounds and compositions for inhibiting adenosine A _2A receptors (A2AR) and / or adenosine A _2B receptors (A2BR) and pharmaceutical compositions containing them. Also provided herein are, for example, methods of treating or preventing diseases, disorders or conditions or their symptoms by inhibiting adenosine A _2A receptors (A2AR) and / or adenosine A _2B receptors (A2BR).

Definitions

Unless otherwise indicated, the following terms shall have the meanings stated below. Other terms are defined elsewhere throughout the description.

The term alkyl by itself or as part of another substituent means, unless otherwise indicated, a linear or branched hydrocarbon radical containing the indicated number of carbon atoms (ie, C _1-8 means from one to eight carbon atoms). Alkyl can contain any number of carbon atoms, ^{such as} C1.2, C1-3, C1-4, ^C 1-5, ^C 1-6, ^C 1-7, ^C 1-8, ^C 1-9, C1- 10, C2-3, ^C2-4, C2-5, ^C 2-6, ^C 3-4, ^C 3-5, ^C 3-6, ^C 4-5, C4-6 ^and C ₅ - _6. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

The term alkylene refers to linear or branched saturated aliphatic radicals containing the indicated number of carbon atoms and linking at least two other groups, i. E. these are divalent hydrocarbon radicals. The two moieties bonded to alkylene can be bonded to the same atom or to different alkylene atoms. For example, a linear alkylene can be a divalent radical - (CH ₂ ) _n -, where n is 1, 2, 3, 4, 5, or 6. Typical alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secbutylene, pentylene and hexylene. Alkylene groups, which are often referred to as X ¹ or X ² groups in this application, may be substituted or unsubstituted. When a group including X ¹ or X ² is optionally substituted, it is understood that optional substitutions may be on the alkylene portion of the moiety.

The term cycloalkyl refers to hydrocarbon rings containing the indicated number of ring atoms (eg, C3-6cycloalkyl) and fully saturated or containing no more than one double bond between the vertices of the ring. The term cycloalkyl also refers to bicyclic and polycyclic hydrocarbon rings such as bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, etc.

In some embodiments, the cycloalkyl compounds of the present invention are monocyclic C _3-6 cycloalkyls.

The term heterocycloalkyl refers to cycloalkyl rings with a specified number of ring vertices (or members) and containing from one to five heteroatoms selected from N, O and S, which replace from one to five carbon atoms at the vertices, and the nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are not necessarily quaternary. Heterocycloalkyl can be a monocyclic, bicyclic, or polycyclic ring system. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorphin-S-thiomorphine-S-psetra , pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. The heterocycloalkyl group can be attached to the rest of the molecule through a ring carbon atom or heteroatom.

In the present invention, a wavy line that crosses a single, double or triple bond in any chemical structure presented herein denotes the point of attachment of a single, double, or triple bond to the rest of the molecule. In addition, a bond going to the center of a ring (eg, a phenyl ring) serves to indicate attachment to any of the available vertices of the ring. Those of skill in the art will understand that multiple substituents shown to be attached to the ring must occupy the vertices of the ring to form stable bonds and otherwise be sterically compatible. For bivalent components, this representation should include both orientations (forward or backward). For example, the -C (O) NH- group must include bonds in any orientation: -C (O) NH- or -NHC (O) -, in the same way, -O-CH2CH2- can mean both -O-CH2CH2-, so and -CH2CH2-O-.

- 8 038488

The terms halo or halogen, by themselves or as part of another substituent, unless otherwise indicated, means a fluorine, chlorine, bromine or iodine atom. In addition, terms such as haloalkyl include monohaloalkyl and polyhaloalkyl. For example, the term C _1-4 haloalkyl may include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term aryl, unless otherwise indicated, means an unsaturated, typically aromatic hydrocarbon group that can be one ring or multiple rings (up to three rings) that are fused together or covalently linked. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.

The term heteroaryl refers to aryl groups (or rings) containing one to five heteroatoms selected from N, O, and S, where nitrogen and sulfur are optionally oxidized and nitrogen atoms are optionally quaternary. The heteroaryl group can be attached to the rest of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridine, thienopyrimidinyl, pyrazolopyrimidine , imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrroladiazolyl rings be selected from among the acceptable substituents described below.

The above terms (eg, alkyl, aryl and heteroaryl) in some embodiments must be optionally substituted. The individual substituents for each type of radical are shown below.

Optional substituents for alkyl radicals (including groups commonly referred to as alkylenes, alkenyls and alkynyls) can be various groups selected from halogen, OR ', -NR'R, -SR', -SiR'RR ', -OC (O) R ', -C (O) R', -CO2R ', -CONR'R, -OC (O) NR'R, -NRC (O) R', -NR'-C (O) NRR ', -NRC (O) ₂ R ', -NH-C (NH ₂ ) = NH, -NR'C (NH ₂ ) = NH, -NH-C (NH ₂ ) = NR', -S (O) R ', - S (O) ₂ R ', -S (O) ₂ NR'R, -NR'S (O) ₂ R, -CN (cyano), -NO ₂ , aryl, aryloxy, oxo, cycloalkyl and heterocycloalkyl in an amount from 0 to (2 '+1), where m' is the total number of carbon atoms in such a radical. R ', R and R' are each independently hydrogen, unsubstituted C _1-8 alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C _1-8 alkoxy or C _1-8 thioalkoxy α or unsubstituted aryl-C _{1- 4} alkyl groups. When R 'and R are attached to the same nitrogen atom, they together with the nitrogen atom can form a 3-, 4-, 5-, 6- or 7-membered ring. For example, -NR'R can be 1-pyrrolidinyl or 4-morpholinyl.

Optional substituents for cycloalkyl and heterocycloalkyl radicals can be various groups selected from alkyl optionally substituted with C (O) OR ', halogen, OR', -NR'R, -SR ', -SiR'RR', -OC (O) R ', -C (O) R', -CO2R ', -CONR'R, -OC (O) NR'R, -NRC (O) R', -NR'-C (O) NRR ', -NRC (O) 2R ', -NH-C (NH2) = NH, -NR'C (NH2) = NH, -NH-C (NH2) = NR', -S (O) R ', -S (O) 2R ', -S (O) ₂ NR'R, -NR'S (O) ₂ R, -CN (cyano), -nO ₂ , aryl, aryloxy and oxo. R ', R and R' are each independently hydrogen, unsubstituted C _1-8 alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C _1-8 alkoxy or C _1-8 thioαalkoxy groups, or unsubstituted aryl-C _{1- 4} alkyl groups.

Likewise, optional substituents for aryl and heteroaryl groups are various groups, which are usually selected from -halogen, -OR ', -OC (O) R', -NR'R, -SR ', -R', -CN, - NO2, -CO2R ', -CONR'R, -C (O) R', -OC (O) NR'R, -NRC (O) R ', -NRC (O) 2R', -NR'-C ( O) NRR ', -NH-C (NH2) = NH, -NR'C (NH2) = NH, -NH-C (NH2) = NR', -S (O) R ', -S (O) ₂ R ', -S (O) 2NR'R, -NR'S (O) ₂ R, -N3, perfluoro (C ₁ -C ₄ ) alkoxy and perfluoro (C ₁ -C ₄ ) alkyl, from 0 to total open valencies in the aromatic ring system; wherein R ', R and R' are independently selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, and C _2-8 alkynyl. Other suitable substituents are the above substituents for aryls attached to the ring atom with an alkylene chain of 1-6 carbon atoms.

Two substituents on adjacent aryl or heteroaryl ring atoms may optionally be replaced with substituents of the formula -TC (O) - (CH ₂ ) qU-, where T and U independently represent -NH-, -O-, -CH2-, or a single bond, aq is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by substituents of the formula -A- (CRfR ^g ) rB-, where A and B independently represent -CH2-, -O- , -NH-, -S-, -S (O) -, -S (O) 2-, -S (O) 2NR'- or a single bond, r is an integer from 1 to 3, a Rf and R ^g , each independently, is H or halogen. One of the simple bonds of the resulting new ring may optionally be replaced by a double bond. Alternatively, two substituents on adjacent aryl or heteroaryl ring atoms can optionally be replaced with substituents of the formula - (CH2) _s -X- (CH ₂ ) t-, where s and t are independently integers from 0 to 3, and X is - O-, -NR'-, -S-, -S (O) -, -S (O) ₂ - or -S (O) ₂ NR'-. The substituent R 'on -NR'- and -S (O) ₂ NR'- is selected from hydrogen or unsubstituted C _1-6 alkyl.

In the present invention, the term heteroatom encompasses oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

- 9 038488

The term pharmaceutically acceptable salts encompasses salts of the active compounds which are prepared with relatively non-toxic acids or bases, depending on the particular substituents on the compounds described herein. Where the compounds of the present invention contain relatively acidic functional groups, base salts can be prepared by contacting the neutral form of such compounds with a sufficient amount of the desired base, neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines and the like, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morphine amines, piperarines triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with sufficient m amount of the required acid, in pure form or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, hydrocarbon, phosphoric, hydrophosphoric, dihydrophosphoric, sulfuric, hydrosulfuric, hydroiodic or phosphorous acids, etc., as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, n-tolylsulfonic, citric, tartaric, methanesulfonic, etc. Also included are salts of amino acids such as arginate, etc. and salts of organic acids such as glucuronic or galacturonic acid, and others (for example, see Berge SM et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain particular compounds of the present invention contain both basic and acidic functional groups, which allow converting these compounds into salts with bases or acids.

The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to the parent forms of the compounds for the purposes of the present invention. In addition to salt forms, the present invention provides compounds that are in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to form the compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are described in more detail elsewhere herein.

In addition to salt forms, the present invention provides compounds that are in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to form the compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention may exist in unsolvated form as well as in solvated form, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are within the scope of the present invention. Some of the compounds of the present invention can exist in several crystalline or amorphous forms. In general, all physical forms are equivalent for the use contemplated by the present invention and are within the scope of the present invention.

Some of the compounds of the present invention contain asymmetric carbon atoms (optical centers) or double bonds; all racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (eg, individual enantiomers) are within the scope of the present invention. When stereochemically represented, they are meant to refer to those compounds in which one of the isomers is present and the other isomer is substantially absent. Virtually no other isomer means that the ratio of the two isomers is at least 80/20, more preferably 90/10 or 95/5 or more. In some embodiments, one of the isomers must

- 10 038488 be present in an amount of at least 99%.

The compounds of the present invention may also contain unnatural fractions of atomic isotopes in one or more of the atoms that make up such compounds. The unnatural proportion of the isotope can range from naturally occurring to up to 100% of the atom in question. For example, the compounds may include radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C), or non-radioactive isotopes such as deuterium ( ² H) or carbon-13 ( ¹³ C). Such isotopic variations can provide additional applications to those described elsewhere in this application. For example, isotopic variants of the compounds of the invention may find additional uses, including, but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the invention may have altered pharmacokinetic and pharmacodynamic characteristics that can enhance safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

The terms patient or subject are used interchangeably and refer to humans or other animals (eg, mammals).

The terms administering, administering and the like, for example, as applied to subjects, cells, tissues, organs or body fluids, refer to contacting, for example, an A2AR / A2BR inhibitor, pharmaceutical composition or diagnostic reagent containing it, with subjects, cells, tissues, organs or body fluids. In the context of cells, administration includes contacting (eg, in vitro or ex vivo) the reagent with the cells, as well as contacting the reagent with a liquid, the liquid being in contact with the cells.

The terms treat, treat, treat, and the like refer to a course of action (such as administering an A2AR / A2BR inhibitor or pharmaceutical composition containing it) after diagnosis, detection, and the like. a disease, disorder or condition or its symptoms in order to eliminate, reduce, suppress, alleviate or improve, temporarily or permanently, at least one of the main causes of the disease, disorder or condition affecting the subject, or at least one of the symptoms, associated with a disease, disorder, condition affecting the subject. Thus, treatment includes suppressing (eg, arresting the development or further development of a disease, disorder, or condition, or associated clinical symptoms) of an active disease.

The term in need of treatment in the present invention refers to a judgment made by a physician or other caregiver that a subject needs or will benefit from treatment. This judgment is made based on various factors that are within the purview of the physician or caregiver.

The terms prevent, prevention, prophylaxis and the like refer to a course of action (such as administering an A2AR / A2BR inhibitor or pharmaceutical composition containing it) taken in such a way (for example, before the onset of a disease, disorder, condition or its symptoms) to prevent, suppress, delay or reduce, temporarily or permanently, the patient's risk of developing a disease, disorder, condition, or the like; (as determined, for example, by the absence of clinical symptoms) or delay its onset, usually in the context of a subject predisposed to a particular disease, disorder or condition. In certain cases, these terms also refer to slowing the progression of a disease, disorder or condition, or inhibiting its transition to a dangerous or other undesirable stage.

The term in need of prophylaxis in the present invention refers to a judgment made by a physician or other caregiver that a subject needs or will benefit from prophylactic treatment. This judgment is made based on various factors that are within the purview of the physician or caregiver.

The expression therapeutically effective amount refers to the administration of an agent to a subject, either alone or as part of a pharmaceutical composition, as a single dose or as part of a series of doses, in an amount capable of exerting any measurable beneficial effect on any symptom, aspect or characteristic of a disease, disorder or a condition when administered to a subject. A therapeutically effective amount can be determined by measuring the appropriate physiological effects and can be adjusted in connection with the dosage regimen and diagnostic analysis of the subject's condition, and the like. For example, measuring the serum level of an A2AR / A2BR inhibitor (or, for example, its metabolite) at a specific time after administration may indicate that a therapeutically effective amount has been used.

The expression in an amount sufficient to effect a change means that there is a marked difference between the level of the indicator measured before (for example, the baseline level) and after the implementation of a particular therapy. Indicators include any objective parameters (for example, serum concentration) or subjective parameters (for example, the well-being of

- 11 038488 subjects).

The term small molecules refers to chemical compounds that have a molecular weight of less than 10, less than 2, or less than 1 kDa. Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules containing inorganic components, molecules containing radioactive atoms, and synthetic molecules. Therapeutically, small molecules can better penetrate cells, be less susceptible to degradation, and are less likely to elicit immune responses than large molecules.

The term ligand refers, for example, to peptides, polypeptides, membrane-bound or membrane molecules, or complexes thereof, which can act as agonists or antagonists of receptors. Ligands encompass natural and synthetic ligands, for example, cytokines, variants, cytokine analogs, muteins and binding compositions derived from antibodies, as well as small molecules. The term also encompasses substances that are neither agonists nor antagonists, but can bind to the receptor without significantly affecting its biological properties, such as signaling or adhesion. In addition, the term includes those membrane ligands that have undergone change, for example, by chemical or recombinant methods, to a soluble version of the membrane-bound ligand. Ligands or receptors can be completely intracellular, i. E. they can be located in the cytosol, nucleus, or some other intracellular compartment. The ligand-receptor complex is referred to as the ligand-receptor complex.

The terms inhibitors and antagonists, or activators and agonists refer to inhibitory or activating molecules, respectively, for example, to activate, for example, a ligand, receptor, cofactor, gene, cell, tissue, or organ. Inhibitors are molecules that reduce, block, prevent, delay activation, inactivate, desensitize, or suppress, for example, a gene, protein, ligand, receptor, or cells. Activators are molecules that enhance, activate, facilitate, enhance activation, sensitize, or stimulate, for example, a gene, protein, ligand, receptor, or cells. Inhibitors can also be defined as molecules that reduce, block, or inactivate constitutive activity. An agonist is a molecule that interacts with a target to induce or enhance the activation of the target. An antagonist is a molecule that counteracts the action of an agonist. The antagonist prevents, reduces, inhibits or neutralizes the activity of the agonist, and the antagonist can also prevent, inhibit or reduce the constitutive activity of the target, for example, a target receptor, even if no agonist has been identified.

The terms modulate, modulation and the like refer to the ability of a molecule (eg, an activator or inhibitor) to increase or decrease the function or activity of A ₂ AR / A _2B R, directly or indirectly. The modulator can act on its own, or it can use a cofactor such as a protein, metal ion, or small molecule. Examples of modulators include low molecular weight compounds and other bioorganic molecules. Numerous libraries of low molecular weight compounds (eg combinatorial libraries) are commercially available and can serve as a starting point for identifying a modulator. Those skilled in the art are able to develop one or more methods (eg, biochemical or cellular assays) that can screen such libraries of compounds to identify one or more compounds with the desired properties; thereafter, the medicinal chemist can optimize such one or more compounds, for example, by synthesizing and evaluating their analogs and derivatives. Also, when identifying activators, synthetic and / or molecular modeling methods can be used.

Activity of a molecule can mean or refer to the binding of a molecule to a ligand or to a receptor; to catalytic activity; the ability to stimulate gene expression or signaling, differentiation or maturation of cells; antigenic activity; to modulation of the activity of other molecules; and others. The term proliferative activity encompasses activity that stimulates, is necessary, or specifically associated with, for example, normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis and angiogenesis.

In the present invention, the terms comparable, comparable activity, activity comparable to, comparable effect, effect comparable to, and the like are relative terms that can be considered quantitatively and / or qualitatively. The meaning of terms often depends on the context in which they are used. For example, two agents that both activate a receptor can be considered to have a comparable effect from a qualitative point of view, but the same two agents can be considered not to give a comparable effect from a quantitative point of view if one agent is able to achieve only 20% of the activity of the other agent. when determined by an art-recognized method (eg, dose response analysis) or an art-recognized animal model. When comparing one result to another (for example, one result with a control standard) comparable often (although not always) means that one result deviates from the control standard by less than 35, 30, 25, 20, 15, 10, 7, 5, 4, 3, 2 or 1%. In certain embodiments, one result is comparable to a control standard if it deviates from it by less than 15%, 10%, or 5%. By way of example, but not limited to, activity or effect

- 12 038488 may refer to efficacy, stability, solubility, or immunogenicity.

Substantially pure means that the component constitutes more than 50% of the total composition of the composition, typically more than 60% of the total polypeptide content. More preferably, substantially pure refers to compositions in which the component of interest is at least 75%, at least 85%, at least 90% or more of the total composition. In some cases, the polypeptide will make up more than 90% or more than 95% of the total composition.

The terms specifically bind or selectively bind with respect to a ligand / receptor pair, antibody / antigen or other binding pair indicate a binding reaction that determines the presence of a protein in a heterogeneous population of proteins and other biologics. Thus, under certain conditions, the specified ligand binds to a specific receptor and does not bind significantly to other proteins present in the sample. In a provided method, an antibody or a binding composition obtained from an antigen binding site of an antibody binds to its antigen or a variant or mutein thereof with an affinity that is at least two times greater, at least 10 times greater, at least 20 times, or at least 100 times greater than the affinity for any other antibody or binding composition derived therefrom. In a preferred embodiment, the antibody should have an affinity greater than 10 ⁹ L / mol as determined, for example, by Scatchard (Munsen et al. 1980, Analyt. Biochem. 107: 220-239).

The term reaction, for example, a cell, tissue, organ or organism, encompasses a change in biochemical or physiological behavior, for example, concentration, density, adhesion or migration in a biological compartment, the level of gene expression or the state of differentiation, the change being correlated with activation, stimulation or treatment, or with internal mechanisms such as genetic programming. In certain contexts, the terms activation, stimulation, and the like refer to cell activation that is regulated by internal mechanisms as well as external or environmental factors; while the terms inhibition, suppression and the like refer to opposite effects.

The terms polypeptide, peptide, and protein, as used interchangeably herein, refer to polymeric forms of amino acids of any length, which may include genetically encoded and non-genetically encoded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides with a modified polypeptide backbone. The terms include fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusion proteins with heterologous and homologous leader sequences, with or without N-terminal methionine residues; immunologically labeled proteins; and etc.

In the present invention, the terms variants and homologues are used interchangeably to refer to those amino acid sequences or DNAs that are analogous to the control amino acid or nucleotide sequences, respectively. The terms encompass naturally occurring variants and non-naturally occurring variants. Naturally occurring variants include homologues (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence, respectively, from one species to another) and allelic variants (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence, respectively, from one individual to another within the species). Thus, variants and homologues include natural DNA sequences and their encoded proteins and their isoforms, as well as splice variants of a protein or gene. The terms also encompass nucleic acid sequences that differ in one or more bases from the natural DNA sequence, but still translate into an amino acid sequence that matches the naturally occurring protein due to the degeneracy of the genetic code. Non-naturally occurring variants and homologues include polypeptides and nucleic acids that contain changes in amino acid or nucleotide sequence, respectively, wherein the sequence changes are introduced artificially (eg, muteins); for example, changes are made in a laboratory by human action (by human hands). Thus, non-naturally occurring variants and homologues may include those that differ from natural sequences in one or more conservative substitutions and / or labels and / or conjugates.

The term muteins in the present invention refers broadly to mutant recombinant proteins. These proteins usually carry one or more amino acid substitutions and are often derived from cloned genes that have undergone site-directed or random mutagenesis, or from fully synthetic genes.

The terms DNA, nucleic acid, nucleic acid molecule, polynucleotide and the like are used interchangeably herein to refer to polymeric forms of nucleotides of any length, be they deoxyribonucleotides or ribonucleotides, or their analogs. Non-limiting examples of polynucleotides include linear and circular nucleic acids, messenger RNA (mRNA), complementary DNA (cDNA), recombinant polynucleotides, vectors, probes, primers, etc.

- 13 038488

Adenosine A _2A receptors and adenosine A _2B receptors and their inhibition.

As indicated above, the practical application of the invention does not require a precise understanding of the basic mechanism of action by which the compounds of the present invention exert their action, but it is believed that the compounds (or a subgroup of them) inhibit adenosine A _2A receptors (A2AR) and / or adenosine A _2B -receptors (A2BR). On the other hand, compounds (or a subgroup of them) can inhibit the functioning of adenylate cyclase. The compounds (or a subgroup of them) can also have an inhibitory effect on adenosine A _2A receptors (A2AR), adenosine A _2B receptors (A2BR) and adenylate cyclase. Although the compounds of the present invention are generally referred to herein as inhibitors of adenosine A _2A receptors (A2AR) and / or adenosine A _2B receptors (A _2B R), it should be understood that the term A2AR / A2BR inhibitors encompasses compounds that act individually by inhibiting A2AR , A2BR, or adenylate cyclases, and / or compounds that act by inhibiting A2AR, A2BR, and adenylate cyclase.

Identification of inhibitors of adenosine A _2A receptors and adenosine A _2B receptors with the desired characteristics.

The present invention relates in part to the identification of inhibitors of adenosine A _2A receptors and / or adenosine A _2B receptors with at least one property or characteristic of therapeutic value. Potential inhibitors can be identified, for example, by an art-recognized method or model, examples of which are described herein.

Once identified, potential inhibitors can be further investigated by methods that provide data on inhibitor characterization (eg, pharmacokinetic parameters, means of determining solubility or stability). Comparison of potential inhibitors with a control standard (which may be the best-in-class inhibitor available) indicates the potential suitability of such candidates.

Compounds of the invention

Provided compounds of formula (I)

P ^1a P ^1b

or their pharmaceutically acceptable salts, hydrates or solvates, where G ¹ means N or CR ^3a ;

G ² means N or CR ^3b ;

G ³ means N or CR ^3c ;

R ^3a , R ^3b and R ^3c are each independently H, deuterium or C _1-6 α alkyl;

R ^1a and R ^{1b are} each independently selected from the group consisting of:

i) H or deuterium, ii) C _1-8 α-alkyl optionally substituted with 1-3 R ⁵ substituents, iii) -X ¹ -O-C _1-8 alkyl optionally substituted with 1-3 R ⁵ substituents, iv) -C (O) -R6,

v) Y optionally substituted with 1-3 R ⁷ substituents, vi) -X1-Y optionally substituted with 1-3 R ⁷ substituents;

or R ^1a and R ^1b together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl ring optionally substituted with 1 to 3 R ⁸ substituents, wherein the heterocycloalkyl contains 02 additional ring-vertex heteroatoms selected from the group consisting of O , N and S;

each Y is C _3-8 cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 additional ring-vertex heteroatoms selected from the group consisting of O, N and S;

R ² and R ⁴ are each independently H, deuterium or C _1-3 alkyl;

Ar ¹ means 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R ⁹ ;

Ar ² means phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R ¹⁰ ;

moreover, 5-6-membered heteroaryl Ar ¹ and Ar ² , each independently, contain 1-3 heteroatoms at the vertices of the ring selected from the group consisting of O, N, N + -O ^- and S;

each X ¹ means C _1-6 α-alkyl;

each R ^{5 is} independently selected from the group consisting of hydroxyl, C _3-8 cycloalkyl, phenyl, —O-phenyl, —C (O) OR ^a, and oxo;

each R ⁶ is C _1-8 alkyl or Y, each of which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, —O-phenyl, phenyl, and —OC _1-8 alkyl;

each R ^{7 is} independently selected from the group consisting of C _1-8 alkyl, hydroxyl, —OC _1-8 alkyl, oxo, and C (O) OR ^a ;

each R ^{8 is} independently selected from the group consisting of C _1-8 α-alkyl, hydroxyl, and oxo;

- 14,038488 each R ^{9 is} independently selected from the group consisting of C1-8 alkyl, C1-8 deuteroalkyl, —O — C1-8 alkyl, —O — C1-8 ^{deuteroalkyl, —X 1 —O — C1-8 alkyl, —OX 1} -O-C1-8alkyl, -X ¹ -O-X ¹ -O-C1-8alkyl, -C (O) OR ^a , halogen, cyano, NR ^b R ^c , Y, -X ¹ -C3-8cycloalkyl and - X2-Z, where X ^{2 is} selected from the group consisting of C1-6 _{alkylene, -C 1-6} alkylene-O-, -C (O) - and -S (O) ₂ -, Z is 4-6 membered heterocycloalkyl containing 1-3 heteroatoms at the vertices of the ring selected from the group consisting of O, N and S, each of said substituents R ⁹ optionally substituted with 1-3 R ¹¹ ;

each R ^{10 is} independently selected from the group consisting of C1-8αalkyl, C1-8deuteroalkyl, halogen, cyano, -O-C1-8αalkyl, -O-C1-8deuteroalkyl, -X ¹ -O-C1-8alkyl, -O-X ¹ -O-C _1-8 α-alkyl, -S (O) ₂ -C _1-6 alkyl, -C (O) NR ^d R ^e and 4-6-membered heteroaryl containing 1-3 heteroatoms at the ring vertices selected from the group consisting of O, N and S, each of said R ¹⁰ substituents being optionally substituted by 1-3 R ¹² , or two R ¹⁰ on adjacent ring vertices of Ar ^{2 are} optionally connected to form a 5-membered heterocyclic ring, optionally substituted 1-2 halogens;

each R ^{11 is} independently selected from the group consisting of hydroxyl, halogen, cyano, —NR ^d R ^e , —C (O) OR ^a , phenyl, C _3-8 cycloalkyl, and C _1-4 alkyl optionally substituted with C (O) OR ^a ;

each R ^{12 is} independently selected from the group consisting of halogen, cyano, hydroxy, —C (O) OR ^a ;

each R ^a means H, deuterium or C _1-6 alkyl;

each R ^b and R ^{c is} independently selected from the group consisting of H, deuterium, C _1-8 α-alkyl,

-S (O) 2-C1-6αalkyl, -C (O) OR ^a and -X1-C (O) OR ^a ;

each R ^d and R ^{e is} independently selected from the group consisting of H, deuterium, C _1-8 α-alkyl,

-S (O) ₂ -C _1-6 α-alkyl;

provided that when each G ¹ and G ² is N, G ³ is CH, R ² is CH3, and each R ^1a and R ^1b is H or deuterium, then Ar ² does not mean 2-thienyl, phenyl, 2-, 3- or 4-methoxyphenyl, 3- or 4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl, or 2- or 4-methylphenyl.

In one particular group of embodiments, compounds of formula (I) are provided wherein Ar ¹ is 5-6 membered heteroaryl optionally substituted with 1-3 R ⁹ .

In another particular group of embodiments, compounds of formula (I) are provided wherein Ar ^{1 is} selected from the group consisting of pyridyl, pyridyl N-oxide, imidazolyl, pyrazolyl and thiazolyl, optionally substituted with 1-3 R ⁹ . In some specific embodiments, Ar ¹ is pyridyl or pyridyl Noxide optionally substituted with 1-3 R ⁹ .

In certain specific embodiments, compounds of formula (I) are provided wherein G ³ is CR ^3c .

In some specific embodiments, compounds of formula (I) are represented by formula (Ia)

where n is an integer from 0 to 2.

In some specific embodiments, compounds of formula (I) are represented by formula (Ib)

In certain specific embodiments, compounds of formula (I), Ia, and (Ib) are provided wherein Ar ^{2 is} substituted with 1-3 R ¹⁰ . In some embodiments, at least one R ¹⁰ is cyano.

In some specific embodiments, compounds of formula (I) are represented by formula (Ic)

where m is an integer from 0 to 2.

In some specific embodiments, compounds of formula (I) are represented by formula (Id)

In certain specific embodiments, provided are compounds of formula (I), (Ia), (Ib), (Ic), and (Id), wherein each R ^{9 is} independently selected from the group consisting of C _1-8 α-alkyl, C _1-8 deutero-α-alkyl, -OC _1-8 α-alkyl,

- 15 038488

-O-C _1-8 deuteroalkyl, -X1-O-C _1-8 alkyl, -O-X1-O-C _1-8 alkyl, -X ¹ -O-X ¹ -O-C _1-8 alkyl, wherein each of said R ⁹ substituents is optionally substituted with 1-3 R ¹¹ .

In certain specific embodiments, provided are compounds of formula (I), (Ia), (Ib), (Ic), and (Id), wherein each R ^{9 is} independently selected from the group consisting of —C (O) OR ^a , —NR ^b R ^c , Y, -X ¹ -C3-8cycloalkyl and -X ² -Z, and X ^{2 is} selected from the group consisting of C1-6 _{alkylene, -C 1-6} alkylene-O-, -C (O) - and -S (O) ₂ -, Z is a 4-6 membered heterocycloalkyl containing 1-3 heteroatoms at the ring vertices selected from the group consisting of O, N and S, each of said R ⁹ substituents being optionally substituted with 1-3 R ¹¹ ...

In some specific embodiments, compounds of formula (I) are represented by formula (Ie)

In certain specific embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) are provided, wherein G ² is N.

In certain specific embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) are provided, wherein G ¹ is N.

In certain specific embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) are provided, wherein G ¹ is CR ^3a .

In certain specific embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) are provided, wherein R ² is H or deuterium.

In certain specific embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) are provided, wherein R ⁴ is H or deuterium.

In certain specific embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) are provided, wherein R ^1b is H or deuterium. In certain specific embodiments, provided are compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie), wherein R ^{1b is} selected from the group consisting of:

i) H or deuterium, ii) C _1-8 alkyl optionally substituted with 1-3 R ⁵ substituents, iii) —X ¹ —O — C _1-8 alkyl optionally substituted with 1-3 R ⁵ substituents.

In certain specific embodiments, provided are compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie), wherein R ^{1b is} selected from the group consisting of:

i) H or deuterium, iv) -C (O) -R ⁶ ,

v) Y, optionally substituted with 1 -3 substituents R ^7, and vi) -X1-Y, optionally substituted with 1-3 substituents R ^7.

In certain specific embodiments, provided are compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie), wherein each R ^{10 is} independently selected from the group consisting of C1-8 alkyl, halogen, cyano, —O — C1-8 alkyl, —X ¹ —O — C1-8 alkyl, —O — X ¹ —O — C _1-8 alkyl, each of said R ¹⁰ substituents being optionally substituted with 1-3 R ¹² .

In some embodiments are provided compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie), wherein each R ^{10 is} independently selected from the group consisting of Ci-8 alkyl, halogen, cyano , -OC _1-8 alkyl.

In certain specific embodiments, compounds of formula (Ic) are provided wherein m is at least 1 and at least one R ¹⁰ is cyano. In certain specific embodiments, compounds of formulas (Id) and (Ie) are provided wherein at least one R ¹⁰ is cyano.

In some individual embodiments, any compounds from the table are provided. 1.

In some specific embodiments, any compounds from the group of compounds shown below are provided:

- 16 038488

In some specific embodiments, Compound I is provided:

In certain specific embodiments, deuterated forms of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) are provided. Deuterium can independently replace hydrogen at any position where hydrogen can be.

Synthesis methods.

In general, the compounds provided herein can be prepared by standard methods as described in the examples below.

Prodrugs and other means of drug delivery and / or half-life extension.

In some aspects of the present invention, the compounds described herein are administered as prodrugs.

In order to provide enhanced therapeutic activity, drug molecules can be engineered to use delivery vehicles. Such carriers are used either in a non-covalent manner, whereby the drug molecule is physicochemically included in the solvent-carrier mixture, or by permanent covalent attachment of the carrier reagent to one of the functional groups of the drug molecule (in general, see WO 2015/0202317).

Some non-covalent approaches are preferred. By way of example, but not limitation, depot preparations are used in some embodiments comprising non-covalent encapsulation of the preparation in polymeric carriers. In such formulations, the drug molecule is mixed with the carrier material and processed so that the drug molecule is distributed throughout the carrier. Examples include aggregates of polymer and microparticulate formulation such as Degradex® microspheres (Phosphorex, Inc.), which are administered as an injection suspension; aggregates of polymer molecules and a gel formulation such as Lupron Depot® (AbbVie Inc.) that are administered as a single bolus injection; and liposome formulations, such as DepoCyt® (Pacira Pharmaceuticals), in which the carrier can be a polymeric or non-polymeric substance capable of dissolving the drug. In such formulations, the release of drug molecules can occur upon swelling or physical destruction of the carrier. In other cases, chemical degradation promotes the diffusion of the drug into the biological environment; moreover, such processes of chemical degradation can be autohydrolytic or catalyzed by enzymes. Among other limitations, non-covalent drug encapsulation requires prevention of uncontrolled drug release, and the dependence of drug release mechanism on biodegradation may cause inter-patient variability.

In preferred embodiments, drug molecules, including both small and large molecules, are conjugated to the carrier via permanent covalent bonds. Some low moles

- 17 038488 Cular agents exhibiting poor solubility in aqueous liquids can be solubilized by conjugation with hydrophilic polymers, examples of which are described elsewhere herein. For high molecular weight proteins, an increase in half-life can be achieved, for example, by permanent covalent modification with palmitoyl and by permanent covalent modification with another protein, which itself has an increased half-life (for example, Albuferon®). Typically, drug molecules exhibit a decrease in biological activity when the drug is covalently conjugated to the carrier.

In some cases, the limitations associated with the fact that drug molecules are contained in non-covalent mixtures with polymers or with permanent covalent attachment can be successfully solved using a prodrug approach for chemical conjugation of a drug with a polymer carrier. In this case, therapeutic agents that are inactive or less active than the drug molecule itself are predictably transformed into active molecular entities. Reducing the biological activity of the prodrug relative to the released drug is beneficial if sustained or controlled release of the drug is required.

The approaches described above have some limitations. Prodrug activation can occur by enzymatic or non-enzymatic cleavage of the temporary bond between the carrier and the drug molecule, or by sequentially combining both (eg, an enzymatic step followed by a non-enzymatic modification). In an in vitro environment devoid of enzymes (for example, an aqueous buffer solution), a temporary ester or amide bond can undergo hydrolysis, but the rate of hydrolysis can be outside the therapeutically useful range. In contrast, esterases or amidases are usually present in the in vivo environment, which can cause a significant catalytic acceleration of hydrolysis kinetics from two to several orders of magnitude (for example, see Greenwald et al. (1999), J. Med. Chem. 42 (18): 3857 -67).

As described herein, prodrugs can be classified as i) bioprecursors and ii) carrier-associated prodrugs. Bioprecursors (precursors) do not contain carrier groupings and are activated by metabolic creation of a functional group. In contrast, in carrier-bound prodrugs, the active is conjugated to the carrier moiety through a temporary association with the functional group of the bioactive object. Preferred functional groups are hydroxyl or amino groups. Both the addition chemistry and the hydrolysis conditions depend on the type of functional group used. The carrier can be biologically inert (eg, PEG) or may have targeting properties (eg, antibody). Cleavage of the carrier molecule from the prodrug bound to the carrier leads to the production of the desired bioactive object, and the nature of the unblocked functional group of the bioactive object often contributes to its biological activity.

In the patent and scientific literature, many such macromolecular prodrugs are described in which the temporary bond is represented by a labile ester bond.

In such cases, the functional group of the bioactive entity is either a hydroxyl group or a carboxyl group (for example, see Cheng et al. (2003), Bioconjugate Chem. 14: 1007-17). In addition, it is often beneficial for biomacromolecules and some low-molecular-weight drugs to bind the carrier to the amino groups of the bioactive object (for example, to the N-terminal or amino groups of lysine in proteins). Upon receipt of a prodrug, amino groups can be more chemoselectively reacted due to their greater nucleophilicity compared to hydroxyl or phenolic groups. This is especially true for proteins and peptides containing very many different reactive functional groups, when non-selective conjugation reactions lead to an undesirable mixture of products requiring extensive study or purification, which reduces the reaction yield and the therapeutic efficiency of the active molecule.

Generally, amide bonds are more resistant to hydrolysis than ester bonds, and the rate of cleavage of the amide bond may be too slow for therapeutic use in carrier-bound prodrugs. Therefore, it can be advantageous to add structural chemical components in order to control the cleavability of the amide bond of the prodrug. These additional cleavage control chemicals, which are not present on the carrier or on the drug itself, are commonly referred to as linkers. Linkers in prodrugs can have a large effect on the rate of hydrolysis of a temporary bond, and variations in the chemical nature of linkers often lead to certain properties. Activation of prodrugs containing biologically active amino groups by specific enzymes for targeted release requires that the linker structure contains a structural motif that is recognized as a substrate by the corresponding endogenous enzyme. In such cases, the cleavage of the temporary bond occurs in a one-step process that is catalyzed by an enzyme. For example, the enzymatic release of cytarabine is carried out by the plasmin protease, the concentration of which is relatively high in various types of tumor masses.

The major disadvantage of predominantly enzymatic degradation is inter-patient variability. Enzyme levels can vary significantly between subjects, resulting in biological variations in the activation of the prodrug by enzymatic digestion. Fer levels

- 18 038488 ments can also vary depending on the site of administration (for example, when administered subcutaneously, some areas of the body produce more predictable therapeutic effects than others). In addition, it can be difficult to establish a correlation of in vivo-in vitro pharmacokinetic properties for prodrugs associated with an enzyme-dependent carrier.

Other prodrug carriers that use temporary bonds with amino groups in the drug molecule are based on a cascade mechanism. Cascade cleavage is provided by linker compounds, which consist of a structural combination of a masking group and an activating group. The masking group is attached to the activating group through a first temporary bond of the ester or carbamate type. The activating group attaches to the amino group of the drug molecule through a second temporary bond (eg, carbamate). The stability or susceptibility to hydrolysis of the second temporary bond depends on the presence or absence of a masking group. In the presence of a masking group, the second temporary bond is very stable and is unlikely to release drug molecules with therapeutically useful kinetics, whereas in the absence of a masking group, this bond becomes very labile, leading to rapid cleavage and release of the drug molecule.

The limiting stage in the cascade mechanism is the splitting of the first temporary bond. The first step can cause a molecular rearrangement of the activating group (e.g., 1,6 elimination, as described in Greenwald et al. (1999), J. Med. Chem. 42: 3657-67), with the rearrangement making the second temporary bond much more labile, which causes its splitting. Ideally, the rate of cleavage of the first temporary bond is identical to the required release rate for the drug molecule in a given therapeutic scenario. In addition, it is desirable that the cleavage of the second temporary bond is substantially instantaneous after it becomes labile upon cleavage of the first temporary bond.

Another embodiment includes polymeric amine-containing prodrugs based on trimethyl lock type lactonization (eg, see Greenwald et al. (2000), J. Med. Chem. 43 (3): 457-87). In this prodrug system, the substituted o-hydroxyphenyl-dimethylpropionic acid is linked to a PEG ester, carbonate or carbamate group as the first temporary bond and to the amino group of the drug molecule using an amide bond as the second temporary bond. The step that determines the release rate of the drug is enzymatic cleavage of the first bond, followed by rapid cleavage of the amide by lactonization with the release of a by-product such as aromatic lactone. The main disadvantage of the prodrug systems described by Greenwald et al. Is the release of highly reactive and potentially toxic aromatic low molecular weight by-products such as quinone methides or aromatic lactones after cleavage of the temporary bond. Potentially toxic substances are released in a 1: 1 stoichiometry with the drug and can reach high concentrations in vivo.

In some embodiments of cascade prodrugs containing aromatic activating groups based on 1,6-elimination, the masking group is structurally separated from the carrier. This can be accomplished by means of a stable bond between the polymer support and the activating group, while the stable bond does not participate in the cascade cleavage mechanism. If the carrier does not serve as a masking group, and the activating group is linked to the carrier through a stable bond, then the release of potentially toxic by-products (such as the activating group) is avoided. Stable attachment of the activating group and polymer also inhibits the release of drug intermediates with a linker with undefined pharmacology.

A first example of the approach described in the previous paragraph involves a polymeric prodrug system based on an activating group from mandelic acid (for example, see Shabat et al. (2004), Chem. Eur. J. 10: 2626-34). In this approach, the masking group is linked to the activating group by a carbamate bond. The activating group is permanently conjugated to the polyacrylamide polymer via an amide bond. After enzymatic activation of the masking group by the catalytic antibody, the masking group is cleaved by cyclization and the drug is released; the activating group is still linked to the polyacrylamide polymer after drug release. There is a similar prodrug system based on an activating group of mandelic acid and a cleavable enzymatically masking group linked to an ester (eg see Lee et al. (2004) Angew Chem. 116: 707-10).

When the above linkers are used, a very reactive aromatic intermediate is still formed in the 1,6-elimination step. Even if the aroma moiety remains permanently attached to the polymeric carrier, side reactions with potentially toxic byproducts or immunogenic effects can occur. Therefore, it is advantageous to create linker technologies for the production of polymeric prodrugs of amine-containing active substances using aliphatic prodrug linkers that do not depend on enzymes and do not form reactive aromatic intermediates upon cleavage. One such example uses maleic anhydride with PEG5000 to reversibly modify amino groups on tissue plasminogen activator and urokinase (e.g., see Garman et al. (1987), FEBS Lett.

- 19 038488

223 (2): 361-65). Regeneration of a functional enzyme from the PEG-uPA conjugate upon incubation in a buffer with pH 7.4 by cleavage of the bond with maleamic acid follows first-order kinetics with a half-life of about 6 hours. A disadvantage of the bond with maleamic acid is the insufficient stability of the conjugate at low pH values.

Another approach involves a cascade PEG prodrug system based on an N, N-6uc- (2hydroxyethyl) glycinamide (bicin) linker (eg, see J. Med. Chem. (2004), 47: 726-34). In this system, two PEG carrier molecules are temporarily bonded to a bicine molecule attached to the amino group of the drug molecule. The first step of prodrug activation involves enzymatic cleavage of the first temporary bonds connecting both PEG carrier molecules to the hydroxy groups of the activating group of bicine. The different bonds between PEG and bicine lead to different kinetics of prodrug activation. The second step of prodrug activation involves cleavage of the second temporary bond connecting the activating group of bicine to the amino group of the drug molecule. The disadvantage of this system is the low rate of hydrolysis of this second temporary amide bond of bicine, which leads to the release of a bicine-modified intermediate prodrug, which may exhibit different pharmacokinetic, immunogenic, toxic and pharmacodynamic properties compared to the native parent drug molecule.

In certain embodiments, dipeptides are used to develop prodrugs for targeting or targeted transport since they are substrates for enzymes or biotransport systems. A non-enzymatic pathway for the formation of dipeptide prodrugs, i.e. the ability to undergo intramolecular cyclization with the formation of the corresponding diketopiperazine (DKP) and the release of the active agent is not yet well defined.

In some embodiments, dipeptides are attached to the drug molecule by ester linkages as described for esters of dipeptides with the formulation of paracetamol (Gomes et al. (2005), Bio & Med Chem. Lett.). In this case, the cyclization reaction consists in a nucleophilic attack of the N-terminal amine of the peptide on the carbon atom of the ester with the formation of a tetrahedral intermediate, followed by the transfer of a proton from the amine to the oxyanion of the leaving group with the simultaneous formation of a peptide bond, giving the cyclic product DKP and a free drug. This method is applicable to hydroxyl-containing formulations in vitro, but has been found to compete with enzymatic hydrolysis of the ester bond in vivo, as the corresponding dipeptide esters release paracetamol at a much higher rate than in buffer (Gomes et al. Molecules, 12 (2007 ), 2484-2506). The susceptibility of dipeptide-based prodrugs to peptidases can be resolved by including at least one unnatural amino acid in the dipeptide motif. However, endogenous enzymes capable of cleaving ester bonds are not limited to peptidases, and the dependence of such cleavage of prodrugs on enzymes still generates unpredictable in vivo behavior.

In some embodiments, enzyme dependence is deliberately introduced into DKP prodrugs, such as when dipeptide ester-type prodrugs are formylated at the N-terminus of the dipeptide and enzymatic deformylation is used to trigger diketopiperazine formation and then cleave the ester-dipeptide bond to release the drug (e.g. , see US patent 7163923). As another example, an octapeptide is attached to the 4-hydroxyl group of vinblastine by an ester bond and undergoes ester cleavage to form DKP after specific enzymatic removal of the N-terminal hexapeptide (see Brady et al. (2002) J. Med. Chem. 45: 4706 -15).

The domain of DKP formation reactions also extends to amide prodrugs. For example, US Pat. No. 5,52,294 describes the activation of prodrugs by diketopiperazine formation for cytarabine prodrugs of the dipeptidylamide type. In this case, a temporary bond is formed between the carbonyl of the dipeptide and the aromatic amino group of cytarabine. However, it is unlikely that such conjugates can exhibit a sustained release effect since they lack the carrier or other component or functionality to extend the half-life.

Dipeptide prodrugs have also been described containing bioactive peptides of the GLP-1 type capable of releasing the peptide by the formation of diketopiperazine in the dipeptide appendage (eg, see WO 2009/099763). The bioactive peptide molecule may include an additional PEG chain on the side chain of one of the amino acid residues to prolong circulation of the bioactive peptide. However, this approach is associated with some significant disadvantages. First, the PEG chain must be linked to the peptide without compromising its bioactivity, which may be difficult to achieve for many peptide-based bioactive agents. Second, since the pegylated peptide is itself bioactive, the dipeptide promolecule affects the bioactivity of the peptide and can negatively affect its binding properties to the receptor.

Specific examples of technologies that can be used with the compounds of the present invention include those developed by ProLynx (San Francisco, CA) and Ascendis Pharma (Palo Alto, CA). The ProLynx technology platform uses a set of new linkers that are programmed to cleave at different rates to provide a controlled, predictable and

- 20 038488 sustained release of small molecules and peptides from circulating semi-solid macromolecular conjugates. The technology allows the required steady-state serum levels of therapeutic agents to be maintained for weeks or months.

The Ascendis Technology Platform combines the benefits of prodrug and sustained release technology to enhance the properties of small molecules and peptides. Patented prodrugs release the unmodified active parent therapeutic agent into the bloodstream at a predetermined rate controlled by physiological pH and temperature. Since the therapeutic agent is released unmodified, it retains its original mechanism of action.

Modifications to improve the performance of inhibitors.

It is often useful and sometimes necessary to improve one of several physical properties of the therapeutic agents disclosed herein and / or their route of administration. Improving physical properties includes, for example, methods of increasing water solubility, bioavailability, serum half-life and / or therapeutic half-life; and / or modulating biological activity.

Modifications known in the art include pegylation, Fc fusion, and albumin fusion. Although such modifications are usually associated with macromolecular agents (eg, polypeptides), more recently, such modifications have been evaluated on certain small molecules. For example, in Chiang M. et al. (J. Am. Chem. Soc., 2014, 136 (9): 3370-73) describes low molecular weight agonists of adenosine receptors 2A, conjugated to the Fc domain of immunoglobulin. Low molecular weight Fc conjugates retain strong interactions with the Fc receptor and adenosine 2A receptor and exhibit superior properties compared to unconjugated small molecule. The covalent attachment of PEG molecules to low molecular weight therapeutic agents has also been described (Li W. et al., Progress in Polymer Science, 2013, 38: 421-44).

Other known modifications include deuteration to improve pharmacokinetic, pharmacodynamic and toxicological profiles. Because of the higher atomic mass of deuterium, the cleavage of a carbon-deuterium bond requires more energy than a carbon-hydrogen bond. Because these stronger bonds are more difficult to break, the metabolic rate of the drug will be slower compared to non-deuterated forms, which facilitates less frequent dosing and may also reduce toxicity (Charles Schmidt, Nature Biotechnology, 2017, 35 (6): 493-494; Harbeson S. and Tung R., Medchem News, 2014, (2): 8-22).

Therapeutic and prophylactic use.

The present invention provides the use of the A _2A R / A _2B R inhibitors described herein for the treatment or prophylaxis of a wide variety of diseases, disorders and / or conditions and / or their symptoms. While specific applications are detailed below, it should be understood that the present invention is not limited thereto. In addition, while general categories of specific diseases, disorders, and conditions are outlined below, some diseases, disorders and conditions may fall into more than one category and others may not fall into any of the categories listed.

In some embodiments, the diseases, disorders and / or conditions described herein are mediated, at least in part, by adenosine A _2A receptors (A2AR). In some embodiments, the diseases, disorders and / or conditions described herein are mediated, at least in part, by adenosine A _2B receptors (A _2B R). In some embodiments, the diseases, disorders and / or conditions described herein are mediated, at least in part, by both A2AR and A _2B R.

In some embodiments, the A2AR / A2BR inhibitors described herein are administered in an amount effective to regress or arrest the progression of A2AR-mediated immunosuppression.

Oncological diseases.

In accordance with the present invention, A2AR / A2BR inhibitors can be used to treat or prevent proliferative diseases or disorders, including cancer, for example, cancer of the uterus, cervix, breast, prostate, testicles, gastrointestinal tract (eg, esophagus, oropharynx , stomach, small or large intestine, colon or rectum), kidney, renal cell carcinoma, bladder, bone, bone marrow, skin, head or neck, liver, gallbladder, heart, lungs, pancreas, salivary glands , adrenal, thyroid, brain (eg, gliomas), ganglia, central nervous system (CNS), and peripheral nervous system (PNS), and cancers of the hematopoietic system and the immune system (eg spleen or thymus). The present invention also provides methods for treating or preventing other cancer-related diseases, disorders or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, viral-induced cancers (for example, epithelial cell cancer, endothelial cell cancer, squamous cell carcinoma, and papilloma virus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratocarcinoma, chemically induced cancers, metastasis and angiogenesis. The invention provides for a decrease in tolerance to tumor cells or antigens of cancer cells, for example, by modulating the activity of regulatory T cells and / or CD8 'T cells (for example, see.

- 21 038488

Ramirez-Montagut et al. (2003) Oncogene 22: 3180-87; and Sawaya et al. (2003), New Engl. J. Med. 349: 150109). In certain embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. The use of the term cancer-related diseases, disorders and conditions should broadly encompass conditions that are directly or indirectly related to cancer, including, for example, angiogenesis and precancerous conditions such as dysplasia.

In some embodiments, the cancer may be metastatic or at risk of becoming metastatic, or may occur in diffuse tissue, including blood or bone marrow cancer (eg, leukemia). In some other embodiments, the compounds of the invention can be used to overcome T cell tolerance.

In some embodiments, the present invention provides methods of treating proliferative diseases, cancers, tumors, or precancerous conditions with A2AR / A2BR inhibitors and at least one additional therapeutic or diagnostic agent, examples of which are provided elsewhere herein.

Immunological and inflammatory diseases. In the present invention, terms such as immunological disease, immunopathology, immunological disorder, inflammatory disease, inflammatory condition, inflammatory disorder and the like should broadly encompass any immunopathology (e.g., autoimmune diseases) or disorders with an inflammatory component that can be treated with those described herein. inhibitors of A2AR / A2BR in order to obtain some therapeutic benefit. Such conditions are often inextricably linked with other diseases, disorders, and conditions. For example, immunopathology can refer to proliferative diseases such as cancer, tumors, and angiogenesis; including infections (acute and chronic), tumors and cancers that are resistant to elimination by the immune system.

The A2AR / A2BR inhibitors of the present invention can be used to enhance or enhance the immune response; improving immunization, including increasing the effectiveness of vaccines; and increased inflammation. The compounds provided herein can be used to treat immunodeficiencies associated with immunodeficiency diseases, immunosuppressive treatments, acute and / or chronic infections, and aging. A2AR / A2BR inhibitors can also be used to stimulate the immune system in patients with iatrogenic immunosuppression, including those who have undergone bone marrow transplantation, chemotherapy, or radiation therapy.

In certain embodiments of the present invention, A2AR / A2BR inhibitors are used to enhance or enhance the immune response to an antigen by providing adjuvant activity. In one specific embodiment, at least one antigen or vaccine is administered to a subject in combination with at least one A2AR / A2BR inhibitor of the present invention to prolong the immune response to the antigen or vaccine. Also provided are therapeutic compositions that include at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, fungi or parts thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines in combination with at least one A2AR / A2BR inhibitor of the present invention.

A non-limiting list of immunological and inflammatory diseases, disorders, and conditions that can be treated or prevented with the compounds and compositions of the present invention include arthritis (e.g., rheumatoid arthritis), renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (for example, if inflammatory cytokines interfere with healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), allergic contact dermatitis and other eczema, systemic sclerosis, transplantation and multiple sclerosis.

Among other immunological diseases, it is suggested that inhibition of A2AR / A2BR function may also play a role in immunotolerance and prevention of fetal rejection in utero.

In some embodiments, the A2AR / A2BR inhibitors described herein can be combined with immunosuppressants to reduce the number of immune effector cells.

Some of the above diseases, disorders and conditions in which A2AR / A2BR inhibitors can be particularly effective (eg, due to the limitations of existing treatments) are described in more detail below.

Rheumatoid arthritis (RA), which is usually characterized by chronic inflammation of the mucous membrane (synovium) of the joints, affects approximately 1% of the US population (2.1 million people). Further understanding of the role of cytokines, including TNF-α and IL-1, in the inflammatory process has led to the development and implementation of a new class of disease-modifying antirheumatic drugs.

- 22 038488 rats (DMARD). These drugs (of which some overlap with RA treatments) include Enbrel (etanercept), Remicade (infliximab), Humira (adalimumab), and Kineret (anakinra). While some of these agents relieve symptoms, inhibit the progression of structural damage, and improve physical function in certain patient populations, there is still a need for alternative agents with improved efficacy, complementary mechanisms of action, and fewer / less serious side effects.

Psoriasis, a constellation of common immunological chronic skin diseases, affects more than 4.5 million people in the United States, of whom 1.5 million have moderate to severe disease. What's more, 10% of people with psoriasis develop psoriatic arthritis, which damages the bones and connective tissue around the joints. An improved understanding of the underlying physiology of psoriasis has led to the development of drugs that, for example, target the activity of T lymphocytes and cytokines responsible for the inflammatory nature of the disease. Such agents include TNF-α inhibitors (also used to treat rheumatoid arthritis (RA), including Enbrel (etanercept), Remicade (infliximab), and Humira (adalimumab)), and T-cell inhibitors such as Amevive (alefacept) and Raptiva ( efalizumab). While some of these agents are somewhat effective in certain patient populations, none have been shown to be effective in treating all patients.

Microbiological diseases.

The present invention provides the use of the A _2A R / A _2B R inhibitors described herein for the treatment and / or prevention of any viral, bacterial, fungal, parasitic or other infectious disease, disorder or condition in which treatment with an A2AR / A2BR inhibitor may be beneficial.

Examples of contemplated viral diseases, disorders and conditions include, but are not limited to, hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), HIV, AIDS (including such manifestations as cachexia, dementia, and diarrhea) , herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, Coxsackie virus and cytomegalovirus (CMV).

Other examples of such diseases and disorders include staphylococcal and streptococcal infections (eg, Staphylococcus aureus and Streptococcus sanguinis, respectively), leishmaniasis, toxoplasmosis, trichomoniasis, giardiasis, Candida albicans, Bacillus anthracis, and Pseudomonas aeruginosa. In some embodiments, the diseases or disorders include Mycobacterium infections (eg, Mycobacterium leprae or Mycobacterium tuberculosis) or infections caused by Listeria monocytogenes or Toxoplasma gondii. The compounds of the invention can be used to treat sepsis, reduce or inhibit bacterial growth, and reduce or inhibit inflammatory cytokines.

Other embodiments provide for the treatment of parasitic infections, including, but not limited to, Leishmania donovani, Leishmania tropica, Leishmania major, Leishmania aethiopica, Leishmania mexicana, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malariae. Often, antiparasitic therapy is given prophylactically (eg, before the subject travels to an area with a high incidence of parasitic infections).

CNS-related and neurological diseases.

Inhibition of A _2A R / A _2B R can also be an important strategy for the treatment of patients with neurological, neuropsychiatric, neurodegenerative or other diseases, disorders and conditions that have some connection with the central nervous system, including disorders associated with impaired cognitive function and motor function. Examples include Parkinson's disease, extrapyramidal syndrome (EPS), dystonia, akathisia, tardive dyskinesia, restless legs syndrome (RLS), epilepsy, periodic limb movements during sleep (PLMS), attention deficit disorder, depression, anxiety, dementia, Alzheimer's disease, Huntington's disease, multiple sclerosis, cerebral ischemia, hemorrhagic stroke, subarachnoid hemorrhage and traumatic brain injury.

_{The A 2A} R / A _2B R inhibitors described herein may be particularly useful in subjects suffering from multiple sclerosis (MS), a severe debilitating autoimmune disease involving multiple sites of inflammation and scarring of myelin in the brain and spinal cord, as current treatments just to alleviate symptoms or slowing down the course of disability.

Likewise, A _2A R / A _2B R inhibitors may be particularly preferred for subjects suffering from neurodegenerative diseases such as Alzheimer's disease (AD), a brain disorder that seriously impairs the thinking, memory and speech processes of patients; and Parkinson's disease (PD), a progressive CNS disease characterized by, for example, abnormal movement, rigidity, and tremor. These diseases are progressive and debilitating and there is no cure.

Other diseases. Embodiments of the present invention provide for the administration of the A2AR / A2BR inhibitors described herein to subjects for the treatment or prevention of any other disease that would benefit at least some level of A2AR / A2BR inhibition. Such diseases, disorders and conditions include, for example, cardiovascular (for example, ischemia of the heart),

- 23 038488 intestinal (eg Crohn's disease), metabolic (eg diabetes), hepatic (eg liver fibrosis, NASH and NAFLD), pulmonary (eg COPD and asthma), ophthalmic (eg diabetic retinopathy) and renal (eg, renal failure) disease.

Pharmaceutical compositions.

_{The A 2A} R / A _2B R inhibitors of the present invention may be in the form of compositions suitable for administration to subjects. In general, such compositions are pharmaceutical compositions containing A2AR / A2BR inhibitors and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In some embodiments, the A2AR / A2BR inhibitors are present in a therapeutically acceptable amount. The pharmaceutical compositions can be used in the methods of the present invention; thus, for example, the pharmaceutical compositions can be administered to subjects ex vivo or in vivo in the practice of the therapeutic and prophylactic methods and uses described herein.

The pharmaceutical compositions of the present invention can be formulated to be compatible with the intended route or route of administration; typical routes of administration are given here. In addition, the pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds as described herein for the treatment or prevention of diseases, disorders and conditions provided by the present invention.

Pharmaceutical compositions containing the active ingredient (for example, an inhibitor of the A _2A R / A _2B R function) can be in a form suitable for oral administration, for example, in the form of tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups, solutions, microspheres or elixirs. Pharmaceutical compositions for oral administration can be prepared by any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more substances such as sweeteners, flavors, colors and preservatives, so as to obtain pharmaceutically elegant and pleasant-tasting preparations. Tablets, capsules, etc. contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such fillers can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.

Tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a long lasting effect. For example, a retardant material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by methods known in the art to produce controlled release osmotic therapeutic tablets. Additional substances include biodegradable or biocompatible particles or polymeric substances such as polyesters, polyamic acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acids, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or copolymers of the lactide / glycolide type or copolymers of the lactide / glycolide type, or copolymers of the lactide / glycolide type ethylene vinyl acetate to control the delivery of the administered composition. For example, an oral agent can be enclosed in microcapsules obtained by coacervation or interfacial polymerization methods using hydroxymethylcellulose or gelatin microcapsules or poly (methyl methacrylate) microcapsules, respectively, or in a colloidal drug delivery system. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microspheres, and lipid-based systems, including oil-injected emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the above formulations should be known to those skilled in the art.

Oral dosage forms can also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or in the form of soft gelatin capsules in which the active the ingredient is mixed with water or an oily medium such as peanut oil, liquid petroleum jelly, or olive oil.

Aqueous suspensions contain active substances in a mixture with excipients suitable for their manufacture. Such excipients can be suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents, for example natural phosphatide (for example, lecithin) or condensation products of alkylene oxide with fatty acids (for example, polyoxyethylene stearate) or condensation products of ethylene oxide with long-chain aliphatic alcohols (for example, for heptadecaethyleneoxycethanol) or condensation products of ethylene oxide fatty acids hexitol (for example, polyoxyethylene sorbitol monooleate) or condensation products of ethylene oxide with partial esters of fatty acids and hexitol anhydrides (for example, polyethylene sorbitan monooleate). Aqueous suspensions can also contain one or more preservatives.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin wax or cetyl alcohol. Sweeteners such as those described above and flavors can be added to provide palatable oral formulations.

Dispersible powders and granules suitable for preparing aqueous suspensions by adding water contain the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are listed herein.

The pharmaceutical compositions of the present invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifying agents can be natural gums such as gum arabic or gum tragacanth; natural phosphatides such as soy lecithin and esters or partial esters of fatty acids and hexitol anhydrides such as sorbitan monooleate; and condensation products of partial ethers with ethylene oxide, for example polyoxyethylene sorbitan monooleate.

Pharmaceutical compositions typically contain a therapeutically effective amount of an A2AR / A2BR inhibitor of the present invention and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, without limitation, antioxidants (for example, ascorbic acid and sodium bisulfate), preservatives (for example, benzyl alcohol, methylparabens, ethyl or n-propyl-n-hydroxybenzoate), emulsifiers, suspending agents, dispersing agents, solvents, fillers, fillers, detergents, buffers, liquid carriers, diluents and / or adjuvants. For example, a suitable liquid carrier may be physiological saline or citrate-buffered saline, with the optional addition of other materials conventional in pharmaceutical compositions for parenteral administration. Other examples of liquid carriers are neutral buffered saline or saline mixed with serum albumin. Those of skill in the art will be well aware of the various buffers that can be used in the pharmaceutical compositions and dosage forms provided herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. By way of example, the components of the buffers can be water-soluble materials such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Suitable buffering agents include, for example, tris buffer, N- (2-hydroxyethyl) piperazine-N '- (2-ethanesulfonic acid) (HEPES), 2- (N-morpholino) ethanesulfonic acid (MES), sodium salt 2- (N-morpholino) ethanesulfonic acid (MES), 3- (N-morpholino) propanesulfonic acid (MOPS) and N-tris- [hydroxymethyl] methyl-3aminopropanesulfonic acid (TAPS).

After preparation of pharmaceutical compositions, they can be stored in sterile vials in the form of a solution, suspension, gel, emulsion, solid or dehydrated or lyophilized powder. Such dosage forms can be stored either in a ready-to-use form, in a lyophilized form, requiring reconstitution before use, in a liquid form, requiring dilution before use, or in another acceptable form. In some embodiments, the pharmaceutical composition is in a disposable container (eg, a disposable vial, ampoule, syringe, or autoinjector (eg, of the EpiPen® type)), and in other embodiments, it is in a refillable container (eg, a refillable vial).

Dosage forms can also include carriers to protect the composition from rapid degradation or clearance from the body, such as controlled release forms, including liposomes, hydrogels, prodrugs, and microcapsule delivery systems. For example, a retarding material such as glyceryl monostearate or glyceryl stearate can be used, alone or in combination with wax. Any drug delivery device can be used to deliver the A2AR / A2BR inhibitors, including implants (eg, implantable pumps) and catheter systems, pumps, and slow injection devices, which are all well known in the art.

Depo injections, which are usually administered subcutaneously or intramuscularly, can also be used to release the A2AR / A2BR inhibitors described herein over a period of time. Depo injections are usually solid or oily base and usually contain at least one of the formulation components described herein. Those of ordinary skill in the art are aware of the possible formulations and uses of depot injections.

Pharmaceutical compositions can be in the form of sterile aqueous or oily suspensions for

- 25,038488 injections. Such suspensions can be prepared in accordance with the prior art using suitable dispersing or wetting agents and suspending agents as described herein. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that can be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL ™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g. glycerol , propylene glycol and liquid polyethylene glycol) and suitable mixtures thereof. In addition, sterile, non-volatile oils are commonly used as a solvent or suspending medium. For this, you can use any mild non-volatile oil, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Prolonged absorption of certain injection forms can be achieved by the inclusion of a substance that slows down absorption (for example, aluminum monostearate or gelatin).

The present invention provides for the administration of the A2AR / A2 _B R inhibitors in the form of suppositories for rectal administration. Suppositories can be prepared by mixing the drug with a suitable non-irritating excipient, which will be solid at ordinary temperatures but liquid at rectal temperatures so that it will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycols.

The A2AR / A2BR inhibitors contemplated by the present invention can be in the form of any other suitable pharmaceutical composition (eg, nebulizer for nasal or inhalation use) currently known or developed in the future.

Methods of administration.

The present invention provides for the administration of the A2AR / A2BR inhibitors and compositions thereof by any suitable route. Suitable routes of administration include oral, parenteral (eg, intramuscular, intravenous, subcutaneous (eg, injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebral, local, intraglinal, intraglinal (eg transdermal), buccal and inhalation. Depo injections, which are usually administered subcutaneously or intramuscularly, can also be used to release the A2AR / A2BR inhibitors described herein over a period of time.

In certain embodiments of the present invention, oral administration is provided. Combined therapy.

The present invention provides for the use of A2AR / A2BR inhibitors alone or in combination with one or more active therapeutic agents. Additional active therapeutic agents can be small chemical molecules; macromolecules such as proteins, antibodies, peptide antibodies, peptides, DNA, RNA, or fragments of such macromolecules, or cell or gene therapy. In this combination therapy, the different active agents often have different, complementary mechanisms of action. Such combination therapy can be particularly advantageous in that it allows the dose of one or more agents to be reduced, thereby reducing or eliminating the adverse effects associated with one or more agents. In addition, such combination therapy can have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

In the present invention, the term combination means therapy that can be carried out separately, for example in separate dosage forms for separate administration (for example, they can be presented in a set), and such therapy that can be carried out together in a single dosage form (i.e. . joint form).

In some embodiments, the A2AR / A2BR inhibitors are administered or used sequentially, for example, one agent is administered prior to the administration of one or more other agents. In other embodiments, the A2AR / A2BR inhibitors are administered simultaneously, eg, two or more agents are administered at the same or about the same time; two or more agents can be present in two or more separate forms, or combined in a single dosage form (ie, joint form). Regardless of whether the two or more agents are administered sequentially or simultaneously, for the purposes of the present invention, they are considered to be administered in combination.

The A2AR / A2BR inhibitors of the present invention can be used in combination with at least one other (active) agent in any manner appropriate under the circumstances. In one embodiment, treatment with at least one active agent and at least one A2AR / A2BR inhibitor of the present invention is maintained over a period of time. In another embodiment, treatment with at least one active agent is reduced or discontinued (eg, if the subject is stable), while treatment with the A2AR / A2BR inhibitor of the present invention is maintained at a constant dosage regimen. In another embodiment, treatment with at least one active agent is reduced or reduced

- 26 038488 is reduced (eg, if the subject is stable) and treatment with the A2AR / A2BR inhibitor of the present invention is reduced (eg, a lower dose, less frequent dosage, or shorter treatment regimen). In yet another embodiment, treatment with at least one active agent is decreased or discontinued (e.g., if the subject is stable), and treatment with an A2AR / A2BR inhibitor of the present invention is increased (e.g., higher dose, more frequent dosage, or longer treatment regimen). ). In yet another embodiment, treatment with at least one active agent is maintained and treatment with an A2AR / A2BR inhibitor of the present invention is reduced or discontinued (eg, lower dose, less frequent dosage, or shorter treatment regimen). In yet another embodiment, treatment with at least one active agent and treatment with an A2AR / A2BR inhibitor of the present invention is reduced or discontinued (eg, lower dose, less frequent dosage, or shorter treatment regimen).

Oncological diseases.

The present invention provides methods of treating and / or preventing proliferative diseases, cancer, tumors or precancerous diseases, disorders or conditions using an A2AR / A2BR inhibitor and at least one additional therapeutic or diagnostic agent. In some embodiments, the additional therapeutic or diagnostic agent is radiation, an immunomodulatory agent, or a chemotherapeutic agent or diagnostic agent. Suitable immunomodulatory agents that can be used in the present invention include CD40L, B7, and B7RP1; activating monoclonal antibodies (mAbs) to stimulating receptors such as anti-CD40, anti-CD38, anti-ICOS and 4-IBB ligand; antigen loading of dendritic cells (in vitro or in vivo); cancer vaccines such as dendritic cell-based cancer vaccines; cytokines / chemokines of type ILL, IL-2, IL-12, IL-18, ELC / CCL19, SLC / CCL21, MCP1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, M- CSF, IL-3, GM-CSF, IL-13 and anti-IL-10; bacterial lipopolysaccharides (LPS); indolamine-2,3-dioxygenase 1 (IDO1) inhibitors and immunostimulatory oligonucleotides.

In some embodiments of the present invention, methods of suppressing tumor growth are provided, comprising administering an A2AR / A2BR inhibitor described herein in combination with a signaling inhibitor (STI) to achieve additive or synergistic suppression of tumor growth. In the present invention, the term signaling inhibitor means a substance that selectively inhibits one or more steps in the signaling pathway. Signaling inhibitors (STIs) of the present invention include (i) Bcr-Abl kinase inhibitors (eg, Gleevec); (ii) inhibitors of the receptor for epidermal growth factor (EGF), including inhibitors of kinase and antibodies; (iii) HER2 / neu receptor inhibitors (eg Herceptin); (iv) inhibitors of kinases of the Akt family or the Akt pathway (eg rapamycin); (v) inhibitors of cell cycle kinases (eg, flavopiridol); and (vi) phosphatidylinositol kinase inhibitors. ^{Also, immunomodulatory agents in combination with the A} 2AR / ^A 2B ^R inhibitors described herein can be used to suppress tumor growth in cancer patients.

Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; nitrogen mustard gas analogs such as chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, fenesterol, prednimustine, trophosphamide, uramustine; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomisins, actinomycin, autramycin, azaserin, bleomycin, cactinomycin, calicheamycin, carbicin, kaminomycin, carcinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-epoxy-5-norubicin idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as antsitabine, azacytidine, 6-azauridine, karmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostan, testolactone; antiadrenal drugs such as amiglutethimide, mitotane, trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisanthrene; edatraxate; defopamine; demecolcine; diaziquon; elformitin; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguason; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pyirubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; sizophyran; spirogermanium; tenuazonic acid; triaziquon; 2,2 ', 2-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannu

- 27,038488 stins; mitobronitol; mitolactol; pipobromane; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids such as paclitaxel and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbin; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; anthracyclines and pharmaceutically acceptable salts, acids or derivatives of any of the above.

Chemotherapeutic agents also include anti-hormonal drugs that act to regulate or inhibit the action of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibiting 4 (5) -imidazoles, 4-hydroxy tamoxifen, trioxifene, keoxifen, onapristone and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as pharmaceutically acceptable salts, acids or derivatives of any of the above. In some embodiments, the combination therapy includes a chemotherapy regimen that includes one or more chemotherapeutic agents. In some embodiments, the combination therapy includes administration of a hormone or hormone-related drug.

Additional treatments that can be used in combination with A2AR / A2BR inhibitors include radiation therapy, monoclonal antibodies against tumor antigens, complexes of monoclonal antibodies and toxins, T-cell adjuvants, bone marrow transplants, or antigen-presenting cells (e.g., dendritic cell therapy), including TLR agonists, which are used to stimulate such antigen-presenting cells.

In some embodiments, the present invention provides for the use of the compounds described herein in combination with adoptive cell therapy, a novel and promising form of personalized immunotherapy in which immune cells with anti-tumor activity are administered to cancer patients. Adoptive cell therapy is being studied using tumor infiltrating lymphocytes (TIL) and T cells engineered to express, for example, chimeric antigen receptors (CAR) or T cell receptors (TCR). Adoptive cell therapy typically involves obtaining T cells from an individual, genetically modifying them to target a specific antigen or to enhance antitumor effects, amplifying them to a sufficient number, and injecting genetically modified T cells into a cancer patient. T cells can be obtained from a patient to whom the expanded cells will later be reinfused (eg, autologous), or can be obtained from donor patients (eg, allogeneic).

In some embodiments, the present invention provides for the use of the compounds described herein in combination with RNA interference therapy for silencing gene expression. RNA interference begins with the cleavage of long double-stranded RNA into small interfering RNAs (siRNAs). A single siRNA strand is incorporated into a ribonucleoprotein complex known as an RNA-induced silencing complex (RISC), which is then used to identify those mRNA molecules that are at least partially complementary to the inserted siRNA strand. RISC can bind or cleave mRNA, thereby inhibiting translation.

Inhibitors of immune checkpoints. The present invention provides for the use of the inhibitors of A _2A R / A _2B R function as described herein in combination with immune checkpoint inhibitors.

The vast array of genetic and epigenetic changes common to all cancers provide a diverse set of antigens that the immune system can use to distinguish tumor cells from normal cells. In the case of T cells, the final amplitude (e.g., cytokine production or proliferation) and quality (e.g., type of immune response generated, such as a cytokine production profile) of the response that is triggered by antigen recognition by the T cell receptor (TCR) is regulated by the balance between costimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are critical for preventing autoimmunity (i.e. maintaining self-tolerance) as well as protecting tissues from damage when the immune system responds to a pathogenic infection. The expression of immune checkpoint proteins can be disrupted by tumors as an important mechanism of immunoresistance.

T cells have been a major focus of efforts to therapeutically manipulate endogenous anti-tumor immunity due to i) their ability to selectively recognize peptides derived from proteins in all cell compartments; ii) their ability to directly recognize and destroy antigen-expressing cells (via CD8 'effector T cells. also known as cytotoxic T lymphocytes (CTLs)); and w) their ability to organize various CD4 + helper T cell immune responses that integrate adaptive and innate effector mechanisms.

In a clinical setting, blockade of immune checkpoints, which leads to increased

- 28,038488 antigen-specific T-cell responses, turned out to be a promising approach in cancer therapy in humans.

T-cell mediated immunity involves several sequential steps, each of which is regulated by balancing stimulatory and inhibitory signals to optimize the response. Although almost all inhibitory signals in the immune response ultimately modulate intracellular signaling pathways, many are triggered via membrane receptors whose ligands are either membrane bound or soluble (cytokines). Although costimulatory and inhibitory receptors and ligands that regulate T cell activation are often not overexpressed in cancer compared to normal tissues, inhibitory ligands and receptors that regulate T cell effector functions in tissues are usually overexpressed in tumor cells or in non-transformed cells associated with the tumor microenvironment. The functions of soluble and membrane-bound immunity checkpoints of the receptor ligand type can be modulated by antibodies-agonists (for costimulatory pathways) or antibodies-antagonists (for inhibitory pathways). Thus, unlike most antibodies currently approved for cancer therapy, antibodies that block immune checkpoints do not directly target tumor cells, but rather lymphocyte receptors or their ligands in order to enhance endogenous antitumor activity [see. Pardoll, (April 2012), Nature Rev. Cancer, 12: 252-64].

Examples of immune checkpoints (ligands and receptors), some of which are selectively activated in various types of tumor cells that are candidates for blocking, include PD1 (programmed cell death protein-1); PDL1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA4 (cytotoxic T lymphocyte associated antigen 4); TIM3 (T-cell membrane protein 3); LAG3 (gene 3 activation of lymphocytes); TIGIT (T-cell immunoreceptor with Ig and ITIM domains) and inhibitory killer cell receptors, which can be divided into two classes based on their structural features: i) immunoglobulin-like killer cell receptors (KIR) and ii) type C lectin receptors (representatives family of transmembrane receptors type II). Other less well-defined immune checkpoints have been described in the literature, including both receptors (for example, the 2B4 receptor (also known as CD244)) and ligands (for example, some inhibitory ligands of the B7 family such as B7-I3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x and VCTN1)) [cf. Pardoll, (April 2012) Nature Rev. Cancer 12: 252-64].

The present invention provides for the use of the inhibitors of A _2A R / A _2B R function described herein in combination with inhibitors of the above receptors and ligands of immune checkpoints, as well as not yet described receptors and ligands of immune checkpoints. Some immunity breakpoint modulators are already available, while others are in advanced stages of development. For example, ipilimumab, a fully humanized anti-CTLA4 monoclonal antibody (Yervoy; Bristol-Myers Squibb), when approved for the treatment of melanoma in 2011, was the first immune checkpoint inhibitor to receive regulatory approval in the United States. Fusion proteins containing CTLA4 and an antibody (CTLA4-Ig; abatcept (Orencia; Bristol-Myers Squibb)) have been used to treat rheumatoid arthritis, and other fusion proteins have been shown to be effective in kidney transplant patients susceptible to Epstein-Barr virus. Anti-PD1 antibodies are under development (eg nivolumab (Bristol-Myers Squibb) and lambrolizumab (Merck)), and anti-PDL1 antibodies are being tested (eg MPDL3280A (Roche)). Nivolumab has performed well in patients with melanoma, lung and kidney cancer.

In one aspect of the present invention, the claimed A2AR / A2BR inhibitors are combined with immuno-oncological agents, which are (i) agonists of stimulatory (including costimulatory) receptors or (ii) antagonists of inhibitory (including co-inhibiting) signals in T cells, both of which cause an increase in antigen-specific T- cellular responses. Some of the stimulating and inhibiting molecules are members of the immunoglobulin superfamily (IgSF). One of the important families of membrane-bound ligands that bind to costimulatory or co-inhibiting receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7 -H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibiting receptors is the TNF family of molecules that bind to members of the related TNF receptor family, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L , 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT13R, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin-α / TNF13, TNFR2, TNFa, LT13R, lymphotoxin-a 1132, FAS, FASL , RELT, DR6, TROY, NGFR.

In another aspect, the immuno-oncological agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines), or

- 29 038488 cytokine that stimulates the activation of T cells to stimulate the immune response.

In one aspect, T cell responses can be stimulated with a combination of the following A2AR / A2 _B R inhibitors and one or more of (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors) of the CTLA-4 type, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin-9, CEASAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4; and / or (ii) agonists of proteins that stimulate the activation of T-cells of the types B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2. Other agents that can be combined with the A _2A R / A _2B R inhibitors of the present invention to treat cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds provided herein can be combined with KIR antagonists such as lyrilumab.

Still other combination therapy agents include agents that inhibit or deplete macrophages or monocytes, including, but not limited to, CSF-1R antagonists such as CSF-1R antibodies, including RG7155 (WO 202011/70024, WO 2011/107553, WO 2011 / 131407, WO 2013/87699, WO 2013/119716, WO 2013/132044) or FPA-008 (WO 2011/140249; WO 2013/169264; WO 2014/036357).

In another aspect, the disclosed A _2A R / A _2B R inhibitors can be used with one or more agonists that bind to positive costimulatory receptors, blockers that impair signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome certain immunosuppressive pathways in the tumor microenvironment, for example, blocking the action of inhibitory receptors (for example, PD-L1 / PD-1 interaction), depleting or inhibiting T _reg cells (for example, using an anti-CD25 monoclonal antibody such as daclizumab or by depletion on beads against CD25 ex vivo) or inducing regression / preventing anergy or depletion of T cells, and agents triggering the activation of innate immunity and / or inflammation at the site of tumors.

In one aspect, the immuno-oncological agent is a CTLA-4 antagonist, such as a CTLA-4 antagonist antibody. Suitable antibodies to CTLA-4 include, for example, Yervoy (ipilimumab) or tremelimumab.

In another aspect, the immuno-oncological agent is a PD-1 antagonist type of a PD-1 antagonist antibody. Suitable antibodies to PD-1 include, for example, Opdivo (nivolumab), Keytruda (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012/145493). Pidilizumab (CT-011) can also serve as an immuno-oncological agent, although its specificity for PD-1 binding has been questioned. Another approach for targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1 called AMP-224.

In another aspect, the immuno-oncological agent is a PD-L1 antagonist such as a PD-L1 antagonist antibody. Suitable antibodies to PD-L1 include, for example, MPDL3280A (RG7446; WO 2010/077634), durvalumab (MEDI4736), BMS-936559 (WO 2007/005874) and MSB0010718C (WO 2013/79174).

In another aspect, the immuno-oncological agent is a LAG-3 antagonist type of antibody LAG-3 antagonist. Suitable antibodies to LAG-3 include, for example, BMS-986016 (WO 10/19570, WO 2014/08218) or IMP-731 or IMP-321 (WO 2008/132601, WO 2009/44273).

In another aspect, the immuno-oncological agent is a CD137 agonist (4-1BB) such as an antibody agonist CD137. Suitable antibodies to CD137 include, for example, urelumab and PF-05082566 (WO 2012/32433).

In another aspect, the immuno-oncological agent is a GITR agonist such as a GITR agonist antibody. Suitable antibodies to GITR include, for example, BMS-986153, BMS-986156, TRX-518 (WO 2006/105021, WO 2009/009116) and MK-4166 (WO 2011/028683).

In another aspect, the immuno-oncological agent is an OX40 agonist, such as an OX40 agonist antibody. Suitable antibodies to OX40 include, for example, MEDI-6383 or MEDI-6469.

In another aspect, the immuno-oncological agent is an OX40L antagonist such as an OX40L antagonist antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO 2006/029879).

In another aspect, the immuno-oncological agent is a CD40 agonist, such as a CD40 antibody agonist. In yet another embodiment, the immuno-oncological agent is a CD40 antagonist such as a CD40 antagonist antibody. Suitable antibodies to CD40 include, for example, lucatumumab or dacetuzumab.

In another aspect, the immuno-oncological agent is a CD27 agonist such as a CD27 agonist antibody. Suitable antibodies to CD27 include, for example, varlilumab.

In another aspect, the immuno-oncological agent is MGA271 (to B7H3) (WO 2011/109400).

The present invention encompasses pharmaceutically acceptable salts, acids or derivatives of any of the above.

- 30 038488

Metabolic and cardiovascular diseases.

The present invention provides methods of treating and / or preventing certain cardiovascular and / or metabolic diseases, disorders and conditions, as well as related disorders, using an A2AR / A2BR inhibitor and at least one additional therapeutic or diagnostic agent.

Examples of therapeutic agents useful in combination therapy for the treatment of hypercholesterolemia (as well as atherosclerosis) include statins (eg, Crestor, Lescol, Lipitor, Mevacor, Pravacol, and Zocor) that inhibit enzymatic cholesterol synthesis; bile acid resins (eg, Colestid, Lo-Cholest, Prevalite, Questran and Welchol), which sequester cholesterol and prevent its absorption; ezetimibe (Zetia), which blocks the absorption of cholesterol; fibric acid (such as Tricor), which lowers triglyceride levels and can moderately raise HDL levels; niacin (such as Niacor), which moderately lowers LDL cholesterol and triglycerides; and / or combinations of the above (e.g., Vytorin (ezetimibe with simvastatin). Alternative cholesterol treatments that may be candidates for use in combination with the A2AR / A2BR inhibitors described herein include various additives and herbs (e.g. garlic, policosanol, and guggul ).

The present invention encompasses pharmaceutically acceptable salts, acids or derivatives of any of the above.

Immunological and inflammatory diseases. The present invention provides methods for the treatment and / or prevention of immunological diseases, disorders and conditions; as well as diseases, disorders and conditions with an inflammatory component; with inhibitors A2AR / A2BR and at least one additional therapeutic or diagnostic agent.

Examples of therapeutic agents useful in combination therapy include, but are not limited to, the following: non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and other propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurboprofen , ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and thioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofacozin, fenclofacentix, fenclofacepenac, fenclofacepenac sulindac, thiopinac, tolmetin, zidomethacin and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and fluumovofenizal (isoxicamic), oxycamic , salicylates (acetylsalicyl oic acid, sulfasalazine) and pyrazolones (apazon, piperilone-free, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone). Other combinations include cyclooxygenase-2 (COX-2) inhibitors.

Other active combination agents include steroids such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, or hydrocortisone. Such combinations can be particularly advantageous as one or more of the side effects of the steroids can be reduced or even eliminated by reducing the required steroid dose.

Additional examples of active agents that can be used in combinations to treat, for example, rheumatoid arthritis include cytokine suppressive anti-inflammatory drugs (CSAIDs); antibodies or antagonists of other human cytokines or growth factors, for example TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP- II, GM-CSF, FGF or PDGF.

Certain combinations of active agents can be activated at various points in the autoimmune and subsequent inflammatory cascade, they include TNF antagonists such as chimeric, humanized or human anti-TNF antibodies, Remicade, anti-TNF antibody fragments (e.g. CDP870) and soluble TNF receptors p55 or p75, derivatives thereof , p75TNFRIgG (Enbrel) or p55TNFRlgG (Lenercept), soluble IL-13 receptors (sIL-13), and TNFα-converting enzyme inhibitors (TACE); similarly, inhibitors of IL-1 (eg, inhibitors of the interleukin-1 converting enzyme) may be effective. Other combinations include interleukin 11, anti-P7 antibodies, and n-selectin glycoprotein ligand (PSGL). Other examples of agents useful in combination with the A2AR / A2BR inhibitors described herein include interferon-131a (Avonex); interferon-13 β (Betaseron); copaxone; hyperbaric oxygen; intravenous immunoglobulin; cladribine and antibodies or antagonists of other human cytokines or growth factors (eg antibodies to ligand CD40 and CD 80).

Microbiological diseases.

The present invention provides methods for the treatment and / or prevention of viral, bacterial, fungal and parasitic diseases, disorders and conditions, as well as disorders associated with them, using A2AR / A2BR inhibitors and at least one additional therapeutic or diagnostic agent (for example, one or several other antiviral

- 31 038488 funds and / or one or more funds not related to antiviral therapy).

Such combination therapy includes antiviral agents targeting different stages of the viral life cycle and having different mechanisms of action, including, but not limited to, the following: inhibitors of viral decapsidation (eg, amantadine and rimantidine); reverse transcriptase inhibitors (eg, acyclovir, zidovudine, and lamivudine); funds aimed at integrase; agents that block the attachment of transcription factors to viral DNA; agents (eg, antisense molecules) that interfere with translation (eg, fomivirsen); agents that modulate the function of translation / ribozymes; protease inhibitors; virus assembly modulators (eg rifampicin); antiretroviral drugs such as nucleoside analogue reverse transcriptase inhibitors (eg azidothymidine (AZT), ddI, ddC, 3TC, d4T); non-nucleoside reverse transcriptase inhibitors (eg efavirenz, nevirapine); nucleotide analogue reverse transcriptase inhibitors; and agents that prevent the release of viral particles (eg, zanamivir and oseltamivir). Treatment and / or prevention of certain viral infections (for example, HIV) often requires a whole group (cocktail) of antiviral agents.

Other antiviral agents contemplated for use in combination with A2AR / A2BR inhibitors include, but are not limited to, the following: abacavir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevirertet, cidofovir, combivir, darunavir, dalavirin docosanol, edoxudine, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosferine, alfa- ginterone 2 , methisazone, nelfinavir, nexavir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, ritonavir, pyramidin, saquinavir, stavudine, telaprevir, tenofovir, tipranavir, thromfluiridin, viderocicovirin and zalcitabine.

The present invention provides for the use of the inhibitors of the A2AR / A2BR function described herein in combination with antiparasitic agents. Such agents include, but are not limited to, thiabendazole, pyrantel pamoate, mebendazole, praziquantel, niclosamide, btionol, oxamnicvin, metriphonate, ivermectin, albendazole, eflornithine, melarsoprol, pentamidine, benznidazole, nifurtimox, and nitroimidazole. Other agents are known to those skilled in the art that can be used in the treatment of parasitic diseases.

Embodiments of the present invention provide for the use of the A2AR / A2BR inhibitors described herein in combination with agents useful in the treatment or prevention of bacterial diseases. Antibacterial agents can be classified in various ways, including mechanism of action, chemical structure, and spectrum of action. Examples of antibacterial agents include agents that target the bacterial cell wall (eg, cephalosporins and penicillins) or the cell membrane (eg, polymyxins), or affect vital bacterial enzymes (eg sulfonamides, rifamycins, and quinolines). Most antibacterial agents aimed at protein synthesis (eg tetracyclines and macrolides) are bacteriostatic, while agents such as aminoglycosides are bactericidal. Another way of classifying antibacterial agents is based on their target specificity; narrow-spectrum agents target specific types of bacteria (eg, gram-positive bacteria such as streptococci), and broad-spectrum agents are active against a wider range of bacteria. Those types of antibacterial agents are known to those skilled in the art that are suitable for use in specific bacterial infections.

Embodiments of the present invention provide for the use of the A2AR / A2BR inhibitors described herein in combination with agents useful in the treatment or prevention of fungal diseases. Antifungal agents include polyenes (eg, amphotericin, nystatin, and pimaricin); azoles (eg fluconazole, itraconazole and ketoconazole); allylamines (eg naftifine and terbinafine) and morpholines (eg amorolfine); as well as antimetabolics (for example, 5-fluorocytosine).

The present invention encompasses pharmaceutically acceptable salts, acids or derivatives of the above agents (and representatives of these classes of agents).

Dosage.

The A2AR / A2BR inhibitors of the present invention can be administered to subjects in an amount that depends, for example, on the purpose of administration (eg, the desired degree of process resolution); the age, weight, sex, health and physical condition of the subject to whom the drug is administered; the route of administration and the nature of the disease, disorder, condition, or symptom. The dosage regimen can also take into account the presence, nature and extent of any side effects associated with the administered agents. Effective dose levels and dosage regimens can be readily determined, for example, from safety and dose escalation tests, in vivo studies (eg, animal models), and other methods known to those of skill in the art.

In general, dosing parameters dictate that the dose level is less than the amount

- 32 038488 which may be irreversibly toxic to the subject (maximum tolerated dose (MTD)), and not less than the amount required to produce a measurable effect on the subject. Such amounts are determined, for example, by pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into account the route of administration and other factors.

An effective dose (ED) is that dose or amount of an agent that elicits a therapeutic response or desired effect in a fraction of the subjects taking it. The average effective dose of an agent, or ED50, is that dose or amount of an agent that induces a therapeutic response or desired effect in 50% of the population to which it is administered. While the ED50 is usually used as a measure of reasonable expectation of a drug's effect, it is not necessarily the dose that the clinician might consider appropriate, given all relevant factors. Thus, in some situations the effective amount will be greater than the calculated ED50, in other situations the effective amount will be less than the calculated ED50, and in other situations the effective amount will be the same as the calculated ED50.

In addition, an effective dose of the A _2A R / A2BR inhibitors of the present invention may be such an amount that, when administered to a subject in one or more doses, produces the desired result over a healthy subject. For example, for a subject suffering from a particular disease, an effective dose may be one that improves a diagnostic parameter, score, marker, and the like. this disease by at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50% , at least 60%, at least 70%, at least 80%, at least 90% or more than 90%, and 100% is defined as a diagnostic parameter, indicator, marker, etc. ... in normal individuals.

In some embodiments, the A2AR / A2BR inhibitors provided by the present invention can be administered (e.g., orally) at a dosage level of 0.01 to 50 mg / kg, or 1 to 25 mg / kg of the subject's body weight per day, one or more times per day. day to get the required therapeutic effect.

For the administration of oral agents, the compositions can be presented in the form of tablets, capsules and the like, containing from 1.0 to 1000 mg of the active ingredient, in particular 1.0, 3.0, 5.0, 10.0, 15, 0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 mg of the active ingredient.

In some embodiments, the dosage of the desired A2AR / A2BR inhibitor is contained in a unit dosage form. The expression unit dosage form refers to physically discrete units, each containing a predetermined amount of an A2AR / A2BR inhibitor, alone or in combination with one or more additional agents sufficient to achieve the desired effect. It is assumed that the parameters of the unit dosage form will depend on the specific agent and the effect achieved.

Sets.

The present invention also provides kits containing the compounds described herein and pharmaceutical compositions thereof. The kits are usually in the form of a physical structure containing various components, as described below, and may be used, for example, in the practice of the methods described above.

The kit can include one or more compounds provided herein (eg, presented in a sterile container), which can be in the form of a pharmaceutical composition suitable for administration to subjects. The compounds described herein may be in a form ready for use (eg, a tablet or capsule), or in a form requiring, for example, reconstitution or dilution (eg, a powder) prior to administration. When the compounds described herein are in a form requiring reconstitution or dilution by the user, the kit can also include diluents (eg, sterile water), buffers, pharmaceutically acceptable excipients, and the like, in the same packaging or separately from the compounds described herein. If a combination therapy is contemplated, the kit may contain several agents separately, or they may be combined in a kit. Each component of the kit can be enclosed in a separate container, and all the different containers can be contained in the same package. The kit of the present invention can be designed for conditions necessary for the proper containment of the components placed therein (for example, refrigeration or freezing).

The kit may contain a label or packaging insert containing identification information for the components it contains and instructions for their use (for example, dosage parameters, clinical pharmacology of the active ingredient, including mechanism of action, pharmacokinetics and pharmacodynamics, side effects, contraindications, etc.) ... Labels or inserts may include manufacturer information such as lot number and expiry date. The label or packaging insert, for example, can be embedded in a physical structure containing the components, contained separately within the physical structure, or attached to kit components (eg, ampoules, vials, or vials).

- 33 038488

Labels or inserts may additionally include or be embedded in a machine-readable medium such as a disc (e.g., hard disk, card, memory disk), optical disc such as CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or electrical media such as RAM, and ROMs or their hybrids such as magnetic or optical media, flash cards or memory cards. In some embodiments, the kit does not include these instructions, but provides a means of obtaining instructions from a remote source, such as the Internet.

experimental part

The following examples are provided in order to provide those of ordinary skill in the art with a complete statement and description of how the present invention is implemented and applied, and not to limit the scope of what the inventors consider to be their invention, nor do they imply that the following experiments conducted or that they represent all experiments that could be conducted. It should be understood that the descriptions of the examples written in the present tense are not necessarily followed, but rather that the descriptions may be performed to obtain data and the like described therein. Efforts have been made to ensure accuracy with respect to the numbers used (eg, quantity, temperature, etc.), but some experimental errors and deviations should be taken into account.

Unless otherwise indicated, fractions are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (° C), and pressure is at or near atmospheric. Standard abbreviations apply, including the following: wt = wild-type; on. = base pairs; so on. = thousand base pairs; nt = nucleotide; a.k. = amino acid; s or sec = seconds; min = minutes; h = hours; ng = nanogram; μg = micrograms; mg = milligram; g = gram; kg = kilogram; dl = deciliter; μl = microliter; ml = milliliter; l = liter; μM = micromolar; mM = millimolar; M = molar; kDa = kilodalton; i / m = intramuscularly; i / b = intraperitoneally; s / c = subcutaneously; QD = once a day; BID = twice a day; QW = once a week; QM = once a month; HPLC = high performance liquid chromatography; BW = body weight; U = unit of measure; NS. = not statistically significant; PBS = phosphate buffered saline; IHC = immunohistochemistry; DMEM = Dulbecco's Modified Eagle's Medium; EDTA = ethylenediaminetetraacetic acid.

Materials and methods.

In the examples below, the following general materials and methods were used where indicated or may be used.

The scientific literature describes standard molecular biology techniques (e.g., see Sambrook and Russell (2001), Molecular Cloning, 3 ^{rd ed, Cold Spring Harbor Laboratory Press} , Cold Spring Harbor, NY;.. And Ausubel et al (2001), Current. Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc., New York, NY; describing cloning into bacterial cells and DNA mutagenesis (vol. 1), cloning into mammalian cells and yeast cells (vol. 2), glycoconjugates and protein expression (vol. 3) and bioinformatics (vol. 4).

The scientific literature describes methods for protein purification, including immunoprecipitation, chromatography, electrophoresis, centrifugation and crystallization, as well as chemical analysis, chemical modifications, post-translational modifications, fusion proteins, and protein glycosylation (for example, see Coligan et al. (2000), Current Protocols in Protein Science, Vols. 1-2, John Wiley and Sons, Inc., NY).

Software packages and databases are available to define, for example, antigenic fragments, leader sequences, protein folds, functional domains, glycosylation sites and sequence alignment (e.g. see GCG Wisconsin Package (Accelrys, Inc., San Diego, CA) and DeCypher ™ (TimeLogic Corp., Crystal Bay, NV).

Methods of analysis and other experimental methods are abundantly presented in the literature, which can serve as a basis for evaluating the compounds described herein. For example, mass spectrometric analysis of ligand binding can be used to determine the various properties of the compounds of the present invention (for example, see Massink A. et al., Purinergic Signaling (2015), 11: 581, https://doi.org/10.1007/ s11302-015-9477-0; Dionisotti S. et al., J Pharmacol Exp Ther (1996) 298: 726-732.

Functional assays can also be used to evaluate the compounds of the present invention. The cAMP assay detailed below was used to evaluate some of the compounds described herein.

An alternative example of a functional assay for assessing IFN-γ secretion is described by Yuan G. et al. (Int. J. Med. Chem., Vol. 2017 (2017), article ID 4852537; https://doi.org/10.1155/2017/4852537). Briefly, during T cell receptor (TCR) activation by CD3 ligand, C57BL / 6 mouse splenocyte T cells are incubated with a receptor agonist to inhibit IFN-γ secretion from A2A receptor-induced immunosuppression by intracellular cAMP. Effective receptor antagonists block the receptor-activated signal, thereby restoring cytokine secretion to enhance and prolong the immune response.

Measurement of the effect of Compound I on adenosine receptors using a functional assay

- 34 038488 for cAMP A2AR / TREx CHO.

The dose-response relationship for NECA (5-N-ethylcarboxamidoadenosine), a non-selective adenosine receptor agonist, was tested daily to determine the EC80 of NECA used in the functional cAMP assay. _{Stably expressed A 2A} R TRex CHO cells were seeded in a 384-well Opti plate (Perkin Elmer) at 1000-2500 cells per well, after which they were incubated with NECA at various concentrations (ranging from 0 μM to 10 μM) at 37 ° С in within 30 minutes. After a 30 minute incubation, 5 μl of anti-cAMP Ulight antibody (dilution 1: 150 with conjugate and Perkin Elmer lysis buffer) and 5 μl of Eu-cAMP indicator (dilution 1:50 with conjugate and lysis buffer from Perkin Elmer) were added to the stimulated cells and incubated for 1 hour. A FRET signal was detected on an Envision multi-label reader (Perkin Elmer) with excitation of the Eu-cAMP indicator at 615 nm and emission at 665 nm. Data analysis was performed using GraphPad Prism to determine EC ₈₀ at NECA.

A functional assay of cAMP antagonists (Perkin Elmer) was performed on stable A _2A R TRex CHO cells. 1x106 cells were added to T75 flasks and cultured at 37 ° C and 5% CO2 overnight. A _2A R TRex CHO cells were induced with 1 μg / ml tetracycline at ~ 70-80% confluence for at least 16 hours. Stably expressed cells were then plated into a white 384-well Opti plate

A _2A R TRex CHO, 1000-2500 cells per well, and then incubated with compound I at various concentrations (ranging from 0 to 10 μM) at 37 ° C for 30 min. After a 30 min incubation, NECA (Sigma Aldrich) was added to the stimulated cells at an EC of ₈₀ and incubated for 30 min at 37 ° C. After a 30-minute incubation, 5 μl of anti-cAMP Ulight antibody and 5 μl of Eu-cAMP indicator were added to the stimulated cells and incubated for 1 hour. A FRET signal was detected with excitation of the Eu-cAMP indicator at 615 nm and radiation at 665 nm.

Data analysis was performed using GraphPad Prism to determine KB for compound I (less than 10 nM).

Examples of

General methods.

It will be clear to those skilled in the art that there are various methods for preparing the molecules represented in the claims. In general, useful methods for synthesizing the compounds of the claims are comprised of four parts that can be performed in any order: coupling of fragments a and b (or formation of fragment ab-c by cyclization of ring b), coupling of fragments b and c (or formation of the ab-c fragment by cyclization of ring b), joining of fragments c and d and modification of functional groups present in all fragments. The retrosynthetic cleavage of compounds of the invention into fragments a-d useful for the construction of compounds is shown below:

abed

Several methods of obtaining the claimed compounds are typical (equations 1-7). Equation 1 shows one way of forming a bond between fragments c and d by the Suzuki reaction. In the case of equation 1, Z can be selected from the corresponding groups such as Cl, Br, I, OTf, etc., -B (OR) 2 is boronic acid or an ester thereof, and the addition is mediated by a transition metal catalyst, preferably palladium with the appropriate ligand.

The attachment can be facilitated by the use of an organic or inorganic base, and many different conditions are known in the art to facilitate the Suzuki reaction. The functionalization of the binding partners can also be reversed, as shown in equation 2. It should be clear to those skilled in the art that there are other possible combinations that also yield the desired product.

- 35 038488

Equation 3 shows another method for producing a cd fragment. In the case of Equation 3, condensation of the appropriate aryl acid with Meldrum's acid and suitable activating reagents (such as EDCI and DMAP, although other reagents also provide the desired product) gives the corresponding aryl ketoester. Subsequently, condensation of the ketoester with guanidine leads to the formation of the corresponding 2-amino-3-hydroxy-5-arylpyrimidine, which in turn can be converted to the corresponding chloride by treatment with POCl ₃ or another suitable reagent.

1) NH but ₂ c _x ² Ar Meldrum _{'s acid o p}

EDCI.DMAP u u

ROH h ₂ n nh ₂ 'Ar

2) POCI ₃

Cl

NH ₂ νΆ Lv. 3 ^^^ Ar

The formation of a bond between fragments c and b can take place before or after the formation of a bond between fragments c and d, and these groups can be further modified before or after the connection of fragments c and b. Equation 4 depicts one of the methods for attaching fragments c and b by the Suzuki reaction.

In the case of Equation 4, Z can be selected from the corresponding groups such as Cl, Br, I, OTf, etc., -B (OR) 2 is boronic acid or an ester thereof, and the addition is mediated by a transition metal catalyst, preferably palladium with the appropriate ligand. The joining can be facilitated by the use of an organic or inorganic base. Many different conditions are known in the art to facilitate the Suzuki reaction. The functionalization of the binding partners can also be reversed as shown in Equation 5. It should be clear to those skilled in the art that there are other possible combinations that also yield the desired product.

Alternatively, fragment b can be obtained by cyclic addition between fragments a and c in a Huisgen 1,3-dipolar cycling reaction of the azide-alkyne type (Equation 6). In the case of Equation 6, appropriately functionalized moieties a and c can be combined together in a cyclic addition reaction between an azide and an alkyne. The reaction can be facilitated by the use of a copper catalyst or other catalyst.

When fragment b is triazole, the ring can also be synthesized by palladium-mediated addition of sodium azide to alkenyl halides (Barluenga et al., Angew. Chem. Int. Ed., 2006, 45, 6893-6896) catalyzed by Amberlyst-15 addition of azide to nitroalkene (Zhang et al., Synthesis, 2016, 48, 131-135), mediated 1 ₂ / TBPB oxidative cyclic addition of N-tosylhydrozones with anilines (Cai et al., Org. Lett., 2014, 16, 5108- 5111) and many other methods (see Synthesis of 1,2,3-triazoles at www.organic-chemistry.org/synthesis/heterocycles/1,2,3-triazoles.shtm). It will be clear to those skilled in the art that there are many different methods available to accomplish this conversion.

Equation 7 depicts one way of forming a bond between moieties a and b through alkylation. In the case of Equation 7, Z is a suitable electrophile such as Cl, Br, I, OTf, and the like, and the combination is mediated by an organic or inorganic base. For the most efficient preparation of any particular compounds of the invention, those skilled in the art will appreciate that the timing and order of attachment of the moieties and modification of the functional groups present in those moieties can vary in the preparation of any given compound.

Ar,

R ²

R ²

HN T '# X

Base R ²

AAg

R ² W

Lvl. 7

The various methods described above have been used to prepare compounds of the invention,

- 36 038488 some of which are presented in the examples. The deuterated forms of the examples below can be synthesized using suitable deuterated intermediates.

Example 1. Synthesis of 3- [2-amino-6- (1 - {[6- (2-hydroxypropan-2-yl) pyridin-2-yl] methyl} -1H-1,2,3triazol-4-yl) pyrimidin-4-yl] -2-methylbenzonitrile

%

Stage 6 Stage 3

Stage 1. In a 250 ml round bottom flask equipped with a magnetic stirrer, boronic acid ester (3.89 g, 16 mmol) and 2-amino-4,6-dichloropyrimidine (3.67 g, 22.4 mmol) were sequentially introduced ... Absolute ethanol (100 ml) was added followed by a solution of KHCO3 (4.81 g, 48 mmol) in deionized water (19 ml). The resulting suspension was degassed with nitrogen for 5 min. Then PdCl ₂ (PPh ₃ ) ₂ (112 mg, 1 mol%) was added and the mixture was heated to 78 ° C for 3 h under nitrogen atmosphere. Ethanol was evaporated under reduced pressure and deionized water (150 ml) was added. The suspension was filtered and the solid was washed with additional water (100 ml). The material was then dissolved in acetone (220 ml) and collected in a 500 ml round bottom flask. A mixture of silica and celite (1: 1, 150 g) was added and the solvent was removed under reduced pressure. The resulting crude material was purified by flash chromatography on silica gel (dichloromethane / ethyl acetate, gradient 0 to 15%). Received the desired product as a white solid (1.91 g, 49%).

LCMS: method A, retention time = 2.93 min; ESI-MS [M + H] + for C ₁₂ H ₉ ClN ₄ : theor. 245.7, fact. 245.2.

Step 2. In a round bottom flask, 5.1 g (20.8 mmol) of chloropyrimidine was suspended in 42 ml of degassed THF. To this suspension were added 8.68 ml (62.4 mmol) of Et ₃ N and 5.95 ml (25.0 mmol) of TIPS-acetylene. The reaction mixture was stirred for 5 min, after which 219 mg (0.312 mmol) of PdCl ₂ (PPh ₃ ) ₂ and 119 mg (0.624 mmol) of CuI were added. The reaction mixture was stirred at 50 ° C for 5 h under N ₂ . After the reaction was cooled to room temperature, the solvent was removed and the crude material was resuspended in 100 ml EtOAc, from which the insoluble solid was filtered off. The filtrate was washed (1: 1) NH ₄ Cl / NH ₄ OH (2x100 ml) and 10% Na ₂ S ₂ O ₄ (1x100 ml). The organic layer was dried with Na ₂ S ₂ O ₄ , evaporated and transferred to the next step without further purification.

Step 3. In a round bottom flask, dissolve the crude TIPS product from the previous step in 42 ml dry THF and cool to 0 ° C. There was added 25 ml (25.0 mmol) of TBAF (1.0 M in THF). The reaction mixture was stirred at 0 ° C for 15 minutes. Saturated NH ₄ Cl (100 ml) was added to quench the reaction. The organics were extracted from the aqueous layer with EtOAc (2x100 ml). The combined organic layer was washed (1: 1) NH ₄ Cl / NH ₄ OH (2x100 ml) and 10% Na ₂ SO ₄ (1x100 ml). The organic layer was dried with Na ₂ SO ₄ and evaporated to give pure product 5 by trituration in 40% CH ₂ Cl ₂ / hexane as a light brown solid. Yield: 3.71 g (76%, over 2 steps).

Step 4. To a solution of methylmagnesium bromide (3M in Et ₂ O, 40 mL, 120 mmol, 4.0 eq.) At 0 ° C in a N2 atmosphere was added a solution of methyl 2- (hydroxymethyl) pyridine-2-carboxylate (5 0 g, 29.9 mmol) in THF (70 ml, 0.4 M) over 30 min. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction mixture was quenched with aqueous NH ₄ Cl (55 ml) and EtOAc (50 ml) was added. The organic phase was separated and the aqueous phase was extracted with EtOAc (3x40 ml). The combined organic extracts were washed with saturated aqueous sodium bisulfite solution (7 x 20 ml), then dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give the title compound (3.45 g, 69% yield; 96% purity by LCMS) in the form of a pale yellow liquid.

LCMS: Method A, retention times = 0.722 and 1.06 min; ESI-MS [M + H] ⁺ for C ₉ H ₁₃ NO ₂ : theor. 167.09, fact. 167.2.

Stage 5. In a solution of 2-hydroxymethyl-6- (1-hydroxy-1-methylethyl) pyridine (5 g, 29.9 mmol,

- 37 038488

1.0 eq.) In PhMe (33 ml, 0.9 M) at 0 ° C under N2, diphenylphosphoryl azide (7.73 ml, 35.9 mmol, 1.2 eq.) Was added, followed by 1.8- diazabicyclo [5.4.0] undec-7-ene (5.37 ml, 35.9 mmol, 1.2 eq.). The resulting mixture was brought to room temperature and stirred for 14 hours. Then it was diluted with ethyl acetate and washed with water, and the organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was dissolved in 1N. aqueous HCl (2 eq., 60 mmol) and extracted with MTBE in hexane (3: 7, 100 ml), the organic layer was washed with water (50 ml), and the combined aqueous layer was neutralized with 2N. aqueous NaOH and extracted with ethyl acetate (3x75 ml), the organic layer was dried (Na ₂ SO ₄ ), filtered through cotton wool and the filtrate was evaporated to give the pure compound as a pale yellow liquid (3.75 g, 75%).

LCMS: method A, retention time = 2.67 min; ESI-MS [M + H] + for C ₉ H ₁₂ N ₄ O: theor. 193.1, fact. 193.2.

Stage 6. A mixture of azide (3.34 g, 17.4 mmol), alkyne (3.71 g, 15.8 mmol), copper (II) sulfate (39 mg; 0.158 mmol) and sodium ascorbate (156 mg, 0.790 mmol) in tert-BuOH / H ₂ O 2: 1 (158 ml) was heated at 60 ° С for 13 h. The solvent was removed in vacuum, and the dry residue was applied to silica gel and purified by chromatography on silica gel (0-100% EtOAc in hexane) to give the desired product as an off-white solid (6.08 g, 90%).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.80 (t, J = 7.8 Hz , 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H ), 7.28 (s, 1H), 7.10 (d, J = 7.6 Hz, 2H), 6.90 (s, 2H), 5.81 (s, 2H), 5.23 (s , 1H), 2.55 (s, 3H), 1.38 (s, 6H).

ESI-MS [M + H] + for C23H23N8O: theor. 427.2, fact. 427.3.

Example 2. Synthesis of 3- [2-amino-6- (1 - {[6- (2-hydroxypropan-2-yl) pyridin-2-yl] methyl} -1H-1,2,3triazol-4-yl) pyrimidin-4-yl] -2-methoxybenzonitrile

Scheme

Stage 1. In a round-bottom flask was suspended 26 g (157.5 mmol) of 3-cyano-2-fluorobenzoic acid in 315 ml (0.5 M) of anhydrous MeOH. To this suspension was added 144 ml (630 mmol) NaOMe (25 wt% in MeOH). The resulting reaction mixture was refluxed under reflux for 2 h under N2. After cooling to room temperature, excess MeOH was evaporated under reduced pressure to give a thick slurry. To this slurry was added 158 ml (473 mmol) of 3 M aqueous HCl. The product precipitated out as a white solid, which was isolated by filtration. Residual water was removed azeotropically with toluene to give 26.2 g (94%) of pure product.

Stage 2. Suspended 43 g of Meldrum's acid (297 mmol) and 35 g of 3-cyano-2-methoxybenzoic acid (198 mmol) in 660 ml (0.3 M) CH ₂ Cl ₂ . To this suspension 57 g (297 mmol) of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) and 24 g (198 mmol) of 4-dimethylaminopyridine (DMAP) were added. The reaction mixture was stirred at room temperature for 2 hours under N ₂ . By this time, the reaction was becoming uniform. Then the reaction mixture was transferred to a separatory funnel and 200 ml of CH ₂ Cl _{2 was} added. The organic layer was washed with 1M HCl (2x300 ml) and saturated NaCl solution (300 ml). The organic layer was dried over MgSO ₄ , evaporated and the crude material was used in the next step without further purification. The crude Meldrum acid adduct from the previous step was suspended in 400 ml of absolute EtOH and refluxed for 1.5 h. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure to 1/4 of the original volume (~ 100 ml). The β-ketoester product in EtOH was used directly in the next step without further purification.

Stage 3. In a round bottom flask was dissolved 19 g (198 mmol) of guanidine hydrochloride in 300 ml (0.7 M) EtOH. There was added 74 ml (198 mmol) of NaOEt (21 wt% in EtOH). The resulting cloudy solution was stirred for 10 min at room temperature, after which 4 in 100 ml EtOH was added (from the precursor of the previous step). The reaction mixture was refluxed under reflux for 72 h under N2. After the reaction was cooled to room temperature, 300 ml of hexane was added. The precipitated product was collected by filtration and used directly in the next step without further purification.

Stage 4. The crude product 5 from the previous stage was suspended in 200 ml of dioxane. _{POCl 3} (186 ml, 2000 mmol) was added thereto. The reaction mixture was heated at 70 ° C for 1.5 h. After cooling to room temperature, the reaction mixture was poured onto crushed ice (~ 1000 g) and stirred. Caution: The temperature was slowly raised to room temperature to quench excess POCl ₃ as the ice melted, avoiding vigorous reaction. After quenching the POCl _3, solid K2CO3 (691 g, 5000 mmol) was added in small portions to quench the formed HCl and H ₃ PO ₄ . The aqueous layer was extracted with CH ₂ Cl ₂ (3x500 ml). The combined organic layer was washed with saturated NaCl solution (500 ml) and dried over MgSO ₄ . The solvent was removed under reduced pressure to give a brown solid. The crude product was triturated in 10% CH ₂ Cl ₂ / hexane to give pure product (28 g, 54% over 4 steps).

Step 5. In a round bottom flask was suspended 7.7 g (29.3 mmol) of chloropyrimidine 6 in 60 ml dioxane / Et ₃ N (1: 1). To this suspension was added TMS-acetylene (20.3 mL, 146 mmol) followed by PdCl ₂ (PPh ₃ ) ₂ (2.6 g, 2.93 mmol) and CuI (558 mg, 2.93 mmol). The reaction mixture was stirred at 80 ° C for 1 h under N2. After the reaction was cooled to room temperature, silica gel (~ 100 g) was added and the solvent was removed under reduced pressure. The crude material adsorbed on silica gel was purified by chromatography using 80% EtOAc / hexane. The yield of product 7 was 5.5 g (58%).

Step 6. In a round bottom flask, 5.1 g (15.7 mmol) of product 7 was dissolved in anhydrous THF (30 ml). Thereto was added 16.5 ml (16.5 mmol) of TBAF (1.0 M in THF). The reaction mixture was stirred at room temperature for 30 minutes. Silica gel (~ 100 g) was added to the reaction mixture and the solvent was evaporated under reduced pressure. The crude material adsorbed on silica gel was purified by chromatography using 50% hexane: CH ₂ Cl ₂ / EtOAc (1: 1). Yield 3.2 g (80%).

Stage 7. In a solution of azide (example 1, stage 5, 294 mg, 1.53 mmol, 1.0 eq.) And alkyne (382 mg, 1.53 mmol, 1.0 eq.) In 2: 1 t- BuOH / H2O (5 ml, 0.3 M), CuSO ₄ (7.2 mg, 0.029 mmol, 5 mol%) and sodium ascorbate (60.0 mg, 0.305 mmol, 20 mol%) were added. The resulting mixture was stirred at 55 ° C for 0.5 h. The reaction mixture was then cooled to room temperature and diluted with CH ₂ Cl ₂ (10 ml). The organic phase was separated and the aqueous phase was again extracted with CH ₂ Cl ₂ (10 ml). The combined extracts were evaporated and the resulting residue was purified by column chromatography (CH ₂ Cl ₂ => CH ₂ Cl ₂ : MeOH 95: 5) to give the title compound (604 mg, 89% yield) as a light beige solid.

¹ H-NMR (400 MHz, CDCl3) δ 8.30 (d, J = 1.0 Hz, 1H), 8.04-7.98 (m, 1H), 7.92 (d, J = 0, 8 Hz, 1H), 7.78-7.64 (m, 2H), 7.37 (d, J = 7.9 Hz, 1H), 7.28 (td, J = 7.8 Hz, 0, 8 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.75 (brs, 2H), 5.15 (brs, 2H), 4.74 (s, 1H), 3 , 94 (d, J = 0.8 Hz, 3H), 1.54 (d, J = 0.8 Hz, 6H).

ESI-MS [M + H] for C ₂₃ H ₂₃ N ₈ O ₂ : theor. 443.19, fact. 443.2.

LCMS: retention time 2.8 min, method A.

Example 3. Synthesis of 3- [2-amino-6- (1 - {[6- (2-hydroxypropan-2-yl) pyridin-2-yl] methyl} -1H-1,2,3triazol-4-yl) pyrimidin-4-yl] -2-fluorobenzonitrile nh ₂

Stage 1. A solution of iPrMgCl-LiCl (100 ml, 130 mmol, 1.3 M in THF) was added dropwise to a solution of 3-bromo-2-fluoro-benzonitrile (26 g, 130 mmol) with stirring at 0 ° C over 20 min. The resulting solution was stirred for 50 min at 0 ° C and ZnCl ₂ (17.72 g, 130 mmol) was added at 0 ° C. The reaction mixture was heated to room temperature and stirred for 25 min at the same temperature. Then compound 1 (16.4 g, 100 mmol) was added and stirred for 10 min. Then Pd (PPh ₃ ) ₄ (2.32 g, 2 mmol) was added and stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (500 ml), extracted with EtOAc (3x300 ml) and dried over Na ₂ SO ₄ . The combined organic layer was evaporated to give 28 g of crude product 2, which was subjected to the next operation without further purification.

Stage 2.PdCl ₂ (PPh ₃ ) ₂ (3.38 g, 4.82 mmol), CuI ((1.84 g, 9 , 65 mol), THF / Et ₃ N (1: 1, 482 ml) and degassed with N ₂ for 30 min.Then triisopropyl-acetylene (130 ml, 579.15 mmol) was added dropwise over 15 min (reaction mixture turned reddish) and the reaction mixture was refluxed for 90 min LCMS and TLC showed complete consumption of 2. The solvent was evaporated on a rotary evaporator The excess Et ₃ N was removed using a toluene azeotrope (2x200 ml). The solvent gradient was varied from 10 to 20 to 30 to 50% EA in hexane Pure solid 3 (15.13 g, 46% over 2 steps) came out at 40% EA in hexane.

Stage 3. To a solution of compound 4 (15 g, 37.97 mmol) with stirring at 0 ° C was added dropwise TBAF (37.97 ml, 1 M in THF) over 15 min and stirred at 0 ° C for < 30 minutes. TLC showed no SM (LCMS unreliable due to nBuN ⁺ cation). The reaction mixture was quenched with saturated aqueous NH4Cl (200 ml) at 0 ° C, extracted with EtOAc (3x250 ml), dried over Na ₂ SO ₄ and evaporated to give crude 4. 200 ml of 10% EtOAc in hexane was added to the crude product, followed by sonicated. The liquid part of the supernatant was separated, and EtOAc / CH ₂ Cl ₂ (1: 1, 200 ml) was added to the solid residue. Hexane (600 ml) was added to the resulting slurry for precipitation and sonicated for 5 min. The precipitate was filtered off and dried under high vacuum to give 4 (7.2 g) in 80% yield.

Stage 4. Was carried out in the same way as in example 1.

1 H-NMR (400 MHz, acetone-d ₆ ) δ 8.62 (s, 1H), 8.45-8.38 (m, 1H), 8.02-7.95 (m, 1H), 7, 88-7.81 (m, 2H), 7.65 (dd, J = 8.0 Hz, 1H), 7.62-7.56 (m, 1H), 7.24 (d, J = 7, 8 Hz, 1H), 6.30 (brs, 2H), 5.86 (s, 2H), 4.62 (s, 1H), 1.48 (s, 6H).

ESI-MS [M + H] ⁺ for C ₂₂ H ₁₉ FN ₈ O: theor. 431.4, fact. 431.2.

Example 4. 3- [2-Amino-6- (1 - {[6- (2-hydroxypropan-2-yl) pyridin-2-yl] methyl} -1H-1,2,3-triazol-4yl) pyrimidine -4-yl] benzonitrile

This compound was obtained analogously to example 2, starting from 3-cyanobenzoic acid.

1H-NMR (400 MHz, DMSO-d6) 8.71 (d, J = 1.2 Hz, 1H), 8.59 (q, J = 1.5 Hz, 1H), 8.47 (dq, J = 8.2, 1.4 Hz, 1H), 8.00 (dq, J = 7.7, 1.4 Hz, 1H), 7.87-7.69 (m, 3H), 7.61 ( dt, J = 8.0, 1.2 Hz, 1H), 7.11 (dt, J = 7.7, 1.1 Hz, 1H), 6.92 (s, 2H), 5.83 (s , 2H), 5.23 (d, J = 1.2 Hz, 1H), 1.38 (d, J = 1.2 Hz, 6H).

ESI-MS [M + H] ⁺ for C ₂₂ H ₂₀ N ₈ O: theor. 413.2, fact. 413.3.

Example 5. 3- [2-Amino-6- (1 - {[6- (2-hydroxypropan-2-yl) pyridin-2-yl] methyl} -1H-1,2,3-triazol-4yl) pyrimidine -4-yl] -2-chlorobenzonitrile

This compound was obtained analogously to example 1, starting from 2-chloro-3-cyanoboronic acid.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.67 (s, 1H), 8.02-7.93 (m, 2H), 7.84 (t, J = 7.8 Hz, 1H ), 7.70 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.25 (d, J = 7.7 Hz, 1H), 6.37 (brs, 2H), 5.87 (s, 2H), 4.63 (s, 1H), 1.48 (s, 6H).

ESI-MS [M + H] ⁺ for C ₂₂ H ₁₉ ClN ₈ O: theor. 447.9, fact. 447.2.

Example 6. 2- [6 - ({4- [2-Amino-6- (2,3-dichlorophenyl) pyrimidin-4-yl] -1H-1,2,3-triazol-1-yl} methyl) pyridine -2-yl] propan-2-ol

This compound was obtained analogously to example 1, starting from 2,3-dichloroboronic acid.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.62 (s, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.74-7.62 (m, 2H ), 7.61-7.45 (m, 3H), 7.23 (d, J = 7.5 Hz, 1H), 6.21 (s, 1H), 5.85 (s, 2H), 1 , 48 (m, 9H).

- 40 038488

LC-MS: retention time 2.96 min, method B; ESI-MS [M + H] + for C ₂₁ H ₁₉ Cl ₂ N ₇ O: theor. 456.1, fact.

456.2.

Example 7. 3- [2-Amino-6- (1 - {[6- (2-hydroxypropan-2-yl) pyridin-2-yl] methyl} -1H-pyrazol-4yl) pyrimidin-4-yl] - 2-methoxybenzonitrile

Stage 1. To a bubbled solution of 2-acetyl-6-methylpyridine (3.0 g, 22.2 mmol, 1.0 eq.) In MeCN (100 ml, 0.2 M) under N2 was added benzoyl peroxide (538 mg, 2.2 mmol, 0.1 eq.) Followed by N-bromosuccinimide (4.7 g, 26.6 mmol, 1.2 eq.). The flask was equipped with a reflux condenser, the mixture was heated to 85 ° C and stirred for 28 h. Then saturated aqueous Na ₂ S ₂ O ₃ (50 ml) was added and the biphasic mixture was stirred for 10 min. The mixture was transferred to a separatory funnel containing a 1: 1 mixture of EtOAc (100 ml) and water saturated with Na ₂ S ₂ O ₃ (100 ml). The organic phase was collected and the aqueous phase was extracted with 2x50 ml EtOAc. The combined organic extracts were dried over MgSO ₄ and evaporated in vacuo. The resulting residue was purified by column chromatography (hexane => hexane: EtOAc 9: 1) to afford the title compound (2.65 g, 56% yield) as a pale orange oil.

Stage 2. Introduced 1- (6- (bromomethyl) pyridin-2-yl) ethan-1-one (1.0 g, 4.7 mmol, 1.0 eq.) And 4-pyrazole boronic acid pinacol ester (997 mg , 5.1 mmol, 1.1 eq.) In MeCN (23 ml, 0.2 M) and added Cs ₂ CO ₃ (1.7 g, 5.1 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 4 hours. The mixture was then diluted with CH ₂ Cl ₂ (20 ml) and filtered through a fritted funnel. The filtrate was evaporated in vacuo to give the title compound, which was used in subsequent reactions without further purification.

Stage 3. A solution of 1- (6 - ((4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridin-2 -yl) ethan-1-one (301 mg, 0.92 mmol, 1.2 eq.) and 3- (2-amino-6-chloropyrimidin-4-yl) -2methoxybenzonitrile (example 2, step 4, 200 mg , 0.77 mmol, 1.0 eq.) In DMF (33 ml, 0.9 M) and 2.0 M aqueous K ₂ CO ₃ (0.8 ml, 2.0 eq.) Were bubbled with N2 for 10 min. Thereafter, Pd (dppf) Cl ₂ (55.6 mg, 0.04 mmol, 0.1 eq.) Was added and the reaction mixture was heated to 100 ° С for 16 h. Then the reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and H2O (10 ml). The two-phase mixture was transferred to a separatory funnel and the organic phase was collected. The aqueous phase was extracted with 2x10 ml CH ₂ Cl ₂ , and the combined organic extracts were dried over MgSO ₄ and evaporated in vacuo. The brown residue was purified by column chromatography (hexane: EtOAc 7: 3 => EtOAc) to give the title compound (190 mg, 58% yield) as a yellow oil.

Stage 4. In a solution of 3- (6- (1 - ((6-acetylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -2-aminopyrimidin4-yl) -2-methoxybenzonitrile (190 mg, 0 , 45 mmol, 1.0 eq.) In THF (8.2 ml, 0.05 M) at 0 ° С in an N2 atmosphere, MeMgBr (0.8 ml, 1.1 mmol, 2.5 eq., 1 , 4 M in a mixture of THF: toluene 3: 1). The resulting mixture was warmed to room temperature and stirred for 21 hours. The reaction was then quenched by the addition of saturated aqueous NH4Cl (10 ml). The biphasic mixture was transferred to a separatory funnel and extracted with 3x10 ml EtOAc. The combined organic extracts were washed with saturated NaCl solution (10 ml), dried over MgSO ₄ and evaporated in vacuo. The residue was purified by reverse phase HPLC (H ₂ O: MeCN with 0.1% CF3CO2H, 19: 1 => 1:19) to afford the title compound (10 mg, 5% yield) as a white solid.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.80 (d, J = 14.1 Hz, 1H), 8.35 (d, J = 6.3 Hz, 1H), 8.15- 8.07 (m, 1H), 7.977.77 (m, 3H), 7.65-7.54 (m, 1H), 7.17-7.09 (m, 1H), 5.58 (s, 2H), 4.00 (s, 3H), 2.65 (s, 3H), 1.48 (s, 9H).

LC-MS: retention time 2.52 min, method B; ESI-MS [M + H] + for C ₂₄ H ₂₃ N ₇ O ₂ : theor. 441.2, fact. 441.3.

Example 8 2- [6 - ({4- [2-Amino-6- (3-fluoro-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1yl} methyl) -2 -pyridyl] -2-propanol

- 41 038488

This compound was obtained analogously to example 1.

'H-NMR (400 MHz, chloroform-d) δ 8.30-8.25 (m, 1H), 7.94-7.89 (m, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.23-7.05 (m, 3H), 5.75 (s, 2H), 5.07 (s, 2H), 4.74 (s, 1H), 3.94 (s, 3H), 1.55 (s, 6H).

LC-MS: retention time 2.89 min, method A; ESI-MS [M + H] ⁺ for C ₂₂ H ₂₃ FN ₇ O ₂ : theor. 436.2, fact. 436.3.

Example 9 2- [6 - ({4- [2-Amino-6- (3-chloro-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1yl} methyl) -2 -pyridyl] -2-propanol

This compound was obtained analogously to example 1.

'H-NMR (400 MHz, chloroform-d) δ 8.27 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.77-7 , 64 (m, 2H), 7.48 (dt, J = 8.0, 1.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.19-7, 08 (m, 2H), 5.75 (s, 2H), 5.11 (s, 2H), 4.73 (s, 1H), 3.77 (s, 3H), 1.55 (s, 6H ).

LC-MS: retention time 3.04 min, method A; ESI-MS [M + H] ⁺ for C ₂₂ H ₂₃ ClN ₇ O ₂ : theor. 452.2, fact. 452.3.

Example '0. m- (2-Amino-6- {1 - [(2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4-pyrimidinyl) benzonitrile

This compound was obtained analogously to example 4.

'h-NMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 8.46 (t, J = 1.6 Hz, 1H), 8.41-8.34 (m, 1H) , 8.31 (dt, J = 8.0, 1.4 Hz, 1H), 7.91 (s, 1H), 7.80-7.68 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.34-7.28 (m, 1H), 5.76 (s, 3H), 5.22 (s, 2H).

ESI-MS [M + H] ⁺ for C ₁₉ H ' ₄ N ₈ : theor. 355.1, fact. 355.2.

Example 11 m- (2-Amino-6- {1 - [(3-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4-pyrimidinyl) benzonitrile

This compound was prepared in analogy to example 4 to obtain 59 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (d, J = 1.1 Hz, 1H), 8.68 (dd, J = 2.2, 1.0 Hz, 1H), 8.57 (dq, J = 3.1, 1.4 Hz, 2H), 8.46 (ddd, J = 8.0, 1.9, 1.1 Hz, 1H), 7.99 (dq, J = 7.8, 1.3 Hz, 1H), 7.82-7.78 (m, 2H), 7.74 (td, J = 7.8, 1.0 Hz, 1H), 7.48 -7.40 (m, 1H), 6.89 (s, 2H), 5.78 (s, 2H).

ESI-MS [M + H] ⁺ for C19H14N8: theor. 355.1, fact. 355.3.

Example 12 m- (2-Amino-6- {1 - [(4-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4-pyrimidinyl) benzonitrile

This compound was prepared analogously to example 4, obtaining 66 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (d, J = 1.2 Hz, 1H), 8.63-8.54 (m, 3H), 8.47 (ddd, J = 8.0, 1.8, 1.1 Hz, 1H), 8.03-7.96 (m, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.78- 7.68 (m, 1H), 7.31-7.23 (m, 2H), 6.90 (s, 2H), 5.81 (s, 2H).

ESI-MS [M + H] + for C ^ HuW theor. 355.1, fact. 355.3.

Example 13 m- {2-Amino-6- {1 - [(6-methyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4-pyrimidinyl) benzonitrile

- 42 038488

This compound was prepared in analogy to example 4 to obtain 14 mg of a tan solid.

1N-NMR (400 MHz, DMSO-d ₆ ) 8.68 (d, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.03-7.96 (m, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.78-7.69 (m, 2H), 7.24 (d , J = 7.8 Hz, 1H), 7.11 (d, J = 1.1 Hz, 1H), 6.92 (s, 2H), 5.78 (d, J = 2.0 Hz, 2H ), 2.45 (s, 3H).

ESI-MS [M + H] + for C ₁₀ H ₁₆ N ₈ : theor. 369.2, fact. 369.3.

Example 14 3- (2-Amino-6- {1 - [(6-methyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4-pyrimidinyl) 2-fluorobenzonitrile

This compound was prepared in analogy to example 3 to obtain 13 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 8.67 (s, 1H), 8.35-8.27 (m, 1H), 8.26-8.18 (m, 1H), 8, 09 (dd, J = 7.7, 6.1 Hz, 2H), 7.72 (t, J = 7.7 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.98 (s, 2H), 5.78 (s, 2H), 2.45 (s, 3H).

ESI-MS [M + H] + for C ₂₀ H ₁₅ FN ₈ : theor. 387.1, fact. 387.3.

Example 15 6- (2-Amino-6- {1 - [(6-methyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4-pyrimidinyl) 2-toluonitrile

This compound was prepared in analogy to example 1 to obtain 75 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 8.66 (d, J = 1.3 Hz, 1H), 7.95-7.86 (m, 1H), 7.80-7.67 ( m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 1.4 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.90 (s, 2H), 5.77 (s, 2H), 2.55 (s, 3H), 2.45 ( s, 3H).

ESI-MS [M + H] + for C ₂₁ H ₁₈ N ₈ : theor. 383.2, fact. 383.3.

Example 16. 3- (2-Amino-6- {1 - [(6-methyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4-pyrimidinyl) 2-anisonitrile

This compound was obtained in analogy to example 2, obtaining 84 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 8.65 (d, J = 1.1 Hz, 1H), 8.07 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 7.99-7.90 (m, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 1.0 Hz, 1H), 7, 49-7.39 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.90 (s, 2H ), 5.77 (s, 2H), 3.84 (d, J = 1.7Hz, 3H), 2.45 (s, 3H).

ESI-MS [M + H] + for C ₂₁ H ₁₈ N ₈ O: theor. 399.2, fact. 399.3.

Example 17 m- (2-Amino-6- {1 - [(3-methyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4-pyrimidinyl) benzonitrile

This compound was obtained analogously to example 4.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 2.1 Hz, 1H), 8.60-8.57 (m, 1H), 8.50-8.44 ( m, 1H), 8.37 (d, J = 4.6 Hz, 1H), 8.03-7.98 (m, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.75 (td, J = 7.7, 2.4 Hz, 2H), 7.35 (dd, J = 7.0, 4.3 Hz, 1H), 5.91 (d, J = 2, 3 Hz, 2H), 4.70 (bs, 2H), 2.41 (s, 3H).

ESI-MS [M + H] + for C ₁₀ H ₁₆ N ₈ O ₃ : theor. 369.2, fact. 369.2.

Example 18 m- [2-Amino-6- (1 - {[6- (trifluoromethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

- 43 038488

This compound was obtained analogously to example 4, obtaining 74 mg of a tan solid

th substance.

-NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 1.1 Hz, 1H), 8.59 (d, J = 1.4 Hz, 1H), 8.47 (ddt, J = 8.0, 1.9, 1.2 Hz, 1H), 8.16 (t, J = 7.9 Hz, 1H), 8.00 (dq, J = 7.7, 1.3 Hz , 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.85-7.80 (m, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7 , 61 (d, J = 7.9 Hz, 1H), 6.93 (s, 2H), 5.99 (s, 2H).

ESI-MS [M + H] + for C ₂₀ H ₁₃ F ₃ N ₈ : theor. 423.1, fact. 423.2.

Example 19 m- [2-Amino-6- (1- {[6- (hydroxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

Aircraft DPPA ---------- ^ΗΟ μΛ> _ν А ^ ОН _{DBU DCM room temp} ΗΟ ^ χΑ _Ν / ΛχΝ ₃ CuSO ₄ «5H ₂ O

Na-ascorbate

Stage 1

NH ₂ N ^ N

HO _ ^ H ₂ 'Y L Ν ^ Ν O J ^N \ / Χ / χΛχΧ -------- Η Ί Stage 2

Stage 1. A mixture of diol (696 mg, 5 mmol) and DBU (0.9 ml, 6 mmol) in dichloromethane (15 ml) was cooled to 0 ° C. DPPA (1.3 ml, 6 mmol) was added dropwise and the resulting mixture was stirred at 0 ° C for 15 min and at room temperature overnight. Celite (5 g) was added, the mixture was evaporated to dryness and purified by silica gel chromatography (hexane / EtOAc 90:10 to 60:40) to give the desired azide (83 mg, 10%).

Stage 2. The specified compound was synthesized in the same manner as in stage 6 of example 1, using an azide derivative and m- (2-amino-6-ethynyl-4-pyrimidinyl) benzonitrile (from example 4).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.59 (dd, J = 1.8, 1.8 Hz, 1H), 8.47 (ddd, J = 8.0, 1.8, 1.1 Hz, 1H), 8.00 (ddd, J = 7.7, 1.7, 1.2 Hz, 1H), 7.85 (dd, J = 7, 7.7.7 Hz, 1H), 7.82 (s, 1H), 7.75 (dd, J = 7.7, 7.7 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.93 (s, 2H), 5.81 (s, 2H), 4.54 (d, J = 5.8 Hz, 3H).

MS [M + H] ⁺ for C ₁₀ H ₁₆ N ₈ O: theor. 385.2, fact. 385.2.

Example 20. m- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

Stage 1. To a suspension of 2,6-pyridinedimethanol (41.8 g, 300 mmol) in dioxane (600 ml) at room temperature under nitrogen atmosphere was added 12 g of sodium hydride (300 mmol, 60% dispersion in mineral oil, 1 eq. ) in dioxane (100 ml). The suspension was stirred for 15 minutes. Methyl iodide (42.6 g, 300 mmol) was added and the resulting mixture was heated to 50 ° C for 2 h. TLC analysis showed a conversion of ~ 50% starting material. The reaction was quenched with water and then extracted with ethyl acetate (3x500 ml). The ethyl acetate layer was washed with water (200 ml) and saturated NaCl solution. The ethyl acetate solution was dried over sodium sulfate for 1 hour, filtered and evaporated. The resulting oily residue was purified on a silica gel column eluting with dichloromethane / methanol (2 to 5% methanol) to give 6.6 g of Compound 1 as a rose oil in 15% yield.

Stage 2. The product from stage 1 (3.4 g, 17.0 mmol) in SOCl ₂ (30 ml) was stirred at 40 ° C overnight. The mixture was evaporated to give the product as a white solid (3.6 g, 100%).

Stage 3. The product from stage 2 (1.16 g, 6.8 mmol, 1.0 eq.) And NaN ₃ (1.3 g, 20.3 mmol, 3.0 eq.) In EtOH was refluxed with a reflux condenser in during the night. The mixture was evaporated to give a crude product which

44 038488 was purified on FCC (PE / EA = 5/1) to give the product as a white solid (0.9 g, 74%).

Step 4. The title compound was synthesized following the general procedure from Example 1 to give 64 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.59 (td, J = 1.8, 0.6 Hz, 1H), 8.47 (ddd, J = 8.0, 1.8, 1.1 Hz, 1H), 8.04-7.96 (m, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.81 (s , 1H), 7.77-7.69 (m, 1H), 7.40-7.36 (m, 1H), 7.25-7.19 (m, 1H), 6.92 (bs, 2H ), 5.83 (s, 2H), 4.46 (s, 2H), 3.35 (s, 3H).

ESI-MS [M + H] + for C21H18N8O: theor. 399.2, fact. 399.3.

The above compound can also be obtained as shown below:

NaH, THF АЧ NaN ₃ YES ^{С |} МеОН 'DMSO' МеО ^ Лук ^ Мз

Stage 1 Stage 2 .HCl

Na-ascorbate

Stage 3

Example 21 6- (3-Fluoro-2-methoxyphenyl) -4- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -2- pyrimidinylamine

This compound was obtained analogously to example 20.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7, 60 (dt, J = 7.9, 1.5 Hz, 1H), 7.45-7.36 (m, 2H), 7.28-7.18 (m, 2H), 6.81 (s, 2H), 5.81 (s, 2H), 4.46 (s, H), 3.84 (s, 3H), 3.35 (s, 3H).

ESI-MS [M + H] + for C21H21FN7O2: theor. 422.2, fact. 422.3.

Example 22. 3- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -2- anisonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.08 (dd, J = 7.9, 1.7 Hz, 1H), 7.99 (dd, J = 7.7, 1.7 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.86 (s, 2H), 4.47 (s, 2H), 3.88 (s, 3H), 3.35 (s, 3H).

ESI-MS [M + H] + for C22H21N8O2: theor. 429.2, fact. 429.3.

Example 23 6- (3-Chloro-2-methoxyphenyl) -4- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -2- pyrimidinylamine

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 0.9 Hz, 1H), 7.94-7.88 (m, 1H), 7.73-7.62 (m , 2H), 7.50-7.43 (m, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.19-7.07 (m, 2H), 5.71 ( s, 2H), 5.24 (s, 2H), 4.58 (s, 2H), 3.88-3.61 (s, 3H), 3.48 (s, 3H).

ESI-MS [M + H] + for C2iH2oC1N702: theor. 438.1, fact. 438.3.

Example 24 5- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -3- toluonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

- 45 038488 'H-NMR (400 MHz, DMSO-de) δ 8.70 (s, 1H), 8.42-8.36 (m, 1H), 8.32 (d, J = 0.8 Hz , 1H), 7.86 (t,

J = 7.8 Hz, 'H), 7.83 (s,' H), 7.81 (s, 1H), 7.39 (dd, J = 7.8, 0.9 Hz, 1H), 7.26-7.20 (m, 1H), 6.92 (s, 2H), 5.83 (s,

2H), 4.47 (s, 2H), 3.35 (s, 3H), 2.46 (s, 3H).

ESI-MS [M + H] + for C _; ; H2N8O: theor. 413.2, fact. 413.3.

Example 25. 3 [2-Amino-6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} - 1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -5-chlorobenzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.62 (t, J = 1.5 Hz, 1H), 8.54 (dd, J = 2.1, 1.6 Hz, 1H), 8.22 (dd, J = 2.1, 1.4 Hz, 1H), 7.90-7.82 (m, 2H), 7.42-7.36 (m , 1H), 7.26-7.19 (m, 1H), 7.00 (s, 2H), 5.83 (s, 2H), 4.47 (s, 2H), 3.35 (s, 3H).

ESI-MS [M + H] + for C21H17ClN ₈ O: theor. 433.1, fact. 433.2.

Example 26 m- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -5methyl-4-pyrimidinyl ] benzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

'H-NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.02 (s, 1H), 7.97-7.92 (m, 1H), 7.88 (m, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H) , 6.61 (s, 2H), 5.83 (s, 2H), 4.47 (s, 2H), 3.35 (s, 3H), 2.37 (s, 3H).

ESI-MS [M + H] + for C22H20N ₈ O: theor. 413.2, fact. 413.2.

Example 27 4- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (o-methoxyphenyl) 2-pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2 (azidomethyl) -6- (methoxymethyl) pyridine and 4-ethynyl-6- (o-methoxyphenyl) -2-pyrimidinylamine (which was prepared analogously to Steps 1- 3 from example 1).

'H-NMR (400 MHz, CDCI3) δ 8.27 (s, 1H), 7.99 (s, 1H), 7.83 (dd, J = 7.7, 1.8 Hz, 1H), 7 , 69 (dd, J = 7.8, 7.8 Hz, 1H), 7.44-7.36 (m, 2H), 7.11-6.96 (m, 3H), 5.71 (s , 2H), 5.12 (s, 2H), 4.58 (s, 2H), 3.90 (s, 3H), 3.49 (s, 3H).

ESI-MS [M + H] + for C ₂₁ H ₂₁ N ₇ O ₂ : theor. 404.2, fact. 404.2.

Example 28 4- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (o-methylphenyl) -2pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 4-ethynyl-6- (o-methylphenyl) -2-pyrimidinylamine (which was prepared analogously to Steps 1 -3 from example 1).

'H-NMR (400 MHz, CDCI3) δ 8.29 (s, 1H), 7.70 (dd, J = 7.8, 7.8 Hz, 1H), 7.56 (s, 1H), 7 , 50-7.38 (m, 2H), 7.37-7.27 (m, 3H), 7.09 (d, J = 8.0 Hz, 1H), 5.72 (s, 2H), 5.19 (s, 2H), 4.59 (s, 2H), 3.49 (s, 3H), 2.44 (s, 3H).

ESI-MS [M + H] + for C ₂₁ H ₂₁ N ₇ O: theor. 388.2, fact. 388.3.

Example 29 4 - (- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (p-fluorophenyl) -2pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 4-ethynyl-6- (p-fluorophenyl) -2-pyrimidinylamine (which

- 46 038488 was prepared analogously to steps 1-3 from example 1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.16-8.07 (m, 2H), 7.88 (s, 1H), 7.71 (d, J = 7.8, 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.21-7.13 (m, 2H), 7.10 (d, J = 7.8 Hz, 1H), 5.73 (s, 2H), 5.08 (s, 2H), 4.59 (s, 2H), 3.50 (s, 3H).

MS [M + H] + for C20H18FN7O: theor. 392.2, fact. 392.2.

Example 30 4- (l - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (o-fluorophenyl) -2pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2 (azidomethyl) -6- (methoxymethyl) pyridine and 4-ethynyl-6- (fluorophenyl) -2-pyrimidinylamine (which was prepared analogously to Steps 1-3 of example 1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.00 (ddd, J = 7.8, 7.8, 1.9 Hz, 1H), 7.92 (d , J = 2.2 Hz, 1H), 7.71 (dd, J = 7.8, 7.8 Hz, 1H), 7.48-7.37 (m, 2H), 7.27 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.17 (ddd, J = 11.3, 8.3, 1.1 Hz, 1H), 7.0.9 (d, J = 8.3 Hz, 1H), 5.72 (s, 2H), 5.16 (s, 2H), 4.59 (s, 2H), 3.49 (s, 3H).

MS [M + H] + for C ₂₀ H ₁₈ FN ₇ O: theor. 392.2, fact. 392.3.

Example 31 4- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (o-chlorophenyl) -2pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 4-ethynyl-6- (chlorophenyl) -2-pyrimidinylamine (which was prepared analogously to Steps 1-3 from example 1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 7.74 (s, 1H), 7.69 (dd, J = 7.8, 7.8 Hz, 1H), 7.66-7.54 (m, 1H), 7.54-7.45 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.40-7.34 ( m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 5.72 (s, 2H), 5.16 (s, 2H), 4.59 (s, 2H), 3, 50 (s, 3H).

MS [M + H] + for C ₂₀ H ₁₈ ClN ₇ O: theor. 408.1, fact. 408.3.

Example 32 4- (l - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (o-trifluoromethoxyphenyl) -2-pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 4-ethynyl-6- (o-trifluoromethoxyphenyl) -2-pyrimidinylamine (which was prepared in a similar manner to Steps 1 -3 from example 1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.83-7.80 (dd, J = 7.8, 1.6 Hz, 1H), 7.77 (s , 1H), 7.71 (dd, J = 7.8, 7.8 Hz, 1H), 7.52-7.36 (m, 4H), 7.11 (d, J = 7.8 Hz, 1H), 5.72 (s, 2H), 5.15 (s, 2H), 4.59 (s, 2H), 3.49 (s, 3H).

MS [M + H] + for C2iHisF ₃ N7O2: theor. 458.1, fact. 458.2.

Example 33 4- [o- (Methoxymethyl) phenyl] -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -2-pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 6-ethynyl-4- [o- (methoxymethyl) phenyl] -2-pyrimidinylamine (which was obtained similar to steps 1-3 from example 1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.70 (dd, J = 7.7, 7.7 Hz, 1H), 7.65 (s, 1H), 7.60-7.52 (m, 2H), 7.51-7.34 (m, 3H), 7.10 (d, J = 7.7Hz 1H), 5.72 (s, 2H), 5.12 (s, 2H), 4.64 (s, 2H), 4.59 (s, 2H), 3.50 (s, 3H), 3.35 (s, 3H).

MS [M + H] + for C22H23N7O2: theor. 418.2, fact.

Example 34 4- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -2- toluonitrile

- 47 038488

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 4- (2-amino-6-ethynyl-4-pyrimidinyl) -2-toluonitrile (which was obtained analogously to steps 1-3 from example 1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 8.32 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.88 ( s, 1H), 7.72 (dd, J = 8.0, 8.0 Hz, 1H), 7.43 (dd, J = 8.0, 8.0 Hz, 2H), 7.12 (d , J = 7.6 Hz, 1H), 5.73 (s, 2H), 5.17 (s, 2H), 4.59 (s, 2H), 3.50 (s, 3H), 2.62 (s, 3H).

MS [M + H] + for C22H20N8O: theor. 413.2, fact. 413.3.

Example 3 5. 6- (3,5-Difluorophenyl) -4- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -2-pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 4- (3,5-difluorophenyl) -6-ethynyl-2-pyrimidinylamine (which was prepared similarly stages 1-3 from example 1).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.92-7.83 (m, 5H), 7.51-7.42 (m, 1H), 7, 40 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 6.95 (bs, 1H), 5.86 (s, 1H), 4, 47 (s, 3H), 3.35 (s, 3H).

MS [M + H] ⁺ for C20H17F2N7O: theor. 410.1, fact. 410.2.

Example 36 6- (3,5-Dimethoxyphenyl) -4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -2-pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 4- (3,5-dimethoxyphenyl) -6-ethynyl-2-pyrimidinylamine (which was prepared similarly stages 1-3 from example 1).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (brs, 1H), 7.86 (dd, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 2.3 Hz, 2H), 7.23 (d, J = 7.7 Hz, 1H), 6.82 (brs , 2H), 6.67 (s, 1H), 5.84 (s, 2H), 4.47 (s, 2H), 3.84 (s, 6H), 3.35 (s, 3H).

MS [M + H] ⁺ for C22H23N7O3: theor. 434.2, fact. 434.3.

Example 37 p- [2-Amino-6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

1 H-NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.34-8.26 (m, 2H), 8.03-7.90 (m, 1H), 7, 88-7.79 (m, 1H), 7.76 (s, 1H), 7.37 (dd, J = 7.9, 7.9 Hz, 1H), 7.21 (dd, J = 7, 9, 7.9 Hz, 1H), 6.90 (s, 2H), 5.81 (s, 2H), 4.45 (s, 2H), 3.35 (s, 3H).

MS [M + H] ⁺ for C21H18N8O: theor. 399.2, fact. 399.3.

Example 3 8.o- [2-Amino-6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

1H-NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H) , 7.80 (s, 1H), 7.74-7.63 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 5.72 (s, 2H), 5.31 (s, 2H), 4.58 (s, 2H), 3, 51-3.43 (s, 3H).

MS [M + H] ⁺ for C ₂₁ H ₁₈ N ₈ O: theor. 399.2, fact. 399.3.

- 48 038488

Example 39 2- {m- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] phenyl} -2-propanol

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 8.24 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.92 ( s, 1H), 7.70 (dd, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.72 (s, 2H), 5.30 (s, 1H), 5.16 (s, 2H), 4.58 (s, 1H), 3.48 (s, 3H), 1.64 (s, 6H).

MS [M + H] + for C25H25N7O2: theor. 432.2, fact. 432.2.

Example 40 6- (m-Cumenyl) -4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinylamine

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 7.96 (s, 1H), 7.94-7.87 (m, 2H), 7.71 (dd, J = 7.7, 7.7 Hz, 1H), 7.49-7.33 (m, 3H), 7.10 (d, J = 7.7 Hz, 1H), 5.73 (s, 2H ), 5.10 (brs, 2H), 4.59 (s, 2H), 3.50 (s, 3H), 3.00 (h, J = 6.9 Hz, 1H), 1.31 (d , J = 6.9 Hz, 6H).

MS [M + H] + for C ₂₃ H ₂₅ N ₇ O: theor. 416.2, fact. 416.4.

Example 41. Ethyl-3- {m- [2-amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) 4 -pyrimidinyl] phenyl} propionate

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

-NMR (400 MHz, chloroform-d) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.96-7.91 (m, 1H), 7.90 (s, 1H ), 7.71 (dd, J = 7.8 Hz, 1H), 7.46-7.36 (m, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 5.73 (s, 2H), 5.10 (brs, 2H), 4.59 (s, 2H), 4.14 (q, J = 7, 2 Hz, 2H), 3.49 (s, 3H), 3.04 (t, J = 7.9 Hz, 3H), 2.68 (t, J = 7.9 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).

MS [M + H] + for C25H27N7O3: theor. 474.2, fact. 474.3.

Example 42 4- [m- (2-Methoxyethoxy) phenyl] -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -2 -pyrimidinylamine

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, chloroform-d) δ 8.29 (s, 1H), 7.89 (s, 1H), 7.75-7.64 (m, 3H), 7.50-7, 29 (m, 2H), 7.11 (d, J = 7.6 Hz, 1H), 7.09-7.03 (m, 1H), 5.72 (s, 2H), 5.08 (brs , 2H), 4.59 (s, 2H), 4.32-4.18 (m, 2H), 3.83-3.75 (m, 2H), 3.50 (s, 3H), 3, 47 (s, 3H).

MS [M + H] + for C ₂₃ H ₂₅ N ₇ O ₃ : theor. 448.2, fact. 448.3.

Example 43 3- {m- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] phenyl} propionic acid

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.15 (brs, 1H), 8.63 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 7 , 6 Hz, 1H), 7.84 (dd, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.47-7.30 (m, 3H), 7.20 (d , J = 7.6 Hz, 1H), 6.74 (s, 1H), 5.80 (s, 2H), 4.45 (s, 2H), 3.34 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H).

MS [M + H] + for C ₂₃ H ₂₃ N ₇ O ₃ : theor. 446.2, fact. 446.3.

Example 44. 3- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -4- fluorobenzonitrile

- 49 038488

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.50-8.43 (m, 1H), 8.14-8.03 (m, 1H), 7 , 84 (dd, J = 8.0, 8.0 Hz, 1H), 7.70-7.57 (m, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7, 22 (d, J = 8.0 Hz, 1H), 5.82 (s, 2H), 4.45 (s, 2H), 3.53 (s, 3H).

MS [M + H] + for C ₂₁ H ₁₇ FN ₈ O: theor. 417.2, fact. 417.3.

Example 45. 3- [2-Amino-6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -2- fluorobenzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 8.29 (dd, J = 7.9, 7.9 Hz, 1H), 8.07 (ddd, J = 7.6, 7.6 Hz, 1H), 7.84 (dd, J = 7.9, 7.9 Hz, 1H), 7.61 (s, 1H), 7.56 (dd, J = 7.9, 7.9 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.94 (s, 2H), 5.79 (s, 2H), 4.44 (s, 2H).

MS [M + H] ⁺ for C ₂₁ H ₁₇ FN ₈ O: theor. 417.2, fact. 417.3.

Example 46 6- (2,3-Difluorophenyl) -4- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -2-pyrimidinylamine

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 7.89-7.72 (m, 2H), 7.63-7.49 (m, 2H), 7 , 41-7.29 (m, 2H), 7.21 (d, J = 7.8 Hz, 1H), 6.99 (brs, 2H), 5.81 (s, 2H), 4.45 ( s, 2H), 3.55 (s, 3H).

MS [M + H] ⁺ for C20H17F2N7O2: theor. 410.1, fact.

Example 47 4- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (m-tolyl) -2pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 9 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.89-7.85 (m, 1H), 7.83 (d, J = 7.2 Hz, 1H) , 7.65 (t, J = 7.7 Hz, 1H), 7.37-7.33 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.26- 7.22 (m, 1H), 7.21 (s, 1H), 7.07-7.03 (m, 1H), 5.67 (s, 2H), 5.13 (s, 2H), 4 , 53 (s, 2H), 3.44 (s, 3H), 2.40-2.37 (m, 3H).

ESI-MS [M + H] ⁺ for C ₂₁ H ₂₁ N ₇ O: theor. 388.1, fact. 388.3.

Example 48 4- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (mmethoxyphenyl) -2-pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 37 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.71-7.63 (m, 3H) , 7.48-7.34 (m, 2H), 7.24-7.17 (m, 1H), 7.09 (ddd, J = 8.2, 2.7, 0.9Hz, 1H) , 6.80 (bs, 2H), 5.81 (s, 2H), 4.46 (s, 2H), 3.84 (s, 3H), 3.34 (s, 3H).

ESI-MS [M + H] + for C ₂ iH ₂ iN7O _2: theor. 404.2, fact. 404.2.

Example 49 6- (m-Fluorophenyl) -4- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinylamine

- 50 038488

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 32 mg of a yellow solid.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.01-7.98 (m, 1H), 7.94 (ddd, J = 10.6, 2.7 , 1.5 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.73 (s, 1H), 7.58 (td, J = 8.0, 6.0 Hz , 1H), 7.42-7.34 (m, 2H), 7.26-7.20 (m, 1H), 6.87 (bs, 2H), 5.83 (s, 2H), 4, 47 (s, 2H), 3.35 (s, 3H).

ESI-MS [M + H] + for C20H18FN7O: theor. 392.2, fact. 392.2.

Example 50 6- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4- [m- (trifluoromethyl) phenyl] -2 -pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give an orange solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 7.9 Hz , 1H), 7.95-7.83 (m, 2H), 7.79 (d, J = 11.5 Hz, 2H), 7.67-7.52 (m, 2H), 7.42- 7.36 (m, 1H), 7.25-7.18 (m, 1H), 6.94 (s, 2H), 5.83 (s, 2H), 4.47 (s, 2H), 3 , 35 (s, 3H).

ESI-MS [M + H] + for C ₂₁ H ₁₈ F ₃ N ₇ O: theor. 442.2, fact. 442.2.

51.

Example

6- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4- [m (methylsulfonyl) phenyl] -2-pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.77-8.59 (m, 2H), 8.49 (ddd, J = 7.9, 1.8, 1.1 Hz, 1H) , 8.08 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.90-7.76 (m, 3H), 7.45-7.36 (m, 1H) , 7.31-7.17 (m, 1H), 6.96 (s, 2H), 5.83 (s, 2H), 4.46 (s, 2H), 3.35 (s, 3H), 3.30 (s, 3H).

ESI-MS [M + H] + for C ₂₁ H ₂₁ N ₇ O ₃ S: theor. 452.2, fact. 452.2.

Example 52 6- (m-Chlorophenyl) -4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 71 mg of a tan solid.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.25-8.15 (m, 1H), 8.10 (dt, J = 7.4, 1.6 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.73 (s, 1H), 7.66-7.50 (m, 2H), 7.44-7.34 (m, 1H), 7.30-7.16 (m, 1H), 6.88 (s, 2H), 5.82 (s, 2H), 4.46 (s, 2H), 3.35 ( s, 3H).

ESI-MS [M + H] + for C ₂₀ H ₁₈ ClN ₇ O: theor. 408.1, fact. 408.2.

Example 53. 3- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -5- fluorobenzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne to give 3 mg of a white solid.

1 H-NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 8.25 (t, J = 1.2 Hz, 1H), 8.15-8.05 (m, 1H), 7 , 88 (s, 1H), 7.737.71 (m, 1H), 7.44-7.27 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 5.74 ( s, 2H), 5.16 (bs, 2H), 4.60 (s, 2H), 3.51 (s, 3H).

ESI-MS [M + H] + for C ₂₁ H ₁₇ FN ₈ O: theor. 417.2, fact. 417.3.

Example 54 3- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4

- 51 038488 pyrimidinyl] -5-anisonitrile

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 56 mg of a white solid.

-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.87-7.85 (m, 1H), 7.81 (s, 1H), 7.60-7.56 (m, 2H), 7.39 (d, J = 8 Hz, 1H ), 7.22 (J = 8 Hz, 1H), 6.92 (bs, 1H), 5.83 (s, 2H), 4.47 (s, 2H), 3.92 (s, 3H), 3.35 (s, 3H).

ESI-MS [M + H] ⁺ for C22H2oN ₈ 02: Theor. 429.2, fact. 429.3.

Example 55 6- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -2- toluonitrile

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 78 mg of a tan solid.

Ή-NMR (400 MHz, DMSO-d6) 8.67 (d, J = 0.8 Hz, 1H), 7.94-7.81 (m, 2H), 7.75 (dd, J = 7, 8, 1.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 0.9 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.88 (s, 2H), 5.81 (s, 2H), 4.46 (s, 2H) , 3.35 (s, 3H), 2.55 (s, 3H).

ESI-MS [M + H] + for C ₂₂ H ₂₀ N ₈ O: theor. 413.2, fact. 413.3.

Example 56 6- (2,2-Difluoro-2H-1,3-benzodioxol-5-yl) -4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} 1H-1,2, 3-triazol-4-yl) -2-pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 30 mg of a yellow solid.

Ή-NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.15 (dd, J = 1.8, 0.4 Hz, 1H), 8.07 (dd, J = 8 , 5, 1.8 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.56 (dd, J = 8.5, 0, 4 Hz, 1H), 7.43-7.35 (m, 1H), 7.22 (dd, J = 7.7, 0.9 Hz,

1H), 6.84 (s, 2H), 5.82 (s, 2H), 4.46 (s, 2H), 3.35 (s, 3H).

ESI-MS [M + H] ⁺ for C ₂₁ H ₁₇ F ₂ N ₇ O ₃ : theor. 454.1, fact. 454.3.

Example 57 4- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (mtrifluoromethoxyphenyl) -2-pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 100 mg of a white solid.

S-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.20-8.17 (m, 1H), 8.12 (s, 1H), 8.12 (bs, 1H ), 7.86 (t, J = 8 Hz, 1H), 7.76 (s, 1H), 7.66 (t, J = 8 Hz, 1H), 7.56-7.54 (m, 1H ), 7.39 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 3.2 Hz, 1H), 6.90 (bs, 2H), 5.83 (s, 2H ), 4.47 (s, 2H), 3.35 (s, 3H).

ESI-MS [M + H] ⁺ for C ₂₁ H ₁₈ F ₃ N ₇ O ₂ : theor. 458.2, fact. 458.3.

Example 58 {m- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] phenyl} (dimethylamino) formaldehyde

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 48 mg of a tan solid.

Ή-NMR (400 MHz, DMSO-d6) δ 8.68 (dd, J = 3.7, 1.1 Hz, 1H), 8.23-8.12 (m, 2H), 7.86 (td , J = 7.8, 4.1 Hz, 1H), 7.74 (dd, J = 3.6, 1.1 Hz, 1H), 7.63-7.51 (m, 2H), 7, 39 (dd, J = 7.8, 3.5 Hz, 1H), 7.22 (dd, J = 7.7, 3.5 Hz, 1H), 6.82 (d, J = 3.5 Hz , 2H), 5.82 (d, J = 3.6 Hz, 2H), 4.47 (d, J = 3.8 Hz, 2H), 3.35 (dd, J = 3.7, 1, 1 Hz, 3H), 3.02 (s, 3H), 2.94 (s, 3H).

- 52 038488

ESI-MS [M + H] + for C23H24N8O2: theor. 445.2, fact. 445.3.

Example 59 {m- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] phenylaminohydroxysulfeno} methane

This compound was obtained analogously to example 1, starting from 3- (methylsulfonylamino) phenylboronic acid.

¹ H-NMR (400 MHz, D ₂ O) δ 8.65 (m, 1H), 8.16-7.94 (m, 1H), 7.68-7.04 (m, 8H), 5, 79 (m, 2H), 3.31 (m, 3H), 3.19 (m, 1H), 2.95 (m, 3H).

LC-MS: retention time 2.28 min, method A; ESI-MS [M + H] + for C ₂₁ H ₂ 3N ₈ O ₃ S: theor. 467.2, fact. 467.2.

Example 60 6- (m-Ethylphenyl) -4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinylamine

This compound was obtained analogously to example 1, starting from 3-ethylphenylboronic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.04 (s, 1H), 7.99 (d, J = 7.1 Hz, 1H), 7, 92-7.81 (m, 2H), 7.53-7.43 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7, 7 Hz, 1H), 5.86 (s, 2H), 4.45 (s, 2H), 3.33 (s, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1 , 23 (td, J = 7.6, 1.0 Hz, 3H).

LC-MS: retention time 2.66 min, method A; ESI-MS [M + H] ⁺ for C ₂₂ H ₂₄ N ₇ O: theor. 402.2, fact. 402.3.

Example 61 {m- [2-Amino-6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] phenyl} acetonitrile

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 103 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 1.1 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J = 7.7 Hz , 1H), 7.90-7.79 (m, 1H), 7.72 (d, J = 1.1 Hz, 1H), 7.59-7.47 (m, 2H), 7.39 ( d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.82 (s, 2H), 5.82 (s, 2H), 4.47 ( s, 2H), 4.16 (s, 2H), 3.35 (d, J = 1.2Hz, 3H).

ESI-MS [M + H] ⁺ for C22H2oN ₈ 0: theor. 413.2, fact. 413.3.

Example 62 6- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4- [m- (1,3-oxazole- 2yl) phenyl] -2-pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 110 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 1.8 Hz, 1H), 8.73-8.67 (m, 1H), 8.32-8.24 ( m, 2H), 8.13 (d, J = 7.7 Hz, 1H), 7.91-7.82 (m, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.71 (dt, J = 8.6, 4.3 Hz, 1H), 7.47-7.43 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7 , 23 (d, J = 7.8 Hz, 1H), 6.91 (s, 2H), 5.83 (d, J = 2.0 Hz, 2H), 4.47 (d, J = 2, 0 Hz, 2H), 3.35 (q, J = 1.4 Hz, 3H).

ESI-MS [M + H] + for C23H2oN ₈ 02: Theor. 441.2, fact. 441.3.

Example 63 4- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (3-pyridyl) -2pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 6-ethynyl-4- (3-pyridyl) -2-pyrimidinylamine (which was prepared analogously to Steps 1 -3 from example 1).

¹ H-NMR (400 MHz, chloroform-d) δ 9.32 (d, J = 2.4 Hz, 1H), 8.71 (dd, J = 4.8, 1.7 Hz, 1H), 8 , 37 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.71 (dd, J = 7 , 8, 7.8 Hz, 1H), 7.46-7.39 (m, 2H), 7.11 (d,

- 53 038488

J = 7.8 Hz, 1H), 5.73 (s, 2H), 5.15 (s, 2H), 4.59 (s, 2H), 3.50 (s, 3H).

MS [M + H] ⁺ for C ₁₉ H ₁₈ N ₈ O: theor. 375.2, fact. 375.3.

Example 64 6- (2-Furanyl) -4- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinylamine

This compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and 6-ethynyl-4- (2-furanyl) -2-pyrimidinylamine.

¹ H-NMR (400 MHz, chloroform-d) δ 8.27 (s, 1H), 7.80 (s, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.61 (dd, J = 1.8, 0.8 Hz, 1H), 7.43-7.39 (m, 1H), 7.20 (dd, J = 3.5, 0.8 Hz, 1H), 7.12-7.08 (m, 1H), 6.57 (dd, J = 3.5, 1.8 Hz, 1H), 5.73 (s, 2H), 5.08 (s, 2H) , 4.59 (s, 2H), 3.50 (s, 3H).

ESI-MS [M + H] ⁺ for C ₁₈ H ₁₇ N ₇ O ₂ : theor. 364.1, fact. 364.2.

Example 65 4- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (1,3-thiazol-2-yl ) 2-pyrimidinylamine

Step 1. To a solution of acidic thiazole derivative (6.46 g, 50.0 mmol) and THF (100 ml) at 0 ° C was added CDI (9.72 g, 60.0 mmol) in one portion. The mixture was then stirred at room temperature for 4 h. In a separate flask, a mixture of potassium ethyl malonate (25.5 g, 150 mmol), MgCl ₂ (14.3 g, 150 mmol) and THF (100 ml) was stirred at 75 ° C for 4 hours. After the completion of the two reactions, the mixture containing the activated acid derivative was introduced into another flask at room temperature. The combined reaction mixture was stirred at 50 ° C for 16 h. The mixture was cooled to room temperature and 2M aqueous HCl (100 ml) was added. The mixture was extracted with ethyl acetate (2x150 ml), washed with saturated NaHCO ₃ , saturated NaCl solution and filtered through a pad of silica gel to give the desired β-ketoester product as a brown oil (9.11 g; 91%).

Step 2. To a solution of guanidine hydrochloride (1.91 g, 20.0 mmol) and ethanol (40 ml) was added sodium ethoxide (1.36 g, 20.0 mmol). The mixture was stirred at room temperature for 10 minutes after which the β-ketoester obtained above (3.98 g, 20.0 mmol) was added. The mixture was stirred at 100 ° C for 16 hours. After cooling to room temperature, hexane (100 ml) was added. The precipitated solids were collected by filtration to give the desired product as a yellow solid (2.88 g, 74%).

Stage 3. A mixture of the product from stage 2 (2.88 g, 14.8 mmol) and POCl ₃ (13.8 ml, 148 mmol) in dioxane (59 ml) was stirred at 70 ° C for 2 hours. Then the mixture was cooled , poured onto ice (75 g), neutralized sat. NaHCO ₃ solution, extracted with ethyl acetate (2x150 ml) and dried over Na ₂ SO ₄ . The crude product was purified by silica gel chromatography (0 to 5% MeOH in CH ₂ Cl ₂ ) to give the desired chloropyrimidine derivative product as a brown solid (1.29 g; 41%).

Steps 4 and 5. A mixture of the product from step 3 (1.29 g; 6.07 mmol), trimethylsilylacetylene (2.59 ml, 18.2 mmol), bis- (triphenylphosphine) palladium chloride (428 mg; 0.61 mmol ), copper (I) iodide (116 mg, 0.61 mmol), triethylamine (3 ml) and DMF (3 ml) were stirred at 80 ° C for 12 h. The volatiles were removed and the crude product was purified by chromatography on silica gel (0 to 100% EtOAc in hexane) to give an alkyne derivative. It was dissolved in MeOH (30 ml), ammonia (4.3 ml, 7M in MeOH) was added and the mixture was stirred at room temperature for 30 min. Volatiles were removed, and the crude product was purified by chromatography on silica gel (from 0 to 50%

EtOAc in CH ₂ Cl ₂ / hexane (1: 1)) to give the desired product as an orange solid (254 mg; 21%).

Step 6. The product was synthesized in the same manner as in example 1, step 6: off-white solid (34 mg, 30%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.97-7.85 (m , 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 5.87 (s, 2H), 4.49 (s , 2H), 3.36 (s, 3H).

ESI-MS [M + H] + for C ₁₇ H ₁₇ N ₈ OS: theor. 381.1, fact. 381.2.

Example 66 4- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (4-methyl-1,3thiazole-2 -yl) -2-pyrimidinylamine

МеО 'AN ^ N ^Ν Λ

T I N — Me

This compound was synthesized analogously to the above example 65.

1H-NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 8.13 (s, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.44- 7.36 (m, 1H), 7.14-7.09 (m, 1H), 7.07 (t, J = 0.9 Hz, 1H), 5.72 (s, 2H), 5.32 (s, 2H), 4.59 (s, 2H), 3.49 (s, 3H), 2.54 (s, 3H).

ESI-MS [M + H] ⁺ for C ₁₈ H ₁₈ N ₈ OS: theor. 395.1, fact. 395.2.

Example 67 4- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (4-methyl-1,3thiazole-2 -yl) -2-pyrimidinylamine

Stages 1-4. The TMS-alkyne derivative was synthesized in the same manner as in example 65: brown solid (193 mg; 1.3% over 4 steps).

Step 5. To a solution of a TMS-alkyne derivative (193 mg, 0.682 mmol) in THF (3.4 ml) at 0 ° C was added TBAF (3.4 ml, 0.750 mmol, 1 M in THF) dropwise. The mixture was stirred at 0 ° C for 15 minutes. The mixture was evaporated and purified by silica gel chromatography (0 to 5% MeOH in CH ₂ Cl ₂ ) to give the desired product as a brown solid (93 mg; 65%).

Step 6. The product was synthesized in the same manner as in example 1, step 6: off-white solid (7 mg, 6%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (s, 1H), 8.70-8.62 (m, 2H), 7.93-7.83 (m, 1H), 7 , 76 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 5.85 (s, 2H), 4 , 47 (s, 2H), 3.34 (s, 3H), 2.80 (s, 3H).

ESI-MS [M + H] ⁺ for C ₁₉ H ₂₀ N ₉ O: theor. 390.2, fact. 390.2.

Example 68 4- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (2H-pyrazol-3yl) -2- pyrimidinylamine

MeO ^ ⁿ 2 '/) N ^ N ^N \ ^N. 'ϊ Λ ^Ν

Ν = Ν

This compound was prepared in analogy to Example 20 from the corresponding azide and alkyne to give 92 mg of a pale yellow solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 7.90-7.81 (m, 2H), 7.77 (s, 1H), 7.38 (d , J = 7.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.82 (t, J = 2.1 Hz, 1H), 6.68 (bs, 2H ), 5.80 (s, 2H), 4.46 (s, 2H), 3.35 (s, 3H).

ESI-MS [M + H] ⁺ for C17H17N9O: theor. 364.2, fact. 364.3.

- 55 038488

Example 69.4- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (1H-pyrazol-4yl) -2 -pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 2.4 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.85 (t, J = 7 , 8 Hz, 1H), 7.49 (s, 1H), 7.38 (dd, J = 7.9, 0.9 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H ), 6.57 (s, 2H), 5.81 (s, 2H), 4.46 (s, 2H), 3.35 (s, 3H).

ESI-MS [M + H] + for C ₁₇ H ₁₇ N ₉ O: theor. 364.2, fact. 364.2.

Example 70 6- (1H-Indazol-6-yl) -4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -2- pyrimidinylamine

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.50 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 8 , 01-7.85 (m, 3H), 7.43 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 5.93 (s, 2H), 4.48 (s, 2H), 3.33 (s, 3H).

MS [M + H] ⁺ for C ₂₁ H ₁₉ N ₉ O: theor. 414.2, fact. 414.3.

Example 71 4- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (7-quinolyl) -2pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 61 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.99 (dd, J = 4.3, 1.9 Hz, 1H), 8.79 (s, 1H), 8.73 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.38-8.31 (m, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.94-7.80 (m 2H), 7.66-7.54 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.90 (s, 2H), 5.84 (s, 2H), 4.52-4.41 (m, 2H), 3.36 (d, J = 1 , 3 Hz, 3H).

ESI-MS [M + H] ⁺ for C23H10N8O: theor. 425.2, fact. 425.3.

Example 72 4- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (8-quinolyl) -2pyrimidinylamine

This compound was prepared analogously to Example 20 from the corresponding azide and alkyne to give 31 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (dt, J = 4.2, 1.5 Hz, 1H), 8.65 (d, J = 1.2 Hz, 1H), 8.49 (dd, J = 8.4, 1.8 Hz, 1H), 8.21-8.09 (m, 2H), 7.93 (d, J = 1.2 Hz, 1H), 7 , 89-7.79 (m, 1H), 7.75 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 7.62 (ddd, J = 8.3, 4, 2, 1.1 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.73 (s, 2H) , 5.82 (s, 2H), 4.47 (s, 2H), 3.36 (d, J = 1.1 Hz, 3H).

ESI-MS [M + H] ⁺ for C ₂₃ H ₂₀ N ₈ O: theor. 425.2, fact. 425.3.

Example 73 4- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (1H-pyrazol-1 yl) - 2-pyrimidinylamine

Stage 3

- 56 038488

Stage 1. NaH (60% dispersion in mineral oil, 840 mg, 21 mmol, 1.05 eq.) Was suspended in

DMF (80 ml) and the suspension was cooled in an ice-water bath. Pyrazole (1.43 g, 21 mmol,

1.05 equiv.). After 45 min, solid dichloropyrimidine (3.26 g, 20 mmol, 1 eq.) Was added and the ice bath removed. After 2 hours, add water and filter the reaction mixture to give the title compound as 2.99 g of a pale yellow solid.

Steps 2 and 3. Analogously to example 1, 30 mg of a yellow solid was obtained.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.52 (dd, J = 2.7, 0.7 Hz, 1H), 7.90 (dd, J = 1.7, 0.7 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.01 (s, 2H), 6.62 (dd, J = 2.7, 1.6 Hz, 1H), 5, 81 (s, 2H), 4.46 (s, 2H), 3.35 (s, 3H).

ESI-MS [M + H] + for C ₁₇ H ₁₇ N ₉ O: theor. 364.2, fact. 364.2.

Example 74 m- [2-Amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -5-methyl-1H-1,2,3-triazol-4yl) -4-pyrimidinyl ] benzonitrile

Stage 1. Received alkyne in the same way as in stage 2 of example 1, using propyne as a reagent to obtain the product.

Stage 2. A mixture of an azide derivative (18 mg, 0.1 mmol) and alkyne (23 mg, 0.1 mmol) in toluene (1 ml) was heated to 120 ° C in a sealed tube for 20 h. The mixture was cooled to room temperature , evaporated to dryness and purified by silica gel chromatography (hexane / EtOAc 70:30 to 0: 100) to give the desired product (4 mg, 10%) along with its regioisomer (2 mg, 5%).

¹ H-NMR (400 MHz, chloroform-d) δ 8.47 (ddd, J = 1.7, 1.7, 0.6 Hz, 1H), 8.32 (ddd, J = 8.0, 1 , 9, 1.2 Hz, 1H), 7.99 (s, 1H), 7.75 (ddd, J = 7.7, 1.7, 1.2 Hz, 1H), 7.67 (dd, J = 7.8, 7.8 Hz, 1H), 7.60 (ddd, J = 7.8, 7.8, 0.6 Hz, 1H), 7.37 (d, J = 7.8 Hz , 1H), 6.89 (d, J = 7.8 Hz, 1H), 5.69 (s, 2H), 5.09 (s, 2H), 4.57 (s, 2H), 3.49 (s, 3H), 2.71 (s, 3H).

MS [M + H] ⁺ for C22H20N8O: theor. 413.2, fact. 413.3.

Example 7 5. m- [2-Amino-6- (1- {[6- (ethoxymethyl) -2-pyridyl] methyl} - 1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.63 (s, 1H), 8.50 (d, J = 7.9 Hz, 1H), 8, 06 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 5.88 (s, 2H), 4.51 ( s, 2H), 3.54 (q, J = 7.0 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H).

ESI-MS [M + H] ⁺ for C22H21N8O: theor. 413.2, fact. 413.3.

Example 76 m- [2-Amino-6- (1 - {[6- (isopropoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 1H), 8.64 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8, 06 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 3.4 Hz, 1H), 7.93-7.86 (m, 1H), 7.82-7.76 (m, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 5.88 (s, 2H), 4.52 (s, 2H), 3.74-3.62 (m, 1H), 1.14 (d, J = 6.1 Hz, 6H).

ESI-MS [M + H] ⁺ for C23H23N8O: theor. 427.2, fact. 427.3.

Example 77 m- [2-Amino-6- (1 - {[6- (1-methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

- 57 038488

Step 1. Dissolve the diol (700 mg, 4.6 mmol) in CH2C12 (10 ml). Imidazole (640 mg, 9.4 mmol) and TBSCl (754 mg, 5 mmol) were added and the mixture was stirred until the starting diol was completely converted. The crude mixture was loaded directly onto a silica gel column (Hex / EtOAc 95: 5) to give the monoprotected alcohol (794 mg, 65%).

The TBS-blocked alcohol from the previous step (794 mg, 3 mmol) was dissolved in THF (6 ml), NaH (60% in mineral oil, 144 mg, 3.6 mmol) was added, stirred for 10 min and methyl iodide (374 μl , 6 mmol). After complete conversion of the starting alcohol, the mixture was quenched with saturated NH4Cl and after the usual work-up, the residue was purified by silica gel chromatography (Hex / EtOAc 95: 5) to give the desired ester (800 mg, 96%).

The TBS derivative obtained above (800 mg, 2.8 mmol) was dissolved in THF (5 ml) and the solution was cooled to 0 ° C, after which TBAF (1 M in THF, 3 ml) was added dropwise. Thereafter, the reaction mixture was quenched with saturated NH4Cl and after the usual work-up, the residue was purified by silica gel chromatography (Hex / EtOAc 90:10 to 60:40) to give the desired primary alcohol (475 mg, quant.).

Stage 2. The alcohol obtained in stage 1 (475 mg, 2.8 mmol) was dissolved in CH ₂ Cl ₂ (3 ml) and SOCl ₂ (397 μl, 2 eq., 5.6 mmol) was added. The resulting solution was stirred until the initial alcohol was completely converted, after which the mixture was evaporated to dryness. The resulting residue was used without further purification. The crude material was dissolved in DMF (5 ml) and sodium azide (273 mmol, 4.2 mmol) was added. The resulting mixture was stirred at 50 ° C for 8 hours and then cooled to room temperature. The crude product was partitioned between water and dichloromethane. The organic layer was evaporated to dryness and the residue was purified by silica gel chromatography (Hex / EtOAc 90:10) to give the desired azide (200 mg, 37% over 2 steps).

Stage 3. Synthesized the specified compound in the same way as in stage 6 of example 1, using the derivative of the azide and m- (2-amino-6-ethynyl-4-pyrimidinyl) benzonitrile (from example 4).

¹ H-NMR (400 MHz, chloroform-d) δ 8.46 (s, 1H), 8.39-8.24 (m, 2H), 7.92 (s, 1H), 7.82-7, 66 (m, 2H), 7.61 (dd, J = 7.8, 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 5.74 (s, 2H), 5.14 (s, 2H), 4.49-4.36 (m, 1H), 3.33 (s, 3H), 1 , 47 (d, J = 6.9 Hz, 3H).

MS [M + H] + for C22H20N8O: theor. 413.2, fact. 413.3.

Example 78 4- (1 - {[6- (1-Methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (1,3-oxazol-2yl ) -2-pyrimidinylamine

Steps 1 and 2. A mixture of a pyrimidine derivative (3.64 g, 10.0 mmol), 2- (tri-nbutylstannyl) oxazole (2.10 ml, 10.0 mmol) and Pd (PPh ₃ ) ₄ (1.16 g, 1.00 mmol) in DMF (20 ml) was stirred at 100 ° C for 5 h. The mixture was cooled to room temperature and ethyl acetate (200 ml) was added. The organics were washed with saturated NaCl solution (4x200 ml) and dried over

- 58 038488

MgSO ₄ . The crude product was purified by silica gel chromatography (0 to 30% EtOAc in hexanes) to give the desired product. TFA (1 ml) and CH2Cl2 (5 ml) were added thereto and the mixture was stirred at room temperature for 10 minutes. The mixture was neutralized with a saturated solution

NaHCO ₃ , diluted with ethyl acetate and dried over Na 2 SO 4 to give the desired product as a yellow solid (322 mg, 8%).

Steps 3 and 4. The final alkyne was synthesized in the same manner as in example 65: brown solid (63 mg, 21% over 2 steps).

Step 5. The product was synthesized in the same manner as in example 1, step 6: yellow solid (13 mg, 10%).

^ -NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.37 (s, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.82 ( s, 1H), 7.54 (s, 1H), 7.39 (d J = 7.8 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 5.85 (s , 2H), 4.35 (q, J = 6.4 Hz, 1H), 3.19 (s, 3H), 1.32 (d, J = 6.6 Hz, 3H).

ESI-MS [M + H] + for C ₁₈ H ₁₉ N ₈ O: theor. 379.2, fact. 379.3.

Example 79 m- [2-Amino-6- (1 - {[6- (1-methoxypropyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4 pyrimidinyl] benzonitrile

A Stage 1 B Stage 2 C

TBAF, THF

Stage 3

Step 1. A solution of aldehyde A (1.0 g, 4 mmol) in THF (20 ml) was cooled in a dry ice / acetone bath. EtMgBr (3M in THF, 2 ml, 6 mmol, 1.5 eq.) Was added along the side of the flask. After 1.5 h, the reaction mixture was quenched with NH4Cl and extracted with EtOAc. The organic layer was evaporated on celite and purified by flash chromatography on SiO ₂ to yield the alcohol B (537 mg) as a white solid vesche Properties.

Stage 2. NaH (60% dispersion in mineral oil, 99 mg, 2.5 mmol, 1.3 eq.) Was added to a solution of alcohol B (537 mg, 1.9 mmol) in THF (8 ml). After 30 min, MeI (0.18 ml, 2.9 mmol, 1.5 eq.) Was added. The reaction mixture was stirred overnight and quenched with H2O, extracted with MTBE, dried and evaporated to give Ether C (559 mg) as a yellow oil.

Step 3. To a solution of ether C (1.9 mmol) in THF (2 ml) was added TBAF (1 M in THF, 2 ml). After 1.5 h, the reaction mixture was evaporated and the crude residue was purified by flash chromatography on SiO ₂ to give alcohol D (299 mg) as a colorless oil.

Steps 4 and 5. The title compound was synthesized according to the procedure for Example 1 to provide 81 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.71 (dd, J = 5.4, 1.9 Hz, 1H), 8.58 (q, J = 3.1, 1.7 Hz, 1H), 8.54-8.40 (m, 1H), 8.06-7.94 (m, 1H), 7.91-7.69 (m, 3H), 7.35 (t, J = 7.1 Hz, 1H), 7.17 (t, J = 6.6 Hz, 1H), 6.90 (s, 2H), 5.84 (d, J = 6.0 Hz, 2H), 4 , 13 (t, J = 6.3 Hz, 1H), 3.19 (dd, J = 5.4, 1.8 Hz, 3H), 1.75-1.62 (m, 2H), 0, 86-0.70 (m, 3H).

ESI-MS [M + H] ⁺ for C ₂₃ H ₂₂ N8O: theor. 427.2, fact. 427.3.

Example 80 m- [2-Amino-6- (1 - {[6- (1-methoxy-2-methylpropyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -4 -pyrimidinyl] benzonitrile

This compound was prepared in analogy to Example 79 to give 86 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (d, J = 2.0 Hz, 1H), 8.58 (t, J = 2.0 Hz, 1H), 8.47 ( dd, J = 8.1, 1.7 Hz, 1H), 8.04-7.96 (m, 1H), 7.90-7.79 (m, 2H), 7.74 (td, J = 7.9, 2.0 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.18 (dd, J = 7.5, 1.8 Hz, 1H), 6, 89 (s, 2H), 5.83 (d, J = 1.7 Hz, 2H), 3.92 (dd, J = 6.2, 2.0 Hz, 1H), 3.20-3.14 (m, 3H), 1.95 (dt,

- 59 038488

J = 12.2, 7.3 Hz, 1H), 0.80 (dd, J = 6.8, 2.0 Hz, 3H), 0.71 (dd, J = 6.8, 2.0 Hz , 3H).

ESI-MS [M + H] ⁺ for C ₂₄ H ₂₄ N ₈ O: theor. 441.2, fact. 441.5.

Example 81 m- [2-Amino-6- (1 - {[6- (cyclopropylmethoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol4-yl) -4-pyrimidinyl] benzonitrile

This compound was prepared in analogy to Example 79 to give 87 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.73-8.69 (m, 1H), 8.58 (q, J = 1.8 Hz, 1H), 8.50-8.44 (m, 1H), 8.02-7.96 (m, 1H), 7.89-7.79 (m, 2H), 7.79-7.71 (m, 1H), 7.38 (d , J = 7.5 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 6.90 (s, 2H), 5.84 (d, J = 3.0 Hz, 2H ), 3.67 (dd, J = 7.9, 3.1 Hz, 1H), 3.22-3.15 (m, 3H), 1.11-1.02 (m, 1H), 0, 55-0.36 (m, 2H), 0.25 (ddd, J = 37.8, 9.0, 4.6Hz, 2H).

ESI-MS [M + H] ⁺ for C ₂₄ H ₂₂ N ₈ O: theor. 439.2, fact. 439.3.

Example 82 m- [2-Amino-6- (1 - {[6- (cyclopentylmethoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol4-yl) -4-pyrimidinyl] benzonitrile

This compound was prepared in analogy to example 79, obtaining 81 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (d, J = 1.1 Hz, 1H), 8.61-8.58 (m, 1H), 8.51-8.42 (m, 1H), 8.01-7.97 (m, 1H), 7.89-7.79 (m, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7, 33 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.89 (s, 2H), 5.84 (s, 2H), 4, 01-3.93 (m, 1H), 3.13 (s, 3H), 2.16 (q, J = 7.9 Hz, 1H), 1.60 (d, J = 8.8 Hz, 1H ), 1.52-1.09 (m, 7H).

ESI-MS [M + H] ⁺ for C ₂₆ H ₂₆ N ₈ O: theor. 467.2, fact. 467.3.

Example 83 m- [2-Amino-6- (1 - {[6- (methoxyphenylmethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

This compound was prepared in analogy to Example 79 to give 90 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.72-8.65 (m, 1H), 8.60 (t, J = 2.0 Hz, 1H), 8.52-8.45 ( m, 1H), 8.00 (ddd, J = 7.8, 2.7, 1.5 Hz, 1H), 7.88-7.80 (m, 2H), 7.75 (td, J = 7.9, 2.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.34 (dd, J = 7.2, 1.8 Hz, 2H), 7, 26 (tt, J = 7.4, 1.4 Hz, 2H), 7.23-7.12 (m, 2H), 6.91 (s, 2H), 5.85-5.76 (m, 2H), 5.32 (d, J = 1.9 Hz, 1H), 3.33-3.31 (m, 3H).

ESI-MS [M + H] ⁺ for C ₂₇ H ₂₂ N ₈ O: theor. 475.2, fact. 475.3.

Example 84. m- {6- [1 - ({6 - [(R) -1-Methoxyethyl] -2-pyridyl} methyl) -1H-1,2,3-triazol-4-yl] -2-amino -4pyrimidinyl} benzonitrile

Stage 5

Step 1. Formic acid (8.0 ml) was added dropwise to triethylamine (13.6 ml) at 0 ° C. The mixture was degassed and then ketone (2.68 g, 10.0 mmol), RuCl (p-cymene) - [(R, R) -Ts-DPEN] (129 mg, 0.200 mmol) and CH ₂ Cl ₂ ( 2.6 ml). The mixture was stirred at room temperature for 14 h, quenched with saturated aqueous NaHCO ₃ solution, diluted with EtOAc (200 ml), washed with saturated NaCl solution and dried over Na ₂ SO ₄ . The crude product was purified by chromatography on silica gel (0 to 5% MeOH in CH ₂ Cl ₂ ) to give the desired product as a brown oil (896 mg;

33%).

Step 2. To a solution of the product from Step 2 (1.14 g, 4.26 mmol) in THF (21 ml) at 0 ° C was added NaH (204 mg, 5.11 mmol, 60% in oil) in one portion. The mixture was stirred at room temperature for 15 min, cooled to 0 ° C and methyl iodide (265 μL, 4.26 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and evaporated on silica gel. The crude product was purified by silica gel chromatography (0 to 30% EtOAc in hexanes) to give the desired product as a colorless oil (803 mg; 67%).

Steps 3, 4. The azide was synthesized in the same manner as in example 79 to give the product as a colorless oil (373 mg, 68% over 2 steps).

Step 5. The product was synthesized in the same manner as in example 1, step 6: off-white solid (97 mg, 79%). The compound was synthesized in the same manner as in example 1, step 6.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.62-8.56 (m, 1H), 8.52-8.43 (m, 1H), 8, 04-7.97 (m, 1H), 7.90-7.82 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8, 2 Hz, 1H), 7.18 (d, J = 6.7 Hz, 1H), 5.85 (s, 2H), 4.34 (q, J = 6.5 Hz, 1H), 3.19 (s, 3H) 1.32 (d, J = 6.5 Hz, 3H).

ESI-MS [M + H] + for C ₂₂ H ₂₁ N ₈ O: theor. 413.2, fact. 413.3.

Example 85. 3- {6- [1 - ({6 - [(R) -1-methoxyethyl] -2-pyridyl} methyl) -1H-1,2,3-triazol-4-yl] -2-amino -4pyrimidinyl} -2-fluorobenzonitrile

The compound was synthesized in the same manner as in example 84, from the corresponding alkyne.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (s, 1H), 8.35-8.26 (m, 1H), 8.14-8.05 (m, 1H), 7 , 91-7.82 (m, 1H), 7.68-7.62 (m, 1H), 7.62-7.53 (m, 1H), 7.39 (d, J = 7.6 Hz , 1H), 7.18 (d, J = 7.0 Hz, 1H), 5.84 (s, 2H), 4.39-4.30 (m, 1H), 3.19 (s, 3H) , 1.32 (d, J = 6.6 Hz, 3H).

ESI-MS [M + H] + for C ₂₂ H ₂₀ FN ₈ O: theor. 431.2, fact. 431.3.

Example 86. m- {6- [1 - ({6 - [(S) -1-methoxyethyl] -2-pyridyl} methyl) -1H-1,2,3-triazol-4-yl] -2-amino -4pyrimidinyl} benzonitrile

Stage 5

Synthesis. An azide was synthesized in the same manner as in example 84, only RuCl (p-cymene) - [(S, S) -Ts-DPEN] was used as a catalyst in step 2.

Step 6. The product was synthesized in the same manner as in example 1, step 6: off-white solid (96 mg, 78%).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.63-8.57 (m, 1H), 8.53-8.44 (m, 1H), 8, 04-7.99 (m, 1H), 7.92-7.82 (m, 2H), 7.80-7.73 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 5.85 (s, 2H), 4.38-4.30 (m, 1H), 3.19 (s, 3H), 1.32 (d, J = 6.5 Hz, 3H).

ESI-MS [M + H] + for C22H2iN ₈ O: theor. 413.2, fact. 413.3.

Example 87. 3- {6- [1 - ({6 - [(S) -1-Methoxyethyl] -2-pyridyl} methyl) -1H-1,2,3-triazol-4-yl] -2-amino -4pyrimidinyl} -2-fluorobenzonitrile

The compound was synthesized in the same manner as in example 86 from the corresponding alkyne.

¹ H-NMR (400 MHz, DMSO-de) δ 8.76 (s, 1H), 8.31 (td, J = 7.8, 1.8 Hz, 1H), 8.13-8.06 ( m, 1H), 7.87 (t,

- 61 038488

J = 7.8 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.3 Hz, 1H),

5.85 (s, 2H), 4.35 (q, J = 6.5 Hz, 1H), 3.19 (s, 3H), 1.32 (d, J = 6.5 Hz, 3H).

ESI-MS [M + H] + for C22H20FN8O: theor. 431.2, fact. 431.2.

Example 88 m- [2-Amino-6- (1- {1- [6- (methoxymethyl) -2-pyridyl] ethyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

Stage 3

Stage 1. A solution of aldehyde (756 mg, 5.0 mmol) in THF (10 ml) was cooled to -78 ° C. MeMgBr (3N in Et ₂ O, 2 ml, 1.2 eq.) Was added dropwise. The resulting mixture was slowly brought to 0 ° C over 2 h and then quenched with saturated NH4Cl solution. After the usual work-up (H ₂ O / EtOAc), the organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (Hex / EtOAc 90:10 to 60:40) to give the corresponding alcohol (635 mg, 76%).

The alcohol obtained in step 1 (600 mg, 3.6 mmol) was dissolved in CH ₂ Cl ₂ (4 ml) and SOCl ₂ (525 μl, 2 eq., 7.4 mmol) was added. The resulting solution was stirred until complete conversion of the starting alcohol, after which the mixture was evaporated to dryness. The resulting residue was used without further purification.

Step 2. The crude material obtained in Step 1 was dissolved in DMF (7 ml) and sodium azide (325 mg, 5 mmol) was added. The resulting mixture was stirred at 80 ° C for 8 hours and then cooled to room temperature. The crude material was partitioned between water and dichloromethane. The organic layer was evaporated to dryness and the residue was purified by silica gel chromatography (Hex / EtOAc 90:10) to give the desired azide (580 mg, 84% over 2 steps).

Stage 3. Synthesized the specified compound in the same way as in stage 6 of example 1, using the azide derivative and m- (2-amino-6-ethynyl-4-pyrimidinyl) benzonitrile (from example 4).

¹ H-NMR (400 MHz, chloroform-d) δ 8.47-8.43 (m, 1H), 8.40 (s, 1H), 8.30 (ddd, J = 8.0, 1.8 , 1.2 Hz, 1H), 7.89 (s, 1H), 7.75 (ddd, J = 7.7, 1.7, 1.2 Hz, 1H), 7.69 (dd, J = 7.8, 7.8 Hz, 1H), 7.60 (dd, J = 7.8, 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7, 12 (d, J = 7.8 Hz, 1H), 5.18 (s, 2H), 4.59 (s, 2H), 3.49 (s, 3H), 2.03 (d, J = 7 , 2 Hz, 3H).

MS [M + H] + for C22H20N8O: theor. 413.2, fact. 413.3.

Example 89. m- {6- {1 - [(6 - {[(S) -Tetrahydrofur-3-yloxy] methyl} -2-pyridyl) methyl] -1H-1,2,3-triazol4-yl} - 2-amino-4-pyrimidinyl) benzonitrile

Stage 1. To a solution of 3- (S) -hydroxytetrahydrofuran (440 mg, 5 mmol) in anhydrous THF (20 ml) with stirring at 0 ° C was added NaH (60%, 400 mg, 10 mmol) in 5 portions. Stirred at the same temperature for 30 minutes. A gray suspension was obtained and 2,6-bis (chloromethyl) pyridine hydrochloride (1.06 g, 5 mmol) was added to this reaction mixture in one portion at 0 ° C. The reaction mixture was stirred at room temperature overnight. Cooled to 0 ° C, quenched with saturated aqueous NH ₄ Cl, diluted with MTBE (10 ml), separated the layers, extracted the aqueous layer with MTBE, and combined the organic layers, dried (Na ₂ SO ₄ ), filtered, and evaporated on a rotary evaporator. The oily residue was dissolved in dichloromethane and purified on a flash column (ISCO, 40 g column, 5-60% ethyl acetate in hexane) to give the pure compound as a colorless liquid

- 62 038488 (480 mg, 42%).

Step 2. The product obtained above (480 mg, 2.1 mmol) was dissolved in anhydrous DMSO (2 ml), NaN ₃ (164 mg, 2.53 mmol) was added and stirred at room temperature for 2 h. LCMS indicated the reaction was complete , and it was diluted with water (15 ml), extracted with MTBE (3x15 ml), dried (Na ₂ SO ₄ ), filtered and evaporated on a rotary evaporator. The oily residue was dried under high vacuum to give the product (455 mg, 92%).

Stage 3. Received the specified compound analogously to example 1, stage 6, from the azide obtained above and the corresponding alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 1.1 Hz, 1H), 8.60 (t, J = 1.5 Hz, 1H), 8.48 (ddd , J = 8.0, 1.9, 1.2 Hz, 1H), 8.01 (dt, J = 7.7, 1.3 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.41 (dd, J = 7.8, 1 , 0 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 6.99 (s, 2H), 5.84 (s, 2H), 4.52 (d, J = 1 , 8 Hz, 2H), 4.30-4.21 (m, 1H), 3.79-3.70 (m, 2H), 3.70-3.61 (m, 2H), 1.97- 1.92 (m, 2H).

ESI-MS [M + H] + for C24H22N8O2: theor. 455.2, fact. 455.3.

Example 90. m- (6- {1 - [(6 - {[(R) -Tetrahydrofur-3-yloxy] methyl} -2-pyridyl) methyl] -1H-1,2,3-triazol4-yl} - 2-amino-4-pyrimidinyl) benzonitrile

This compound was prepared analogously to example 89 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.73 (t, J = 1.2 Hz, 1H), 8.60 (dt, J = 1.8, 1.0 Hz, 1H), 8 , 48 (ddd, J = 8.0, 1.9, 1.2 Hz, 1H), 8.01 (dt, J = 7.7, 1.4 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.84 (d, J = 1.1 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.41 (dd, J = 7 , 8, 0.9 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.04 (s, 2H), 5.84 (s, 2H), 4.53 (d , J = 1.8 Hz, 2H), 4.314.19 (m, 1H), 3.83-3.58 (m, 4H), 1.97-1.92 (m, 2H).

ESI-MS [M + H] + for C ₂₄ H ₂₂ N ₈ O ₂ : theor. 455.2, fact. 455.3.

Example 91 m- {2-Amino-6- [1 - ({6 - [(2-methoxyethoxy) methyl] -2-pyridyl} methyl) -1H-1,2,3-triazole-4yl] -4- pyrimidinyl} benzonitrile

This compound was prepared analogously to example 89 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.59 (td, J = 1.8, 0.6 Hz, 1H), 8.47 (ddd, J = 8.0, 1.8, 1.2 Hz, 1H), 8.00 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H), 7.87 (t, J = 7 , 8 Hz, 1H), 7.82 (s, 1H), 7.77-7.71 (m, 1H), 7.43-7.39 (m, 1H), 7.25-7.21 ( m, 1H), 6.93 (s, 2H), 5.83 (s, 2H), 4.54 (s, 2H), 3.66-3.57 (m, 2H), 3.52-3 , 43 (m, 2H), 3.24 (s, 3H).

ESI-MS [M + H] + for C23H22N8O2: theor. 443.2, fact. 443.3.

Example 92. 3- {2-Amino-6- [1 - ({6 - [(2-methoxyethoxy) methyl] -2-pyridyl} methyl) -1H-1,2,3-triazole-4yl] -4- pyrimidinyl} -2-anisonitrile

This compound was prepared analogously to example 89 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 8.01 (dd, J = 7.9, 1.8 Hz, 1H), 7.91 (s, 1H) , 7.78-7.62 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.35-7.26 (m, 1H), 7.12 (d, J = 1.1 Hz, 1H), 5.71 (s, 2H), 5.12 (s, 2H), 4.70 (s, 2H), 3.94 (m, 3H), 3.77-3 , 71 (m, 2H), 3.65-3.59 (m, 2H), 3.41 (s, 3H).

ESI-MS [M + H] + for C ₂₄ H ₂₄ N ₈ O ₃ : theor. 473.2, fact. 473.3.

Example 93. 3- (2-Amino-6- {1 - [(6-cyclopropyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4pyrimidinyl) -2-anisonitrile

OTBS

TBAF THF

Stage 2

he

DPPA, DBU CICH ₂ CH ₂ CI 50 ° C

Stage 3

NH,

[Г η Pd (OAc) ₂ , РСу ₃ , К _? RO.

J JL otrs

Br ^ 'X TOI / H2O. 100 ° C |> BfOH) ,,

Stage 1

N ₃

CuSO ^ oh ^ O

Na-ascorbate

Stage 4

- 63 038488

Stage 1. Into a mixture of 2-bromopyridine derivative (14 g, 46.4 mmol), cyclopropyl boronic acid (8 g, 93 mmol), K ₃ PO ₄ (34.5 g, 162.4 mmol) and PCy ₃ ( 1.3 g, 4.64 mmol) in 210 ml of toluene / H ₂ O 20: 1 was added Pd (OAc) ₂ (516 mg, 2.3 mmol). The reaction mixture was stirred at 100 ° C for 12 h under N ₂ . Saturated NH ₄ Cl (50 ml) was added to quench the reaction and the aqueous layer was extracted with EtOAc (2x70 ml). The combined organic layer was dried over Na ₂ SO ₄ , evaporated and transferred to the next step without further purification.

Step 2. The crude TBS ester from the previous step was dissolved in 100 ml THF and 46.4 ml 1 M TBAF in THF was added dropwise. After 15 min, 50 ml of saturated NH ₄ Cl was added to quench the reaction and the aqueous layer was extracted with EtOAc (2x70 ml). The combined organic layer was dried over Na ₂ SO ₄ , evaporated and purified by silica gel chromatography to give the desired alcohol (6.3 g, 91% over 2 steps).

Step 3. An azide was synthesized in the same manner as in step 5 in example 1: colorless oil (6.2 g, 85%).

Stage 4. Synthesized the specified compound in the same way as in stage 6 in example 1.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.5 Hz , 1H), 7.66 (dd, J = 7.7, 7.7 Hz, 1H), 7.62 (s, 1H), 7.42 (dd, J = 7.5, 7.5 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 2.09-2.02 (m, 1H), 0.93-0.88 (m, 2H), 0.82-0.78 (m, 2H).

ESI-MS [M + H] ⁺ for C ₂₃ H ₁₀ N ₈ O: theor. 425.2, fact. 425.3.

Example 94 m- (2-Amino-6- {1 - [(6-cyclopropyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4pyrimidinyl) benzonitrile

This compound was prepared analogously to example 93 from the corresponding azide and alkyne.

-NMR (400 MHz, chloroform-d) δ 8.49-8.39 (m, 1H), 8.35-8.23 (m, 2H), 7.93-7.81 (m, 1H) , 7.80-7.68 (m, 1H), 7.63-7.45 (m, 2H), 7.14-7.03 (m, 1H), 7.02-6.89 (m, 1H), 5.63 (s, 2H), 5.25 (s, 2H), 2.08-1.95 (m, 1H), 1.05-0.92 (m, 4H).

LC-MS: retention time 3.15 min, method A; ESI-MS [M + H] ^- for C ₂₂ H ₁₉ N ₈ : theor. 395.2, fact. 395.3.

Example 95 3- (2-Amino-6- {1 - [(6-cyclopropyl-2-pyridyl) methyl] -1 H-1,2,3-triazol-4-yl} -4pyrimidinyl) -2-fluorobenzonitrile

This compound was prepared analogously to example 93 from the corresponding azide and alkyne.

-NMR (400 MHz, chloroform-d) δ 8.38-8.18 (m, 2H), 7.91-7.82 (m, 1H), 7.76-7.64 (m, 1H) , 7.57-7.46 (m, 1H), 7.42-7.31 (m, 1H), 7.14-7.04 (m, 1H), 7.00-6.91 (m, 1H), 5.62 (s, 2H), 5.29 (s, 2H), 2.09-1.95 (m, 1H), 1.07-0.89 (m, 4H).

LC-MS: retention time 3.15 min, method A; ESI-MS [M + H] + for C ₂₂ H ₁₈ FN ₈ : theor. 413.2, fact. 413.3.

Example 96 4- {1 - [(6-Cyclopropyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -6- (2,3-difluorophenyl) 2-pyrimidinylamine

This compound was prepared analogously to example 93 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, chloroform-d) δ 8.29 (s, 1H), 7.87 (s, 1H), 7.78-7.69 (m, 1H), 7.52 (dd, J = 7.8, 7.8 Hz, 1H), 7.32-7.13 (m, 2H), 7.09 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 5.62 (s, 2H), 5.19 (brs, 2H), 2.08-1.98 (m, 1H), 1.05-0.94 (m, 4H ).

MS [M + H] + for C ₂₁ H ₁₇ F ₂ N ₇ : theor. 406.2, fact. 406.3.

Example 97 4- {1 - [(6-Cyclopropyl-2-pyridyl) methyl] -1H-1,2,3-triazole-4-6- (m-fluorophenyl) -2pyrimidinylamine

This compound was prepared analogously to example 93 from the corresponding azide and alkyne.

- 64 038488

-NMR (400 MHz, CD3OD-d4) 8.60 (s, 1 H), 7.93 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 12 Hz, 1H) , 7.77 (s, 1H),

7.64 (t, J = 8 Hz, 1H), 7.52 (q, J = 8 Hz, 1H), 7.25 (t, J = 8 Hz, 1H), 7.17 (d, J = 4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H),

5.72 (s, 1H), 2.09-2.02 (m, 1H), 0.98-0.91 (m, 4H).

ESI-MS [M + H] + for C ₂₁ H ₁₈ FN ₇ : theor. 388.4, fact. 388.3.

Example 98 3- (2-Amino-6- {1 - [(6-isopropyl-2-pyridyl) methyl] -III-1,2,3-triazol-4-yl} -4pyrimidinyl) -2-anisonitrile

Stage 1. A solution of 2-bromo-6 - ({[dimethyl (2-methyl-2-propanyl) silyl] oxy} methyl) pyridine (2.8 g, 9.2 mmol, 1.0 eq.) And pinacol ether isopropenylboronic acid (2.3 g, 13.9 mmol, 1.5 eq.) in dioxane (37 ml, 0.25 M) and 2.0 M aqueous Na ₂ CO ₃ (14 ml, 3.0 eq.) purged with N2 for 10 min. After that, Pd (PPh ₃ ) ₄ (717 mg, 0.46 mmol, 0.05 eq.) Was added and the reaction mixture was heated to 95 ° С for 18 h. Then the reaction mixture was diluted with CH ₂ Cl ₂ (100 ml) , transferred to a separatory funnel and washed with H ₂ O (100 ml). The organic phase was collected and the aqueous phase was extracted with CH ₂ Cl ₂ (2x100 ml). The combined organic extracts were dried over MgSO ₄ and evaporated in vacuo. The resulting oil was purified by column chromatography (EtOAc: hexane 0: 1 to 1: 9) to afford the title compound (2.2 g, 90% yield) as a colorless oil.

Stage 2. A solution of isopropenylpyridine from stage 1 (2.2 g, 8.4 mmol, 1.0 eq.) In ethanol (20 ml, 0.5 M) with acetic acid (0.1 ml) was purged with N2 for 5 min, and then PtO2 (117 mg, 0.52 mmol, 0.05 eq.) was added. The suspension was flushed with H ₂ from a balloon for 10 min, and then the reaction mixture was stirred in an atmosphere of H ₂ (balloon) for 20 h. After that, the reaction mixture was filtered through celite, the filter cake was washed with methanol (2x10 ml), and the filtrate was evaporated into vacuum. The resulting oil was used in the next step without further purification.

Step 3. The intermediate from the previous step was added to 1.0 M TBAF in THF (20 ml, 2.0 eq.) And the solution was stirred at room temperature for 45 min. Then the reaction mixture was loaded directly onto SiO ₂ and purified by column chromatography (MeOH: CH ₂ Cl ₂ from 0: 1 to 1: 9) to give (6-isopropyl-2-pyridyl) methanol (1.1 g, 87% yield) ) in the form of a colorless oil.

Step 4. To a solution of (6-isopropyl-2-pyridyl) methanol (1.1 g, 7.0 mmol, 1.0 eq.) In toluene (14 ml, 0.5 M) was added diphenylphosphoryl azide (1.8 ml , 8.4 mmol, 1.2 eq.), Followed by 1,8-diazabicyclo [5.4.0] undec-7-ene (1.3 ml, 8.4 mmol, 1.2 eq.). The resulting mixture was heated to 60 ° C for 1.5 h. The reaction mixture was then loaded directly onto SiO ₂ and purified by column chromatography (EtOAc: hexane 0: 1 to 1:19) to give 2- (azidomethyl) -6- isopropylpyridine (890 mg, 72% yield) as a colorless oil.

Stage 5. Synthesized the specified compound in the same way as in stage 6 of example 1.

Ή-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H) 7.94 (d, J = 7.7 Hz, 1H ), 7.80-7.75 (m, 1H), 7.63 (s, 1H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 5.81 (s, 2H), 3.03-2.96 (m, 1H), 1, 19 (d, J = 6.9 Hz, 6H).

ESI-MS [M + H] ⁺ for C ₂₃ H ₂₂ N ₈ O: theor. 427.2, fact. 427.3.

Example 99 m- (2-Amino-6- {1 - [(6-isopropyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -4pyrimidinyl) benzonitrile

- 65 038488

This compound was prepared analogously to example 98 from the corresponding azide and alkyne.

-NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 8.54 (s, 1H), 8.45 (d, J = 8.1 Hz, 1H), 7.94-7, 86 (m, overlapped, 3H), 7.74 (dd, J = 8.0, 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.28, J = 8.0 Hz, 1H), 5.86 (s, 2H), 3.10 (sept, 7.0 Hz, 1H), 1.29 (d, J = 7.0 Hz, 6H).

ESI-MS [M + H] + for C ₂₂ H ₂₀ N ₈ : theor. 397.2, fact. 397.3.

Example 100 6- (m-Fluorophenyl) -4- {1 - [(6-isopropyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -2pyrimidinylamine

This compound was prepared analogously to example 98 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, CD ₃ OD-d ₄ ) 8.65 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8, 0 Hz, 1H), 7.73-7.78 (m, 3H), 7.53 (d, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz, 1H), 7.16 (d, J = 4 Hz, 1H), 7.20 (dt, J = 8.4 Hz, 1H), 7.1 (d, J = 8.0 Hz, 1H), 5.79 (s, 2H ), 3.04-3.07 (m, 1H), 1.28 (d, J = 4Hz, 6H).

ESI-MS [M + H] ⁺ for C ₂₁ H ₂₀ FN ₇ : theor. 390.4, fact. 390.3.

Example 101 3- (2-Amino-6- {1 - [(6-isopropyl-2-pyridyl) methyl] -1 H-1,2,3-triazol-4-yl} -4pyrimidinyl) -2-fluorobenzonitrile

This compound was prepared analogously to example 98 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.59 (d, J = 0.8 Hz, 1H), 8.45-8.36 (m, 1H), 7.98 (dddd, J = 7.7, 6.0, 1.8, 0.8 Hz, 1H), 7.85 (dd, J = 2.7, 0.8 Hz, 1H), 7.74 (td, J = 7 , 8, 0.7 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.15 (dd, J = 7.6, 0.9 Hz, 1H), 6.30 (s, 2H), 5.80 (s, 2H), 3.03 (hept, J = 6.8 Hz, 1H), 1.24 (dd, J = 6.9, 0.8 Hz, 6H).

ESI-MS [M + H] ⁺ for C ₂₂ H ₁₉ FN ₈ : theor. 415.2, fact. 415.3.

Example 102 6- (2,3-Difluorophenyl) -4- {1 - [(6-isopropyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -2pyrimidinylamine

This compound was prepared analogously to example 98 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.72 (s, 1H), 7.89-7.87 (s, 2H), 7.79 (t, J = 7.9 Hz, 1H ), 7.51 (q, J = 8.6 Hz, 1H), 7.39-7.34 (m, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 5.85 (s, 2H), 3.07 (p, J = 7.2 Hz, 1H), 1.25 (dd, J = 6.9, 1.2 Hz, 6H).

ESI-MS [M + H] ⁺ for C21H19F2N / theory. 408.2, fact. 408.3.

Example 103 6- (2-Amino-6- {1 - [(6-isopropyl-2-pyridyl) methyl] -1 H-1,2,3-triazol-4-yl} -4pyrimidinyl) -2-toluonitrile

This compound was prepared analogously to example 98 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, acetone ^) δ 8.58 (s, 1H), 7.86-7.70 (m, 3H), 7.53 (td, J = 7.8, 0.7 Hz , 1H), 7.44 (d, J = 0.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H ), 6.22 (s, 2H), 5.80 (s, 2H), 3.04 (p, J = 6.9 Hz, 1H), 1.25 (dd, J = 6.9, 0, 9 Hz, 6H).

ESI-MS [M + H] ⁺ for C ₂₃ H ₂₂ N ₈ : theor. 411.2, fact. 411.3.

Example 104. 3- (2-Amino-6- {1 - [(6-isopropyl-2-pyridyl) methyl] -1 H-1,2,3-triazol-4-yl} -4pyrimidinyl) -2-ethoxybenzonitrile

This compound was prepared analogously to example 98 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, acetone-ds) δ 8.72 (d, J = 1.7 Hz, 1H), 8.25-8.18 (m, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.89 (dd, J = 7.7, 2.0 Hz, 1H), 7.82-7.73 (m, 1H), 7.47 (td, J = 7 , 7, 1.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.22 (d,

- 66 038488

J = 7.9 Hz, 1H), 5.84 (d, J = 1.7 Hz, 3H), 4.16 (q, J = 8.0 Hz, 2H), 3.05 (p, J = 6.6 Hz, 1H), 1.38 (td, J = 7.0, 1.8 Hz,

4H), 1.25 (dd, J = 6.9, 1.9 Hz, 6H).

ESI-MS [M + H] + for C ₂₄ H ₂₄ N ₈ O: theor. 441.2, fact. 441.3.

Example 105 m- [2-Amino-6- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

Stage 4

Stage 1. To a suspension of CuCN (2.24 g, 25.0 mmol) in THF (50 ml) at -78 ° C was added t-Bu MgCl (50.0 ml, 50.0 mmol, 1 M in THF). The mixture was stirred at -78 ° C for 30 minutes. The bromopyridine derivative (1.51 g, 5.00 mmol) was added dropwise and the mixture was stirred at -78 ° C for 2 h. The mixture was warmed to room temperature for 14 h and NH ₃ (50 ml, 25% in water ), and then 50 ml of ethyl acetate. The mixture was stirred at room temperature for 30 minutes and filtered to remove solids. The organic phase was dried with a saturated solution of NaCl and MgSO ₄ and passed through a plug of silica gel, eluting with ethyl acetate. The organic phase was evaporated to give the desired product as a yellow oil, which was used directly in the next step.

Steps 2, 3. An azide was synthesized in the same manner as in example 79: colorless oil (253 mg, 27% over 3 steps).

Step 4. The product was synthesized in the same manner as in example 1, step 6: yellow solid (86 mg, 70%).

Ή NMR- (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.63 (s, 1H), 8.50 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.95 (s, 1H), 7.84-7.73 (m, 2H), 7.53-7.33 (m, 1H), 7, 14 (dd, J = 7.7, 0.9Hz, 1H), 5.88 (s, 2H), 1.25 (s, 9H).

ESI-MS [M + H] + for C ₂₃ H ₂₃ N ₈ : theor. 411.2, fact. 411.3.

Example 106 6- (3-Chloro-2-methoxyphenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol4-yl) - 2-pyrimidinylamine

This compound was prepared analogously to example 105 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 7.8, 1.9 Hz, 1H), 7.62-7.55 (m, 1H), 7.49-7.42 (m, 1H), 7.31-7.24 (m, 1H), 7.19-7.11 (m, 1H), 7.01 (d, J = 7.6 Hz, 1H), 5.68 (s, 2H), 5.23 (s, 2H), 3.75 (s, 2H), 1.34 (s, 9H).

ESI-MS [M + H] + for C ₂₃ H ₂₄ ClN ₇ O: theor. 450.2, fact. 450.3.

Example 107 6- (3-Fluoro-2-methoxyphenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol4-yl) - 2-pyrimidinylamine

This compound was prepared analogously to example 105 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (s, 1H), 7.79-7.71 (m, 1H), 7.65-7.57 (m, 2H), 7 , 45-7.36 (m, 2H), 7.28-7.19 (m, 1H), 7.07 (d, J = 7.4Hz, 1H), 6.80 (s, 2H), 5.80 (s, 2H), 3.85 (s, 3H), 1.26 (s, 9H).

ESI-MS [M + H] + for C ₂₃ H ₂₅ FN ₇ O: theor. 434.2, fact. 434.4.

Example 108 3- [2-Amino-6- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] - 2-anisonitrile

- 67 038488

This compound was prepared analogously to example 105 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.07 (dd, J = 7.9, 1.7 Hz, 1H), 7.99-7.95 ( m, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.40 ( d, J = 7.9 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.83 (s, 2H), 3.86 (s, 3H), 1.26 ( s, 9H).

ESI-MS [M + H] + for C ₂₄ H ₂₅ N ₈ O: theor. 441.2, fact. 441.3.

Example 109. 3- [2-Amino-6- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] - 2-fluorobenzonitrile

This compound was prepared analogously to example 105 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.31 (td, J = 7.8, 1.8 Hz, 1H), 8.13-8.07 ( m, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.1 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 5.84 (s, 2H), 1.25 (s, 9H).

ESI-MS [M + H] + for C ₂₃ H ₂₂ FN ₈ : theor. 429.2, fact. 429.3.

Example 110 6- (2,3-Difluorophenyl) -4- (1- {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) 2 -pyrimidinylamine

This compound was prepared analogously to example 105 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, CDCh) δ 8.38 (s, 1H), 7.87 (s, 1H), 7.77-7.70 (m, 1H), 7.60 (dd, J = 8.0, 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.28-7.13 (m, 2H), 7.02 (d, J = 7 , 8 Hz, 1H), 5.69 (s, 2H), 5.17 (brs, 2H), 1.35 (s, 9H).

MS [M + H] + for C22H21F2N7: theor. 422.2, fact. 422.3.

Example 111 6- [2-Amino-6- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] - 2-toluonitrile

This compound was prepared analogously to Example 105 from the corresponding azide and alkyne to give 73 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 7.90 (dt, J = 7.7, 1.3 Hz, 1H), 7.75 (td, J = 7.8, 1.2 Hz, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.46-7.33 (m, 1H), 7.28 (d, J = 1.2 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.90 (s, 2H), 5.81 (s, 2H), 2.55 (d, J = 1.1 Hz, 3H), 1.26 (d, J = 1.3 Hz, 9H).

ESI-MS [M + H] + for C ₂₄ H ₂₄ N ₈ : theor. 425.2, fact. 425.4.

Example 112 6- (m-Fluorophenyl) -4- (1 - {[6-tert-butyl) 2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinylamine

This compound was prepared analogously to example 105 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, CD3OD) 8.64 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H) , 7.74 (s, 1H), 7.67 (t, J = 8 Hz, 1H), 7.47 (q, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H ), 7.20 (dt, J = 8.4 Hz, 1H), 7.1 (d, J = 8.0 Hz, 1H), 5.75 (s, 2H), 1.28 (s, 9H ).

ESI-MS [M + H] + for C22H22FN7: theor. 404.4, fact. 404.4.

Example 113 2- [6 - ({4- [2-Amino-6- (o-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 2-methylpropionitrile

- 68 038488

This compound was prepared analogously to example 1 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, chloroform-d) δ 8.34 (s, 1H), 8.01 (ddd, J = 7.8, 7.8, 1.9 Hz, 1H), 7.92 (d , J = 2.2 Hz, 1H), 7.74 (dd, J = 7.8, 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.48 -7.42 (m, 1H), 7.31-7.22 (m, 1H), 7.22-7.14 (m, 2H), 5.74 (s, 2H), 5.30 (s , 2H), 5.14 (brs, 2H), 1.74 (s, 6H).

MS [M + H] + for C22H17FN8: theor. 415.2, fact. 415.2.

Example 114 5- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -3 - {[6- (tert-butyl) -2-pyridyl] methyl} 3H-1,2,3-triazole -4-carboxylic acid

Stage 2

X = CHO and CO ₂ H

Stage 1. A mixture of chloride (500 mg, 2.17 mmol) and propinol (0.5 ml) in DMF (3 ml) and Et ₃ N (5 ml) was degassed for 5 min. PdCl ₂ (dppf) (79 mg, 5 mol%) and CuI (41 mg, 10 mol%) were added and the mixture was heated to 75 ° C for 1 h. After the usual workup followed by purification on silica gel (hexane / CH ₂ Cl ₂ 1: 1) / EtOAc 100: 0 to 0: 100) gave the desired alkyne (210 mg, 39%).

Step 2. A mixture of an alkyne derivative (70 mg) and an azide derivative (60 mg, 1.1 eq.) Was heated in toluene at 120 ° C for 30 h. Excess solvent was removed in vacuo and the residue was purified on a flash column to give m- {2-amino-6- [5- (hydroxymethyl) -1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl] -4-pyrimidinyl} benzonitrile.

¹ H-NMR (400 MHz, chloroform-d) δ 8.42 (s, 1H), 8.35-8.25 (m, 1H), 8.02 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.64-7.53 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.63 (brs, 1H), 5.73 (s, 2H), 5.23 (s, 2H), 5.07 (brs, 2H), 1.24 (s, 9H).

MS [M + H] ⁺ for C24H24N8O: theor. 441.2, fact. 441.4.

Stage 3. Introduced m- {2-amino-6- [5- (hydroxymethyl) -1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H1,2,3-triazol-4-yl ] -4-pyrimidinyl} benzonitrile (35 mg, 0.08 mmol) in CH ₂ Cl ₂ (3 ml) and MnO ₂ (1.05 g) was added. The resulting mixture was stirred for 24 hours at room temperature. Filtration through celite followed by purification by silica gel chromatography (CH ₂ Cl ₂ / EtOAc 90:10 to 20:80) afforded the corresponding aldehyde (15 mg, 43%) and acid (11 mg, 31%).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.63 (d, J = 7.9 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.84 (dd, J = 7.9, 7.9 Hz, 1H), 7.71 (dd, J = 7.9, 7.9 Hz, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.20 (brs, 2H), 7.13 (d, J = 7.9 Hz, 1H), 6.31 (s, 2H), 1.18 (s, 9H).

MS [M + H] ⁺ for C ₂₄ H ₂₂ N ₈ O ₂ : theor. 455.2, fact. 455.3.

Example 115 m- [2-Amino-6- (1 - {[6- (1-hydroxycyclobutyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -4-pyrimidinyl] benzonitrile

nh ₂

N ^ N

Step 1. A round bottom flask was charged with 2.0 g (6.7 mmol) of a commercially available 2-bromopyridine derivative. To the same flask was added 13.0 ml of anhydrous THF and cooled to -78 ° C under nitrogen atmosphere. 2.7 ml of n-BuLi (2.5 M in THF) was added dropwise to the reaction mixture at -78 ° C and stirred for 30 min. Cyclobutanone (0.58 mL, 7.9 mmol) was then added in one portion and the reaction mixture was warmed to room temperature for 2 h (LCMS indicated formation of the desired adduct). The reaction mixture was again cooled to 0 ° C and 6.7 ml of TBAF (1 M in

- 69 038488

THF). After stirring the reaction for 15 minutes at 0 ° C., 50.0 ml of a saturated aqueous NH4Cl solution was added to quench the reaction. The aqueous layer was extracted with EtOAc (2x50 ml), dried over Na ₂ SO ₄ and evaporated. The crude material was purified by silica gel chromatography to provide the desired pyridine diol (570 mg, 48% over 2 steps).

Stage 2. To a solution of diol (570.0 mg, 3.2 mmol) from stage 1 in CH ₂ Cl ₂ (4.0 ml) were added diphenylphosphorylazide (0.8 ml, 3.8 mmol) and DBU (0.6 ml, 3.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 hours under N ₂ . After removal of CH ₂ Cl _{2, the} residue was redissolved in EtOAc and then washed with H2O (2x25 ml). The organic layer was dried over Na ₂ SO ₄ and evaporated. The crude material was purified by silica gel chromatography to provide the desired azide (450 mg, 69%).

Stage 3. Received the specified compound analogously to example 1 (stage 6) from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, chloroform-d) δ 8.43 (td, J = 1.8, 0.6 Hz, 1H), 8.33 (s, 1H), 8.29 (ddd, J = 8.0, 1.8, 1.2 Hz, 1H), 7.88 (s, 1H), 7.81-7.72 (m, 2H), 7.62-7.54 (m, 2H) , 7.16 (dd, J = 7.6, 0.9Hz, 1H), 5.74 (s, 2H), 5.37 (s, 2H), 5.03 (s, 1H), 2, 68-2.38 (m, 4H), 2.18-2.07 (m, 1H), 1.93-1.75 (m, 1H).

ESI-MS [M + H] + for C ₂₃ H ₂₀ N ₈ O: theor. 425.2, fact. 425.3.

Example 116 m- [2-Amino-6- (1 - {[6- (1-hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -4-pyrimidinyl] benzonitrile

This compound was prepared analogously to example 115 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, chloroform-d) δ 8.46 (td, J = 1.7, 0.6 Hz, 1H), 8.36-8.28 (m, 2H), 7.91 ( s, 1H), 7.807.69 (m, 2H), 7.61 (td, J = 7.8, 0.6 Hz, 1H), 7.39 (dd, J = 8.0, 0.9 Hz , 1H), 7.13 (dd, J = 7.6, 0.9 Hz, 1H), 5.76 (s, 2H), 5.18 (s, 2H), 4.70 (s, 1H) , 2.10-1.78 (m, 8H).

ESI-MS [M + H] + for C ₂₄ H ₂₂ N ₈ O: theor. 439.2, fact. 439.3.

Example 117 1- [6 - ({4- [2-Amino-6- (2,3-difluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl ] cyclopentanol

This compound was prepared analogously to example 115 from the corresponding azide and alkyne.

1 H-NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.78-7.71 (m, 1H), 7.71 (dd, J = 7.9, 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1h), 7.30-7.22 (m, 1H), 7 , 22-7.14 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 5.74 (s, 2H), 5.16 (s, 2H), 2.12- 1.79 (m, 8H).

MS [M + H] + for C23H21F2N7O: theor. 450.2, fact. 450.3.

Example 118 3- [2-Amino-6- (1 - {[6- (1-hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -4-pyrimidinyl] - 2-fluorobenzonitrile

This compound was prepared analogously to example 115 from the corresponding azide and alkyne.

1H-NMR (400 MHz, chloroform-d) δ 8.34 (s, 1H), 8.33-8.22 (m, 1H), 7.92-7.85 (m, 1H), 7.81 -7.61 (m, 2H), 7.47-7.34 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 5.75 (s, 2H), 5, 24 (s, 2H), 4.63 (brs, 1H), 2.13-1.61 (m, 8H).

MS [M + H] + for C ₂₄ H ₂₁ FN ₈ O: theor. 457.2, fact. 457.4.

Example 119 1- [6 - ({4- [2-Amino-6- (o-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] cyclopentanol

This compound was prepared analogously to example 115 from the corresponding azide and alkyne.

1 H-NMR (400 MHz, chloroform-d) δ 8.29 (s, 1H), 8.01 (dd, J = 7.7, 7.7 Hz, 1H), 7.94 (s, 1H), 7.71 (dd, J = 7.4, 7.4Hz, 1H), 7.44 (s, 1H), 7.37 (d, J = 7.7Hz, 1H), 7.22-7 , 14 (m, 1H), 7.10 (d, J = 7.4 Hz, 1H), 5.75 (s, 2H), 5.10 (s, 2H), 4.68 (brs, 1H) , 2.12-1.77 (m, 8H).

MS [M + H] + for C ₂₃ H ₂₂ FN ₇ O: theor. 432.2, fact. 432.3.

- 70 038488

Example 120. 3- {6- [1 - ({6 - [(S) -3-hydroxy-1-pyrrolidinyl] -2-pyridyl} methyl) -1H-1,2,3-triazole-4yl] -2 -amino-4-pyrimidinyl} -2-anisonitrile

Stage 1. Azide (96.2 mg, 0.451 mmol), alkyne (113 mg, 0.451 mmol), CuSO ₄ -5H ₂ O (6 mg, 22.6 mmol, 5 mol%), sodium ascorbate (17.9 mg, 90.3 μmol, 20 mol%) and tBuOH / H ₂ O 2: 1 (1.81 ml, 0.25 M). The resulting mixture was heated at 55 ° C for 2 hours. The mixture was then cooled to room temperature and diluted with CH ₂ Cl ₂ (3 ml). The phases were separated and the aqueous phase was again extracted with CH ₂ Cl ₂ (3 ml). The combined organic extracts were evaporated in vacuo. The crude residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH gradient) to afford the product (176 mg, 84% yield) as a beige solid.

Stage 2. Bromopyridine substrate (20.0 mg, 43.1 μmol, 1.0 eq.), (S) -3-hydroxypyrrolidine (4.50 mg, 51.7 μmol, 1.2 eq.), NaOtBu (8.30 mg, 86.2 μmol, 2.0 eq.), Pd-G3 precatalyst (300 μg, 0.431 μmol, 1 mol.%), BrettPhos (200 μg, 0.431 μmol, 1 mol%) and dioxane (100 μL, 0.45 M). The resulting mixture was degassed by evacuating and starting again with N ₂ (3x), and then stirred at 100 ° C for 3 h. After that, the reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through celite. The filtrate was evaporated in vacuo and the crude residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH gradient) to give the product (5 mg, 25% yield) as an off-white solid.

¹ H-NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 8.03-7.97 (m, 1H), 7.90 (s, 1H), 7.70-7, 63 (m, 1H), 7.46-7.35 (m, 1H), 7.32-7.26 (m, 1H), 6.50 (d, J = 7.2 Hz, 1H), 6 , 32 (d, J = 8.5 Hz, 1H), 5.52 (s, 2H), 5.16 (s, 2H), 4.67-4.55 (m, 1H), 3.94 ( s, 3H), 3.65-3.50 (m, 4H), 2.22-2.06 (m, 2H).

LC-MS: retention time 2.32 min, method A; ESI-MS [M + H +] for C ₂₄ H ₂₄ N ₉ O ₂ : theor. 470.2, fact. 470.3.

Example 121 3- {6- [1 - ({6 - [(R) -3-Hydroxy-1-pyrrolidinyl] -2-pyridyl} methyl) -1H-1,2,3-triazole-4yl] -2 -amino-4-pyrimidinyl} -2-anisonitrile

This compound was prepared analogously to example 120 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 8.01 (dd, J = 7.6, 1.7 Hz, 1H), 7.89 (s, 1H) , 7.72-7.64 (m, 1H), 7.45-7.38 (m, 1H), 7.31-7.26 (m, 1H), 6.50 (d, J = 7, 1 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.52 (s, 2H), 5.16 (s, 2H), 4.65-4.59 (m, 1H), 3.93 (s, 3H), 3.64-3.51 (m, 4H), 2.20-2.07 (m, 2H).

LC-MS: retention time 2.32 min, method A; ESI-MS [M + H] ⁺ for C ₂₄ H ₂₄ N ₉ O ₂ : theor. 470.2, fact. 470.4.

Example 122 1 - {[6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] carbonyl} -4-piperidinecarboxylic acid

- 71 038488

Stage 1. Cycloaddition was carried out in the same manner as in stage 6 of example 1, obtaining methyl-6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -III-1,2, 3-triazol-1-yl} methyl) -2pyridinecarboxylate.

'll-NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.59 (dt, J = 1.8, 1.0 Hz, 1H), 8.48 (ddd, J = 8.0, 1.8, 1.1 Hz, 1H), 8.09-8.03 (m, 2H), 8.00 (dt, J = 7.7, 1.3 Hz, 1H), 7 , 82 (s, 1H), 7.78-7.72 (m, 1H), 7.55 (dd, J = 6.5, 2.3Hz, 1H), 6.95 (s, 2H), 5.94 (s, 2H), 3.88 (s, 3H).

ESI-MS [M + H] + for C ₂₁ H ₁₆ N ₈ O ₂ : theor. 413.1, fact. 413.2.

Stage 2. Into a solution of methyl 6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -III-1,2,3-triazole-1yl} methyl) -2-pyridinecarboxylate ( 10 mg, 0.024 mmol) in t-BuOH (0.2 ml) and H2O (0.1 ml), LiOH H2O (1.5 mg, 0.036 mmol, 1.5 eq.) Was added at room temperature. The mixture was stirred overnight and washed with MTBE. The reaction was quenched by the addition of 1M HCl (about 50 μl), extracted with EtOAc and evaporated to give 9.7 mg of the compound as a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.61 (td, J = 1.8, 0.6 Hz, 1H), 8.49 (ddd, J = 8.0, 1.9, 1 , 1 Hz, 1H), 8.13-7.99 (m, 3H), 7.89 (s, 1H), 7.84-7.71 (m, 1H), 7.55 (dd, J = 6.8, 2.1 Hz, 1H), 5.95 (s, 2H), 5.36 (bs, 3H).

ESI-MS [M + H] ⁺ for C20H14N ₈ O2: theor. 399.1, fact. 399.2.

Stage 3. A mixture of the acid obtained above (30 mg, 0.075 mmol), amine (50 mg, 0.15 mmol), pyridine (0.5 ml) and T ₃ R (0.2 ml) was stirred at 50 ° C for 1 h. The mixture was loaded directly onto silica gel for purification (CH ₂ Cl ₂ : MeOH 100: 0 to 95: 5) to give the amide (35 mg, 90%). Hydrolysis of this ester yielded the desired acid (23 mg, 66%).

¹ H-NMR (400 MHz, acetone-d6) δ 8.63 (s, 1H), 8.58 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.98 (dd, J = 8.0, 8.0 Hz, 1H), 7.94-7.86 (m, 1H), 7.89 (s, 1H), 7.75 (dd, J = 8.0 , 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 6.30 (brs, 1H), 5.91 (s, 2H), 4.48-4.39 (m, 1H), 3.84-3.75 (m, 1H), 3.15-2.95 (m, 2H), 2, 69-2.57 (m, 1H), 2.06-1.84 (m, 3H), 1.73-1.59 (m, 2H).

MS [M + H] ⁺ for C26H23N9O3: theor. 510.2, fact. 510.3.

Example 123 6- ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) nicotinic acid

Stage 1. Methyl 6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) nicotinate was synthesized analogously to example 122.

¹ H-NMR (400 MHz, chloroform-d) δ 9.22 (dd, J = 2.1, 0.9 Hz, 1H), 8.46 (s, 1H), 8.40 (s, 1H) , 8.32 (dd, J = 8.1, 2.1 Hz, 2H), 7.91 (s, 1H), 7.77 (dt, J = 7.7, 1.4 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.37-7.30 (m, 1H), 5.81 (s, 2H), 5.23 (s, 2H), 3.96 (s, 3H).

ESI-MS [M + H] ⁺ for C21H16N ₈ O2: theor. 413.1, fact. 413.2.

Step 2. Saponification of methyl 6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) nicotinate gave the title compound.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.10-8.94 (m, 1H), 8.81 (s, 1H), 8.61 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.33 (dd, J = 8.1, 2.2 Hz, 1H), 8.02 (dd, J = 7.8, 1.4 Hz, 1H), 7.86 (s, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 5.98 (s, 2H).

ESI-MS [M + H] ⁺ for C20H14N ₈ O2: theor. 399.1, fact. 399.2.

Example 124 2 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) iso nicotinic acid

- 72 038488

Stage 1. Methyl 2 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) isonicotinate was synthesized analogously to example 122, obtaining 88 mg tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.83-8.71 (m, 2H), 8.59 (t, J = 1.6 Hz, 1H), 8.47 (dt, J = 8.2, 1.3 Hz, 1H), 8.00 (dt, J = 7.8, 1.3 Hz, 1H), 7.88 (t, J = 1.2 Hz, 1H), 7, 84-7.80 (m, 2H), 7.74 (t, J = 7.9 Hz, 1H), 6.93 (s, 2H), 5.98 (s, 2H), 3.90 (s , 3H).

ESI-MS [M + H] + for C ₂₁ H ₁₆ N ₈ O ₂ : theor. 413.1, fact. 413.2.

Step 2. Saponification of methyl 2 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) isonicotinate gave the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 8.75 (d, J = 5.0 Hz, 1H), 8.62 (t, J = 1.7 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.90 (s, 1H), 7.85 ( s, 1H), 7.84-7.71 (m, 2H), 6.00 (s, 2H), 5.44 (bs, 3H).

ESI-MS [M + H] ⁺ for C20H14N8O2: theor. 399.1, fact. 399.2.

Example 125 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] propionic acid

Stage 1. The azide derivative was synthesized in the same way as in Stage 5 of Example 1. From 500 mg (2.6 mmol) of alcohol, the desired azide (265 mg, 46%) was obtained after chromatography on silica gel (hexane / EtOAc 90:10 to 70:30 ).

Stage 2. Cycloaddition of the azide and alkyne derivatives was carried out in the same way as in stage 6 of example 1 to obtain methyl 3- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1, 2,3-triazole-1yl} methyl) -2-pyridyl] propionate.

¹ H-NMR (400 MHz, chloroform-d) δ 8.46 (ddd, J = 1.7, 1.7, 0.6 Hz, 1H), 8.35 (s, 1H), 8.32 ( ddd, J = 8.0, 1.9, 1.2 Hz, 1H), 7.90 (s, 1H), 7.76 (ddd, J = 7.7, 1.7, 1.2 Hz, 1H), 7.71-7.52 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 (m, J = 8.0 Hz, 1H), 5, 67 (s, 2H), 5.16 (s, 2H), 3.66 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7 , 3 Hz, 2H).

MS [M + H] ⁺ for C23H20N8O2: theor. 441.2, fact. 441.3.

Stage 3. To a solution of methyl ether (45 mg, 0.1 mmol) in THF (1 ml) was added an aqueous solution of LiOH (0.2 ml, 1 M). The resulting mixture was vigorously stirred at room temperature for 6 hours. Then it was quenched by the addition of acetic acid (excess) and evaporated on silica. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ / MeOH 100: 0 to 90:10) to give 3- [6 - ({4- [2amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H -1,2,3-triazol-1-yl} methyl) -2-pyridyl] propionic acid (40 mg, 95%).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.60 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.77 (dd, J = 7.7, 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 5.82 (s, 1H), 2.96 (t, J = 7.2 Hz, 2H), 2 , 64 (t, J = 7.2 Hz, 2H).

MS [M + H] ⁺ for C22H18N8O2: theor. 427.2, fact. 427.2.

Example 126 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 2,2-dimethylpropionic acid

- 73 038488

Step 1. To a mixture of alcohol (781 mg, 4 mmol) and imidazole (465 mg, 8 mmol) in CH2C12 (15 ml) was added TBSCl (723 mg, 4.8 mmol). After complete conversion of the starting material, silica was added and the resulting mixture was evaporated to dryness. Purification by silica gel chromatography (hexane / EtOAc 95: 5 to 80:20) afforded the silyl ether as a pale yellow oil (1.14 g, 92%).

Step 2. A mixture of ester (1.5 g, 5 mmol) in THF (8 ml) was treated with LiHMDS (1 M in THF, 12 ml) at -78 ° C. The solution was stirred for 20 min at the same temperature and MeI (13 mmol) was added. The mixture was stirred from -78 ° C to room temperature overnight. After the usual work-up, the residue was purified by silica gel chromatography (hexane / EtOAc 95: 5 to 85:15) to give the dialkylated ether (350 mg, 21%). Silyl ether (350 mg, 1.05 mmol) was dissolved in THF (2 ml) and acetic acid (20 μl) was added followed by TBAF (1 M in THF, 2 ml). The mixture was stirred for 2 h at room temperature and after the usual work-up, the residue was purified by silica gel chromatography (CH ₂ Cl ₂ / Hexane (1: 1) / EtOAc 95: 5 to 70:30) to give the primary alcohol (95 mg, 40%).

Stage 3. The synthesis of the azide derivative was carried out in the same way as in stage 5 of example 1 (100 mg, 94%).

Step 4. Cycloaddition was carried out in the same manner as in Step 6 of Example 1, and the resulting ester was hydrolyzed analogously to Example 125 to give the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.82 (s, 1H), 8.62 (s, 1H), 8.58 (d, J = 7.9 Hz, 1H), 7, 90-7.99 (m, 2H),

7.70-7.82 (m, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 7.9 Hz, 1H), 6.27 (brs , 2H), 5.79 (s, 2H), 2.63 (s, 2H), 1.30 (s, 6H).

MS [M + H] + for C24H22N8O2: theor. 455.2, fact. 455.3.

Example 127 3 - [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2 pyridyl] butyric acid

2. LiOH _: THF

Stage 1. A mixture of phosphonate (1.48 g, 6.6 mmol) in THF (10 ml) was treated with NaH (60% in mineral oil, 264 mg, 6.6 mmol) and after 10 min a ketone solution (1.59 d, 6 mmol) in THF (2 ml). The resulting mixture was stirred overnight; Celite was added and the mixture was evaporated to dryness and then purified by chromatography on silica gel (hexane / EtOAc 95: 5 to 80:20) to give a mixture of Z: E α, β-unsaturated ether (1.22 g, 61%).

Pd / C (10%, 60 mg) was added to a degassed solution of α, β-unsaturated ether (660 mg, 1.96 mmol) in THF (10 ml). The suspension was placed under H ₂ ( _r ) and stirred for 4 h. After filtration through celite and evaporation of the solvent to dryness, the reduced alkane (660 mg, quant.) Was obtained.

Stage 2. The azide derivative was synthesized analogously to example 79 (468 mg, 96% in 2 stages).

Step 3. Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to obtain the title compound.

- 74 038488

1H-NMR (400 MHz, DMSO-d6) δ 12.04 (brs, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J = 7.8, 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.88 (s, 2H), 5.79 (s, 2H), 3.33-3.19 (m, 1H), 2.67 (dd, J = 15.8, 7.2 Hz, 1H), 2.44 (dd, J = 15.8, 7.3 Hz, 1H), 2.52-2.38 (m, 4H), 1.16 (d, J = 7.0 Hz, 3H).

MS [M + H] + for C23H20N8O2: theor. 441.2, fact. 441.3.

Example 128 3- [6 - ({4- [2-Amino-6- (2,3-difluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl ] butyric acid

Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to obtain the title compound.

¹ H-NMR (400 MHz, acetone ^) δ 8.61 (s, 1H), 7.93-7.85 (m, 1H), 7.84 (s, 1H), 7.75 (dd, J = 7.8, 7.8 Hz, 1H), 7.53-7.41 (m, 1H), 7.38-7.31 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 6.27 (brs, 2H), 5.80 (s, 2H), 3.40 (qt, J = 7.0 , 6.6 Hz, 1H), 2.85 (dd, J = 15.8, 7.7 Hz, 1H), 2.59 (dd, J = 15.8, 6.8 Hz, 1H), 2 , 08 (s, 2H), 1.29 (dd, J = 7.0 Hz, 3H).

MS [M + H] ⁺ for C ₂₂ H ₂₁ F ₂ N ₇ O ₂ : theor. 452.2, fact. 452.3.

Example 129 2- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] cyclopropanecarboxylic acid

2. LiOH, THF

Stage 3

Step 1. A solution of Me ₃ SOI (1.93 g, 8.75 mmol) in DMSO (8 ml) was treated with NaH (60% in mineral oil, 320 mg, 8 mmol). The resulting mixture was stirred for 30 min and then a solution of α, β-unsaturated ether (1.5 g, 4.9 mmol) in DMSO (4 ml) was added. The resulting mixture was stirred at 50 ° C for 2 h and then worked up (EtOAc / H ₂ O). The residue obtained after evaporation of the organic layers was purified by silica gel chromatography (hexane / EtOAc 95: 5 to 85:15) to give the cyclopropyl derivative (500 mg, cis / trans 65:35, 32%). Silyl ether (500 mg, 3.1 mmol) was dissolved in THF (3 ml) and acetic acid (40 μl) was added followed by TBAF (1 M in THF, 3 ml). The mixture was stirred for 2 h at room temperature, and after the usual work-up, the residue was purified by chromatography on silica gel (CH ₂ Cl ₂ / hexane (1: 1) / EtOAc 95: 5 to 50:50) to give the primary alcohol (320 mg, cis / trans-isomers 65:35, quant.).

Stage 2. The azide derivative was synthesized in the same way as in stage 5 of example 1 (275 mg, 76%, isomer mixture 65:35).

Step 3. Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to obtain the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (brs, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.45 (dd, J = 8 , 0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.77-7.67 (m, 2H), 7.38 (d , J = 8.0 Hz, 1H), 7.10 (dt, J = 8.0 Hz, 1H), 6.88 (brs, 2H), 5.75 (s, 2H), 2.59-2 , 51 (m, 1H), 1.94-1.84 (m, 1H), 1.43-1.28 (m, 1H).

MS [M + H] ⁺ for C ₂₃ H ₁₈ N ₈ O ₂ : theor. 439.2, fact. 439.3.

Example 130 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-methylbutyric acid

- 75 038488

Stage 1. A solution of n-butyllithium (144 ml, 360 mmol, 2.5 M in hexane) in ether (120 ml) was cooled to -78 ° C and 2-bromo-6-methylpyridine (41.0 ml, 360 mmol). The reaction mixture was warmed to 0 ° C and stirred at this temperature for 15 minutes. In a separate flask, dibutyl sulfide (54.5 ml, 312 mmol) and copper (I) iodide (34.3 g, 180 mmol) were mixed and the mixture was stirred for 5 min until smooth. Ether (240 ml) was added, the solution was cooled to 0 ° C and the above pyridine solution was added dropwise. The mixture was stirred for an additional 20 min at 0 ° C, after which a solution of acrylate (16.7 g, 120 mmol) in ether (120 ml) was added. The reaction mixture was warmed to room temperature over 14 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2x200 ml), washed with saturated NaCl solution and dried over sodium sulfate. The crude product was purified by silica gel chromatography (0 to 20% EtOAc in hexanes) to give the desired Michael adduct as a brown oil (16.44 g; 59%).

Stage 2. A mixture of the product from stage 1 (16.44 g, 70.8 mmol), sodium chloride (1.24 g, 21.2 mmol), water (1.42 ml) and DMSO (71 ml) was stirred at 160 ° C for 3 h. The reaction mixture was cooled, MTBE (500 ml) was added, the organic phase was washed with water (4x400 ml) and dried over sodium sulfate. The crude material was dissolved in 3.0 M HCl in methanol (236 ml) and stirred at 50 ° C for 60 hours. The reaction mixture was slowly quenched with sodium bicarbonate solution, filtered and evaporated. The crude product was purified by silica gel chromatography (7.5% EtOAc in hexane) to give the desired product as a colorless oil (8.73 g; 59%).

Stage 3. To a solution of the product from stage 2 (8.73 g, 42.1 mmol) in dichloromethane (168 ml) at 0 ° C was slowly added m-CPBA (19.9 g, 84.2 mmol, 75% in water ) in solid form for 5 min. The reaction mixture was stirred at 0 ° С for 1 h and at room temperature for 14 h. The organic layer was washed with 0.1 M NaOH solution, dried over sodium sulfate and evaporated. The crude material was redissolved in dichloromethane (84 ml), cooled to 0 ° C. and TFAA (59 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was slowly quenched with saturated Na ₂ CO ₃ solution and extracted with ethyl acetate (3x200 ml). The crude product was purified by silica gel chromatography (0 to 75% EtOAc in hexanes) to afford the desired product as a red oil (5.55 g; 59%).

Step 4. To a mixture of the product from Step 3 (5.55 g, 24.9 mmol), DPPA (6.42 g, 29.8 mmol) and toluene (25 ml) was added DBU (4.46 ml, 29.8 mmol). The reaction mixture was stirred at room temperature for 14 hours. The mixture was purified by silica gel chromatography (0 to 20% EtOAc in hexanes) to give the desired product as a colorless oil (5.53 g; 89%).

Step 5. Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to give the title compound as a white solid (33 mg, 24%).

¹ H-NMR (400 MHz, DMSO-d6) δ 11.86 (br s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.47 (d, J = 8 , 3 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.82 (s, 1H), 7.79-7.69 (m, 2H), 7.38 (d , J = 7.9 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.91 (s, 2H), 5.80 (s, 2H), 2.65 (s , 2H), 1.32 (s, 6H).

ESI-MS [M + H] + for C ₂₄ H ₂₃ N ₈ O ₂ : theor. 455.2, fact. 455.3.

Example 131 3- [6 - ({4- [2-Amino-6- (3-cyano-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2 -pyridyl] -3-methylbutyric acid

- 76 038488

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

1-NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 8.10-8.04 (m, 1H), 7.97-7.90 (m, 1H), 7, 67-7.61 (m, 2H), 7.43 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.90 (s, 2H), 5.76 (s, 2H), 3.85 (s, 3H), 2.31 (s, 2H), 1.32 (s , 6H).

ESI-MS [M + H] + for C ₂ 5H25N ₈ O3: theor. 485.2, fact. 485.3.

Example 132. 3- [6 - ({4- [2-Amino-6- (3-fluoro-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1yl} methyl) -2 -pyridyl] -3-methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

-NMR (400 MHz, DMSO-d6) δ 11.87 (brs, 1H), 8.63 (s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.64 ( s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.45-7.40 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.23 (td, J = 8.0, 5.1 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.79 (s, 2H), 5.79 (s , 2H), 3.84 (s, 3H), 2.66 (s, 2H), 1.33 (s, 6H).

ESI-MS [M + H] + for C ₂₄ H ₂₅ FN ₇ O ₃ : theor. 478.2, fact. 478.2.

Example 133 3- [6 - ({4- [2-Amino-6- (2,3-difluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl ] -3-methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

-NMR (400 MHz, acetone-d6) δ 8.61 (s, 1H), 7.93-7.85 (m, 1H), 7.84 (s, 1H), 7.79 (dd, J = 7.8, 7.8 Hz, 1H), 7.53-7.41 (m, 2H), 7.40-7.29 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.26 (s, 2H), 5.81 (s, 2H), 2.70 (s, 2H), 1.44 (s, 6H).

MS [M + H] + for C23H21F2N7O2: theor. 466.2, fact. 466.3.

Example 134. 3- [6 - ({4- [2-Amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) - 2-pyridyl] -3-methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

-NMR (400 MHz, DMSO-d6) δ 11.79 (brs, 1H), 8.66 (s, 1H), 8.34-8.24 (m, 1H), 8.07 (ddd, J = 7.7, 6.0, 1.9 Hz, 1H), 7.73 (dd, J = 7.8, 7.8 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.56 (dd, J = 7.8, 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 7.8 Hz, 1H), 6.95 (s, 2H), 5.78 (s, 2H), 2.63 (s, 2H), 1.30 (s, 6H).

MS [M + H] + for C ₂₄ H ₂₁ FN ₈ O ₂ : theor. 471.2, fact. 471.2.

Example 135 3- [6 - ({4- [2-Amino-6- (2-chloro-3-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1yl} methyl) -2 -pyridyl] -3-methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

-NMR (400 MHz, acetone-d6) δ 10.71 (brs, 1H), 8.62 (s, 1H), 7.99 (dd, J = 7.7, 1.7 Hz, 1H), 7.94 (dd, J = 7.8, 1.7 Hz, 1H), 7.78 (dd, J = 7.8, 7.8 Hz, 1H), 7.69 (dd, J = 7, 8 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.37 (brs, 2H), 5.80 (s, 2H), 2.81 (s, 2H), 1.43 (s, 6H).

MS [M + H] + for C24H21ClN ₈ O2: theor. 489.1, fact. 489.2.

Example 136 3- [6 - ({4- [2-Amino-6- (3-cyanotolyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-methylbutyric acid

This compound was prepared analogously to Example 130 from the corresponding azide and alkyne to give 73 mg of a tan solid.

L-NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.66 (d, J = 0.7 Hz, 1H), 7.89 (dd, J = 7.7, 1 , 4 Hz, 1H), 7.807.69 (m, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.27 (d , J = 0.5 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.87 (s,

- 77 038488

2H), 5.79 (s, 2H), 2.65 (s, 2H), 2.55 (s, 3H), 1.33 (s, 6H).

ESI-MS [M + H] + for C ₂₅ H ₂₄ N ₈ O ₂ : theor. 469.2, fact. 469.3.

Example 137.3- [6 - ({4- [2-Amino-6- (o-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] -3- methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, acetone ^) δ 8.59 (d, J = 1.1 Hz, 1H), 8.12 (tt, J = 7.9, 1.5 Hz, 1H), 7.87 (dd, J = 2.4, 1.2 Hz, 1H), 7.78 (td, J = 7.9, 1.1 Hz, 1H), 7.55 (dd, J = 8.2, 7 , 1 Hz, 1H), 7.46 (dd, J = 8.0, 1.1 Hz, 1H), 7.39-7.24 (m, 2H), 7.21 (dt, J = 7, 6, 1.0 Hz, 1H), 6.22 (s, 2H), 5.80 (s, 2H), 3.31 (s, 2H), 2.05 (p, J = 2.2 Hz, 1H), 1.44 (s, 6H).

ESI-MS [M + H] + for C23H22FN7O2: theor. 448.2, fact. 448.3.

Example 138 3- [6 - ({4- [2-Amino-6- (m-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

-NMR (400 MHz, acetone-d6) δ 8.98 (s, 1H), 8.14-8.06 (m, 1H), 8.06-7.97 (m, 2H), 7.80 (td, J = 7.9, 1.3 Hz, 1H), 7.71-7.60 (m, 1H), 7.50-7.37 (m, 2H), 7.33-7.26 (m, 1H), 6.67 (s, 1H), 5.87 (d, J = 1.2 Hz, 2H), 2.79 (s, 2H), 1.41 (s, 6H).

ESI-MS [M + H] + for C23H22FN7O2: theor. 448.2, fact. 448.3.

Example 139 3- [6 - ({4- [2-Amino-6- (3,4-difluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl ] -3-methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

-NMR (400 MHz, acetone-d ₆ ) δ 8.95 (d, J = 1.3 Hz, 1H), 8.25 (ddt, J = 11.7, 7.8, 1.8 Hz, 1H), 8.21-8.12 (m, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.80 (td, J = 7.9, 1.5 Hz, 1H ), 7.56 (dtd, J = 10.1, 8.5, 1.4 Hz, 1H), 7.46 (dt, J = 8.0, 1.2 Hz, 1H), 7.33- 7.25 (m, 1H), 5.86 (s, 2H), 2.08-2.01 (m, 3H), 1.41 (d, J = 1.4Hz, 6H).

ESI-MS [M + H] + for C23H21F2N7O2: theor. 466.2, fact. 466.3.

Example 140. 3- [6 - ({4- [2-Amino-6- (2,5-difluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl ] -3-methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, acetone-d ₆ ) δ 8.75 (s, 1H), 7.98-7.85 (m, 2H), 7.79 (td, J = 7.9, 1.7 Hz, 1H), 7.50-7.42 (m, 1H), 7.43-7.34 (m, 2H), 7.24 (d, J = 7.5 Hz, 1H), 5.83 (s, 2H), 2.80 (s, 2H), 1.43 (s, 6H).

ESI-MS [M + H] + for C23H21F2N7O2: theor. 466.2, fact. 466.2.

Example 141 3- [6 - ({4- [2-Amino-6- (3-chloro-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) - 2-pyridyl] -3-methylbutyric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, chloroform-d) δ 8.57 (s, 1H), 7.89 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.60 ( dd, J = 7.9, 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 1.7 Hz, 1H), 7.42-7.38 (m, 1H), 7 , 23 (d, J = 7.6 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 5.78 (s, 2H), 5.65 (s, 2H), 3 , 73 (s, 3H), 2.82 (s, 2H), 1.50 (s, 6H).

ESI-MS [M + H] + for C24H24CMO3: theor. 494.2, fact. 494.2.

Example 142. 3- [6 - ({4- [2-Amino-6- (3-cyano-2-ethoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) - 2-pyridyl] -3-methylbutyric acid

- 78 038488

3- [6 - ({4- [2-amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -SH-1,2,3-triazol-1yl} methyl) -2-pyridyl ] -3-methylbutyric acid (22 mg, 0.044 mmol) in EtOH (1 ml) and excess EtONa was added. The reaction mixture was stirred at 45 ° C overnight and then quenched with excess acetic acid. After evaporating the solvents, the residue was purified by silica gel chromatography (CH ₂ Cl ₂ / MeOH 100: 0 to 90:10) to give the desired compound (14 mg, 60%).

¹ H-NMR (400 MHz, acetone ^) δ 8.61 (s, 1H), 8.20 (dd, J = 7.9, 1.4 Hz, 1H), 7.99 (s, 1H), 7.85 (dd, J = 7.7Hz, J = 1.8Hz, 1H), 7.79 (dd, J = 7.9, 7.7Hz, 1H), 7.50-7.39 (m, 2H), 7.23 (dd, J = 7.7 Hz, 2H), 6.27 (brs, 2H), 5.80 (s, 2H), 4.11 (q, J = 7, 0 Hz, 1H), 2.80 (s, 2H), 1.43 (s, 6H), 1.37 (t, J = 7.0 Hz, 3H).

MS [MH] ^- for C26H26N8O3: theor. 497.2, fact. 497.3.

Example 143. 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -5-methyl-1H-1,2,3-triazole-1yl} methyl) -2 -pyridyl] -3-methylbutyric acid

Cycloaddition and hydrolysis reactions were carried out as in Examples 114 and 125, respectively, to obtain the title compound.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 7.9 Hz , 1H), 7.84 (s, 1H), 7.80-7.71 (m, 2H), 7.35 (d, J = 7.9 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 5.77 (s, 2H), 2.74 (s, 3H), 2.58 (s, 2H), 1.24 (s, 6H).

MS [M + H] + for C ₂₅ H ₂₄ N ₈ O ₂ : theor. 469.2, fact. 469.3.

Example 144. 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-ethylvaleric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.62 (s, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.96 (s, 1H), 7.82-7.73 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H) , 7.15 (d, J = 7.8 Hz, 1H), 5.86 (s, 2H), 2.66 (s, 2H), 1.75 (q, J = 7.2 Hz, 4H) , 0.54 (t, J = 7.2 Hz, 6H).

MS [M + H] + for C ₂₆ H ₂₆ N ₈ O ₂ : theor. 483.2, fact. 483.3.

Example 145 3- [6 - ({4- [2-Amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2 -pyridyl] -3-methylvaleric acid

Stage 1. A mixture of methyl cyanoacetate (24.8 g, 250 mmol), 2-butanone (112 ml, 1.25 mol), ammonium acetate (1.93 g, 25.0 mmol) and acetic acid (2.86 ml) (50.0 mmol) was stirred at 75 ° C for 4 h. Excess 2-butanone was removed under reduced pressure and the crude material was dissolved in MTBE. The organic phase was washed with saturated aqueous NaHCO ₃ and dried over Na ₂ SO ₄ . The crude product was purified by silica gel chromatography (0 to 30% EtOAc in hexanes) to afford the desired product as a colorless oil (23.53 g; 61%).

Stages 2-5. An azide was synthesized in the same manner as in example 130: colorless oil (3.77 g, 25% over 4 steps).

Step 6. Prepared the title compound in analogy to example 130 from the appropriate azide and alkyne to give an off-white solid (24 mg, 23%).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.35-8.28 (m, 1H), 8.11-8.05 (m, 1H), 7, 67 (t, J = 7.8 Hz, 1H), 7.64-7.61 (m, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.98 (s, 2H), 5.78

- 79 038488 (s, 2H), 2.57 (d, J = 14.6 Hz, 1H), 2.35 (d, J = 14.6 Hz, 1H), 1.80-1.70 (m , 1H), 1.70-1.57 (m, 1H), 1.34 (s, 3H),

0.50 (t, J = 8.0 Hz, 3H).

ESI-MS [M + H] + for C25H24FN8O2: theor. 487.2, fact. 487.3.

Example 146. 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-methylvaleric acid

This compound was prepared analogously to example 130 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.65-8.58 (m, 1H), 8.51-8.45 (m, 1H), 8, 03 (dt, J = 7.7, 1.3 Hz, 1H), 7.88 (s, 1H), 7.76 (td, J = 7.8, 1.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 5.83 (s, 2H), 2.81 (d, J = 15.2 Hz , 1H), 2.50 (d, J = 15.2 Hz, 1H), 1.71 (dq, J = 14.6, 7.3 Hz, 1H), 1.60 (dq, J = 14, 3, 7.3 Hz, 1H), 1.35 (s, 3H), 0.53 (t, J = 7.4 Hz, 3H).

ESI-MS [M + H] + for C25H25N8O2: theor. 469.2, fact. 469.3.

Example 147. (S) -3- [6 - ({4- [2-Amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl } methyl) -2-pyridyl] -3-methylvaleric acid.

Example 148 (R) -3- [6 - ({4- [2-Amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl] -3-methylvaleric acid but

but

Example 148

Stage 1. Obtained in example 145 methyl-3- [6 - ({4- [2-amino-6- (3-cyano-2-fluorophenyl) -4pyrimidinyl] -1H-1,2,3-triazole-1- yl} methyl) -2-pyridyl] -3-methylvalerate was separated by chiral HPLC (AD-H; ethanol + 0.5% DEA / CO ₂ ) to give the desired chiral esters as white solids - enantiomer 147A (170 mg, 45%) and enantiomer 148B (174 mg, 46%).

Stage 2. Conducted hydrolysis of the enantiomeric esters (147A and 148B) in the same way as in example 125, obtaining the indicated compounds (examples 147 and 148).

Example 147. White solid (86 mg, 52%).

¹ H-NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H), 8.66 (s, 1H), 8.31 (td, J = 7.8, 1.8 Hz, 1H), 8.12-8.05 (m, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.57 (t , J = 7.8 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.96 (s, 2H ), 5.80 (s, 2H), 2.79 (d, J = 15.1 Hz, 1H), 2.50 (d, J = 15.1 Hz, 1H), 1.79-1.66 (m, 1H), 1.66-1.55 (m, 1H), 1.35 (s, 3H), 0.53 (t, J = 7.4 Hz, 3H).

ESI-MS [MH] ^- for C ₂₅ H ₂₂ FN ₈ O ₂ : theor. 485.2, fact. 485.2.

Example 148 White solid (89 mg, 53%).

¹ H-NMR (400 MHz, DMSO-d6) δ 11.84 (brs, 1H), 8.66 (s, 1H), 8.35-8.27 (m, 1H), 8.13-8.04 ( m, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.96 (s, 2H), 5.80 (s, 2H), 2.79 (d, J = 15.1 Hz, 1H), 2.50 (d, J = 15.0 Hz, 1H), 1.78-1.66 (m, 1H), 1, 66-1.55 (m, 1H), 1.35 (s, 3H), 0.53 (t, J = 7.4Hz, 3H).

ESI-MS [MH] ^- for C ₂ 5H ₂₂ FN8O ₂ : theor. 485.2, fact. 485.3.

Example 149. {1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] cyclobutyl} acetic acid

- 80 038488

Stage 1. Into a solution of n-BuLi (2.5 M in hexane, 5.4 ml, 13.5 mmol, 1.5 eq.) In Et ₂ O (4.5 ml) under N2 at -78 ° С 2-bromo-6-methylpyridine (1.5 ml, 13.5 mmol, 1.5 eq.) was added slowly dropwise. In a separate flask, dibutyl sulfide (2.6 ml, 13.5 mmol, 1.5 eq.) And CuI (1.3 g, 6.8 mmol, 0.75 eq.) Were mixed under N2, stirred for 15 min. , and then introduced into Et ₂ O (11.3 ml) and cooled to 0 ° C. After 15 min, a solution of 2-bromo-6-methylpyridine was slowly introduced through a cannula into a flask containing dibutyl sulfide and CuI. The resulting mixture was stirred at 0 ° C for 20 minutes. Thereafter, a solution of methyl cyanocyclobutylidene acetate (1.4 g, 9.0 mmol, 1.0 eq.) In Et ₂ O (9.0 ml) was added to the reaction mixture at 0 ° C. Upon completion of the addition, the reaction was warmed to room temperature. After 20 h, the reaction mixture was cooled to 0 ° C and quenched by the addition of saturated aqueous NH ₄ Cl (50 ml). The biphasic mixture was diluted with EtOAc (560 ml) and transferred to a separatory funnel. Collected the organic phase and the aqueous phase was extracted with EtOAc (2x30 ml). The combined organic extracts were dried over MgSO ₄ and evaporated in vacuo. The resulting residue was purified by column chromatography (EtOAc: hexane 1: 9 => 2: 3) to give methyl cyano [1- (6-methyl-2-pyridyl) cyclobutyl] acetate (535 mg, 24% yield).

Stage 2. A solution of methyl-cyano [1- (6-methyl-2-pyridyl) cyclobutyl] acetate (535 mg, 2.2 mmol, 1.0 eq.) And NaCl (38 mg, 0.65 mmol, 0, 3 eq.) In DMSO (2.2 ml, 1.0 M) and H ₂ O (45 μl) was heated to 160 ° C for 3.5 h. After that, the reaction mixture was cooled to room temperature and diluted with MTBE (10 ml) and H2O (10 ml). Collected the organic phase and the aqueous phase was extracted with MTBE (2x10 ml). The combined organic extracts were dried over Na ₂ SO ₄ and evaporated in vacuo. The resulting residue was purified by column chromatography (EtOAc: hexane 0: 1 => 2: 3) to give [1- (6-methyl-2-pyridyl) cyclobutyl] acetonitrile (161 mg, 39% yield).

A solution of [1- (6-methyl-2-pyridyl) cyclobutyl] acetonitrile (161 mg, 0.86 mmol, 1.0 eq.) In 3 M HCl in methanol (2.9 ml, 0.3 M) was heated to 60 ° C for 8.5 h. Then the reaction mixture was evaporated in vacuo. The resulting residue was taken up in CH ₂ Cl ₂ (10 ml) and washed with a mixture of H ₂ O and saturated aqueous NaHCO ₃ 1: 1 (10 ml). The organic phase was collected, dried over Na ₂ SO ₄ and evaporated in vacuo, cooled to room temperature and diluted with MTBE (10 ml) and water (10 ml). Collected the organic phase and the aqueous phase was extracted with MTBE (2x10 ml). The resulting residue was purified by column chromatography (EtOAc: hexane 1: 9 => 2: 3) to give methyl [1- (6-methyl-2-pyridyl) cyclobutyl] acetate (148 mg, 78% yield).

Stage 3. In a solution of methyl- [1- (6-methyl-2-pyridyl) cyclobutyl] acetate (148 mg, 0.67 mmol, 1.0 eq.) In CH ₂ Cl ₂ (2.7 ml, 0, 25 M) at 0 ° C was added 3-chloroperbenzoic acid (154.9 mg, 0.67 mmol, 1.0 eq). The reaction mixture was slowly warmed to room temperature and then stirred for 14 h. After that, the reaction mixture was applied directly to SiO2 and purified by column chromatography (MeOH: CH ₂ Cl ₂ 0: 1 => 1: 9) to give methyl- [ 1- (6-methyl-2-pyridyl) cyclobutyl] acetate N-oxide (157 mg, 99% yield).

In a solution of methyl- [1- (6-methyl-2-pyridyl) cyclobutyl] acetate-N-oxide (157 mg, 0.67 mmol, 1.0 eq.) In CH ₂ Cl ₂ (1.3 ml, 0 , 5 M) trifluoroacetic anhydride (940 μL, 6.6 mmol, 10.0 eq.) Was added at 0 ° C. The solution was stirred at 0 ° C for 15 min and then warmed to room temperature. After 6 h, the reaction mixture was cooled to 0 ° C and quenched with 2.0 M Na ₂ CO ₃ (5 ml). The biphasic mixture was stirred at 0 ° C for 1 h and then diluted with CH ₂ Cl ₂ (10 ml). Collected the organic phase, washed with H ₂ O (10 ml) and then dried over MgSO ₄ and evaporated in vacuo. The residue was purified by column chromatography (MeOH: CH ₂ Cl ₂ 0: 1 => 1: 9) to give methyl- {1- [6- (hydroxymethyl) -2-pyridyl] cyclobutyl} acetate (128 mg, 82% yield) ...

Stage 4. In a solution of methyl- {1- [6- (hydroxymethyl) -2-pyridyl] cyclobutyl} acetate (128 mg,

- 81 038488

0.55 mmol, 1.0 eq.) In toluene (1.1 ml, 0.5 M) was added diphenylphosphoryl azide (141 μl, 0.65 mmol,

1.2 eq. ) followed by 1,8-diazabicyclo [5.4.0] undec-7-ene (98 μL, 0.65 mmol, 1.2 eq.). The resulting mixture was heated to 60 ° C for 4 h. The reaction mixture was then applied directly to SiO ₂ and purified by column chromatography (EtOAc: hexane 0: 1 => 3: 7) to give methyl- {1- [6- (azidomethyl ) -2pyridyl] cyclobutyl} acetate (101 mg, 72% yield) as a colorless oil.

Stage 5. Received the specified compound analogously to example 130.

1H-NMR (400 MHz, acetone-d ₆ ) δ 8.66-8.57 (m, 2H), 8.52 (dd, J = 8.0, 1.4 Hz, 1H), 7.97- 7.87 (m, 2H), 7.837.72 (m, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.24-7.17 (m, 1H), 6.35 (s, 2H), 5.79 (s, 2H), 3.31 (s, 1H), 2.58-2.45 (m, 2H), 2.17-2.02 (m, 2H), 1.88 (dd, J = 10.3, 5.5Hz, 1H).

ESI-MS [M + H] + for C25H22N8O2: theor. 467.2, fact. 467.3.

Example 150. {1- [6 - ({4- [2-Amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) - 2-pyridyl] cyclobutyl} acetic acid

This compound was prepared analogously to example 149 from the corresponding azide and alkyne.

1H-NMR (400 MHz, acetone-d ₆ ) δ 8.66 (s, 1H), 8.41 (t, J = 7.8 Hz, 1H), 8.04-7.96 (m, 1H) , 7.88-7.75 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 ( d, J = 7.6 Hz, 1H), 5.81 (d, J = 0.9 Hz, 2H), 2.98 (s, 1H), 2.57-2.46 (m, 2H), 2.33 (s, 2H), 2.16-2.02 (m, 1H), 1.92-1.85 (m, 1H).

ESI-MS [M + H] + for C25H21FN8O2: theor. 485.2, fact. 485.3.

Example 151. {1- [6 - ({4- [2-Amino-6- (3-cyano-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2-pyridyl] cyclobutyl} acetic acid

This compound was prepared analogously to example 149 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, acetone ^) δ 8.80 (s, 1H), 8.16 (dt, J = 7.9, 1.6 Hz, 1H), 7.96-7.88 (m , 2H), 7.81 (td, J = 7.8, 1.4 Hz, 1H), 7.47 (td, J = 7.8, 1.4 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 5.83 (s, 2H), 4.00 (s, 3H), 2.98 (d, J = 1.4 Hz, 2H), 2.62-2, 45 (m, 2H), 2.16-2.02 (m, 1H), 2.35-2.32 (m, 2H), 1.88 (dt, J = 10.9, 5.3 Hz, 1H).

ESI-MS [M + H] + for C26H24N8O3: theor. 497.2, fact. 497.3.

Example 152. {3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] tetrahydrofuran-3-yl} acetic acid

1.nBuLi

2. Gul. Bu ₂ S

Br- ^ N Me 3. CN

CO ₂ Me

Stage 1

Yield 31%

NaCI, DMSO / H ₂ O 160 ° С, 6 h

Stage 2

tСРВА, СН ₂ С1 ₂ from 0 ° С to c.t.

Stage 4

HCI / MeOH

60 ° C, 3 h

16% for 2 stages

Stage 3

DPPA, DBU

PhMe, 40 ° C

Stage 6

TFAA, CH ₂ C12

40 ° C, 6 h, and then Na, CO.

Stage 5

Step 1. CuI (8.57 g, 44.8 mmol, 1.5 eq.) Was introduced into a round bottom flask, followed by the addition of Bu ₂ S (13.5 ml, 77.5 mmol, 2.6 eq.). Then Et ₂ O (70 ml) was added and the solution was cooled to 0 ° C. In a separate flask, n-BuLi (3.8 M in Et ₂ O, 89.5 mmol, 3.0 eq.) Was cooled to -78 ° C. Then brompicoline was added

- 82 038488 (10.2 ml, 89.5 mmol, 3.0 eq.) In pure form. The resulting mixture was stirred for 10 min and then transferred through the cannula into a flask containing CuI / Bu ₂ S. The resulting mixture was stirred for 20 min at 0 ° C, and then Michael acceptor solution (5 g, 29.9 mmol, 1.0 eq.) In Et ₂ O (37.5 ml, 0.8 M). The resulting mixture was stirred for 20 hours while slowly warming to room temperature. After 20 h, the reaction mixture was cooled to 0 ° C, quenched with saturated aqueous NH4Cl and diluted with EtOAc. Air was bubbled through the reaction mixture for 6 hours. The reaction mixture was then extracted with EtOAc and CH ₂ Cl ₂ . The combined organic extracts were washed with H2O (2 times) and saturated NaCl solution, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The crude residue was purified by flash silica gel column chromatography (hexane => 80% hexane / EtOAc => 100% EtOAc) to afford the desired product as a colorless oil (488 mg, 6% yield).

Stage 2. A mixture of ester (488 mg, 1.88 mmol, 1.0 eq.) And NaCl (33 mg, 0.56 mmol, 0.3 eq.) In DMSO / H2O (100: 1, 3.75 ml, 0.5 M) was heated to 160 ° C for 6 h. After that, the reaction mixture was cooled to room temperature and diluted with H2O and EtOAc (1: 1, 10 ml). Separate the layers and extract the mixture with EtOAc (3 times). The combined organic extracts were washed with saturated NaCl solution, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The crude residue was used without further purification in step 3.

Stage 3. Obtained in stage 2, the crude residue was dissolved in 3N. HCl in MeOH (2.04 ml). The reaction mixture was stirred at 60 ° C for 3 hours. After that, the reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was dissolved in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (3 times), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH gradient) to afford the product (72.8 mg, 16% yield over two steps).

Stage 4. To an ice-cooled solution of pyridine (72.8 mg, 0.309 mmol, 1.0 eq.) In CH ₂ Cl ₂ (0.31 ml, 1 M) was added mCPBA (89 mg, 0.387 mmol, 1.25 eq. .). The resulting solution was brought to room temperature and stirred at room temperature for 3 hours. Then the reaction mixture was diluted with CH ₂ Cl ₂ , washed with saturated aqueous K ₂ CO ₃ , dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The crude residue was used directly in step 5 without further purification.

Step 5. To a solution of the crude product obtained in Step 4 in CH2Cl2 (0.31 ml) was added TFAA (0.15 ml). The resulting solution was stirred at 40 ° C for 8 hours. After complete conversion to the TFA ester, the reaction mixture was cooled to room temperature and evaporated in vacuo. The crude residue was again dissolved in CH ₂ Cl ₂ (0.31 ml) and an aqueous solution of Na ₂ CO ₃ (2 M, 0.31 ml) was added. The mixture was stirred at room temperature for 1 h. After that, the reaction mixture was extracted with CH2Cl2 (3 times), dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH gradient) to afford the product (55 mg, 70% yield over two steps).

Stage 6. DPPA (0.06 ml, 0.263 mmol, 1, 2 eq.) Followed by DBU (0.04 ml, 0.263 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature for 10 min and then at 40 ° C for 4 h. The reaction mixture was then evaporated in vacuo and the resulting residue was purified by flash column chromatography on silica gel (hexane / EtOAc) to give the product in the form of a pale colorless oil (31.6 mg, 52% yield).

Steps 7 and 8. Carried out analogously to example 130.

¹ H-NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.40 (s, 1H), 8.30-8.22 (m, 1H), 7.84 (s, 1H) , 7.79-7.68 (m, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.31 ( d, J = 7.4 Hz, 1H), 5.71-5.54 (m, 4H), 4.32-4.17 (m, 1H), 4.09-3.95 (m, 3H) , 3.10 (d, J = 15.6 Hz, 1H), 2.88 (d, J = 15.4 Hz, 1H), 2.50-2.27 (m, 2H).

LC-MS: retention time 2.73 min, method A; ESI-MS [M-H ⁺ ] ^- for C ₂₅ H ₂₃ N ₈ O ₃ : theor. 483.2, fact. 483.3.

Example 153. {3- [6 - ({4- [2-Amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2-pyridyl] tetrahydrofuran-3-yl} acetic acid

This compound was prepared analogously to example 152.

¹ H-NMR (400 MHz, chloroform-d) δ 8.72 (d, J = 1.1 Hz, 1H), 8.25 (t, J = 7.7 Hz, 1H), 7.89 (s , 1H), 7.73 (t, J = 7.9 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.31 (d, J = 7.5 Hz, 1H ), 5.70-5.59 (m, 2H), 5.56 (s, 2H), 4.25 (d, J = 9.3 Hz, 1H), 4.08-3.99 (m, 3H), 3.07 (d, J = 15.5 Hz, 1H), 2.86 (d, J = 15.2 Hz, 1H), 2.52-2.26 (m, 2H).

LC-MS: retention time 2.73 min, method A; ESI-MS [M + H ⁺ ] ^- for C ₂₅ H ₂₂ FN ₈ O ₃ : theor. 501.2, fact. 501.3.

Example 154. {4- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) - 83 038488

2-pyridyl] tetrahydro-2H-pyran-4-yl} acetic acid

This compound was prepared analogously to example 152.

¹ H-NMR (400 MHz, chloroform-d) δ 8.69 (s, 1H), 8.44 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 7.84 -7.70 (m, 3H), 7.60 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 5.82 (s, 2H), 5.68 (s, 2H), 3.91-3.80 (m, 2H), 3.63-3.52 (m, 2H ), 2.73 (s, 2H), 2.52-2.39 (m, 2H), 2.13-1.96 (m, 2H). LC-MS:

retention time 2.76 min, method A; ESI-MS [M-H +] for C ₂₆ H ₂₅ N ₈ O ₃ : theor. 497.2, fact. 497.3.

Example 155. {4- [6 - ({4- [2-Amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) - 2-pyridyl] tetrahydro-2H-pyran-4-yl} acetic acid

This compound was prepared analogously to example 152.

¹ H-NMR (400 MHz, chloroform-d) δ 8.67 (s, 1H), 8.27 (t, J = 7.4 Hz, 1H), 7.86-7.82 (m, 1H) , 7.80-7.70 (m, 2H), 7.42-7.34 (m, 2H), 7.31 (d, J = 7.4 Hz, 1H), 5.80 (s, 2H ), 5.68 (s, 2H), 3.91-3.80 (m, 2H), 3.62-3.52 (m, 2H), 2.72 (s, 2H), 2.52- 2.37 (m, 2H), 2.13-1.95 (m, 2H).

LC-MS: retention time 2.76 min, method A; ESI-MS [M-H +] ^- for C ₂₆ H ₂₄ FN ₈ O ₃ : theor. 515.2, fact. 515.3.

Example 156 4- [6 - ({4- [2-Amino-6- (3-cyano-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2 -pyridyl] -4-methylvaleric acid

Stage 1. Mixed (6-bromo-pyridin-2-yl) methanol (75.0 g, 399.0 mmol, 1.0 eq.) And imidazole (29.9 g, 439 mmol, 1.1 eq.) in CH ₂ Cl ₂ (800 ml, 0.5 M). TBSCl (66.3 g, 439 mmol, 1.1 eq.) Was added portionwise to this solution at 0 ° C, which immediately caused the formation of a white precipitate. The reaction mixture was warmed to room temperature and stirred for 20 minutes, after which the consumption of starting material was checked by TLC and LCMS. The reaction mixture was filtered to remove imidazolium chloride and the solid was washed with CH ₂ Cl ₂ in one go (100 ml). Methanol (100 ml) was added to the filtrate and evaporated to a liquid cloudy oil, from which salts still precipitated upon evaporation. This crude mixture was filtered through a 3-inch pad of silica gel with 750 ml of 15% ethyl acetate in hexane. The filtrate was evaporated to a liquid oil (121.5 g, 100.8% yield).

Step 2. Dicyclohecylamine (9.08 ml, 9.95 g, 54.9 mmol, 1.3 eq.) Was added to a 500 ml 2-necked round bottom flask dried over a flame and diluted with 100 ml of anhydrous toluene. The resulting solution was cooled to 0 ° C, n-BuLi (20.76 ml, 2.5 M in hexane, 1.23 eq.) Was added dropwise and the reaction mixture was stirred for 20 min at this temperature. Then methyl isobutyrate (5.40 ml, 4.80 g, 46.84 mmol, 1.11 eq.) Was added dropwise over 20-30 min. Slow addition at this stage is critical to avoid self-condensation of the isobutyrate. The solution was stirred for an additional 30 min, and then the starting bromopyridine (12.76 g, ~ 11 ml, 42.2 mmol, 1.0 eq.) Was added over

- 84 038488 min. After adding pyridine, the solution turned dark reddish brown. Thereafter, the reaction flask was aspirated and refilled with nitrogen x3. Long (~ 1-2 min) vacuum periods are recommended according to the Hartwig method. Then the dimer bromine (tri-tert-butylphosphine) palladium (I) [P (tBu) ₃ Pd (μ-Br)] _{2 was} added in a stream of nitrogen (24.8 mg, 0.032 mmol, 0.00076 eq.), After which the reaction was sealed, brought to room temperature and stirred for 1 h. After that, another weighed portion of the catalyst (27.6 mg, 0.036 mmol, 0.00084 eq.) was added and the reaction mixture was stirred for another 4 h. There was incomplete conversion of the starting bromide, therefore, an additional portion of catalyst (27.6 mg) was added and the reaction was stirred overnight. The reaction was suppressed by the addition of methyl tert-butyl ether (100 ml), and then added dropwise 1.0N. aqueous HCl (70 ml). The resulting solid was filtered off and the aqueous layer was removed from the resulting biphasic solution. The organic layer was washed with saturated NaHCO ₃ , saturated NaCl solution, dried over Na ₂ SO ₄ and evaporated. The crude oil from the reaction was chromatographed on silica gel (5-20% ethyl acetate / hexane) to give a light yellow oil (9.64 g, 29.85 mmol, 71% yield).

Note. On a larger scale (~ 100 mmol), methyl isobutyrate was added dropwise using a dropping funnel. The addition of pure isobutyrate on this scale was challenging as even the slowest addition through the funnel was too fast in this context. Too rapid addition of butyrate leads to the formation of by-product A (shown below), which can only be separated by column chromatography after the LiBH4 reduction step.

МеО ₂ С.

By-product A.

Stage 3. Starting material - ester of pyridyl (9.64 g, 29.85 mmol, 1.0 eq.) Was introduced into 60 ml of anhydrous THF (0.5 M) and cooled to 0 ° C. Lithium borohydride (57.7 mL, 2.0 M in THF, 115.4 mmol, 4 eq.) Was added dropwise via an addition funnel, after which the reaction mixture was warmed to room temperature and then heated to 45 ° C for 6 h. After that, the reaction mixture was cooled to 0 ° C and quenched by adding dropwise a saturated aqueous solution of NH ₄ Cl. Water was added periodically when salt formation interfered with stirring of the reaction mixture. After complete quenching of the remaining borohydride, the reaction mixture was diluted with water to completely dissolve the salts and extracted twice with ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over sodium sulfate, filtered and evaporated. The crude product as an oil was wet loaded onto a silica gel column and chromatographed on a 5-20% ethyl acetate / hexane gradient. 7.2 g of a clear oil was obtained (84% yield).

Step 4. starting material - alcohol (. 11.5 g, 38.8 mmol, 1.0 eq) in CH ₂ Cl ₂ (155 mL, 0.25 mol) at room temperature was added periodinane Dess-Martin (18 16 g, 42.68 mmol, 1.1 eq.). The reaction was completed after 15 minutes. Thereafter, the reaction mixture was cooled to 0 ° C, and 200 ml of a 1: 1 mixture of saturated sodium bicarbonate and saturated sodium thiosulfate was slowly added thereto. When heated to 25 ° C, a slight evolution of gas occurred due to the protonation of bicarbonate - this gas evolution occurs violently if the reaction is vigorously shaken even before a significant amount of the by-product, acetic acid, has been quenched. After complete neutralization of acetic acid, the organic layer was separated, and the aqueous layer was washed once with another portion of CH ₂ Cl ₂ . The combined organic phase was washed with sat. NaHCO ₃ , water, saturated NaCl solution and evaporated. Evaporation forms salts in the crude oil from the reaction. It was filtered through a small pad of silica gel with 20% ethyl acetate in hexane and evaporated to a light yellow oil (10.88 g, 96% yield).

Step 5. Added triethyl phosphonoacetate (4.15 ml, 4.69 g, 20.9 mmol, 1.1 eq.) In THF (69 ml, 0.3 M) and cooled to 0 ° C. NaH (836 mg, 20.9 mmol, 1.1 eq., 60% in mineral oil) was carefully added to the resulting solution in portions, and the mixture was stirred for 5 min to completely deprotonate the phosphonoacetate. The starting aldehyde (5.59 g, 19.0 mmol) was then added as a solution in THF (19 ml, 1.0 M). The reaction mixture was brought to room temperature and stirred overnight (~ 14 h). Thereafter, the reaction mixture was evaporated directly on celite and purified on a silica gel column (ethyl acetate / hexane, 0-20%). 6.91 g of a clear oil was obtained (100% yield).

Stage 6. Palladium-carbon (10 wt.%, 689 mg, 10 wt.% Equiv.) Was introduced into a 100 ml flask equipped with a stirrer. The flask was aspirated three times and refilled with nitrogen gas, after which the starting material (6.89 g, 19.0 mmol) was added to a methanol solution (0.5 M, 38 ml). The solution was purged with hydrogen gas for 10 min and then stirred at room temperature under H ₂ atmosphere for 4 h. The reaction was monitored by LCMS (SM ion: m / z 364, product: m / z 366). No new peaks were observed on LCMS or new spots on TLC, so LCMS or 1H-NMR is required to monitor the progress of the reaction. After complete consumption of the starting material, the reaction mixture was filtered through a small pad of silica gel, which was then washed with a solution of methanol: CH ₂ Cl ₂ 1: 1. Then races

- 85 038488, the solution was evaporated and transferred to the next stage without further purification. Starting material (6.94 g, 19.0 mmol, 1.0 eq.) Was dissolved in THF (19 ml, 1.0 M). The resulting solution was cooled to 0 ° C and tetrabutylammonium fluoride (19.0 ml, 1.0 M in THF, 1.0 eq.) Was added. The reaction mixture was brought to room temperature and the conversion was complete within 15 minutes. The reaction mixture was loaded directly onto celite and purified by column (0-50% ethyl acetate / hexane) to give 4.46 g of a clear oil (94% yield, 2 steps).

Step 7. The starting alcohol (4.46 g, 17.77 mmol, 1.0 eq.) Was dissolved in toluene (23.3 ml, 0.8 M). To this solution was added diphenylphosphoryl azide (4.62 ml, 5.87 g, 21.32 mmol, 1.2 eq.) And then DBU (3.21 ml, 3.25 g, 21.32 mmol, 1, 2 equiv.). The resulting solution instantly turns cloudy a few seconds after the complete addition of DBU, with moderate exotherm. This exothermic effect is tolerable on a small scale, but safety issues can arise on a large scale - it is recommended to cool the reaction solution to 0 ° C before adding DPPA and DBU on a larger scale. The reaction mixture was left stirring for 14 hours at room temperature, after which the reaction was considered complete when the pyridyl ether phosphate was consumed. The reaction mixture was distributed between ethyl acetate and water. The organic layers were separated, washed with saturated NaCl solution and dried over sodium sulfate. The crude reaction mixture was purified on a silica gel column (10% ethyl acetate / hexane, isocratic) to give 4.77 g of the azide product as a clear liquid oil (97% yield).

Stage 8.Azide (414 mg, 1.5 mmol), alkyne (375 mg, 1.5 mmol), CuSO ₄ -5H ₂ O (19 mg, 5 mol%) and sodium ascorbate (59 mg , 20 mol.%). Added a mixture of tert-butanol and water 2: 1 (ml) and the resulting mixture was heated to 65 ° C. After complete consumption of the starting materials according to LCMS data (2 h), the mixture was loaded directly onto a silica gel column and purified by flash chromatography (hexane / ethyl acetate from 0 to 100%) to obtain the desired adduct in 97% yield as a pale yellow solid (750 mg). The ether from step A (750 mg, 1.46 mmol) was dissolved in THF (8 ml) and the resulting solution was stirred vigorously. Then a solution of lithium hydroxide (1 M, 3.0 ml) was added and the mixture was vigorously stirred at 35 ° C until the starting ether was completely consumed (12 h). The medium was cooled to room temperature and an excess of acetic acid (0.6 ml) was added to quench the reaction mixture. After stirring for 10 min, silica (15 g) was added and the reaction mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel (CH ₂ Cl ₂ / 0.1% acetic acid in ethyl acetate 0 to 100%) to give the title acid in 73% yield as a white solid (530 mg).

'H-NMR (400 MHz, αcetone-d ₆ ) δ 8.61 (s, 1H), 8.16 (s, J = 7.8 Hz, 1H), 7.88-7.84 (m, 2H ), 7.80 (dd, J = 7.6, 7.6 Hz, 1H), 6.23 (brs, 2H), 5.83 (s, 2H), 3.93 (s, 3H), 2 , 85 (brs, 4H), 1.34 (s, 6H).

ESI-MS [M + H] + for C26H26N ₈ O3: theor. 499.2, fact. 499.3.

Example 157 4- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 4-methylvaleric acid

This compound was obtained analogously to example 156.

¹ H-NMR (400 MHz, CD3OD) δ 8.92 (m, 1H), 8.58 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 7.96 (m , 2H), 7.79-7.73 (m, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.27 (dd, J = 7.7, 2.7 Hz, 1H), 5.84 (s, 2H), 2.01-1.93 (m, 4H), 1.30 (s, 6H).

ESI-MS [M + H] ⁺ for C ₂₅ H ₂₄ N ₈ O ₂ : theor. 469.2, fact. 469.3.

Example 158 4- [6 - ({4- [2-Amino-6- (3-cyanotolyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 4-methylvaleric acid but ₂ s

This compound was prepared in analogy to Example 156 to give 65 mg of a tan solid.

'H-NMR (400 MHz, DMSO-de) δ 11.93 (s, 1H), 8.68 (d, J = 1.0 Hz, 1H), 7.90 (dd, J = 7.7, 1.3 Hz, 1H), 7.807.73 (m, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7 , 27 (d, J = ', 0 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.88 (s, 2H), 5.81 (s, 2H), 2 , 55 (s, 3H), 1.94-1.84 (m, 4H), 1.28-1.20 (m, 6H).

ESI-MS [M + H] ⁺ for C; .. H2N8O2: theor. 483.2, fact. 483.2.

Example 159 4- [6 - ({4- [2-Amino-6- (3-cyano-2-fluorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2 -pyridyl] -4-methylvaleric acid

- 86 038488

This compound was obtained analogously to example 156.

Ή-NMR (400 MHz, DMSO-de) δ 8.67 (s, 1H), 8.29 (dd, J = 7.2, 7.2 Hz, 1H), 8.07 (dd, J = 6 , 8, 6.8 Hz, 1H), 7.75 (dd, J = 7.7, 7.7 Hz, 1H), 7.61 (s, 1H), 7.56 (dd, J = 7, 8, 7.8 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.94 (brs, 2H) , 5.80 (s, 2H), 1.87 (brs, 4H), 1.21 (s, 6H).

ESI-MS [M + H] + for C ₂₅ H ₂₃ FN ₈ O ₂ : theor. 487.2, fact. 487.3.

Example 160 4- [6 - ({4- [2-Amino-6- (2,3-dichlorophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl ] -4-methylvaleric acid but ₂ with nh ₂ μθ'Ί'ΧΧ n ^ n 9 ¹ Me AAL Cl

AND ABOUT

This compound was obtained analogously to example 156.

¹ H-NMR (400 MHz, acetone ^) δ 8.62 (d, J = 1.0 Hz, 1H), 7.84-7.74 (m, 1H), 7.70 (ddd, J = 8 , 0, 1.7, 1.1 Hz, 1H), 7.61-7.44 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.22 (s, 1H), 5.83 (s, 2H), 1.96 (d, J = 1.0 Hz, 4H), 1.34 (s, 6H).

ESI-MS [M + H] ⁺ for C ₂₄ H ₂₃ Cl ₂ N ₇ O ₂ , theor. 512.1, fact. 512.2.

Example 161 4- [6 - ({4- [2-Amino-6- (3-chloro-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) - 2-pyridyl] -4-methylvaleric acid

This compound was obtained analogously to example 156.

1H-NMR (400 MHz, chloroform-d) δ 11.31 (s, 1H), 8.53 (s, 1H), 7.85 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.567.50 (m, 1H), 7.47 (dd, J = 8.0, 1.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.18-7.06 (m, 2H), 5.68 (s, 2H), 3.73 (s, 3H), 2.20-2.09 (m, 4H), 1.34 (s, 6H).

ESI-MS [M + H] ⁺ for C25H26ClN7O3: theor. 508.2, fact. 508.2.

Example 162 4- [6 - ({4- [2-Amino-6- (3-fluoro-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2 -pyridyl] -4-methylvaleric acid

This compound was obtained analogously to example 156.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 12.01 (brs, 1H), 8.65 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.41 (ddd, J = 11.5, 8.2, 1.7 Hz, 1H), 7.36 ( d, J = 7.9 Hz, 1H), 7.23 (td, J = 8.0, 5.1 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6, 79 (s, 2H), 5.81 (s, 2H), 3.85 (s, 3H), 1.96-1.82 (m, 4H), 1.24 (s, 6H).

ESI-MS [MH] ^- for C25H25FN7O ₃ : theor. 490.2, fact. 490.2.

Example 163 4- [6 - ({4- [2-Amino-6- (3-cyano-2-ethoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) - 2-pyridyl] -4-methylvaleric acid

This compound was obtained analogously to example 156.

-NMR (400 MHz, acetone-d6) δ 8.61 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.00 (s, 1H), 7.85 ( d, J = 7.9 Hz, 1H), 7.79 (dd, J = 7.9, 7.9 Hz, 1H), 7.48-7.38 (m, 2H), 7.21 (d , J = 7.7 Hz, 1H), 6.24 (brs, 2H), 5.80 (s, 2H), 4.11 (q, J = 7.0 Hz, 2H), 2.07-2 , 03 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H), 1.36-1.26 (m, 2H), 1.34 (s, 6H).

MS [M + H] ⁺ for C27H2 ₈ N ₈ O ₃ : theor. 513.2, fact. 513.3.

Example 164 4- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] cyclohexanecarboxylic acid.

Example 165 4- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1 H-1,2,3-triazol-1-yl} methyl) -2- 87 038488 pyridyl] cyclohexanecarboxylic acid

Stage 1. A solution of 2-bromo-6 - ({[dimethyl (2-methyl-2-propanyl) silyl] oxy} methyl) pyridine (1.1 g, 3.6 mmol, 1.0 eq.), 4- ethoxycarbonyl-1-cyclohexenylboronic acid (1.0 g, 3.6 mmol, 1.0 eq.) and K ₂ CO ₃ (1.2 g, 10.7 mmol, 3.0 eq.) in dioxane / H ₂ O 9: 1 (18 ml, 0.2 M) was bubbled with N ₂ for 10 min. After that, Pd (PPh ₃ ) ₄ (206 mg, 0.18 mmol, 0.05 eq.) Was added and the reaction mixture was heated to 90 ° С for 22 h. After that, the reaction mixture was diluted with EtOAc (40 ml), transferred to separatory funnel and washed with H ₂ O (40 ml). Collected the organic phase and the aqueous phase was extracted with EtOAc (2x40 ml). The combined organic extracts were dried over MgSO ₄ and evaporated in vacuo. The resulting oil was purified by column chromatography (EtOAc: hexane: 0: 1 => 3:17) to afford the title compound (590 mg, 44% yield) as a colorless oil.

Stage 2. A solution of the product obtained above (590 mg, 1.6 mmol, 1.0 eq.) In ethanol (5.2 ml, 0.3 M) was purged with N ₂ for 5 min, and then PtO ₂ (36 mg, 0.16 mmol, 0.1 eq.). The suspension was hydrogenated in an atmosphere of H ₂ (balloon) for 4 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was washed with EtOH (2x10 ml) and the filtrate was evaporated in vacuo. The resulting oil was purified by column chromatography (EtOAc: hexane: 0: 1 => 1: 9) to give the product (270 mg, 46% yield) as a colorless oil.

Stage 3. The TBS-protected compound from stage 2 (270 mg, 0.71 mmol, 1.0 eq.) Was introduced into 1.0 M TBAF in THF (1.4 ml, 1.4 mmol, 2.0 eq.) And stirred the solution at room temperature for 30 min. The reaction mixture was loaded directly onto SiO ₂ and purified by column chromatography (EtOAc: hexane 1: 1 => 1: 0) to give ethyl 4- [6- (hydroxymethyl) -2-pyridyl] cyclohexanecarboxylate (156 mg, yield 83%) as a yellow oil.

Step 4. To a solution of ethyl 4- [6- (hydroxymethyl) -2-pyridyl] cyclohexanecarboxylate (156 mg, 0.59 mmol, 1.0 eq.) In toluene (1.2 ml, 0.5 M) was added diphenylphosphoryl azide (150 μl, 0.71 mmol, 1.2 eq.) followed by 1,8-diazabicyclo [5.4.0] undec-7-ene (110 μl, 0.71 mmol, 1.2 eq.). The resulting mixture was heated to 60 ° C for 4 h. The reaction mixture was then loaded directly onto SiO ₂ and purified by column chromatography (EtOAc: hexane: 1: 9 => 3: 7) to give ethyl 4- [6- (azidomethyl ) -2pyridyl] cyclohexanecarboxylate (120 mg, 71% yield) as a yellow oil.

Step 5. Received the target compounds in the same way as in example 125, and the cis / trans-isomers were separated by reverse phase HPLC. The first emerging compound was randomly identified as the trans isomer, and the second emerging as the cis isomer.

Example 164.

¹ H-NMR (400 MHz, acetone ^) δ 8.68-8.58 (m, 2H), 8.53 (ddd, J = 8.0, 1.9, 1.2 Hz, 1H), 7 , 99-7.91 (m, 2H), 7.83-7.73 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7 , 7 Hz, 1H), 6.58 (s, 1H), 5.83 (s, 2H), 2.74 (t, J = 11.6 Hz, 1H), 2.40-2.30 (m , 1H), 2.12-1.98 (m, 4H), 1.60 (tt, J = 24.6, 12.6Hz, 4H).

- 88 038488

ESI-MS [M + H] + for C26H24N8O2: theor. 481.2, fact. 481.3.

Example 165.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.70-8.58 (m, 2H), 8.53 (ddd, J = 8.0, 1.9, 1.2 Hz, 1H) , 7.97-7.89 (m, 2H), 7.82-7.70 (m, 2H), 7.28-7.16 (m, 2H), 6.42 (s, 2H), 5 , 80 (s, 2H), 2.70 (p, J = 4.3 Hz, 1H), 2.18 (dd, J = 13.5, 3.7 Hz, 2H), 2.06 (d, J = 2.2Hz, 1H), 2.03-1.87 (m, 2H), 1.82-1.63 (m, 3H).

ESI-MS [M + H] ⁺ for C26H24WO2: theor. 481.2, fact. 481.3.

Example 166 4- {1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2 -pyridyl] ethyl} cyclohexanecarboxylic acid

Step 1. To a solution of a cyclohexylcarboxylic acid derivative (950 mg, 5.1 mmol) in 10 ml of CH ₂ Cl ₂ , oxalyl chloride (0.48 ml, 5.61 mmol) was added dropwise followed by 1 drop of DMF. The reaction mixture was stirred at room temperature for 10 hours. The solvent was removed under reduced pressure and the crude acid chloride was used in the acylation reaction. In a separate flask, 2.5 M n-BuLi (2.8 ml, 6.96 mmol) was added dropwise to a solution of bromopyridine derivative (2.0 g, 6.63 mmol) in 22 ml THF, cooled to -78 ° C, and stirred for 15 minutes. Then a solution of CuCN (653.5 mg, 7.3 mmol) and LiCl (619 mg, 14.6 mmol) in 7 ml THF was added and stirred for 15 min. To this reaction mixture was added dropwise 5 ml of the above-prepared acid chloride solution at -78 ° C. The reaction mixture was then gradually brought to ambient temperature over 3 hours. The reaction was quenched with NH ₄ Cl and the aqueous layer was extracted with EtOAc (2x30 ml). The combined organic layer was dried over Na ₂ SO ₄ , evaporated and purified by silica gel chromatography to give the desired product (500 mg, 25%).

Step 2. KOtBu (172 mg, 1.53 mmol) was suspended in a dry vial in 3.5 ml of anhydrous THF. The suspension was cooled to 0 ° C and methyltriphenylphosphonium bromide (548 mg, 1.53 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. To this yellow reaction mixture at 0 ° C. was added 1 ml of the ketone solution from step 1 (500 mg, 1.3 mmol) in THF. The reaction mixture was then gradually brought to ambient temperature over 2 hours. The reaction was quenched with saturated NaHCO ₃ and the aqueous layer was extracted with EtOAc (2x30 ml). The combined organic layer was dried over Na ₂ SO ₄ , evaporated and purified by silica gel chromatography to give the desired product (276 mg, 55%).

Step 3. The alkene from step 2 (276 mg, 0.7 mmol) was dissolved in MeOH and 2 drops of HOAc were added. The solution was purged with N2 and PtO ₂ (16 mg, 0.07 mmol) was added. The reaction vessel was sealed, purged with H2 and stirred at room temperature under an atmosphere of H2 for 1 hour. The Pt catalyst was removed by filtration and the solvent was removed under reduced pressure. The crude material was redissolved in 3 ml of THF and 0.8 ml of 1 M TBAF was added. After 3 h, the solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography to give the desired

- 89 038488 alcohol (126 mg, 70% for 2 stages).

Stage 4. To a mixture of the product from stage 3 (133 mg, 0.5 mmol) and DPPA (0.13 ml, 0.58 mmol) in

ClCH ₂ CH ₂ Cl (1 ml) DBU (0.087 ml, 0 (58 mmol) was added. The reaction mixture was stirred at 50 ° C for 12 h. The solvent was removed under reduced pressure and the mixture was purified by chromatography on silica gel to give the desired azide in the form of a colorless oil (124 mg; 82%).

Stage 5. The specified compound was synthesized analogously to example 125.

¹ H-NMR (400 MHz, DMSC-d6) δ 11.99-11.82 (m, 1H), 8.70-8.63 (m, 1H), 8.59-8.51 (m, 1H ), 8.44 (dd, J = 8.1, 1.5 Hz, 1H), 7.97 (dd, J = 7.7, 1.4 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 2h), 7.16 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 7, 7 Hz, 1H), 6.87 (s, 2H), 5.79 (s, 2H), 2.57 (p, J = 7.0 Hz, 1H), 2.07-1.91 (m, 1H), 1.82 (t, J = 16.0 Hz, 2H), 1.71 (m, 1H), 1.48 (m, 1H), 1.32-1.01 (m, 5H), 0.98-0.72 (m, 2H).

ESI-MS [M + H] + for C2sH2sN ₈ O2: theor. 509.2, fact. 509.3.

Example 167 Methyl 4 - {(R) -1- [6- (hydroxymethyl) -2-pyridyl] ethyl} cyclohexanecarboxylate.

Example 168. Methyl 4 - {(S) -1- [6- (hydroxymethyl) -2-pyridyl] ethyl} cyclohexanecarboxylate

Stage 1. The two enantiomers were separated using a chiral column AD-H (L = 250 mm, ID = 30 mm, particle size 5 μm). Mobile phase: MeOH / CO ₂ . Flow rate (g / min): 80. Co-solvent flow rate (ml / min): 10.4. Enantiomer 1: Yield = 37%; her = 98%; enantiomer 2: yield = 38%; her = 99%. The absolute stereochemistry was set arbitrarily.

Example 169 4 - [(R) -1- [6 - ({4- [2-amino-6- (3-cyano-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3 triazole- 1-yl} methyl) -2-pyridyl] ethyl] cyclohexanecarboxylic acid

This compound was prepared analogously to example 125 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.76-7.63 (m, 3H), 7.65-7.55 (m, 1H), 7.30 -7.16 (m, 2H), 7.08 (d, J = 7.8 Hz, 1H), 6.87 (s, 2H), 5.75 (d, J = 13.8 Hz, 1H) , 5.55 (d, J = 13.9 Hz, 1H), 3.89 (s, 3H), 2.59 (dq, J = 8.5, 6.8 Hz, 1H), 2.24- 2.13 (m, 1h), 1.91 (m, 2h), 1.70-1.44 (m, 4H), 1.37 (d, J = 13.0 Hz, 1H), 1.30 -1.22 (m, 3H), 1.05 (m, 1h), 0.97-0.80 (m, 1H).

ESI-MS [M + H] ⁺ for C29H30N ₈ O3: theor. 539.2, fact. 539.3.

Example 170.4 - [(S) -1- [6 - ({4- [2-amino-6- (3-cyano-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3triazole-1 -yl} methyl) -2-pyridyl] ethyl] cyclohexanecarboxylic acid

This compound was prepared analogously to example 125 from the corresponding azide and alkyne.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 11.97 (brs, 1H), 8.65 (s, 1H), 8.06 (dd, J = 8.2, 1.4 Hz, 1H) , 7.94 (dd,

- 90 038488

J = 7.7, 1.8 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.07 (d,

J = 7.7 Hz, 1H), 6.86 (s, 2H), 5.79 (s, 2H), 3.83 (s, 3H), 2.59 (p, J = 7.0 Hz, 1H), 2.06-1.95 (m, 1H), 1.92-1.77 (m,

2H), 1.73 (d, J = 13.1 Hz, 1H), 1.56-1.42 (m, 1H), 1.34-1.04 (m, 6H), 0.99-0 , 74 (m, 2H).

ESI-MS [M + H] + for C29H31N8O3: theor. 539.2, fact. 539.3.

Example 171 2- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] cyclopentanecarboxylic acid

BuLi, B (ОМе) ₃

THF. (МеО) ₂ В from -78 ° С to 25 ° С, 18h

Stage 1

OTBS

Pd (PPh ₃ ) ₄ , Na ₂ CO ₃ Toluene, 75 ° C, 2 h

Stage 2

OTf

Pto ₂ , H _{2 EY with} TBAF. THF,

CH.I !! O .. G PS OG S.,

Stage 4 \ I Stage 3

NH ₂

N ^ N

Stage 5 2) LiOH

Stage 6

Stage 1. The bromopyridine derivative (2.22 g, 7.3 mmol) was dissolved in THF (7.3 ml) and added dropwise to a solution of n-BuLi (2.5 M in hexane, 3.52 ml, 8.8 mmol) cooled to -78 ° C. After stirring for 30 min, trimethyl borate (0.68 mL, 8.8 mmol) was added, the reaction mixture was brought to room temperature and stirred overnight. The resulting solution was evaporated and used without further purification.

Step 2. The crude product from step 1 (7.3 mmol) was dissolved in toluene (3.0 ml). The triflate derivative (200 mg, 0.73 mmol) was added and the solution was degassed by passing nitrogen through for 2 min. Pd (PPh ₃ ) ₄ (13.0 mg, 0.011 mmol) and Na ₂ CO ₃ (2 M aq., 0.44 ml, 0.88 mmol) were added, the reaction mixture was sealed under nitrogen and heated to 75 ° C. for 2 hours. Then the reaction mixture was evaporated and used further without purification.

Step 3. The crude product from step 2 (7.4 mmol) was dissolved in THF (7.4 ml) and TBAF (1.0 M in THF, 7.4 ml, 7.4 mmol) was added at 25 ° C. The reaction mixture was stirred for 5 h, evaporated on celite and purified by flash chromatography on silica gel (ethyl acetate / hexane 10% to 20%). Yield: 253 mg (14%, 3 steps).

Step 4. The benzyl alcohol obtained in Step 3 (294 mg, 1.19 mmol) was mixed with PtO ₂ (27 mg, 0.12 mmol) in methanol (12 ml) and the resulting solution was purged with hydrogen for 5 minutes. The reaction mixture was sealed and stirred vigorously for 3 hours. The reaction solution was evaporated on celite and the crude material was purified by flash chromatography on silica gel (ethyl acetate / hexane 10% to 50%). Yield: 198 mg (67%).

Stage 5. The benzyl alcohol product from stage 4 (198.2 mg, 0.80 mmol) was dissolved in toluene (1.0 ml) and cooled to 0 ° C, and then DPPA (0.21 ml, 0.96 mmol) and DBU (0.15 ml, 0.96 mmol). The reaction mixture was stirred at room temperature for 16 hours. After that, the reaction mixture was partitioned between ethyl acetate and water, the organic layer was collected and evaporated on celite. The resulting crude material was purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 0 to 20%). Yield: 207 mg (95%).

Step 6. Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to obtain the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.90 (s, 0.5H), 8.70 (s, 0.5H), 8.44-8.39 (m, 1H), 8.29 -8.23 (m, 1H), 7.847.82 (m, 1H), 7.77-7.55 (m, 3H), 7.31-7.21 (m, 2H), 5.76 (brs , 0.5H), 5.70-5.57 (m, 2H), 5.37 (brs, 1H), 3.643.51 (m, 2H), 3.26 (ddd, J = 7.1, 7 , 1, 7.1 Hz, 0.5H), 2.90 (ddd, J = 9.3, 9.3, 9.3 Hz, 0.5H), 2.36-1.75 (m, 5H ).

ESI-MS [M + H] + for C25H22N8O2: theor. 467.2, fact. 467.3.

Example 172. 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] cyclopentanecarboxylic acid

- 91 038488

Stage 1. A mixture of boronate (830 mg, 1.95 mmol), vinyl triflate (mixture of regioisomers 1: 1, 432 mg, 1.5 mmol), palladium tetrakis (69 mg, 4 mol.%) In degassed toluene (4, 5 ml) and sodium carbonate (2M, 1.2 ml) were heated to 75 ° C for 2 h. After routine work-up and chromatography on silica gel (hexane / EtOAc 100: 0 to 80:20), the conjugated product was obtained (366 mg , 68%). The product (366 mg, 1.0 mmol) was dissolved in THF (2 ml) and acetic acid (10 μl) was added followed by TBAF (1 M in THF, 1.2 ml). The mixture was stirred 2 h at room temperature and after the usual work-up, the residue was purified by silica gel chromatography (hexane / EtOAc 90:10 to 50:50) to give the primary alcohol (171 mg, 69%).

Stage 2. A mixture of alkenes (170 mg, 0.69 mmol) was added to degassed EtOH (2 ml) and AcOH (30 μl). _{PtO 2} (5 mg) was added and the suspension was placed under an atmosphere of H2. After 4 h at room temperature, the mixture was filtered through celite, evaporated to dryness and purified by silica gel chromatography (hexane / EtOAc 90:10 to 50:50) to give reduced cyclopentane (77 mg, 45%). An azidation step was performed according to Example 79 to give the desired azide derivative (82 mg, 96%).

Step 3. Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to obtain the title compound as a 95: 5 mixture of diastereoisomers. The minor isomer is not described here.

¹ H-NMR (400 MHz, acetone ^) δ 8.80 (s, 1H), 8.60 (s, 1H), 8.55-8.48 (m, 1H), 7.97-7.89 (m, 1H), 7.92 (s, 1H), 7.82-7.68 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.50 (brs, 2H), 5.81 (s, 2H), 3.45-3.27 (m, 1H), 3.09-2.92 (m , 1H), 2.44-2.18 (m, 2H), 2.17-1.94 (m, 4H).

MS [M + H] + for C25H22N8O2: theor. 467.2, fact. 467.3.

Example 173 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-hydroxycyclopentanecarboxylic acid

2. LiOH _: THF

Step 1. To a solution of bromide (903 mg, 3 mmol) in THF (5 ml) at -78 ° C was added p-BuLi (2.5 M in hexane, 1.2 ml, 3 mmol). The resulting mixture was stirred at -78 ° C for 30 min and then a ketone solution (460 μL, 3 mmol) was added. After another hour, the reaction was quenched with sat. NH ₄ Cl. Chromatography on silica gel (hexane / EtOAc 95: 5 to 85:15) afforded the tertiary alcohol (680 mg, 60%).

Dissolve silyl ether (680 mg, 1.8 mmol) in THF (2 ml) and add acetic acid (20 μl) followed by TBAF (1 M in THF, 2.5 ml). The mixture was stirred for 2 h at room temperature, and after the usual work-up, the residue was purified by silica gel chromatography (CH ₂ Cl ₂ / hexane (1: 1) / EtOAc 95: 5 to 70:30) to give the primary alcohol (274 mg, 57% ).

Stage 2. This stage was performed according to example 172, receiving the target azide (281 mg, 94%).

Stage 3. Cycloaddition was carried out in the same manner as in stage 6 of example 1, and the hydrolysis of the resulting ester analogous to example 125, obtaining a mixture of diastereoisomers

- 92 038488

3: 1.

'll-NMR (400 MHz, acetone-d ₆ ) δ 8.79 (s, 0.25H, smaller dia), 8.65 (s, 0.75H, larger dia), 8.57 (s, 1H) , 8.53-8.46 (m, 1H), 7.96-7.86 (m, 1H), 7.90 (s, 1H), 7.82 (dd, J = 8.0, 8, 0 Hz, 1H), 7.80-7.68 (m, 2H), 7.30 (d, J = 8.0 Hz, 0.25H, smaller dia), 7.25 (d, J = 8, 0Hz, 0.75H, larger dia), 6.52 (brs, 0.5H, smaller dia), 6.32 (brs, 1.5H, larger dia), 5.85 (s, 2H), 3, 27-3.17 (m, 0.25H, smaller dia), 3.18-3.08 (m, 0.75H, larger dia), 2.64-2.10 (m, 5H), 2.07 -2.03 (m, 1H), 1.95-1.82 (m, 1H).

MS [M + H] + for C25H22N8O3: theor. 483.2, fact. 483.3.

Example 174 3- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-hydroxycyclobutanecarboxylic acid

This compound was synthesized analogously to example 173.

¹ H-NMR (400 MHz, acetone-d6) δ 8.68 (s, 1H), 8.59 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.97 -7.88 (m, 1H), 7.90 (s, 1H), 7.86 (dd, J = 7.6, 7.9 Hz, 1H), 7.76 (dd, J = 7.6 , 7.9 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6.24 (brs, 2H), 5.91 (s, 2H), 3.19-3.05 (m, 1H), 2.79-2.69 (m, 2H), 2.63-2.47 (m, 2H).

MS [M + H] + for C24H2oN ₈ 0 ₃ : theor. 469.2, fact. 469.3.

Example 175. {4- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] -4-hydroxy-1-piperidyl} acetic acid

Step 1. To a solution of bromide (1.5 g, 5 mmol) in THF (10 ml) at -78 ° C was added p-BuLi (2.5 M in hexane, 2.1 ml, 5.5 mmol). The resulting mixture was stirred at -78 ° C for 30 min and then a ketone solution (996 mg, 5 mmol) was added dropwise. After another 1 h, the reaction was quenched with sat. NH ₄ Cl. Chromatography on silica gel (hexane / EtOAc 95: 5 to 85:20) afforded the tertiary alcohol (1.3 g, 62%).

Dissolve silyl ether (1.3 g, 3.1 mmol) in THF (6 ml) and add acetic acid (40 μl) followed by TBAF (1 M in THF, 5 ml). The mixture was stirred for 2 h at room temperature and after the usual work-up, the residue was purified by silica gel chromatography (CH2Cl2 / Hexane (1: 1) / EtOAc 95: 5 to 50:50) to give the primary alcohol (850 mg, 89%).

Stage 2. This stage was performed according to example 172, receiving the target azide (790 mg, 87%).

Stage 3. To a mixture of alkyne (66 mg, 0.3 mmol) and azide (100 mg, 0.3 mmol) in tBuOH / H ₂ O (2: 1, 1 ml), CuSO4 (2.4 mg) and ascorbate were added sodium (12 mg). The resulting mixture was stirred at 60 ° C for 3 h. The crude mixture was loaded directly onto silica gel and purified by column chromatography (hexane / EtOAc 100: 0 to 0: 100) to give the cycloadduct (160 mg, 96%). The protected Boc amine (78 mg) was added to TFA (0.2 ml) and stirred for 30 min at room temperature. After evaporation of the volatiles, the TFA amine salt was obtained (77 mg, quant.).

Step 4. TFA amine salt (77 mg) was dissolved in THF (1 ml) and triethylamine (0.3 ml) was added followed by ethyl bromoacetate (60 μl). The resulting mixture was stirred for 3 h at room temperature and then purified by column chromatography on silica gel (hexane / EtOAc 95: 5 to 60:40) to give the alkylated amine (74 mg, quant.). The resulting ester (65 mg) was dissolved in THF (1.5 ml) and LiOH (1 M, 0.4 ml) was added. After vigorous stirring at 40 ° C for 3 h, the reaction was quenched by the addition of acetic acid (0.2 ml) and the crude product was loaded directly onto silica gel for column purification (CH2Cl2 / MeOH 100: 0 to 70:30) to give the target acid (70 mg, 98%).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.84 (dd, J = 7.9, 7.9 Hz, 1H), 7.79 (s, 1H), 7.72 (dd, J = 7.9, 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.96 (brs, 2H), 5.81 (s, 2H), 3.28 (s, 1H), 3.18-2.90 (m, 4H), 2.35-2.24 (m, 2H), 1.60 (d, J = 13.7 Hz, 2H).

- 93 038488

MS [M + H] + for C26H25N9O3: theor. 512.5, fact. 512.3.

Example 176. {4- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] -1-piperidyl} acetic acid

This compound was prepared analogously to example 125 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, CD3OD) δ 8.75 (d, J = 1.4 Hz, 1H), 8.55-8.49 (m, 1H), 8.47-8.37 (m, 1H), 7.90-7.84 (m, 1H), 7.84-7.75 (m, 2H), 7.75-7.66 (m, 1H), 7.32 (dd, J = 7.9, 4.0 Hz, 2H), 5.80 (s, 2H), 3.64 (s, 2H), 3.11 (d,

J = 36.7 Hz, 5H), 2.15 (q, J = 15.6, 13.3 Hz, 5H).

ESI-MS [M + H] ⁺ for C26H25N9O2: theor. 496.2, fact. 496.3.

Example 177 [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridylamino] acetic acid

TBSCI

Imidazole

CH ₂ C1 ₂

Stage 1

MeOrC ^ -Br K ₂ CO ₃ . Acetone MeO ₂ C ^XX 'N reflux condenser, 20 h ⁿ

8% for 2 stages Stage 2

OTBS

МеО

N ₃

DPPA.DBU

CH2CI2 МеО from 0 ° С to 25 ° С, Ϊ6 h 52% for 2 stages Stage 4

HE

TBAF, THF from 0 ° С to 25 ° С, 3 h Stage 3

CuSO ₄ -5H ₂ O

Na-ascorbate, then LiOH ^CN HO ₂ C-d

HN

CN

Stage 5

Step 1. To a solution of aminopyridine (604 mg, 4.06 mmol) and imidazole (332.3 mg, 4.88 mmol) in methylene chloride (8 ml) was added TBSCl (736.9 mg, 4.88 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and evaporated on celite, and the resulting crude material was purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 20 to 40%). The resulting white crystalline material was transferred to the next step, assuming a yield of 100%.

Step 2: The crude TBS-protected product from Step 1 (4.06 mmol) was added to a pressure relief septum vial to which K ₂ CO ₃ (673 mg, 4.87 mmol) and acetone (3.2 ml). Methyl bromoacetate (384 μl, 4.06 mmol) was added and the solution was refluxed under reflux for 20 h. Another portion of methyl bromoacetate (192 μl, 2.03 mmol) was added and the reaction mixture was heated for another 22 h. the mixture was partitioned between ethyl acetate and saturated NaHCO ₃ , the aqueous layer was extracted three times with ethyl acetate, and the combined organic layer was washed with saturated NaCl solution and dried over sodium sulfate. The resulting solution was evaporated on celite and purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 0 to 10%). Yield: 100.1 mg (8%, 2 steps).

Step 3. The arylglycine product from step 2 (100.1 mg, 0.32 mmol) was dissolved in THF (0.33 ml) and cooled to 0 ° C. TBAF (1.0 M in THF, 0.33 ml) was added in one portion and the solution was brought to room temperature over 1 h. Then saturated NaHCO _{3 was} added and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a saturated NaCl solution, dried over sodium sulfate, evaporated, and transferred to the next stage without further purification.

Step 4. The crude alcohol product from step 3 (0.32 mmol) was dissolved in methylene chloride (0.4 ml) and cooled to 0 ° C. DPPA (84.5 μl, 0.39 mmol) and DBU (58.8 μl, 0.39 mmol) were sequentially added, the reaction mixture was warmed to room temperature and stirred for 3 hours.The resulting solution was evaporated on celite and purified by flash -chromatography on silica gel (ethyl acetate / hexane, gradient from 0 to 30%). Yield: 37.2 mg (52%, 2 steps).

Step 5. Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to obtain the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.57 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7, 99 (d, J = 7.6 Hz, 1H),

- 94 038488

7.81 (s, 1H), 7.73 (dd, J = 8.0, 7.6 Hz), 7.44 (m, 1H), 6.56 (m, 1H), 6.41 (m , 1H), 5.58 (s, 2H), 3.93 (s, 2H).

ESI-MS [M + H] + for C ₂₁ H ₁₇ N ₉ O ₂ : theor. 428.2, fact. 428.2.

Example 178 2- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridylamino] - 2-methylpropionic acid

Step 1. The starting aminopyridine derivative (520 mg, 4.2 mmol) was dissolved in acetone (8.4 ml). 1,1,1-Trichloro-2-methyl-2-propanol hemihydrate (1.17 g, 6.3 mmol) was added and the solution cooled to 0 ° C. Powdered KOH (939 mg, 16.8 mmol) was added to the cold solution and the reaction mixture was stirred for 1 h at 0 ° С and for another 16 h at room temperature overnight. The reaction was quenched with 2 ml of AcOH, evaporated and redissolved in methanol. The solution was filtered and evaporated on celite. The resulting crude product was purified by flash chromatography on silica gel (methanol / methylene chloride, gradient 0 to 10%) as a yellow oil.

Step 2. The resulting carboxylic acid (457 mg, 1.41 mmol) was dissolved in methylene chloride (5.6 ml) and methanol (1.4 ml) and cooled to 0 ° C. Trimethylsilyldiazomethane (1.75 mL, 3.5 mmol) was added dropwise to the cold solution. Upon completion of the addition, the reaction was quenched with AcOH, evaporated and redissolved in methylene chloride and then evaporated on celite. The resulting crude product was purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 5 to 10%).

Step 3. The carboxylate ester from step 2 (206 mg, 0.61 mmol) was dissolved in THF (6.1 ml) and cooled to 0 ° C. Added TBAF (1.0 M in THF, 0.61 ml, 0.61 mmol) at 0 ° C and brought the reaction mixture to room temperature. After stirring for 1 h, the reaction was quenched with saturated NaHCO ₃ , partitioned between ethyl acetate and H2O. The organic layer was washed with saturated NaCl solution, dried over sodium sulfate and evaporated. The resulting product was transferred to the next stage without further purification.

Step 4. The benzyl alcohol from step 3 (136 mg, 0.61 mmol) was dissolved in methylene chloride (6.1 ml) and cooled to 0 ° C. DPPA (158 μl, 0.72 mmol) and DBU (110 μl, 0.72 mmol) were sequentially added and the reaction mixture was heated to 40 ° C. After 24 h, the reaction mixture was evaporated on celite and purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 0 to 30%).

Step 5. Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to obtain the title compound.

¹ H-NMR (400 MHz, CDOD) δ 8.71 (s, 1H), 8.53 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.88-7 , 81 (m, 2H), 7.68 (dd, J = 7.8, 7.8 Hz, 1H), 7.39 (dd, J = 8.6, 7.1 Hz, 1H), 6, 62 (d, J = 7.1 Hz, 1H), 6.49 (d, J = 8.6 Hz, 1H), 5.49 (s, 2H, 1.49 (s, 6H).

ESI-MS [M + H] ⁺ for C ₂₃ H ₂₁ N ₉ O ₂ : theor. 456.2, fact. 456.3.

Example 179 (S) -1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2 -pyridyl] -2-pyrrolidinecarboxylic acid

- 95 038488

Stage 1. A mixture of bromide (2.33 g, 7.75 mmol) and amine (2.0 g, 15.5 mmol) together with CuI (296 mg, 20 mol.%) And K ₂ CO ₃ (2, 14 g, 15.5 mmol) was added to DMF (7.8 ml). The resulting mixture was stirred for 2 h at 90 ° C and then cooled to room temperature, after which methyl iodide (965 μL, 15.5 mmol) was added. The mixture was stirred for an additional 2 h. After the usual work-up (H ₂ O / EtOAc), the residue was purified by silica gel chromatography (hexane / EtOAc 90:10 to 80:20) to give the conjugated product (1.65 g, 61%).

The product obtained above (1.65 g, 4.7 mmol) was dissolved in THF (4 ml) and acetic acid (40 μl) was added followed by TBAF (1Mb THF, 6 ml). The mixture was stirred for 2 h at room temperature and after the usual work-up, the residue was purified by silica gel chromatography (CH ₂ Cl ₂ / hexane (1: 1) / EtOAc 95: 5 to 50:50) to give the primary alcohol (730 mg, 66% ).

Step 2. An azide derivative was synthesized in the same manner as in Step 5 of Example 1 using the alcohol derivative obtained above (380 mg, 1.6 mmol). Purification by silica gel chromatography (hexane / EtOAc 100: 0 to 85:15) provided the desired product (330 mg, 79%).

Stage 3. Synthesized (S) -1- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) - 2-pyridyl] -2-pyrrolidinecarboxylate in the same manner as in step 6 of example 1.

Ή-NMR (400 MHz, chloroform-d) δ 8.46 (s, 1H), 8.35 (d, J = 1.4 Hz, 1H), 8.34 (s, 1H), 8.33- 8.28 (m, 1H), 7.89 (s, 1H), 7.77-7.70 (m, 1H), 7.58 (dd, J = 7.6 Hz, 1H), 7.45 (dd, J = 7.6 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 5.46 (s , 2H), 5.26 (brs, 2H), 4.54 (dd, J = 8.7, 3.2 Hz, 1H), 3.66 (s, 3H), 3.64-3.56 ( m, 1H), 3.50-3.36 (m, 1H), 2.41-2.08 (m, 3H).

MS [M + H] + for C25H23N9O2: theor. 482.2, fact. 482.3.

Stage 4. In solution (S) -1- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl] -2-pyrrolidinecarboxylate (80 mg, 0.17 mmol) in THF (1 ml) was added an aqueous solution of LiOH (0.35 ml, 1 M). The resulting mixture was vigorously stirred at room temperature overnight and then quenched by the addition of acetic acid (excess) and evaporated on silica. The residue was purified by silica gel chromatography (CH ₂ Cl 2 / MeOH 100: 0 to 90:10) to give the desired acid (40 mg, 52%).

-NMR (400 MHz, DMSO-d6) δ 12.38 (brs, 1H), 8.60 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 7.97 (dd, J = 7.7 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J = 7.9 Hz, 1H), 7.50 ( dd, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.45 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 5.56 (s, 2H), 4.35 (d, J = 7.2 Hz, 1H), 3.53-3.30 (m, 2H), 2.30-2.15 (m , 1H), 2.06-1.84 (m, 3H).

MS [M + H] + for CANA: theor. 468.2, fact. 468.3.

Example 180 (R) -1 - [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) - 2-pyridyl] -2-pyrrolidinecarboxylate

This compound was synthesized analogously to example 179.

Ή-NMR (400 MHz, chloroform-d) δ 8.46 (s, 1H), 8.35 (d, J = 1.4 Hz, 1H), 8.34 (s, 1H), 8.33- 8.28 (m, 1H), 7.89 (s, 1H), 7.77-7.70 (m, 1H), 7.58 (dd, J = 7.6 Hz, 1H), 7.45 (dd, J = 7.6 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 5.46 (s , 2H), 5.26 (brs, 2H), 4.54 (dd, J = 8.7, 3.2 Hz, 1H), 3.66 (s, 3H), 3.64-3.56 ( m, 1H),

- 96 038488

3.50-3.36 (m, 1H), 2.41-2.08 (m, 3H).

MS [M + H] ⁺ for C ₂ 5H ₂₃ N9O ₂ : theor. 482.4, fact. 482.3.

Example 181. (R) - 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) - 2-pyridyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 179.

'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 7, 97 (dd, J = 7.7 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J = 7.9 Hz, 1H), 7.50 (dd, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.45 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 5.56 ( s, 2H), 4.35 (d, J = 7.2 Hz, 1H), 3.53-3.30 (m, 2H), 2.30-2.15 (m, 1H), 2.06 -1.84 (m, 3H).

MS [M + H] + for C ₂₄ H ₂ 'N ₉ O ₂ : theor. 468.2, fact. 468.3.

Example 182 (R) - 1- [6 - ({4- [2-Amino-6- (3-cyano-2-methoxyphenyl) -4-pyrimidinyl] -1H-1,2,3-triazol1-yl} methyl) -2-pyridyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 179.

'H-NMR (400 MHz, acetone-d ₆ ) δ 11.93 (brs, 1H), 8.65 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7, 89 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 7.8, 8.0 Hz, 1H), 7.43 (dd, J = 7.8, 8.0 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 6.28 (brs , 2H), 5.61 (d, J = 14.7 Hz, 1H), 5.56 (d, J = 14.7 Hz, 1H), 4.58-4.56 (m, 1H), 3 , 95 (s, 3H), 3.61-3.41 (m, 2H), 2.37-2.22 (m, 1H), 2.22-1.99 (m, 3H).

MS [M + H] ⁺ for C25H23N9O3: theor. 498.2, fact. 498.4.

Example 183 4- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-morpholinecarboxylic acid

This compound was synthesized analogously to example 179.

'H-NMR (400 MHz, DMSO-d6) δ 12.72 (brs, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 7, 8 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.73 (dd, J = 7.8, 7.8 Hz, 1H) , 7.56 (dd, J = 7.8, 7.8 Hz, 1H), 6.86 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.54 ( d, J = 7.8 Hz, 1H), 5.61 (s, 3H), 4.86 (s, 1H), 4.25 (d, J = 11.2 Hz, 1H), 3.90 ( d, J = 11.2 Hz, 1H), 3.85-3.39 (m, 3H), 3.26-3.11 (m, 1H).

MS [M + H] ⁺ for C24H21N9O3: theor. 484.2, fact. 484.3.

Example 184 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-azetidinecarboxylic acid

Stage 1. A mixture of amine (690 mg, 6 mmol), bromide (1.51 g, 5 mmol), Cs ₂ CO ₃ (2.44 g, 7.5 mmol), BrettPhosPd G3 (180 mg, 4 mol.% ) and BrettPhos (107 mg, 4 mol%) in degassed tBuOH (12 ml) were stirred at 100 ° C overnight. Then the mixture was cooled to room temperature and DMF was added

- 97 038488 (3 ml), followed by MeI (373 μl, 6 mmol). The resulting mixture was stirred for an additional 4 hours. After routine work-up and chromatography on silica gel (hexane / EtOAc 95: 5 to 85:15), the conjugated product was obtained (180 mg, 10%).

Dissolve silyl ether (180 mg, 0.5 mmol) in THF (1 ml) and add acetic acid (10 μl) followed by TBAF (1 M in THF, 1.5 ml). The mixture was stirred for 2 h at room temperature and after the usual work-up, the residue was purified by chromatography on silica gel (CH ₂ Cl ₂ / hexane (1: 1) / EtOAc 95: 5 to 50:50) to give the primary alcohol (108 mg, quant. ).

Step 2. An azide derivative was synthesized in the same manner as in Step 5 of Example 1 using the alcohol obtained above (90 mg, 68%).

Stage 3. Synthesized methyl-1- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) -2- pyridyl] -3-azetidinecarboxylate in the same manner as in step 6 of example 1.

¹ H-NMR (400 MHz, chloroform-d) δ 8.45 (s, 1H), 8.35 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J = 7.8, 7.8 Hz, 1H), 7.59 (dd, J = 7.8, 7.8 Hz, 1H), 7.43 ( dd. J = 7.8, 7.8 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 6.25 (d, J = 7.6 Hz, 1H), 5, 54 (s, 2H), 5.22 (s, 2H), 4.26-4.11 (m, 4H), 3.75 (s, 3H), 3.65-3.48 (m, 1H) ...

MS [M + H] + for C ₂₄ H ₂₁ N ₉ O ₂ : theor. 468.2, fact. 468.2.

Stage 4. Hydrolysis of methyl 1- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H1,2,3-triazol-1-yl} methyl) -2 -pyridyl] -3-azetidinecarboxylate with LiOH to give the title compound.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.79 (s, 1H), 7.72 (dd, J = 7.9, 7.9 Hz, 1H), 7.52 (dd, J = 7.9, 7.2 Hz, 1H), 6.88 (s, 2H), 6.49 (d, J = 7.2 Hz, 1H), 6.36 (d, J = 7.9 Hz, 1H), 5.62 (s, 3H), 4.06 (dd, J = 8.4, 5.8 Hz, 2H), 3.93 (dd, J = 8.4, 5.8 Hz, 2H ), 3.48 (tt, J = 8.4, 5.8 Hz, 2H).

MS [M + H] + for C ₂₃ H ₁₉ N ₉ O ₂ : theor. 454.2, fact. 454.3.

Example 185 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 184.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.79 (s, 1H), 7.72 (dd, J = 7.9, 7.9 Hz, 1H), 7.48 (dd, J = 7.9, 7.9 Hz, 1H), 6.87 (brs, 2H), 6.43 (d, J = 7.9 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 5.60 (s, 2H), 3.62-3.20 (m, 5H), 3.18-3.06 (m, 1H), 2.20-2.02 (m, 2H) ...

MS [M + H] + for C24H21N9O2: theor. 468.4, fact. 468.3.

Example 186 (R) -1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimudinyl] -1H-1,2,3-triazole-1yl} methyl) -2 -pyridyl] -3-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 184.

¹ H-NMR (400 MHz, DMSO-d6) δ 12.44 (brs, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 7, 9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.79 (s, 1H), 7.72 (dd, J = 7.9, 7.9 Hz, 1H) , 7.48 (dd, J = 7.9, 7.9 Hz, 1H), 6.87 (brs, 2H), 6.43 (d, J = 7.9 Hz, 1H), 6.39 ( d, J = 7.9 Hz, 1H), 5.60 (s, 2H), 3.62-3.20 (m, 5H), 3.18-3.06 (m, 1H), 2.20 -2.02 (m, 2H).

MS [M + H] + for C24H21N9O2: theor. 468.2, fact. 468.3.

Example 187 (S) -1- [6- ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimudinyl] -1H-1,2,3-triazol-1 yl} methyl) - 2-pyridyl] -3-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 184.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.44 (brs, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 7 , 9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.79 (s, 1H), 7.72 (dd, J = 7.9, 7.9 Hz, 1H ), 7.48 (dd, J = 7.9, 7.9 Hz, 1H), 6.87 (brs, 2H), 6.43 (d, J = 7.9 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 5.60 (s, 2H), 3.62-3.20 (m, 5H), 3.18-3.06 (m, 1H), 2, 20-2.02 (m, 2H).

MS [M + H] + for C ₂₄ H ₂₁ N ₉ O ₂ : theor. 468.2, fact. 468.3.

Example 188 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-piperidinecarboxylic acid

- 98 038488

Step 1. A mixture of bromopyridine derivative (1.51 g, 5.00 mmol) and methylpiperidine-3 carboxylate (1.07 g, 7.50 mmol) in toluene (2.5 ml) was stirred at 110 ° C for 14 h. The mixture was cooled, sat. NaHCO ₃ and the mixture was extracted with ethyl acetate (3x20 ml). The crude product was purified by silica gel chromatography (0 to 5% MeOH in CH ₂ Cl ₂ ) to give the desired product as a clear oil (481 mg; 26%).

Stage 2. To a solution of the product from stage 1 (481 mg, 1.32 mmol) in THF (2.9 ml) at 0 ° C was added TBAF (1.45 ml, 1.45 mmol, 1 M in THF) dropwise ... The mixture was stirred at 0 ° C for 15 minutes. The mixture was evaporated and purified by silica gel chromatography (0 to 10% MeOH in CH2Cl2) to give the desired product.

Step 3. To a solution of the product from Step 2 and DPPA (341 μl, 1.58 mmol) in CH ₂ Cl ₂ (1.3 ml) was added DBU (236 μl, 1.58 mmol). The mixture was stirred at 40 ° C for 14 h. The mixture was evaporated and purified by silica gel chromatography (0 to 5% MeOH in CH ₂ Cl ₂ ) to give the desired product as a colorless oil (144 mg; 40%, 2 steps) ...

Step 4. The product was synthesized in the same manner as in example 125: yellow solid (12 mg, 8%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.32 (brs, 1H), 8.64 (s, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8, 47 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.82-7.78 (m, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.56-7.49 (m, 1H), 6.88 (s, 2H), 6.80 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 5.63 (s, 2H), 4.27 (d, J = 13.1 Hz, 1H), 3.99 (d, J = 13.1 Hz , 1H), 3.07-2.86 (m, 2H), 2.44-2.31 (m, 1H), 2.01-1.86 (m, 1H), 1.71-1.52 (m, 2H), 1.49-1.32 (m, 1H).

ESI-MS [M + H] + for C25H24N9O2: theor. 482.2, fact. 482.3.

Example 189 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 4-piperidinecarboxylic acid

Stage 3

2) LiOH, THF

Stage 4

Stages 1-3. An azide was synthesized in the same manner as in example 188: colorless oil (154 mg, 11%, 3 steps).

- 99 038488

Step 4. The product was synthesized in the same manner as in example 125: yellow solid (12 mg, 19%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.59 (s, 1H), 8.47 (d, J = 6.8 Hz, 1H), 8, 01 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.49 (d, J = 7.2 Hz, 1H), 5.65 (s, 2H), 4.15 ( d, J = 13.1 Hz, 2H), 2.90 (t, J = 12.1 Hz, 2H), 2.48-2.42 (m, 1H), 1.82 (d, J = 13 , 1 Hz, 2H), 1.46 (q, J = 11.4 Hz, 2H).

ESI-MS [M + H] + for C25H24N9O2: theor. 482.2, fact. 482.3.

Example 190 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -III-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 2-piperidinecarboxylic acid

Stage 1. A mixture of bromopyridine derivative (3.02 g, 10.0 mmol), pipcolic acid (2.58 g, 20.0 mmol), copper (I) iodide (380 mg, 2.00 mmol), K ₂ CO ₃ (2.74 g, 20.0 mmol) and DMF (10 ml) under a nitrogen atmosphere was stirred at 110 ° C for 1 h. The mixture was cooled to room temperature, methyl iodide was added dropwise and the mixture was stirred at room temperature for 14 h. Ethyl acetate (100 ml) was added, the organic phase was washed with saturated NaCl solution (4x75 ml) and dried over Na ₂ SO ₄ . The crude product was purified by silica gel chromatography (0 to 5% MeOH in CH ₂ Cl ₂ ) to give the desired product as a clear oil (778 mg; 21%).

Steps 2, 3. An azide was synthesized in the same manner as in example 188: colorless oil (354 mg, 60% over 2 steps).

Step 4. The product was synthesized in the same manner as in example 125: yellow solid (40 mg, 28%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.55 (brs, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 8.47 (d, J = 8 , 2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.70 (m, 1H), 7.56-7 , 48 (m, 1H), 6.88 (s, 2H), 6.74 (d, J = 8.9 Hz, 1H), 6.47 (d, J = 7.4 Hz, 1H), 5 , 60 (s, 2H), 5.14 (s, 1H), 4.02 (d, J = 12.5 Hz, 1H), 3.00 (t, J = 12.6 Hz, 1H), 2 , 16 (d, J = 12.9 Hz, 1H), 1.81-1.53 (m, 3H), 1.52-1.35 (m, 1H), 1.33-1.18 (m , 1H).

ESI-MS [M + H] + for C25H24N9O2: theor. 482.2, fact. 482.3.

Example 191 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 4-piperidyl} acetic acid

- 100 038488

Stage 1. A mixture of bromopyridine derivative (1.88 g, 10.0 mmol), methyl 4-piperidyl acetate (1.57 g, 10.0 mmol), diisopropylethylamine (2.61 ml, 15.0 mmol) and toluene was stirred at 110 ° C for 2 days. The mixture was evaporated and purified by silica gel chromatography (0 to 10% MeOH in CH ₂ Cl ₂ ) to give the desired product which was used directly in the next step.

Step 2. An azide was synthesized in the same manner as in Example 188 to give the product as a yellow oil (284 mg, 10%, 2 steps).

Step 3. The product was synthesized in the same manner as in example 125: white solid (92 mg, 62%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.05 (brs, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 7 , 9 Hz, 1H), 7.99 (d, J = 6.5 Hz, 1H), 7.81 (s, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7, 51 (t, J = 8.0 Hz, 1H), 6.89 (s, 2H), 6.76 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 5.62 (s, 2H), 4.23 (d, J = 13.0 Hz, 2H), 2.75 (t, J = 12.8, 2.6 Hz, 2H), 2.14 (d, J = 6.9 Hz, 2H), 1.95-1.81 (m, 1H), 1.68 (d, J = 12.9 Hz, 2H), 1.11 (q , J = 12.8, 11.8 Hz, 2H).

ESI-MS [M + H] ⁺ for C26H26N9O: theor. 496.2, fact. 496.4.

Example 192 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimudinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 4-methyl-4-piperidinecarboxylic acid

This compound was synthesized in the same manner as in example 191.

¹ H-NMR (400 MHz, DMSO-d6) δ 12.36 (br s, 1H), 8.65 (s, 1H), 8.58 (t, J = 1.7 Hz, 1H), 8, 47 (d, J = 7.9 Hz, 1H), 7.99 (dt, J = 7.7, 1.4 Hz, 1H), 7.81 (s, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.52 (dd, J = 8.6, 7.2 Hz, 1H), 6.89 (s, 2H), 6.78 (d, J = 8.6 Hz , 1H), 6.47 (d, J = 7.2 Hz, 1H), 5.63 (s, 2H), 3.84 (d, J = 13.6 Hz, 2H), 3.14-3 , 04 (m, 2H), 1.98

1.87 (m, 2H), 1.38-1.26 (m, 2H), 1.12 (s, 3H).

ESI-MS [M + H] + for C26H26N9O: theor. 496.2, fact. 496.3.

Example 193. {4- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] -1-piperazinyl} acetic acid

Stage 1. To a solution of bromopyridine (3.0 g, 16.0 mmol), 1-Boc-piperazine (2.48 g, 13.3 mmol) in toluene (32 ml) was added KOtBu (2.24 g, 20, 0 mmol) followed by racemic BINAP (165.6 mg, 0.266 mmol) and Pd (OAc) ₂ (29.9 mg, 133 mmol). The solution was purged with nitrogen for 1 min, sealed and heated to 90 ° C for 2.5 h. The reaction solution was evaporated on celite and purified by flash chromatography on silica gel (ethyl acetate / [hexane: CH ₂ Cl ₂ 1: 1], gradient from 10 to 50%).

Stage 2. The resulting benzyl alcohol (1.0 g, 3.4 mmol) was dissolved in toluene (4.3 ml) and cooled to 0 ° C, then DPPA (0.89 ml, 4.1 mmol) and DBU were added sequentially (0.62 ml, 4.1 mmol). The reaction mixture was heated to 35 ° C and stirred for 16 hours. After that, the reaction mixture was partitioned between ethyl acetate and water, the organic layer was collected and evaporated on celite. The resulting crude material was purified by flash chromatography on silica gel (5% ethyl acetate in hexane).

Stage 3. Received benzylazide (79.5 mg, 0.25 mmol), arylalkine (55.1 mg, 0.25 mmol), CuSO ₄ pentahydrate (6.2 mg, 0.025 mmol) and Na ascorbate (10 mg, 0 , 05 mmol) was mixed in t-BuOH / H ₂ O 2: 1 (1.0 ml) and methylene chloride (0.5 ml). The reaction mixture was heated at 60 ° C for 1 h and then evaporated on celite. The crude product was purified by flash chromatography on silica gel (ethyl acetate 101 038488 tat / [hexane: CH2C12 1: 1], gradient 0 to 100%).

Step 4. The triazole product from Step 3 (127.7 mg, 0.24 mmol) was dissolved in methylene chloride (1.2 ml) and cooled to 0 ° C., followed by dropwise addition of TFA (1.2 ml). The solution was removed from the cooling bath and brought to room temperature with stirring for 2.5 hours. The resulting solution was evaporated and transferred to the next step without further purification.

Step 5. The trifluoroacetate salt product (130.9 mg, 0.24 mmol) was dissolved in THF (0.3 ml) and triethylamine (0.198 ml, 1.42 mmol) was added. After stirring for 2 hours, the reaction mixture was partitioned between saturated NaHCO ₃ and ethyl acetate. The organic phase was collected, washed with saturated NaCl solution, dried over sodium sulfate and evaporated on celite. The crude product was purified by flash chromatography on silica gel (methanol / methylene chloride 0.5 to 5%).

Step 6. To a solution of methyl ether (93.7 mg, 0.18 mmol) in THF (0.9 ml) was added LiOH (aq., 3 M, 0.061 ml) at room temperature. The reaction mixture was stirred for 16 hours and then evaporated to dryness. The resulting solid was dissolved in 1 ml H2O and 1N HCI was added. HCl (0.368 ml). The resulting solution was stirred for 10 minutes and then frozen and lyophilized to give the title compound.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.57 (s, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.81 (s, 1H), 7.73 (dd, J = 7.7, 7.7 Hz, 1H), 7.63 (dd, J = 8.6, 7.3 Hz, 1H), 6.94 (brs, 2H), 6.89 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 7.3 Hz, 1H), 5.67 (s, 2H), 4.13 (s, 2H), 3.44 (brs, 8H).

ESI-MS [M + H] + for C25H24N10O2: theor. 497.2, fact. 497.3.

Example 194 [(S) -4- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimudinyl] -1H-1,2,3-triazole-1yl} methyl) - 2-pyridyl] -3-methyl-1-piperazinyl] acetic acid

This compound was synthesized in the same manner as in example 193.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (brs, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 8 , 1 Hz, 1H), 8.00 (d, J = 7.7, 1H), 7.83 (s, 1H), 7.74 (dd, J = 7.8, 7.8 Hz, 1H) , 7.62 (dd, J = 8.6, 7.3 Hz, 1H), 7.01 (brs, 2H), 6.82 (d, J = 8.6 Hz, 1H), 6.63 ( d, J = 7.3 Hz, 1H), 5.67 (s, 2H), 4.74 (brs, 1H), 4.26-4.05 (m, 2H), 3.61-3.45 (m, 3H), 3.263.11 (m, 3H), 1.18 (d, J = 6.7Hz, 3H).

ESI-MS [M + H] + for C ₂₆ H ₂₆ N ₁₀ O ₂ : theor. 511.2, fact. 511.3.

Example 195 [(R) -4- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) - 2-pyridyl] -3-methyl-1-piperazinyl] acetic acid

This compound was synthesized in the same manner as in example 193.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 7.7, 1H), 7.83 (s, 1H), 7.74 (dd, J = 7.8, 7.8 Hz, 1H), 7.62 (dd, J = 8 , 6, 7.3 Hz, 1H), 6.96 (brs, 2H), 6.82 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H ), 5.67 (s, 2H), 4.73 (brs, 1H), 4.26-4.05 (m, 2H), 3.61-3.45 (m, 3H), 3.25- 3.11 (m, 3H), 1.18 (d, J = 6.7Hz, 3H).

ESI-MS [M + H] + for C ₂₆ H ₂₆ N ₁₀ O ₂ : theor. 511.2, fact. 511.3.

Example 196 1- {[6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] methyl} -3-pyrrolidinecarboxylic acid

Step 1. To a mixture of the dichloromethyl pyridine derivative (1.0 g, 4.7 mmol) and the HCl salt of pyrrolidine 3-methylcarboxylate in 10 ml DMF was added K ₂ CO ₃ (2.6 g, 18.4 mmol). The reaction mixture was heated at 90 ° C for 10 hours. After the mixture was cooled to room temperature, the solids were filtered off and the crude product (as a solution in DMF) was used in the next step without further purification.

Step 2. To the crude product from Step 1 (as a solution in DMF) was added NaN ₃ (336 mg, 5.2 mmol) and stirred for 10 h at room temperature. The reaction mixture was diluted with 30 ml EtOAc and then washed with H ₂ O (5x30 ml). The organic layer was dried over Na ₂ SO ₄ , evaporated and purified by silica gel chromatography to give the desired azide (582 mg, 45% over 2 steps).

Stage 3. Synthesized the specified compound analogously to example 125.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 8.76 (d, J = 1.0 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.44 (dd, J = 8.1, 1.5 Hz, 1H), 8.03-7.91 (m, 2H), 7.79 (s, 1H), 7.76 -7.70 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 6.86 (s, 2H) , 5.89 (s, 2H), 4.53 (m, 2H), 3.74 (m, 6H), 2.05 (m, 1H).

ESI-MS [M + H] + for C25H23N9O2: theor. 482.2, fact. 482.3.

Example 197 1 - {[6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] cyclopropylmethyl} -4-piperidinecarboxylic acid

Stage 1.N-butyllithium (8.4 ml, 21.0 mmol, 2.5 M in hexane). The mixture was stirred at -78 ° C for 30 min and a solution of N-methoxy-Nmethylcyclopropanamide (2.84 g, 22.0 mmol) in THF (20 ml) was added dropwise at the same temperature. The mixture was warmed to room temperature over 14 h and quenched with sat. aqueous NH ₄ Cl. Ethyl acetate (100 ml) was added and the organic phase was washed with saturated NaCl solution and dried over MgSO ₄ . The crude product was purified by silica gel chromatography (0 to 20% EtOAc in hexanes) to afford the desired product as a yellow oil (4.14 g; 71%).

Stage 2. To a solution of the product from stage 1 (1.33 g, 4.55 mmol) in MeOH (23 ml) at 0 ° C was added NaBH ₄ (190 mg, 5.00 mmol) in several portions. The mixture was stirred at room temperature for 30 minutes. Sat. Was added. NH ₄ Cl, the organic layers were extracted with ethyl acetate (2x50 ml) and dried over Na ₂ SO ₄ to give the desired product which was used directly in the next step.

Stage 3. To a solution of the product from stage 2, DMAP (56 mg, 0.455 mmol), Et ₃ N (955 μL, 6.85 mmol) and MsCl (387 μL, 5.00 mmol). The mixture was stirred at 0 ° C for 15 min and evaporated to give the desired product, which was used directly in the next step.

Step 4. A mixture of the product from step 3, methylpiperidine-4-carboxylate (716 mg, 5.00 mmol), diisopropylethylamine (1.59 ml, 9.10 mmol) and DMSO (5 ml) was stirred at 100 ° C for 6 h. The mixture was cooled, ethyl acetate (100 ml) was added and the organic phase was washed with saturated NaCl solution (4x100 ml). The crude product was purified by silica gel chromatography (0 to 10% MeOH in CH ₂ Cl ₂ ) to give the desired product as a brown oil (152 mg; 8% over 3 steps).

Stages 5-6. An azide was synthesized in the same manner as in example 79, only in the TBAF deprotection step, AcOH (25 μl, 0.436 mmol): brown oil (69 mg, 58% over 2 steps) was included.

Step 7. The product was synthesized in the same manner as in example 125: white solid

- 103 038488 (43 mg, 38%).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.59 (s, 1H), 8.47 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.82 (s, 1H), 7.78-7.71 (m, 2H), 7.35 (d, J = 7.8 Hz, 1H) , 7.10 (d, J = 7.7 Hz, 1H), 6.92 (s, 2H), 5.82 (s, 2H), 2.77 (d, J = 10.6 Hz, 2H) , 2.34 (s, 4H), 1.99-1.82 (m, 3H), 1.77 (s, 2H), 1.70 (d, J = 12.8 Hz, 2H), 1, 47 (q, J = 11.4 Hz, 2H).

ESI-MS [M + H] + for C29H30N9O2: theor. 536.2, fact. 536.3.

Example 198 1- {1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2 -pyridyl] ethyl} -4-piperidinecarboxylic acid

This compound was synthesized analogously to example 197.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 1.2 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.45 (dd , J = 8.1, 1.6 Hz, 1H), 7.97 (dd, J = 7.7, 1.3 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H) , 7.76-7.68 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.92 ( s, 2H), 5.79 (s, 2H), 3.53 (q, J = 6.8 Hz, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 1, 89 (t, J = 11.1 Hz, 2H), 1.70-1.53 (m, 3H), 1.45 (m, 2H), 1.22 (d, J = 6.7 Hz, 3H ).

ESI-MS [M + H] + for C27H27N9O2: theor. 510.2, fact. 510.3.

Example 199 1- {1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2 -pyridyl] ethyl} -3-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 197.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (m, 1H), 8.57 (s, 1H), 8.45 (d, J = 7.2 Hz, 1H), 8, 00-7.93 (m, 1H), 7.81-7.69 (m, 3H), 7.37 (dd, J = 7.9, 3.4 Hz, 1H), 7.08 (dd, J = 7.7, 4.0 Hz, 1H), 6.94 (s, 2H), 5.79 (s, 2H), 2.702.60 (m, 1H), 2.45 (s, 1H), 2.38 (m, 1H), 2.33-2.19 (m, 2H), 1.99-1.84 (m, 1H), 1.70 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H).

ESI-MS [M + H] + for C ₂₆ H ₂ 5N ₉ O ₂ : theor. 496.2, fact. 496.3.

Example 200. 1- {1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2 -pyridyl] ethyl} -3-azetidinecarboxylic acid

This compound was synthesized analogously to example 197.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.50-8.42 (m, 1H ), 7.97 (dd, J = 7.5, 1.4 Hz, 1H), 7.81-7.67 (m, 3H), 7.32 (d, J = 7.8 Hz, 1H) , 7.08 (d, J = 7.7 Hz, 1H), 6.94 (s, 2H), 5.78 (s, 2H), 3.26 (m, 1H), 3.07 (m, 2H), 2.95 (t, J = 7.1 Hz, 1H), 2.66 (m, 1H), 1.55 (m, 1H), 1.05 (d, J = 6.5 Hz, 3H).

ESI-MS [M + H] + for C25H23N9O2: theor. 482.2, fact. 482.3.

Example 201 (S) -1- [(R) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -3-pyrrolidinecarboxylic acid

- 104 038488

Stage 1. A mixture of 2-acetyl-6-methylpyridine (20.0 g, 148 mmol), benzoyl peroxide (4.78 g, 14.8 mmol, 75% in water), NBS (29.0 g, 163 mmol) and acetonitrile (300 ml) under nitrogen atmosphere was stirred at 85 ° C for 19 h. The mixture was cooled, 10% Na ₂ S ₂ O ₃ (aq.) was added and acetonitrile was removed under reduced pressure. Added water (100 ml) and sat. aqueous Na ₂ S ₂ O ₃ , the mixture was extracted with ethyl acetate (2x200 ml) and the organic phase was dried over Na ₂ SO ₄ . The crude material was purified by silica gel chromatography (0-10% EtOAc in hexane) to give a mixture of the desired product and 2-acetyl-6-methylpyridine (molar ratio 4: 1, respectively) as a yellow oil (19.98 g; 68 %).

Step 2. A mixture of material from step 1, sodium azide (7.88 g, 121 mmol) and DMSO (101 ml) was stirred at room temperature for 4 hours. Ethyl acetate (500 ml) was added. The organic phase was washed with water (4x300 ml), saturated NaCl solution (300 ml) and dried over Na ₂ SO ₄ . The crude product was purified by silica gel chromatography (0-10% EtOAc in hexanes) to afford the desired product as a colorless oil (13.8 g; 97%).

Step 3. Formic acid (8.0 ml) was added dropwise to triethylamine (13.6 ml) at 0 ° C. The mixture was degassed and then the product from step 2 (1.76 g, 10.0 mmol), RuCl (p-cymene) - [(R, R) Ts-DPEN] (64 mg, 0.100 mmol) and CH ₂ Cl ₂ (2.7 ml). The mixture was stirred at room temperature for 5 hours and evaporated on silica gel. The crude product was purified by silica gel chromatography (0 to 40% EtOAc in hexanes) to afford the desired product as a colorless oil (1.52 g; 85%).

Step 4. To a solution of NCS (1.48 g, 11.1 mmol) in THF (21 ml) at 0 ° C was added a solution of triphenylphosphine (2.91 g, 11.1 mmol) in THF (21 ml). The mixture was stirred at room temperature for 30 min and a solution of the product from step 3 (1.52 g, 8.53 mmol) in THF (2 ml) was added. The mixture was stirred at 50 ° C for 6 h and evaporated on silica gel. The crude product was purified by silica gel chromatography (0-10% EtOAc in hexanes) to afford the desired product as a colorless oil (1.28 g; 77%).

Step 5. A mixture of the product from step 4 (295 mg, 1.50 mmol), (S) -methyl pyrrolidine-3-carboxylate hydrochloride (745 mg, 4.50 mmol), K2CO3 (1.24 g, 9.00 mmol) and acetonitrile (1.5 ml) was stirred at 60 ° C for 14 hours. Water (20 ml) was added, the crude product was extracted with ethyl acetate (2x20 ml) and evaporated on silica gel. The crude product was purified by silica gel chromatography (0 to 10% MeOH in CH ₂ Cl ₂ ) to give the desired product as a colorless oil (419 mg; 97%).

Step 6. The title compound was synthesized in analogy to example 125: brown solid (111 mg, 72%).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.84-7.77 (m, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 5.5 Hz, 1H), 6.92 (s, 2H), 5.82 (s, 2H), 3.45-3.34 ( m, 1H), 2.90-2.78 (m, 1H), 2.64-2.53 (m, 3H), 2.41-2.29 (m, 1H), 1.95-1, 83 (m, 2H), 1.26 (d, J = 4.2Hz, 3H).

ESI-MS [M + H] + for C ₂₆ H ₂₆ N ₉ O ₂ : theor. 496.2, fact. 496.3.

Example 202. (R) -1 - [(R) -1- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -3-pyrrolidinecarboxylic acid

- 105 038488

This compound was synthesized analogously to example 201.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.03 -7.95 (m, 1H), 7.85-7.77 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.92 (s, 2H), 5.82 (s, 2H), 3.47-3.35 (m, 1H ), 2.93-2.82 (m, 1H), 2.78-2.68 (m, 1H), 2.63-2.52 (m, 2H), 2.41-2.31 (m , 1H), 1.97-1.82 (m, 2H), 1.31-1.22 (m, 3H).

ESI-MS [M + H] + for C26H26N9O2: theor. 496.2, fact. 496.3.

Example 203 (S) -1- [(R) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 201.

-NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.97 ( d, J = 7.8 Hz, 1H), 7.85 (dd, J = 7.8, 7.8 Hz, 1H), 7.82 (s, 1H), 7.72 (dd, J = 7 , 8, 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz,

1H), 6.89 (brs, 2H), 5.84 (s, 2H), 4.25 (q, J = 6.8 Hz, 1H), 3.58-3.47 (m, 1H), 3.06-2.96 (m, 1H), 2.76-2.61 (m, 1H), 1.99-1.77 (m, 2H), 1.68-1.48 (m, 2H ), 1.36 (d, J = 6.8 Hz, 3H).

MS [M + H] ⁺ for C26H25N9O2: theor. 496.2, fact. 496.3.

Example 204 1 - [(R) -1 - [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2-pyridyl] ethyl] -4-piperidinecarboxylic acid

This compound was synthesized analogously to example 201.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.84 (s, 1H), 8.58 (s, 1H), 8.46 (d, J = 8, 0 Hz, 1H), 8.067.93 (m, 2H), 7.83 (s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7, 8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 6.92 (s, 2H), 5.94 (s, 2H), 4.65-4.53 (m, 1H), 3.62-3.46 (m, 1H), 3.30-3.19 (m, 1H), 2.92-2.75 (m, 1H), 2.74-2.57 ( m, 1H), 2.40-2.28 (m, 1H), 1.98-1.69 (m, 4H), 1.57 (d, J = 6.7Hz, 3H).

LC-MS: retention time 3.25 min, method A; ESI-MS [M + H] ⁺ for C ₂₇ H ₂₈ N ₉ O ₂ : theor. 510.2, fact. 510.3.

Example 205. (R) -1 - [(R) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -3-piperidinecarboxylic acid

This compound was synthesized analogously to example 201.

-NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.88 (s, 1H), 8.60 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.067.92 (m, 2H), 7.87 (s, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 6.99 (s, 2H), 5.93 (s, 2H), 4.66 (s, 1H), 3, 71-3.61 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.08 (m, 1H), 3.06-2.83 (m, 1H), 2.832.67 (m, 1H), 2.67-2.54 (m, 1H), 1.98-1.83 (m, 1H), 1.82-1.63 (m, 2H), 1, 58 (d, J = 6.8 Hz, 3H), 1.39-1.24 (m, 1H).

LC-MS: retention time 2.35 min, method A; ESI-MS [M + H] ⁺ for C ₂₇ H ₂₈ N ₉ O ₂ : theor. 510.2, fact. 510.3.

Example 206 (S) -1- [(R) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -3-piperidinecarboxylic acid

- 106 038488

This compound was synthesized analogously to example 201.

1H-NMR (400 MHz, CD3OD) δ 9.05 (s, 1H), 8.48 (s, 1H), 8.41-8.35 (m, 1H), 7.94 (d, J = 8 , 1 Hz, 1H), 7.877.79 (m, 1H), 7.75 (s, 1H), 7.71-7.61 (m, 1H), 7.59-7.53 (m, 1H) , 7.52-7.43 (m, 2H), 5.88 (s, 2H), 4.47 (m, 1H), 3.07 (m, 1H), 2.79 m, 4H), 1 , 95 (m, 2H), 1.84-1.74 (m, 1H), 1.63 (d, J = 4.5Hz, 3H), 1.53 (m, 1H).

ESI-MS [M + H] + for C ₂₇ H ₂₇ N ₉ O ₂ : theor. 510.2, fact. 510.3.

Example 207 1 - [(R) -1 - [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1 H-1,2,3-triazol-1 yl } methyl) -2-pyridyl] propyl] -4-piperidinecarboxylic acid

This compound was synthesized analogously to example 201.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.56 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 7, 97 (d, J = 7.8, 1H), 7.78 (s, 1H), 7.77-7.67 (m, 2H), 7.22 (d, J = 7.8 Hz, 1H) , 7.15 (d, J = 7.8 Hz, 1H), 6.88 (brs, 2H), 5.81 (s, 2h), 3.47-3.35 (m, 2H), 2, 79-2.59 (m, 2H), 1.95-1.28 (m, 8H), 0.66 (t, J = 7.4Hz, 3H).

MS [M + H] + for C2 ₈ H2 ₉ N ₉ O2: theor. 524.2, fact. 524.4.

Example 208 1 - [(S) -1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl ) -2-pyridyl] ethyl] - 3-azetidinecarboxylic acid

This compound was synthesized analogously to example 201.

1H-NMR (400 MHz, CD3OD) δ 9.04-8.95 (brm, 1H), 8.57 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8, 02-7.89 (m, 3H), 7.75 (dd, J = 8.1 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 5.91 (s, 1H), 4.85-4.73 (m, 1H), 4.54-4.38 (m, 2H), 4.22-4, 09 (m 1H), 4.05-3.97 (m, 1H), 3.75-3.67 (m, 0.5H), 3.59-3.49 (m, 0.5H), 1 , 53 (d, J = 6.3 Hz, 3H).

ESI-MS [M + H] + for C25H23N9O2: theor. 482.2, fact. 482.3.

Example 209 (R) -1 [(S) - 1- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1 H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] - 3-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 201.

1H-NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 8.45 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.94-7, 87 (m, 1H), 7.847.78 (m, 1H), 7.74 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7 , 9 Hz, 2H), 5.93-5.78 (m, 2H), 4.50-4.40 (m, 1H), 3.46 (m, 1H), 3.32-2.97 ( m, 4H), 2.30-2.14 (m, 2H), 1.60 (d, J = 5.3 Hz, 3H).

ESI-MS [M + H] + for C ₂ 6H2 ₅ N9O2: theor. 496.2, fact. 496.3.

Example 210. (S) -1 - [(S) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1 H-1,2,3- triazol-1 yl} methyl) -2-pyridyl] ethyl] - 3-pyrrolidinecarboxylic acid

CO ₂ H

This compound was synthesized analogously to example 201.

- 107 038488

1H-NMR (400 MHz, CD3OD) δ 9.53 (brs, 1H), 8.67-8.61 (m, 2H), 8.19 (brs, 1H), 8.00 (m, 2H), 7.77 (brs,

1H), 7.60 (brs, 1H), 7.49 (brs, 1H). 5.98 (s, 2H), 4.69 (m, 1H), 4.06-3.98 (m, 1H), 3.58-3.48 (m, 2H), 3.29-3, 16 (m, 1H), 2.50-2.29 (m, 2H).

ESI-MS [M + H] ⁺ for C26H25N9O2: theor. 496.2, fact. 496.3.

Example 211. (R) -1 - [(S) -1- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triαzole -1yl} methyl) -2-pyridyl] ethyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized analogously to example 201.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.59 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.83 (dd, J = 8.0, 8.0 Hz, 1H), 7.72 (dd, J = 8.0, 8.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.90 (brs, 2H), 5.85 (d, J = 15.2 Hz, 1H), 5.79 (d, J = 15.2 Hz, 1H), 5.74 (s, 2H), 4.26 (q, J = 6.6 Hz, 1H), 3.783.70 (m, 1H), 3.06-2.90 (m, 1H), 2.64 (q, J = 8.4 Hz, 1H), 2, 10-2.04 (m, 1H), 1.67-1.54 (m, 1H), 1.37 (d, J = 6.6Hz, 3H).

MS [M + H] + for C ₂₆ H ₂₅ N ₉ O ₂ : theor. 496.2, fact. 496.3.

Example 212 (R) -1 - [(S) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -3-piperidinecarboxylic acid

This compound was synthesized analogously to example 201.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.58 (s, 1H), 8.50-8.43 (m, 1H), 8.04-7, 94 (m, 2H), 7.82 (s, 1H), 7.79-7.70 (m, 1H), 7.60-7.50 (m, 1H), 7.43 (d, J = 7.9 Hz, 1H), 6.97-6.82 (brs, 2H), 5.93 (s, 2H), 4.67 (s, 1H), 3.71-3.61 (m, 1H ), 3.59-3.52 (m, 1H), 3.24-3.08 (m, 1H), 3.06-2.83 (m, 1H), 2.83-2.67 (m , 1H), 2.67-2.54 (m, 1H), 1.98-1.83 (m, 1H), 1.82-1.63 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.39-1.24 (m, 1H).

LC-MS: retention time 2.27 min, method A; ESI-MS [M + H] + for C ₂₇ H ₂₈ N ₉ O ₂ : theor. 510.2, fact. 510.4.

Example 213 (S) -1- [(S) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -3-piperidinecarboxylic acid _g with ₂ n

This compound was synthesized analogously to example 201.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.89-8.85 (m, 1H), 8.58 (s, 1H), 8.47 (d, J = 8.1 Hz, 1H) , 8.01-7.95 (m, 2H), 7.86-7.85 (m, 1H), 7.73 (dd, J = 7.9, 7.9 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.43 (dd, J = 6.8 Hz, 1H), 6.96 (brs, 2H), 5.91 (s, 2H), 4.64 (brs, 1H), 3.66-3.63 (m, 0.5H), 3.54-3.51 (m, 0.5H), 3.32-3.30 (m, 0.5H) , 3.18-3.14 (m, 0.5H), 1.89-1.67 (m, 3H), 1.60-1.58 (m, 3H), 1.39-1.21 ( m, 1H).

ESI-MS [M + H] + for C ₂₇ H ₂₇ N ₉ O ₂ : theor. 510.2, fact. 510.3.

Example 214 (S) -1- [(S) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -2-piperidinecarboxylic acid

This compound was synthesized analogously to example 201.

¹ H-NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 8.48-8.41 (m, 1H), 8.39-8.27 (m, 1H), 7.93 ( td, J = 7.8, 0.9 Hz, 1H), 7.80 (dq, J = 7.7, 1.1 Hz, 1H), 7.74 (s, 1H), 7.68-7 , 59 (m, 1H), 7.55-7.44 (m, 2H), 5.90 (s, 2H), 3.65 (s, 1H), 3.35-3.23 (m, 1H ), 3.21-2.81 (m, 1H), 2.20-2.04 (m, 1H), 2.00-1.74 (m, 1H), 1.73-1.32 (m , 8H).

LC-MS: retention time 2.32 min, method A; ESI-MS [M + H] + for C ₂₇ H ₂₈ N ₉ O ₂ : theor. 510.2, fact. 510.4.

Example 215 (R) -1 - [(S) -1 - [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole -1 yl} methyl) -2-pyridyl] ethyl] -2-piperidinecarboxylic acid

- 108 038488

This compound was synthesized analogously to example 201.

1H-NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.47 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.95 (dd, J = 7.8, 7.8 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.77 (s, 1H), 7.66 (dd, J = 7.8 , 7.8 Hz, 1H), 7.54-7.50 (m, 2H), 5.92 (s, 2H), 3.68 (m, 1H), 3.31-3.29 (m, 1H), 3.16 (m, 1H), 3.02 (m, 1H), 2.17-2.14 (m, 1H), 1.88 (m, 1H), 1.65-1.51 (m, 6H).

ESI-MS [M + H] + for C ₂₇ H ₂₇ N ₉ O ₂ : theor. 510.2, fact. 510.3.

Example 216 1 - [(S) -1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2-pyridyl] ethyl] -4-piperidinecarboxylic acid he

This compound was synthesized analogously to example 201.

¹ H-NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.93 (s, 1H), 8.63-8.53 (m, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.05-7.92 (m, 2H), 7.88 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7, 57 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 5.93 (s, 2H), 4.58 (m, 1H), 3, 52-3.44 (m, 1H), 3.22 (m, 1H), 2.83 (m, 1H), 2.65 (m, 1H), 2.32 (m, 1H), 1.94 -1.74 (m, 4H), 1.56 (d, J = 6.4Hz, 3H).

ESI-MS [M + H] + for C27H27N9O2: theor. 510.2, fact. 510.3.

Example 217 1 - [(S) -1- [6 - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) -2-pyridyl] propyl] -4-piperidinecarboxylic acid

This compound was synthesized analogously to example 201.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.56 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 7, 97 (d, J = 7.8, 1H), 7.78 (s, 1H), 7.77-7.67 (m, 2H), 7.22 (d, J = 7.8 Hz, 1H) , 7.15 (d, J = 7.8 Hz, 1H), 6.88 (brs, 2H), 5.81 (s, 2H), 3.47-3.35 (m, 2H), 2, 79-2.59 (m, 2H), 1.95-1.28 (m, 8H), 0.66 (t, J = 7.4Hz, 3H).

MS [M + H] + for C ₂₈ H ₂₉ N ₉ O ₂ : theor. 524.2, fact. 524.4.

Example 218. m- {6- [1 - ({6 - [(R) -1- (Methylsulfonulamino) etul] -2-pyridyl} methyl) -1H-1,2,3-triαzole

4-yl] -2-amino-4-pyrimidinyl} benzonitrile

NaH

DMF, 70 ° C

CuSO ₄ '5H ₂ O Na-ascorbate

Stage 2

Stage 1

Stage 1. Into an ice-cooled solution of methanesulfonamide (68.2 mg, 0.717 mmol, 2.0 eq.) In DMF (0.2 ml) was added NaH (60% dispersion in oil, 29 mg, 0.717 mmol, 2.0 eq. .). The resulting mixture was stirred at 0 ° C for 20 minutes. A solution of 2 - [(S) -1-chloroethyl] -6 (azidomethyl) pyridine derivative (example 201, step 4, 70.5 mg, 0.358 mmol, 1.0 eq.) In DMF (0.2 ml) was added and the resulting mixture was heated to 70 ° C and stirred at this temperature for 16 h. Then the reaction mixture was cooled to 0 ° C and the residual NaH was quenched by the addition of H2O. The mixture was extracted with EtOAc (3x3 ml). The combined extracts were washed with saturated NaCl solution, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH gradient) to give the product (23.3 mg, 25% yield).

- 109 038488

Stage 2. Performed in the same way as in example 1 (stage 6).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.52-8.41 (m, 2H), 8.35-8.28 (m, 1H), 7.87 (s, 1H), 7.80 -7.68 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.30-7.19 (m, 2H), 5.84-5.76 (m, 1H ), 5.73 (d, J = 6.1 Hz, 2H), 5.27 (s, 3H), 4.75 (p, J = 7.1 Hz, 1H), 2.77 (s, 3H ), 1.54 (d, J = 6.8 Hz, 3H).

LC-MS: retention time 2.61 min, method A; ESI-MS [M + H] ⁺ for C ₂₂ H ₂₂ N ₉ O ₂ S: theor. 476.2, fact. 476.3.

Example 219. m- {6- [1 - ({6 - [(S) -1 - (Methylsulfonylamino) ethyl] -2-pyridyl} methyl) -1H-1,2,3-triazole

4-yl] -2-amino-4-pyrimidinyl} benzonitrile

SO ₂ Me

NH

CN

This compound was synthesized by 2 - [(R) -1-chloroethyl] -6- (azidomethyl) pyridine.

analogously to example 218, only ¹ H-NMR (400 MHz, chloroform-d) δ 8.52-8.41 (m, 2H), 8.35-8.28 (m, 1H), 7.87 (s , 1H), 7.80-7.68 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.30-7.19 (m, 2H), 5.84- 5.76 (m, 1H), 5.73 (d, J = 6.1 Hz, 2H), 5.27 (s, 3H), 4.75 (p, J = 7.1 Hz, 1H), 2.77 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H).

LC-MS: retention time 2.61 min, method A; ESI-MS [M + H] + for C ₂₂ H ₂₂ N ₉ O ₂ S: theor. 476.2, fact. 476.2.

Example 220. m- [2-Amino-6- (1 - {[6- (methylsulfonylamino) -2-pyridyl] methyl} -III-1,2,3-triazol-4yl) -4-pyrimidinyl] benzonitrile h ₂ n

CuSO ₄ "5H ₂ O

Na-ascorbate / sCI, Et ₃ N, D

2.NaN ₃ , DMF

Stage 1

CN

Stage 1. A mixture of amino alcohol (250 mg, 2 mmol) and triethylamine (1.5 ml) in CH ₂ Cl ₂ (8 ml) was cooled to -78 ° C. Mesyl chloride (575 μl, 6 mmol) was added and the resulting mixture was stirred at -78 ° C to room temperature overnight. Celite was added and the mixture was evaporated to dryness. Purification by chromatography on silica gel (hexane / EtOAc 90:10 to 60:40) afforded the trimesylated product (538 mg, 75%).

The above compound (538 mg, 1.5 mmol) was dissolved in DMF (3 ml) and sodium azide (146 mg, 2.25 mmol) was added. The resulting mixture was stirred at 50 ° C for 3 h. After the usual work-up, the residue was purified by silica gel chromatography (hexane / EtOAc 90:10 to 70:30) to give the title azide (415 mg, 93%).

Stage 2. Synthesized m- {2-amino-6- [1 - ({6- [bis- (methylsulfonyl) amino] -2-pyridyl} methyl) -1H1,2,3-triazol-4-yl] -4 -pyrimidinyl} benzonitrile in the same manner as in Step 6 of Example 1 using bis- (methylsulfonyl) [6- (azidomethyl) -2-pyridyl] amine and m- [6-ethynyl-2- (methylamino) -4pyrimidinyl] benzonitrile.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.58 (s, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.05 (dd, J = 7.8, 7.8 Hz, 1H), 8.01-7.95 (m, 1H), 7.79 (s, 1H), 7.76-7.65 (m, 2H ), 7.49 (d, J = 7.8 Hz, 1H), 6.90 (brs, 2H), 5.95 (s, 2H), 3.55 (s, 6H).

MS [M + H] ⁺ for C ₂₁ H ₁₉ N ₉ O ₄ S ₂ : theor. 526.1, fact. 526.3.

Stage 3. Dissolved m- {2-amino-6- [1 - ({6- [bis- (methylsulfonyl) amino] -2-pyridyl} methyl) -1H1,2,3-triazol-4-yl] -4 β-pyrimidinyl} benzonitrile (110 mg, 0.2 mmol) in THF (1 ml) and a solution of TBAF (1 M in THF, 0.3 ml) was added. The solution was stirred at room temperature for 2 hours. The crude mixture was loaded directly onto silica gel and purified by chromatography (hexane / EtOAc 90:10 to 0: 100) to afford the title compound (78 mg, 87%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 8 , 0 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.77-7.66 (m, 2H), 6.99 (d , J = 7.4 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 3.18 (s , 3H).

MS [M + H] ⁺ for C20H17N9O2S: theor. 448.1, fact. 448.3.

Example 221 m- {2-Amino-6- [1 - ({6 - [(methylsulfonylamino) methyl] -2-pyridyl} methyl) -1H-1,2,3triazol-4-yl] -4-pyrimidinyl} benzonitrile

- 110 038488

Stage 3

Step 1. Dissolve the dichloride-HCl salt (2.5 g, 11.8 mmol) in DMF (20 ml). KHCO3 (2.36 g, 23.6 mmol) and potassium phthalimide (4.37 g, 23.6 mmol) were added and the resulting mixture was stirred for 2 days. After work up (CH ₂ Cl ₂ / H ₂ O), the residue was purified by chromatography (hexane / EtOAc 90:10 to 70:30) to give the phthalimide derivative (2.0 g, 59%).

The product obtained above (2.0 g, 7 mmol) and sodium azide (683 mg, 10.5 mmol) were mixed in DMF (10 ml). The mixture was stirred overnight at room temperature and then partitioned between CH ₂ Cl ₂ and water. The organic layer was evaporated to dryness and the residue was purified by silica gel chromatography (hexane / EtOAc 95:15 to 80:20) to give the corresponding azide (1.8 g, 88%).

Step 2. The product from Step 1 (1.4 g, 4.77 mmol) was dissolved in EtOH (12 ml) and hydrazine hydrate (300 μl, 5.25 mmol) was added. The resulting mixture was stirred for 1 h at room temperature and 5 h at 50 ° С. Excess solvent was removed in vacuo and the crude material was adsorbed onto silica gel and purified by silica gel chromatography (CH ₂ Cl ₂ / MeOH 100: 0 to 90:10) to afford the primary amine (500 mg, 64%). Primary amine (500 mg, 3 mmol) and triethylamine (1 ml) were mixed in CH ₂ Cl ₂ (5 ml) and the mixture was cooled to -30 ° C. Mesyl chloride (232 μl, 3 mmol) was added and the mixture was stirred at -30 ° C to room temperature overnight. Celite was added and the mixture was evaporated to dryness and then purified by silica gel chromatography (hexane / EtOAc 90:10 to 70:30) to give the mesylated azide (150 mg, 21%).

Stage 3. Synthesized the specified compound in the same way as in stage 6 of example 1.

¹ H-NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.69 (dd, J = 7.8, 7.8 Hz, 1H), 7.50-7.37 (m, 2H), 7.29-7.22 (m, 1H), 7.22-7.12 (m, 2H), 7.07 (d, J = 7.8 Hz, 1H), 6.90 (s , 1H), 5.68 (s, 2H), 4.98 (bs, 2H), 4.57 (s, 2H), 3.48 (d, J = 0.8 Hz, 3H).

MS [M + H] + for C ₂₁ H ₁₉ N ₉ O ₂ S: theor. 462.1, fact. 462.2.

Example 222 m- {2-Amino-6- [1 - ({6- [1,1-dimethyl-2- (methylsulfonylamino) ethyl] -2-pyridyl} methyl) 1H-1,2,3-triazole- 4-yl] -4-pyrimidinyl} benzonitrile

BUT.

TsCI, KON

From 0 ° C to 25 ° C

OTBS _______ — _____ TsO.

h

Stage 1

KCN DMSO .OTBS ---------- ► ° C. 5 h 43% (2 stages)

Stage 2

NC. OTBS

OTBS

OTBS

DPPA, DBU

Toluene ° C, 1 h 92%

Stage 7

MsCI, Et ₃ N CH ₂ CI ₂ , 40 ° C

28%

Stage 5

Stage 8

CuSO ₄ -5H ₂ O

Na-ascorbate

56%

Stage 3

1) LiAIH ₄ , THF from 0 ° C to 25 ° C '2) TBSCI, ^NC imidazole m' 73% (2 stages)

Stage 4

TBAF, THF

82%

Stage 6

NaH, Mel DMF

N ₃

Step 1. Powdered KOH (8.7 g, 154.8 mmol) was added to monoprotected 2,6-pyridinedimethanol (19.6 g, 77.4 mmol) in THF (390 mL) at 0 ° C. The solution was stirred at 0 ° C for 30 min and then TsCl (19.2 g, 100.7 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 18 h, filtered, and the filtrate was evaporated to an oil, which was used further without further purification.

- 111 038488

Step 2. KCN (5.2 g, 80 mmol) was added to the product from step 1 (77.4 mmol) in DMSO (150 ml) at room temperature. The reaction mixture was heated to 40 ° C for 5 h. The resulting solution was cooled to room temperature and washed twice with MTBE. MTBE was collected and washed with water, and organic matter was evaporated on celite. The crude product was purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 5 to 25%). Yield: 8.63 g (43%, 2 steps).

Step 3. The benzyl nitrile product from step 2 (5 g, 19.0 mmol) was dissolved in THF (38 ml), KOtBu (1.0 M in THF, 41.8 ml, 41.8 mmol) was added at room temperature and stirred within 1 min. Then MeI (2.6 ml, 41.8 mmol) was added in one portion and the reaction mixture was stirred for 10 min. The solution was partitioned between ethyl acetate and water, the organic layer was collected, evaporated on celite and purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 0 to 10%). Yield: 2.79 g (51%).

Stage 4. A solution of LiAlH4 (2.3 M in 2-Me-THF, 0.87 ml, 2 mmol) was cooled to 0 ° C and the tertiary nitrile product from stage 3 (500 mg, 1.72 mmol) was slowly added in THF (3.4 ml). The reaction mixture was stirred for 7 h at room temperature, cooled again to 0 ° C, and carefully quenched with water. The reaction mixture was filtered through celite and evaporated. The residue was dissolved in methylene chloride (9.0 ml) and cooled to 0 ° C, and then TBSCl (260 mg, 1.72 mmol) and imidazole (117 mg, 1.72 mmol) were added. After 30 min, the solution was evaporated on celite and the crude material was purified by flash chromatography on silica gel (methanol / ethyl acetate, gradient 0 to 70%). Yield: 370 mg (73%, 2 steps).

Step 5. To a solution of the amine product from step 4 (370 mg, 1.26 mmol) and triethylamine (0.176 ml, 1.26 mmol) in methylene chloride (2.5 ml) was added methanesulfonyl chloride (0.1 ml, 1.26 mmol ). The reaction mixture was warmed to 40 ° C and stirred for 16 h. The resulting solution was partitioned between ethyl acetate and water, the organic layer was evaporated on celite and the crude material was purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 20 to 100%). Yield: 130.3 mg (28%).

Step 6. To a solution of the sulfonamide product from Step 5 (130.3 mg, 0.35 mmol) in THF (1.8 ml) was added TBAF (1.0 M in THF, 0.35 ml, 0.35 mmol). The reaction was evaporated on celite and the resulting crude product was purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 30% to 100%). Yield: 74.3 mg (82%).

Step 7. Pyridyl alcohol product from step 5 (74.3 mg, 0.29 mmol) was dissolved in toluene and DPPA (0.075 ml, 0.35 mmol) and DBU (0.053 ml, 0.35 mmol) were added sequentially. The solution was heated to 50 ° C for 1 hour. Then the reaction mixture was partitioned between ethyl acetate and water, and the organic layer was evaporated on celite. The resulting crude product was purified by flash chromatography on silica gel (ethyl acetate / hexane, gradient 20% to 40%). Yield: 75.2 mg (92%).

Stage 8. This stage was performed according to stage 6 of example 1.

¹ H-NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.34-8.31 (m, 2H), 7.90 (s, 1H), 7.77-7.69 ( m, 2H), 7.61 (dd, J = 7.8, 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 7 , 8 Hz, 1H), 5.72 (s, 2H), 5.28 (brt, J = 6.6 Hz, 1H), 5.18 (brs, 2H), 3.35 (d, J 6, 6 Hz, 2H), 2.94 (s, 3H), 1.36 (s, 6H).

ESI-MS [M + H] ⁺ for C24H25N9O2S: theor. 504.2, fact. 504.3.

Example 223. 3- {2-Amino-6- [1 - ({6- [1,1-dimethyl-2- (methylsulfonylamino) ethyl] -2-pyridyl} methyl) 1H-1,2,3-triazole- 4-yl] -4-pyrimidinyl} -2-fluorobenzonitrile

This compound was synthesized analogously to example 222.

¹ H-NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.30 (dd, J = 7.6, 7.6 Hz, 1H), 7.91 (s, 1H), 7 , 75-7.70 (m, 2H), 7.40 (dd, J = 7.8, 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7, 16 (d, J = 7.6 Hz, 1H), 5.72 (s, 2H), 5.28 (bs, 2H), 5.20 (brs, 1H), 3.34 (d, J = 5 , 3 Hz, 2H), 2.94 (s, 3H), 1.36 (s, 6H).

ESI-MS [M + H] + for C24H24FN9O2S: theor. 522.2, fact. 522.2.

Example 224 m- [2-Amino-6- (1 - {[m- (methoxymethyl) phenyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

1H-NMR (400 MHz, CDCl3) δ 8.49-8.44 (m, 1H), 8.31 (ddd, J = 8.0, 1.8, 1.2 Hz, 2H), 8.09 (s, 1H), 7.90 (s, 1H), 7.76 (dt, J = 7.8, 1.3 Hz, 1H), 7.64-7.57 (m, 1H), 7, 41-7.31 (m, 3H), 5.61 (s, 2H), 5.11 (s, 2H), 4.46 (s, 2H), 3.42 (s, 3H).

ESI-MS [M + H] + for C22H19N7O: theor. 398.2, fact. 398.3.

Example 225 m- [2-Amino-6- (1- {[p- (2-methoxyethoxy) phenyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

- 112 038488

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, CDCl ₃ ) δ 8.46 (td, J = 1.7, 0.6 Hz, 1H), 8.31 (ddd, J = 8.0, 1.8, 1.2 Hz, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.76 (ddd, J = 7.7, 1.7, 1.2 Hz, 1H), 7.60 (td, J = 7.8, 0.6 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 5 , 54 (s, 2H), 5.10 (s, 2H), 4.21-4.03 (m, 2H), 3.89-3.66 (m, 2H), 3.46 (s, 3H ).

ESI-MS [M + H] + for C ₂₃ H ₂₁ N ₇ O ₂ : theor. 428.2, fact. 428.3.

Example 226 m- (2-Amino-6- {1- [(2,4-difluorophenyl) methyl] -1H-1,2,3-triazol-4-yl} -4pyrimidinyl) benzonitrile

This compound was prepared analogously to example 20 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, CDCl ₃ ) δ 8.46 (td, J = 1.8, 0.6 Hz, 1H), 8.31 (ddd, J = 8.0, 1.8, 1.2 Hz, 1H), 8.17 (d, J = 0.6 Hz, 1H), 7.90 (s, 1H), 7.76 (ddd, J = 7.7, 1.7, 1.2 Hz , 1H), 7.61 (td, J = 7.8, 0.6 Hz, 1H), 7.37 (td, J = 8.6, 8.2, 6.1 Hz, 1H), 6, 93 (dddd, J = 10.8, 7.8, 4.2, 2.5 Hz, 2H), 5.64 (s, 2H), 5.12 (s, 2H).

ESI-MS [M + H] ⁺ for C2oHi _{3 F2N 7} : theor. 390.1, fact. 390.2.

Example 227. m - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) benzoic acid

This compound was prepared analogously to example 125 from the corresponding azide and alkyne.

-NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 8.51 (s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 7.96 -7.83 (m, 3H), 7.73 (s, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H) , 7.48 (t, J = 7.9 Hz, 1H), 6.85 (s, 2H), 5.75 (s, 2H), 5.70 (d, J = 2.1 Hz, 1H) ...

ESI-MS [MH] ^- for C ₂₁ H ₁₅ N ₇ O ₂ : theor. 396.1, fact. 396.1.

Example 228 o - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1 H-1,2,3-triazol-1 yl} methyl) benzoic acid

This compound was prepared analogously to example 125 from the corresponding azide and alkyne.

ESI-MS [MH] ^- for C ₂₁ H ₁₅ N ₇ O ₂ : theor. 396.1, fact. 396.1.

Example 229 [o - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) phenyl] acetic acid

This compound was prepared analogously to example 125 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, DMSO-d6) δ 8.58 (dt, J = 1.8, 1.0 Hz, 1H), 8.51 (s, 1H), 8.46 (ddd, J = 8 , 0, 1.8, 1.1 Hz, 1H), 8.00 (dt, J = 7.7, 1.3 Hz, 1H), 7.79 (s, 1H), 7.77-7, 69 (m, 1H), 7.38-7.26 (m, 3H), 7.22 (dd, J = 7.9, 2.0Hz, 1H), 6.90 (s, 2H), 5 , 75 (s, 2H), 3.80 (s, 2H).

ESI-MS [M + H] ⁺ for C22Hi ₇ N ₇ O2: theor. 412.1, fact. 412.2.

Example 230 [m - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) phenyl] acetic acid

Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to give the compound as a tan solid.

Ή-NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.87 (s , 1H), 7.76 (d,

- 113 038488

J = 7.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.40-7.28 (m, 3H), 5.58 (s, 2H), 3, 67 (s, 2H).

One aromatic hydrogen is masked by residual solvent.

ESI-MS [M + H] + for C ₂₂ H ₁₇ N ₇ O ₂ : theor. 412.2, fact. 412.3.

Example 231 2- [m - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) phenyl] -2-methylpropionic acid

This compound was prepared analogously to example 125 from the corresponding azide and alkyne.

Ή-NMR (400 MHz, chloroform-d) δ 8.32 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.86 ( s, 1H), 7.797.73 (m, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.48-7.34 (m, 2H), 7.31 (s, 1H ), 7.16 (d, J = 7.4 Hz, 1H), 6.18 (s, 2H), 5.53 (s, 2H), 1.59 (s, 6H).

LC-MS: retention time 2.50 min, method A; ESI-MS [M-H] ^- for C ₂₄ H ₂₁ N ₇ O ₂ : theor. 439.2, fact. 440.3.

Example 232 3- [3 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2fluorophenyl] - 3-methylbutyric acid

Stage 6

Stage 1. Dissolved bromide A (1.03 g, 5 mmol), Pd (OAc) ₂ (34 mg, 0.15 mmol, 3 mol.%), Dppf (166 mg, 0.3 mmol, 6 mol.% ), Et ₃ N (1.4 ml, 10 mmol, 2 eq.) And butyl vinyl ether (1.94 ml, 15 mmol, 3 eq.) In EtOH (10 ml) under N2 and heated to 80 ° С. The reaction mixture was stirred overnight and cooled to ambient temperature, filtered through celite and evaporated. The residue was dissolved in 30 ml of CH ₂ Cl ₂ and 30 ml of 5% HCl and the biphasic mixture was vigorously stirred for about 1 hour. The layers were separated, the organic layer was dried, evaporated and purified by flash chromatography on SiO ₂ to give ketone B (519 mg) in the form of oil.

Stage 2. To a solution of ketone B (519 mg) and imidazole (315 mg, 4.6 mmol, 1.5 eq.) In CH ₂ Cl ₂ (10 ml) was added TBSCl (558 mg, 3.7 mmol, 1, 2 equiv.). After 30 min, ~ 3 drops of MeOH were added, followed by H2O and CH ₂ Cl ₂ . The layers were separated, the organic layer was dried and evaporated to give crude ketone C.

Stage 3. NaH (60% dispersion in mineral oil, 136 mg, 3.4 mmol, 1.1 eq.). After 20 min, a solution of ketone C (about 3.09 mmol) in THF (3 ml) was added. The reaction mixture was stirred overnight, evaporated on celite and purified by flash chromatography on SiO ₂ to give ester D (999 mg, ~ 3: 1 E: Z) as an oil.

Stage 4. To a solution of CuI (1.08 g, 5.7 mmol, 2 eq.) In Et ₂ O (6 ml) with cooling in an ice bath was added MeLi (1.6 M in THF, 5 ml, 8 mmol) ... After 15 min, Et ₂ O was removed by passing N 2 through the solution. The residue was redissolved in CH ₂ Cl ₂ (6 ml) and a solution of ester D (705 mg, 2 mmol) in CH ₂ Cl ₂ (10 ml) was added. Then TMSCl (0.72 ml, 5.7 mmol, 2 eq.) Was added and the mixture was brought to room temperature overnight. The mixture was cooled in an ice bath and quenched with 20 ml NH ₄ Cl / NH ₄ OH 1: 1 in H2O. The layers were separated, the organic layer was dried and evaporated to give crude ester E.

Step 5 The above obtained ester E was converted to the corresponding azide F according to the procedure of Example 79.

Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to obtain the title compound (66 mg).

Ή-NMR (400 MHz, DMSO-d ₆ ) 11.89 (s, 1H), 8.62 (s, 1H), 8.58 (t, J = 1.7 Hz, 1H), 8.46 ( dt, J = 8.1, 1.4 Hz,

1H), 7.99 (dt, J = 7.7, 1.3 Hz, 1H), 7.79 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7, 39-7.31 (m, 1H), 7.23-7.11 (m, 2H), 6.91 (s, 2H), 5.77 (s, 2H), 2.68 (s, 2H) , 1.42 (s, 6H).

ESI-MS [M + H] + for C25H22FN7O2: theor. 472.2, fact. 472.4.

Example 233 [m- ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1 yl} methyl) phenyl] glycolic acid

Step 1. Dissolve ketoester A (961 mg, 5 mmol) in MeCN (13.5 ml) and degas the resulting solution with N ₂ for 15 min. NBS (935 mg, 5.25 mmol, 1.05 eq.) And Bz ₂ O ₂ (61 mg, 0.25 mmol, 0.05 eq.) Were added and the reaction mixture was heated to 70 ° C for 2.5 h. The reaction mixture was cooled to ambient temperature and evaporated. The residue was purified by flash chromatography on SiO ₂ (0-20% EtOAc / hexane) to give the bromide (543 mg). Benzyl bromide (543 mg) was converted to azide B with NaN ₃ in DMSO (about 400 mg).

Step 3. Triazole C was synthesized by the general procedure for CuAAC (example 1, step 6) with azide B to obtain 36 mg of an orange wax.

Step 4. To a solution of triazole D (35 mg, 0.08 mmol) in EtOH (1 ml) was added NaBH (4.4 mg, 0.12 mmol, 1.5 eq.) At ambient temperature. The reaction mixture was stirred for 80 min and evaporated. The residue was diluted with CH ₂ Cl ₂ , washed with H ₂ O, dried and evaporated to give alcohol E (7.8 mg).

Stage 5. To a solution of alcohol E (7.8 mg, 0.017 mmol) in THF was added 1 M LiOH (34 μL, 0.034 mmol, 2 eq.). The reaction mixture was stirred overnight and evaporated to give the titled compound (7.7 mg) as a white solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.62-8.53 (m, 2H), 8.47 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7 , 35 (d, J = 6.7 Hz, 1H), 7.24 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 6.90 (s, 2H), 5.67 (d, J = 5.6Hz, 2H), 5.16 (s, 1H), 4.36 (d, J = 4.7Hz, 1H).

ESI-MS [M + H] ⁺ for C22H17N7O3: theor. 428.2, fact. 428.2.

Example 234 {[6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] methoxy} acetic acid

Step 1. To a solution of ethyl glycolate (476 μl, 5.00 mmol) in THF (10 ml) at 0 ° C was added NaH (400 mg, 10.0 mmol, 60% in oil) in one portion. The mixture was stirred at room temperature for 15 minutes. Dichloride (1.06 g; 5.00 mmol) was then added and the mixture was stirred at room temperature for 14 h. The mixture was evaporated and purified by chromatography on silica gel (0 to 75% EtOAc in hexane) to give the desired product as a colorless oils (534 mg; 44%).

- 115 038488

Stage 2. A mixture of the product from stage 1 (534 mg, 2.51 mmol), sodium azide (195 mg, 3.01 mmol) and

DMSO (5 ml) was stirred at room temperature for 2 h. MTBE (50 ml) was added, the organic phase was washed with water (4x50 ml) and dried over Na ₂ SO ₄ to give the desired product as a colorless oil (719 mg; 100% ).

Step 3. Cycloaddition and hydrolysis reactions were carried out in the same manner as in Example 125 to give the title compound: white solid (67 mg, 51%).

¹ H-NMR (400 MHz, DMSO-d6) δ 12.71 (brs, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 8, 0 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.87 (t, J = 7.8, 2.3 Hz, 1H), 7.81 (s, 1H) , 7.74 (t, J = 7.8, 2.4 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.90 (s, 2H), 5.82 (s, 2H), 4.61 (s, 2H), 4.14 (s, 2H).

ESI-MS [M + H] + for C ₂₂ H ₁₉ N ₈ O ₃ : theor. 443.2, fact. 443.2.

Example 235. {1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 2-pyridyl ] ethoxy} acetic acid

Stage 1 Stage 2

2. Li OH, THF

Stage 3

Step 1. A solution of alcohol (660 mg, 2.47 mmol) in DMF (6 ml) was treated with NaH (60% in mineral oil, 118 mg, 2.96 mmol). The mixture was stirred for 10 min and then methyl bromoacetate (280 μl, 2.96 mmol) was added. After 2 h, the reaction mixture was worked up (EtOAc / H ₂ O) and the residue was purified by silica gel chromatography (hexane / EtOAc 95: 5 to 85:15) to give the alkylated alcohol (316 mg, 38%).

Dissolve silyl ether (316 mg, 0.94 mmol) in THF (3 ml) and add acetic acid (20 μl) followed by TBAF (1 M in THF, 1.5 ml). The mixture was stirred for 2 h at room temperature and after the usual work-up, the residue was purified by silica gel chromatography (dichloromethane / hexane (1: 1) / EtOAc 95: 5 to 50:50) to give the primary alcohol (210 mg, quant.).

Stage 2. This stage was performed according to example 79, receiving azide (165 mg, 71%).

Stage 3. Received the specified compound analogously to example 125 from the corresponding azide and alkyne.

¹ H-NMR (400 MHz, chloroform-d) δ 8.44 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.10 (s, 1H), 7.89 ...

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 7, 97 (d, J = 7.8 Hz, 1H), 7.84 (dd, J = 7.8, 7.8 Hz, 1H), 7.80 (s, 1H), 7.72 (dd, J = 7.8, 7.8 Hz, 1H), 7.43 (dd, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.89 (s , 1H), 5.82 (s, 2H), 4.60-4.52 (m, 1H), 3.95 (d, J = 16.3 Hz, 1H), 3.85 (d, J = 16.3 Hz, 1H), 3.30 (s, 1H), 2.10-2.04 (m, 1H), 1.34 (d, J = 6.5 Hz, 3H).

MS [M + H] + for C ₂₃ H ₂₀ N ₈ O ₃ : theor. 457.2, fact. 457.2.

Example 236 [m - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) phenoxy] acetic acid o

Stage 2

Stage 1. A mixture of diol (2.4 g, 19 mmol), K2CO3 (4.0 g, 28.5 mmol) and methyl bromoacetate (1.80 ml, 19 mmol) in acetone (15 ml) was stirred overnight at 65 ° C. The crude mixture was filtered, evaporated to dryness and purified by silica gel chromatography (hexane / EtOAc 90:10 to 65:35),

- 116 038488 obtaining alkyl-containing phenol (1.4 g, 38%).

To a mixture of the above alcohol (1.4 g, 7.1 mmol) and DPPA (1.68 ml, 7.81 mmol) in toluene (15 ml) was added DBU (1.17 ml, 7.81 mmol). The resulting solution was stirred at 65 ° C for 4 h and then purified by silica gel chromatography (hexane / EtOAc 95: 5 to 90:10) to give the azide (1.18 g, 75%).

Stage 2. Methyl- [m - ({4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) phenoxy] acetate was synthesized in the same as in example 125.

¹ H-NMR (400 MHz, chloroform-d) δ 8.44 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.10 (s, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.59 (dd, J = 7.7, 7.7 Hz, 1H), 7 , 32 (dd, J = 7.7, 7.7 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H) , 7.88 (s, 2H), 5.57 (s, 2H), 5.16 (s, 2H), 4.63 (s, 2H), 3.79 (s, 3h).

MS [M + H] + for C23H19N7O3: theor. 442.2, fact. 442.3.

Example 237. 1- [m - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -III-1,2,3-triazole-1yl} methyl) phenylsulfonyl] -3-azetidinecarboxylic acid

Stage 1. Sulfonyl chloride (1 g, 5.24 mmol, 1.0 eq.) And azetidine hydrochloride (914 mg, 6.03 mmol, 1.15 eq.) Were mixed in CH ₂ Cl ₂ (5.24 ml, 1 M) at room temperature and added Et ₃ N (2.56 ml, 18.4 mmol, 3.5 eq.). The resulting mixture was stirred for 3 hours at room temperature. Thereafter, the reaction mixture was evaporated in vacuo to give the crude product, which was used without further purification.

Step 2. To a solution of the arena (1.40 g, 5.22 mmol, 1.0 eq.) In CH ₃ CN (74 mL, 0.07 M) was added NBS (1,02 g, 5.74 mmol, 1 , 10 eq.), And then benzoyl peroxide (75% purity, 269 mg, 0.834 mmol, 0.16 eq.). The resulting mixture was degassed by passing N ₂ for 10 min, and then the mixture was refluxed with a reflux condenser for 18 h. After that, the reaction mixture was cooled to room temperature, diluted with a mixture of CH ₂ Cl ₂ and saturated NaCl solution 1: 1 (150 ml) and extracted CH ₂ Cl ₂ (3 times). The combined extracts were dried (MgSO ₄ ), filtered and evaporated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (hexane / EtOAc gradient) to afford the product (1.36 g, 75% yield).

Step 3. To a solution of NaN ₃ (382 mg, 5.88 mmol, 1.5 eq.) In DMSO (9,19 ml, 0.64 M) at room temperature was added a solution of benzyl bromide (1.36 g, 3.92 mmol , 1.0 eq.) In DMSO (6.5 ml, 0.6 M). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was then diluted with H ₂ O / EtOAc 1: 1 (50 ml) and the mixture was extracted with EtOAc (3 times). The combined extracts were washed with H ₂ O (50 ml), saturated NaCl solution (50 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo. The resulting residue was purified by flash silica gel column chromatography (hexane / EtOAc gradient) to afford the product (699 mg, 58% yield).

Steps 4 and 5. Carried out in the same way as in example 125.

1H-NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 8.04-7 , 99 (m, 2H), 7.98 (d, J = 1.2 Hz, 1H), 7.84-7.78 (m, 1H), 7.78-7.67 (m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 5.74 (s, 2H), 5.30 (s, 2H), 4.244.13 (m, 2H), 3.87 (t, J = 7.9 Hz, 2H), 3.54-3.39 (m, 1H).

LC-MS: retention time 2.61 min, method A; ESI-MS [M-H] ^- for C ₂₄ H ₁₉ N ₈ O ₄ S: theor. 515.1, fact. 515.3.

Example 238 m- (2-Amino-6- {1 - [(o-aminophenyl) methyl] -1H-1,2,3-triazol-4-yl} -4pyrimidinyl) benzonitrile

- 117 038488

Stage 1. 4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1 - {[o- (tert-butoxycarbonylamino) phenyl] methyl} -III-1,2,3-triazole was synthesized in the same way as in Example 1, Step 6, to obtain 41 mg of a white solid.

Ή-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.58 (td, J = 1.8, 0.6 Hz, 1H), 8.49-8.43 (m , 2H), 7.99 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H), 7.79 (s, 1H), 7.77-7.71 (m, 1H), 7.38 (dd, J = 8.1, 1.6 Hz, 1H), 7.34 (td, J = 8.0, 7.5, 1.6 Hz, 1H), 7.18 (td, J = 7.4, 1.6 Hz, 1H), 7.14-7.09 (m, 1H), 6.88 (s, 2H), 5.73 (s, 2H), 1.43 (s , 9H).

ESI-MS [M + H] + for C25H24N8O2: theor. 469.2, fact. 469.4.

Stage 2. Into a suspension of 4- [2-amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1 - {[o- (tert-butoxycarbonylamino) phenyl] methyl} -1H-1,2,3-triazole (20 mg, 0.04 mmol) in CH ₂ Cl ₂ (0.4 ml) was added TFA (40 μl) at room temperature. The mixture was stirred overnight and evaporated to dryness. The residue was dissolved in EtOAc and washed with NaHCO ₃ . The organic layer was dried and evaporated to give 16 mg of a white solid.

1H-NMR (400 MHz, DMSO-d6) δ 8.57 (td, J = 1.8, 0.6 Hz, 1H), 8.45 (ddd, J = 8.0, 1.8, 1, 1 Hz, 1H), 8.43 (s, 1H), 7.99 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H), 7.78 (s, 1H), 7, 77-7.70 (m, 1H), 7.11-7.03 (m, 2H), 6.92 (s, 2H), 6.72 (dd, J = 8.5, 1.2 Hz, 1H), 6.57 (td, J = 7.4, 1.2 Hz, 1H), 5.76 (s, 1H), 5.58 (s, 2H), 5.35 (s, 2H).

ESI-MS [M + H] + for C ₂ oHi6W theor. 369.2, fact. 369.3.

Example 239 m- [2-Amino-6- (1 - {[o- (methylsulfonylamino) phenyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile

E

Step 1. Dissolve the protected aniline substrate A (750 mg) in CH ₂ Cl ₂ (12 ml) and add TFA (1.5 ml) at room temperature. The mixture was stirred for 3 hours and evaporated to dryness. The residue was dissolved in EtOAc and washed with NaHCO3. The organic layer was dried and evaporated to give aniline B (490 mg) as a yellow oil.

Step 2. Aniline B (148 mg, 1 mmol) was dissolved in CH ₂ Cl ₂ (10 ml) and Et ₃ N (0.56 ml, 4 mmol, 4 eq.) Was added. The mixture was cooled in an ice bath and MsCl (0.23 ml, 3 mmol, 3 eq.) Was added. After 15 min, the reaction mixture was quenched with 1 M HCl and extracted with CH ₂ Cl ₂ . The combined organic layers were dried, evaporated and purified by flash chromatography on SiO ₂ to give the sulfonamide C (190 mg) as a colorless oil.

Step 3. The triazole D was synthesized according to the procedure for CuAAC from Example 1, step 6 with sulfonamide C to give 100 mg of a white solid.

Step 4. Triazole D (100 mg, 0.19 mmol) was dissolved in THF (2 ml) and TBAF (1 M in THF, 0.22 ml, 0.22 mmol, 1.2 eq.) Was added at room temperature. Upon completion of the reaction by TLC, the reaction mixture was evaporated and purified by flash chromatography on SiO ₂ (MeOH / CH ₂ Cl ₂ , 0-10%) to give the title compound as a white solid (30 mg).

¹ H-NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.58 (s, 2H), 8.46 (d, J = 3.2 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.80 (s, 1H), 7.74 (t, J = 8 Hz, 1H), 7.43-7.41 (m, 2H), 7 , 32-7.30 (m, 1H), 7.14 (d, J = 8 Hz, 1H), 6.92 (bs, 2H),

- 118 038488

5.85 (s, 2H), 3.02 (s, 3H).

ESI-MS [M + H] + for ^ iHuNAS: theor. 447.1, fact. 447.3.

Example 240. 3- [2-Amino-6- (1 - {[o- (methylsulfonylamino) phenyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] -2-anisonitrile

This compound was prepared analogously to example 239 from the corresponding azide and alkyne to give 41 mg of a pink foam.

¹ H-NMR (400 MHz, DMSO-d6) 9.47 (s, 1H), 8.54 (d, J = 1.2 Hz, 1H), 8.06 (dd, J = 7.8, 1 , 7 Hz, 1H), 7.94 (dt,

J = 7.7, 1.5 Hz, 1H), 7.62 (d, J = 1.1 Hz, 1H), 7.46-7.40 (m, 2H), 7.35-7.26 (m, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.946.83 (m, 2H), 5.83 (s, 2H), 3.84 (d, J = 1, 2 Hz, 3H), 3.02 (d, J = 1.2 Hz, 3H).

ESI-MS [M + H] ⁺ for C22H20NAS: theor. 477.1, fact. 477.3.

Example 241. 1- [5 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 1,3- thiazol-2-yl] -4-piperidinecarboxylic acid

MeOH, 50 ° C

Stage 3

Step 1. Dissolve 2-chloro-5- (chloromethyl) thiazole (1.0 g, 6.0 mmol) in DMSO (30 ml) and add NaN ₃ (506 mg, 7.8 mmol). The reaction mixture was stirred at room temperature overnight, partitioned between MTBE and water, and the organic layer was evaporated on celite. The resulting crude product was purified by flash chromatography on silica gel (ethyl acetate / hexane, 10%) to provide the desired product as a white solid.

Stage 2. A cycloaddition of the azide-alkyne type was carried out analogously to example 1 (stage 6).

Stage 3. To a solution of the triazole product from stage 2 (24 mg, 0.06 mmol) in wet THF (4% H ₂ O, 0.6 ml) was added methylpiperidine-4-carboxylate (20.5 μl, 0.152 mmol) and LiOH (1 M in H ₂ O, 7 μl). The reaction mixture was heated to 60 ° C. After 36 hours, another portion of piperidine (61.5 μl, 0.456 mmol) was added and the reaction mixture was stirred for a total of 48 hours. The resulting solution was evaporated and redissolved in THF (1.0 ml) and methanol (1.0 ml). LiOH (1 M in H ₂ O, 250 μl) was added and the solution was heated to 50 ° C for 4 h. The solution was evaporated, added to a minimum volume of DMSO and purified by preparative HPLC to give the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.53 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7, 98 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.72 (dd, J = 8.0, 8.0 Hz, 1H), 6.88 (brs, 2H ), 6.80 (s, 1H), 5.53 (s, 2H), 3.76 (d, J = 12.0 Hz, 2H), 3.04 (dd, J = 12.0, 12, 0 Hz, 2H), 2.46-2.43 (m, 1H), 1.88 (d, J = 12.0 Hz, 2H), 1.55 (dd, J = 12.0, 12.0 Hz, 2H).

ESI-MS [M + H] ⁺ for C2 ₃ H21N ₉ O2S: theor. 488.2, fact. 488.2.

Example 242 1- [4 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyrimidinyl] -1H-1,2,3-triazol-1-yl} methyl) 1,3- thiazol-2-yl] -4-piperidinecarboxylic acid nh ₂ N ^ N

NaN ₃ M || J μ Cl DMSO _a / ^ N from 25 ° C to 40 ° C, CuSO ₄ * 5H ₂ O h Na-ascorbate

Stage 1 Stage 2

MeOH, 50 ° C

Stage 3

- 119 038488

This compound was obtained in the same manner as in example 241, starting from 2-chloro-4 (chloromethyl) -thiazole.

1H-NMR (400 MHz, DMSO-d6) δ 8.58-8.55 (overlap, 2H), 8.44 (d, J = 8.0 Hz, 1H), 7.98 (d,

J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.72 (dd, J = 8.0, 7.6 Hz, 1H), 7.32 (s, 1H), 5, 77 (s, 2H), 3.78-3.74 (m, 2H), 3.10-3.04 (m, 2H), 1.88-1.86 (m, 2h), 1.55- 1.53 (m, 2H).

ESI-MS [M + H] + for C23H21N9O2S: theor. 488.2, fact. 488.2.

Example 243 m- (2-Amino-6- {1 - [(1H-imidazol-2-yl) methyl] -1H-1,2,3-triazol-4-yl} -4pyrimidinyl) benzonitrile

Stage 1. A mixture of a commercial derivative of chloride (306 mg, 2 mmol) and sodium azide (390 mg, 6 mmol) in MeCN (6 ml) and DMF (1 ml) was stirred at 50 ° C for 2 h. Then cooled to room temperature. temperature and the acetonitrile was evaporated. The residue was directly purified by silica gel chromatography (Hex / EtOAc 50:50 to 0: 100) to give the desired azide (150 mg, 61%).

Step 2. The specified compound was synthesized in the same manner as in step 6 from example 1, using the azide derivative and m- (2-amino-6-ethynyl-4-pyrimidinyl) benzonitrile (from example 4).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.61-8.58 (m, 1H), 8.57 (s, 1H), 8.48-8.42 (m, 1H), 8 , 00 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H), 7.80 (s, 1H), 7.75 (dd, J = 7.7, 7.7 Hz, 1H ), 7.18 (brs, 1H), 6.93 (s, 3H), 5.74 (s, 2H).

MS [M + H] ⁺ for C17H13N9: theor. 344.4, fact. 344.2.

Example 244 m- (2-Amino-6- {1 - [(1H-pyrazol-4-yl) methyl] -1H-1,2,3-triazol-4-yl} -4pyrimidinyl) benzonitrile

This compound was synthesized in the same manner as in Step 6 of Example 1 using 4- (azidomethyl) -1H-pyrαzole and m- (2-amino-6-ethynyl-4-pyrimidinyl) benzonitrile.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (brs, 2H), 8.46 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.81 (s,

2H), 7.75 (dd, J = 7.9, 7.9 Hz, 2H), 6.90 (s, 2H), 5.60 (s, 2H).

MS [M + H] ⁺ for C ₁₇ H ₁₃ N ₉ : theor. 344.4, fact. 344.3.

Example 245 m- [2- (Isopropylamino) -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol4-yl) -4-pyrimidinyl] benzonitrile

Isopropylamine, EtOAc

SO ₂ Me ² (HO) ₂ B

CN

Me

Cl 'Cl

Me

Pd (PPh ₃ ) ₄ dioxane / Ma ₂ CO _{3 (ah)}

CN 2. Ammonia in MeOH. Me

1. TM S-acetyle n

PdCI ₂ (PPh3) ₄ Me

Cui, DMF / Et ₃ N

CN

Stage 1

Me

CN

Stage 2

MeO

N ₃

CuSO ₄ -5H ₂ O Na-ascorbate

Stage 3

Step 1. To a solution of dichlorosulfone (3.4 g, 15 mmol) in EtOAc (20 ml) at 0 ° C was added isopropylamine (1.48 ml, 18 mmol) dropwise. The resulting mixture was stirred at 0 ° C for 1 hour and then at room temperature for 1 hour. The crude mixture was partitioned between water and EtOAc. The organic layers were evaporated to dryness and purified by silica gel chromatography (hexane / EtOAc 95: 5 to 85:15) to give dichloroaminopyrimidine (2.0 g, 65%).

Dichloride (930 mg, 4.5 mmol) and boronic acid (667 mg, 4.5 mmol) were added to dioxane (15 ml) and sodium carbonate (2M in water, 5 ml) and the mixture was degassed with nitrogen for 10 min. Pd (PPh ₃ ) ₄ (255 mg, 0.23 mmol) was added and the mixture was heated to 75 ° C for 3 h. After the usual work-up, the residue was purified by chromatography on silica gel (CH2Cl2 / EtOAc 100: 0 to 90:10) to obtain the target monochloride (520 mg, 42%).

Stage 2. This stage was carried out analogously to stages 2-3 of example 1, using NH ₃ instead of

- 120 038488

TBAF in TMS deblocking stage (380 mg, 36% chloride).

Step 3. The compound was synthesized in the same manner as in Step 6 of Example 1 using 2- (azidomethyl) -6- (methoxymethyl) pyridine and m- [6-ethynyl-2- (isopropylamino) -4pyrimidinyl] benzonitrile.

-NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 7.81 (s, 1H), 7.77-7.73 (m, 1H), 7.71 (dd, J = 8.0 Hz, 1H), 7.59 (dd, J = 7.8 Hz, 1H), 7, 40 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.73 (s, 2H), 5.08 (d, J = 7.9 Hz, 1H), 4.58 (s, 2H), 4.30 (h, J = 6.7 Hz, 1H), 3.49 (s, 3H), 1.29 (d, J = 6.5 Hz, 6H).

MS [M + H] + for C ₂₄ H ₂₄ N ₈ O: theor. 441.2, fact. 441.3.

Example 246 m- [6- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (methylamino) 4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 245 using 2- (azidomethyl) 6- (methoxymethyl) pyridine and m- [6-ethynyl-2- (methylamino) -4-pyrimidinyl] benzonitrile.

¹ H-NMR (400 MHz, CDCls) δ 8.51 (s, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 7.84 (s, 1H), 7.78 -7.73 (m, 1H), 7.71 (dd, J = 7.6 Hz, 1H), 7.60 (dd, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 5.73 (s, 2H), 5.21 (q, J = 5.2 Hz, 1H), 4 , 59 (s, 2H), 3.50 (s, 3H), 3.11 (d, J = 5.2 Hz, 3H).

MS [M + H] ⁺ for C22H20N ₈ O: theor. 413.2, fact. 413.2.

Example 247 m- [2- (Dimethylamino) -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 245.

¹ H-NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.37-8.30 (m, 2H), 7.76 (s, 1H), 7.75-7.67 ( m, 2H), 7.57 (dd, J = 7.9, 7.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8 , 0 Hz, 1H), 5.73 (s, 2H), 4.58 (s, 2H), 3.48 (s, 3H), 3.28 (s, 6H).

MS [M + H] ⁺ for C23H22N ₈ O: theor. 427.2, fact. 427.3.

Example 248 m- [2- (Cyclopropylamino) -6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 245.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 7.88 ( s, 1H), 7.78-7.66 (m, 2H), 7.59 (dd, J = 7.9, 7.9 Hz, 1H), 7.40 (dd, J = 7.6 Hz , 1H), 7.11 (d, J = 7.9 Hz, 1H), 5.72 (s, 2H), 5.43 (d, J = 2.6 Hz, 1H), 4.58 (s , 2H), 3.49 (s, 3H), 2.95-2.85 (m, 1H), 0.91-0.81 (m, 2H), 0.64-0.55 (m, 2H ).

MS [M + H] ⁺ for C24H22N ₈ O: theor. 439.2, fact. 439.3.

Example 249 m- {2 - [(R) -3-Hydroxy-1-pyrrolidinyl] -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} 1H-1,2,3-triazole -4-yl) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 245.

¹ H-NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.32 (s, 1H), 8.31 (s, 1H), 7.77 (s, 1H), 7.73 -7.66 (m, 2H), 7.55 (dd, J = 7.9, 7.9 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.11 ( d, J = 7.8 Hz, 1H), 5.72 (s, 2H), 4.63 (brs, 1H), 4.58 (s, 2H), 3.78 (brs, 4H), 3, 48 (s, 3H), 2.22-2.02 (m, 3H).

MS [M + H] ⁺ for C25H24N ₈ O2: theor. 469.2, fact. 469.3.

Example 250 [6- (m-Cyanophenyl) -4- {1 - [(6-cyclopropyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -2pyrimidinylamino] acetic acid

- 121 038488

2) LiOH

This compound was synthesized in the same manner as in example 245, and the hydrolysis reaction was carried out analogously to example 125.

¹ H-NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.70 (s, 1H), 8.60 (d, J = 1.7 Hz, 1H), 8.54 -8.42 (m, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.87 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H) , 7.65 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 5 , 73 (s, 2H), 4.05 (m, 2H), 2.05 (m, 1H), 0.95-0.85 (m, 2H), 0.80 (m, 2H).

ESI-MS [M + H] + for C ₂₄ H ₂₀ N ₈ O ₂ : theor. 453.2, fact. 453.3.

Example 251. [6- (m-Cyanophenyl) -4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) 2-pyrimidinylamino] acetic acid

Stage 1. Tert-butyl- [6- (m-cyanophenyl) -4- (1 - {[6- (methoxymethyl) -2pyridyl] methyl} -1H-1,2,3-triazol-4-yl) - 2-pyrimidinylamino] acetate analogously to example 245.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.52-8.43 (m, 1H), 8.31 (m, 2H), 7.88 (d, J = 2.2 Hz, 1H), 7.76-7.65 (m, 2H), 7.57 (t, J = 7.9, 1H), 7.44-7.36 (m, 1H), 7.08 (d, J = 7 , 7 Hz, 1H), 5.79 (m, 1H), 5.71 (s, 2H), 4.57 (s, 2H), 4.16 (s, 2H), 3.47 (s, 3H ), 1.46 (s, 9H).

ESI-MS [M + H] ⁺ for CnH ^ theor. 513.2, fact. 513.3.

Stage 2. Received above tert-butyl- [6- (m-cyanophenyl) -4- (1 - {[6- (methoxymethyl) -2pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2-pyrimidinylamino] acetate was hydrolyzed with TFA to give the title compound.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1H), 8.60 (d, J = 1.7 Hz, 1H), 8.52-8.43 (m, 1H) , 7.99 (d, J = 7.6 Hz, 1H), 7.84 (m, 2H), 7.73 (t, J = 7.7 Hz, 1H), 7.65 (s, 1H) , 7.37 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 5.82 (s, 2H), 4.45 (s, 2H) , 4.06 (m, 2H), 3.33 (s, 3H).

ESI-MS [M + H] ⁺ for C ₂₃ H ₂₀ N ₈ O ₃ : theor. 457.2, fact. 457.3.

Example 252 [6- (m-Cyanophenyl) -4- (1 - {[6- (1-hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -2-pyrimidinylamino ]acetic acid

Stage 1

Stage 1. Tert-butyl- [6- (m-cyanophenyl) -4- (1 - {[6- (1-hydroxycyclopentyl) -2pyridyl] methyl} -1H-1,2,3-triazol-4-yl ) -2-pyrimidinylamino] acetate analogously to example 245.

1H-NMR (400 MHz, CDCl3) δ 8.52-8.45 (m, 1H), 8.37-8.27 (m, 2H), 7.89 (s, 1H), 7.77-7 , 66 (m, 2H), 7.617.55 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 5 , 74 (s, 2H), 4.56 (s, 1H), 4.17 (s, 2H), 2.17-1.62 (m, 8H), 1.47 (s, 9H).

ESI-MS [M + H] ⁺ for C30H32N8O3: theor. 553.3, fact. 553.3.

Stage 2. Received above tert-butyl- [6- (m-cyanophenyl) -4- (1 - {[6- (1-hydroxycyclopentyl) -2pyridyl] methyl} -1H-1,2,3-triazole-4- yl) -2-pyrimidinylamino] acetate was hydrolyzed with TFA to give the title compound.

1 H-NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1H), 8.60 (s, 1H), 8.52-8.45 (m, 1H), 8.03-7, 94 (m, 1H), 7.87 (s, 1H), 7.82-7.70 (m, 2H), 7.62 (d, J = 7.9 Hz, 2H), 7.11 (d , J = 7.6 Hz, 1H), 5.81 (s, 2H), 4.06 (s, 2H), 2.00 (m, 2H), 1.80 (m, 2H), 1.69 (m, 4H).

ESI-MS [M + H] ⁺ for C ₂₆ H24 ^ Oz: theor. 497.2, fact. 497.3.

Example 253 [6- (m-Cyanophenyl) -4- (1 - {[6- (1-methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -2-pyrimidinylamino ]acetic acid

- 122 038488

This compound was synthesized in the same manner as in example 251.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.63-8.53 (m, 1H), 8.53-8.40 (m, 1H), 7, 99 (d, J = 7.6 Hz, 1H), 7.90-7.80 (m, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.69-7.55 (m, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 5.83 (s, 2H), 4.33 (q, J = 6.4 Hz, 1H), 4.06 (m, 2H), 3.18 (s, 3H), 1.31 (d, J = 5.6 Hz, 3H).

ESI-MS [M + H] + for C24H22N8O3: theor. 471.2, fact. 471.2.

Example 254 [6- (m-Cyanophenyl) -4- (1 - {[6- (trifluoromethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4yl) -2-pyrimidinylamino] acetic acid

This compound was synthesized in the same manner as in example 251.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.60 (s, 1H), 8.52-8.45 (m, 1H), 8.14 (t, J = 7.9 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.69-7.63 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 5.97 (s, 2H), 4.05 ( s, 3H).

ESI-MS [M + H] + for C22Hi ₅ F3N ₈ O2: theor. 481.2, fact. 481.2.

Example 255 [6- (m-Cyanophenyl) -4- {1 - [(6-isopropyl-2-pyridyl) methyl] -1H-1,2,3-triazol-4-yl} -2pyrimidinylamino] acetic acid

This compound was synthesized in the same manner as in example 251.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (s, 1H), 8.60 (d, J = 1.7 Hz, 1H), 8.52-8.45 (m, 1H ), 7.99 (d, J = 7.6 Hz, 1H), 7.91-7.82 (m, 1H), 7.77-7.68 (m, 2H), 7.62 (s, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 5.80 (s, 2H), 4.10-3, 88 (m, 2H), 2.97 (sep, J = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H).

ESI-MS [M + H] + for C ₂₄ H ₂₂ N ₈ O ₂ : theor. 455.2, fact. 455.3.

Example 256 [6- (m-Cyanophenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinylamino ]acetic acid

This compound was synthesized in the same manner as in example 251.

¹ H-NMR (400 MHz, methanol-d4) δ 8.69 (s, 1H), 8.54 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.91 -7.82 (m, 2H), 7.78-7.63 (m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 5.79 (s, 2H), 4.20 (s, 2H), 1.32 (s, 9H).

LC-MS: retention time 3.20 min, method A; ESI-MS [M + H] + for C ₂₅ H ₂ 5N ₈ O ₂ : theor. 469.2, fact. 469.3.

Example 257 3- [6- (m-Cyanophenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) 2-pyrimidinylamino] propionic acid

This compound was synthesized in the same manner as in Example 250 to obtain 53 mg of a white solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 32.6 Hz, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.00 (dq, J = 8.1, 1.2 Hz, 1H), 7.84 (s, 1H), 7.80-7.71 (m, 2H), 7.50-7.35 (m, 2H ), 7.11 (s, 1H), 5.83 (s, 2H), 3.63 (s, 2H), 2.60 (t, J = 6.8 Hz, 2H), 1.31-1 , 22 (m, 9H).

ESI-MS [M + H] + for C26H26N8O2: theor. 483.2, fact. 483.4.

Example 258 (S) -2- [6- (m-Cyanophenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazole- 4yl) -2-pyrimidinylamino] propionic acid

- 123 038488

This compound was synthesized in the same manner as in Example 250 to obtain 121 mg of a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (d, J = 1.2 Hz, 1H), 8.63 (d, J = 1.4 Hz, 1H), 8.51 ( d, J = 8.0 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.94-7.85 (m, 1H), 7.76 (td, J = 7 , 9, 7.2, 3.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 5.84 (s, 2H), 4.49 (d, J = 35.1 Hz, 1H), 1.45 (d, J = 7.2 Hz, 3H), 1.26 (s, 9H).

ESI-MS [M + H] + for C26H26N8O2: theor. 483.2, fact. 483.4.

Example 259 (R) -2- [6- (m-Cyanophenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazole- 4yl) -2-pyrimidinylamino] propionic acid

This compound was synthesized in the same manner as in Example 250 to obtain 121 mg of a white solid.

1H-NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 1.2 Hz, 1H), 8.63 (d, J = 1.4 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.94-7.85 (m, 1H), 7.76 (td, J = 7.9 , 7.2, 3.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 5.84 (s , 2H), 4.49 (d, J = 35.1 Hz, 1H), 1.45 (d, J = 7.2 Hz, 3H), 1.26 (s, 9H).

ESI-MS [M + H] ⁺ for C ₂₆ H ₂₆ N ₈ O ₂ : theor. 483.2, fact. 483.4.

Example 260 3- [6- (m-Cyanophenyl) -4- (1 - {[6- (trifluoromethyl) -2-pyridyl] methyl} - 1H-1,2,3-triazol-4yl) -2-pyrimidinylamino ] propionic acid

This compound was synthesized in the same manner as in Example 250 to obtain 54 mg of a white solid.

1H-NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 33.0 Hz, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.16 ( t, J = 7.9 Hz, 1H), 8.05-7.97 (m, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 5.99 (s, 2H), 3.64 (s, 2H), 2.61 (t, J = 7.0 Hz, 2H).

ESI-MS [M + H] ⁺ for C23Hi ₇ F3N ₈ O2: theor. 495.2, fact. 495.2.

Example 261. (S) -2- [6- (m-Cyanophenyl) -4- (1 - {[6- (trifluoromethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol4-yl) -2-pyrimidinylamino] propionic acid

This compound was synthesized in the same manner as in Example 250 to obtain 38 mg of a yellowish brown solid.

1H-NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.63 (td, J = 1.8, 0.6 Hz, 1H), 8.55-8.47 (m , 1H), 8.16 (t, J = 7.9 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.94-7.86 (m, 2H), 7 , 83-7.70 (m, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 4.50 (d, J = 37.7 Hz, 1H), 1.45 (d, J = 7.3 Hz, 3H).

ESI-MS [M + H] ⁺ for C23Hi ₇ F3N ₈ O2: theor. 495.2, fact. 495.3.

Example 262 (R) -2- [6- (m-Cyanophenyl) -4- (1 - {[6- (trifluoromethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol4-yl) -2-pyrimidinylamino] propionic acid

This compound was synthesized in the same manner as in Example 250 to obtain 50 mg of a yellowish brown solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.63 (td, J = 1.8, 0.6 Hz, 1H), 8.55-8.47 ( m, 1H), 8.16 (t, J = 7.9 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.94-7.86 (m, 2H), 7.83-7.70 (m, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.00 (s,

- 124 038488

2H), 4.50 (d, J = 37.7 Hz, 1H), 1.45 (d, J = 7.3 Hz, 3H).

ESI-MS [M + H] + for C23H17F3N8O2: theor. 495.2, fact. 495.3.

Example 263 3- [6- (m-Cyanophenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) 2-pyrimidinylamino] -3-methylbutyric acid

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, DMSO-d6) δ 11.98 (brs, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.76-7.72 (m, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.01 (s, 1H), 5.82 (s, 2H), 2.91 (s, 2H), 1.53 (s, 6H), 1.23 (s , 9H).

ESI-MS [M + H] ⁺ for C2 ₈ H30N ₈ O2: theor. 511.2, fact. 511.4.

Example 264 1- [6- (m-Cyanophenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) 2-pyrimidinylamino] cyclopropanecarboxylic acid

This compound was synthesized in the same manner as in example 250.

1 H-NMR (400 MHz, CDCl ₃ ) δ 8.48-8.34 (m, 2H), 8.34-8.18 (m, 1H), 8.00-7.84 (m, 1H), 7.77-7.66 (m, 1H), 7.66-7.48 (m, 2H), 7.34-7.20 (m, 1H), 7.01 (d, J = 9.9 Hz, 1H), 6.36-6.03 (m, 1H), 5.72-5.55 (m, 2H), 1.77-1.61 (m, 2H), 1.45-1, 13 (m, 11H).

LC-MS: retention time 3.35 min, method A; ESI-MS [M + H] ⁺ for C ₂₇ H ₂₇ N ₈ O ₂ : theor. 495.2, fact. 495.3.

Example 265 1- [6 - ({4- [6- (m-Cyanophenyl) -2- (isopropylamino) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl ] -3-azetidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.53-8.42 (m, 1H), 8.00 (d, J = 7.9 Hz, 1H) , 7.80-7.70 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 6.54- 6.50 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.64 (s, 2H), 4.284.18 (m, 1H), 4.08 (t, J = 8.7 Hz, 2H), 3.95 (t, J = 7.1 Hz, 2H), 3.52-3.44 (m, 1H), 1.22 (d, J = 6.4 Hz , 6H).

ESI-MS [M + H] ⁺ for C ₂₆ H ₂₅ N ₉ O ₂ : theor. 496.2, fact. 496.3.

Example 266 1- {6 - [(4- {2 - [(R) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} -1H1,2,3-triazole-1 - yl) methyl] -2-pyridyl} -3-azetidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.55-8.44 (m, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.84 (s, 1H), 7.80-7.67 (m, 2H), 7.55 (t, J = 7.9 Hz, 1H), 6.52 (d, J = 7.3 Hz , 1H), 6.38 (d, J = 8.3 Hz, 1H), 5.65 (s, 2H), 4.55 (s, 1H), 4.13-3.91 (m, 5H) , 3.87 (q, J = 7.8 Hz, 1H), 3.75 (q, J = 7.6 Hz, 1H), 3.64-3.57 (m, 1H), 3.54- 3.46 (m, 1H), 2.51 (s, 1H), 2.26-2.17 (dd, J = 13.1, 7.1 Hz, 1H), 2.00-1.93 ( m, 1H).

ESI-MS [M + H] ⁺ for C2 ₇ H25N9O3: theor. 524.2, fact. 524.3.

Example 266. Methyl- (S) -1- [6 - ({4- [6- (m-cyanophenyl) -2- (2-hydroxy-2-methylpropylamino) -4pyrimidinyl] -1H — 1,2,3- triazol-1-yl} methyl) -2-pyridyl] -2-pyrrolidinecarboxylate

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 8.38 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.84 (s , 1H), 7.73 (d,

- 125 038488

J = 7.2 Hz, 1H), 7.58 (dd, J = 8.0, 8.0 Hz, 1H), 7.44 (dd, J = 8.0, 8.0 Hz, 1H), 6.56 (d, J = 7.2 Hz, 1H), 6.37 (d,

J = 8.0 Hz, 1H), 5.73 (brs 1H), 5.52-5.36 (m, 2H), 4.56-4.47 (m, 1H), 3.64 (s, 3H), 3.62-3.54 (m, 2H), 3.48-3.38 (m, 2H), 2.38-2.04 (m, 4H), 1.30 (s, 6H) ...

MS [M + H] + for C ₂₉ H ₃₁ N9O ₃ : theor. 554.3, fact. 554.4.

Example 267 (S) -1- [6 - ({4- [6- (m-Cyanophenyl) -2- (2-hydroxy-2-methylpropylamino) -4-pyrimidinyl] 1H-1,2,3-triazole -1 -yl} methyl) -2-pyridyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.39 (brs, 1H), 8.60 (s, 1H), 8.49 (d, J = 7.9 Hz, 1H), 7, 98 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J = 7.7 Hz, 1H), 7.50 (dd, J = 7.7 Hz, 1H), 7.00 (brs, 1H), 6.47 (d, J = 6.0 Hz, 1H), 6.39 (d, J = 8.5 Hz, 1H), 5.59 ( d, J = 15.2 Hz, 1H), 5.53 (d, J = 15.2 Hz, 1H), 4.60 (brs, 1H), 4.34 (d, J = 8.7 Hz, 1H), 3.533.33 (m, 3H), 2.27-2.12 (m, 1H), 2.06 (s, 1H), 2.04-1.84 (m, 2H), 1.14 (s, 6H).

MS [M + H] ⁺ for C28H29N9O3: theor. 540.3, fact. 540.3.

Example 268 Methyl- (R) -1- {6 - [(4- {2 - [(R) -tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4pyrimidinyl} -1H-1,2, 3-triazol-1-yl) methyl] -2-pyridyl} -2-pyrrolidinecarboxylate

This compound was synthesized in the same manner as in example 250.

^ -NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.39 (s, 1H), 8.34 (d, J = 7.8 Hz, 2H), 7.86 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.59 (dd, J = 7.8, 7.8 Hz, 1H), 7.46 (dd, J = 7.8 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.39 (d, J = 7.8Hz, 1H), 5.53-5.39 (m, 2H), 4 , 80 (brs, 1H), 4.54 (d, J = 8.0 Hz, 1H), 4.18-3.85 (m, 3H), 3.81-3.72 (m, 1H), 3.63-3.57 (m, 1H), 3.65 (s, 3H), 3.50-3.39 (m, 1H), 2.46-2.34 (m, 1H), 2, 34-2.22 (m, 1H), 2.22-2.00 (m, 3H), 2.01-1.89 (m, 1H).

MS [M + H] ⁺ for C29H29N9O3: theor. 552.3, fact. 552.4.

Example 269 (R) -1- {6 - [(4- {2 - [(R) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} 1H-1,2,3 -triazol-1-yl) methyl] -2-pyridyl} -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.41 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.84 (s , 1H), 7.78-7.69 (m, 1H), 7.56 (dd, J = 7.8, 7.8 Hz, 1H), 7.48 (dd, J = 7.2, 7 , 2 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.45 (dd, J = 8.0 Hz, 1H), 5.68 (d, J = 6.8 Hz, 1H), 5.53 (dd, J = 15.2 Hz, 1H), 5.41 (dd, J = 15.2 Hz, 1H), 5.29 (s, 2H), 4.77- 4.65 (m, 1H), 4.59-4.50 (m, 1H), 4.11-3.95 (m, 2H), 3.95-3.84 (m, 1H), 3, 72 (dd, J = 9.5, 3.8 Hz, 1H), 3.58-3.32 (m, 2H), 2.422.95 (m, 3H), 1.99-1.85 (m, 1H).

MS [M + H] ⁺ for C28H27N9O3: theor. 538.2, fact. 538.3.

Example 270. (R) -1- {6 - [(4- {2 - [(S) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} 1H-1,2,3 -triazol-1-yl) methyl] -2-pyridyl} -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, acetone-d6) δ 11.48 (brs, 1H), 8.67 (brs, 1H), 8.59 (s, 1H), 8.51 (d, J = 8, 0 Hz, 1H), 7.94-7.88 (m, 1H), 7.87 (s, 1H), 7.74 (dd, J = 8.0, 8.0 Hz, 1H), 7, 56 (dd, J = 8.5, 7.2 Hz, 1H), 6.76 (d, J = 6.6 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 6.50 (d, J = 8.5 Hz, 1H), 5.63 (s, 1H), 5.58 (s, 2H), 4.76-4.67 (m, 1H), 4.54 -4.47 (m, 1H), 4.12-4.02 (m, 1H), 3.95 (q, J = 7.4 Hz, 1H), 3.86-3.68 (m, 2H ), 3.61-3.50 (m, 1H), 3.44 (q, J = 8.2 Hz, 1H), 2.39-2.12 (m, 4H), 2.03-1, 96 (m, 1H).

MS [M + H] ⁺ for C28H27N9O3: theor. 538.2, fact. 538.3.

Example 271. (S) -1- {6 - [(4- {2 - [(S) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} 1H-1,2,3 -triazol-1-yl) methyl] -2-pyridyl} -2-pyrrolidinecarboxylic acid

- 126 038488

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CD3OD) δ 10.42 (s, 1H), 10.16 (s, 1H), 10.07 (d, J = 8.0 Hz, 1H), 9.47 (s , 1H), 9.439.34 (m, 1H), 9.25 (t, J = 7.8 Hz, 1H), 8.99 (t, J = 7.9 Hz, 1H), 8.07 (d , J = 7.1 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.11 (s, 2H), 6.29 (s, 1H), 5.79 (s , 1H), 5.71-5.63 (m, 1H), 5.58 (q, J = 7.6 Hz, 1H), 5.46 (q, J = 7.6 Hz, 1H), 5 , 33 (dd, J = 9.0, 3.9 Hz, 1H), 5.29-5.17 (m, 1H), 5.11-4.97 (m, 1H), 4.00-3 , 76 (m, 2H), 3.76-3.41 (m, 4H).

LC-MS: retention time 3.15 min, method A; ESI-MS [M + H] + for C ₂₈ H ₂₈ N ₉ O ₃ : theor. 538.2, fact. 538.4.

Example 272 (S) -1- {6 - [(4- {2- [da-T tetrahydrofuran-3 -ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} 1H-1,2,3- triazol-1-yl) methyl] -2-pyridyl} -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CD3OD) δ 10.42 (s, 1H), 10.16 (s, 1H), 10.07 (d, J = 8.0 Hz, 1H), 9.47 (s , 1H), 9.439.34 (m, 1H), 9.25 (t, J = 7.8 Hz, 1H), 8.99 (t, J = 7.9 Hz, 1H), 8.07 (d , J = 7.1 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.11 (s, 2H), 6.29 (s, 1H), 5.79 (s , 1H), 5.71-5.63 (m, 1H), 5.58 (q, J = 7.6 Hz, 1H), 5.46 (q, J = 7.6 Hz, 1H), 5 , 33 (dd, J = 9.0, 3.9 Hz, 1H), 5.29-5.17 (m, 1H), 5.11-4.97 (m, 1H), 4.00-3 , 76 (m, 2H), 3.76-3.41 (m, 4H).

LC-MS: retention time 3.15 min, method A; ESI-MS [M + H] + for C ₂₈ H ₂₈ N ₉ O ₃ : theor. 538.2, fact. 538.3.

Example 273 (S) -1- [6 - ({4- [6- (m-Cyanophenyl) -2- (cyclopropylamino) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) -2-pyridyl] -2 - pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.66 (brs, 1H), 8.63 (brs, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7, 98-7.88 (m, 1H), 7.90 (s, 1H), 7.74 (dd, J = 8.0, 8.0 Hz, 1H), 7.55 (dd, J = 8, 0.8 Hz, 1H), 6.77 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H) , 5.62 (s, 2H), 5.58 (s, 1H), 4.49 (dd, J = 8.6, 3.1 Hz, 1H), 3.61-3.39 (m, 2H ), 3.05-2.92 (m, 1H), 2.34-2.01 (m, 4H), 0.90-0.75 (m, 2H), 0.69-0.57 (m , 2H).

MS [M + H] + for C27H25N9O2: theor. 508.2, fact. 508.4.

Example 274 (R) -1- [6 - ({4- [6- (m-Cyanophenyl) -2- (cyclopropylamino) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) -2-pyridyl] -2 - pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, acetone-d6) δ 8.67 (s 1H), 8.64 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.95- 7.93 (m, 1H), 7.92 (s, 1H), 7.76 (dd, J = 8.0, 8.0 Hz, 1H), 7.56 (dd, J = 8.5, 7.2 Hz, 1H), 6.78 (s, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 5 , 63 (s, 2H), 5.59 (s, 1H), 4.54-4.46 (m, 1H), 3.60-3.51 (m, 1H), 3.46 (q, J = 8.0 Hz, 1H), 3.31 (d, J = 0.9 Hz, 1H), 3.05-2.94 (m, 1H), 2.35-2.12 (m, 3H) , 0.88-0.78 (m, 2H), 0.68-0.59 (m, 2H).

MS [M + H] + for C ₂₇ H ₂₅ N ₉ O ₂ : theor. 508.2, fact. 508.3.

Example 275 (S) -1- {6 - [(4- {6- (m-Cyanophenyl) -2 - [(cyclopropylmethyl) amino] -4-pyrimidinyl} -1H

1,2,3-triazol-1-yl) methyl] -2-pyridyl} -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CD3OD) δ 8.69 (s, 1H), 8.53 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 7.85 (d , J = 7.7 Hz, 1H), 7.76 (s, 1H), 7.72-7.64 (m, 1H), 7.59-7.45 (m, 1H), 6.65 ( d, J = 7.2 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.55 (s, 2H),

- 127 038488

4.47 (d, J = 8.6 Hz, 1H), 3.58 (s, 1H), 3.51-3.36 (m, 2H), 2.39-2.22 (m, 1H) , 2.20-1.95 (m, 3H), 1.37-1.10 (m,

2H), 0.57-0.49 (m, 2H), 0.37-0.28 (m, 2H).

LC-MS: retention time 3.50 min, method A; ESI-MS [M + H] + for C ₂₈ H ₂₈ N ₉ O ₂ : theor. 522.2, fact.

522.3.

Example 276 (S) -1- [6 - ({4- [6- (m-Cyanophenyl) -2- (isopropylamino) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) -2-pyridyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, acetone-d6) δ 8.67 (brs, 1H), 8.61 (s, 1H), 8.53 (d, J = 7.7 Hz, 1H), 7.92 ( d, J = 7.7 Hz, 1H), 7.84 (s, 1H), 7.76 (dd, J = 7.2, 7.2 Hz, 1H), 7.56 (dd, J = 8 , 5, 8.5 Hz, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 6.34 (s, 1H ), 5.59 (s, 2H), 4.54-4.46 (m, 1H), 4.46-4.33 (m, 1H), 3.61-3.52 (m, 1H), 3.45 (q, J = 8.2 Hz, 1H), 2.36-2.10 (m, 2H), 2.09-2.00 (m, 2H), 1.31 (d, J = 6.5 Hz, 1H).

MS [M + H] + for C ₂₇ H ₂₇ N ₉ O ₂ : theor. 510.2, fact. 510.3.

Example 277 (R) -1- [6 - ({4- [6- (m-Cyanophenyl) -2- (isopropylamino) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) -2-pyridyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

Ή-NMR (400 MHz, acetone-d6) δ 11.33 (s, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.75 (dd, J = 7.8, 7.8 Hz, 1H), 7.56 (dd, J = 7.8, 7.8 Hz, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.50 (d, J = 8.5 Hz, 1H ), 6.34 (brs, 1H), 5.59 (s, 2H), 4.54-4.46 (m, 1H), 4.46-4.33 (m, 1H), 3.62- 3.38 (m, 2H), 2.33-2.14 (m, 2H), 2.14-2.01 (m, 2H), 1.31 (d, J = 6.6Hz, 6H) ...

ESI-MS [M + H] + for C27H27N9O2: theor. 510.6, fact. 510.4.

Example 278 (S) -1- [6 - ({4- [6- (m-Cyanophenyl) -2- (2-methoxyethylamino) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) -2-pyridyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.61 (s, 1H), 8.55-8.44 (m, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.88-7.79 (m, 1H), 7.75 (dd, J = 8.0, 8.0 Hz, 1H), 7.55 (s, 1H) , 7.59-7.49 (m, 1H), 6.55-6.38 (m, 2H), 5.62 (s, 2H), 4.47-4.34 (m, 1H), 3 , 67-3.34 (m, 7H), 3.28 (s, 3H), 2.30-1.89 (m, 2H).

MS [M + H] + for C27H27N9O3: theor. 526.2, fact. 526.3.

Example 279 (R) -1- [6 - ({4- [6- (m-Cyanophenyl) -2- (2-methoxyethylamino) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) -2-pyridyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

Ή-NMR (400 MHz, acetone ^) δ 11.54 (brs, 1H), 8.69 (s, 1H), 8.63 (s, 1H), 8.54 (d, J = 8.0 Hz , 1H), 7.967.89 (m, 1H), 7.87 (s, 1H), 7.76 (dd, J = 8.0, 8.0 Hz, 1H), 7.56 (dd, J = 8.5, 7.2 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 5.59 (s, 2H), 4.51 (d, J = 7.4 Hz, 1H), 3.76 (q, J = 5.6 Hz, 2H), 3.64 (dd, J = 5.6, 5.6 Hz, 2H), 3.59-3.51 (m, 1H), 3.51-3.41 (m, 1H), 3.35 (s, 3H), 2.37-2.10 (m, 2H), 2.10-2.01 (m, 2H).

MS [M + H] + for C27H27N9O3: theor. 526.2, fact. 526.4.

Example 280. 3- {6 - [(4- {2 - [(R) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} -1H1,2,3-triazole-1 - yl) methyl] -2-pyridyl} propionic acid

- 128 038488

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 8.62 (s, 1H), 8.54 (d, J = 7.9 Hz, 1H), 7.93 (dq, J = 7.7 Hz, 1H), 7.90 (s, 1H), 7.82-7.71 (m, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.75 (brs, 1H), 5.80 (s, 2H), 4.72 (brs, 1H), 4.11-4.03 (m, 1H), 3 , 95 (q, J = 7.6 Hz, 1H), 3.86-3.68 (m, 2H), 3.09 (t, J = 7.3 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 2.41-2.29 (m, 1H), 2.07-1.99 (m, 2H).

MS [M + H] ⁺ for C26H24N8O3: theor. 497.2, fact. 497.3.

Example 281 3- {6 - [(4- {2 - [(S) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} -1H1,2,3-triazole-1 - yl) methyl] -2-pyridyl} butyric acid

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, acetone-d6) δ 10.66 (brs, 1H), 8.72 (brs. 1H), 8.61 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.77 (dd, J = 7.8, 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.74 (s, 1H), 5.81 (s, 2H), 4.69 (s, 1H), 4.11-3.90 (m, 3H), 3.86-3.67 (m, 2H), 3.46-3.34 (m, 1H), 2, 87 (dd, J = 16.0, 7.6 Hz, 1H), 2.59 (dd, J = 16.0, 6.8 Hz, 1H), 2.41-2.27 (m, 1H) , 2.11-1.92 (m, 1H), 1.29 (d, J = 6.9Hz, 3H).

MS [M + H] + for C27H26N8O3: theor. 511.2, fact. 511.4.

Example 282. 3- {6 - [(4- {2 - [(R) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} -1H1,2,3-triazole-1 - yl) methyl] -2-pyridyl} butyric acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, acetone-d6) δ 10.70 (brs, 1H), 8.72 (brs. 1H), 8.61 (s, 1H), 8.54 (d, J = 7, 8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.77 (dd, J = 7.8, 7.8 Hz, 1H) , 7.31 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.74 (s, 1H), 5.81 (s, 2H) , 4.69 (s, 1H), 4.11-3.90 (m, 3H), 3.86-3.67 (m, 2H), 3.46-3.34 (m, 1H), 2 , 87 (dd, J = 16.0, 7.6 Hz, 1H), 2.59 (dd, J = 16.0, 6.8 Hz, 1H), 2.41-2.27 (m, 1H ), 2.11-1.92 (m, 1H), 1.29 (d, J = 6.9Hz, 3H).

MS [M + H] ⁺ for C27H26N8O3: theor. 511.2, fact. 511.3.

Example 283 3- [6 - ({4- [6- (m-Cyanophenyl) -2- (2-methoxyethylamino) -4-pyrimidinyl] -1H-1,2,3triazol-1-yl} methyl) -2 -pyridyl] -3 -methylbutyric acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, acetone-d6) δ 8.63 (s, 1H), 8.56 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.83-7.73 (m, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H) , 6.47 (brs, 1H), 5.82 (s, 2H), 5.62 (s, 1H), 3.82-3.59 (m, 4H), 3.34 (s, 3H), 2.80 (s, 2H), 1.95 (s, 6H).

MS [M + H] ⁺ for C27H2 ₈ N ₈ O3: theor. 513.2, fact. 513.4.

Example 284. 3- {6 - [(4- {2 - [(S) -2-Methoxy-1-methylethylamino] -6- (m-cyanophenyl) -4-nyrimidinyl} -1H1,2,3-triazole- 1 -yl) methyl] -2-pyridyl} -3 -methylbutyric acid Me

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, acetone-d ₆ ) δ 10.70 (brs, 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.53 (d, J = 8 , 0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.82-7.70 (m, 1H), 7.45 (d , J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.31 (s, 1H), 5.81 (s, 2H), 4.56-4 , 41 (m, 1H), 3.56 (dd, J = 11.4, 6.1 Hz, 1H), 3.45 (dd, J = 11.4, 5.8 Hz, 1H), 3, 35 (s, 3H), 2.81 (s, 2H), 1.44 (s, 6H), 1.29 (d, J = 6.7Hz, 3H).

MS [M + H] ⁺ for C ₂₈ H ₃₀ N ₈ O ₃ : theor. 427.2, fact. 427.4.

Example 285 3- {6 - [(4- {2 - [(R) -2-Methoxy-1-methylethylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} 1H-1,2,3-triazole -1-yl) methyl] -2-pyridyl} -3 -methylbutyric acid

- 129 038488

This compound was synthesized in the same manner as in example 250.

Ή-NMR (400 MHz, acetone-d ₆ ) δ 8.66 (s, 1H), 8.61 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.82-7.70 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H) , 7.22 (d, J = 7.6 Hz, 1H), 6.31 (s, 1H), 5.81 (s, 2H), 4.564.41 (m, 1H), 3.56 (dd, J = 11.4, 6.1 Hz, 1H), 3.45 (dd, J = 11.4, 5.8 Hz, 1H), 3.35 (s, 3H), 2.81 (s, 2H ), 1.44 (s, 6H), 1.29 (d, J = 6.7Hz, 3H).

MS [M + H] + for C2 ₈ NzoChoz: theor. 427.2, fact. 427.3.

Example 286. (4- {6 - [(4- {2 - [(R) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} -1H1,2,3-triazole-1 -yl) methyl] -2-pyridyl} -1-piperidyl) acetic acid

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.42 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 8.0, 8.0 Hz, 1H), 7.71 (s, 1H), 7.62 (dd, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.0 , 8.0 Hz, 2H), 5.78 (s, 2H), 4.62 (brs, 1H), 4.11-3.93 (m, 2H), 3.92-3.81 (m, 1H), 3.78-3.64 (m, 4H), 3.62 (s, 2H), 3.21-2.97 (m, 3H), 2.39-2.25 (m, 1H) , 2.17-2.08 (m, 1H), 2.17-1.93 (m, 4H).

MS [M + H] ⁺ for C30H31N9O3: theor. 566.3, fact. 566.4.

Example 287. (4- {6 - [(4- {2 - [(R) -2-Methoxy-1-methylethylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} 1H-1,2,3- triazol-1-yl) methyl] -2-pyridyl} -1-piperidyl) acetic acid

This compound was synthesized in the same manner as in example 250.

S-NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 8.47 (s, 1H), 8.40 (d, J = 7.9 Hz, 1H), 7.86-7, 73 (m, 2H), 7.73 (s, 1H), 7.76-7.62 (m, 1H), 7.66 (dd, J = 8.0, 8.0 Hz, 1H), 5 , 79 (s, 2H), 4.50-4.38 (m, 1H), 3.73-3.49 (m, 4H), 3.45 (dd, J = 7.4, 5.4Hz , 1H), 3.39 (s, 2H), 3.34 (s, 3H), 3.21-2.98 (m, 3H), 2.21-2.05 (m, 4H), 1, 29 (d, J = 6.7 Hz, 3H).

MS [M + H] ⁺ for C30H33N9O3: theor. 568.3, fact. 568.4.

Example 288. 2- {6 - [(4- {2 - [(R) -Tetrahydrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimidinyl} -1H1,2,3-triazole-1- yl) methyl] -2-pyridyl} cyclopentanecarboxylic acid

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, CD3OD) δ 8.73-8.71 (m, 1H), 8.58 (s, 1H), 8.47-8.41 (m, 1H), 7.87-7 , 85 (m, 1H), 7.82-7.80 (m, 1H), 7.74-7.68 (m, 2H), 7.27-7.20 (m, 2H), 5.79 (s, 1H), 5.74 (s, 1H), 4.77-4.69 (m, 1H), 4.134.01 (m, 1H), 4.04-3.98 (m, 1H), 3.91-3.86 (m, 1H), 3.76 (dd, J = 8.9, 3.9 Hz, 1H), 3.64-3.59 (m, 0.5H), 3, 51-3.47 (m, 0.5H), 3.26-3.21 (m, 0.5H), 3.14-3.08 (m, 0.5H), 2.41-2.31 (m, 1H), 2.19-1.65 (m, 8H).

ESI-MS [M + H] ⁺ for C29H28N8O3: theor. 537.2, fact. 537.3.

Example 289 m- [6- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (1pyrrolidinyl) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in example 250.

S-NMR (400 MHz, CDCl3) δ 8.57-8.50 (m, 1H), 8.40-8.29 (m, 2H), 7.78 (s, 1H), 7.76-7 , 66 (m, 2H), 7.627.54 (m, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 5 , 73 (s, 2H), 4.59 (s, 2H), 3.69 (m, 4H), 3.50 (s, 3H), 2.03 (s, 4H).

- 130 038488

ESI-MS [M + H] + for C25H24N8O: theor. 453.2, fact. 453.3.

Example 290. m- {2 - [(Cyclopropylmethyl) amino] -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H1,2,3-triazol-4-yl) -4- pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.59 (s, 1H), 8.48 (d, J = 8.1 Hz, 1H), 7.99 ( dt, J = 7.6, 1.3 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.79 (s, 1H), 7.74 (t, J = 7 , 8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 5.82 (s, 2H), 4, 45 (s, 2H), 3.33 (s, 3H), 3.30 (d, J = 7.1 Hz, 2H), 3.16-3.13 (m, 1H), 1.13 (s , 1H), 0.49-0.35 (m, 2H), 0.26 (dd, J = 5.8, 4.3Hz, 2H).

LC-MS: retention time 3.48, method A; ESI-MS [M + H] + for C ₂₅ H ₂₅ N ₈ O: theor. 453.2, fact. 453.2.

Example 291. m- [2- (Cyclopentylamino) -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3 triazol-4-yl) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 8.36-8.26 (m, 2H), 7.81 (d, J = 3.9 Hz, 1H), 7.78-7.66 (m, 2H), 7.59 (td, J = 7.8, 3.4 Hz, 1H), 7.44-7.36 (m, 1H), 7.14- 7.08 (m, 1H), 5.73 (s, 2H), 5.30-5.11 (m, 1H), 4.59 (s, 2H), 4.41 (m, 1H), 3 , 50 (s, 3H), 2.19-2.03 (m, 2H), 1.83-1.63 (m, 4H), 1.62-1.40 (m, 2H).

ESI-MS [M + H] ⁺ for C ₂₆ H ₂₆ N ₈ O: theor. 467.2, fact. 467.3.

Example 292 m- [2- (2-Hydroxy-2-methylpropylamino) -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} 1H-1,2,3-triazol-4-yl ) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.33 (s, 1H), 8.27 (dd, J = 8.0, 1.1 Hz, 1H), 7, 82 (s, 1H), 7.757.65 (m, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7, 08 (d, J = 7.7 Hz, 1H), 5.77 (s, 1H), 5.70 (s, 2H), 4.57 (s, 2H), 3.53 (d, J = 5 , 3 Hz, 2H), 3.46 (s, 3H), 1.29 (s, 6H).

ESI-MS [M + H] ⁺ for C25H26N ₈ O2: theor. 471.2, fact. 471.3.

Example 293 m- [2- (2-Methoxyethylamino) -6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3 triazol-4-yl) -4- pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

1 H-NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.34-8.26 (m, 2H), 7.82 (s, 1H), 7.76-7.65 ( m, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 5.71 (s, 2H), 5.58 (t, J = 5.7 Hz, 1H), 4.57 (s, 2H), 3.73 (q, J = 5.3 Hz, 2H), 3.65-3.56 (m, 2H), 3.48 (s, 3H), 3.39 (s, 3H).

ESI-MS [M + H] ⁺ for C24H24N ₈ O2: theor. 457.2, fact. 457.3.

Example 294 m- {2 - [(S) -Temrahydrofuran-3-ylamino] -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} 1H-1,2,3-triazole-4 -yl) -4-pyrimidinyl} benzonitrile

Η Ν '

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.36-8.26 (m, 2H), 7.87 (s, 1H), 7.79-7.67 (m , 2H), 7.64-7.54 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 5 , 73 (s, 2H), 5.38 (d, J = 7.1 Hz, 1H), 4.74 (s, 1H), 4.59 (s, 2H), 4.10-3.97 ( m, 2H), 3.90 (td, J = 8.4, 5.5 Hz, 1H), 3.77 (dd, J = 9.3, 3.5 Hz, 1H), 3.50 (s , 3H), 2.38 (m, 1H),

- 131 038488

1.94 (m, 1H).

ESI-MS [M + H] + for C25H24N8O2: theor. 469.2, fact. 469.3.

Example 295. m- {2 - [(R) -Tetraudrofuran-3-ylamino] -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} 1H-1,2,3-triazole-4 -yl) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

1 H-NMR (400 MHz, CDCl ₃ ) δ 8.49-8.42 (m, 1H), 8.35-8.26 (m, 2H), 7.89-7.84 (m, 1H), 7.77-7.68 (m, 2H), 7.63-7.53 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 5.72 (s, 2H), 5.41 (s, 1H), 4.74 (m, 1H), 4.58 (s, 2H), 4.10-3, 95 (m, 2H), 3.90 (m, 1H), 3.82-3.71 (m, 1H), 3.48 (m, 1H), 2.37 (m, 1H), 1.94 (m, 1H).

ESI-MS [M + H] ⁺ for C2 ₅ H24N ₈ O2: theor. 469.2, fact. 469.3.

Example 296 m- [2- (4-Hydroxycyclohexylamino) -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H1,2,3-triazol-4-yl) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in example 250.

1 H-NMR (400 MHz, CDCl ₃ ) δ 8.46-8.40 (m, 1H), 8.30 (d, J = 5.0 Hz, 2H), 7.80 (s, 1H), 7 , 76-7.66 (m, 2H), 7.61-7.54 (m, 1H), 7.43-7.36 (m, 1H), 7.11 (d, J = 7.8Hz , 1H), 5.72 (s, 2H), 5.14 (d, J = 7.8 Hz, 1H), 4.57 (s, 2H), 4.02-3.87 (m, 1H) , 3.70 (m, 1H), 3.48 (s, 3H), 2.25-2.11 (m, 2H), 2.10-1.96 (m, 2H), 1.57-1 , 43 (m, 2H), 1.401.26 (m, 2H).

ESI-MS [M + H] ⁺ for C27H2 ₈ N ₈ O2: theor. 497.3, fact. 497.3.

Example

297.

m- {2- [(1 R, 2R) -2-Methoxycyclopentylamino] -6- (1- {[6- (methoxymethyl) -2 pyridyl] methyl} -1H-1,2,3-triazol-4-yl ) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.83 (s , 1H), 7.77-7.66 (m, 2H), 7.61-7.53 (m, 1H), 7.43-7.37 (m, 1H), 7.11 (d, J = 7.7 Hz, 1H), 5.72 (s, 2H), 5.29-5.13 (m, 1H), 4.57 (s, 2H), 4.46-4.30 (m, 1H), 3.73 (m, 1H), 3.48 (s, 3H), 3.41 (s, 3H), 2.27 (m, 1H), 1.94 (m, 1H), 1, 88-1.65 (m, 3H), 1.601.44 (m, 1H).

ESI-MS [M + H] ⁺ for C27H2 ₈ N ₈ O2: theor. 497.3, fact. 497.3.

Example 298 m- {2 - [(R) -Tetrahydrofuran-3 -ylamino] -6- (1 - {[6- (1-methoxyethyl) -2-pyridyl] methyl} 1H-1,2,3-triazole -4-yl) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

1 H-NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 8.32 (m, 2H), 7.87 (s, 1H), 7.76-7.68 (m, 2H) , 7.62-7.55 (m, 1H), 7.41-7.36 (m, 1H), 7.10 (d, J = 7.7 Hz, 1H), 5.73 (s, 2H ), 5.40 (d, J = 7.0 Hz, 1H), 4.72 (s, 1H), 4.49-4.37 (m, 1H), 4.07-3.98 (m, 2H), 3.94-3.85 (m, 1H), 3.76 (dd, J = 9.3, 3.4 Hz, 1H), 3.32 (s, 3H), 2.45-2 , 27 (m, 1H), 1.94 (dddd, J = 13.0, 7.4, 5.7, 4.0 Hz, 1H), 1.46 (d, J = 6.5 Hz, 3H ).

ESI-MS [M + H] ⁺ for C26H26N ₈ O2: theor. 483.2, fact. 483.3.

Example 299 m- [2- (2-Hydroxyethylamino) -6- (1 - {[6- (1-methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -4 -pyrimidinyl] benzonitrile

- 132 038488

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 8.35 (s, 1H), 8.31-8.23 (m, 1H), 7.84 (s, 1H) , 7.76-7.64 (m, 2H), 7.57 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 5.72 (m, 3H), 4.48-4.35 (m, 1H), 3.88 (m, 2H), 3.78-3.63 (m, 2H), 3 , 32 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H).

ESI-MS [M + H] ⁺ for C24H24N8O2: theor. 457.2, fact. 457.3.

Example 300. m- {2 - [(1R, 2R) -2-Hydroxycyclopentylamino] -6- (1 - {[6- (1-methoxyethyl) -2pyridyl] methyl} -1H-1,2,3-triazole- 4-yl) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, CDQ3) δ 8.36 (m, 2H), 8.27 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.75 (dd, J = 7.7, 1.4 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.39 ( d, J = 7.8 Hz, 1H), 7.08-7.00 (m, 1H), 5.72 (s, 2H), 5.49 (s, 1H), 4.43 (m, 1H ), 4.18-4.06 (m, 1H), 4.00 (s, 1H), 3.32 (s, 3H), 2.26 (m, 1H), 2.12 (m, 1H) , 1.94-1.68 (m, 3H), 1.61 (m, 1H), 1.46 (d, J = 6.6Hz, 6H).

ESI-MS [M + H] ⁺ for C27H2 ₈ N ₈ O2: theor. 497.2, fact. 497.3.

Example 301. m- [6- (1 - {[6- (1-Methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (2-methoxy- 1phenylethylamino) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

1 H-NMR (400 MHz, CDQ3) δ 8.17 (s, 2H), 7.80 (s, 1H), 7.74-7.61 (m, 2H), 7.52 (m, 1H), 7.45 (d, J = 7.4 Hz, 3H), 7.42-7.38 (m, 1H), 7.37-7.31 (m, 2H), 7.29-7.22 ( m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.06 (d, J = 5.9 Hz, 1H), 5.70 (s, 2H), 5.25 ( m, 1H), 4.43 (q, J = 6.4 Hz, 1H), 3.80-3.62 (m, 2H), 3.40 (s, 3H), 3.33 (s, 3H ), 1.48 (d, J = 5.6 Hz, 1H).

ESI-MS [M + H] ⁺ for C31H30N8O2: theor. 547.3, fact. 547.3.

Example 302 m- [2- (2-Methoxyethylamino) -6- (1 - {[6- (1-methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -4 -pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, CDCl3) δ 8.47 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 7.9 Hz, 2H), 7.83 (d, J = 1.4 Hz, 1H), 7.757.67 (m, 2H), 7.61-7.52 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.08 ( d, J = 7.8 Hz, 1H), 5.72 (s, 2H), 5.57 (t, J = 5.7 Hz, 1H), 4.43 (m, 1H), 3.73 ( t, J = 5.2 Hz, 2H), 3.61 (t, J = 5.3 Hz, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 1.46 ( d, J = 6.6 Hz, 3H).

ESI-MS [M + H] ⁺ for C ₂₅ H ₂₆ N ₈ O ₂ : theor. 471.2, fact. 471.3.

Example 3 03. m- [6- (1 - {[6- (1-Methoxyethyl) -2-pyridyl] methyl} - 1H-1,2,3-triazol-4-yl) -2- (2phenoxyethylamino) - 4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (s, 1H), 8.61 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.04 -7.96 (m, 1H), 7.91-7.81 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.31-7.23 (m, 2H), 7.20 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.91 (t, J = 7.3, 1.1 Hz, 1H), 5.85 (s, 2H), 4.34 (q, J = 6.5 Hz, 1H), 4.20 (t , J = 6.0 Hz, 2H),

- 133 038488

3.82 (s, 2H), 3.19 (s, 3H), 1.32 (d, J = 6.5Hz, 3H). ESI-MS

[M + H] + for C30H29N8O2: theor. 533.2, fact. 533.3.

Example 304 m- [2- (Dimethylamino) -6- (1 - {[6- (1-hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, CDC ^) δ 8.53 (s, 1H), 8.42-8.31 (m, 2H), 7.78 (s, 1H), 7.77-7.68 ( m, 2H), 7.59 (dd, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.76 (s, 2H), 4.55 (s, 1H), 3.30 (m, 6H), 2.14-1.81 (m, 8H).

MS [M + H] + for C26H26N8O: theor. 467.2, fact. 467.3.

Example 305 m- [2- (Cyclopropylamino) -6- (1 - {[6- (1-hydroxycyclopentyl) -2-pyridyl] methyl} -1H1,2,3-triazol-4-yl) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.77-7.72 (m, 1H), 7.71 (dd, J = 7.6 Hz, 1H) 7.59 (dd, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 5.75 (s, 2H), 5.42 (s, 1H), 4.60 (s, 1H), 2.90 (p, J = 7.9 Hz, 1H), 2.07-1.80 (m, 8H), 0.97-0.76 (m, 2H), 0, 63-0.57 (m, 2H).

MS [M + H] + for C ₂₇ H ₂₆ N ₈ O: theor. 479.2, fact. 479.3.

Example 306 m- [6- (1- {[6- (1-Hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (1 pyrrolidinyl) - 4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, CDCl3) δ 8.57-8.52 (m, 1H), 8.38-8.30 (m, 2H), 7.78 (s, 1H), 7.76-7 , 67 (m, 2H), 7.627.55 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 5 , 75 (s, 2H), 4.56 (s, 1H), 3.69 (m, 4H), 2.08-1.74 (m, 12H).

ESI-MS [M + H] + for C2 ₈ H2 ₈ N ₈ O: theor. 493.2, fact. 493.3.

Example 307 m- [2- (Cyclopentylamino) -6- (1 - {[6- (1-hydroxycyclopentyl) -2-pyridyl] methyl} -1H1,2,3-triazol-4-yl) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in example 250.

S-NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.36-8.25 (m, 2H), 7.81 (s, 1H), 7.77-7.68 (m , 2H), 7.64-7.53 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 5 , 75 (s, 2H), 5.21 (d, J = 7.2 Hz, 1H), 4.59 (s, 1H), 4.42 (m, 1H), 2.18-2.07 ( m, 2H), 2.07-1.92 (m, 4H), 1.87 (m, 6H), 1.73 (m, 2H), 1.54 (m, 2H).

ESI-MS [M + H] + for C ₂₉ H ₃₀ N ₈ O: theor. 507.3, fact. 507.3.

Example 308 m- [6- (1- {[6- (1-H-hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2 (tetrahydro-2H- pyran-4-ylamino) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.63-8.54 (m, 1H), 8.52-8.42 (m, 1H), 8.04 -7.91 (m, 1H), 7.85-7.69 (m, 3H), 7.64 (t, J = 6.7 Hz, 1H), 7.20-7.05 (m, 1H ), 5.85-5.79 (m, 2H), 5.77-5.70 (m, 1H), 4.16-4.00

- 134 038488 (m, 1H), 3.94-3.81 (m, 2H), 3.43 (s, 2H), 2.05-1.49 (m, 12H), 1.22 (d, J = 5.0 Hz, 1H).

LC-MS: Retention time 3.03 min, Method A; ESI-MS [M + H] + for C ₂₉ H ₃₁ N ₈ O ₂ : theor. 523.3, fact.

523.3.

Example 309 m- [6- (1 - {[6- (1-Hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (2hydroxy-2- methylpropylamino) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.43-8.33 (m, 2H), 8.31-8.22 (m, 1H), 7.83 (s, 1H), 7.75 -7.64 (m, 2H), 7.56 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.09 ( d, J = 7.6 Hz, 1H), 5.76 (s, 1H), 5.72 (s, 2H), 4.63 (s, 1H), 3.53 (d, J = 6.1 Hz, 2H), 2.02-1.75 (m, 8H), 1.29 (s, 6H).

ESI-MS [M + H] + for

C28H30N8O2: theor. 511.3, fact. 511.3.

Example 310 m- [6- (1 - {[6- (1-Hydroxycyclopentyl) -2-pyridyl] methyl} - 1H-1,2,3-triazol-4-yl) -2- (2methoxyethylamino) -4 -pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.36-8.27 (m, 2H), 7.82 (s, 1H), 7.75-7.65 (m, 2H), 7.60-7.52 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H) , 5.73 (s, 2H), 5.59 (t, J = 5.7 Hz, 1H), 4.60 (s, 1H), 3.73 (m, 2H), 3.66-3, 55 (m, 2H), 3.39 (s, 3H), 2.10-1.73 (m, 8H).

ESI-MS [M + H] ⁺ for C ₂ 4H ₂₈ N ₈ O ₂ : theor. 597.2, fact. 597.2.

Example 311. m- {2 - [(S) -Tetrahydrofuran-3-ylamino] -6- (1 - {[6- (1-hydroxycyclopentyl) -2pyridyl] methyl} -1H-1,2,3-triazole- 4-yl) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 1H), 8.31 (d, J = 9.7 Hz, 2H), 7.86 (s, 1H), 7.78- 7.66 (m, 2H), 7.58 (dd, J = 8.5, 7.2 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.11 (d , J = 7.6 Hz, 1H), 5.74 (s, 2H), 5.43 (d, J = 7.1 Hz, 1H), 4.72 (m, 1H), 4.59 (s , 1H), 4.07-3.95 (m, 2H), 3.89 (ddd, J = 9.9, 7.8, 5.8 Hz, 1H), 3.76 (dd, J = 9 , 3, 3.4Hz, 1H), 2.432.26 (m, 1H), 2.01-1.76 (m, 9H).

ESI-MS [M + H] + for C ₂₈ H ₂₈ N ₈ O ₂ : theor. 509.2, fact. 509.2.

Example 312. m- {2 - [(R) -Tetrahydrofuran-3-ylamino] -6- (1 - {[6- (1-hydroxycyclopentyl) -2pyridyl] methyl} -1H-1,2,3-triazole- 4-yl) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 8.34-8.24 (m, 2H), 7.85 (s, 1H), 7.78-7.66 (m, 2H), 7.62-7.54 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 1.1 Hz, 1H) , 5.74 (s, 2H), 5.55-5.33 (m, 1H), 4.73 (s, 1H), 4.60 (s, 1H), 4.09-3.95 (m , 2H), 3.89 (m, 1H), 3.76 (dd, J = 9.3, 3.5 Hz, 1H), 2.44-2.28 (m, 1H), 2.08- 1.76 (m, 9H).

ESI-MS [M + H] + for C ₂₈ H ₂₈ N ₈ O ₂ : theor. 509.2, fact. 509.3.

Example 313 m- [2- (4-Hydroxycyclohexylamino) -6- (1- {[6- (1-hydroxycyclopentyl) -2pyridyl] methyl} -1H-1,2,3-triazol-4-yl) - 4-pyrimidinyl] benzonitrile

- 135 038488

This compound was synthesized in the same manner as in example 250.

1 H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 1H), 8.30 (m, 2H), 7.81 (s, 1H), 7.77-7.67 (m, 2H) , 7.63-7.55 (m, 1H), 7.42-7.34 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 5.75 (s, 2H ), 5.10 (d, J = 7.9 Hz, 1H), 4.62 (s, 1H), 3.96 (m, 1H), 3.76-3.63 (m, 1H), 2 , 20 (s, 1H), 2.11-1.26 (m, 16H).

ESI-MS [M + H] + for C30H32N8O2: theor. 537.3, fact. 537.3.

Example 314. m- {2 - [(1R, 2R) -2-Methoxycyclopentylamino] -6- (1 - {[6- (1-hydroxycyclopentyl) -2pyridyl] methyl} -1H-1,2,3-triazole- 4-yl) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.30-8.23 (m, 1H), 7 , 84 (s, 1H), 7.777.67 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7 , 11 (d, J = 7.6 Hz, 1H), 5.75 (s, 2H), 5.21 (d, J = 7.2 Hz, 1H), 4.60 (s, 1H), 4 , 47-4.31 (m, 1H), 3.73 (dt, J = 6.5, 3.5 Hz, 1H), 3.41 (s, 3H), 2.35-2.17 (m , 1H), 2.08-1.65 (m, 12H), 1.54 (m, 1H).

ESI-MS [M + H] ⁺ for C30H32N8O2: theor. 537.3, fact. 537.4.

Example 315. m- {2 - [(1 R, 2R) -2-H-hydroxycyclopentylamino] -6- (1 - {[6- (1-hydroxycyclopentyl) -2pyridyl] methyl} -1H-1,2,3- triazol-4-yl) -4-pyrimidinyl} benzonitrile

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.43 (m, 2H), 8.26 (d, J = 7.7 Hz, 1H), 7.84 (s, 1H), 7.77- 7.72 (m, 1H), 7.727.65 (m, 1H), 7.62-7.55 (m, 1H), 7.41-7.33 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.38 (s, 1H), 5.72 (s, 2H), 5.53 (m, 1H), 4.66 (m, 1H), 3.98 ( s, 1H), 2.34-2.21 (m, 2H), 2.12 (m, 2H), 2.04-1.68 (m, 8H), 1.61 (m, 2H).

ESI-MS [M + H] ⁺ for C ₂₉ H ₃₀ N ₈ O ₂ : theor. 523.3, fact. 523.4.

Example 316 m- [6- (1 - {[6- (1-Hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (2hydroxyethylamino) -4 -pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.48-8.38 (m, 2H), 8.35-8.26 (m, 1H), 7.87 (s, 1H), 7.80 -7.68 (m, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 5.75 (s, 2H), 5.68 (s, 1H), 3.89 (t, J = 4.9 Hz, 2H), 3.72 (t, J = 5.4Hz, 2H), 2.01 (m, 4H), 1.88 (m, 2H), 1.61 (m, 2H).

ESI-MS [M + H] ⁺ for C ₂₆ H ₂₆ N ₈ O ₂ : theor. 483.2, fact. 483.3.

Example 317 (S) -1- {6 - [(4- {2 - [(S) -2-Methoxy-1-phenylethylamino] -6- (m-cyanophenyl) -4pyrimidinyl} -1H-1,2, 3-triazol-1-yl) methyl] -2-pyridyl} -3-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.78-8.36 (m, 4H), 7.95 (s, 1H), 7.73 (d, J = 19.9 Hz, 2H ), 7.51 (m, 2H), 7.47-7.40 (m, 1H), 7.29 (m, 2H), 7.19 (s, 1H), 6.38 (s, 1H) , 6.32 (dd, J = 8.6, 3.3Hz, 1H), 5.57 (s, 2H), 5.36 (s, 1H), 3.73 (s, 1H), 3, 55 (m, 2H), 3.28 (m, 5H), 2.65 (s, 1H), 1.99 (m, 2H), 1.29-1.07 (m, 1H).

- 136 038488

ESI-MS [M + H] + for C ₃₃ H ₃₁ N9O ₃ : theor. 602.3, fact. 602.4.

Example 318 (S) -1- {6 - [(4- {2 - [(R) -2-Methoxy-1-phenylethylamino] -6- (m-cyanophenyl) -4pyrimidinyl} -1H-1,2, 3-triazol-1-yl) methyl] -2-pyridyl} -3-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 250.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.78-8.36 (m, 4H), 7.95 (s, 1H), 7.73 (d, J = 19.9 Hz, 2H) , 7.51 (m, 2H), 7.47-7.40 (m, 1H), 7.29 (m, 2H), 7.19 (s, 1H), 6.38 (s, 1H), 6.32 (dd, J = 8.6, 3.3Hz, 1H), 5.57 (s, 2H), 5.36 (s, 1H), 3.73 (s, 1H), 3.55 (m, 2H), 3.28 (m, 5H), 2.65 (s, 1H), 1.99 (m, 2H), 1.29-1.07 (m, 1H).

ESI-MS [M + H] + for C ₃₃ H ₃₁ N ₉ O ₃ : theor. 602.3, fact. 602.4.

Example 319. 3- [6 - ({4- [6- (m-Cyanophenyl) -2- (isopropylamino) -4-pyrimidinyl] -1H-1,2,3-triazole-1yl} methyl) -2-pyridyl ] -3-methylbutyric acid

Me

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.61 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.00 ( d, J = 7.8 Hz, 1H), 7.83-7.70 (m, 3H), 7.43-7.34 (m, 1H), 7.12 (d, J = 7.6 Hz , 1H), 5.82 (s, 2H), 4.34-4.16 (m, 1H), 2.66 (s, 2H), 1.33 (s, 6H), 1.22 (d, J = 6.3 Hz, 6H).

ESI-MS [M + H] + for C27H2 ₈ N ₈ O2: theor. 497.2, fact. 497.4.

Example 320. 3- [6 - ({4- [6- (m-Cyanophenyl) -2- (cyclopropylamino) -4-pyrimidinyl] -1H-1,2,3-triazol1-yl} methyl) -2-pyridyl ] -3-methylbutyric acid

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, DMSO-d6) δ 8.84-8.68 (m, 1H), 8.63 (s, 1H), 8.57-8.47 (m, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.86 (s, 1H), 7.80-7.72 (m, 2H), 7.65 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 5.82 (s, 2H), 2.95-2.87 (m, 1H), 2, 66 (s, 2H), 1.33 (s, 6H), 0.77-0.70 (m, 2H), 0.59-0.52 (m, 2H).

ESI-MS [M + H] + for C27H26N8O2: theor. 495.2, fact. 495.3.

Example 321 3- {6 - [(4- {2 - [(R) -Tetraudrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimudinyl} -1H1,2,3-triazole-1- yl) methyl] -2-pyridyl} -3-methylbutyric acid

This compound was synthesized in the same manner as in example 250.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 1H), 8.50 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.80-7.72 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H) , 5.82 (s, 2H), 4.56 (s, 1H), 4.01 (dd, J = 8.8, 6.2 Hz, 1H), 3.87 (q, J = 7.5 Hz, 1H), 3.80-3.71 (m, 1H), 3.67-3.55 (m, 1H), 2.66 (s, 2H), 2.29-2.16 (m, 1H), 2.05-1.90 (m, 1H), 1.33 (s, 6H).

ESI-MS [M + H] + for C2 ₈ H2 ₉ N ₈ O3: theor. 525.2, fact. 525.3.

Example 322. 3- {6 - [(4- {2 - [(S) -Tetraudrofuran-3-ylamino] -6- (m-cyanophenyl) -4-pyrimudinyl} -1H1,2,3-triazole-1- yl) methyl] -2-pyridyl} -3-methylbutyric acid

This compound was synthesized in the same manner as in example 250.

- 137 038488

-NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.55-8.46 (m, 1H), 8.01 (d, J = 6.5 Hz, 1H), 7.85 (s, 1H),

7.82-7.71 (m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 5.82 (s , 2H), 4.63-4.47 (m, 1H), 4.01 (dd,

J = 8.8, 6.2 Hz, 1H), 3.92-3.82 (m, 1H), 3.81-3.71 (m, 1H), 3.67-3.56 (m, 1H), 2.66 (s, 2H), 2.29-2.16 (m, 1H),

2.04-1.90 (m, 1H), 1.33 (s, 6H).

ESI-MS [M + H] + for C2 ₈ H29N ₈ O3: theor. 525.2, fact. 525.3.

Example 323. 3- [6 - ({4- [6- (m-Cyanophenyl) -2 - {[(5-oxo-2-pyrrolidinyl) methyl] amino} -4pyrimidinyl] -S-1,2,3- triazol-1-yl} methyl) -2-pyridyl] -3-methylbutyric acid

This compound was synthesized in the same manner as in example 250.

-NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (m, 1H), 8.60 (s, 1H), 8.49 (m, 3H), 7.99 (dd, J = 7, 7, 1.4 Hz, 1H), 7.82 (s, 1H), 7.74 (m, 2H), 7.50 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.5Hz, 1H), 5.79 (s, 2H), 3.63 (m, 3H), 2.68-2.60 (m, 2H), 2.24-2.02 (m, 3H), 1.82 (m, 1H), 1.37-1.24 (s, 6H).

ESI-MS [M + H] + for C ₂₉ H ₂₉ N ₉ O ₃ : theor. 552.2, fact. 552.3.

Example 324 m- [6- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (2phenoxyacetylamino) -4-pyrimidinyl ] benzonitrile

Mixed m- [2-amino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyrimidinyl] benzonitrile (20 mg, 0.045 mmol) and phenoxyacetyl chloride (8 mg, 0.045 mmol) in pyridine at room temperature and heated with stirring at 100 ° C for 30 min. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, purified by reverse phase HPLC followed by flash column chromatography to give the purified compound (20 mg, 81%).

-NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 1.9 Hz, 1H), 8.66-8.56 (m, 1H), 8.44-8.33 (m, 1H), 8.20-7.91 (m, 1H), 7.75-7.87 ( m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.30-7.15 (m, 3H), 6.98-6.90 (m, 2H), 5.85 (d, J = 2.0 Hz, 2H), 5.78-5.67 (m, 1H), 5.17 (d, J = 1.9 Hz, 2H), 4.43 (d, J = 1.9 Hz, 2H), 3.31 (s, 3H).

ESI-MS [M + H] + for C29H24N ₈ O3: theor. 533.2, fact. 533.3.

Example 325 m- [2-Acetylamino-6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) 4-pyrimidinyl] benzonitrile

МеО ^ HАс 'ζ Э Ν ^ Ν

I II I

N = N

This compound was synthesized in the same manner as in example 324.

-NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.40 (s, 1H), 8.39-8.33 (m, 1H), 8.26 (s, 1H) , 8.07 (brs, 1H), 7.84-7.78 (m, 1H), 7.73 (dd, J = 7.6, 7.6 Hz, 1H), 7.65 (dd, J = 7.8, 7.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.20-7 , 13 (m, 1H), 5.74 (s, 2H), 4.59 (s, 2H), 4.12 (qd, J = 7.2, 1.6 Hz, 1H), 3.50 ( s, 3H), 2.65 (s, 3H).

MS [M + H] + for C23H2oN ₈ 02: theor. 441.2, fact. 441.3.

Example 326 m- [2- (2-Methoxyacetylamino) -6- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in example 324.

LC-MS: retention time 2.91 min, method A; ESI-MS [M + H] + for C ₂₄ H ₂₃ N ₈ O ₃ : theor. 471.2, fact. 471.3.

Example 327 m- [2- (2-Ethoxyacetylamino) -6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -4-pyrimidinyl ] benzonitrile

- 138 038488 o

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.56-8.51 (m, 1H), 8.47 (d, J = 0.7 Hz, 1H), 8 , 43 (ddt, J = 8.0, 1.8, 0.9 Hz, 1H), 8.34-8.28 (m, 1H), 7.84-7.77 (m, 1H), 7 , 71 (t, J = 7.8 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 5.74 (s, 2H), 4.59 (s, 2H), 4.18 (s, 2H), 3.78-3.64 (m, 2H), 3.49 (s, 3H), 1.36 (td, J = 7.0, 0.7Hz, 3H).

LC-MS: retention time 3.03 min, method A; ESI-MS [M + H] + for C ₂₄ H ₂₃ N ₈ O ₃ : theor. 485.2, fact. 485.3.

Example 328 m- [6- {1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl} -2 [(tetrahydrofuran-2-yl) carbonylamino] -4-pyrimidinyl] benzonitrile o

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.55 (t, J = 1.7 Hz, 1H), 8.47 (s, 1H), 8.45-8 , 40 (m, 1H), 8.31 (d, J = 1.3 Hz, 1H), 7.80 (dt, J = 7.7, 1.4 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 5.74 (s, 2H), 4.59 (s, 2H), 4.57-4.51 (m, 1H), 4.14 (q, J = 7.0 Hz, 1H), 4.06-3.97 (m, 1H), 3.50 (s, 3H), 2.45-2.19 (m, 2H), 1.99 (dp, J = 13, 3, 6.1 Hz, 2H).

LC-MS: retention time 3.03 min, method A; ESI-MS [M + H] ⁺ for C ₂₆ H ₂₅ N ₈ O ₃ , theor. 497.2, fact. 497.3.

Example 329. m- [6- {1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl} -2 - [(tetrahydro2H-pyran-2 -yl) carbonylamino] -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.56 (tt, J = 1.7, 0.8 Hz, 1H), 8.48 (d, J = 1, 3 Hz, 1H), 8.44 (dddd, J = 8.0, 1.9, 1.2 Hz, 1H), 8.30 (d, J = 1.3 Hz, 1H), 7.82- 7.68 (m, 3H), 7.67-7.61 (m, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.7 Hz , 1H), 5.78-5.60 (s, 2H), 4.59 (s, 2H), 3.50 (s, 3H), 2.23 (d, J = 11.8 Hz, 1H) , 1.94 (d, J = 28.3 Hz, 2H), 1.76-1.44 (m, 6H).

LC-MS: retention time 3.33 min, method A; ESI-MS [M + H] ⁺ for C ₂₇ H ₂₇ N ₈ O ₃ : theor. 511.2, fact. 511.3.

Example 330 m- [6- {1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl} -2- (2phenoxypropionylamino) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, chloroform-d) δ 9.06 (s, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.45-8.37 (m, 1H), 8.32 (s, 1H), 7.84-7.76 (m, 1H), 7.72 (dd, J = 7.8, 7.8 Hz, 1H), 7.64 (dd , J = 7.8, 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.397.30 (m, 2H), 7.12 (d, J = 7, 8 Hz, 1H), 7.09-6.99 (m, 3H), 5.74 (s, 2H), 4.89 (brs, 1H), 4.59 (s, 2H), 3.50 ( s, 3H), 1.72 (d, J = 6.4Hz, 3H).

MS [M + H] ⁺ for C ₃₀ H ₂₆ N ₈ O ₃ : theor. 547.2, fact. 547.3.

Example

331.

m- [2- (2-Hydroxy-2-methylpropionylamino) -6- (1 - {[6- (methoxymethyl) -2 pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4 -pyrimidinyl] benzonitrile

- 139 038488

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.93 (s, 1H), 8.76 (s, 1H), 8.64 (d, J = 8, 0 Hz, 1H), 8.40 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 5.84 (s , 2H), 4.45 (s, 2H), 3.33 (s, 3H), 1.39 (s, 6H).

LC-MS: retention time 2.85 min, method A; ES-MS [M + H] + for C ₂₅ H ₂₅ N ₈ O ₃ : theor. 485.2, fact. 485.3.

Example 332. 2-Fluoro-3 - [6- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} - 1H-1,2,3-triazol-4-yl) -2- (2phenoxyacetylamino) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.99 (brs, 1H), 8.51 (dd, J = 7.8, 7.8 Hz, 1H), 8.46 (s, 1H) 8 , 40 (s, 1H), 7.78 (dd, J = 7.6, 7.6 Hz, 1H), 7.72 (dd, J = 7.8, 7.8 Hz, 1H), 7, 50-7.39 (m, 2H), 7.36 (dd, J = 7.8, 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.09 -6.99 (m, 2H), 5.74 (s, 2H), 4.79 (s, 2H), 4.59 (s, 2H), 3.50 (s, 2H).

MS [M + H] + for C ₂₉ H ₂₃ FN ₈ O ₃ : theor. 551.2, fact. 551.3.

Example 33 3.1- [6- (2-Furanyl) -4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinylamino] - 2-phenoxy-1-ethanone

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, CDCL) δ 8.85 (s, 1H), 8.45-8.40 (m, 1H), 8.20-8.18 (m, 1H), 7.71 ( td, J = 7.9, 2.1 Hz, 1H), 7.67-7.64 (m, 1H), 7.44-7.39 (m, 1H), 7.39-7.30 ( m, 3H), 7.11 (d, J = 7.7 Hz, 1H), 7.08-7.00 (m, 3H), 6.61 (ddd, J = 3.5, 2.6, 1.6 Hz, 1H), 5.74 (d, J = 2.0 Hz, 2H), 4.83 (s, 2H), 4.59 (d, J = 1.9 Hz, 2H), 3 , 49 (s, 3H).

ESI-MS [M + H] + for C ₂₆ H ₂₃ N ₇ O ₄ : theor. 498.2, fact.

498.3.

Example 334 m- [2- (2-Methoxyacetylamino) -6- (1 - {[6- (1-methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3 triazol-4-yl) - 4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.02 (s, 1H), 8.56-8.51 (m, 1H), 8.49 (s, 1H), 8.42 (dt, J = 7.9, 1.5 Hz, 1H), 8.32 (s, 1H), 7.80 (dq, J = 7.7, 1.4 Hz, 1H), 7.68 (dtd, J = 27.0, 7.8, 1.1 Hz, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.09 (dd, J = 7.8, 1.2 Hz, 1H ), 5.74 (s, 2H), 4.43 (q, J = 6.5 Hz, 1H), 4.16 (s, 2H), 3.56 (s, 3H), 3.33 (s , 3H), 1.46 (dd, J = 6.5, 1.2 Hz, 3H).

LC-MS: retention time 3.00 min, method A; ESI-MS [M + H] + for C ₂₅ H ₂₅ N ₈ O ₃ : theor. 485.2, fact. 485.3.

Example 335 m- [6- (1- {[6- (1-Methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (2phenoxyacetylamino) -4 -pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.93 (s, 1H), 8.91 (s, 1H), 8.74 (s, 1H), 8.60 (d, J = 8 , 0 Hz, 1H), 8.37 (d, J = 0.9 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.82 (dt, J = 25.2 , 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.27 (dd, J = 8.4, 7.0 Hz, 2H), 7.19 (d , J = 7.7 Hz, 1H), 6.93 (ddd, J = 12.2, 6.6, 3.8 Hz, 3H), 5.86 (s, 2H), 5.18 (s, 2H), 4.30 (q, J = 6.5 Hz, 1H), 3.16 (d, J = 0.9 Hz, 3H), 1.42-1.21 (m, 3H).

ESI-MS [M + H] + for C ₃ oH26N ₈ 03: theor. 547.2, fact. 548.3.

Example 336 1- [4- (1 - {[6- (1-Methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (1,3- oxazol2-yl) -2-pyrimidinylamino] -2-phenoxy-1-ethanone

- 140 038488

This compound was synthesized in the same manner as in example 324.

¹ H-NMR (400 MHz, CD3OD) δ 8.86 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 7.85 (t, J = 8.0 Hz , 1H), 7.52 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.34-7.25 (m, 3H), 7.05 (d, J = 7.9 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 5.82 (s, 2H), 5.13 (s, 2H), 4.40 (q, J = 6.5 Hz, 1H), 3.26 (s, 3H), 1.38 (d, J = 6.5 Hz, 3H).

ESI-MS [M + H] + for C26H25N8O4: theor. 513.2, fact. 513.3.

Example 337 m- [2- (2-Methoxyacetylamino) -6- (1 - {[6- (1-methoxypropyl) -2-pyridyl] methyl} -1H-1,2,3 triazol-4-yl) - 4-pyrimidinyl] benzonitrile o

This compound was synthesized in the same manner as in Example 324 to obtain 16 mg of a tan solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.90 (d, J = 1.1 Hz, 1H), 8.75 (d, J = 1.5 Hz , 1H), 8.66-8.56 (m, 1H), 8.37 (d, J = 1.1 Hz, 1H), 8.12-7.98 (m, 1H), 7.87 ( t, J = 7.8 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 5.88 (s, 2H), 4.38 (s, 2H), 4.13 (t, J = 6.2 Hz, 1H), 3.39 (s, 3H), 3.18 (s, 3H), 1.68 (p, J = 7.0 Hz, 2H), 0.84-0.72 (m, 3H).

ESI-MS [M + H] ⁺ for C26H26N8O3: theor. 499.2, fact. 499.3.

Example 338 m- [6- (1 - {[6- (1-Methoxypropyl) -2-pyridyl] methyl} - 1H-1,2,3-triazol-4-yl) -2- (2 phenoxyacetylamino) - 4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in Example 324 to obtain 31 mg of a tan solid.

¹ H-NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.56-8.46 (m, 2H), 8.45-8.39 (m, 1H), 8.38- 8.26 (m, 1H), 7.80 (dq, J = 7.7, 1.3 Hz, 1H), 7.71 (td, J = 7.9, 1.9 Hz, 1H), 7 , 64 (td, J = 7.7, 1.7 Hz, 1H), 7.41-7.31 (m, 3H), 7.12-7.01 (m, 4H), 5.79-5 , 68 (m, 2H), 4.80 (s, 2H), 4.21 (dd, J = 7.0, 5.4 Hz, 1H), 3.31 (s, 3H), 1.87- 1.72 (m, 2H), 0.97-0.84 (m, 3H).

ESI-MS [M + H] ⁺ for C31H28N8O3: theor. 561.2, fact. 561.4.

Example 339 m- [2- (2-Methoxyacetylamino) -6- (1- {[6- (1-methoxy-2-methylpropyl) -2-pyridyl] methyl} 1H-1,2,3-triazole-4 -yl) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in Example 324 to obtain 16 mg of a yellowish brown solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.89 (d, J = 1.3 Hz, 1H), 8.75 (d, J = 1.7 Hz , 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 1.4 Hz, 1H), 8.12-7.99 (m, 1H), 7 , 87 (t, J = 7.8 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 5.88 (s, 2H), 4.38 (s, 2H), 3.92 (d, J = 5.8 Hz, 1H), 3.39 (s, 3H), 3.16 (s, 3H), 1.94 (q, J = 6.7 Hz, 1H), 0.80 (dd, J = 6.7, 1.3 Hz, 3H) , 0.71 (dd, J = 6.9, 1.3 Hz, 3H).

ESI-MS [M + H] ⁺ for C27H28N8O3: theor. 513.2, fact. 513.4.

Example 340. m- [6- (1 - {[6- (1-Methoxy-2-methylpropyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2 (2 -phenoxyacetylamino) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 324, obtaining 33 mg of yellowish

- 141 038488 brown solid.

-NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.55-8.51 (m, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8, 46-8.40 (m, 1H), 8.33 (d, J = 1.6 Hz, 1H), 7.81 (dt, J = 7.7, 1.4 Hz, 1H), 7.74 -7.60 (m, 2H), 7.40-7.31 (m, 3H), 7.26 (d, J = 2.7Hz, 1H), 7.11-7.01 (m, 3H ), 5.75 (s, 2H), 4.80 (s, 2H), 4.00 (dd, J = 6.3, 1.7 Hz, 1H), 3.28 (s, 3H), 2 , 10-1.97 (m, 1H), 0.92 (dd, J = 6.8, 1.7 Hz, 3H), 0.82 (dd, J = 6.8, 1.7 Hz, 3H ).

ESI-MS [M + H] ⁺ for C32H30N8O3: theor. 575.3, fact. 575.4.

Example 341 m- [6- (1 - {[6- (Cyclopropylmethoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2 (2-methoxyacetylamino) -4- pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in Example 324 to obtain 17 mg of a yellowish brown solid.

-NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.90 (d, J = 1.4 Hz, 1H), 8.75 (s, 1H), 8.61 ( d, J = 7.7 Hz, 1H), 8.37 (d, J = 1.3 Hz, 1H), 8.11-8.03 (m, 1H), 7.90-7.83 (m , 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H ), 5.89 (s, 2H), 4.38 (s, 2H), 3.67 (d, J = 7.7 Hz, 1H), 3.39 (s, 3H), 3.19 (s , 3H), 1.160.97 (m, 1H), 0.55-0.37 (m, 2H), 0.35-0.16 (m, 2H).

ESI-MS [M + H] + for C ₂₇ H ₂₆ N ₈ O ₃ : theor. 511.2, fact. 511.3.

Example 342 m- [6- (1 - {[6- (Cyclopropylmethoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2 (2-phenoxyacetylamino) -4- pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in Example 324 to obtain 31 mg of a yellowish brown solid.

-NMR (400 MHz, CDQ3) δ 9.01 (s, 1H), 8.54-8.48 (m, 2H), 8.41 (ddt, J = 8.0, 1.8, 1, 1 Hz, 1H), 8.32 (d, J = 1.1 Hz, 1H), 7.79 (dq, J = 7.7, 1.3 Hz, 1H), 7.71 (td, J = 7.8, 1.1 Hz, 1H), 7.67-7.60 (m, 1H), 7.40 (dt, J = 7.8, 1.0 Hz, 1H), 7.37-7 , 31 (m, 2H), 7.12 (dt, J = 7.7, 1.1 Hz, 1H), 7.08-7.00 (m, 3H), 5.75 (s, 2H), 4.79 (s, 2H), 3.72 (dd, J = 7.9, 1.0 Hz, 1H), 3.32 (s, 3H), 1.18-1.08 (m, 1H) , 0.91-0.79 (m, 1H), 0.62 (dddd, J = 12.1, 8.6, 5.7, 1.1 Hz, 1H), 0.54-0.34 ( m, 3H).

ESI-MS [M + H] ⁺ for C32H2 ₈ N ₈ O3: theor. 573.2, fact. 573.3.

Example 343 m- [6- (1 - {[6- (Cyclopentylmethoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2 (2-methoxyacetylamino) -4- pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in Example 324 to obtain 15 mg of a yellowish brown solid.

¹ H-NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.74 (dd, J = 2.4, 1.1 Hz, 1H), 8.61 (d, J = 8.1 Hz, 1H), 8.36 (d, J = 1.3 Hz, 1H), 8.05 (dd, J = 7, 5, 1.4 Hz, 1H), 7.88-7.76 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 5.88 (s, 2H), 4.37 (d, J = 1.3 Hz, 2H), 3.96 (d, J = 7.8 Hz, 1H), 3.39 ( s, 3H), 3.13 (s, 3H), 2.21-2.09 (m, 1H), 1.59 (d, J = 10.3 Hz, 1H), 1.51-1.09 (m, 7H).

ESI-MS [M + H] ⁺ for C29H30N8O3: theor. 539.3, fact. 539.3.

Example 344 m- [6- (1 - {[6- (Cyclopentylmethoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2 (2-phenoxyacetylamino) -4- pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in Example 324 to obtain 15 mg of a yellowish brown solid.

Ή-NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 1.7 Hz, 1H), 8.66-8.53 (m, 1H), 8.38 (d, J = 1.3 Hz, 1H), 8.06 (dd, J = 7.8, 1.4 Hz, 1H ), 7.94-7.73 (m, 2H), 7.37-7.17 (m, 4H), 7.04-6.85 (m, 3H), 5.88 (s, 2H), 5.19 (s, 2H), 3.95 (d, J = 7.6 Hz, 1H), 3.11 (s, 3H), 2.14 (q, J = 1.1 Hz, 1H), 1.58 (d,

- 142 038488

J = 9.6Hz, 1H), 1.53-1.08 (m, 7H).

ESI-MS [M + H] + for C ₃₄ H ₃₂ N ₈ O ₃ : theor. 601.3.

Example 345 m- [2- (2-Methoxyacetylamino) -6- (1 - {[6- (methoxyphenylmethyl) -2-pyridyl] methyl} -1H1,2,3-triazol-4-yl) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in Example 324 to obtain 17 mg of a tan solid.

Ή-NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.62 (d, J = 7.7 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H) , 7.89-7.76 (m, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.27- 7.14 (m, 4H), 5.85 (s, 2H), 5.32 (s, 1H), 4.38 (s, 2H), 3.39 (s, 3H), 3.30 (s , 3H).

ESI-MS [M + H] + for C30H26NA: theor. 547.2, fact. 547.3.

Example 346 m- [6- (1 - {[6- (Methoxyphenylmethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (2phenoxyacetylamino) -4-pyrimidinyl ] benzonitrile

This compound was synthesized in the same manner as in Example 324 to obtain 31 mg of a tan solid.

-NMR (400 MHz, CDCl ₃ ) δ 9.01 (s, 1H), 8.54 (td, J = 1.7, 0.9 Hz, 1H), 8.48-8.39 (m, 2H), 8.37-8.29 (m, 1H), 7.81 (dq, J = 8.6, 1.2 Hz, 1H), 7.73-7.61 (m, 2H), 7 , 52-7.47 (m, 1H), 7.40 (dtd, J = 6.8, 1.3, 0.7 Hz, 2H), 7.387.32 (m, 2H), 7.32-7 , 27 (m, 2H), 7.24-7.18 (m, 1H), 7.10-7.02 (m, 4H), 5.70 (d, J = 2.1 Hz, 2H), 5.37 (s, 1H), 4.81 (s, 2H), 3.43 (s, 3H).

ESI-MS [M + H] + for C35H28NA: theor. 609.2, fact. 609.4.

Example 347 m- [6- (1- {[6- (1-H hydroxycyclobutyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (2 phenoxyacetylamino) -4-pyrimidinyl] benzonitrile

This compound was synthesized in the same manner as in example 324.

Ή-NMR (400 MHz, CDCl ₃ ) δ 9.02 (brs, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.43 (d, J = 7.8 Hz , 1H) 8.34 (s, 1H), 7.85-7.75 (m, 2H), 7.66 (dd, J = 7.8, 7.8 Hz, 1H), 7.59 (d , J = 7.8 Hz, 1H), 7.36 (dd, J = 7.8, 7.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 1H), 7.12 -6.97 (m, 3H), 5.77 (s, 2H), 4.79 (s, 2H), 2.66-2.43 (m, 4H), 2.20-2.01 (m , 1H), 1.96-1.80 (m, 1H).

MS [M + H] + for C31H26NA: theor. 559.2, fact. 559.4.

Example 348 m- [6- (1- {[6- (1-Hydroxycyclopentyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2- (2phenoxyacetylamino) -4 -pyrimidinyl] benzonitrile o

This compound was synthesized in the same manner as in example 324.

S-NMR (400 MHz, CDCl3) δ 9.02 (brs, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.46-8.40 (m, 1H), 8.34 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.73 (dd, J = 7.8, 7.8 Hz, 2H), 7.66 (dd , J = 7.8, 7.8 Hz, 2H), 7.44-7.27 (m, 2H), 7.14-6.97 (m, 3H), 5.77 (s, 2H), 4.79 (brs, 2H), 2.07-1.91 (m, 8H).

MS [M + H] + for C32H28NA: theor. 573.2, fact. 573.4.

Example 349 6- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1H-pyrazol-3-yl) -4-phenyl-2 pyrimidinylamine

- 143 038488

Stage 1. A mixture of 3-pyrazole boronate derivative (875 mg, 3.2 mmol), chloropyrimidine derivative (500 mg, 2.5 mmol) and K ₂ CO ₃ (1.04 g, 7.5 mmol) was suspended in 10 ml DMF and 2.5 ml H2O. The contents were degassed by passing N2 through the solution. _{Pd (PPh 3} ) ₄ (290 mg, 0.25 mmol) was added to this degassed reaction mixture and heated at 90 ° C for 10 h. After the reaction was cooled to room temperature, 10 ml of saturated NaCl solution was added and the aqueous layer was extracted with EtOAc ( 2x25 ml). The combined organic layer was dried over Na ₂ SO ₄ , evaporated and purified by silica gel chromatography to give the desired product (522 mg, 65%).

Stage 2. To a solution of THP-pyrazole from stage 1 (114 mg, 0.36 mmol) in 2 ml of MeOH was added 2 ml of 4N. HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated under pressure and the crude product was used in the next step without further purification.

Step 3. To a mixture of the crude product from Step 2 (0.36 mmol), a chloromethylpyridine derivative (112.4 mg, 0.54 mmol) in 2 mL of anhydrous MeCN was added K ₂ CO ₃ (248 mg, 1.8 mmol). The reaction mixture was heated at 60 ° C for 5 h. After the reaction was cooled to room temperature, 10 ml of saturated NaCl solution was added and the aqueous layer was extracted with EtOAc (2x10 ml). The combined organic layer was dried over Na2SO4, evaporated and purified by silica gel chromatography to give the desired product A0001028 (94 mg, 70%).

¹ H-NMR (400 MHz, CDCl3) δ 8.10-8.01 (m, 1H), 7.68-7.61 (m, 2H), 7.58 (d, J = 2.4 Hz, 1H), 7.48-7.44 (m, 3H), 7.34 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6, 92-6.87 (m, 1H), 5.56 (s, 4H), 5.43 (s, 2H), 4.58 (s, 2H), 3.48 (s, 3H).

ESI-MS [M + H] + for C ₂ iH ₂ oN60: theor. 373.2, fact. 373.2.

Example 350 6- [2-Amino-6- (1 - {[6- (1-hydroxy-1 -methylethyl) -2-pyridyl] methyl} -1 H-pyrazol-4-yl) -4 pyrimidinyl] -2 -toluonitrile

Stage 3

Stage 1. In a solution of 2- (6- (hydroxymethyl) pyridin-2-yl) propan-2-ol (2.13 g, 12.7 mmol, 1.0 eq.) In CH ₂ Cl ₂ (127 ml, 0.1 M) under N2, CBr ₄ (4.7 g, 14.0 mmol, 1.1 eq.) Was added followed by triphenylphosphine (3.7 g, 14.0 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was then transferred to a separatory funnel and washed with saturated aqueous NaHCO ₃ (150 ml). The organic phase was collected, dried over MgSO ₄ and evaporated in vacuo. The resulting oil was purified by column chromatography (CH ₂ Cl ₂ => CH ₂ Cl ₂ : MeOH 9: 1) to give 2- (6- (bromomethyl) pyridin-2-yl) propan-2-ol (2.0 g, yield 69%) as a yellow oil.

Stage 2. Introduced 2- (6- (bromomethyl) pyridin-2-yl) propan-2-ol (1.0 g, 4.3 mmol, 1.0 eq.) And 4-pyrazoleboronic acid pinacol ester (928 mg , 4.8 mmol, 1.1 eq.) In MeCN (23 ml, 0.2 M) and added Cs ₂ CO ₃ (1.6 g, 4.8 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 3 h. Upon completion, the mixture was diluted with CH ₂ Cl ₂ (20 ml) and filtered through a fritted funnel. The filtrate was evaporated in vacuo to give 2- (6 - ((4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1Hpyrazol-1-yl) methyl) pyridin-2 -yl) propan-2-ol, which was used in the following reactions without further

- 144 038488 of the next cleaning.

Stage 3. Weighed portions of 2- (6 - {[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1Н-pyrazol-1yl] methyl} -2-pyridyl ) -2-propanol (86 mg, 0.25 mmol, 1 eq.), 6- (2-amino-6-chloro-4-pyrimidinyl) -2toluonitrile (67 mg, 0.28 mmol, 1.1 eq. ) and Na ₂ CO ₃ (53 mg, 0.5 mmol, 2 eq.) directly into the vial. H ₂ O (0.5 ml) and dioxane (1 ml) were _{added and the resulting N 2} suspension was degassed for about 15 minutes. Pd (dppf) Cl ₂ (9.2 mg, 0.013 mmol, 5 mol 1%) was added and the vial was heated in an aluminum heating block at 130 ° C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and H ₂ O and extracted. The combined organic layers were dried and evaporated. Purification by HPLC (2-100% H ₂ O / MeCN + 0.1% TFA) afforded 33 mg of a white solid.

¹ H-NMR (400 MHz, CD3OD) δ 8.48 (t, J = 0.8 Hz, 1H), 8.16 (t, J = 0.8 Hz, 1H), 7.79-7.72 (m, 2H), 7.68 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 8.3, 7.4 Hz, 1H), 7.09-6.92 (m, 2H), 5.49 (d, J = 7.3 Hz, 2H), 2.57 (s, 3H), 1.49 ( d, J = 0.9 Hz, 6H).

ESI-MS [M + H] + for C ₂₄ H ₂ 3N7O: theor. 426.2, fact. 426.3.

Example 351 pyrimidinylamine

6- (1- {[6- (Methoxymethyl) -2-pyridyl] methyl} -1 N-pyrazol-4-yl) -4-phenyl-2-

This compound was synthesized in the same manner as in example 350, from the corresponding derivatives of boronate and chloropyrimidine.

¹ H-NMR (400 MHz, CDCh) δ 8.16 (d, J = 0.7 Hz, 1H), 8.12 (d, J = 0.7 Hz, 1H), 8.05-7.96 (m, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.54-7.44 (m, 3H), 7.39-7.33 (m, 1H), 7, 20 (s, 1H), 6.98-6.93 (m, 1H), 5.50 (s, 2H), 5.07 (s, 2H), 4.59 (s, 2H), 3.49 (s, 3H).

ESI-MS [M + H] + for C ₂ iH ₂ oN60: theor. 373.2, fact. 373.2.

Example

352.

3- [2-Amino-6- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-pyrazol-4-yl) -4 pyrimidinyl] -2-anisonitrile

This compound was synthesized in the same manner as in example 350, from the corresponding derivatives of boronate and chloropyrimidine.

¹ H-NMR (400 MHz, CDCh) δ 8.20 (s, 1H), 8.08 (s, 1H), 8.03 (dd, J = 7.8, 1.8 Hz, 1H), 7 , 70-7.64 (m, 1H), 7.59-7.53 (m, 1H), 7.35-7.27 (m, 2H), 7.25 (d, J = 6.8Hz , 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.45 (s, 2H), 5.07 (s, 2H), 3.87 (s, 3H), 1.34 (s, 9H).

ESI-MS [M + H] + for C ₂₃ H ₂ 5N7O: theor. 440.2, fact. 440.3.

353.

Example

3- [2-Amino-6- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-pyrazol-4-yl) -4pyrimidinyl] -2-fluorobenzonitrile

This compound was synthesized in the same way, from boronate and chloropyrimidine derivatives.

as in example 350, from the corresponding pro ¹ H-NMR (400 MHz, CDCh) δ 8.32 (t, J = 7.7, 1H), 8.22 (s, 1H), 8.09 (s, 1H ), 7.71 (dddd, J = 7.7, 5.8, 1.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.30-7.22 (m, 2H), 6.87 (d, J = 7.7 Hz, 1H), 5.45 (s, 2H), 5.12 ( s, 2H), 1.35 (s, 9H).

ESI-MS [M + H] + for C ₂₄ H ₂₂ FN7: theor. 428.2, fact. 428.4.

Example 354 m- [6-Amino-4- (1- {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyridyl] benzonitrile

- 145 038488

Stage 1. Dichloropyridine (652 mg, 4.0 mmol, 1.0 eq.) And boronic acid (588 mg, 4.0 mmol, 1.0 eq.) Were dissolved in CH3CN (16 ml, 0.25 M). An aqueous solution of K ₂ CO ₃ (2 M, 2 ml, 4.0 mmol, 1.0 eq.) Was _{added and the resulting solution was degassed by passing N 2} for 10 min. Then Pd (PPh ₃ ) ₄ (231 mg, 0.2 mmol, 5 mol%) was added and the mixture was heated at 80 ° C under nitrogen atmosphere for 20 h. Then the reaction mixture was diluted with EtOAc (20 ml), filtered through celite and evaporated in vacuo. The crude residue was purified by flash column chromatography on silica gel (hexane / EtOAc, gradient 0 to 100%) to give the product as a white solid (211 mg, 23% yield).

Stage 2. Suspended aryl chloride (336 mg, 1.5 mmol, 1.0 eq.), Pd (OAc) ₂ (16.8 mg, 0.075 mmol, 5 mol.%), XPhos (71.5 mg, 0, 15 mmol, 10 mol%) and Cs ₂ CO ₃ (1.47 g, 4.5 mmol, 3.0 eq.) In dioxane (7.5 ml, 0.2 M). The solution was degassed by passing N ₂ for 5 min and then stirred at room temperature for 20 min. TMSA (1.04 ml, 7.5 mmol, 5.0 eq.) Was added with a syringe and the resulting mixture was stirred at 100 ° С for 3 h. Then the reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml), filtered through celite and evaporated in vacuo to give the crude product, which was used without further purification in step 3.

Step 3. In a 40 ml vial, suspended the crude protected TMS alkyne from step 2 in MeOH (2.9 ml) and add a solution of ammonia in MeOH (7N, 0.42 ml). The resulting mixture was stirred at room temperature for 2 hours. Then the reaction mixture was evaporated in vacuo. The crude brown residue was purified by flash column chromatography on silica gel (hexane / EtOAc, gradient 0 to 100%) to give the alkyne as a pale beige solid (73.6 mg, 23% yield over two steps).

Stage 4. Performed in the same way as in example 1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (d, J = 5.5 Hz, 1H), 8.51 (dd, J = 4.6, 2.8 Hz, 1H), 8.37 (t, J = 6.4 Hz, 1H), 8.06 (t, J = 6.5 Hz, 1H), 7.91-7.78 (m, 2H), 7.78-7 , 71 (m, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.40 (t, J = 6.6 Hz, 1H), 7.29 (t, J = 6, 7 Hz, 1H), 5.86-5.80 (m, 2H), 4.47-4.41 (m, 2H), 3.35-3.29 (m, 3H).

LC-MS: retention time 2.290 min, method A; ESI-MS [M + H] + for C ₂₂ H ₂₀ N ₇ O: theor. 398.2, fact. 398.1.

Example 355 m- [6-Amino-4- (1- {[6- (1-methoxyethyl) -2-pyridyl] methyl} -1 H-1,2,3-triazol-4-yl) -2pyridyl] benzonitrile

This compound was synthesized in the same manner as in example 354.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.36-8.29 (m, 1H), 8.26-8.18 (m, 1H), 8.13-8.05 (m, 1H) , 7.73 (td, J = 7.7, 4.5 Hz, 1H), 7.69-7.61 (m, 1H), 7.59-7.48 (m, 2H), 7.41 (dd, J = 7.9, 4.0 Hz, 1H), 7.13 (dd, J = 7.7, 4.0 Hz, 1H), 7.03-6.98 (m, 1H), 5.77-5.68 (m, 2H), 4.64 (brs, 2H), 4.51-4.36 (m, 1H), 3.39-3.28 (m, 3H), 1, 51-1.43 (m, 3H).

LC-MS: retention time 2.30 min, method A; ESI-MS [M + H] ⁺ for C ₂₃ H ₂₂ N ₇ O: theor. 412.2, fact. 412.3.

Example 356 (R) -1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyridyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] -2-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 354.

- 146 038488

S-NMR (400 MHz, CDCI3) δ 8.35 (s, 1H), 7.85 (s, 1H), 7.58-7.47 (m, 2H), 7.46-7.35 (m , 2H), 7.12 (t,

J = 7.8 Hz, 1H), 6.89 (d, J = 1.2 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 5.47 (d, J = 14.1 Hz, 1H),

5.15 (d, J = 14.1 Hz, 1H), 4.63 (t, J = 5.8 Hz, 1H), 3.66-3.57 (m, 1H), 3.49-3 , 38 (m, 1H), 2.39-2.18 (m, 3H), 2.172.05 (m, 1H).

LC-MS: retention time 2.29 min, method A; ESI-MS [M + H] + for C ₂₅ H ₂₃ N ₈ O ₂ : theor. 467.2, fact. 467.3.

Example 357 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyridyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 3-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 354.

-NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (s, 1H), 8.48 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.70-7.62 (m, 1H), 7.61 (s, 1H), 7.48 (dd, J = 8.0, 8.0 Hz, 1H), 7, 05 (s, 1H), 6.49-6.35 (m, 2H), 6.26 (s, 2H), 5.56 (s, 2H), 3.62-3.20 (m, 5H) , 2.20-2.02 (m, 2H).

MS [M + H] ⁺ for C ₂₅ H ₂₂ N ₈ O ₂ : theor. 467.2, fact. 467.3.

Example 358 1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyridyl] -1H-1,2,3-triazol-1-yl} methyl) -2pyridyl] - 4-piperidinecarboxylic acid

This compound was synthesized in the same manner as in example 354.

S-NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 8.16 (s, 1H), 8.10-8.01 (m, 1H), 7.71-7.63 ( m, 1H), 7.57-7.49 (m, 2H), 7.49-7.42 (m, 1H), 6.92-6.87 (m, 1H), 6.69 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 7.1 Hz, 1H), 5.49 (s, 2H), 4.45-4.34 (m, 2H), 3, 14-3.01 (m, 2H), 2.72-2.59 (m, 1H), 2.11-1.93 (m, 2H), 1.79-1.60 (m, 2H).

LC-MS: retention time 2.27 min, method A; ESI-MS [M + H] ⁺ for C ₂₆ H ₂₅ N ₈ O ₂ : theor. 481.2, fact. 481.3.

Example 359 1 - [(R) -1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyridyl] -1H-1,2,3-triazol-1-yl } methyl) 2-pyridyl] ethyl] -4-piperidinecarboxylic acid

Stage 1. Dissolved pyridyl chloride (297 mg, 1.04 mmol,

1.0 eq.) And piperidine (476 mg,

3.33 mmol, 3.2 eq.) In anhydrous CH3CN (1.73 ml). The reaction mixture was then stirred at 60 ° C for 3.5 h. After that, the reaction mixture was evaporated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH) to give the product (292 mg, yield 71%).

Stage 2. To an ice-cooled solution of TBS-protected alcohol (292 mg, 0.744 mmol, 1.0 eq.) In THF (1.9 ml, 0.4 M) was added TBAF (1 M solution in THF, 0 , 74 ml, 0.74 mmol, 1.0 eq.). The resulting solution was stirred at 0 ° C for 30 minutes. Thereafter, the reaction mixture was evaporated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH gradient) to give the product as a colorless oil (190 mg, 92% yield).

Stage 3. DPPA (0.17 ml, 0.776 mmol, 1.2 eq.) Followed by DBU (0.12 ml, 0.776 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature for 10 min and then at 40 ° C for 4 h. Then the reaction mixture was evaporated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel (hexane / EtOAc) to give the product as a light beige oil (98.6 mg, 50% yield).

Steps 4 and 5. Carried out in the same way as in example 125.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.44 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 8.38 (d, J = 8 , 0 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.70-7.61 (m, 2H ), 7.58 (d, J = 1.1 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.27 (s, 2H ), 5.87 (s, 2H), 4.64-4.45 (m, 1H), 3.62-3.46 (m, 1H), 3.24-3.05 (m, 1H), 2.88-2.54 (m, 2H), 2.45-2.20 (m, 1H), 1.96-1.64 (m, 4H), 1.56 (d, J = 6.8 Hz, 3H).

LC-MS: retention time 2.02 min, method A; ESI-MS [M + H] + for C ₂₈ H ₂₉ N ₈ O ₂ : theor. 509.2, fact. 509.3.

Example 360. 1 - [(S) -1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyridyl] -1H-1,2,3-triazol-1-yl } methyl) 2-pyridyl] ethyl] -4-piperidinecarboxylic acid

This compound was synthesized in the same manner as in example 359.

¹ H-NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.01 (s, 1H), 8.46 (s, 1H), 8.37 (d, J = 8, 1 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.92-7.82 (m, 1H), 7.73-7.63 (m, 2H), 7, 56 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 5.88 (s, 2H), 4, 63-4.49 (m, 1H), 3.61-3.50 (m, 1H), 3.21-3.10 (m, 1H), 2.88-2.56 (m, 2H), 2.38-2.22 (m, 1H), 1.96-1.63 (m, 4H), 1.56 (d, J = 6.7Hz, 3H).

LC-MS: retention time 2.02 min, method A; ESI-MS [M + H] ⁺ for C ₂₈ H ₂₉ N ₈ O ₂ : theor. 509.2, fact. 509.3.

Example 361 1 - [(S) -1- [6 - ({4- [2-Amino-6- (m-cyanophenyl) -4-pyridyl] -1H-1,2,3-triazol-1-yl } methyl) 2-pyridyl] propyl] -4-piperidinecarboxylic acid

This compound was synthesized in the same manner as in example 359.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 9.31 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8, 42 (d, J = 8.1 Hz, 1H), 8.06-7.95 (m, 2H), 7.85 (s, 1H), 7.77 (t, J = 7.8 Hz, 1H ), 7.58 (dd, J = 7.9, 3.3 Hz, 2H), 5.98-5.91 (m, 2H), 4.34 (d, J = 10.8 Hz, 1H) , 3.63-3.52 (m, 1H), 3.21-3.09 (m, 1H), 2.80-2.63 (m, 1H), 2.27-1.61 (m, 8H), 0.59 (t, J = 7.3 Hz, 3H).

LC-MS: retention time 2.08 min, method A; ESI-MS [M + H] ⁺ for C ₂₉ H ₃₁ N ₈ O ₂ : theor. 523.3, fact. 523.3.

Example 362 [6- (m-Cyanophenyl) -4- (1 - {[6- (tert-butyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyridylamino ]acetic acid

This compound was synthesized in the same manner as in example 354.

¹ H-NMR (400 MHz, CDCl3) δ 8.33-8.09 (m, 2H), 7.63-7.33 (m, 4H), 7.04-6.86 (m, 3H), 5.63 (s, 2H), 4.21 (s, 2H), 1.31 (s, 9H).

LC-MS: retention time 3.35 min, method A; ESI-MS [M + H] ⁺ for C ₂₆ H ₂₆ N ₇ O ₂ : theor. 468.2, fact. 468.3.

Example 363 (S) -1- {6 - [(4- {2 - [(S) -2-Methoxy-1-phenylethylamino] -6- (m-cyanophenyl) -4-pyridyl} -1H1,2, 3-triazol-1-yl) methyl] -2-pyridyl} -3-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 354.

¹ H-NMR (400 MHz, CDO3) δ 8.45 (s, 1H), 8.12-8.02 (m, 2H), 7.64-7.53 (m, 2H), 7.52- 7.34 (m, 5H), 7.337.22 (m, 2H), 6.84 (s, 1H), 6.65-6.56 (m, 1H), 6.34 (d, J = 8, 5 Hz, 1H), 5.62-5.39 (m, 2H), 5.30 (s, 2H), 5.21 (dd,

- 148 038488

J = 8.4, 3.9 Hz, 1H), 4.01-3.65 (m, 2H), 3.60-3.48 (m, 1H), 3.46 (s, 3H), 3 , 37-3.14 (m, 1H), 2.44-2.23 (m, 2H),

1.32-1.17 (m, 1H).

LC-MS: retention time 3.25 min, method A; ESI-MS [M + H] + for C ₃₄ H ₃₃ N ₈ O ₃ : theor. 601.3, fact.

601.4.

Example 364. (S) -1- {6 - [(4- {2 - [(R) -2-Methoxy-1-phenylethylamino] -6- (m-cyanophenyl) -4-pyridyl} -1H1,2, 3-triazol-1-yl) methyl] -2-pyridyl} -3-pyrrolidinecarboxylic acid

This compound was synthesized in the same manner as in example 354.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 8.11-8.04 (m, 2H), 7.62-7.53 (m, 2H), 7.51 -7.35 (m, 5H), 7.337.23 (m, 2H), 6.84 (s, 1H), 6.62-6.55 (m, 1H), 6.36-6.30 (m , 1H), 5.60-5.40 (m, 2H), 5.30 (s, 2H), 5.19 (dd, J = 8.2, 4.0 Hz, 1H), 3.96- 3.70 (m, 2H), 3.65-3.47 (m, 1H), 3.46 (s, 3H), 3.37-3.12 (m, 1H), 2.43-2, 18 (m, 2H), 1.33-1.18 (m, 1H).

LC-MS: retention time 3.25 min, method A; ESI-MS [M + H] + for C ₃₄ H ₃₃ N ₈ O ₃ : theor. 601.3, fact.

601.4.

Example m- [4- (1 - {[6- (Methoxymethyl) -2-pyridyl] methyl} -1N-1,2,3-triazol-4-yl) -6- (2365.

phenoxyacetylamino) -2-pyridyl] benzonitrile

Methodology. To a solution of aminopyridine (30.6 mg, 76.9 μmol, 1.0 eq.) In pyridine (0.3 ml) in a glass vial was added 2-phenoxyacetyl chloride (0.01 ml, 76.9 μmol, 1.0 eq. .) The resulting solution was stirred at 100 ° C for 1 hour. Then the reaction mixture was cooled to 25 ° C and evaporated in vacuo. The crude residue was purified by flash column chromatography (CH ₂ Cl ₂ / MeOH) to give the product (15 mg, 25% yield).

¹ H-NMR (400 MHz, CDCl3) δ 9.10-8.97 (m, 1H), 8.56-8.48 (m, 1H), 8.47-8.40 (m, 1H), 8.33-8.25 (m, 2H), 8.25-8.18 (m, 1H), 7.79-7.67 (m, 2H), 7.65-7.55 (m, 1H ), 7.48-7.35 (m, 3H), 7.17 (t, J = 7.0 Hz, 1H), 7.12-7.03 (m, 3H), 5.75 (s, 2H), 4.68 (s, 2H), 4.61 (s, 2H), 3.51 (s, 3H).

LC-MS: retention time 3.38 min, method A; ESI-MS [M + H] + for C ₃₀ H ₂₆ N ₇ O ₃ : theor. 532.2, fact. 532.3.

Example 366 1- [6 - ({4- [6- (m-Cyanophenyl) -2- (2-methoxyacetylamino) -4-pyridyl] -1 H-1,2,3-triazol-1 yl} methyl) -2-pyridyl] -4-piperidinecarboxylic acid

This compound was synthesized in the same manner as in example 365.

¹ H-NMR (400 MHz, acetone-d6) δ 9.22 (s, 1H), 8.84-8.77 (m, 2H), 8.57-8.54 (m, 1H), 8, 53-8.46 (m, 1H), 8.32-8.26 (m, 1H), 7.89-7.81 (m, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.57-7.47 (m, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 7.3 Hz, 1H), 5, 65 (s, 2H), 4.34-4.20 (m, 2H), 4.13 (s, 2H), 3.55 (s, 3H), 3.07-2.92 (m, 2H) , 2.66-2.48 (m, 1H), 1.99-1.82 (m, 2H), 1.71-1.51 (m, 2H).

LC-MS: retention time 3.13 min, method A; ESI-MS [M + H] + for C ₂₉ H ₂₉ N ₈ O ₄ : theor. 553.2, fact. 553.4.

Example 367 m- [6- (2-Methoxyacetylamino) -4- (1 - {[6- (1-methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -2 -pyridyl] benzonitrile

This compound was synthesized in the same manner as in example 365.

¹ H-NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.50-8.36 (m, 2H), 8.32-8.18 (m, 3H), 7.77- 7.67 (m, 2H), 7.58 (tt, J = 7.8, 0.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.11 (dd , J = 7.6, 1.2 Hz, 1H), 5.73 (s, 2H), 4.48-4.37 (m, 1H), 4.07 (s, 2H), 3.56 ( s, 3H), 1.47 (d, J = 6.6 Hz, 3H).

- 149 038488

LC-MS: retention time 2.25 min, method A; ESI-MS [M + H] + for C ₂₆ H26N7O ₃ : theor. 484.2, fact.

484.3.

Example 368 m- [6- (2-Ethoxyacetylamino) -4- (1- {[6- (1-methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3triazol-4-yl) -2 -pyridyl] benzonitrile o

This compound was synthesized in the same manner as in example 365.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.02 (s, 1H), 8.48 (d, J = 1.2 Hz, 1H), 8.44 (t, J = 1.7 Hz, 1H), 8.29 (dt, J = 8.1, 1.5 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.22 (s, 1H), 7, 76-7.68 (m, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.45-7.38 (m, 1H), 7.11 (d, J = 7, 6 Hz, 1H), 5.74 (s, 2H), 4.44 (q, J = 6.5 Hz, 1H), 4.11 (s, 2H), 3.72 (q, J = 7, 0 Hz, 2H), 3.34 (s, 3H), 1.47 (d, J = 6.5 Hz, 3H), 1.37 (t, J = 7.0 Hz, 3H).

LC-MS: retention time 3.27 min, method A; ESI-MS [M + H] ⁺ for C ₂₇ H ₂₉ N ₇ O ₃ : theor. 499.2, fact. 499.3.

Example 369 m- [4- (1 - {[6- (1-Methoxyethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -6- (2phenoxyacetylamino) -2 -pyridyl] benzonitrile o

This compound was synthesized in the same manner as in example 365.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 8.52 (d, J = 1.2 Hz, 1H), 8.43 (t, J = 1.8 Hz, 1H), 8.32-8.20 (m, 3H), 7.78-7.66 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.45-7 , 32 (m, 2H), 7.15-6.99 (m, 4H), 5.75 (s, 2H), 4.68 (s, 2H), 4.45 (q, J = 6.5 Hz, 1H), 3.35 (s, 3H), 1.48 (d, J = 6.8 Hz, 2H).

LC-MS: retention time 3.59 min, method A; ESI-MS [M + H] ⁺ for C ₃₁ H ₂₈ N ₇ O ₃ : theor. 546.2, fact. 546.3.

Example 370 m- [6-Amino-2- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -4pyridyl] benzonitrile one

Stage 1. In a 40 ml vial with a magnetic stirrer were mixed dichloropyridine (652 mg, 4.0 mmol, 1.0 eq.), PdCl ₂ (PPh ₃ ) ₂ (140 mg, 0.2 mmol, 5 mol%) and CuI (76 mg, 0.4 mmol, 10 mol%) in Et ₃ N / DMF (1: 1, 16 ml, 0.25 M). The resulting mixture was degassed by passing N ₂ for 10 minutes. Then TMSA (2.2 ml, 16 mmol, 4.0 eq.) Was added by syringe and the resulting mixture was stirred at 80 ° С for 3 h. After that, the reaction mixture was cooled to room temperature and evaporated in vacuum. The resulting mixture was redissolved in EtOAc (30 ml) and filtered through celite. The mixture was evaporated again in vacuo and the resulting residue was purified by flash column chromatography on silica gel (hexane / EtOAc, gradient 0 to 100%) to give the TMS-protected alkyne (692 mg, 77% yield).

Stage 2. Chloropyridine (334 mg, 1.34 mmol, 1.0 eq.) And boronic acid (196 mg, 1.34 mmol, 1.0 eq.) Were mixed in dioxane (4.5 ml, 0.3 M ). An aqueous solution of K ₂ CO ₃ (2 M, 0.67 ml, 1.34 mmol, 1.0 eq.) Was _{added and the resulting solution was degassed by passing N 2} for 10 min. Pd (OAc) ₂ (15 mg, 0.067 mmol, 5 mol%) and S-Phos (55 mg, 0.134 mmol, 10 mol%) were added and the reaction mixture was stirred at 120 ° С for 1 h. the mixture was cooled to room temperature, diluted with EtOAc (20 ml), filtered through celite and evaporated in vacuo to give the crude product which was used in step 3 without further purification.

Step 3. Dissolve the crude TMS-protected alkyne from step 2 into a 40 ml vial.

- 150 038488

THF (2.7 ml) and a solution of TBAF (1 M, 1.34 ml) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then evaporated in vacuo and the crude residue was purified by flash column chromatography on silica gel (hexane / EtOAc, gradient from 0 to 100%) to give the product as a beige solid (145 mg, 49% yield over two steps).

Stage 4. Performed in the same way as in example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.97-7.87 (m, 2H), 7.76 (d, J = 1.4 Hz, 1H), 7.73-7.66 (m, 2H), 7.58 (td, J = 7.8, 0.7 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7 , 08 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 5.72 (s, 2H), 4.62-4.54 (m, 4H), 3.50 (s, 3H).

LC-MS: retention time 2.25 min, method A; ESI-MS [M + H] + for C ₂₂ H ₂₀ N ₇ O: theor. 398.2, fact. 398.2.

Example 371 m- [6-Amino-4- (1 - {[6- (methoxymethyl) -2-pyridyl] methyl} -1H-1,2,3-triazol-4-yl) -2pyrimidinyl] benzonitrile

Stage 1. Dichloropyridine (656 mg, 4.0 mmol, 1.0 eq.) And boronic acid (588 mg, 4.0 mmol, 1.0 eq.) Were dissolved in CH3CN (16 ml, 0.25 M). An aqueous solution of K ₂ CO ₃ (2 M, 2 ml, 4.0 mmol, 1.0 eq.) Was _{added and the resulting solution was degassed by passing N 2} for 10 min. Then Pd (PPh ₃ ) ₄ (231 mg, 0.2 mmol, 5 mol%) was added and the mixture was heated to 80 ° C for 12 h under nitrogen atmosphere. Thereafter, the reaction mixture was diluted with EtOAc (20 ml), filtered through celite and evaporated in vacuo. The crude residue was purified by flash column chromatography on silica gel (hexane / EtOAc, gradient 0 to 100%) to give the product as a white solid (360.4 mg, 39% yield).

Stage 2. In a 40 ml vial with a magnetic stirrer, diaryl chloride (360 mg, 1.56 mmol, 1.0 eq.), PdCl ₂ (PPh ₃ ) ₂ (54.8 mg, 0.0781 mmol, 5 mol. %) and CuI (29.8 mg, 0.156 mmol, 10 mol%) in a mixture of Et ₃ N / DMF (1: 1, 6.24 ml, 0.25 M). The resulting mixture was degassed by passing N ₂ for 10 minutes. Then TMSA (0.86 ml, 6.25 mmol, 4.0 eq.) Was added by syringe and the resulting mixture was stirred at 80 ° C for 3 h. After that, the reaction mixture was cooled to room temperature and evaporated in vacuo. The resulting mixture was redissolved in EtOAc (10 ml) and filtered through celite. The mixture was again evaporated in vacuo and the resulting residue was used directly in the next step without further purification.

Step 3. In a 40 ml vial, suspend the crude TMS protected alkyne from step 2 in MeOH (3.12 ml) and add a solution of ammonia in MeOH (7N, 0.90 ml). The resulting mixture was stirred at room temperature for 2 hours. Then the reaction mixture was evaporated in vacuo. The crude brown residue was purified by flash column chromatography on silica gel (hexane / EtOAc, gradient 0 to 100%) to give the alkyne as a pale brown solid (59.7 mg, 17% yield over two steps).

Stage 4. Performed in the same way as in example 1.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.74 (s, 1H), 8.65 (dt, J = 8.0, 1.4 Hz, 1H) , 7.98 (dt, J = 1.1, 1.4 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 1.1 Hz, 1H), 7.12 (s, 1H), 5.81 (s, 2H), 4.48 (s, 2H), 3.35 (s, 3H).

LC-MS: retention time 2.07 min, method A; ESI-MS [M + H] ⁺ for C ₂₁ H ₁₉ N ₈ O: theor. 399.2, fact. 399.2.

Example 372. 2 - ({4- [2-Amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl] -1H-1,2,3-triazol-1yl} methyl) -6- ( 2-hydroxypropan-2-yl) pyridin-1-i-1-olate

- 151 038488

Stage 2

Stage 1. To an azide solution (example 1, product of stage 5, 384 mg, 2 mmol, 1 eq.) With stirring at room temperature was added m-CPBA (~ 75 wt.%, 507 mg, 2.2 mmol, 1, 1 eq.). The mixture was stirred until the reaction was complete as determined by LC-MS analysis. The mixture was evaporated and purified by flash chromatography on SiO ₂ to give the N-oxide derivative as a yellow oil (366 mg, 88% yield).

Step 2. Perform in the same manner as in example 1, step 6 to obtain the title compound as a light brown solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 7.72-7.68 (m, 1H), 7.68-7.64 (m, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.48-7.33 (m, 4H), 7.16 (dd, J = 7.7, 2.0 Hz, 1H), 5.91 ( s, 2H), 5.17 (bs, 2H), 2.66-2.57 (m, 3H), 1.69 (d, J = 1.1 Hz, 6H).

ESI-MS [M + H] + for C ₂₃ H ₂₂ N ₈ O ₂ : theor. 443.2, fact. 443.4.

Example 373. 3- {2-Amino-6- [1 - ({6- [2-hydroxy ( ² H ₆ ) propan-2-yl] pyridin-2-yl} methyl) -1H-1,2,3triazole -4-yl] pyrimidin-4-yl} -2-methylbenzonitrile

МеО. XX .OH 0-25 ° C, 3 h HO. XX .OH 0 ~ 25 ° C, 12 h NO. XX, N _a

XN “---——— * XN ----------- χ N ^J

О Yield 59 / о _{ОС СОз} Yield 85% d ₃ c _CD?

Stage 1 Stage 2 nh ₂ nXn Me

Yield 82%

Stage 3

Stage 1. To an ice-cooled solution of _{magnesium methyl-d 3-} iodide (47.9 ml, 47.8 mmol, 1 M, 4.0 eq.) Under N2 was added a solution of pyridyl ether (2.00 g, 12.0 mmol, 1.0 eq.) in THF (22.0 ml, 0.54 M) over 30 min. Then the ice bath was removed and the reaction mixture was stirred at 25 ° C for 3 h. The reaction mixture was then cooled to 0 ° C and quenched by the dropwise addition of saturated aqueous NH ₄ Cl solution (50 ml). The mixture was extracted with EtOAc (3x50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting residue was purified by flash silica gel column chromatography (hexane / EtOAc 1: 1) to afford the product (1.22 g, 59% yield).

Stages 2 and 3. Carried out in the same way as in example 1.

¹ H-NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.77-7.62 (m, 3H), 7.54 (s, 1H), 7.43-7.34 ( m, 2H), 7.14 (d, J = 7.6 Hz, 1H), 5.75 (s, 2H), 5.11 (s, 2H), 4.69 (s, 1H), 2, 63 (s, 3H).

LC-MS: retention time 2.71 min, method A; ESI-MS [M + H ⁺ ] ⁺ for C ₂₃ H ₁₇ D ₆ N ₈ O: theor. 433.2, fact. 433.3.

Biological example.

Certain compounds were evaluated for activity at adenosine A _2A receptors as described above for the cAMP assay. KB is a measure of antagonism / inhibition (similar to IC ₅₀ ). The results are presented in the table.

Specific examples (activity: IC ₅₀ / K _B for A2AR: + means> 1 μM, ++ means 100 nM to 1 μM, +++ means <100 nM).

Activity.

- 152 038488

- 153 038488

- 154 038488

- 155 038488

- 156 038488

- 157 038488

- 158 038488

- 159 038488

- 160 038488

- 161 038488

- 162 038488

- 163 038488

- 164 038488

- 165 038488

- 166 038488

- 167 038488

- 168 038488

- 169 038488

- 170 038488

- 171 038488

- 172 038488

- 173 038488 but

O

O

O

- 174 038488

- 175 038488

- 176 038488

- 177 038488

- 178 038488

- 179 038488 he

but

- 180 038488

- 181 038488

- 182 038488

O

- 183 038488

- 184 038488

- 185 038488

- 186 038488

- 187 038488

- 188 038488

- 189 038488

- 190 038488

- 191 038488

- 192 038488

- 193 038488

- 194 038488

- 195 038488

- 196 038488

- 197 038488

- 198 038488

- 199 038488

- 200 038488

- 201 038488

- 202 038488

- 203 038488

- 204 038488

- 205 038488

- 206 038488

- 207 038488

- 208 038488

- 209 038488

- 210 038488

- 211 038488

- 212 038488

- 213 038488

- 214 038488

- 215 038488

- 216 038488

- 217 038488

- 218 038488

- 219 038488

Specific embodiments of the present invention are described herein, including the best method known to the inventors for carrying out the invention. Upon reading the foregoing description, variations of the disclosed embodiments may become apparent to those skilled in the art, and it is expected that those skilled in the art can use such variations as required. Accordingly, it is intended that the invention may be practiced in other ways than specifically described herein, and that the invention includes all modifications and equivalents of the subject matter recited in the appended claims, to the extent permitted by applicable law. Moreover, the invention encompasses any combination of the above-described elements in all possible variations, unless otherwise indicated herein or otherwise clearly contradicted by context.

All publications, patent applications, accession numbers, and other references cited herein are incorporated herein by reference as if each individual publication or patent application were specifically and individually indicated as incorporated by reference.

Claims (77)

CLAIM 1. Compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein G ¹ is N or CR ^3a ; G ² means N or CR ^3b ; G ³ means N or CR ^3c ; R ^3a , R ^3b and R ^3c are each independently H, deuterium or C _1-6 alkyl; R ^1a and R ^1b are each independently selected from the group consisting of: i) H or deuterium, ii) C _1-8 alkyl optionally substituted with 1-3 R ⁵ substituents, iii) -X ¹ -O-C _1-8 alkyl optionally substituted with 1-3 R ⁵ substituents, iv) -C (O) -R ⁶ , v) Y optionally substituted with 1-3 R ⁷ substituents, and vi) -Xl-Y optionally substituted with 1-3 R ⁷ substituents; or R ^1a and R ^1b together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl ring optionally substituted with 1-3 R ⁸ substituents, the heterocycloalkyl containing 02 additional heteroatoms selected from the group consisting of O, N and S; 220 038488 each Y is C _3-8 cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 additional heteroatoms selected from the group consisting of O, N and S; R ² and R ⁴ are each independently H, deuterium or C _1-3 alkyl; Ar ¹ means 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R ⁹ ; Ar ² means phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R ¹⁰ ; where the 5-6-membered heteroaryl at Ar ¹ and Ar ² each independently contains 1-3 heteroatoms selected from the group consisting of O, N, N + -O ^- and S; each X ¹ means C _1-6 alkylene; each R ^{5 is} independently selected from the group consisting of hydroxyl, C _3-8 cycloalkyl, phenyl, —O-phenyl, —C (O) OR ^a, and oxo; each R ⁶ is C _1-8 alkyl or Y, each of which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, —O-phenyl, phenyl and —OC _1-8 alkyl; each R ^{7 is} independently selected from the group consisting of C _1-8 alkyl, hydroxyl, —OC _1-8 alkyl, oxo, and C (O) OR ^a ; each R ^{8 is} independently selected from the group consisting of C _1-8 alkyl, hydroxyl, and oxo; each R ^{9 is} independently selected from the group consisting of C1-8 alkyl, C1-8 deuteroalkyl, —O — C1-8 alkyl, —O — C1-8 deuteroalkyl, —X ¹ —O — C1-8 alkyl, —O — X ¹ —O— C1-8alkyl, -X ¹ -O-X ¹ -O-C1-8alkyl, -C (O) OR ^a , halogen, cyano, NR ^b R ^c , Y, -X ¹ -C3-8cycloalkyl and -X ² - Z, where X ^{2 is} selected from the group consisting of C1-6 _{alkylene, —C 1-6} alkylene-O—, —C (O) - and —S (O) ₂ -, Z is a 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N and S, each of said R ⁹ substituents being optionally substituted with 1-3 R ¹¹ ; each R ^{10 is} independently selected from the group consisting of C1-8 alkyl, C1-8 deuteroalkyl, halogen, cyano, —O — C1-8 alkyl, —O — C1-8 deuteroalkyl, —X ¹ —O — C1-8 alkyl, —O — X ¹ -O-C _1-8 alkyl, -S (O) ₂ -C _1-6 alkyl, -C (O) NR ^d R ^e and 4-6 membered heteroaryl containing 1-3 heteroatoms selected from the group, consisting of O, N and S, each of said substituents R ¹⁰ optionally substituted by 1-3 R ¹² , or two R ¹⁰ on adjacent ring atoms of Ar ^{2 are} optionally connected to form a 5-membered heterocyclic ring, optionally substituted by 1-2 halogens; each R ^{11 is} independently selected from the group consisting of hydroxyl, halogen, cyano, —NR ^d R ^e , —C (O) OR ^a , phenyl, C _3-8 cycloalkyl, and C _1-4 alkyl optionally substituted with C (O) OR ^a ; each R ^{12 is} independently selected from the group consisting of halogen, cyano, hydroxy, —C (O) OR ^a ; and each R ^a is H, deuterium or C _1-6 dlkyl; each R ^b and R ^{c is} independently selected from the group consisting of H, deuterium, C _1-8 alkyl, -S (O) 2-C1-6alkyl, -C (O) OR ^a and -X ¹ -C (O) OR ^a ; each R ^d and R ^{e is} independently selected from the group consisting of H, deuterium, C _1-8 alkyl, -S (O) ₂ -C _1-6 alkyl; provided that when each G ¹ and G ² is N, G ³ is CH, R ² is CH3, and each R ^1a and R ^1b is H or deuterium, then Ar ² does not mean 2-thienyl, phenyl, 2-, 3- or 4-methoxyphenyl, 3- or 4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl, or 2- or 4-methylphenyl. 2. A compound according to claim 1, wherein Ar ^{1 is} selected from the group consisting of pyridyl, pyridyl N-oxide, imidazolyl, pyrazolyl, and thiazolyl, optionally substituted with 1-3 R ⁹ . 3. A compound according to claim 2, wherein Ar ¹ is pyridyl optionally substituted with 1-3 R ⁹ . 4. A compound according to any one of claims 1 to 3, wherein G ³ is CR ^3c . 5. A compound according to any one of claims 1 to 4, wherein the compound of formula (I) is represented by formula (Ia) H ^ R ^1b y /) r2 G ^245> NI JI jl ^R4 N ⁼ G ^R3C (la), where n is an integer from 0 to 2. 6. A compound according to any one of claims 1 to 5, wherein the compound of formula (I) is represented by formula (Ib) _%. R ^{, b} 7. A compound according to any one of claims 1-6, wherein Ar ^{2 is} substituted by 1-3 R ¹⁰ and at least one R ¹⁰ is cyano. 8. A compound according to any one of claims 1 to 7, wherein the compound of formula (I) is represented by formula (Ic) - 221 038488 where m is an integer from 0 to 2. 9. A compound according to any one of claims 1 to 8, wherein the compound of formula (I) is represented by formula (Id) 10. A compound according to any one of claims 1 to ^{9, wherein each R 9 is} independently selected from the group consisting of C1.8 alkyl, C1.8 deuteroαalkyl, -O-C1.8alkyl, -O-C1.8deuteroαalkyl, -X ¹ -O -C1. ₈ alkyl, -O-X ¹ -O-C1.8 alkyl, -X ¹ -O-X ¹ -O-C1. ₈ alkyl, each of said R ⁹ substituents being optionally substituted with 1-3 R ¹¹ . 11. A compound according to any one of claims 1 to ^{9, wherein each R 9 is} independently selected from the group consisting of —C (O) OR ^a , —NR ^b R ^c , Y, —X ¹ -C3.8 cycloalkyl and —X ² -Z, and X ^{2 is} selected from the group consisting of C1. ₆ alkylene, -C ₁ . ₆ alkylene-O-, -C (O) - and -S (O) ₂ -, Z means 4-6 membered heterocycloalkyl containing 1-3 heteroatoms at the vertices of the ring selected from the group consisting of O, N and S wherein each of said R ⁹ substituents is optionally substituted with 1-3 R ¹¹ . 12. A compound according to any one of claims 1-10, wherein the compound of formula (I) is represented by formula (Ie) 13. A compound according to any one of claims 1-12, wherein G ² is N. 14. A compound according to any one of claims 1-13, wherein G ¹ is N. 15. A compound according to any one of claims 1-13, where G ¹ means CR ^3a 16. A compound according to any one of claims 1-15, wherein R ² is H. 17. A compound according to any one of claims 1-16, wherein R ⁴ is H. 18. A compound according to any one of claims 5-17, wherein R ^1b is H. 19. A compound according to any one of claims 5-18, wherein each R ^{10 is} independently selected from the group consisting of C1-8 alkyl, halogen, cyano, —O — C1-8 alkyl, —X ¹ —O — C1-8 alkyl, —O —X ¹ —O — C _1-8 alkyl, each of said R ¹⁰ substituents being optionally substituted with 1-3 R ¹² . 20. A compound according to claim 19, wherein each R ^{10 is} independently selected from the group consisting of C _1-8 alkyl, halogen, cyano, —OC _1-8 alkyl. 21. A compound according to claim 1 selected from the group consisting of: - 222 038488 - 223 038488 - 224 038488 - 225 038488 - 226 038488 - 227 038488 - 228 038488 - 229 038488 - 230 038488 - 231 038488 - 232 038488 - 233 038488 - 234 038488 - 235 038488 - 236 038488 - 237 038488 - 238 038488 - 239 038488 - 240 038488 - 241 - 242 038488 - 243 038488 - 244 038488 - 245 038488 22. A compound according to claim 1 selected from the group consisting of: - 246 038488 or a pharmaceutically acceptable salt thereof. 23. A compound according to claim 1, represented by the formula, or a pharmaceutically acceptable salt thereof. 24. A compound according to claim 1, represented by the formula 25. A compound according to claim 1, represented by the formula 26. A compound according to claim 1, represented by the formula 27. A pharmaceutical composition for inhibiting at least one of A ₂ A and A _2B adenosine receptors, comprising a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable excipient. 28. A method of treating a disease, disorder or condition mediated, at least in part, by adenosine A _2A receptors (A _2A R) or adenosine A _2B receptors (A _2B R), the method comprising administering to a subject in need thereof an effective amount connections according to claims 1-26. 29. The method of claim 28, wherein the disease, disorder or condition is at least partially mediated by A _2A R. 30. The method of claim 28, wherein the disease, disorder or condition is at least partially mediated by A _2B R. 31. The method of claim 28, wherein the disease, disorder or condition is at least in part mediated by both A _2A R and A _2B R receptors. 32. The method of claim 29, wherein said compound is administered in an amount effective to regress or arrest the progression of A _2A R mediated immunosuppression. - 247 038488 33. The method of any one of claims 28-32, wherein the disease, disorder or condition is cancer. 34. The method according to claim 33, wherein the cancer is cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovaries, testicles, head, neck, skin, mesothelium , leukocytes, esophagus, breast, muscles, connective tissue, lungs, adrenal glands, thyroid gland, kidney or bone, or glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, basal cell carcinoma of the skin or seminal ovary. 35. The method of claim 33, wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, Kaposi's sarcoma, renal - cell carcinoma, head and neck cancer and esophageal cancer. 36. The method of claim 33, wherein the cancer is selected from the group consisting of prostate cancer, lung cancer, non-small cell lung carcinoma, colorectal cancer, pancreatic cancer, and breast cancer. 37. The method according to claim 36, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula 38. The method according to claim 36, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula 39. The method according to any one of claims 28 to 32, wherein the disease, disorder or condition is an immunological disease, disorder or condition. 40. The method of claim 39, wherein the immunological disease, disorder or condition is selected from the group consisting of rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart insufficiency, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, Crohn's disease, ulcerative colitis, allergic contact dermatitis and other eczema, systemic sclerosis and multiple sclerosis. 41. A combination for inhibiting at least one of the A2A and A2B adenosine receptors, comprising a compound according to any one of claims 1 to 26 and at least one additional therapeutic agent, where the additional therapeutic agent is selected from the group consisting of a chemotherapeutic agent, a control inhibitor points of immunity and radiation therapy. 42. The combination of claim 41, wherein the at least one additional therapeutic agent is an immune checkpoint inhibitor. 43. The combination of claim 42, wherein the immune checkpoint inhibitor blocks the activity of at least one of PD1 (programmed cell death protein-1), PDL1 (PD1 ligand), CTLA4 (cytotoxic T-lymphocyte-associated antigen-4), TIGIT (cellular immunoreceptor with Ig and ITIM domains) or TIM3 (T-cell membrane protein-3). 44. The combination of claim 43, wherein the immune checkpoint inhibitor blocks PD1 or PDL1 activity. 45. The combination of claim 44, wherein the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, avelumab, atezolizumab, and durvalumab. 46. The combination of claim 44 or 45, further comprising an additional therapeutic agent that blocks TIGIT activity. 47. The combination of claim 46, wherein the additional therapeutic agent blocks TIGIT activity by activating its ligand. 48. The combination of claim 42, wherein the immune checkpoint inhibitor blocks TIGIT activity. 49. The combination of claim 48, wherein the immune checkpoint inhibitor blocks TIGIT activity by activating its ligand. 50. A combination according to any one of claims 42 to 49, further comprising a chemotherapeutic agent. 51. The combination of claim 50, wherein the chemotherapeutic agent comprises a platinum-based or anthracycline-based chemotherapeutic agent. - 248 038488 52. The combination of claim 51, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, and doxorubicin. 53. A combination according to any one of claims 42-52, further comprising radiation therapy. 54. The combination of claim 41, wherein the at least one additional therapeutic agent is a chemotherapeutic agent. 55. The combination of claim 54, wherein the chemotherapeutic agent is a platinum-based or anthracycline-based chemotherapeutic agent. 56. The combination of claim 55, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, and doxorubicin. 57. The combination of claim 55 or 56, further comprising radiation therapy. 58. A method of treating cancer in a subject, which comprises administering to the subject an effective amount of a compound according to claims 1 to 26 and at least one additional therapeutic agent, where the additional therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an immune checkpoint inhibitor and a radiation therapy. 59. The method of claim 58, wherein the at least one additional therapeutic agent is an immune checkpoint inhibitor. 60. The method of claim 59, wherein the immune checkpoint inhibitor blocks the activity of at least one of PD1 (programmed cell death protein-1), PDL1 (PD1 ligand), CTLA4 (cytotoxic T-lymphocyte-associated antigen-4), TIGIT (cellular immunoreceptor with Ig and ITIM domains) or TIM3 (T-cell membrane protein-3). 61. The method of claim 60, wherein the immune checkpoint inhibitor blocks PD1 or PDL1 activity. 62. The method of claim 61, wherein the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, avelumab, atezolizumab, and durvalumab. 63. The method of claim 61 or 62, further comprising an additional therapeutic agent that blocks TIGIT activity. 64. The method of claim 63, wherein the additional therapeutic agent blocks TIGIT activity by activating its ligand. 65. The method of claim 59, wherein the immune checkpoint inhibitor blocks TIGIT activity. 66. The method of claim 65, wherein the immune checkpoint inhibitor blocks TIGIT activity by activating its ligand. 67. The method of any one of claims 59-66, further comprising a chemotherapeutic agent. 68. The method of claim 67, wherein the chemotherapeutic agent comprises a platinum-based or anthracycline-based chemotherapeutic agent. 69. The method of claim 68, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, and doxorubicin. 70. A method according to any one of claims 59, 60, further comprising radiation therapy. 71. The method of claim 58, wherein the at least one additional therapeutic agent is a chemotherapy regimen. 72. The method of claim 71, wherein the chemotherapy regimen comprises a platinum-based or anthracycline-based chemotherapeutic agent. 73. The method of claim 72, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, and doxorubicin. 74. The method of claim 72 or 73, further comprising radiation therapy. 75. The method of any one of claims 58 to 73, wherein the compound and at least one additional therapeutic agent are administered in combination. 76. The method of any one of claims 58 to 73, wherein the compound and at least one additional therapeutic agent are administered sequentially. 77. The method of any one of claims 58 to 73, wherein the treatment periods for the compound and the at least one additional therapeutic agent overlap.